Datasets:

turingmachine

/

hupd-npe-balanced-same-year-same-class-subset

like 0

ACCEPTED

Sampling device and sampling method

A sampling device (1) comprises a sampling container (4) for reception of a sample volume and a connecting piece (7) adapted to be connected to a fitting (2) mounted on a processing installation. The connecting piece (7) has a sample passage which is provided with a stationary valve port (12) and a corresponding valve member (14) which is displaceable between a closed and an open position. The stationary valve part (12) and the displaceable valve member (14) are integrated in the sampling container (4). The valve member (14) is spring-loaded towards its closed position and adapted to be automatically displaced to its open position upon connection of the connecting piece (7) with the fitting (2).

1. A sampling device (1) comprising a sampling container (4) for reception of a sample volume and a connecting piece (7) adapted to be connected to a fitting (2) mounted on a vessel (3) or pipe of a processing installation or the like, the connecting piece (7) having a sample passage which is provided with a stationary valve part (12) and a corresponding valve member (14) which is displaceable between a closed position, in which it abuts the stationary valve part (12) and closes the sample passage, and an open position, in which the sample passage is open, whereby the valve member (14) is spring-loaded towards its closed position and adapted to be automatically displaced to its open position upon connection of the connecting piece (7) with the fitting (2), characterized in that the stationary valve part (12) or the valve member (14) is formed as a conical face forming part of a wall surrounding the inside volume of the sampling container (4), and in that the other one of said stationary valve part (12) and said valve member, (14) has the form of a truncated cone carried by a spindle extending coaxially through the inside volume of the sampling container. 2. A sampling device according to claim 1, characterized in that the connecting piece (7) is adapted to be displaced in a longitudinal direction of the container (4) during at least part of the operation of connecting it to the fitting (2), and in that the displaceable valve member (14) is adapted to abut an edge (20) of the fitting (2) during at least part of said displacement. 3. A sampling device according to any one of the preceding claims, characterized in that the connecting piece (7) is adapted to be screwed onto the fitting (2). 4. A sampling device according to any one of the preceding claims, characterized in that the sampling container (4) comprises an outer container (5) and an inner container (6), the inner container (6) being arranged displaceably in a longitudinal direction of the outer container (5), in that the outer container (5) at a first end is formed integrally with the connecting piece (7) and at a second end is provided with a bottom (10), in that the inner container (6) at a first end is formed integrally with an annular sealing surface (15), thereby forming the displaceable valve member (14), and at a second end has a bottom (16) in which a spindle passage (17) is provided, in that a spindle (11) has a first end which is provided with the stationary valve part (12) and a second end which is fixed to the bottom (10) of the outer container (5), and in that the spindle passage (17) is arranged tightly around and displaceably along the spindle (11). 5. A sampling device according to claim 4, characterized in that the outer length of the outer container (5) is between 100 mm and 300 mm, in that the outer diameter of the outer container (5) is between ½ and ⅔ of the outer length of the outer container (5), and in that the smallest diameter of the annular sealing surface (15) of the inner container (6) is between ¼ and ⅔ of the outer diameter of the outer container (5). 6. A sampling device according to claim 4 or 5, characterized in that the outer container (5) and the inner container (6) are formed from Plexiglass, glass, tempered glass or the like, and in that the stationary valve part (12) is formed from polytetrafluoroethylene or the like. 7. A sampling device according to any one of the preceding claims, characterized in that the sampling device (1) comprises a fitting (2) mating the connecting piece (7) and having an installation end adapted to be installed onto the vessel or pipe of said processing installation or the like, and in that the fitting (2) has a tubular part (24) provided with an inner shielding meter (25) adapted to shield the stationary valve part (12) in the connected state of the connecting piece (7) and the fitting (2). 8. A sampling device according to claim 7, characterized in that the tubular part (24) of the fitting (2) is provided with a covering member (31) adapted to cover the displaceable valve member (14) in the connected state of the connecting piece (7) and the fitting (2). 9. A sampling device according to claim 8, characterized in that the shielding member (25) is adapted to seal against the covering member (31) in the disconnected state of the connecting piece (7) and the fitting (2). 10. A sampling device according to claim 8 or 9, characterized in that a circumferential contour (29) of the shielding member (25) fits a circumferential contour (30) of the stationary valve part (12), in that the shielding member (25) is adapted to be displaced with the stationary valve part (12) against a spring-load during at least part of the operation of connecting the connecting piece (7) to the fitting (2), in that a circumferential contour (32) of the covering member (31) fits a circumferential contour (33) of the displaceable valve member (14), in that the covering member (31) is fixedly mounted in the fitting (2), in that the circumferential contour (29) of the shielding member (25) fits the circumferential contour (32) of the covering member (31), and in that the circumferential contour (30) of the stationary valve part (12) fits the circumferential contour (33) of the displaceable valve member (14). 11. A sampling device according to any one of the claims 8 to 10, characterized in that the shielding member (25) has a conical sealing surface (34) corresponding to a conical sealing surface (35) on the covering member (31). 12. A sampling device according to any one of the claims 8 to 11, characterized in that the shielding member (25) is spring-loaded against the covering member (31) by means of a spring (28) located in a tube element (25) in which a spindle of the shielding member (25) is guided, in that the tube element (26) is guided axially in the tubular part (24) of the fitting (2), and in that the tube element (26) is fixed in a plate (27) adapted to abut an edge (38) of a flange (37) on the vessel or pipe of the processing installation or the like, in the mounted state of the fitting on said flange. 13. A sampling device according to any one of the claims 7 to 12, characterized in that the fitting comprises a shut-off valve (22). 14. A sampling device according to any one of the claims 9 to 13, characterized in that the sampling device (1) comprises a nozzle (41) adapted to be connected to the fitting (2) and having an internal projection (44) adapted to keep the shielding member (25) displaced against the spring-load in the connected state of the nozzle (41) to the fitting (2), and in that the nozzle (41) has a tube connection (43) for supply or discharge of cleaning or washing fluid. 15. A sampling method for taking a sample of a product from a processing installation or the like, comprising the steps of connecting a connecting piece (7) of a sampling device (1) to a fitting (2) mounted on a vessel (3) or pipe of the processing installation or the like, displacing a valve member (14) in a sample passage of the connecting piece (7) from a closed position, in which it abuts a stationary valve part (12) and thereby closes the sample passage, to an open position, in which the sample passage is open, allowing product to pass from the processing installation or the like, through the sample passage, and into a sampling container (4) of the sampling device (1), displacing the valve member (14) from its open position to its closed position, and disconnecting the connecting piece (7) from the fitting (2), whereby the valve member (14) in displaced from its closed position to its open position against a spring-load, and whereby the valve member (14) is automatically displaced to its open position upon connection of the connecting piece (7) with the fitting (2), characterized by that, in the open position of the valve member (14), the product passes through a conical annular passage formed between a conical face forming part of a wall surrounding the inside volume of the sampling container (4) and a truncated cone carried by a spindle extending coaxially through the inside volume of the sampling container. 16. A sampling method according to claim 15, characterized by that the valve member (14) is displaced to its open position by means of a covering member (31) fixedly mounted in the fitting (2) and abutting the valve member (14) during at least part of the operation of connecting the connecting piece (7) to the fitting (2), whereby a circumferential contour (32) of the covering member (31) fits a circumferential contour (33) of the valve member (14), by that a shielding member (25) mounted displaceably in the fitting (2) abuts the stationary valve part (12), whereby a circumferential contour (29) of the shielding member (25) fits a circumferential contour (30) of the stationary valve part (12), and whereby the shielding member (25) is displaced against a spring-load during at least part of the operation of connecting the connecting piece (7) to the fitting (2), and by that, after disconnecting the connecting piece (7) from the fitting (2), the circumferential contour (29) of the shielding member (25) fits the circumferential contour (32) of the covering member (31), and the circumferential contour (30) of the stationary valve part (12) fits the circumferential contour (33) of the displaceable valve member (14). 17. A sampling method according to claim 15 or 16, characterized by that a shut-off valve (22) of the fitting (2) is opened and subsequently closed in the fully connected state of the connecting piece (7) and the fitting (2) in order to allow the product to pass through the fitting (2). 18. A sampling method according to claim 16, characterized by that, in the disconnected state of the connecting piece (7) and the fitting (2), a nozzle (41) is connected to the fitting (2), whereby an internal projection (44) in the nozzle (41) keeps the shielding member (25) displaced against the spring-load in the connected state of the nozzle (41) to the fitting (2), and by that a cleaning or washing fluid is supplied to or discharged from the fitting through the nozzle (41).

The present invention relates to a sampling device comprising a sampling container for reception of a sample volume and a connecting piece adapted to be connected to a fitting mounted on a vessel or pipe of a processing installation or the like, the connecting piece having a sample passage which is provided with a stationary valve part and a corresponding valve member which is displaceable between a closed position, in which it abuts the stationary valve part and closes the sample passage, and an open position, in which the sample passage is open, whereby the valve member is spring-loaded towards its closed position and adapted to be automatically displaced to its open position upon connection of the connecting piece with the fitting. EP 0141. 940 codesponding to U.S. Pat. No. 4,580,452 discloses a sampling container being connected through a pipe to a manually operated sampling valve which way be screwed into a fitting mounted on a conduit forming part of a chemical plant installation. The fitting is also provided with a manually operated valve in order to close the outlet from the conduit when the sampling valve is not connected to the fitting. To take a sample, firstly the sampling valve must be screwed into the fitting, the two valves must be opened and subsequently closed, and the sampling valve must be disconnected from the fitting. Obviously, this procedure is time-consuming, and furthermore there is a risk of forgetting to close one of the valves after having taken a sample, whereby possibly hazardous product could escape from the sampling system. Additionally, the configuration of the sampling container and its connected valve is awkward to handle and susceptible to damages if dropped, which may result in product spillage. Furthermore, the device is suitable for the sampling of fluids only, as products such as powder or granules would clog up the passages through the valves and the pipe. DE 40 34 700 describes a dual-valve system for the taking of a fluid sample from a pipe system. A first valve member in the form of a truncated cone is arranged in a pipe rotatably about an axis perpendicular to the direction of flow in the pipe and has a through passage in-line with the pipe opening when set to its open position. In this open position, a sample may be taken from the pipe through a second valve arranged in a connection piece inserted in the lower side of the truncated cone. After having taken a sample, both valves are closed, and the internal product-contaminated surfaces which are situated between the two closed valves are cleaned by means of a spray device. However, this procedure is most cumbersome and time-consuming. Furthermore, the system also has the disadvantage that the second valve must be closed manually in order to prevent spillage of the product sampled. The sampling container protrudes radially from the second valve and makes the device awkward in use. DE 43 01 174 discloses a sampling valve having a semi-cylindrical valve member arranged rotatably in a bore extending tangentially to the inner surface of a pipe wall. An external sampling container is screwed into a fitting which is mounted on the outside of the pipe wall and is in fluid connection with the bore through a passage. When the valve member is in its open position, a fluid may pass from the pipe to the sampling container. After removing the sampling container from the fitting, the container is open to the surroundings and consequently product may be spilled. DE 197 35 586 shows a sampling valve having an outlet opening through the wall of a pipe and a corresponding valve member which by means of a spindle is manually operable from the outside of the pipe. A sampling container for the reception of a fluid may be held under the outlet opening when the valve is opened. U.S. Pat. No. 4,689,306 describes a device for sterile sampling from a fermenter. The device comprises a sample collector having a normally closed valve mounted on its neck inside a valve housing and a sampler having a normally closed valve, also located in a valve housing, and being positioned on the fermenter. To take a sample, the neck of the sample collector is positioned against the sampler, whereby rods of said valves press against each other, thereby opening the valves and allowing product to enter the sample collector through the valve housings. U.S. Pat. No. 4,699,356 describes a fluid sampling valve, within the body of which there is a central bore interconnecting a sample end and a vessel end, thereby allowing fluid communication through the valve. Within the central bore, there is a cylindrical valve stem having at one end proximate to the sample end a conically-faced head being urged toward a sealing ring in the sample end by a spring, thereby closing the central bore against the surroundings. By inserting a hollow cylindrical sampling probe through said sealing ring, the conically-faced valve head is lifted from the sealing ring, and fluid communication is provided through a hole in the wall of the hollow sampling probe to the fluid sample container. U.S. Pat. No. 4,150,575 describes a fluid sampling system comprising a fluid coupling and a sampler in which the coupling is included. The fluid coupling comprises a coupling valve that includes an annular valve seat axially slidable within a valve housing of the fluid coupling. The seat has a conical central opening, within which a valve closure member is slidable and includes a tapered head shaped and dimensioned to fit tightly within the seat. In order to take a sample, the coupling is connected to a coupling receiver comprising a receiver housing and a plug which form a fluid tight seal in a manner similar to that of the coupling valve. Upon connection, the valves open, and fluid can then enter a cross-bore in the closure member of the valve leading to a small diameter axial bore by which it exits from the opposite end of the coupling. The sampling device according to the invention is characterized in that the stationary valve part or the valve member is formed as a conical face forming part of a wall surrounding the inside volume of the sampling container, and in that the other one of said stationary valve part and said valve member has the form of a truncated cone carried by a spindle extending coaxially through the inside volume of the sampling container. Because the integrated design ensures a short and unimpeded path for the product to be sampled, the sampling device according to the present invention is very suitable for the sampling of powders, granules and the like, as well as any type of fluid or flowable product. The sampling container will always be automatically closed by means of the valve member upon disconnection of the container from the fitting, and product spillage through the connection piece may be hindered, even if the container should be dropped. Furthermore, the integrated design of the stationary valve part and the valve member in the sampling container provides for a more robust construction and a device which is easier and therefore safer to handle. Consequently, also the risk of dropping the device is reduced. The displaceable valve member has a conical sealing surface corresponding to a conical sealing surface on the stationary valve part. This ensures a good sealing effect. In a simple and therefore reliable embodiment, the connecting piece is adapted to be displaced in a longitudinal direction of the container during at least part of the operation of connecting it to the fitting, and the displaceable valve member is adapted to abut an edge of the fitting during at least part of said displacement. The valve member will then be displaced in the sampling container to its open position as a result of the displacement of the connecting piece in the direction against the fitting. In a preferred embodiment, the connecting piece is adapted to be screwed onto the fitting. This ensures a strong connection between the connecting piece and the fitting. The device may in this way be designed explosion proof, for instance in order to be able to withstand an internal pressure of 10 bar In an advantageous embodiment, the sampling container comprises an outer container and an inner container, the inner container is arranged displaceably in a longitudinal direction of the outer container, the outer container is at a first end formed integrally with the connecting piece and is at a second end provided with a bottom, the inner container is at a first end formed integrally with an annular sealing surface, thereby forming the displaceable valve member, and has at a second end a bottom in which a spindle passage is provided, a spindle has a first end which is provided with the stationary valve part and a second end which is fixed to the bottom of the outer container, and the spindle passage is arranged tightly around and displaceably along the spindle. By the provision of two containers arranged one inside the other, an even more robust construction is achieved, especially in terms of the ability to withstand a high internal pressure, but also considering the risk of dropping the container. Furthermore, the device is simple to manufacture because very few components are required. In an embodiment, the outer length of the outer container is between 100 mm and 300 mm, the outer diameter of the outer container is between ½ and ⅔ of the outer length of the outer container, and the smallest diameter of the annular sealing surface of the inner container is between ¼ and ⅔ of the outer diameter of the outer container. In an advantageous embodiment, the outer container and the inner container are formed from Plexiglass (registered trademark), glass, tempered glass or the like, and the stationary valve part is formed from polytetrafluoroethylene or the like. This configuration allows visual inspection of the product sample through the Plexiglass or glass, and a good sealing effect is obtained between Plexiglass or glass and polytetrafluoroethylene. In a further embodiment, the sampling device comprises a fitting mating the connecting piece and having an installation end adapted to be installed onto the vessel or pipe of said processing installation or the like, and the fitting has a tubular part provided with an inner shielding member adapted to shield the stationary valve part in the connected state of the connecting piece and the fitting. Thereby the outward surface of the stationary valve part is shielded against the sample product during taking of the sample and consequently this surface will be free from product after removal of the sampling container from the fitting. This may be an advantage especially in case of hazardous products. Further, the product flow may be guided and thereby facilitated by the shielding member. In a further embodiment, the tubular part of the fitting is provided with a covering member adapted to cover the displaceable valve member in the connected state of the connecting piece and the fitting. Thereby also the displaceable valve member will be free from product after removal of the sampling container from the fitting and the cleanliness of the device is further improved. In a further embodiment, the shielding member is adapted to seal against the covering member in the disconnected state of the connecting piece and the fitting. This prevents product from leaking from the fitting after removal of the sampling container from the fitting. Especially in case of toxic products, this may be an advantage. In a further embodiment, a circumferential contour of the shielding member fits a circumferential contour of the stationary valve part, the shielding member is adapted to be displaced with the stationary valve part against a spring-load during at least part of the operation of connecting the connecting piece to the fitting, a circumferential contour of the covering member fits a circumferential contour of the displaceable valve member, the covering member is fixedly mounted in the fitting, the circumferential contour of the shielding member fits the circumferential contour of the covering member, and the circumferential contour of the stationary valve part fits the circumferential contour of the displaceable valve member. Thereby a product sample may be taken out from a processing installation in a fully contained way, so that, after disconnection of the sampling container from the fitting, substantially no product will leak to the surroundings of the fitting and the sampling container. In this way, the operator will practically not be exposed to the product sampled. The shielding member may have a conical sealing surface corresponding to a conical sealing surface on the covering member. This ensures improved sealing effect. In a further embodiment, the shielding member is spring-loaded against the covering member by means of a spring located in a tube element in which a spindle of the shielding member is guided, the tube element is guided axially in the tubular part of the fitting, and the tube element is fixed in a plate adapted to abut an edge of a flange on the vessel or pipe of the processing installation or the like, in the mounted state of the fitting on said flange. Thereby the shielding member will be automatically spring-loaded against the covering member upon installation of the fitting on the flange. In an advantageous embodiment, the fitting comprises a shut-off valve. This may especially be advantageous if no shielding and covering members are provided in the fitting, or if both high and low pressures may occur in the vessel or pipe of the processing installation. In the latter case the shut-off valve ensures that the shielding member is not lifted from the covering member as a result of a pressure difference between the internal of the processing system and the exterior surroundings. In a further embodiment, the sampling device comprises a nozzle adapted to be connected to the fitting and having an internal projection adapted to keep the shielding member displaced against the spring-load in the connected state of the nozzle to the fitting, and the nozzle has a tube connection for supply or discharge of cleaning or washing fluid. Thereby the interior of the fitting may be cleaned or washed after the taking of a sample. The present invention also relates to a sampling method for taking a sample of a product from a processing installation or the like, comprising the steps of connecting a connecting piece of a sampling device to a fitting mounted on a vessel or pipe of the processing installation or the like, displacing a valve member in a sample passage of the connecting piece from a closed position, in which it closes the sample passage, to an open position, in which the sample passage is open, allowing product to pass from the processing installation or the like, through the sample passage, and into a sampling container of the sampling device, displacing the valve member from its open position to its closed position, and disconnecting the connecting piece from the fitting, whereby the valve member is displaced from its closed position to its open position against a spring-load, and whereby the valve member is automatically displaced to its open position upon connection of the connecting piece with the fitting. The sampling method is characterized by that, in the open position of the valve member, the product passes trough a conical annular passage formed between a conical face forming part of a wall surrounding the inside volume of the sampling container and a truncated cone carried by a spindle extending coaxially through the inside volume of the sampling container. Thereby the above-mentioned advantages are obtained. In a further embodiment of the sampling method, the valve member is displaced to its open position by means of a covering member fixedly mounted in the fitting and abutting the valve member during at least part of the operation of connecting the connecting piece to the fitting, whereby a circumferential contour of the covering member fits a circumferential contour of the valve member, by that a shielding member mounted displaceably in the fitting abuts the stationary valve part, whereby a circumferential contour of the shielding member fits a circumferential contour of the stationary valve part, and whereby the shielding member is displaced against a spring-load during at least part of the operation of connecting the connecting piece to the fitting, and by that, after disconnecting the connecting piece from the fitting, the circumferential contour of the shielding member fits the circumferential contour of the covering member, and the circumferential contour of the stationary valve part fits the circumferential contour of the displaceable valve member. Thereby a sample may be taken out in a fully contained way as explained above. In a further embodiment of the sampling method, a shut-off valve of the fitting is opened and subsequently closed in the fully connected state of the connecting piece and the fitting in order to allow the product to pass through the fitting. Thereby the above-mentioned advantages are obtained. In a further embodiment of the sampling method, in the disconnected state of the connecting piece and the fitting, a nozzle is connected to the fitting, whereby an internal projection in the nozzle keeps the shielding member displaced against the spring-load in the connected state of the nozzle to the fitting and a cleaning or washing fluid is supplied to or discharged from the fitting through the nozzle. Thereby the above-mentioned advantages are obtained. The invention will be described in more detail below by means of examples of embodiments with reference to the schematic drawing, in which FIG. 1 is a partially sectional view of a sampling device according to the invention, connected to a fitting, FIG. 2 is a sectional view of the sampling device in FIG. 1, after disconnection from the fitting, FIGS. 3 and 4 are sectional views of other embodiments of the sampling device, FIG. 5 is a sectional view of a flange and a fitting for connection to the sampling device, before mounting the fitting on the flange, FIG. 6 to 8 are sectional views of a further embodiment of the sampling device, in the connected state of the connecting piece on the fitting, in the partially disconnected state, and in the fully disconnected state, respectively, FIG. 9 to 11 are sectional views of a nozzle of the sampling device, in the connected state of the nozzle on the fitting, in the partially disconnected state, and in the fully disconnected state, respectively. FIG. 1 shows a sampling device 1 according to the invention, connected to a fitting 2 mounted on a vessel 3 of a processing installation of which is shown only part of a wall. The sampling device 1 has sampling container 4 comprising an outer cylindrical container 5 and an inner cylindrical container 6 arranged concentric inside the outer container 5 so that it is displaceable in the axial direction of the latter. The sampling device 1 and the method of sampling according to the invention may be used in all industries, e.g. such as pharmaceutical, biotechnological and chemical, for all kinds of processing equipment or storage containers as well as pipe systems, and for all kinds of products, e.g. such as powders, granules, liquid products and gaseous products, as well as any possible combination of products. For powders and granules, the processing installation to take samples from may e.g. be fluid bed equipment, granulation equipment, agglomeration equipment, coating equipment, layering equipment, extrusion equipment, spray drying equipment, packaging equipment etc. Furthermore, heavy, sticky or viscous products or products having limited flow capabilities may be sampled by means of the device and the sampling method according to the invention. At a first end, the outer container 5 is formed integrally with a connecting piece 7 in the form of an internal thread 8 which in FIG. 1 has been screwed onto an outer thread 9 of the fitting 2. At a second end, the outer container 5 has a bottom 10, to which a spindle 11 is fixed rigidly and from which the spindle 11 extends coaxially in the outer container 5 to the area of the first end of the outer container, where a stationary valve part 12 in the form of a truncated cone is formed integrally with the spindle 11 and concentric with this. The stationary valve part 12 has a conical sealing surface 13 facing the interior of the sampling container 4. At a first end, the inner container 6 is formed integrally with a displaceable valve member 14 in the form of a conical sealing surface 15 facing away from the interior of the sampling container 4 and corresponding to the conical sealing surface 13 of the stationary valve part 12. At a second end, the inner container 6 has a bottom 16 in which is formed a concentric spindle passage 17 sealed displaceably against the spindle 11 by means of an O-ring 18. Between the bottom 16 of the inner container 6 and the bottom 10 of the outer container 5 is arranged a compression spring 19 around the spindle 11, thereby spring-loading the inner container 6 with its integral valve member 14 towards a closed position of the displaceable valve member 14, in which position the conical sealing surface 15 of the valve member 14 abuts the conical sealing surface 13 of the stationary valve part 12, as shown in FIG. 2 where the sampling container 4 has been disconnected from the fitting 2. In the connected state of the connecting piece 7 to the fitting 2, as shown in FIG. 1, the valve member 14 formed on the internal container 6 abuts an edge 20 of the fitting 2, whereby the valve member 14 is maintained in its open position displaced against the load of the compression spring 19 so that a passage 21 is open between the displaceable valve member 14 and the stationary valve part 12. In order to take a sample from the vessel 3, the closed sampling container 4 shown in FIG. 2 is screwed onto the fitting 2 whereby the displaceable valve member 14 is displaced to its open position shown in FIG. 1. Subsequently, a shut-off valve 22 comprised by the fitting 2 is operated manually by means of a handle 23 so that product may pass from the interior of the vessel 3 to an internal tubular part 24 of the fitting 2 and into the open sampling container 4. The open position of the handle 23 is indicated by means of dash-dot lines. The outer and inner containers 5, 6 may advantageously be formed from Plexiglass (registered trademark), glass, tempered glass or the like, whereby the amount of product entering the sampling container 4 may be observed visually. After having taken an appropriate sample, the shut-off valve 22 is closed and the sampling container 4 is screwed off the fitting 2 whereby the valve member 14 is displaced to its closed position as shown in FIG. 2. Subsequently, the sampling container 4 may be handled without risk of product leakage and possibly transported before the sample is poured out of the container 4. In order to pour out the product contained in the sampling container 4, the container may be screwed on a suitable laboratory equipment having a part fitting the connecting piece 7 similar to the fitting 2, i.e. having an outer thread similar to the thread 9 and an edge similar to the edge 20 adapted to abut the displaceable valve member 14 and thereby maintain this in its open position. FIG. 3 shows another embodiment of the sampling device according to the invention. The embodiment differs from the one shown in FIG. 1 in that the fitting 2 is provided with an internal shielding member 25 which is guided in a tube element 26 fixed in a plate 27 which is guided and axially displaceable in the tubular part 24 of the fitting 2. By means of a compression spring 28 located in the tube element 26, the shielding member 25 is spring-loaded to abut the stationary valve part 12 upon connection of the connecting piece 7 to the fitting 2. The shielding member 25 has a circumferential contour 29 fitting a circumferential contour 30 of the stationary valve part 12. FIG. 6 to a show another embodiment of the sampling device 1. The embodiment differs from the one shown in FIG. 1 in that the fitting 2 furthermore is provided with both a shielding member 25 and a covering member 31 formed integrally with the tubular part 24 of the fitting 2. The covering member 31 has a circumferential contour 32 fitting both a circumferential contour 33 of the displaceable valve member 14 and a circumferential contour 29 of the shielding member 25. The stationary valve part 12 has a circumferential contour 30 fitting both the circumferential contour 33 of the displaceable valve member 14 and the circumferential contour 29 of the shielding member 25. Furthermore, the shielding member 25 has a conical sealing surface 34 corresponding to a conical sealing surface 35 of the covering member 31. FIG. 6 shows the connected state of the connecting piece 7 of the sampling container 4 on the fitting 2, in which state the displaceable valve member 14 and the shielding member 25 are in their open positions. FIG. 7 shows a partly disconnected state of the connecting piece 7 and the fitting 2, in which state both the displaceable valve member 14 and the shielding member 25 are in their closed positions and the thread 8 of the connecting piece 7 is engaging the thread 9 of the fitting 2 in order to secure tight connection between the sampling container 4 and the fitting 2. FIG. 8 shows the disconnected state of the connecting piece 7 and the fitting 2, in which state the displaceable valve member 14 and the shielding member 25 are in their closed positions. With this embodiment it is possible to take a sample in a fully contained way so that the surroundings and the operator are practically not exposed to the product sampled. After having taken the sample, the sampling container 4 may, as explained above, be transported to and screwed on a suitable laboratory equipment whereby the product sampled may be transferred to said equipment, also in a fully a contained way. In a typical execution, the outer container 5 has an outer length of approximately 130 mm, an outer diameter of approximately 75 mm and a wall thickness of approximately 10 mm and the inner container 6 has an inner diameter of approximately 40 mm and an inner length between its bottom 16 and its annular sealing surface 15 of approximately 65 mm. In this execution, the length of the internal thread 8 of the outer container 5 is approximately 18 mm and the outer length of the fitting 2 is approximately 53 mm. The diameter of the circumferential contour 32 of the covering member 31 fitting the circumferential contour 29 of the shielding member 25 is approximately 34 mm. In another typical execution, said dimensions have been multiplied by two. The dimensions and the materials may also typically be chosen so as to ensure that the device is explosion proof for a required pressure. The embodiments of the sampling device 1 shown in FIGS. 1 to 3 and 6 to 8 are especially suitable if the pressure in the vessel or pipe of the processing installation to be sampled from is below atmospheric, as substantially the same pressure will be present in the sampling container 4 after having taken the sample. Consequently, the pressure difference between the surroundings and the internal of the sampling container 4 will assist the spring 19 in keeping the valve member 14 in its closed position after taking the sample and disconnecting the container 4 from the fitting 2. FIG. 5 shows the fitting 2 of the sampling device 1 in FIGS. 6 to 8, before mounting a flange 36 of the fitting 2 on a flange 37 of the processing installation. As indicated by means of dash-dot lines, the plate 27 is displaceable axially in the tubular part 24 of the fitting 2 and upon connection of the flange parts 36, 37, an edge 38 of the vessel of the processing installation will abut the plate 27, thereby displacing the plate to the position indicated by means of the dash-dot lines, whereby the compression spring 28 will be compressed and thereby preload the shielding member 25 against the covering member 31. FIG. 4 shows still another embodiment of the sampling device 1 according to the invention. In this embodiment parts similar to parts in the embodiment in FIG. 6 to 8 are indicated with similar reference numbers. The sampling container 4 has an annular stationary valve part 12 formed integrally around its inlet opening. The displaceable valve member 14 is by means of a spindle 39 guided in a tube element 40 at the bottom of the sampling container 4. The fitting 2 is provided with a spring-loaded annular displaceable shielding member 25 and a conical fixed covering member 31. This embodiment also permits the taking of samples in a fully contained way and is especially suitable if the pressure in the vessel or pipe of the processing installation to be sampled from is above atmospheric, as substantially the same pressure will be present in the sampling container 4 after having taken the sample. Consequently, the pressure difference between the surroundings and the internal of the sampling container 4 will assist the spring 19 in keeping the valve member 14 in its closed position after taking the sample and disconnecting the container 4 from the fitting 2. This will prevent even a small amount of product in leaking upon disconnection of the sampling container 4 from the fitting 2. The embodiments shown in FIGS. 4 and 6 to 8 may be used with or without the shut-off valve 22 shown in FIG. 1, depending on the situation, for instance whether the pressure in the installation to be sampled from is constantly above or below atmospheric or may change. FIGS. 9 to 11 show an embodiment of the sampling device 1 comprising a nozzle 41 comprising a connecting piece 42 which may be connected with the fitting 2 and which has a tube connection 43 for the supply of or discharge of cleaning or washing fluid to or from the fitting 2. The tube connection 43 comprises an internal projection 44 which in the connected state of the nozzle 41 on the fitting 2 maintains the shielding member 25 in its open position, thereby allowing cleaning or washing fluid to pass in or out through the fitting 2. FIG. 9 shows the connected state, FIG. 10 shows a partly connected state, in which the connecting piece 42 is mounted on the fitting 2, but in which the tube connection 43 is not fully connected to the connecting piece 42 so that the shielding member 25 is still in its closed position, and FIG. 11 shows the fully disconnected state.

20040826

20070710

20050901

98760.0

SHAH, SAMIR M

SAMPLING DEVICE AND SAMPLING METHOD

UNDISCOUNTED

ACCEPTED

ACCEPTED

Virus causing respiratory tract illness in susceptible mammals

The invention relates to the field of virology. The invention provides an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) within the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus and components thereof.

1. An isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxouiridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus 2. An isolated negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxovirdae and identifiable as phylogenetically corresponding to the genus Metapneumovirus by determining a nucleic acid sequence of said virus and testing it in phylogenetic tree analyses wherein maximum likelihood trees are generated using 100 bootstraps and 3 jumbles and finding it to be more closely phylogenetically corresponding to a virus isolate deposited as I-2614 with CNCM, Paris than it is corresponding to a virus isolate of avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis. 3. A virus according to claim 2 wherein said avian pneumovirus comprises APV type C (APV-C). 4. A virus according to claim 1 to 3 wherein said nucleic acid sequence comprises an open reading frame (ORF) encoding a viral protein of said virus. 5. A virus according to claim 4 wherein said open reading frame is selected from the group of ORFs encoding the N, P, M, and F proteins. 6. A virus according to claim 5 wherein said open reading frame is selected from the group of ORFs encoding the SH or G proteins. 7. A virus according to anyone of claims 1 to 6 comprising a nucleic acid or functional fragment phylogenetically corresponding to a sequence shown in FIG. 6. 8. A virus according to anyone of claims 1 to 7 comprising an MPV isolate deposited as I-2614 with CNCM, Institute Pasteur, Paris or a virus isolate phylogenetically corresponding therewith. 9. A virus according to claim 8 isolatable from a human with respiratory tract illness. 10. An isolated or recombinant nucleic acid or MPV-specific functional fragment thereof obtainable from a virus according to anyone of claims 1 to 9. 11. A vector comprising a nucleic acid according to claim 10. 12. A host cell comprising a nucleic acid according to claim 10 or a vector according to claim 11. 13. An isolated or recombinant proteinaceous molecule or MPV-specific functional fragment thereof encoded by a nucleic acid according to claim 10. 14. An antigen comprising a proteinaceous molecule or MPV-specific functional fragment thereof according to claim 13. 15. An antibody specifically directed against an antigen according to claim 14. 16. A method for identifying a viral isolate as an MPV comprising reacting said viral isolate or a component thereof with an antibody according to claim 15. 17. A method for identifying a viral isolate as an MPV comprising reacting said viral isolate or a component thereof with a nucleic acid according to claim 10. 18. A method according to claim 16 or 17 wherein said MPV comprises a human MPV. 19. A viral isolate identifiable with a method according to anyone of claims 16 to 18 as a mammalian negative-sense single stranded RNA virus within the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus. 20. A method for virologically diagnosing an MPV infection of a mammal comprising determining in a sample of said mammal the presence of a viral isolate or component thereof by reacting said sample with a nucleic acid according to claim 10 or an antibody according to claim 15. 21. A method for serologically diagnosing an MPV infection of a mammal comprising determining in a sample of said mammal the presence of an antibody specifically directed against an MPV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof according to claim 13 or an antigen according to claim 14. 22. A diagnostic kit for diagnosing an MPV infection comprising a virus according to anyone of claims 1 to 9, a nucleic acid according to claim 10, a proteinaceous molecule or fragment thereof according to claim 13, an antigen according to claim 14 and/or an antibody according to claim 15. 23. Use of a virus according to any one claims 1 to 9, a nucleic acid according to claim 10, a vector according to claim 11, a host cell according to claim 12, a proteinaceous molecule or fragment thereof according to claim 13, an antigen according to claim 14, or an antibody according to claim 15 for the production of a pharmaceutical composition. 24. Use according to claim 23 for the production of a pharmaceutical composition for the treatment or prevention of an MPV infection. 25. Use according to claim 23 or 24 for the production of a pharmaceutical composition for the treatment or prevention of respiratory tract illnesses. 26. A pharmaceutical composition comprising a virus according to any one claims 1 to 9, a nucleic acid according to claim 10, a vector according to claim 11, a host cell according to claim 12, a proteinaceous molecule or fragment thereof according to claim 13, an antigen according to claim 14, or an antibody according to claim 15. 27. A method for the treatment or prevention of an MPV infection comprising providing an individual with a pharmaceutical composition according to claim 26. 28. A method for the treatment or prevention of a respiratory illness comprising providing an individual with a pharmaceutical composition according to claim 26. 29. A method according to claim 27 or 28 wherein said individual comprises a human. 30. A method to obtain an antiviral agent useful in the treatment of respiratory tract illness comprising establishing a cell culture or experimental animal comprising a virus according to any one of claims 1 to 9, treating said culture or animal with an candidate antiviral agent, determining the effect of said agent on said virus or its infection of said culture or animal, and selecting an anitviral agent with the desired effect. 31. An antiviral agent obtainable according to the method of claim 30. 32. Use of an antiviral agent according to claim 31 for the preparation of a pharmaceutical composition. 33. Use according to claim 33 for the preparation of a pharmaceutical composition for the treatment of respiratory tract illness. 34. Use according to claim 32 or 33 for the preparation of a pharmaceutical composition for the treatment of an MPV infection. 35. A pharmaceutical composition comprising an antiviral agent according to claim 31. 36. A method for the treatment or prevention of an MPV infection comprising providing an individual with a pharmaceutical composition according to claim 35. 37. A method for the treatment or prevention of a respiratory illness comprising providing an individual with a pharmaceutical composition according to claim 35. 38. A method according to claim 36 or 37 wherein said individual comprises a human. 39. A method for virologically diagnosing an MPV infection of an animal comprising determining in a sample of said animal the presence of a viral isolate or component thereof by reacting said sample with a nucleic acid or an antibody specifically reactive with a component of an avian pneumovirus (APV), said nucleic acid or antibody being cross-reactive with a component MPV. 40. A method for serologically diagnosing an MPV infection of an animal comprising determining in a sample of said animal the presence of an antibody directed against an MPV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof or antigen derived from an APV isolate or component thereof, said molecule, fragment or antigen selected for being essentially homologous with a component of MPV. 41. A method for virologically diagnosing an APV infection of a bird comprising determining in a sample of said bird the presence of a viral isolate or component thereof by reacting said sample with a nucleic acid according to claim 10 or an antibody according to claim 15 said nucleic acid or antibody being cross-reactive with a component of APV. 42. A method for serologically diagnosing an APV infection of a bird comprising determining in a sample of said bird the presence of an antibody specifically directed against an APV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof according to claim 13 or an antigen according to claim 14, said molecule, fragment or antigen selected for being essentially homologous with a component of APV. 43. A method according to anyone of claims 39 to 42 wherein said APV comprises APV-C. 44. Use of a diagnostic test designed to detect APV specific antibodies for the detection of an antibody directed against MPV. 45 Use according to claim 44 wherein said test comprises an enzyme immune assay (EIA). 46. A method for the detection of an antibody directed against MPV in a sample comprising testing said sample in a diagnostic test designed to detect APV specific antibodies. 47. A method according to claim 46 wherein said test comprises an enzyme immune assay (EIA).

The invention relates to the field of virology. In the past decades several etiological agents of mammalian disease, in particular of respiratory tract illnesses (RTI), in particular of humans, have been identified7. Classical etiological agents of RTI with mammals are respiratory syncytial viruses belonging to the genus Pneumovirus found with humans (hRSV) and ruminants such as cattle or sheep (bRSV and/or oRSV). In human RSV differences in reciprocal cross neutralization assays, reactivity of the G proteins in immunological assays and nucleotide sequences of the G gene are used to define 2 hRSV antigenic subgroups. Within the subgroups the aa sequences show 94% (subgroup A) or 98% (subgroup B) identity, while only 53% aa sequence identity is found between the subgroups. Additional variability is observed within subgroups based on monoclonal antibodies, RT-PCR assays and RNAse protection assays. Viruses from both subgroups have a worldwide distribution and may occur during a single season. Infection may occur in presence of pre-existing immunity and the antigenic variation is not strictly required to allow re-infection. See for example Sullender, W. M., Respiratory Syncytial Virus Genetic and Antigenic Diversity. Clinical Microbiology Reviews, 2000. 13(1): p. 1-15; Collins, P. L., McIntosh, K. and Chanock, R. M., Respiratory syncytial virus. Fields virology, ed. B. N. Knipe, Howley, P. M. 1996, Philadelphia: lippencott-raven. 1313-1351; Johnson, P. R., et al., The G glycoprotein of human respiratory syncytial viruses of subgroups A and B: extensive sequence divergence between antigenically related proteins. Proc Natl Acad Sci USA, 1987. 84(16): p. 5625-9; Collins, P. L., The molecular Biology of Human Respiratory Syncytial Virus (RSV) of the Genus Pneumovirus, in The Paramyxoviruses, D. W. Kingsbury, Editor. 1991, Plenum Press: New York. p. 103-153. Another classical Pneumovirus is the pneumonia virus of mice (PVM), in general only found with laboratory mice. However, a proportion of the illnesses observed among mammals can still not be attributed to known pathogens. The invention provides an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus. Said virus is identifiable as phylogenetically corresponding to the genus Metapneumouvirus by determining a nucleic acid sequence of said virus and testing it in phylogenetic analyses, for example wherein maximum likelihood trees are generated using 100 bootstraps and 3 jumbles and finding it to be more closely phylogenetically corresponding to a virus isolate deposited as I-2614 with CNCM, Paris than it is corresponding to a essentially avian virus isolate of avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis. For said phylogenetic analyses it is most useful to obtain the nucleic acid sequence of a non-MPV as outgroup to be compared with, a very useful outgroup isolate can be obtained from avian pneumovirus serotype C (APV-C), as is for example demonstrated in FIG. 5 herein. Although phylogenetic analyses provides a convenient method of identifying a virus as an MPV several other possibly more straightforward albeit somewhat more course methods for identifying said virus or viral proteins or nucleic acids from said virus are herein also provided. As a rule of thumb an MPV can be identified by the percentages of a homology of the virus, proteins or nucleic acids to be identified in comparison with isolates, viral proteins, or nucleic acids identified herein by sequence or deposit. It is generally known that virus species, especially RNA virus species, often constitute a quasi species wherein a cluster of said viruses displays heterogeneity among its members. Thus it is expected that each isolate may have a somewhat different percentage relationship with one of the various isolates as provided herein. When one wishes to compare with the deposited virus I-2614, the invention provides an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus by determining an amino acid sequence of said virus and determining that said amino acid sequence has a percentage amino acid homology to a virus isolate deposited as I-2614 with CNCM, Paris which is essentially higher than the percentages provided herein for the L protein, the M protein, the N protein, the P protein, or the F protein, in comparison with APV-C or, likewise, an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxoviridae is provided as identifiable as phylogenetically corresponding to the genus Metapneumovirus by determining a nucleic acid sequence of said virus and determining that said nucleic acid sequence has a percentage nucleic acid identity to a virus isolate deposited as I-2614 with CNCM, Paris which is essentially higher than the percentages identified herein for the nucleic acids encoding the L protein, the M protein, the N protein, the P protein, or the F protein as identified herein below in comparison with APV-C. Again as a rule of thumb one may consider an MPV as belonging to one of the two serological groups of MPV as identified herein when the isolates or the viral proteins or nuclear acids of the isolates that need to be identified have percentages homology that fall within the bounds and metes of the percentages of homology identified herein for both separate groups, taking isolates 00-1 or 99-1 as the respective isolates of comparison. However, when the percentages of homology are smaller or there is more need to distinguish the viral isolates from for example APV-C it is better advised to resort to the phylogenetic analyses as identified herein. Again one should keep in mind that said percentages can vary somewhat when other isolates are selected in the determination of the percentage of homology. With the provision of this MPV, the invention provides diagnostic means and methods and therapeutic means and methods to be employed in the diagnosis and/or treatment of disease, in particular of respiratory disease, in particular of mammals, more in particular in humans. However, due to the, albeit distant, genetic relationship of the essentially mammalian MPV with the essentially avian APV, in particular with APV-C, the invention also provides means and methods to be employed in the diagnosis and treatment of avian disease. In virology, it is most advisory that diagnosis and/or treatment of a specific viral infection is performed with reagents that are most specific for said specific virus causing said infection. In this case this means that it is preferred that said diagnosis and/or treatment of an MPV infection is performed with reagents that are most specific for MPV. This by no means however excludes the possibility that less specific, but sufficiently cross-reactive reagents are used instead, for example because they are more easily available and sufficiently address the task at hand. Herein it is for example provided to perform virological and/or serological diagnosis of MPV infections in mammals with reagents derived from APV, in particular with reagents derived from APV-C, in the detailed description herein it is for example shown that sufficiently trustworthy serological diagnosis of MPV infections in mammals can be achieved by using an ELISA specifically designed to detect APV antibodies in birds. A particular useful test for this purpose is an ELISA test designed for the detection of APV antibodies (e.g in serum or egg yolk), one commercialy available version of which is known as APV-Ab SVANOVIR® which is manufactured by SVANOVA Biotech AB, Uppsal Science Park Glunten SE-751 83 Uppsala Sweden. The reverse situation is also the case, herein it is for example provided to perform virological and/or serological diagnosis of APV infections in mammals with reagents derived from MPV, in the detailed description herein it is for example shown that sufficiently trustworthy serological diagnosis of APV infections in birds can be achieved by using an ELISA designed to detect MPV antibodies. Considering that antigens and antibodies have a lock-and-key relationship, detection of the various antigens can be achieved by selecting the appropriate antibody having sufficient cross-reactivity. Of course, for relying on such cross-reactivity, it is best to select the reagents (such as antigens or antibodies) under guidance of the amino acid homologies that exist between the various (glyco)proteins of the various viruses, whereby reagents relating to the most homologous proteins will be most useful to be used in tests relying on said cross-reactivity. For nucleic aciddetection, it is even more straightforward, instead of designing primers or probes based on heterologous nucleic acid sequences of the various viruses and thus that detect differences between the essentially mammalian or avian Metapneumoviruses, it suffices to design or select primers or probes based on those stretches of virus-specific nucleic acid sequences that show high homology. In general, for nucleic acid sequences, homology percentages of 90% or higher guarantee sufficient cross-reactivity to be relied upon in diagnostic tests utilizing stingent conditions of hybridisation. The invention for example provides a method for virologically diagnosing a MPV infection of an animal, in particular of a mammal, more in particular of a human being, comprising determining in a sample of said animal the presence of a viral isolate or component thereof by reacting said sample with a MPV specific nucleic acid a or antibody according to the invention, and a method for serologically diagnosing an MPV infection of a mammal comprising determining in a sample of said mammal the presence of an antibody specifically directed against an MPV or component thereof by reacting said sample with a MPV-specific proteinaceous molecule or fragment thereof or an antigen according to the invention. The invention also provides a diagnostic kit for diagnosing an MPV infection comprising an MPV, an MPV-specific nucleic acid, proteinaceous molecule or fragment thereof, antigen and/or an antibody according to the invention, and preferably a means for detecting said MPV, MPV-specific nucleic acid, proteinaceous molecule or fragment thereof, antigen and/or an antibody, said means for example comprising an excitable group such as a fluorophore or enzymatic detection system used in the art (examples of suitable diagnostic kit format comprise IF, ELISA, neutralization assay, RT-PCR assay). To determine whether an as yet unidentified virus component or synthetic analogue thereof such as nucleic acid, proteinaceous molecule or fragment thereof can be identified as MPV-specific, it suffices to analyse the nucleic acid or amino acid sequence of said component, for example for a stretch of said nucleic acid or amino acid, preferably of at least 10, more preferably at least 25, more preferably at least 40 nucleotides or amino acids (respectively), by sequence homology comparison with known MPV sequences and with known non-MPV sequences APV-C is preferably used) using for example phylogenetic analyses as provided herein. Depending on the degree of relationship with said MPV or non-MPV sequences, the component or synthetic analogue can be identified. The invention also provides method for virologically diagnosing an MPV infection of a mammal comprising determining in a sample of said mammal the presence of a viral isolate or component thereof by reacting said sample with a cross-reactive nucleic acid derived from APV (preferably serotype C) or a cross-reactive antibody reactive with said APV, and a method for serologically diagnosing an MPV infection of a mammal comprising determining in a sample of said mammal the presence of a cross-reactive antibody that is also directed against an APV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof or an antigen derived from APV. Furthermore, the invention provides the use of a diagnostic kit initially designed for AVP or AVP-antibody detection for diagnosing an MPV infection, in particular for detecting said MPV infection in humans. The invention also provides method for virologically diagnosing an APV infection in a bird comprising determining in a sample of said bird the presence of a viral isolate or component thereof by reacting said sample with a cross-reactive nucleic acid derived from MPV or a cross-reactive antibody reactive with said MPV, and a method for serologically diagnosing an APV infection of a bird comprising determining in a sample of said bird the presence of a cross-reactive antibody that is also directed against an MPV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof or an antigen derived from MPV. Furthermore, the invention provides the use of a diagnostic kit initially designed for MPV or MPV-antibody detection for diagnosing an APV infection, in particular for detecting said APV infection in poultry such as a chicken, duck or turkey. As said, with treatment, similar use can be made of the cross-reactivity found, in particular when circumstances at hand make the use of the more homologous approach less straightforward. Vaccinations that can not wait, such as emergency vaccinations against MPV infections can for example be performed with vaccine-preparations derived from APV(preferably type C) isolates when a more homologous MPV vaccine is not available, and, vice versa, vaccinations against APV infections can be contemplated with vaccine preparations derived from MPV. Also, reverse genetic techniques make it possible to generate chimeric APV-MPV virus constructs that are useful as a vaccine, being sufficiently dissimilar to field isolates of each of the respective strains to be attenuated to a desirable level. Similar reverse genetic techniques will make it also possible to generate chimeric paramyxovirus-metapneumovirus constructs, such as RSV-MPV or PI3-MPV constructs for us in a vaccine preparation. Such constructs are particularly useful as a combination vaccine to combat respiratory tract illnesses. The invention thus provides a novel etiological agent, an isolated essentially mammalian negative-sense single stranded RNA virus (herein also called MTV) belonging to the subfamily Pneumovirinae of the family Paramyxoviridae but not identifiable as a classical pneumovirus, and belonging to the genus Metapneumovirus, and MPV-specific components or synthetic analogues thereof. Mammalian viruses resembling metapneumoviruses, i.e. metapneumoviruses isolatable from mammals that essentially function as natural host for said virus or cause disease in said mammals, have until now not been found. Metapneumoviruses, in general thought to be essentially restricted to poultry as natural host or aetiological agent of disease, are also known as avian pneumoviruses. Recently, an APV isolate of duck was described (FR 2 801 607), further demonstrating that APV infections are essentially restricted to birds as natural hosts. The invention provides an isolated mammalian pneumovirus (herein also called MPV) comprising a gene order and amino acid sequence distinct from that of the genus Pneumovirus and which is closely related and considering its phylogenetic relatedness likely belonging to the genus Metapneumovirus within the subfamily Pneumovirinae of the family Paramyxoviridae. Although until now, metapneumoviruses have only been isolated from birds, it is now shown that related, albeit materially distinct, viruses can be identified in other animal species such as mammals. Herein we show repeated isolation of MPV from humans, whereas no such reports exists for APV. Furthermore, unlike APV, MPV essentially does not or only little replicates in chickens and turkeys where it easily does in cynomolgous macaques. No reports have been found on replication of APV in mammals. In addition, whereas specific anti-sera raised against MPV neutralize MPV, anti-sera raised against APV A, B or C do not neutralize MPV to the same extent, and this lack of full cross reactivity provides another proof for MPV being a different metapneumovirus. Furthermore, where APV and MPV share a similar gene order, the G and SH proteins of MPV are largely different from the ones known of APV in that they show no significant sequence homologies on both the amino acid or nucleic acid level. Diagnostic assays to discriminate between APV and MPV isolates or antibodies directed against these different viruses can advantageously be developed based on one or both of these proteins (examples are IF, ELISA, neutralization assay, RT-PCR assay). However, also sequence and/or antigenic information obtained from the more related N, P, M, F and L proteins of MPV and analyses of sequence homologies with the respective proteins of APV, can also be used to discriminate between APV and MPV. For example, phylogenetic analyses of sequence information obtained from MPV revealed that MPV and APV are two different viruses. In particular, the phylogenetic trees show that APV and MPV are two different lineages of virus. We have also shown that MPV is circulating in the human population for at least 50 years, therefore interspecies transmission has probably taken place at least 50 years ago and is not an everyday event. Since MPV CPE was virtually indistinguishable from that caused by hRSV or hPIV-1 in tMK or other cell cultures, the MPV may have well gone unnoticed until now. tMK (tertiary money kidney cells, i.e. MK cells in a third passage in cell culture) are preferably used due to their lower costs in comparison to primary or secondary culltures. The CPE is, as well as with some of the classical Paramyxoviridae, characterized by syncytium formation after which the cells showed rapid internal disruption, followed by detachment of the cells from the monolayer. The cells usually (but not always) displayed CPE after three passages of virus from original material, at day 10 to 14 post inoculation, somewhat later than CPE caused by other viruses such as hRSV or hPIV-1. Classically, as devastating agents of disease, paramyxoviruses account for many animal and human deaths worldwide each year. The Paramyxouiridae form a family within the order of Mononegavirales (negative-sense single stranded RNA viruses), consisting of the sub-familys Paramyxovirinae and Pneumovirinae. The latter sub-family is at present taxonomically divided in the genera Pneumovirus and Metapneumovirus1 . Human respiratory syncytial virus (hRSV), the type species of the Pneumovirus genus, is the single most important cause of lower respiratory tract infections during infancy and early childhood worldwide2. Other members of the Pneumovirus genus include the bovine and ovine respiratory syncytial viruses and pneumonia virus of mice (PVM). Avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis, an upper respiratory tract infection of turkeys3, is the sole member of the recently assigned Metapneumovirus genus, which, as said was until now not associated with infections, or what is more, with disease of mammals. Serological subgroups of APV can be differentiated on the basis of nucleotide or amino acid sequences of the G glycoprotein and neutralization tests using monoclonal antibodies that also recognize the G glycoprotein, Within subgroups A, B and D the G protein shows 98.6 to 99.7% aa sequence identity within subgroups while between the subgroups only 31.2-38% aa identity is observed. See for example Collins, M. S., Gough, R. E. and Alexander, D. J., Antigenic differentiation of avian pneumouirus isolates using polyclonal antisera and mouse monoclonal antibodies. Avian Pathology, 1993. 22: p. 469-479.; Cook, J. K. A., Jones, B. V., Ellis, M. M., Antigenic differentiation of strains of turkey rhinotracheitis virus using monoclonal antibodies. Avian Pathology, 1993. 22: p. 257-273; Bayon-Auboyer, M. H., et al., Nucleotide sequences of the F, L and G protein genes of two non-A/non-B avian pneumouiruses (APV) reveal a novel APV subgroup. J Gen Virol, 2000. 81(Pt 11): p. 2723-33; Seal, B. S., Matrix protein gene nucleotide and predicted amino acid sequence demonstrate that the first US avian pneumovirus isolate is distinct from European strains. Virus Res, 1998. 58(1-2): p. 45-52; Bayon-Auboyer, M. H., et al., Comparison of F-, G- and N-based RT-PCR protocols with conventional virological procedures for the detection and typing of turkey rhinotracheitis virus. Arch Virol, 1999. 144(6): p. 1091-109; Juhasz, K and A. J. Easton, Extensive sequence variation in the attachment (G) protein gene of avian pneumovirus: evidence for two distinct subgroups. J Gen Virol, 1994. 75(Pt 11): p. 2873-80. A further serotype of APV is provided in WO00/20600, which describes the Colorado isolate of APV and compared it to known APV or TRT strains with in vitro serum neutralization tests. First, the Colorado isolate was tested against monospecific polyclonal antisera to recognized TRT isolates. The Colorado isolate was not neutralized by monospecific antisera to any of the TRT strains. It was, however, neutralized by a hyperimmune antiserum raised against a subgroup A strain. This antiserum neutralized the homologous virus to a titre of 1:400 and the Colorado isolate to a titer of 1: 80. Using the above method, the Colorado isolate was then tested against TRT monoclonal antibodies. In each case, the reciprocal neutralization titer was<10. Monospecific antiserum raised to the Colorado isolate was also tested against TRT strains of both subgroups. None of the TRT strains tested were neutralized by the antiserum to the Colorado isolate. The Colorado strain of APV does not protect SPF chicks against challenge with either a subgroup A or a subgroup B strain of TRT virus. These results suggest that the Colorado isolate may be the first example of a further serotype of avian pneumovirus, as also suggested by Bayon-Auboyer et al (J. Gen. Vir. 81:2723-2733 (2000). In a preferred embodiment, the invention provides an isolated MPV taxonomically corresponding to a (hereto unknown mammalian) metapneumovirus comprising a gene order distinct from that of the pneumoviruses within the sub-family Pneumovirinae of the family Paramyxoviridae. The classification of the two genera is based primarily on their gene constellation; metapneumoviruses generally lack non-structural proteins such NS1 or NS2 (see also Randhawa et al., J. Vir. 71:9849-9854 (1997) and the gene order is different from that of pneumoviruses (RSV: '3-NS1-NS2-N-P-M-SH-G-F-M2-L-5′, APV: '3-N-P-M-F-M2-SH-G-L-5′)4,5,6. MPV as provided by the invention or a virus isolate taxonomically corresponding therewith is upon EM analysis revealed by paramyxovirus-like particles. Consistent with the classification, MPV or virus isolates phylogenetically corresponding or taxonomically corresponding therewith are sensitive to treatment with chloroform; are cultured optimally on tMK cells or cells functionally equivalent thereto and are essentially trypsine dependent in most cell cultures. Furthermore, the typical CPE and lack of haemagglutinating activity with most classically used red blood cells suggested that a virus as provided herein is, albeit only distantly, related to classical pneumoviruses such as RSV. Although most paramyxoviruses have haemagglutinating acitivity, most of the pneumoviruses do not13. An MPV according to the invention also contains a second overlapping ORF (M2-2) in the nucleic acid fragment encoding the M2 protein, as in general most other pneumoviruses such as for example also demonstrated in Ahmadian et al., J. Gen. Vir. 80:2011-2016 (1999). To find further viral isolates as provided by the invention it suffices to test a sample, optionally obtained from a diseased animal or human, for the presence of a virus of the sub-family Pneumovirinae, and test a thus obtained virus for the presence of genes encoding (functional) NS1 or NS2 or essentially demonstrate a gene order that is different from that of pneumoviruses such as RSV as already discussed above. Furthermore, a virus isolate phylogenetically corresponding and thus taxonomically corresponding with MPV may be found by cross-hybridisation experiments using nucleic acid from a here provided MPV isolate, or in classical cross-serology experiments using monoclonal antibodies specifically directed against and/or antigens and/or immunogens specifically derived from an MPV isolate. Newly isolated viruses are phylogenetically corresponding to and thus taxonomically corresponding to MPV when comprising a gene order and/or amino acid sequence sufficiently similar to our prototypic MPV isolate(s), or are structurally corresponding therewith, and show close relatedness to the genus Metapneumovirus within the subfamily Pneumovirinae. The highest amino sequence homology, and defining the structural correspondence on the individual protein level, between MPV and any of the known other viruses of the same family to date (APV subtype C) is for matrix 87%, for nucleoprotein 88%, for phosphoprotein 68%, for fusionprotein 81% and for parts of the polymerase protein 56-64%, as can be deduced when comparing the sequences given in FIG. 6 with sequences of other viruses, in particular of AVP-C. Individual proteins or whole virus isolates with, respectively, higher homology to these mentioned maximum values are considered phylogenetically corresponding and thus taxonomically corresponding to MPV, and comprise a nucleic acid sequence structurally corresponding with a sequence as shown in FIG. 6. Herewith the invention provides a virus phylogenetically corresponding to the deposited virus. It should be noted that, similar to other viruses, a certain degree of variation is found between different isolated essentially mammalian negative-sense single stranded RNA virus isolates as provided herein. In phylogenetic trees, we have identified at least 2 genetic clusters of virus isolates based on comparitive sequence analyses of parts of the L, M, N and F genes. Based on nucleotide and amino-acid differences in the viral nucleic acid or amino acid sequences (the viral sequences), and in analogy to other pneumoviruses such as RSV, these MPV genotypes represent subtypes of MPV. Within each of the genetic clusters of MPV isolates, the percentage identity at the nucleotide level was found to be 94-100 for L, 91-100 for M, 90-100 for N and 93-100 for F and at the amino acid level the percentage identity was found to be 91-100 for L, 98-100 for M, 96-100 for N and 98-100 for F. A further comparison can be found in FIGS. 18 to 28. The minimum percentage identity at the nucleotide level for the entire group of isolated essentially mammalian negative-sense single stranded RNA virus as provided herein (MPV isolates) identified so far was 81 for L and M, 83 for N and 82 for F. At the amino acid level, this percentage was 91 for L and N, 94 for M, and 95 for F. The viral sequence of a MPV isolate or an isolated MPV F gene as provided herein for example shows less than 81% nucleotide sequence identity or less than 82%(amino acid sequence identity with the respective nucleotide or amino acid sequence of an APV-C fusion (F) gene as for example provided by Seal et al., Vir. Res. 66:139147 (2000). Also, the viral sequence of a MPV isolate or an an isolated MPV L gene as provided herein for example shows less than 61% nucleotide sequence identity or less than 63% amino acid sequence identity with the respective nucleotide or amino acid sequence of an APV-A polymerase gene as for example provided by Randhawa et al., J. Gen. Vir. 77:3047-3051 (1996). Sequence divergence of MPV strains around the world may be somewhat higher, in analogy with other viruses. Consequently, two potential genetic clusters are identified by analyses of partial nucleotide sequences in the N, M, F and L ORFs of 9 virus isolates. 90-100% nucleotide identity was observed within a cluster, and 81-88% identity was observed between the clusters. Sequence information obtained on more virus isolates confirmed the existence of two genotypes. Virus isolate ned/00/01 as prototype of cluster A, and virus isolate ned/99/01 as prototype of cluster B have been used in cross neutralization assays to test whether the genotypes are related to different serotypes or subgroups. From these data we conclude that essentially mammalian virus isolates displaying percentage amino acid homology higher than 64 for L, 87 for M, 88 for N, 68 for P, 81 for F 84 for M2-1 or 58 for M2-2 to isolate I-2614 may be classified as an isolated essentially mammalian negative-sense single stranded RNA virus as provided herein. In particular those virus isolates in general that have a minimum percentage identity at the nucleotide sequence level with a prototype MPV isolate as provided herein of 81 for L and M, 83 for N and/or 82 for F are members of the group of MPV isolates as provided herein. At the amino acid level, these percentage are 91 for L and N, 94 for M, and/or 95 for F. When the percentage amino acid sequence homology for a given virus isolate is higher than 90 for L and N, 93 for M, or 94 for F, the virus isolate is similar to the group of MPV isolates displayed in FIG. 5. When the percentage amino acid sequence homology for a given virus isolate is higher than 94 for L, 95 for N or 97 for M and F the virus isolate can be identified to belong to one of the genotype clusters represented in FIG. 5. It should be noted that these percentages of homology, by which genetic clusters are defined, are similar to the degree of homology found among genetic clusters in the corresponding genes of RSV. In short, the invention provides an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus by determining a nucleic acid sequence of a suitable fragment of the genome of said virus and testing it in phylogenetic tree analyses wherein maximum likelihood trees are generated using 100 bootstraps and 3 jumbles and finding it to be more closely phylogenetically corresponding to a virus isolate deposited as I-2614 with CNCM, Paris than it is corresponding to a virus isolate of avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis. Suitable nucleic acid genome fragments each useful for such phylogenetic tree analyses are for example any of the RAP-PCR fragments 1 to 10 as disclosed herein in the detailed description, leading to the various phylogenetic tree analyses as disclosed herein in FIG. 4 or 5. Phylogenetic tree analyses of the nucleoprotein (N), phosphoprotein (P), matrixprotein (M) and fusion protein (1) genes of MPV revealed the highest degree of sequence homology with APV serotype C, the avian pneumovirus found primarily in birds in the United States. In a preferred embodiment, the invention provides an isolated essentially mammalian negative-sense single stranded RNA virus (MPV) belonging to the sub-family Pneumovirinae of the family Paramyxoviridae and identifiable as phylogenetically corresponding to the genus Metapneumovirus by determining a nucleic acid sequence of a suitable fragment of the genome of said virus and testing it in phylogenetic tree analyses wherein maximum likelihood trees are generated using 100 bootstraps and 3 jumbles and finding it to be more closely phylogenetically corresponding to a virus isolate deposited as I-2614 with CNCM, Paris than it is corresponding to a virus isolate of avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis, wherein said suitable fragment comprises an open reading frame encoding a viral protein of said virus. A suitable open reading frame (ORF) comprises the ORF encoding the N protein. When an overall amino acid identity of at least 91%, preferably of at least 95% of the analysed N-protein with the N-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. As shown, the first gene in the genomic map of MPV codes for a 394 amino acid (aa) protein and shows extensive homology with the N protein of other pneumoviruses. The length of the N ORF is identical to the length of the N ORF of APV-C (table 5) and is smaller than those of other paramyxoviruses (Barr et al., 1991). Analysis of the amino acid sequence revealed the highest homology with APV-C (88%), and only 7-11% with other paramyxoviruses (Table 6). Barr et al (1991) identified 3 regions of similarity between viruses belonging to the order Mononegauirales: A, B and C (FIG. 8). Although similarities are highest within a virus family, these regions are highly conserved between virus familys. In all three regions MPV revealed 97% aa sequence identity with APV-C, 89% with APV-B, 92 with APV-A, and 66-73% with RSV and PVM. The region between aa residues 160 and 340 appears to be highly conserved among metapneumoviruses and to a somewhat lesser extent the Pneumovirinae (Miyahara et al., 1992; Li et al., 1996; Barr et al., 1991). This is in agreement with MPV being a metapneumovirus, this particular region showing 99% similarity with APV C. Another suitable open reading frame (ORF) useful in phylogenetic analyses comprises the ORF encoding the P protein. When an overall amino acid identity of at least 70%, preferably of at least 85% of the analysed P-protein with the P-protein of isolate 1-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. The second ORF in the genome map codes for a 294 aa protein which shares 68% aa sequence homology with the P protein of APV-C, and only 22-26% with the P protein of RSV (Table 6). The P gene of MPV contains one substantial ORF and in that respect is similar to P from many other paramyxoviruses (Reviewed in Lamb and Kolakofsky, 1996; Sedlmeier et al., 1998). In contrast to APV A and B and PVM and similar to RSV and APV-C the MPV P ORF lacks cysteine residues. Ling (1995) suggested that a region of high similarity between all pneumoviruses (aa 185-241) plays a role in either the RNA synthesis process or in maintaining the structural integrity of the nucleocapsid complex. This region of high similarity is also found in MPV (FIG. 9) especifically when conservative substitutions are taken in account, showing 100% similarity with APV-C, 93% with APV-A and B, and approximately 81% with RSV. The C-terminus of the MPV P protein is rich in glutamate residues as has been described for APVs (Ling et al., 1995). Another suitable open reading frame (ORF) useful in phylogenetic analyses comprises the ORF encoding the M protein. When an overall amino acid identity of at least 94%, preferably of at least 97% of the analysed M-protein with the M-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. The third ORF of the MPV genome encodes a 254 aa protein, which resembles the M ORFs of other pneumoviruses. The M ORF of MPV has exactly the same size as the M ORFs of other metapneumoviruses (Table 5) and shows high aa sequence homology with the matrix proteins of APV (76-87%) lower homology with those of RSV and PVM (37-38%) and 10% or less homology with those of other paramyxoviruses (Table 6). Easton (1997) compared the sequences of matrix proteins of all pneumoviruses and found a conserved hexapeptide at residue 14 to 19 that is also conserved in MPV (FIG. 10). For RSV, PVM and APV small secondary ORFs within or overlapping with the major ORF of M have been identified (52 aa and 51 aa in bRSV, 75 aa in RSV, 46 aa in PVM and 51 aa in APV) (Yu et al., 1992; Easton et al., 1997; Samal et al., 1991; Satake et al., 1984). We noticed two small ORFs in the M ORF of MPV. One small ORF of 54 aa residues was found within the major M ORF, starting at nucleotide 2281 and one small ORF of 33 aa residues was found overlapping with the major ORF of M starting at nucleotide 2893 (data not shown). Similar to the secondary ORFs of RSV and APV there is no significant homology between these secondary ORFs and secondary ORFs of the other pneumoviruses, and apparent start or stop signals are lacking. In addition, evidence for the synthesis of proteins corresponding to these secondary ORFs of APV and RSV has not been reported. Another suitable open reading frame (ORF) useful in phylogenetic analyses comprises the ORF encoding the F protein. When an overall amino acid identity of at least 95%, preferably of at least 97% of the analysed F-protein with the F-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. The F ORF of MPV is located adjacent to the M ORF, which is characteristic for members of the Metapneumovirus genus. The F gene of MPV encodes a 539 aa protein, which is two aa residues longer than F of APV-C (Table 5). Analysis of the aa sequence revealed 81% homology with APV-C, 67% with APV-A and B, 33-39% with pneumovirus F proteins and only 10-18% with other paramyxoviruses (Table 6). One of the conserved features among F proteins of paramyxoviruses, and also seen in MPV is the distribution of cysteine residues (Morrison, 1988; Yu et al., 1991). The metapneumoviruses share 12 cysteine residues in F1 (7 are conserved among all paramyxoviruses), and two in F2 (1 is conserved among all paramyxoviruses). Of the 3 potential N-linked glycosylation sites present in the F ORF of MPV, none are shared with RSV and two (position 66 and 389) are shared with APV. The third, unique, potential N-linked glycosylation site for MPV is located at position 206 FIG. 11). Despite the low sequence homology with other paramyxoviruses, the F protein of MPV revealed typical fusion protein characteristics consistent with those described for the F proteins of other Paramyxoviridae family members (Morrison, 1988). F proteins of Paramyxoviridae members are synthesized as inactive precursors (F0) that are cleaved by host cell proteases which generate amino terminal F2 subunits and large carboxy terminal F1 subunits. The proposed cleavage site (Collins et al., 1996) is conserved among all members of the Paramyxoviridae family. The cleavage site of MPV contains the residues RQSR. Both arginine (R) residues are shared with APV and RSV, but the glutamine (Q) and serine (S) residues are shared with other paramyxoviruses such as human parainfluenza virus type 1, Sendai virus and morbilliviruses (data not shown). The hydrophobic region at the amino terminus of F1 is thought to function as the membrane fusion domain and shows high sequence similarity among paramyxoviruses and morbilliviruses and to a lesser extent the pneumoviruses (Morrison, 1988). These 26 residues (position 137-163, FIG. 11) are conserved between MPV and APV C, which is in agreement with this region being highly conserved among the metapneumoviruses (Naylor et al., 1998; Seal et al., 2000). As is seen for the F2 subunits of APV and other paramyxoviruses, MPV revealed a deletion of 22 aa residues compared with RSV (position 107-128, FIG. 11). Furthermore, for RSV and APV, the signal peptide and anchor domain were found to be conserved within subtypes and displayed high variability between subtypes (Plows et al., 1995; Naylor et al., 1998). The signal peptide of MPV (aa 10-35, FIG. 11) at the amino terminus of F2 exhibits some sequence similarity with APV-C (18 out of 26 aa residues are similar) and less conservation with other APVs or RSV. Much more variability is seen in the membrane anchor domain at the carboxy terminus of F1, although some homology is still seen with APV-C. Another suitable open reading frame (ORF) useful in phylogenetic analyses comprises the ORF encoding the M2 protein. When an overall amino acid identity of at least 85%, preferably of at least 90% of the analysed M2-protein with the M2-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. M2 gene is unique to the Pneumovirinae and two overlapping ORFs have been observed in all pneumoviruses. The first major ORF represents the M2-1 protein which enhances the processivity of the viral polymerase (Collins et al., 1995; Collins, 1996) and its readthrough of intergenic regions (Hardy et al., 1998; Fearns et al., 1999). The M2-1 gene for MPV, located adjacent to the F gene, encodes a 187 aa protein (Table 5), and reveals the highest (84%) homology with M2-1 of APV-C (Table 6). Comparison of all pneumovirus M2-1 proteins revealed the highest conservation in the amino-terminal half of the protein (Collins et al., 1990; Zamora et al., 1992; Ahmadian et al., 1999), which is in agreement with the observation that MPV displays 100% similarity with APV-C in the first 80 aa residues of the protein (FIG. 12A). The MPV M2-1 protein contains 3 cysteine residues located within the first 30 aa residues that are conserved among all pneumoviruses. Such a concentration of cysteines is frequently found in zinc-binding proteins (Ahmadian et al., 1991; Cuesta et al., 2000). The secondary ORFs M2-2) that overlap with the M2-1 ORFs of pneumoviruses are conserved in location but not in sequence and are thought to be involved in the control of the switch between virus RNA replication and transcription (Collins et al., 1985; Elango et al., 1985; Baybutt et al., 1987; Collins et al., 1990; Ling et al., 1992; Zamora et al., 1992; Alansari et al., 1994; Ahmadian et al., 1999; Bermingham et al., 1999). For MPV, the M2-2 ORF starts at nucleotide 512 in the M2-1 ORF (FIG. 7), which is exactly the same start position as for APV-C. The length of the M2-2 ORFs are the same for APV-C and MPV, 71 aa residues (Table 5). Sequence comparison of the M2-2 ORF (FIG. 12B) revealed 56% aa sequence homology between MPV and APV-C and only 26-27% aa sequence homology between MPV and APV-A and B (Table 6). Another suitable open reading frame (ORE) useful in phylogenetic analyses comprises the ORF encoding the L protein. When an overall amino acid identity of at least 91%, preferably of at least 95% of the analysed L-protein with the L-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. In analogy to other negative strand viruses, the last ORF of the MPV genome is the RNA-dependent RNA polymerase component of the replication and transcription complexes. The L gene of MPV encodes a 2005 aa protein, which is 1 residue longer than the APV-A protein (Table 5). The L protein of MPV shares 64% homology with APV-A, 42-44% with RSV, and approximately 13% with other paramyxoviruses (Table 6). Poch et al. (1989; 1990) identified six conserved domains within the L proteins of non-segmented negative strand RNA viruses, from which domain III contained the four core polymerase motifs that are thought to be essential for polymerase function. These motifs (A, B, C and D) are well conserved in the MPV L protein: in motifs A, B and C: MPV shares 100% similarity with all pneumoviruses and in motif D MPV shares 100% similarity with APV and 92% with RSV's. For the entire domain III (aa 625-847 in the L ORF), MPV shares 83% identity with APV, 67-68% with RSV and 26-30% with other paramyxoviruses (FIG. 15). In addition to the polymerase motifs the pneumovirus L proteins contain a sequence which conforms to a consensus ATP binding motif K(X)21GEGAGN(X)20K (Stec, 1991). The MPV L ORF contains a similar motif as APV, in which the spacing of the intermediate residues is off by one: K(x)22GEGAGN(X)19K. A much preferred suitable open reading frame (ORE) useful in phylogenetic analyses comprises the ORF encoding the SH protein. When an overall amino acid identity of at least 30%, preferably of at least 50%, more preferably of at least 75% of the analysed SH-protein with the SH-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. The gene located adjacent to M2 of MPV encodes a 183 aa protein (FIG. 7). Analysis of the nucleotide sequence and its deduced amino acid sequence revealed no discernible homology with other RNA virus genes or gene products. The SH ORF of MPV is the longest SH ORF known to date (Table 5). The composition of the aa residues of the SH ORF is relatively similar to that of APV, RSV and PVM, with a high percentage of threonine and serine (22%, 18%, 19%, 20.0%, 21% and 28% serine/threonine content for MPV, APV, RSV A, RSV B, bRSV and PVM respectively). The SH ORF of MPV contains 10 cysteine residues, whereas APV SH contains 16 cysteine residues. All pneumoviruses have similar numbers of potential N-glycosylation sites (MPV 2, APV 1, RSV 2, bRSV 3, PVM 4). The hydrophobicity profiles for the MPV SH protein and SH of APV and RSV revealed similar structural characteristics (FIG. 13B). The SH ORFs of APV and MPV have a hydrophylic N-terminus (aa 1-30), a central hydrophobic domain (aa 30-53) which can serve as a potential membrane spanning domain, a second hydrophobic domain around residue 160 and a hydrophilic C-terminus. In contrast, RSV SH appears to lack the C-terminal half of the APV and MPV ORFs. In all pneumovirus SH proteins the hydrophobic domain is flanked by basic amino acids, which are also found in the SH ORF for MPV (aa 29 and 54). Another much preferred suitable open reading frame (ORF) useful in phylogenetic analyses comprises the ORF encoding the G protein. When an overall amino acid identity of at least 30%, preferably of at least 50%, more preferably of at least 75% of the analysed G-protein with the G-protein of isolate I-2614 is found, the analysed virus isolate comprises a preferred MPV isolate according to the invention. The G ORF of MPV is located adjacent to the SH gene and encodes a 236 amino acid protein. A secondary small ORF is found immediately following this ORF, potentially coding for 68 aa residues (pos. 6973-7179,), but lacking a start codon. A third major ORF, in a different reading frame, of 194 aa residues (fragment 4, FIG. 7) is overlapping with both of these ORFs, but also lacks a startcodon (nucleotide 6416-7000). This major ORF is followed by a fourth ORF in the same reading frame (nt 7001-7198), possibly coding for 65 aa residues but again lacking a start codon. Finally, a potential ORF of 97 aa residues (but lacking a startcodon) is found in the third reading frame (nt 6444-6737, FIG. 1). Unlike the first ORF, the other ORFs do not have apparent gene start or gene end sequences (see below). Although the 236 aa residue G ORF probably represents at least a part of the MPV attachment protein it can not be excluded that the additional coding sequences are expressed as separate proteins or as part of the attachment protein through some RNA editing event. It should be noted that for APV and RSV no secondary ORFs after the primary G ORF have been identified but that both APV and RSV have secondary ORFs within the major ORF of G. However, evidence for expression of these ORFs is lacking and there is no homology between the predicted aa sequences for different viruses (Ling et al., 1992). The secondary ORFs in MPV G do not reveal characteristics of other G proteins and whether the additional ORFs are expressed requires further investigation. BLAST analyses with all four ORFs revealed no discernible homology at the nucleotide or aa sequence level with other known virus genes or gene products. This is in agreement with the low sequence homologies found for other G proteins such as hRSV A and B (53%) (Johnson et al., 1987) and APV A and B (38%) (Juhasz et al., 1994). Whereas most of the MPV ORFs resemble those of APV both in length and sequence, the G ORF of MPV is considerably smaller than the G ORF of APV (Table 5). The aa sequence revealed a serine and threonine content of 34%, which is even higher than the 32% for RSV and 24% for APV. The G ORF also contains 8.5% proline residues, which is higher than the 8% for RSV and 7% for APV. The unusual abundance of proline residues in the G proteins of APV, RSV and MPV has also been observed in glycoproteins of mucinous origin where it is a major determinant of the proteins three dimensional structure (Collins et al., 1983; Wertz et al., 1985; Jentoft, 1990). The number of potential N-linked glycosylation sites in G of MPV is similar to other pneumoviruses: MPV has 5, whereas hRSV has 7, bRSV has 5, and APV has 3 to 5. The predicted hydrophobicity profile of MPV G revealed characteristics similar to the other pneumoviruses. The amino-terminus contains a hydrophylic region followed by a short hydrophobic area (aa 33-53) and a mainly hydrophilic carboxy terminus (FIG. 14B). This overall organisation is consistent with that of an anchored type II transmembrane protein and corresponds well with these regions in the G protein of APV and RSV. The G ORF of MPV contains only 1 cysteine residue in contrast to RSV and APV (5 and 20 respectively). According to classical serological analyses as for example known from Francki, R. I. B., Fauquet, C. M., Knudson, D. L., and Brown, F., Classification and nomenclature of viruses. Fifth report of the international Committee on Taxonomy of Viruses. Arch Virol, 1991. Supplement 2: p. 140-144. an MPV isolate is also identifiable as belonging to a serotype as provided herein, being defined on the basis of its immunological distinctiveness, as determined by quantitative neutralization with animal antisera (obtained from for example ferrets or guinnea pigs as provided in the detailed description). Such a serotype has either no cross-reaction with others or shows a homologous-to heterologous titer ratio>16 in both directions. If neutralization shows a certain degree of cross-reaction between two viruses in either or both directions (homologous-to-heterologous tier ration of eight or 16), distinctiveness of serotype is assumed if substantial biophysical/biochemical differences of DNA's exist. If neutralization shows a distinct degree of cross-reaction between two viruses in either or both directions (homologous-to-heterologous tier ration of smaller than eight), identity of serotype of the isolates under study is assumed. As said, useful prototype isolates, such as isolate 1-2614, herein also known as MPV isolate 00-1, are provided herein. A further classification of a virus as an isolated essentially mammalian negative-sense single stranded RNA virus as provided herein can be made on the basis of homology to the G and/or SH proteins. Where in general the overall amino acid sequence identity between APV (isolated from birds) and MPV (isolated from humans) N, P, M, F, M2 and L ORFs was 64 to 88 percent, and nucleotide sequence homology was also found between the non-coding regions of the APV and MPV genomes, essentially no discernable amino acid sequence homology was found between two of the ORFs of the human isolate (MPV) and any of the ORFs of other paramyxoviruses. The amino acid content, hydrophobicity profiles and location of these ORFs in the viral genome show that they represent G and SH protein analogues. The sequence homology between APV and MPV, their similar genomic organization (3′-N-P-M-F-M2-SH-G-L-5′) as well as phylogenetic analyses provide further evidence for the proposed classification of MPV as the first mammalian metapneumovirus. New MPV isolates are for thus example identified as such by virus isolation and characterisation on tMK or other cells, by RT-PCR and/or sequence analysis followed by phylogenetic tree analyses, and by serologic techniques such as virus neutralisation assays, indirect immunofluorescence assays, direct immunofluorescence assays, FACs analyses or other immunological techniques. Preferably these techniques are directed at the SH and/or G protein analogues. For example the invention provides herein a method to identify further isolates of MPV as provided herein, the method comprising inoculating a essentially MPV-uninfected or specific-pathogen-free guinea pig or ferret (in the detailed description the animal is inoculated intranasally but other ways of inoculation such as intramuscular or intradermal inoculation, and using an other experimental animal, is also feasible) with the prototype isolate I-2614 or related isolates. Sera are collected from the animal at day zero, two weeks and three weeks post inoculation. The animal specifically seroconverted as measured in virus neutralisation (VN) assay and indirect. IFA against the respective isolate I-2614 and the sera from the seroconverted animal are used in the immunological detection of said further isolates. As an example, the invention provides the characterisation of a new member in the family of Paramyxoviridae, a human metapneumovirus or metapneumovirus-like virus (since its final taxonomy awaits discussion by a viral taxonomy committee the MPV is herein for example described as taxonomically corresponding to APV) (MPV) which may cause severe RTI in humans. The clinical signs of the disease caused by MPV are essentially similar to those caused by hRSV, such as cough, myalgia, vomiting, fever, broncheolitis or pneumonia, possible conjunctivitis, or combinations thereof. As is seen with hRSV infected children, especifically very young children may require hospitalisation. As an example an MPV which was deposited Jan. 19, 2001 as I-2614 with CNCM, Institute Pasteur, Paris or a virus isolate phylogenetically corresponding therewith is herewith provided. Therewith, the invention provides a virus comprising a nucleic acid or functional fragment phylogenetically corresponding to a nucleic acid sequence shown in FIG. 6a, 6b, 6c, or structurally corresponding therewith. In particular the invention provides a virus characterised in that after testing it in phylogenetic tree analyses wherein maximum likelihood trees are generated using 100 bootstraps and 3 jumbles it is found to be more closely phylogenetically corresponding to a virus isolate deposited as I-2614 with CNCM, Paris than it is related to a virus isolate of avian pneumovirus (APV) also known as turkey rhinotracheitis virus (TRTV), the aetiological agent of avian rhinotracheitis. It is particularly useful to use an AVP-C virus isolate as outgroup in said phylogenetic tree analyses, it being the closest relative, albeit being an essentially non-mammalian virus. We propose the new human virus to be named human metapneumovirus or metapneumovirus-like virus (MPV) based on several observations. EM analysis revealed paramyxovirus-like particles. Consistent with the classification, MPV appeared to be sensitive to treatment with chloroform. MPV is cultured optimal on tMK cells and is trypsine dependent. The clinical symptoms caused by MPV as well as the typical CPE and lack of haemagglutinating activity suggested that this virus is closely related to hRSV. Although most paramyxoviruses have haemaglutinating acitivity, most of the pneumoviruses do not13. As an example, the invention provides a not previously identified paramyxovirus from nasopharyngeal aspirate samples taken from 28 children suffering from severe RTI. The clinical symptoms of these children were largely similar to those caused by hRSV. Twenty-seven of the patients were children below the age of five years and half of these were between 1 and 12 months old. The other patient was 18 years old. All individuals suffered from upper RTI, with symptoms ranging from cough, myalgia, vomiting and fever to broncheolitis and severe pneumonia. The majority of these patients were hospitalised for one to two weeks. The virus isolates from these patients had the paramyxovirus morphology in negative contrast electron microscopy but did not react with specific antisera against known human and animal paramyxoviruses. They were all closely related to one another as determined by indirect immunofluorescence assays (IFA) with sera raised against two of the isolates. Sequence analyses of nine of these isolates revealed that the virus is somewhat related to APV. Based on virological data, sequence homology as well as the genomic organisation we propose that the virus is a member of Metapneumovirus genus. Serological surveys showed that this virus is a relatively common pathogen since the seroprevalence in the Netherlands approaches 100% of humans by the age of five years. Moreover, the seroprevelance was found to be equally high in sera collected from humans in 1958, indicating this virus has been circulating in the human population for more than 40 years. The identification of this proposed new member of the Metapneumovirus genus now also provides for the development of means and methods for diagnostic assays or test kits and vaccines or serum or antibody compositions for viral respiratory tract infections, and for methods to test or screen for antiviral agents useful in the treatment of MPV infections. To this extent, the invention provides among others an isolated or recombinant nucleic acid or virus-specific functional fragment thereof obtainable from a virus according to the invention. In particular, the invention provides primers and/or probes suitable for identifying an MPV nucleic acid. Furthermore, the invention provides a vector comprising a nucleic acid according to the invention. To begin with, vectors such as plasmid vectors containing (parts of) the genome of MPV, virus vectors containing (parts of) the genome of MPV. (For example, but not limited to other paramyxoviruses, vaccinia virus, retroviruses, baculovirus), or MPV containing (parts of) the genome of other viruse or other pathogens are provided. Furthermore, a number of reverse genetics techniques have been described for the generation of recombinant negative strand viruses, based on two critical parameters. First, the production of such virus relies on the replication of a partial or full-length copy of the negative sense viral RNA (vRNA) genome or a complementary copy thereof (cRNA). This vRNA or cRNA can be isolated from infectious virus, produced upon in-vitro transcription, or produced in cells upon transfection of nucleic acids. Second, the production of recombinant negative strand virus relies on a functional polymerase complex. Typically, the polymerase complex of pneumoviruses consists of N, P, L and possibly M2 proteins, but is not necessarily limited thereto. Polymerase complexes or components thereof can be isolated from virus particles, isolated from cells expressing one or more of the components, or produced upon transfection of specific expression vectors. Infectious copies of MPV can be obtained when the above mentioned vRNA, cRNA, or vectors expressing these RNAs are replicated by the above mentioned polymerase complex16,17.18,19,20,21,22. For the generation of minireplicons or, a reverse genetics system for generating a full-length copy comprising most or all of the genome of MPV it suffices to use 3′end and/or 5′end nucleic acid sequences obtainable from for example APV (Randhawa et al., 1997) or MPV itself. Also, the invention provides a host cell comprising a nucleic acid or a vector according to the invention. Plasmid or viral vectors containing the polymerase components of MPV (presumably N, P, L and M2, but not necessarily limited thereto) are generated in prokaryotic cells for the expression of the components in relevant cell types (bacteria, insect cells, eukaryotic cells). Plasmid or viral vectors containing full-length or partial copies of the MPV genome will be generated in prokarotic cells for the expression of viral nucleic acids in-vitro or in-vivo. The latter vectors may contain other viral sequences for the generation of chimeric viruses or chimeric virus proteins, may lack parts of the viral genome for the generation of replication defective virus, and may contain mutations, deletions or insertions for the generation of attenuated viruses. Infectious copies of MPV (being wild type, attenuated, replication-defective or chimeric) can be produced upon co-expression of the polymerase components according to the state-of-the-art technologies described above. In addition, eukaryotic cells, transiently or stably expressing one or more full-length or partial MPV proteins can be used. Such cells can be made by transfection (proteins or nucleic acid vectors), infection (viral vectors) or transduction (viral vectors) and may be useful for complementation of mentioned wild type, attenuated, replication-defective or chimeric viruses. A chimeric virus may be of particular use for the generation of recombinant vaccines protecting against two or more viruses23,24,26. For example, it can be envisaged that a MPV virus vector expressing one or more proteins of RSV or a RSV vector expressing one or more proteins of MPV will protect individuals vaccinated with such vector against both virus infections. A similar approach can be envisaged for PI3 or other paramyxoviruses. Attenuated and replication-defective viruses may be of use for vaccination purposes with live vaccines as has been suggested for other viruses25.26. In a preferred embodiment, the invention provides a proteinaceous molecule or metapneumovirus-specific viral protein or functional fragment thereof encoded by a nucleic acid according to the invention. Useful proteinaceous molecules are for example derived from any of the genes or genomic fragments derivable from a virus according to the invention. Such molecules, or antigenic fragments thereof, as provided herein, are for example useful in diagnostic methods or kits and in pharmaceutical compositions such as sub-unit vaccines. Particularly useful are the F, SH and/or G protein or antigenic fragments thereof for inclusion as antigen or subunit immunogen, but inactivated whole virus can also be used. Particulary useful are also those proteinaceous substances that are encoded by recombinant nucleic acid fragments that are identified for phylogenetic analyses, of course preferred are those that are within the preferred bounds and metes of ORFs useful in phylogenetic analyses, in particular for eliciting MPV specific antibodies, whether in vivo (e.g. for protective puposes or for providing diagnostic antibodies) or in vitro (e.g. by phage display technology or another technique useful for generating synthetic antibodies). Also provided herein are antibodies, be it natural polyclonal or monoclonal, or synthetic (e.g. (phage) library-derived binding molecules) antibodies that specifically react with an antigen comprising a proteinaceous molecule or MPV-specific functional fragment thereof according to the invention. Such antibodies are useful in a method for identifying a viral isolate as an MPV comprising reacting said viral isolate or a component thereof with an antibody as provided herein. This can for example be achieved by using purified or non-purified MPV or parts thereof (proteins, peptides) using ELISA, RIA, FACS or similar formats of antigen detection assays (Current Protocols in Immunology). Alternatively, infected cells or cell cultures may be used to identify viral antigens using classical immunofluorescence or immunohistochemical techniques. Other methods for identifying a viral isolate as a MPV comprise reacting said viral isolate or a component thereof with a virus specific nucleic acid according to the invention, in particular where said mammalian virus comprises a human virus. In this way the invention provides a viral isolate identifiable with a method according to the invention as a mammalian virus taxonomically corresponding to a negative-sense single stranded RNA virus identifiable as likely belonging to the genus Metapneumovirus within the sub-family Paeumovirinae of the family Paramyxoviridae. The method is useful in a method for virologically diagnosing an MPV infection of a mammal, said method for example comprising determining in a sample of said mammal the presence of a viral isolate or component thereof by reacting said sample with a nucleic acid or an antibody according to the invention. Examples are further given in the detailed description, such as the use of PCR (or other amplification or hybridization techniques well known in the art) or the use of immunofluorescence detection (or other immunological techniques known in the art). The invention also provides a method for serologically diagnosing a MPV infection of a mammal comprising determining in a sample of said mammal the presence of an antibody specifically directed against a MPV or component thereof by reacting said sample with a proteinaceous molecule or fragment thereof or an antigen according to the invention. Methods and means provided herein are particularly useful in a diagnostic kit for diagnosing a MPV infection, be it by virological or serological diagnosis. Such kits or assays may for example comprise a virus, a nucleic acid, a proteinaceous molecule or fragment thereof, an antigen and/or an antibody according to the invention. Use of a virus, a nucleic acid, a proteinaceous molecule or fragment thereof, an antigen and/or an antibody according to the invention is also provided for the production of a pharmaceutical composition, for example for the treatment or prevention of MPV infections and/or for the treatment or prevention of respiratory tract illnesses, in particular in humans. Attenuation of the virus can be achieved by established methods developed for this purpose, including but not limited to the use of related viruses of other species, serial passages through laboratory animals or/and tissue/cell cultures, site directed mutagenesis of molecular clones and exchange of genes or gene fragments between related viruses. A pharmaceutical composition comprising a virus, a nucleic acid, a proteinaceous molecule or fragment thereof, an antigen and/or an antibody according to the invention can for example be used in a method for the treatment or prevention of a MPV infection and/or a respiratory illness comprising providing an individual with a pharmaceutical composition according to the invention. This is most useful when said individual comprises a human, especifically when said human is below 5 years of age, since such infants and young children are most likely to be infected by a human MPV as provided herein. Generally, in the acute phase patients will suffer from upper respiratory symptoms predisposing for other respiratory and other diseases. Also lower respiratory illnesses may occur, predisposing for more and other serious conditions. The invention also provides method to obtain an antiviral agent useful in the treatment of respiratory tract illness comprising establishing a cell culture or experimental animal comprising a virus according to the invention, treating said culture or animal with an candidate antiviral agent, and determining the effect of said agent on said virus or its infection of said culture or animal. An example of such an antiviral agent comprises a MPV-neutralising antibody, or functional component thereof, as provided herein, but antiviral agents of other nature are obtained as well. The invention also provides use of an antiviral agent according to the invention for the preparation of a pharmaceutical composition, in particular for the preparation of a pharmaceutical composition for the treatment of respiratory tract illness, especifically when caused by an MPV infection, and provides a pharmaceutical composition comprising an antiviral agent according to the invention, useful in a method for the treatment or prevention of an MPV infection or respiratory illness, said method comprising providing an individual with such a pharmaceutical composition. The invention is further explained in the detailed description without limiting it thereto. FIGURE LEGENDS FIG. 1A comprises table 1: Percentage homology found between the amino acid sequence of isolate 00-1 and other members of the Pneumovirinae. Percentages (×100) are given for the amino acid sequences of N, P, M, F and two RAP-PCR fragments in L (8 and 9/10). Accession numbers used for the analyses are described in the materials and methods section. FIG. 1B comprises table 2: Seroprevalence of MPV in humans categorised by age group using immunofluorescence and virus neutralisation assays. FIG. 2: Schematic representation of the genome of APV with the location and size of the fragments obtained with RAP-PCR and RT-PCR on virus isolate 00-1. Fragments 1 to 10 were obtained using RAP-PCR. Fragment A was obtained with a primer in RAP-PCR fragment 1 and 2 and a primer designed based on alignment of leader and trailer sequences of APV and RSV6. Fragment B was obtained using primers designed in RAP-PCR fragment 1 and 2 and RAP-PCR fragment 3. Fragment C was obtained with primers designed in RAP-PCR fragment 3 and RAP-PCR fragment 4,5,6 and 7. For all phylogenetic trees, (FIGS. 3-5) DNA sequences were aligned using the ClustalW software package and maximum likelihood trees were generated using the DNA-ML software package of the Phylip 3.5 program using 100 bootstraps and 3 jumbles15. Previously published sequences that were used for the generation of phylogenetic trees are available from Genbank under accessions numbers: For all ORFs: hRSV: NC001781; bRSV: NC001989; For the F ORF: PVM, D11128; APV-A, D00850; APV-B, Y14292; APV-C, AF187152; For the N ORF: PVM, D10331; APV-A, U39295; APV-B, U39296; APV-C, AF176590; For the M ORF: PMV, U66893; APV-A, X58639; APV-B, U37586; APV-C, AF262571; For the P ORF: PVM, 09649; APV-A, U22110, APV-C, AF176591. Phylogenetic analyses for the nine different virus isolates of MPV were performed with APV strain C as outgroup. Abbreviations used in figures: hRSV: human RSV; bRSV: bovine RSV; PVM: pneumonia virus of mice; APV-A,B, and C: avian pneumovirus typa A, B and C. FIG. 3 Comparison of the N, P, M and F ORF's of members of the subfamily Pneumovirinae and virus isolate 00-1. The alignment shows the amino acid sequence of the complete N, P, M and F proteins and partial L proteins of virus isolate 00-1.Amino acids that differ between isolate 00-1 and the other viruses are shown, identical amino acids are represented by periods, gaps are represented as dashes. Numbers correspond to amino acid positions in the proteins. Accession numbers used for the analyses are described in the materials and methods section. APV-A, B or C: Avian Pneumovirus type A, B or C, b-or hRSV: bovine or human respiratory syncytial virus, PVM: pneumonia virus of mice. L8: fragment 8 obtained with RAP-PCR located in L, L9/10: consensus of fragment 9 and 10 obtained with RAP-PCR, located in L. For the P allignment, no APV-B sequence was available from the Genebank, For the L alligment only bRSV, hRSV and APV-A sequences were available. FIG. 4: Phylogenetic analyses of the N, P, M, and F ORF's of members of the genus Pneumovirinae and virus isolate 00-1. Phylogenetic analysis was performed on viral sequences from the following genes: F (panel A), N (panel B), M (panel C), and P (panel D). The phylogenetic trees are based on maximum likelyhood analyses using 100 bootstraps and 3 jumbles. The scale representing the number of nucleotide changes is shown for each tree. FIG. 5: Phylogenetic relationship for parts of the F (panel A), N (panel B), M (panel C) and L panel D) ORFs of nine of the primary MPV isolates with APV-C, it's closest relative genetically. The phylogenetic trees are based on maximum likelyhood analyses. The scale representing the number of nucleotide changes is shown for each tree. Accesion numbers for APV-C: panel A: D00850; panel B: U39295; panel C: X58639; and panel D: U65312. FIG. 6A: Nucleotide and amino acid sequence information from the 3′end of the genome of MPV isolate 00-ORF's are given. N: ORF for nucleoprotein; P: ORF for phosphoprotein; M: ORF for matrix protein; F: ORF for fusion protein; GE: gene end; GS: gene start. FIGS. 6B and C: Nucleotide and amino acid sequence information from obtained fragments in the polymerase gene (L) of MPV isolates 00-1. Positioning of the fragments in L is based on protein homologies with APV-C (accession number U65312). The translated fragment 8 (FIG. 6B.) is located at amino acid number 8 to 243, and the consensus of fragments 9 and 10 (FIG. 6C) is located at amino acid number 1358 to 1464 of the APV-C L ORF. FIG. 7 Genomic map of MPV isolate 00-1. The nucleotide positions of the start and stop codons are indicated under each ORF. The double lines which cross the L ORF indicate the shortened representation of the L gene. The three reading frames below the map indicate the primary G ORF (nt 6262-6972) and overlapping potential secondary ORFs. FIG. 8: Alignment of the predicted amino acid sequence of the nucleoprotein of MPV with those of other pneumoviruses. The conserved regions identified by Barr (1991) are represented by boxes and labelled A, B, and C. The conserved region among pneumoviruses (Li, 1996) is shown gray shaded. Gaps are represented by dashes, periods indicate the positions of identical amino acid residues compared to MPV. FIG. 9: Amino acid sequence comparison of the phosphoprotein of MPV with those of other pneumoviruses. The region of high similarity (Ling, 1995) is boxed, and the glutamate rich region is grey shaded. Gaps are represented by dashes and periods indicate the position of identical amino acid residues compared to MPV. FIG. 10: Comparison of the deduced amino acid sequence of the matrix protein of MPV with those of other pneumoviruses. The conserved hexapeptidesequence (Easton, 1997) is grey shaded. Gaps are represented by dashes and periods indicate the position of identical amino acid residues relative to MPV. FIG. 11: Allignment of the predicted amino acid sequence of the fusion protein of MPV with those of other pneumoviruses. The conserved cysteine residues are boxed, N-linked glycosylation sites are underlined, the cleavage site of F0 is double underlined, the fusion peptide, signal peptide and membrane anchor domain are shown grey shaded. Gaps are represented by dashes and periods indicate the position of identical amino acids relative to MPV. FIG. 12 Comparison of amino acid sequence of the M2 ORFs of MPV with those of other pneumoviruses. The alignment of M2-1 ORFs is shown in panel A, with the conserved amino terminus (Collins, 1990; Zamora, 1999) shown grey shaded. The three conserved cysteine residues are printed bold face and indicated by #. The alignment of M2-2 ORFs is shown in panel B. Gaps are represented by dashes and periods indicate the position of identical amino acids relative to MPV. FIG. 13 Amino acid sequence analyses of the SH ORF of MPV. (A) Amino acid sequence of the SH ORF of MPV, with the serine and threonine residues grey shaded, cysteine residues in bold face and the hydrophobic region double underlined. Potential N-linked glycosylation sites are single underlined. Numbers indicate the positions of the basic amino acids flanking the hydrophobic domain. (B) Alignment of the hydrophobicity plots of the SH proteins of MPV, APV-A and hRSV-B. The procedure of Kyte and Doolittle (1982) was used with a window of 17 amino acids. Arrows indicate a strong hydrophobic domain. Positions within the ORF are given on the X-axis. FIG. 14 Amino acid sequence analyses of the G ORF of MPV. (A) Amino acid sequence of the G ORF of MPV, with serine, threonine and proline residues grey shaded, the cysteine residue is in bold face and the hydrophobic region double underlined. The potential N-linked glycosylation sites are single underlined. (B) Alingment of the hydrophobicity plots of the G proteins of MPV, APV-A and hRSV-B. The procedure of Kyte and Doolittle (1982) was used with a window of 17 amino acids. Arrows indicate the hydrophobic region, and positions within the ORF are given at the X-axis. FIG. 15 Comparison of the amino acid sequences of a conserved domain of the polymerase gene of MPV and other paramyxoviruses. Domain III is shown with the four conserved polymerase motifs (A, B, C, D) in domain III (Poch 1998, 1999) boxed. Gaps are represented by dashes and periods indicate the position of identical amino acid residues relative to MPV. hPIV3: human parainfluenza virus type 3; SV: sendai virus; hPIV-2: human parainfluenza virus type 2; NDV: New castle disease virus; MV: measles virus; nipah: Nipah virus. FIG. 16: Phylogenetic analyses of the M2-1 and L ORFs of MPV and selected paramyxoviruses. The M2-1 ORF was aligned with the M2-1 ORFs of other members of the genus Pneumovirinae (A) and the L ORF was aligned with L ORFs members of the genus pneumovirinae and selected other paramyxoviruses as described in the legends of FIG. 15(B). Phylogenetic trees were generated by maximum likelihood analyses using 100 bootstraps and 3 jumbles. The scale representing the number of nucleotide changes is shown for each tree. Numbers in the trees represent bootstrap values based on the consensus trees. FIG. 17: Noncoding sequences of hMPV isolate 00-1. (A) The noncoding sequences between the ORFs and at the genomic termini are shown in the positive sense. From left to right, stop codons of indicated ORFs are shown, followed by the noncoding sequences, the gene start signals and start codons of the indicated subsequent ORFs. Numbers indicate the first position of start and stop codons in the hMPV map. Sequences that display similarity to published gene end signals are underlined and sequences that display similarity to UAAAAAU/A/C are represented with a line above the sequence. (B) Nucleotide sequences of the genomic termini of hMPV. The genomic termini of hMPV are aligned with each other and with those of APV. Underlined regions represent the primer sequences used in RT-PCR assays which are based on the 3′ and 5′ end sequences of APV and RSV (Randhawa et al., 1997; Mink et al., 1991). Bold italicalized nucleotides are part of the gene start signal of the N gene. Le: leader, Tr: trailer. FIG. 18: Comparison of two prototypic hMPV isolates with APV-A and APV-C; DNA similarity matrices for nucleic acids encoding the various viral proteins. FIG. 19: Comparison of two prototypic hMPV isolates with APV-A and APV-C; protein similarity matrices for the various viral proteins. FIG. 20: Amino acid alignment of the nucleoprotein of two prototype hMPV isolates FIG. 21: Amino acid alignment of the phosphoprotein of two prototype hMPV isolates FIG. 22: Amino acid alignment of the matrix protein of two prototype hMPV isolates FIG. 23: Amino acid alignment of the fusion protein of two prototype hMPV isolates FIG. 24: Amino acid alignment of the M2-1 protein of two prototype hMPV isolates FIG. 25: Amino acid alignment of the M2-2 protein of two prototype hMPV isolates FIG. 26: Amino acid alignment of the short hydrophobic protein of two prototype hMPV isolates FIG. 27: Amino acid alignment of the attachement glycoprotein of two prototype hMPV isolates FIG. 28: Amino acid alignment of the N-terminus of the polymerase protein of two prototype hMPV isolates FIG. 29: Results of RT-PCR assays on throat and nose swabs of 12 guinea pigs inoculated with ned/00/01 and/or ned/99/01. FIG. 30A: IgG response against ned/00/01 and ned/99/01 for guinea pigs infected with ned/00/01 and re-infected with ned/00/01 (GP 4, 5 and 6) or ned/99/01 (GP 1 and 3). FIG. 30B: IgG response against ned/00/01 and ned/99/01 for guinea pigs infected with ned/99/01 and re-infected with either ned/00/01 (GP's 8 and 9) or with ned/99/01 (GP's 10, 11, 12). FIG. 31: Specificity of the ned/00/01 and ned/99/01 ELISA on sera taken from guinea pigs infected with either ned/00/01 or ned/99/01. FIG. 32: Mean IgG response against ned/00/01 and ned/99/01 ELISA of 3 homologous (00-1/00-1), 2 homologous (99-1/99-1), 2 heterologous (99-1/00-1) and 2 heterologous (00-1/99-1) infected guinea pigs. FIG. 33: Mean percentage of APV inhibition of hMPV infected guinea pigs. FIG. 34: Virus neutralisation titers of ned/O/1 and ned/99101 infected guinea pigs against ned/00/01, ned/99/01 and APV-C. FIG. 35: Results of RT-PCR assays on throat swabs of cynomolgous macaques inoculated (twice) with ned/00/01. FIG. 36A (top two panels): IgA, IgM and IgG response against ned/10/01 of 2 cynomologous macaques (re)infected with ned/00/01. FIG. 36B (bottom panels) IgG response against APV of 2 cynbomologous macaques infected with ned/00/01. FIG. 37: Comparison of the use of the hMPV ELISA and the APV inhibition ELISA for the detection of IgG antibodies in human sera. DETAILED DESCRIPTION Virus Isolation and Characterisation From 1980 till 2000 we found 28 unidentified virus isolates from patients with severe Respiratory disease. These 28 unidentified virus isolates grew slowly in tMK cells, poorly in VERO cells and A549 cells and could not or only little be propagated in MDCK or chicken embryonated fibroblast cells. Most of these virus isolates induced CPE after three passages on tMK cells, between day ten and fourteen. The CPE was virtually indistinguishable from that caused by hRSV or hPIV in tMK or other cell cultures, characterised by syncytium formation after which the cells showed rapid internal disruption, followed by detachment of the cells from the monolayer. The cells usually (sometimes later) displayed CPE after three passages of virus from original material, at day 10 to 14 post inoculation, somewhat later than CPE caused by other viruses such as hRSV or hPIV. We used the supernatants of infected tMK cells for EM analysis which revealed the presence of paramyxovirus-like virus particles ranging from 150 to 600 nanometer, with short envelope projections ranging from 13 to 17 nanaometer. Consistent with the biochemical properties of enveloped viruses such as the Paramyxoviridae, standard chloroform or ether treatment8 resulted in>104 TCID50 reduction of infectivity for tMK cells. Virus-infected tMK cell culture supernatants did not display heamagglutinating activity with turkey, chicken and guinea pig erythrocytes. During culture, the virus replication appeared to be trypsine dependent on the cells tested. These combined virological data allowed that the newly identified virus was taxonomically classified as a member of the Paramyxoviridae family. We isolated RNA from tMK cells infected with 15 of the unidentified virus isolates for reverse transcription and polymerase chain reaction (RT-PCR) analyses using primer-sets specific for Paramyxovirinae9, hPIV 1-4, sendai virus, simian virus type 5, New-Castle disease virus, hRSV, morbilli, mumps, Nipah, Hendra, Tupaia and Mapuera viruses. RT-PCR assays were carried out at low stringency in order to detect potentially related viruses and RNA isolated from homologous virus stocks were used as controls. Whereas the available controls reacted positive with the respective virus-specific primers, the newly identified virus isolates did not react with any primer set, indicating the virus was not closely related to the viruses tested. We used two of the virus-infected tMK cell culture supernatants to inoculate guinea pigs and ferrets intranasaly. Sera were collected from these animals at day zero, two weeks and three weeks post inoculation. The animals displayed no clinical symptoms but all seroconverted as measured in virus neutralization (VN) assays and indirect IFA against the homologous viruses. The sera did not react in indirect IFA with any of the known paramyxoviruses described above and with PVM. Next, we screened the so far unidentified virus isolates using the guinea pig and ferret pre- and post-infection sera, of which 28 were clearly positive by indirect IFA with the post-infection sera suggesting they were serological closely related or identical. RAP PCR To obtain sequence information on the unknown virus isolates, we used a random PCR amplification strategy known as RAP-PCR10. To this end, tMK cells were infected with one of the virus isolates (isolate 00-1) as well as with hPIV-1 which served as a control. After both cultures displayed similar levels of CPE, virus in the culture supernatants was purified on continuous 20-60% sucrose gradients. The gradient fractions were inspected for virus-like particles by EM, and RNA was isolated from the fraction containing approximately 50% sucrose, in which nucleocapsids were observed. Equivalent amounts of RNA isolated from both virus fractions were used for RAP-PCR, after which samples were run side by side on a 3% NuSieve agarose gel. Twenty differentially displayed bands specific for the unidentified virus were subsequently purified from the gel, cloned in plasmid pCR2.1 (Invitrogen) and sequenced with vector-specific primers. When we used these sequences to search for homologies against sequences in the Genbank database using the BLAST software (www.ncbi.nlm.nih.gov/BLAST/) 10 out of 20 fragments displayed resemblance to APV/TRTV sequences. These 10 fragments were located in the genes coding for the nucleoprotein (N; fragment 1 and 2), the matrix protein (M; fragment 3), the fusion protein (F; fragment 4, 5, 6, 7,) and the polymerase protein (A; fragment 8,9,10) (FIG. 2). We next designed PCR primers to complete the sequence information for the 3′ end of the viral genome based on our RAP PCR fragments as well as published leader and trailer sequences for the Pneumovirinae6. Three fragments were amplified, of which fragment A spanned the extreme 3′ end of the N open reading frame (ORF), fragment B spanned the phosphoprotein (P) ORF and fragment C closed the gap between the M and F ORFs (FIG. 2). Sequence analyses of these three fragments revealed the absence of NS1 and NS2 ORFs at the extreme 3′ end of the viral genome and positioning of the F ORF immediately adjacent to the M ORF. This genomic organisation resembles that of the metapneumovirus APV, which is also consistent with the sequence homology. Overall the translated sequences for the N, P, M and F ORFs showed an average of 30-33% homology with members of the genus Pneumovirus and 66-68% with members of the genus Metapneumovirus. For the SH and G ORF's no discernable homology was found with members of either of the genera. The amino acid homologies found for N showed about 40% homology with hRSV and 88% with APV-C, its closest relative genetically, as for example can be deduced by comparing the amino acid sequence of FIG. 3 with the amino acid sequence of the respective N proteins of other viruses. The amino acid sequence for P showed about 25% homology with hRSV and about 66-68% with APV-C, M showed about 36-39% with hRSV and about 87-89% with APV-C, F showed about 40% homology with hRSV and about 81% with APV-C, M2-1 showed about 34-36% homology with pneumoviruses and 84-86% with APV-C, M2-2 showed 15-17% homology with pneumoviruses and 56% with APV-C and the fragments obtained in L showed an average of 44% with pneumoviruses and 64% with APV-C. Phylogeny Although BLAST searches using nucleotide sequences obtained from the unidentified virus isolate revealed homologies primarily with members of the Pneumovirinae, homologies based on protein sequences revealed some resemblance with other paramyxoviruses as well (data not shown). As an indication for the relation between the newly identified virus isolate and members of the Pneumovirinae, phylogenetic trees were constructed based on the N, P, M and F ORFs of these viruses. In all four phylogenetic trees, the newly identified virus isolate was most closely related to APV (FIG. 4). From the four serotypes of APV that have been described11, APV serotype C, the metapneumovirus found primarily in birds in the USA, showed the closest resemblance to the newly identified virus. It should be noted however, that only partial sequence information for APV serotype D is available. To determine the relationship of our various newly identified virus isolates, we constructed phylogenetic trees based on sequence information obtained from eight to nine isolates (8 for F, 9 for N, M and L). To this end, we used RT-PCR with primers designed to amplify short fragments in the N, M, F and L ORFs, that were subsequently sequenced directly. The nine virus isolates that were previously found to be related in serological terms (see above) were also found to be closely related genetically. In fact, all nine isolates were more closely related to one another than to APV. Although the sequence information used for these phylogenetic trees was limited, it appears that the nine isolates can be divided in two groups, with isolate 94-1, 99-1 and 99-2 clustering in one group and the other six isolates (94-2; 93-1; 93-2; 93-3; 93-4; 00-1) in the other (FIG. 5). Seroprevalence To study the seroprevalence of this virus in the human population, we tested sera from humans in different age categories by indirect IFA using tMK cells infected with one of the unidentified virus isolates. This analysis revealed that 25% of the children between six and twelve months had antibodies to the virus, and by the age of five nearly 100% of the children were seropositive. In total 56 serum samples tested by indirect IFA were tested by VN assay. For 51 (91%) of the samples the results of the VN assay (titre>8) coincided with the results obtained with indirect IFA (titre>32). Four samples that were found positive in IFA, were negative by VN test (titre<8) whereas one serum reacted negative in IFA (titre<32) and positive in the VN test (titre 16) (table 2). IFA conducted with 72 sera taken from humans in 1958 (ages ranging from 8-99 years)12,27 revealed a 100% seroprevalence, indicating the virus has been circulating in the human population for more than 40 years. In addition a number of these sera were used in VN assays to confirm the IFA data (table 2). Genetic analyses of the N, M, P and F genes revealed that MPV has higher sequence homology to the recently proposed genus Metapneumovirinae (average of 63%) as compared to the genus Pneumovirinae (average of 30%) and thus demonstrates a genomic organization similar to and resembling that of APV/TRTV. In contrast to the genomic organisation of the RSVs (‘3-NS1-NS2-N-P-M-SH-G-F-M2-L-5’), metapneumoviruses lack NS1 and NS2 genes and have a different positioning of the genes between M and L ('3-N-P-M-F-M2-SH-G-15′). The lack of ORFs between the M and F genes in our virus isolates and the lack of NS1 and NS2 adjacent to to N, and the high amino acid sequence homology found with APV are reasons to propose the classification of MPV isolated from humans as a first member of the Metapneumovirus genus of mammalian, in particular of human origin. Phylogenetic analyses revealed that the nine MPV isolates from which sequence information was obtained are closely related. Although sequence information was limited, they were in fact more closely related to one another than to any of the avian metapneumoviruses. Of the four serotypes of APV that have been described, serotype C was most closely related to MPV based on the N, P, M and F genes. It should be noted however that for serotype D only partial sequences for the F gene were available from Genbank and for serotype B only M, N and F sequences were available. Our MPV isolates formed two clusters in phylogenetic trees. For both hRSV and APV different genetic and serological subtypes have been described. Whether the two genetic clusters of MPV isolates represent serogical subgroups that are also functionally different remains unknown at presentOur serological surveys showed that MPV is a common human pathogen. The repeated isolation of this virus from clinical samples from children with severe RTI indicates that the clinical and economical impact of MPV may be high. New diagnostic assays based on virus detection and serology will allow a more detailed analysis of the incidence and clinical and economical impact of this viral pathogen. The slight differences between the IFA and VN results (5 samples) maybe due to the fact that in the IFA only IgG serum antibodies were detected whereas the VN assay detects both classes and sub-classes of antibodies or differences may be due to the differences in sensitivity between both assays. For IFA a cut off value of 16 is used, whereas for VN a cut off value of 8 is used. On the other hand, differences between IFA versus VN assay may also indicate possible differences between different serotypes of this newly identified virus. Since MPV seems most closely related to APV, we speculate that the human virus may have originated from birds. Analysis of serum samples taken from humans in 1958 revealed that MPV has been widespread in the human population for more then 40 years indicating that a tentative zoonosis event must have taken place long before 1958. Materials and Methods Specimen Collection Over the past decades our laboratory has collected nasopharyngeal aspirates from children suffering from RTI, which are routinely tested for the presence of viruses. All nasopharyngeal aspirates were tested by direct immunofluorescence assays (DIF) using fluorescence labelled antibodies against influenza virus types A, and B, hRSV and human parainfluenza virus (hPIV) types 1 to 3. The nasopharyngeal aspirates were also processed for virus isolation using rapid shell vial techniques14 on various cellines including VERO cells, tertiary cynomolgous monkey kidney (tMK) cells, human endothelial lung (HEL) cells and marbin dock kidney (MDCK) cells. Samples showing cytophatic effects (CPE) after two to three passages, and which were negative in DIF, were tested by indirect immunofluorescence assays (IFA) using virus specific antibodies against influenza virus types A, B and C, hRSV types A and B, measles virus, mumps virus, human parainfluenza virus (hPIV) types 1 to 4, sendai virus, simian virus type 5, and New-Castle disease virus. Although for many cases the aetiological agent could be identified, some specimens were negative for all these viruses tested. Direct Immunofluorescence Assay (DIF) Nasopharyngeal aspirate samples from patients suffering from RTI were used for DIF and virus isolation as described14,15. Samples were stored at −70° C. In brief, nasopharyngeal aspirates were diluted with 5 ml Dulbecco MEM (BioWhittaker, Walkersville, Md.) and thoroughly mixed on a vortex mixer for one minute. The suspension was thus centrifuged for ten minutes at 840×g. The sediment was spread on a multispot slide (Nutacon, Leimuiden, The Netherlands), the supernatant was used for virus isolation. After drying, the cells were fixed in aceton for 1 minute at room temperature. After washing the slides were incubated for 15 minutes at 37° C. with commercial available FITC-labelled virus specific anti-sera such as influenza A and B, hRSV and hPIV 1 to 3 (Dako, Glostrup, Denmark). After three washings in PBS and one in tap water, the slides were included in a glycerol/PBS solution (Citifluor, UKC, Canterbury, UK) and covered. The slides were analysed using a Axioscop fluorescence microscope (Carl Zeiss B. V, Weesp, the Netherlands. Virus isolation For virus isolation tMK cells (RIVM, Bilthoven, The Netherlands) were cultured in 24 well plates containing glass slides (Costar, Cambridge, UK, with the medium described below supplemented with 10% fetal bovine serum (BioWhittaker, Vervier, Belgium). Before inoculation the plates were washed with PBS and supplied with Eagle's MEM with Hanks' salt (ICN, Costa mesa, CA) of which half a litre was supplemented with 0.26 gram HaHCO3, 0.025 M Hepes (Biowhittaker), 2 mM L-glutamine (Biowhittaker), 100 units penicilline, 100 μg streptomycine (Biowhittaker), 0.5 gram lactalbumine (Sigma-Aldrich, Zwijndrecht, The Netherlands), 1.0 gram D-glucose (Merck, Amsterdam, The Netherlands), 5.0 gram peptone (Oxoid, Haarlem, The Netherlands) and 0.02% trypsine (Mfe Technologies, Bethesda, Md.). The plates were inoculated with supernatant of the nasopharyngeal aspirate samples, 0,2 ml per well in triplicate, followed by centrifuging at 840×g for one hour. After inoculation the plates were incubated at 37° C. for a maximum of 14 days changing the medium once a week and cultures were checked daily for CPE. After 14 days cells were scraped from the second passage and incubated 14 days. This step was repeated for the third passage. The glass slides were used to demonstrate the presence of the virus by indirect IFA as described below. Animal Immunisation Ferret and guinea pig specific antisera for the newly discovered virus were generated by experimental intranasal infection of two specific pathogen free ferrets and two guinea pigs, housed in separate pressurised glove boxes. Two to three weeks later all the animals were bled by cardiac puncture, and their sera were used as reference sera. The sera were tested for all previous described viruses with indirect IFA as described below. Antigen Detection by Indirect IFA We performed indirect IFA on slides containing infected tMK cells. After washing with PBS the slides were incubated for 30 minutes at 37° C. with virus specific anti-sera. We used monoclonal antibodies in DIF against influenza A, B and C, hPIV type 1 to 3 and hRSV as described above. For hPIV type 4, mumps virus, measles virus, sendai virus, simian virus type 5, New-Castle Disease virus polyclonal antibodies (RIVM) and ferret and guinea pig reference sera were used. After three washings with PBS and one wash with tap water, the slides were stained with a secondary antibodies directed against the sera used in the first incubation. Secondary antibodies for the polyclonal anti sera were goat-anti-ferret (KPL, Guilford, UK, 40 fold diluted), mouse-anti-rabbit (Dako, Glostrup, Denmark, 20 fold diluted), rabbit-anti-chicken (KPL, 20 fold dilution) and mouse-anti-guinea pig (Dako, 20 fold diluted). Slides were processed as described for DIF. Detection of Antibodies in Humans by Indirect IFA For the detection of virus specific antibodies, infected tMK cells were fixed with cold acetone on coverslips, washed with PBS and stained with serum samples at a 1 to 16 dilution. Subsequently, samples were stained with FITC-labelled rabbit anti human antibodies 80 times diluted in PBS (Dako). Slides were processed as described above. Virus Culture of MPV Sub-confluent mono-layers of tMK cells in media as described above were inoculated with supernatants of samples that displayed CPE after two or three passages in the 24 well plates. Cultures were checked for CPE daily and the media was changed once a week. Since CPE differed for each isolate, all cultures were tested at day 12 to 14 with indirect IFA using ferret antibodies against the new virus isolate. Positive cultures were freeze-thawed three times, after which the supernatants were clarified by low-speed centrifugation, aliquoted and stored frozen at −70° C. The 50% tissue culture infectious doses (TCID50) of virus in the culture supernatants were determined as described16. Virus Neutralisation Assay VN assays were performed with serial two-fold dilutions of human and animal sera starting at an eight-fold dilution. Diluted sera were incubated for one hour with 100 TCID50 of virus before inoculation of tMK cells grown in 96 well plates, after which the plates were centrifuged at 840×g. The media was changed after three and six days and IFA was conducted with ferret antibodies against MPV 8 days after inoculation. The VN titre was defined as the lowest dilution of the serum sample resulting in negative IFA and inhibition of CPE in cell cultures. Virus Characterisation Haemagglutination assays and chloroform sensitivity tests were performed as described8,14. For EM analyses, virus was concentrated from infected cell culture supernatants in a micro-centrifuge at 4° C. at 17000×g, after which the pellet was resuspended in PBS and inspected by negative contrast EM. For RAP-PCR, virus was concentrated from infected tMK cell supernatants by ultra-centrifugation on a 60% sucrose cussion (2 hours at 150000×g, 4° C.). The 60% sucrose interphase was subsequently diluted with PBS and layered on top of a 20-60% continuous sucrose gradient which was centrifuged for 16 hours at 275000×g at 4° C. Sucrose gradient fractions were inspected for the presence of virus-like particles by EM and poly-acrylamide gel electrophoresis followed by silver staining. The approximately 50% sucrose fractions that appeared to contain nucleocapsids were used for RNA isolation and RAP-PCR. RNA Isolation RNA was isolated from the supernatant of infected cell cultures or sucrose gradient fractions using a High Pure RNA Isolation kit according to instructions from the manufacturer (Roche Diagnostics, Almere, The Netherlands). RT-PCR Virus-specific oligonucleotide sequences for RT-PCR assays on known paramyxoviruses are described in addenda 1. A one-step RT-PCR was performed in 50 μl reactions containing 50 mM Tris.HCl pH 8.5, 50 mM NaCl, 4 mM MgCl2, 2 mM dithiotreitol, 200 μM each dNTP, 10 units recombinant RNAsin (Promega, Leiden, the Netherlands), 10 units AMV RT (Promega, Leiden, The Netherlands), 5 units Amplitaq Gold DNA polymerase (PE Biosystems, Nieuwerkerk aan de IjsseL The Netherlands) and 5 μl RNA. Cycling conditions were 45 min. at 42° C. and 7 min. at 95° C. once, 1 min at 95° C., 2 min. at 42° C. and 3 min. at 72° C. repeated 40 times and 10 min. at 72° C. once. RAP-PCR RAP-PCR was performed essentially as described10. The oligonucleotide sequences are described in addenda 2. For the RT reaction, 2 μl RNA was used in a 10 μl reaction containing 10 ng/μl oligonucleotide, 10 mM dithiotreitol, 500 μm each dNTP, 25 mM Tris-HCl pH 8.3, 75 mM KCl and 3 mM MgCl2. The reaction mixture was incubated for 5 min. at 70° C. and 5 min. at 37° C., after which 200 units Superscript RT enzyme (LifeTechnologies) were added. The incubation at 37° C. was continued for 55 min. and the reaction terminated by a 5 min. incubation at 72° C. The RT mixture was diluted to give a 50 μl PCR reaction containing 8 ng/μl oligonucleotide, 300 μm each dNTP, 15 mM Tris-HCL pH 8.3, 65 mM KCl, 3.0 mM MgCl2 and 5 units Taq DNA polymerase (PE Biosystems). Cycling conditions were 5 min. at 94° C., 5 min. at 40° C. and 1 min. at 72° C. once, followed by 1 min. at 94° C., 2 min. at 56° C. and 1 min. at 72° C. repeated 40 times and 5 min. at 72° C. once. After RAP-PCR, 15 μl the RT-PCR products were run side by side on a 3% NuSieve agarose gel (FMC BioProducts, Heerhugowaard, The Netherlands). Differentially displayed fragments specific for MPV were purified from the gel with Qiaquick Gel Extraction kit (Qiagen, Leusden, The Netherlands) and cloned in pCR2.1 vector (Invitrogen, Groningen, The Netherlands) according to instructions from the manufacterer. Sequence Analysis RAP-PCR products cloned in vector pCR2.1 (Invitrogen) were sequenced with M13-specific oligonucleotides. DNA fragments obtained by RT-PCR were purified from agarose gels using Qiaquick Gel Extraction kit (Qiagen, Leusden, The Netherlands), and sequenced directly with the same oligonucleotides used for PCR. Sequence analyses were performed using a Dyenamic ET terminator sequencing kit (Amersham Pharmacia Biotech, Roosendaal, The Netherlands) and an ABI 373 automatic DNA sequencer (PE Biosystem). All techniques were performed according to the instructions of the manufacturer. Generating Genomic Fragments of MPV by RT-PCR To generate PCR fragments spanning gaps A, B and C between the RAP-PCR fragments (FIG. 2) we used RT-PCR assays as described before on RNA isolated from virus isolate 00-1. The following primers were used: For fragment A: TR1 designed in the leader: (5′-AAAGAATTCACGAGAAAAAAACGC-3′) and N1 designed at the 3′end of the RAP-PCR fragments obtained in N (5′-CTGTGGTCTCTAGTCCCACTTC-3′) For fragment B: N2 designed at the 5′end of the RAP-PCR fragments obtained in N: (5′-CATGCAAGCTTATGGGGC-3′) and M1 designed at the 3′end of the RAP-PCR fragments obtained in M: (5′-CAGAGTGGTTATTGTCAGGGT-3). For fragment C: M2 designed at the 5′end of the RAP-PCR fragment obtained in M: (5′-GTAGAACTAGGAGCATATG-3′) and F1 designed at the 3′end of the RAP-PCR fragments obtained in F: (5′-TCCCCAATGTAGATACTGCTTC-3′). Fragments were purified from the gel, cloned and sequenced as described before. RT-PCR for Diagnosing MPV. For the amplification and sequencing of parts of the N, M, F and L ORFs of nine of the MPV isolates, we used primers N3 (5′-GCACTCAAGAGATACCCTAG-3′) and N4 (5′-AGACTTTCTGCTTTGCTGCCTG-3′), amplifying a 151 nucleotide fragments, M3 (5′-CCCTGACAATAACCACTCTG-3′) and M4 (5′-GCCAACTGATTTGGCTGAGCTC-3′) amplifying a 252 nucleotide fragment, F7 (5′-TGCACTATCTCCTCTTGGGGCTTTG-3) and F8 (5′-TCAAAGCTGCTTGACACTGGCC-3′) amplifying a 221 nucleotide fragment and L6 (5′-CATGCCCACTATAAAAGGTCAG-3′) and L7 (5′-CACCCCAGTCTTTCTTGAAA-3) amplifying a 173 nucleotide fragment respectively. RT-PCR, gel purification and direct sequencing were performed as described above. Furthermore, probes used were: Probe used in M: 5′-TGC TTG TAC TTC CCA AAG-3′ Probe used in N: 5′-TAT TTG AAC AAA AAG TGT-3′ Probe used in L: 5′-TGGTGTGGGATATTAACAG-3′ Phylogenetic Analyses For all phylogenetic trees, DNA sequences were alligned using the ClustalW software package and maximum likelihood trees were generated using the DNA-ML software package of the Phylip 3.5 program using 100 bootstraps and 3 jumblesl15. Previously published sequences that were used for the generation of phylogenetic trees are available from Genbank under accessions numbers: For all ORFs: hRSV: NC001781; bRSV: NC001989; For the F ORF: PVM, D11128; APV-A, D00850; APV-B, Y14292; APV-C, AF187152; For the N ORF: PVM, D10331; APV-A, U39295; APV-B, U39296; APV-C, AF176590; For the M ORF: PMV, U66893; APV-A, X58639; APV-B, U37586; APV-C, AF262571; For the P ORF: PVM, 09649; APV-A, U22110, APV-C, AF176591. Phylogenetic analyses for the nine different virus isolates of MPV were performed with APV strain C as outgroup. Abbreviations used in figures: hRSV: human RSV; bRSV: bovine RSV; PVM: pneumonia virus of mice; APV-A, B, and C: avian pneumovirus typ A, B and C. Examples of Methods to Identify MPV Specimen Collection In order to find virus isolates nasopharyngeal aspirates, throat and nasal swabs, broncheo alveolar lavages preferably from mammals such as humans, carnivores (dogs, cats, mustellits, seals etc.), horses, ruminants (cattle, sheep, goats etc.), pigs, rabbits, birds (poultry, ostriches, etc) should be examined. From birds cloaca swabs and droppings can be examined as well Sera should be collected for immunological assays, such as ELISA and virus neutralisation assays. Collected virus specimens were diluted with 5 ml Dulbecco MEM medium (BioWhittaker, Walkersville, Md.) and thoroughly mixed on a vortex mixer for one minute. The suspension was thus centrifuged for ten minutes at 840×g. The sediment was spread on a multispot slide (Nutacon, Leimuiden, The Netherlands) for immunofluorescence techniques, and the supernatant was used for virus isolation. Virus Isolation For virus isolation tMK cells (RIVM, Bilthoven, The Netherlands) were cultured in 24 well plates containing glass slides (Costar, Cambridge, UK), with the medium described below supplemented with 10% fetal bovine serum BioWhittaker, Vervier, Belgium). Before inoculation the plates were washed with PBS and supplied with Eagle's MEM with Hanks' salt (ICN, Costa mesa, CA) supplemented with 0.52/liter gram NaHCO3, 0.025 M Hepes (Biowhittaker), 2 mM L-glutamine (Biowhittaker), 200 units/liter penicilline, 200 μg/liter streptomycine (Biowhittaker), 1 gram/liter lactalbumine (Sigma-Aldrich, Zwijndrecht, The Netherlands), 2.0 gram/liter D-glucose (Merck, Amsterdam, The Netherlands), 10 gram/liter peptone (Oxoid, Haarlem, The Netherlands) and 0.02% trypsine (Life Technologies, Bethesda, M). The plates were inoculated with supernatant of the nasopharyngeal aspirate samples, 0,2 ml per well in triplicate, followed by centrifuging at 840×g for one hour. After inoculation the plates were incubated at 37° C. for a maximum of 14 days changing the medium once a week and cultures were checked daily for CPE. After 14 days, cells were scraped from the second passage and incubated for another 14 days. This step was repeated for the third passage. The glass slides were used to demonstrate the presence of the virus by indirect IFA as described below. CPE was generally observed after the third passage, at day 8 to 14 depending on the isolate. The CPE was virtually indistinghuisable from that caused by hRSV or hPIV in tMK or other cell cultures. However, hRSV induces CPE starting around day 4. CPE was characterised by syncytia formation, after which the cells showed rapid internal disruption, followed by detachment of cells from the monolayer. For some isolates CPE was difficult to observe, and IFA was used to confirm the presence of the virus in these cultures. Virus culture of MPV Sub-confluent monolayers of tMK cells in media as described above were inoculated with supernatants of samples that displayed CPE after two or three passages in the 24 well plates. Cultures were checked for CPE daily and the media was changed once a week. Since CPE differed for each isolate, all cultures were tested at day 12 to 14with indirect IFA using ferret antibodies against the new virus isolate. Positive cultures were freeze-thawed three times, after which the supernatants were clarified by low-speed centrifugation, aliquoted and stored frozen at −70° C. The 50% tissue culture infectious doses (TCID50) of virus in the culture supernatants were determined following established techniques used in the field16. Virus Characterisation Haemagglutination assays and chloroform sensitivity tests were performed following well established and described techniques used in the field14. For EM analyses, virus was concentrated from infected cell culture supernatants in a micro-centrifuge at 4° C at 17000×g, after which the pellet was resuspended in PBS and inspected by negative contrast EM. Antigen Detection by Indirect IRA Collected specimens were processed as described and sediment of the samples was spread on a multispot slide. After drying, the cells were fixed in aceton for 1 minute at room temperature. Alternatively, virus was cultured on tMK cells in 24 well slides containing glass slides. These glass slides were washed with PBS and fixed in aceton for 1 minute at room temperature. After washing with PBS the slides were incubated for 30 minutes at 37° C. with polyclonal antibodies at a dilution of 1:50 to 1:100 in PBS. We used immunised ferrets and guinea pigs to obtain polyclonal antibodies, but these antibodies can be raised in various animals, and the working dilution of the polyclonal antibody can vary for each immunisation. After three washes with PBS and one wash with tap water, the slides were incubated at 37° C. for 30 minutes with FITC labeled goat-anti-ferret antibodies (KPL, Guilford, UK, 40 fold diluted). After three washes in PBS and one in tap water, the slides were included in a glycerol/PBS solution (Citifluor, UKC, Canterbury, UK) and covered. The slides were analysed using an Axioscop fluorescence microscope (Carl Zeiss B. V., Weesp, the Netherlands). Detection of Antibodies in Humans, Mammals, Ruminants or Other Animals by Indirect IFA For the detection of virus specific antibodies, infected tMK cells with MPV were fixed with acetone on coverslips (as described above), washed with PBS and incubated 30 minutes at 37° C. with serum samples at a 1 to 16 dilution. After two washes with PBS and one with tap water, the slides were incubated 30 minutes at 37° C. with FITC-labelled secondary antibodies to the species used (Dako). Slides were processed as described above. Antibodies can be labelled directly with a fluorescent dye, which will result in a direct immuno fluorescence assay. FITC can be replaced with any fluorescent dye. Animal Immunisation Ferret and guinea pig specific antisera for the newly discovered virus were generated by experimental intranasal infection of two specific pathogen free ferrets and two guinea pigs, housed in separate pressurised glove boxes. Two to three weeks later the animals were bled by cardiac puncture, and their sera were used as reference sera. The sera were tested for all previous described viruses with indirect IFA as described below. Other animal species are also suitable for the generation of specific antibody preparations and other antigen preparations may be used. Virus Neutralisation Assay (VN Assay) VN assays were performed with serial two-fold dilutions of human and animal sera starting at an eight-fold dilution. Diluted sera were incubated for one hour with 100 TCID50 of virus before inoculation of tMK cells grown in 96 well plates, after which the plates were centrifuged at 840×g. The same culture media as described above was used. The media was changed after three and six days, and after 8 days IFA was performed (see above). The VN titre was defined as the lowest dilution of the serum sample resulting in negative IFA and inhibition of CPE in cell cultures. RNA Isolation RNA was isolated from the supernatant of infected cell cultures or sucrose gradient fractions using a High Pure RNA Isolation kit according to instructions from the manufacturer (Roche Diagnostics, Almere, The Netherlands). RNA can also be isolated following other procedures known in the field (Current Protocols in Molecular Biology). RT-PCR A one-step RT-PCR was performed in 50 μl reactions containing 50 mM Tris.HCl pH 8.5, 50 mM NaCl, 4 mM MgCl2, 2 mM dithiotreitol, 200 μM each dNTP, 10 units recombinant RNAsin (Promega, Leiden, the Netherlands), 10 units AMV RT (Promega, Leiden, The Netherlands), 5 units Amplitaq Gold DNA polymerase (PE Biosystems, Nieuwerkerk aan de Ijssel, The Netherlands) and 5 μl RNA. Cycling conditions were 45 min. at 42 CC and 7 min. at 95° C. once, 1 min at 95° C., 2 min. at 42° C. and 3 min. at 72° C. repeated 40 times and 10 min. at 72° C. once. Primers used for diagnostic PCR: In the nucleoprotein: N3 (5′-GCACTCAAGAGATACCCTAG 3′) and N4 (5′-AGACTTTCTGCTTTGCTGCCTG-3′), amplifying a 151 nucleotide fragment. In the matrixprotein: M3 (5′-CCCTGACAATAACCACTCTG-3′) and M4 (5′-GCCAACTGATTTGGCTGAGCTC-3′) amplifying a 252 nucleotide fragment In the polymerase protein: L6 (5′-CATGCCCACTATAAAAGGTCAG-3′) and L7 (5′-CACCCCAGTCTTTCTTGAAA-3′) amplifying a 173 nucleotide fragment. Other primers can be designed based on MPV sequences, and different buffers and assay conditions may be used for specific purposes. Sequence Analysis Sequence analyses were performed using a Dyenamic ET terminator sequencing kit (Amersham Pharmacia Biotech, Roosendaal, The Netherlands) and an ABI 373 automatic DNA sequencer (PE Biosystem). All techniques were performed according to the instructions of the manufacturer. PCR fragments were sequenced directly with the same oligonucleotides used for PCR, or the fragments were purified from the gel with Qiaquick Gel Extraction kit (Qiagen, Leusden, The Netherlands) and cloned in pCR2.1 vector (Invitrogen, Groningen, The Netherlands) according to instructions from the manufacturer and subsequently sequenced with M13-specific oligonucleotides. Oligonucleotides Used for Analysing the 3′end of the Genome (Absence of NS1I/NS2). Primer TR1 (5′-AAAGAATTCACGAGAAAAAAACGC-3) was designed based on published sequences of the trailer and leader for hRSV and APV, published by Randhawa (1997) and primer N1 ('5‘-CTGTGGTCTCTAGTCCCACTTC-3’) was designed based on obtained sequences in the N protein. The RT-PCR assay and sequencing was performed as described above. The RT-PCR gave a product of approximately 500 base pairs which is to small to contain information for two ORFS, and translation of these sequences did not reveal an ORF. Detection of Antibodies in Humans, Mammals, Ruminants or Other Animals by ELISA In Paramyxoviridae, the N protein is the most abundant protein, and the immune response to this protein occurs early in infection. For these reasons, a recombinant source of the N proteins is preferably used for developing an ELISA assay for detection of antibodies to MPV. Antigens suitable for antibody detection include any MPV protein that combines with any MPV-specific antibody of a patient exposed to or infected with MPV virus. Preferred antigens of the invention include those that predominantly engender the immune response in patients exposed to MPV, which therefore, typically are recognised most readily by antibodies of a patient. Particularly preferred antigens include the N, F and G proteins of MPV. Antigens used for immunological techniques can be native antigens or can be modified versions thereof. Well known techniques of molecular biology can be used to alter the amino acid sequence of a MPV antigen to produce modified versions of the antigen that may be used in immunologic techniques. Methods for cloning genes, for manipulating the genes to and from expression vectors, and for expressing the protein encoded by the gene in a heterologous host are well-known, and these techniques can be used to provide the expression vectors, host cells, and the for expressing cloned genes encoding antigens in a host to produce recombinant antigens for use in diagnostic assays. See for instance: Molecular cloning, A laboratory manual and Current Protocols in Molecular Biology. A variety of expression systems may be used to produce MPV antigens. For instance, a variety of expression vectors suitable to produce proteins in E. Coli, B. subtilis, yeast, insect cells and mammalian cells have been described, any of which might be used to produce a MPV antigen suitable to detect anti-MPV antibodies in exposed patients. The baculovirus expression system has the advantage of providing necessary processing of proteins, and is therefor preferred. The system utilizes the polyhedrin promoter to direct expression of MPV antigens. (Matsuura et al. 1987, J. Gen. Virol. 68: 1233-1250). Antigens produced by recombinant baculo-viruses can be used in a variety of immunological assays to detect anti-MPV antibodies in a patient. It is well established, that recombinant antigens can be used in place of natural virus in practically any immunological assay for detection of virus specific antibodies. The assays include direct and indirect assays, sandwich assays, solid phase assays such as those using plates or beads among others, and liquid phase assays. Assays suitable include those that use primary and secondary antibodies, and those that use antibody binding reagents such as protein A. Moreover, a variety of detection methods can be used in the invention, including calorimetric, fluorescent, phosphorescent, chemiluminescent, luminescent and radioactive methods. EXAMPLE 1 Of Indirect Anti-MPV IgG EIA Using Recombinant N Protein An indirect IgG EIA using a recombinant N protein (produced with recombinant baculo-virus in insect (Sf9) cells) as antigen can be performed. For antigen preparation, Sf9 cells are infected with the recombinant baculovirus and harvested 3-7 days post infection. The cell suspension is washed twice in PBS, pH 7.2, adjusted to a cell density of 5.0×106 cells/ml, and freeze-thawed three times. Large cellular debris is pelleted by low speed centrifugation (500×g for 15 min.) and the supernatant is collected and stored at −70° C. until use. Uninfected cells are processed similarly for negative control antigen. 100 μl of a freeze-thaw lysate is used to coat microtiter plates, at dilutions ranging from 1:50 to 1:1000. An uninfected cell lysate is run in duplicate wells and serves as a negative control. After incubation overnight, plates are washed twice with PBS/0.05%Tween. Test sera are diluted 1:50 to 1:200 in ELISA buffer PBS, supplemented to 2% with normal goat sera, and with 0.5% bovine serum albumine and 0.1% milk), followed by incubation wells for 1 hour at 37° C. Plates are washed two times with PBS/0.05% Tween. Horseradish peroxidase labelled goat anti-human (or against other species) IgG, diluted 1:3000 to 1:5000 in ELISA buffer, added to wells, and incubated for 1 hour at 37°. The plates are then washed two times with PBS/0.05% Tween and once with tap water, incubated for 15 minutes at room temperature with the enzyme substrate TMB, 3,3′,5,5′ tetramethylbenzidine, such as that obtained from Sigma, and the reaction is stopped with 100 μl of 2 M phosphoric acid. Colorimetric readings are measured at 450 nm using an automated microtiter plate reader. EXAMPLE 2 Capture anti-MPV IgM EIA Using a Recombinant Nucleoprotein A capture IgM EIA using the recombinant nucleoprotein or any other recombinant protein as antigen can be performed by modification of assays as previously described by Erdman et al (1990) J. Clin. Microb. 29: 1466-1471. Affinity purified anti-human IgM capture antibody (or against other species), such as that obtained from Dako, is added to wells of a microtiter plate in a concentration of 250 ng per well in 0.1 M carbonate buffer pH 9.6. After overnight incubation at room temperature, the plates are washed two times with PBS/0.05% Tween. 100 μl of test serum diluted 1:200 to 1:1000 in ELISA buffer is added to triplicate wells and incubated for 1 hour at 37° C. The plates are then washed two times with in PBS/0.05% Tween. The freeze-thawed (infected with recombinant virus) Sf21 cell lysate is diluted 1:100 to 1: 500 in ELISA buffer is added to the wells and incubated for 2 hours at 37° C. Uninfected cell lysate serves as a negative control and is run in duplicate wells. The plates are then washed three times in PBS/0.06% Tween and incubated for 1 hour at 37° C. with 100 μl of a polyclonal antibody against MPV in a optimal dilution in ELISA buffer. After 2 washes with PBS/0.05% Tween, the plates are incubated with horseradish peroxide labeled secondary antibody (such as rabbit anti ferret), and the plates are incubated 20 minutes at 37° C. The plates are then washed five times in PBS/0105% Tween, incubated for 15 minutes at room temperature with the enzyme substrate TMB, 3,3′,5,6′ tetramethylbenzidine, as, for instance obtained from “Sigma”, and the reaction is stopped with 100 μl of 2M phosphoric acid. Colormetric readings are measured at 450 nm using automated microtiter plate reader. The sensitivities of the capture IgM EIAs using the recombinant nucleoprotein (or other recombinant protein) and whole MPV virus are compared using acute-and convalescent-phase serum pairs form persons with clinical MPV virus infection. The specificity of the recombinant nucleoprotein capture EIA is determined by testing serum specimens from healthy persons and persons with other paramyxovirus infections. Potential for EIAs for using recombinant MPV fusion and glycoprotein proteins produced by the baculovirus expression. The glycoproteins G and F are the two transmembraneous envelope glycoproteins of the MPV virion and represent the major neutralisation and protective antigens. The expression of these glycoproteins in a vector virus system sych as a baculovirus system provides a source of recombinant antigens for use in assays for detection of MPV specific antibodies. Moreover, their use in combination with the nucleoprotein, for instance, further enhances the sensitivity of enzyme immunoassays in the detection of antibodies against MPV. A variety of other immunological assays (Current Protocols in Immunology) may be used as alternative methods to those described here. In order to find virus isolates nasopharyngeal aspirates, throat and nasal swabs, broncheo alveolar lavages and throat swabs preferable from but not limited to humans, carnivores (dogs, cats, seals etc.), horses, ruminants (cattle, sheep, goats etc.), pigs, rabbits, birds (poultry, ostridges, etc) can be examined. From birds, cloaca and intestinal swabs and droppings can be examined as well. For all samples, serology (antibody and antigen detection etc.), virus isolation and nucleic acid detection techniques can be performed for the detection of virus. Monoclonal antibodies can be generated by immunising mice (or other animals) with purified MPV or parts thereof (proteins, peptides) and subsequently using established hybridoma technology (Current protocols in Immunology). Alternatively, phage display technology can be used for this purpose (Current protocols in Immunology). Similarly, polyclonal antibodies can be obtained from infected humans or animals, or from immunised humans or animals (Current protocols in Immunology). The detection of the presence or absence of NS1 and NS2 proteins can be performed using western-blotting, IFA, immuno precipitation techniques using a variety of antibody preparations. The detection of the presence or absence of NS1 and NS2 genes or homologues thereof in virus isolates can be performed using PCR with primer sets designed on the basis of known NS1 and/or NS2 genes as well as with a variety of nucleic acid hybridisation techniques. To determine whether NS1 and NS2 genes are present at the 3′ end of the viral genome, a PCR can be performed with primers specific for this 3′ end of the genome. In our case, we used a primer specific for the 3′ untranslated region of the viral genome and a primer in the N ORF. Other primers may be designed for the same purpose. The absence of the NS1/NS2 genes is revealed by the length and/or nucleotide sequence of the PCR product. Primers specific for NS1 and/or NS2 genes may be used in combination with primers specific for other parts of the 3′ end of the viral genome (such as the untranslated region or N, M or F ORFs) to allow a positive identification of the presence of NS1 or NS2 genes. In addition to PCR, a variety of techniques such as molecular cloning, nucleic acid hybridisation may be used for the same purpose. EXAMPLE 3 Different Serotypes/Subgroups of MPV Two potential genetic clusters are identified by analyses of partial nucleotide sequences in the N, M, F and L ORFs of 9 virus isolates. 90-100% nucleotide identity was observed within a cluster, and 81-88% identity was observed between the clusters. Sequence information obtained on more virus isolates confirmed the existence of two genotypes. Virus isolate ned/00/01 as prototype of cluster A, and virus isolate ned/99/01 as prototype of cluster B have been used in cross neutralization assays to test whether the genotypes are related to different serotypes or subgroups. Results Using RT-PCR assays with primers located in the polymerase gene, we identified 30 additional virus isolates from nasopharyngeal aspirate samples. Sequence information of parts of the matrix and polymerase genes of these new isolates together with those of the previous 9 isolates were used to construct phylogenetic trees (FIG. 16). Analyses of these trees confirmed the presence of two genetic clusters, with virus isolate ned/00/00-1 as the prototype virus in group A and virus isolate ned/99/01 as the prototype virus in group B. The nucleotide sequence identity within a group was more than 92%, while between the clusters the identity was 81-85%. Virus isolates ned/00/01 and ned/99/01 have been used to inoculate ferrets to raise virus-specific antisera. These antisera were used in virus neutralization assays with both viruses. TABLE 3 Virus neutralization titers isolate 00-1 isolate 99-1 preserum □2 □2 ferret A (00-1) ferret A 64 □2 22 dpi (00-1) preserum □2 □2 ferret B (99-1) ferret B 4 64 22 dpi (99-1) For isolate 00-1 the titer differs 32 (64/2) fold For isolate 99-1 the titer differs 16 (64/4) fold In addition, 6 guinea pigs have been inoculated with either one of the viruses (ned/00/01 and ned/99/01). RT-PCR assays on nasopharyngeal aspirate samples showed virus replication from day 2 till day 10 post infection. At day 70 post infection the guinea pigs have been challenged with either the homologous or the heterologous virus, and for in all four cases virus replication has been noticed. TABLE 4 primary virus secondary virus infection replication infection replication guinea pig 1-3 00-1 2 out of 3 99-1 1 out of 2 guinea pig 4-6 00-1 3 out of 3 00-1 1 out of 3 guinea pig 7-9 99-1 3 out of 3 00-1 2 out of 2 guinea pig 10-12 99-1 3 out of 3 99-1 1 out of 3 note: for the secondary infection guinea pig 2 and 9 were not there any more. Virus neutralization assays with anti sera after the first challenge showed essentially the same results as in the VN assays performed with the ferrets (>16-fold difference in VN titer). The results presented in this example confirm the existence of two genotypes, which correspond to two serotypes of MPV, and show the possibility of repeated infection with heterologous and homologous virus. EXAMPLE 4 Further Sequence Determination This example describes the further analysis of the sequences of MPV open reading frames (ORFs) and intergenic sequences as well as partial sequences of the genomic termini. Sequence analyses of the nucleoprotein (N), phosphoprotein (P), matrixprotein (M) and fusion protein (F) genes of MPV revealed the highest degree of sequence homology with APV serotype C, the avian pneumovirus found primarily in birds in the United States. These analyses also revealed the absence of non-structural proteins NS1 and NS2 at the 3′ end of the viral genome and positioning of the fusion protein immediately adjacent to the matrix protein. Here we present the sequences of the 22K (M2) protein, the small hydrophobic (SH) protein, the attachment (G) protein and the polymerase (L) protein genes, the intergenic regions and the trailer sequence. In combination with the sequences described previously the sequences presented here complete the genomic sequence of MPV with the exception of the extreme 12-15 nucleotides of the genomic termini and establish the genomic organisation of MPV. Side by side comparisons of the sequences of the MPV genome with those of APV subtype A, B and C, RSV subtype A and B, PVM and other paramyxoviruses provides strong evidence for the classification of MPV in the Metapneumovirus genus. Results Sequence Strategy MPV isolate 00-1 (van den Hoogen et al., 2001) was propagated in tertiary monkey kidney (tMK cells and RNA isolated from the supernatant 3 weeks after inoculation was used as template for RT-PCR analyses. Primers were designed on the basis of the partial sequence information available for MTV 00-1 (van den Hoogen et al., 2001) as well as the leader and trailer sequences of APV and RSV (Randhawa et al., 1997; Mink et al., 1991). Initially, fragments between the previously obtained products, ranging in size from 500 bp to 4 Kb in length, were generated by RT-PCR amplification and sequenced directly. The genomic sequence was subsequently confirmed by generating a series of overlapping RT-PCR fragments ranging in size from 500 to 800 bp that represented the entire MPV genome. For all PCR fragments, both strands were sequenced directly to minimize amplification and sequencing errors. The nucleotide and amino acid sequences were used to search for homologies with sequences in the Genbank database using the BLAST software (www.ncbi.nlm.nih.gov/BLAST). protein names were assigned to open reading frames (ORFs) based on homology with known viral genes as well as their location in the genome. Based on this information, a genomic map for MPV was constructed FIG. 7). The MPV genome is 13378 nucleotides in length and its organization is similar to the genomic organization of APV. Below, we present a comparison between the ORFs and non-coding sequences of MPV and those of other paramyxoviruses and discuss the important similarities and differences. The Nucleoprotein (N) Gene As shown, the first gene in the genomic map of MPV codes for a 394 amino acid (aa) protein and shows extensive homology with the N protein of other pneumoviruses. The length of the N ORF is identical to the length of the N ORF of APV-C (Table 5) and is smaller than those of other paramyxoviruses (Barr et al., 1991). Analysis of the amino acid sequence revealed the highest homology with APV-C (88%), and only 7-11% with other paramyxoviruses (Table 6). Barr et al (1991) identified 3 regions of similarity between viruses belonging to the order Mononegavirales: A, B and C (FIG. 8). Although similarities are highest within a virus family, these regions are highly conserved between virus familys. In all three regions MPV revealed 97% aa sequence identity with APV-C, 89% with APV-B, 92% with APV-A, and 66-73% with RSV and PVM. The region between aa residues 160 and 340 appears to be highly conserved among metapneumoviruses and to a somewhat lesser extent the Pneumovirinae (Miyahara et al., 1992; Li et al., 1996; Barr et al., 1991). This is in agreement with MPV being a metapneumovirus, showing 100% similarity with APV C. The Phosphoprotein (P) Gene The second ORF in the genome map codes for a 294 aa protein which shares 68% aa sequence homology with the P protein of APV-C, and only 22-26% with the P protein of RSV (Table 6). The P gene of MPV contains one substantial ORF and in that respect is similar to P from many other paramyxoviruses (Reviewed in Lamb and Kolakofsky, 1996; Sedlmeier et al., 1998). In contrast to APV A and B and PVM and similar to RSV and APV-C the MPV P ORF lacks cysteine residues. Ling (1995) suggested that a region of high similarity between all pneumoviruses (aa 185-241) plays a role in either the RNA synthesis process or in maintaining the structural integrity of the nucleocapsid complex. This region of high similarity is also found in MPV (FIG. 9) especifically when conservative substitutions are taken in account, showing 100% similarity with APV-C, 93% with APV-A and B, and approximately 81% with RSV. The C-terminus of the MPV P protein is rich in glutamate residues as has been described for APVs (Ling et al., 1995). The Matrix (M) Protein Gene The third ORF of the MPV genome encodes a 254 aa protein, which resembles the M ORFs of other pneumoviruses. The M ORF of MPV has exactly the same size as the M ORFs of other metapneumoviruses (Table 5) and shows high aa sequence homology with the matrix proteins of APV (78-87%), lower homology with those of RSV and PVM (37-38%) and 10% or less homology with those of other paramyxoviruses (Table 6). Easton (1997) compared the sequences of matrix proteins of all pneumoviruses and found a conserved heptadpeptide at residue 14 to 19 that is also conserved in MPV (FIG. 10). For RSV, PVM and APV small secondary ORFs within or overlapping with the major ORF of M have been identified (52 aa and 51 aa in bRSV, 75 aa in RSV, 46 aa in PVM and 51 aa in APV) (Yu et al., 1992; Easton et al., 1997; Samal et al., 1991; Satake et al., 1984). We noticed two small ORFs in the M ORF of MPV. One small ORF of 54 aa residues was found within the major M ORF (fragment 1, FIG. 7), starting at nucleotide 2281 and one small ORF of 33 aa residues was found overlapping with the major ORF of M starting at nucleotide 2893 (fragment 2, FIG. 7). Similar to the secondary ORFs of RSV and APV there is no significant homology between these secondary ORFs and secondary ORFs of the other pneumoviruses, and apparent start or stop signals are lacking. In addition, evidence for the synthesis of proteins corresponding to these secondary ORFs of APV and RSV has not been reported. The Fusion Protein (F) Gene The F ORF of MPV is located adjacent to the M ORF, which is characteristic for members of the Metapneumovirus genus. The F gene of MPV encodes a 539 aa protein, which is two aa residues longer than F of APV-C (Table 5). Analysis of the aa sequence revealed 81% homology with APV-C, 67% with APV-A and B, 33-39% with pneumovirus F proteins and only 10-18% with other paramyxoviruses (Table 6). One of the conserved features among F proteins of paramyxoviruses, and also seen in MPV is the distribution of cysteine residues (Morrison, 1988; Yu et al., 1991). The metapneumoviruses share 12 cysteine residues in F1 (7 are conserved among all paramyxoviruses), and two in F2 (1 is conserved among all paramyxoviruses). Of the 3 potential N-linked glycosylation sites present in the F ORF of MPV, none are shared with RSV and two (position 74 and 389) are shared with APV. The third, unique, potential N-linked glycosylation site for MPV is located at position 206 (FIG. 11). Despite the low sequence homology with other paramyxoviruses, the F protein of MPV revealed typical fusion protein characteristics consistent with those described for the F proteins of other Paramyxoviridae family members (Morrison, 1988). F proteins of Paramyxoviridae members are synthesized as inactive precursors (F0) that are cleaved by host cell proteases which generate amino terminal F2 subunits and large carboxy terminal F1 subunits. The proposed cleavage site (Collins et al., 1996) is conserved among all members of the Paramyxoviridae family. The cleavage site of MPV contains the residues RQSR. Both arginine (R) residues are shared with APV and RSV, but the glutamine (Q) and serine (S) residues are shared with other paramyxoviruses such as human parainfluenza virus type 1, Sendai virus and morbilliviruses (data not shown). The hydrophobic region at the amino terminus of F1 is thought to function as the membrane fusion domain and shows high sequence similarity among paramyxoviruses and morbilliviruses and to a lesser extent the pneumoviruses (Morrison, 1988). These 26 residues (position 137-163, FIG. 11) are conserved between MPV and APV-C, which is in agreement with this region being highly conserved among the metapneumoviruses (Naylor et al., 1998; Seal et al., 2000). As is seen for the F2 subunits of APV and other paramyxoviruses, MPV revealed a deletion of 22 aa residues compared with RSV (position 107-128, FIG. 11). Furthermore, for RSV and APV, the signal peptide and anchor domain were found to be conserved within subtypes and displayed high variability between subtypes Plows et al., 1995; Naylor et al., 1998). The signal peptide of MPV (aa 10-35, FIG. 11) at the amino terminus of F2 exhibits some sequence similarity with APV-C (18 out of 26 aa residues are similar), and less conservation with other APVs or RSV. Much more variability is seen in the membrane anchor domain at the carboxy terminus of F1, although some homology is still seen with APV-C. The 22K (M2) Protein The M2 gene is unique to the Pneumovirinae and two overlapping ORFs have been observed in all pneumoviruses. The first major ORF represents the M2-1 protein which enhances the processivity of the viral polymerase (Collins et al., 1995; Collins, 1996) and its readthrough of intergenic regions (Hardy et al., 1998; Fearns et al., 1999). The M2-1 gene for MPV, located adjacent to the F gene, encodes a 187 aa protein (Table 5), and reveals the highest (84%) homology with M2-1 of APV-C (Table 6). Comparison of all pneumovirus M2-1 proteins revealed the highest conservation in the amino-terminal half of the protein (Collins et al., 1990; Zamora et al., 1992; Ahmadian et al., 1999), which is in agreement with the observation that MPV displays 100% similarity with APV-C in the first 80 aa residues of the protein (FIG. 12A). The MPV M2-1 protein contains 3 cysteine residues located within the first 30 aa residues that are conserved among all pneumoviruses. Such a concentration of cysteines is frequently found in zinc-binding proteins (Ahmadian et al., 1991; Cuesta et al., 2000). The secondary ORFs (M2-2) that overlap with the M2-1 ORFs of pneumoviruses are conserved in location but not in sequence and are thought to be involved in the control of the switch between virus RNA replication and transcription (Collins et al., 1985; Elango et al., 1985; Baybutt et al., 1987; Collins et al., 1990; Ling et al., 1992; Zamora et al., 1992; Alansari et al., 1994; Ahmadian et al., 1999; Bermingham et al., 1999). For MPV, the M2-2 ORF starts at nucleotide 512 in the M2-1 ORF (FIG. 7), which is exactly the same start position as for APV-C. The length of the M2-2 ORFs are the same for APV-C and MPV, 71 aa residues (Table 5). Sequence comparison of the M2-2 ORF (FIG. 12B) revealed 64% aa sequence homology between MPV and APV-C and only 44-48% aa sequence homology between MPV and APV-A and B (Table 6). The Small Hydrophobic Protein (SH)ORF The gene located adjacent to M2 of hMPV probably encodes a 183 aa SH protein (FIGS. 1 and 7). There is no discernible sequence identity between this ORF and other RNA virus genes or gene products. This is not surprising since sequence similarity between pneumovirus SH proteins is generally low. The putative SH ORF of hMPV is the longest SR ORF known to date (Table 1). The aa composition of the SR ORF is relatively similar to that of APV, RSV and PVM, with a high percentage of threonine and serine residues (22%, 18%, 19%, 20.0%, 21% and 28% for hMPV, APV, RSV A, RSV B, bRSV and PVM respectively). The SR ORF of hMPV contains 10 cysteine residues, whereas APV SR contains 16 cysteine residues. The SH ORF of hMPV contains two potential N-linked glycosylation sites (aa 76 and 121), whereas APV has one, RSV has two or three and PVM has four. The hydrophilicity profiles for the putative hMPV SE protein and SH of APV and RSV revealed similar characteristics (FIG. 7B). The SH ORFs of APV and hMPV have a hydrophilic N-terminus, a central hydrophobic domain which can serve as a potential membrane spanning domain (aa 30-53 for hMPV), a second hydrophobic domain (aa 155-170) and a hydrophilic C-terminus. In contrast, RSV SH appears to lack the C-terminal part of the APV and hMPV ORFs. In all pneumovirus SH proteins the hydrophobic domain is flanked by basic aa residues, which are also found in the SR ORF for hMPV (aa 29 and 54). The Attachment Glycoprotein (G) ORF The putative G ORF of hMPV is located adjacent to the putative SR gene and encodes a 236 aa protein (nt 6262-6972, FIG. 1). A secondary small ORF is found immediately following this ORF, potentially coding for 68 aa residues (nt 6973-7179) but lacking a start codon. A third potential ORF in the second reading frame of 194 aa residues is overlapping with both of these ORFs but also lacks a start codon (nt 6416-7000). This ORF is followed by a potential fourth ORF of 65 aa residues in the same reading frame (nt 7001-7198), again lacking a start codon. Finally, a potential ORF of 97 aa residues (but lacking a start codon) is found in the third reading frame (nt 6444-6737, FIG. 1). Unlike the first ORF, the other ORFs do not have apparent gene start or gene end sequences (see below). Although the 236 aa G ORF probably represents at least a part of the hMPV attachment protein it can not be excluded that the additional coding sequences ae expressed as separate proteins or as part of the attachment protein through some RNA editing event. It should be noted that for APV and RSV no secondary ORFs after the primary G ORF have been identified but that both APV and RSV have secondary ORFs within the major ORF of G. However, evidence for expression of these ORFs is lacking and there is no sequence identity between the predicted aa sequences for different viruses (Ling et al., 1992). The secondary ORFs in hMPV G do not reveal characteristics of other G proteins and whether the additional ORFs are expressed requires further investigation. BLAST analyses with all ORFs revealed no discernible sequence identity at the nucleotide or aa sequence level with other known virus genes or gene products. This is in agreement with the low percentage sequence identity found for other G proteins such as those of hRSV A and B (53%) (Johnson et al., 1987) and APV A and B (38%) (Juhasz and Easton, 1994). Whereas most of the hMPV ORFs resemble those of APV both in length and sequence, the putative G ORF of 236 aa residues of hMPV is considerably smaller than the G ORF of APV (Table 1). The as sequence revealed a serine and threonine content of 34%, which is even higher than the 32% for RSV and 24% for APV. The putative G ORF also contains 8.5% proline residues, which is higher than the 8% for RSV and 7% for APV. The unusual abundance of proline residues in the G proteins of APV, RSV and hMPV has also been observed in glycoproteins of mucinous origin where it is a major determinant of the proteins three dimensional structure (Collins and Wertz, 1983; Wertz et al., 1985; Jentoft, 1990). The G ORF of hMPV contains five potential N-linked glycosylation sites, whereas hRSV has seven, bRSV has five and APV has three to five. The predicted hydrophilicity profile of hMPV G revealed characteristics similar to the other pneumoviruses. The N-terminus contains a hydrophilic region followed by a short hydrophobic area (aa 33-53 for hMPV) and a mainly hydrophilic C-terminus (FIG. 8B). This overall organization is consistent with that of an anchored type II transmembrane protein and corresponds well with these regions in the G protein of APV and RSV. The putative G ORF of hMPV contains only 1 cysteine residue in contrast to RSV and APV (5 and 20 respectively). Of note, only two of the four secondary ORFs in the G gene contained one additional cysteine residue and these four potential ORFs revealed 12-20% serine and threonine residues and 6-11% proline residues. The Polymerase Gene (L) In analogy to other negative strand viruses, the last ORF of the MPV genome is the RNA-dependent RNA polymerase component of the replication and transcription complexes. The L gene of MPV encodes a 2005 aa protein, which is 1 residue longer than the APV-A protein (Table 5). The L protein of MPV shares 64% homology with APV-A, 42-44% with RSV, and approximately 13% with other paramyxoviruses (Table 6). Poch et al. (1989; 1990) identified six conserved domains within the L proteins of non-segmented negative strand RNA viruses, from which domain III contained the four core polymerase motifs that are thought to be essential for polymerase function. These motifs (A, B, C and D) are well conserved in the MPV L protein: in motifs A, B and C: MPV shares 100% similarity with all pneumoviruses and in motif D MPV shares 100% similarity with APV and 92% with RSVs. For the entire domain III (aa 627-903 in the L ORF), MPV shares 77% identity with APV, 61-62% with RSV and 23-27% with other paramyxoviruses (FIG. 15). In addition to the polymerase motifs the pneumovirus L proteins contain a sequence which conforms to a consensus ATP binding motif K(X)21GEGAGN(X)20K (Stec, 1991). The MPV L ORF contains a similar motif as APV, in which the spacing of the intermediate residues is off by one: K(X)22GEGAGN(X)19K. Phylogenetic Analyses As an indicator for the relationship between MPV and members of the Pneumovirinae, phylogenetic trees based on the N, P, M, and F ORFs have been constructed previously (van den Hoogen et al., 2001) and revealed a close relationship between MPV and APV-C. Because of the low homology of the MPV SH and G genes with those of other paramyxoviruses, reliable phylogenetic trees for these genes can not be constructed. In addition, the distinct genomic organization between members of the Pneumovirus and Metapneumovirus genera make it impossible to generate phylogenetic trees based on the entire genomic sequence. We therefore only constructed phylogenetic trees for the M2 and L genes in addition to those previously published. Both these trees confirmed the close relation between APV and MPV within the Pneumovirinae subfamily (FIG. 16). MPV Non-Coding Sequences The gene junctions of the genomes of paramyxoviruses contain short and highly conserved nucleotide sequences at the beginning and end of each gene (gene start and gene end signals), possibly playing a role in initiation and termination of transcription (Curran et al., 1999). Comparing the intergenic sequences between all genes of MPV revealed a consensus sequence for the gene start signal of the N, P, M, F, M2 and G: GGGACAAGU (FIG. 17A), which is identical to the consensus gene start signal of the metapneumoviruses (ling et al., 1992; Yu et al., 1992; Li et al., 1996; Bäyon-Auboyer et al., 2000). The gene start signals for the SH and L genes of MPV were found to be slightly different from this consensus (SH: GGGAUAAAU, L: GAGACAAAU). For APV the gene start signal of L was also found to be different from the consensus: AGGACCAAT (APV-A) (Randhawa et al., 1996) and GGGACCAGT (APV-D) (Bäyon-Auboyer et al., 2000). In contrast to the similar gene start sequences of MPV and APV, the consensus gene end sequence of APV, UAGUUAAU (Randhawa et al., 1996), could not be found in the MPV intergenic sequences. The repeated sequence found in most genes, except the G-L intergenic region, was U AAAAA U/A/C, which could possibly act as gene end signal. However, since we sequenced viral RNA rather than mRNA, definitive gene end signals could not be assigned and thus requires further investigation. The intergenic regions of pneumoviruses vary in size and sequence (Curran et al., 1999; Blumberg et al., 1991; Collins et al., 1983;). The intergenic regions of MPV did not reveal homology with those of APV and RSV and range in size from 10 to 228 nucleotides (FIG. 17B). The intergenic region between the M and F ORFs of MPV contains part of a secondary ORF, which starts in the primary M ORF (see above). The intergenic region between SH and G contains 192 nucleotides, and does not appear to have coding potential based on the presence of numerous stop-codons in all three reading frames. The intergenic region between G and L contains 241 nucleotides, which may include additional ORFs (see above). Interestingly, the start of the L ORF is located in these secondary ORFs. Whereas the L gene of APV does not start in the preceding G ORF, the L ORF of RSV also starts in the preceding M2 gene. At the 3′ and 5′extremities of the genome of paramyxoviruses short extragenic region are referred to as the leader and trailer sequences, and approximately the first 12 nucleotides of the leader and last 12 nucleotides of the trailer are complementary, probably because they each contain basic elements of the viral promoter (Curran et al., 1999; Blumberg et al., 1991; Mink et al., 1986). The 3′leader of MPV and APV are both 41 nucleotides in length, and some homology is seen in the region between nucleotide 16 and 41 of both viruses (18 out of 26 nucleotides) (FIG. 17B). As mentioned before the first 15 nucleotides of the MPV genomic map are based on a primer sequence based on the APV genome. The length of the 5′trailer of MPV (188 nucleotides) resembles the size of the RSV 5′trailer (155 nucleotides), which is considerably longer than that of APV (40 nucleotides). Alignments of the extreme 40 nucleotides of the trailer of MPV and the trailer of APV revealed 21 out of 32 nucleotides homology, apart from the extreme 12 nucleotides which represent primer sequences based on the genomic sequence of APV. Our sequence analyses revealed the absence of NS1 and NS2 genes at the 3′end of the genome and a genomic organisation resembling the organisation of metapneumoviruses (3′-N-P-M-F-M2-SH-G-L5′). The high sequence homology found between MPV and APV genes further emphasises the close relationship between these two viruses. For the N, P, M, F, M2-1 and M2-2 genes of MPV an overall amino acid homology of 79% is found with APV-C. In fact, for these genes APV-C and MPV revealed sequence homologies which are in the same range as sequence homologies found between subgroups of other genera, such as RSV-A and B or APV-A and B. This close relationship between APV-C and MPV is also seen in the phylogenetic analyses which revealed MPV and APV-C always in the same branch, separate from the branch containing APV-A and B. The identical genomic organisation, the sequence homologies and phylogentic analyses are all in favour of the classification of MPV as the first member in the Metapneumovirus genus that is isolatable from mammals. It should be noted that the found sequence variation between different virus isolates of MPV in the N, M, F and L genes revealed the possible existence of different genotypes (van den Hoogen et al., 2001). The close relationship between MPV and APV-C is not reflected in the host range, since APV infects birds in contrast to MPV (van den Hoogen et al., 2001). This difference in host range may be determined by the differences between the SH and G proteins of both viruses that are highly divergent. The SH and G proteins of MPV did not reveal significant aa sequence homology with SH and G proteins of any other virus. Although the amino acid content and hydrophobicity plots are in favour of defining these ORFs as SH and G, experimental data are required to assess their function. Such analyses will also shed light on the role of the additional overlapping ORFs in these SH and G genes. In addition, sequence analyses on the SH and G genes of APV-C might provide more insight in the function of the SH and G proteins of MPV and their relationship with those of APV-C. The noncoding regions of MPV were found to be fairly similar to those of APV. The 3′leader and 5′ trailer sequences of APV and MPV displayed a high degree of homology. Although the lengths of the intergenic regions were not always the same for APV and MPV, the consensus gene start signals of most of the ORFs were found to be identical. In contrast, the gene end signals of APV were not found in the MPV genome. Although we did find a repetitive sequence (U AAAAA U/A/C) in most intergenic regions, sequence analysis of viral mRNAs is required to formally delineate those gene end sequences. It should be noted that sequence information for 15 nucleotides at the extreme 3′end and 12 nucleotides at the extreme 5′end is obtained by using modified rapid amplification of cDNA ends (RACE) procedures. This technique has been proven to be successful by others for related viruses (Randhawa, J. S. et al., Rescue of synthetic minireplicons establishes the absence of the NS1 and NS2 genes from avian pneumovirus. J. Virol, 71, 9849-9854 (1997); Mink, M. A., et al. Nucleotide sequences of the 3′ leader and 5′ trailer regions of human respiratory syncytial virus genomic RNA. Virology 185, 615-24 (1991).) To determine the sequence of the 3′ vRNA leader sequence, a homopolymer A tail is added to purified vRNA using poly-A-polymerase and the leader sequence subsequently amplified by PCR using a poly-T primer and a primer in the N gene. To determine the sequence of the 5′ vRNA trailer sequence, a cDNA copy of the trailer sequence is made using reverse transcriptase and a primer in the L gene, followed by homopolymer dG tailing of the cDNA with terminal transferase. Subsequently, the trailer region is amplified using a poly-C primer and a primer in the L gene. As an alternative strategy, vRNA is ligated to itself or synthetic linkers, after which the leader and trailer regions are amplified using primers in the L and N genes and linker-specific primers. For the 5′ trailer sequence direct dideoxynucleotide sequencing of purified vRNA is also feasible (Randhawa, 1997). Using these approaches, we can analyse the exact sequence of the ends of the hMPV genome. The sequence information provided here is of importance for the generation of diagnostic tests, vaccines and antivirals for MPV and MPV infections. Materials and Methods Sequence analysis Virus isolate 00-1 was propagated to high titers (approximately 10,000 TCID50/ml) on tertiary monkey kidney cells as described previously (van den Hoogen et al., 2001). Viral RNA was isolated from supernatants from infected cells using a High Pure RNA Isolating Kit according to instructions from the manufacturer (Roch Diagnostics, Almere, The Netherlands). Primers were designed based on sequences published previously (van den Hoogen et al., 2001) in addition to sequences published for the leader and trailer of APV/RSV (Randhawa et al., 1997; Mink et al., 1991) and are available upon request. RT-PCR assays were conducted with viral RNA, using a one-tube assay in a total volume of 50 μl with 50 mM Tris pH 8.5, 50 mM NaCl, 4.5 mM MgCl2, 2 mM DTT, 1 μM forward primer, 1M reverse primer, 0.6 mM dNTPs, 20 units RNAsin (Promega, Leiden, The Netherlands), 10 U AMV reverse transcriptase (Promega, Leiden, The Netherlands), and 5 units Taq Polymerase (PE Applied Biosystems, Nieuwerkerk aan de IJssel, The Netherlands). Reverse transcription was conducted at 42° C. for 30 minutes, followed by 8 minutes inactivation at 95° C. The cDNA was amplified during 40 cycles of 95° C., 1 min.; 42° C., 2 min. 72° C., 3 min. with a final extension at 72° C. for 10 minutes. After examination on a 1% agarose gel, the RT-PCR products were purified from the gel using a Qiaquick Gel Extraction kit (Qiagen, Leusden, The Netherlands) and sequenced directly using a Dyenamic ET terminator sequencing kit (Amersham Pharmacia Biotech, Roosendaal, the Netherlands) and an ABI 373 automatic DNA sequencer (PE Applied Biosystem, Nieuwerkerk aan den IJssel, the Netherlands), according to the instructions of the manufacturer. Sequence alignments were made using the clustal software package available in the software package of BioEdit version5.0.6. (http://jwbrown.mbio.ncsu.edu/ Bioedit//bioedit.html; Hall, 1999). Phylogenetic Analysis To construct phylogenetic trees, DNA sequences were aligned using the ClustalW software package and maximum likelihood trees were generated using the DNA-ML software package of the Phylip 3.5 program using 100 bootstraps and 3 jumbles. Bootstrap values were computed for consensus trees created with the consense package (Felsenstein, 1989). The MPV genomic sequence is available from Genbank under accession number AF371337. All other sequences used here are available from Genbank under accession numbers AB046218 (measles virus, all ORFs), NC-001796 human parainfluenza virus type 3, all ORFs), NC-001552 (Sendai virus, all ORFs), X57559 (human parainfluenza virus type 2, all ORFs), NC-002617 (New Castle Disease virus, all ORFs), NC-002728 (Nipah virus, all ORFs), NC-001989 (bRSV, all ORFs), M11486 RSV A, all ORFs except L), NC-001803 (hRSV, L ORF), NC-001781 (hRSV B, all ORFs), D10331 (PVM, N ORF), U09649 (PVM, P ORF), U66893 (PVM, M ORF), U66893 (PVM, SH ORF), D11130 (PVM, G ORF), D11128 (F ORF). The PVM M2 ORF was taken from Ahmadian (1999), AF176590 (APV-C, N ORF), U39295 (APV-A, N ORF), U39296 (APV-B, N ORF), AF262571 (APV-C, M ORF), U37586 (APV-B, M ORF), X58639 (APV-A, M ORF), AF176591 (APV-C, P ORF), AF325443 (APV-B, P ORF), U22110 (APV-A, P ORF), AF187152 (APV-C, F ORF), Y14292 (APV-B, F ORF), D00850 (APV-A, F ORF), AF176592 (APV-C, M2 ORF), AF35650 (APV-B, M2 ORF), X63408 (APV-A, M2 ORF), U65312 (APV-A, L ORF), S40185 (APV-A, SH ORF). TABLE 5 Lengths of the ORFs of MPV and other paramyxoviruses. N1 P M F M2-1 M2-2 SH G L MPV 394 294 254 539 187 71 183 236 2005 APV A 391 278 254 538 186 73 174 391 2004 APV B 391 279 254 538 186 73 —2 414 —2 APV C 394 294 254 537 184 71 —2 —2 —2 APV D —2 —2 —2 —2 —2 —2 —2 389 —2 hRSV A 391 241 256 574 194 90 64 298 2165 hRSV B 391 241 249 574 195 93 65 299 2166 bRSV 391 241 256 569 186 93 81 257 2162 PVM 393 295 257 537 176 77 92 396 —2 others3 418-542 225-709 335-393 539-565 —4 —4 —4 —4 2183-2262 Footnotes: 1length in amino acid residues. 2sequences not available 3others: human parainfluenza virus type 2 and 3, Sendai virus, measles virus, nipah virus, phocine distemper virus, and New Castle Disease virus. 4ORF not present in viral genome TABLE 6 Amino acid sequence identity between the ORFs of MPV and those of other paramyxoviruses1. 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Deduced amino acid sequence of the fusion glycoprotein of turkey rhinotracheitis virus has greater identity with that of human respiratory syncytial virus, a pneumovirus, than that of paramyxoviruses and morbilliviruses. J Gen Virol 72, 75-81. YU, Q., DAVIS, P. J., LI, J., and CAVANAGH, D. (1992). Cloning and sequencing of the matrix protein (M) gene of turkey rhinotracheitis virus reveal a gene order different from that of respiratory syncytial virus. Virology 186, 426-34. ZAMORA, M., and SAMAL, S. K. (1992). Sequence analysis of M2 mRNA of bovine respiratory syncytial virus obtained from an F-M2 dicistronic mRNA suggests structural homology with that of human respiratory syncytial virus. J Gen Virol 73, 737-41. Primers used for RT-PCR detection of known paramyxo-viruses. Primers for hPIV-1 to 4, mumps, measles, Tupaia, Mapuera and Hendra are developed in house and based on allignments of available sequences. Primers for New Castle Disease Virus are taken from Seal, J., J. et al, Clin. Microb., 2624-2630, 1995. Primers for Nipah and general paramyxovirus-PCR are taken from: Chua, K. B., et al; Science, 288 26 may 2000 Virus primers located in protein HPIV-1 fwd 5′-TGTTGTCGAGACTATTCCAA-3′ HN Rev 5′-TGTTG(T/A)ACCAGTTGCAGTCT-3′ HIPV-2 Fwd 5′-TGCTGCTTCTATTGAGAAACGCC-3′ N Rev 5′-GGTGAC/T TC(T/C)AATAGGGCCA-3′ HPIV-3 Fwd 5′-CTCGAGGTTGTCAGGATATAG-3′ HN Rev 5′-CTTTGGGAGTTGAACACAGTT-3′ HPIV-4 Fwd 5′-TTC(A/G)GTTTTAGCTGCTTACG-3′ N Rev 5′-AGGCAAATCTCTGGATAATGC-3′ Mumps Fwd 5′-TCGTAACGTCTCGTGACC-3′ SH Rev 5′-GGAGATCTTTCTAGAGTGAG-3′ NDV Fwd 5′-CCTTGGTGAiTCTATCCIAG-3′ F Rev 5′-CTGCCACTGCTAGTTGiGATAATCC-3′ Tupaia Fwd 5′-GGGCTTCTAAGCGACCCAGATCTTG-3′ N Rev 5′-GAATTTCCTTATGGACAAGCTCTGTGC-3′ Mapuera Fwd 5′-GGAGCAGGAACTCCAAGACCTGGAG-3′ N Rev: 5′-GCTCAACCTCATCACATACTAACCC-3′ Hendra Fwd 5′-GAGATGGGCGGGCAAGTGCGGCAACAG-3′ N Rev 5′-GCCTTTGCAATCAGGATCCAAATTTGGG-3′ Nipah Fwd 5′-CTGCTGCAGTTCAGGAAACATCAG-3′ N Rev 5′-ACCGGATGTGCTCACAGAACTG-3′ HRSV Fwd 5′-TTTGTTATAGGCATATCATTG-3′ F Rev 5′-TTAACCAGCAAAGTGTTA-3′ Measles Fwd 5′-TTAGGGCAAGAGATGGTAAGG-3′ N Rev 5′-TTATAACAATGATGGAGGG-3′ General Paramyxoviridae: Fwd 5′-CATTAAAAAGGGCACAGACGC-3′ P Rev 5′-TGGACATTCTCCGCAGT-3′ Primers for RAP-PCR: ZF1: 5′-CCCACCACCAGAGAGAAA-3′ ZF4: 5′-ACCACCAGAGAGAAACCC-3′ ZF7: 5′-ACCAGAGAGAAACCCACC-3′ ZF10: 5′-AGAGAGAAACCCACCACC-3′ ZF13: 5′-GAGAAACCCACCACCAGA-3′ ZF16: 5′-AAACCCACCACCAGAGAG-3′ CS1: 5′-GGAGGCAAGCGAACGCAA-3′ CS4: 5′-GGCAAGCGAACGCAAGGA-3′ CS7: 5′-AAGCGAACGCAAGGAGGC-3′ CS10: 5′-CGAACGCAAGGAGGCAAG-3′ CS13: 5′-ACGCAAGGAGGCAAGCGA-3′ CS16: 5′-GAAGGAGGCAAGCGAACG-3′ 20 fragments successfully purified and sequenced: 10 fragments found with sequence homology in APV Fragment 1 ZF 7, 335 bp N gene Fragment 2 ZF 10, 235 bp N gene Fragment 3 ZF 10, 800 bp M gene Fragment 4 CS 1, 1250 bp F gene Fragment 5 CS 10, 400 bp F gene Fragment 6 CS 13, 1450 bp F gene Fragment 7 CS 13, 750 bp F gene Fragment 8 ZF 4, 780 bp L gene (protein level) Fragment 9 ZF 10, 330 bp L gene (protein level) Fragment 10 ZE 10, 250 bp L gene (protein level) Primers used for RAP-PCR amplification of nucleic acids from the prototype isolate. EXAMPLE 5 Further Exploration of the Two Subtypes of hMPV Based on phylogenetic analysis of the different isolates of hMPV obtained so far, two genotypes have been identified with virus isolate 00-1 being the prototype of genotype A and isolate 99-1 the prototype of genotype B. We hypothesise that the genotypes are related to subtypes and that re-infection with viruses from both subgroups occur in the presence of pre-existing immunity and the antigenic variation may not be strictly required to allow re-infection. Furthermore, hMPV appears to be closely related to avian pneumovirus, a virus primarily found in poultry. The nucleotide sequences of both viruses show high percentages of homology, with the exception of the SH and G proteins. Here we show that the viruses are cross-reacting in tests, which are based primarily on the nucleoprotein and matrixprotein, but they respond differently in tests, which are based on the attachment proteins. The differences in virus neutralisation titers provide further proof that the two genotypes of hMPV are two different serotypes of one virus, where APV is a different virus. The Cross Reaction Between the Two Serotypes and the Cross Reaction Between APV an hMPV Methods Protocol for IgG, IgA and IgM antibody detection for hMPV: The indirect IgG EIA for hMPV was performed in microtitre plates essentially as described previously (Rothbarth, P. H. et al., 1999; Influenza virus serology-a comparative study. J. of Vir. Methods 78 (1999) 163-169. Briefly, concentrated hMPV was solubilized by treatment with 1% Triton X-100 an coated for 16 hr at room temperature into ,microtitre plates in PBS after determination of the optimal working dilution by checkerboard titration. Subsequently, 100 ul volumes of 1:100 diluted human serum samples in EIA buffer were added to the wells and incubated for 1 h at 37C. Binding of human IgG was detected by adding a goat anti-human IgG peroxidase conjugate (Biosource, USA). Adding TMB as substrate developed plates and OD was measured at 450 nm. the results were expressed as the S(ignal)/N(egative) ratio of the OD. A serum was considered positive for IgG, if the SIN ratio was beyond the negative control plus three times the standard. hMPV antibodies of the IgM and IgA classes were detected in sera by capture EIA essentially as described previously (Rothbarth, P. H et al. 1999; Influenza virus serolgy-a comparative study. J. Vir. methods 78 (1999) 163-169. For the detection of IgA and IgM commercially available microtiter plates coated with anti human IgM or IgA specific monoclonal antibodies were used. Sera were diluted 1:100 and after incubation of 1 hr at 37C., an optimal working dilution of hMPV is added at each well (100 ul). Incubated 1 hr 37C.. After washing polyclonal anti hMPV labeled with peroxidase was added, the plate was incubated 1 hr 37C. Adding TMB as substrate developed plates and OD was measured at 450 nm. the results were expressed as the S(ignal)/N(egative) ratio of the OD. A serum was considered positive for IgG, if the S/N ratio was beyond the negative control plus three times the standard. AVP antibodies were detected in an AVP inhibition assay. Protocol for APV inhibition test is included the APV-Ab SVANOVIR® enzyme immunoassay which is manufactured by SVANOVA Biotech AB, Uppsal Science Park Glunten SE-751 83 Uppsala Sweden. The results were expressed as the S(ignal)/N(egative) ratio of the OD. A serum was considered positive for IgG, if the S/N ratio was beyond the negative control plus three times the standard. 1. Guinea Pigs A. (re) Infection of Guinea Digs with Both Subtypes of hMPV Virus isolates ned/00/01 (subtype A) and ned/99/01 (subtype B) have been used to inoculate 6 guinea pigs per subtype (intratracheal, nose and eyes). 6 GP's infected with hMPV 00-1 (10e6,5 TCID50) 6 GPs infected with hMPV 99-1 (10e4,1 TCID50) 54 Days after the primary infection, the guinea pigs have been inoculated with the homologous and heterologous subtypes (10e4 TCID50/ml): 2 guinea pigs: 1st infection 00-1; 2nd 99-1 (heterologous) 3 guinea pigs: 1st infection 00-1; 2nd 00-1 (homologous) 2 guinea pigs: 1st infection 99-1; 2nd 00-1 (heterologous) 3 guinea pigs: 1st infection 99-1; 2nd 99-1 homologous) Throat and nose swabs have been collected for 12 days (1st infection) or 8 days (2nd infection) post infection, and have been tested for presence of the virus by RT-PCR assays. Results of RT-PCR Assay: FIG. 29 Summary of results: guinea pigs inoculated with virus isolate ned/00/01 show infection of the upper respiratory tract day 1 to 10 post infection. Guinea pigs inoculated with ned/99/01 show infection of the upper respiratory tract day 1 to 5 post infection. Infection with ned/99/01 appears to be less severe than infection with ned/00/01. A second inoculation of the guinea pigs with the heterologous virus results in re-infection in 3 out of 4 guinea pigs and with the homologous virus in 2 out of 6 guinea pigs. No or only little clinical symptoms were noted in those animals that became re-infected, and no clinical symptoms were seen in those animals that were protected against the re-infections, demonstrating that even with wild-type virus, a protective effect of the first infection is evident, showing the possible use of heterologous (and of course homologues) isolates as a vaccine, even in an unattenuated form. Both subtypes of hMPV are able to infect guinea pigs, although infection with subtype B (ned/99/01) seems less severe (shorter period of presence of the virus in nose and throat) than infection with subtype A (ned/00/01). This may be due to the higher dose given for subtype A, or to the lower virulence of subtype B. Although the presence of pre-existing immunity does not completely protect against re-infection with both the homologous and heterologous virus, the infection appears to be less prominent in that a shorter period of presence of virus was noted and not all animals became virus positive. B. Serology of Guinea Pigs Infected with Both Subtypes of hMPV At day 0, 52, 70, 80, 90, 110, 126 and 160 sera were collected from the guinea pigs and tested at a 1:100 dilution in a whole virus ELISA against ned/00/01 and ned/99/01 antigen. FIGS. 30A and B: IgG response against ned/00/01 and ned/99/01 for each individual guinea pig FIG. 31: Specificity of the ned/00/01 and ned/99/01 ELISA Only data from homologous reinfected guinea pigs have been used. FIG. 32: Mean IgG response against ned/00/01 and ned/99/01 ELISA of 3 homologous (00-1100-1), 2 homologous (99-1/99-1), 2 heterologous (99-1100-1) and 2 heterologous (00-1/99-1) infected guinea pigs. Summary of Results: Only a minor difference in response to the two different ELISA's is observed. Whole virus ELISA against 00-1 or 99-1 cannot be used to discriminate between the two subtypes. C. Reactivity of Sera Raised Against hMPV in Guinea Pigs with APV Antigen Sera collected from the infected guinea pigs have been tested with an APV inhibition ELISA FIG. 33: Mean percentage of APV inhibition of hMPV infected guinea pigs. Summary of Results: Sera raised against hMPV in guinea pigs, react in the APV inhibition test in a same manner as they react in the hMPV IgG ELISA's. Sera raised against ned/99/01 reveal a lower percentage of inhibition in the APV inhibition ELISA than sera raised against ned/00/01. Guinea pigs infected with ned/99/01 might have a lower titer (as is seen in the hMPV ELISA's) or the cross-reaction of ned/99/01 with APV is less than that of ned/00/01. Nevertheless, the APV-Ab inhibition ELISA can be used to detect hMPV antibodies in guinea pigs. {D. Virus Neutralisation Assays with Sera Raised Against hMPV in Guinea Pigs. Sera collected at day 0, day 52, 70 and 80 post infection were used in a virus (cross) neutralisation assay with ned/00/01, ned/99/01 and APV-C. Starting dilution was 1 to 10 and 100 TCID50 virus per well was used. After neutralisation, the virus was brought on tMK cells, 15 min. centrifuged at 3500 RPM, after which the media was refreshed. The APV tests were grown for 4 days and the hMPV tests were grown for 7 days. Cells were fixed with 80% aceton, and IFA's were conducted with monkey-anti hMPV fitc labeled. Wells that were negative in the staining were considered as the neutralising titer. For each virus a 10-log titration of the virus stock and 2 fold titration of the working solution was included. FIG. 34: Virus neutralisation titers of ned/00/01 and ned/99/01 infected guinea pigs against ned/00/01, ned/99/01 and APV-C. 2. Cynomologous Macaques A. (Re) Infection of Cynomologous Macagues with Both Subtypes of hMPV Virus isolates ned/00/01 (subtype A) and ned/99/01 (subtype B) (1e5 TCID50) have been used to inoculate 2 cynomologous macaques per subtype (intratracheal, nose and eyes). Six months after the primary infection, the macaque have been inoculated for the second time with ned/00/01. Throat swabs have been collected for 14 days (1st infection) or 8 days (2nd infection) post infection, and have been tested for presence of the virus by RT-PCR assays. FIG. 36: Results of RT-PCR assays on throat swabs of cynomolgous macaques inoculated (twice) with ned/00/01. Summary of Results: Summary of results: cynomologous macaques inoculated with virus isolate ned/00/01 show infection of the upper respiratory tract day 1 to 10 post infection. Clinical symptoms included a suppurative rhinitis. A second inoculation of the macaques with the homologous virus results in re-infection, as demonstrated by PCR, however, no clinical symptoms were seen. B. Serology on Sera Collected of hMPV Infected Cynomologous Macaques. From the macaques which received ned/00/01 sera were collected during 6 months after the primary infection (re-infcetion occurred at day 240 for monkey 3 and day 239 for monkey 6). Sera were used to test for the presence of IgG antibodies against either ned/00/01 or APV, and for the presence against IgA and IgM antibodies against ned/00/01. Results: FIG. 36A IgA, IgM and IgG response against ned/00/01 of 2 cynomologous macaques (re)infected with ned/00/01. FIG. 36B IgG response against APV of 2 cynbomologous macaques infected with ned/00101. Summary of Results: Two macaques have been succesfully infected with ned/00101 and in the presence of antibodies against ned/00/01 been reinfected with the homologous virus. The response to IgA and IgM antibodies shows the raise in IgM antibodies after the first infection, and the absence of it after the reinfection. IgA antibodies are only detected after the re-infection, showing the immediacy of the immune response after a first infection. Sera raised against hMPV in macaques which were tested in an APV inhibition ELISA show a similar response as to the hMPV IgG ELISA. Discussion/Conclusion hMPV antibodies in cynomologous macaques are detected with the APV inhibition ELISA with a similar sensitivity as with an hMPV ELISA, and therefore the APV inhibition EIA is suitable for testing human samples for the presence of hMPV antibodies. C. Virus (Cross) Neutralisation Assays with Sera Collected from hMPV Infected Cynomologous Macaques Summary of results: The sera taken from day 0 to day 229 post primary infection show only low virus neutralisation titers against ned/00/01 (0-80), the sera taken after the secondary infection show high neutralisation titers against ned/00/01:>1280. Only sera taken after the secondary infection show neutralisation titers against ned/99/01 (80-640), and none of the sera neutralise the APV C virus. There is no cross reaction between APV-C and hMPV in virus (cross)neutralisation assays, where there is a cross reaction between ned/00/01 and ned/99/01 after a boost of the antibody response. 3. Humans Sera of patients ranging in age of<6 months to>20 years of age have previously been tested in IFA and virus neutralisation assays against ned/00/01. (See tabel 1 of patent). Here we have tested a number of these sera for the presence of IgG, IgM and IgA antibodies in an ELISA against ned/00/01, and we tested the samples in the APV inhibition ELISA. Results: FIG. 37 Comparison of the use of the hMPV ELISA and the APV inhibition ELISA for the detection of IgG antibodies in human sera, there is a strong correlation between the IgG hMPV test and the APV-Ab test, therefore the APV-Ab test is essentially able to detect IgG antibodies to hmPV in humans. 4. Poultry 96 chickens have been tested in both the APV inhibition ELISA and the ned/00/01 ELISA for the presence of IgG antibodies against APV. Summary of results: Both the hMPV ELISA and the APV inhibition ELISA detect antibodies against APV (data not shown). Summary of Results. We found two genotypes of hMPV with ned/00/01 being the prototype of subgroup A and ned/99/01 the prototype of subgroup B. “According to classical serogical analyses (as for example known Francki, R. I. B., Fauquet, C. M., Knudson, D. L., and Brown, F., Classification and nomenclature of viruses. Fifth report of the international Committee on Taxonomy of Viruses. Arch Virol, 1991. Supplement 2: p. 140-144), two subtypes can be defined on the basis of its immunological distinctiveness, as determined by quantitative neutralization assays with animal antisera. Two distinct serotypes have either no cross-reaction with each other or show a homologous-to heterologous titer ratio>16 in both directions. If neutralization shows a certain degree of cross-reaction between two viruses in either or both directions (homologous-to-heterologous titer ration of eight or 16), distinctiveness of serotype is assumed if substantial biophysical/biochemical differences of DNA's exist. If neutralization shows a distinct degree of cross-reaction between two viruses in either or both directions (homologous-to-heterologous titer ration of smaller than eight), identity of serotype of the isolates under study is assumed.” For RSV it is known that re-infection occurs in the presence of pre-existing immunity (both homologous and heterologous). Infection of guinea pigs and cynomologous macaques with both the homologous and heterologous serotypes of hMPV revealed that this is also true for hMPV. In addition, IgA and IgM ELISA's against hMPV revealed the reaction of IgA antibodies only occurs after re-infection. Sera raised against hMPV or APV respond in an equal way in APV and hMPV ELISAs. From the nucleotide sequence comparisons, it is known that the viruses show about 80% amino acid homology for the N, P, M, and F genes. In ELISA's the N and M proteins are the main antigens to react. Virus neutralisation assays (known to react against the surface glycoproteins G, SH and F) show a difference between the two different sera. Although APV en hMPV cross react in ELISAs, phylogenetic analyses of the nucleotide sequences of hMPV and APV, the differences in virus neutralisation titers of sera raised against the two different viruses, and the differences in host usage again reveal that APV-C and hMPV are two different viruses. Based on the results we speculate that hMPV infection in mammals is possible a result of a zoonotic event from birds to mammals. But the virus has adapted in such a way (i.e. the G and SH proteins) that a return (from mammals to birds) zoonotic event seems unlikely, considering the presence of AVP in birds. Addendum Background Information on Pneumovirinae The family of Paramyxoviridae contains two subfamilys: the Paramyxovirinae and the Pneumovirinae. The subfamily Pneumovirinae consists of two genera: Pneumovirus and Metapneumovirus. The genus Pneumovirus contains the human, bovine, ovine and caprine respiratory syncytial viruses and the pneumonia virus of mice (PVM). The genus Metapneumovirus contains the avian pneumoviruses (APV, also referred to as TRTV). The classification of the genera in the subfamily Pneumovirinae is based on classical virus characteristics, gene order and gene constellation. Viruses of the genus Pneumovirus are unique in the family of Paramyxoviridae in having two nonstructural proteins at the 3′end of the genome (3′-NS1-NS2-N-P-M-SH-G-F-M2-L-5′). In contrast, viruses in the genus Metapneumovirus lack the NS1 and NS2 genes and the organisation of genes between the M and L coding regions is different: 3′-N-P-M-F-M2-SH-G-L-5′. All members of the subfamily Paramyxovirinae have haemagluttinating activity, but this function is not a defining feature for the subfamily Pneumovirinae, being absent in RSV and APV but present in PMV. Neuraminidase activity is present in members of the genera Paramyxovirus and Rubulavirus (subfamily Paramyxovirinae) but is absent in the genus Morbillivirus (subfamily Paramyxovirinae) and the genera Pneumovirus and Metapneumovirus (subfamily Pneumovirinae). A second distinguishing feature of the subfamily Pneumovirinae is the apparent limited utilization of alternative ORFs within mRNA by RSV. In contrast, several members of the subfamily Paramyxovirinae, such as Sendai and Measles viruses, access alternative ORFs within the mRNA encoding the phosphoprotein (P) to direct the synthesis of a novel protein. The G protein of the Pneumovirinae does not have sequence relatedness or structural similarity to the HN or H proteins of Paramyxovirinae and is only approximately half the size of their chain length. In addition, the N and P proteins are smaller than their counterparts in the Paramyxovirinae and lack unambigous sequence homology. Most nonsegmented negative stranded RNA viruses have a single matrix (M) protein. Members of the subfamily Pneumovirinae are an exception in having two such proteins, M and M2. The M protein is smaller than its Paramyxovirinae counterparts and lacks sequence relatedness with Paramyxovirinae. When grown in cell cultures, members of the subfamily Pneumovirinae show typical cytopathic effects; they induce characteristic syncytia formation of cells. (Collins, 1996). The subfamily Pneumovirinae, genus Pneumovirus hRSV is the type-species of the genus Pneumovirus and is a major and widespread cause of lower respiratory tract illness during infancy and early childhood (Selwyn, 1990). In addition, hRSV is increasingly recognised as an important pathogen in other patient groups, including immune compromised individuals and the elderly. RSV is also an important cause of community-acquired pneumonia among hospitalised adults of all ages (Englund, 1991; Falsey, 2000; Dowell, 1996). Two major antigenic types for RSV (A and B) have been identified based on differences in their reactivity with monoclonal and polyclonal antibodies and by nucleic acid sequence analyses (Anderson, 1985; Johnson, 1987; Sullender, 2000). In particular the G protein is used in distinguishing the two subtypes. RSV-A and B share only 53% amino acid sequence homology in G, whereas the other proteins show higher homologies between the subtypes (table 1) (Collins, 1996). Detection of RSV infections has been described using monoclonal and polyclonal antibodies in immunofluorescence techniques (DIF, IFA), virus neutralisation assays and ELISA or RT-PCR assays (Rothbarth, 1988; Van Milaan, 1994; Coggins, 1998). Closely related to hRSV are the bovine (bRSV), ovine (oRSV) and caprine RSV (oRSV), from which bRSV has been studied most extensively. Based on sequence homology with hRSV, the ruminant RSVs are classified within the Pneumovirus genus, subfamily Pneumovirinae (Collins, 1996). Diagnosis of ruminant RSV infection and subtyping is based on the combined use of serology, antigen detection, virus isolation and RT-PCR assays (Uttenthal, 1996; Valarcher, 1999; Oberst, 1993; Vilcek, 1994). Several analyses on the molecular organisation of bRSV have been performed using human and bovine antisera, monoclonal antibodies and cDNA probes. These analyses revealed that the protein composition of hRSV and bRSV are very similar and the genomic organisation of bRSV resembles that of hRSV. For both bRSV and hRSV, the G and F proteins represent the major neutralisation and protective antigens. The G protein is highly variable between the hRSV subtypes and between hRSV and bRSV (53 and 28% respectively) (Prozzi, 1997; Lerch, 1990). The F proteins of hRSV and bRSV strains present comparable structural characteristics and antigenic relatedness. The F protein of bRSV shows 80-81% homology with hRSV, while the two hRSV subtypes share 90% homology in F (Walravens, K. 1990). Studies based on the use of hRSV and bRSV specific monoclonal antibodies have suggested the existence of different antigenic subtypes of bRSV. Subtypes A, B, and AB are distinguished based on reaction patterns of monoclonal antibodies specific for the G protein (Furze, 1994; Prozzi, 1997; Elvander, 1998). The epidemiology of bRSV is very similar to that of hRSV. Spontaneous infection in young cattle is frequently associated with severe respiratory signs, whereas experimental infection generally results in milder disease with slight pathologic changes Elvander, 1996). RSV has also been isolated from naturally infected sheep (oRSV) (LeaMaster, 1983) and goats (cRSV) (Lehmkuhl, 1980). Both strains share 96% nucleotide sequence with the bovine RSV and are antigenically crossreacting. Therefore, these viruses are also classified within the Pneumovirus genus. A distinct member of the subfamily Pneumovirinae, genus Pneumovirus is the Pneumonia virus of mice (PVM). PVM is a common pathogen in laboratory animal colonies, particularly those containing atymic mice. The naturally acquired infection is thought to be asymptomatic, though passage of virus in mouse lungs resulted in overt signs of disease ranging from an upper respiratory tract infection to a fatal pneumonia (Richter, 1988; Weir, 1988). Restricted serological crossreactivity between the nucleocapsid protein (N) and the phosphoprotein (P) of PVM and hRSV has been described but none of the external proteins show cross-reactivity, and the viruses can be distinguished from each other in virus neutralisation assays (Chambers, 1990a; Gimenez, 1984; Ling, 1989a). The glycoproteins of PVM appear to differ from those of other paramyxoviruses and resemble those of RSV in terms of their pattern of glycosylation. They differ, however, in terms of processing. Unlike RSV, but similar to the other paramyxoviruses, PVM has haemagglutinating activity with murine erythrocytes, for which the G protein appears to be responsible since a monoclonal antibody to this protein inhibits haemagglutination (Ling, 1989b). The genome of PVM resembles that of hRSV, including two nonstructural proteins at its 3′end and a similar genomic organisation (Chambers, 1990a; Chambers, 1990b). The nucleotide sequences of the PVM NS1/NS2 genes are not detectably homologous with those of hRSV (Chambers, 1991). Some proteins of PVM show strong homology with hRSV (N: 60%, and F: 38 to 40%) while G is distinctly different (the amino acid sequence is 31% longer) (Barr, 1991; Barr, 1994; Chambers, 1992). The PVM P gene, but not that of RSV or APV, has been reported to encode a second ORF, representing a unique PVM protein (Collins, 1996). New PVM isolates are identified by virus isolation, heamagglutination assays, virus neutralisation assay and various immuno-fluorescence techniques. Table with addedum: Amino acid homology between the different viruses within the within the genus Pneumovirus of the subfamilyPneumovirinae. oRSV v. bRSV v. bRSV v. PVM vs. Gene hRSV's bRSV's hRSV hRSV oRSV hRSV NS1 87 68-69 89 * NS2 92 83-84 87 * N 96 93 60 P — 81 M — 89 F 89 80-81 38-40 G 53 88-100 21-29 38-41 60-62 * M2 92 94 41 SH 76 45-50 56 L — * No detectable sequence homology The Genus Metapneumovirus Avian pneumoviruses (APV) has been identified as the aetiological agent of turkey rhinotracheitis (McDougall, 1986; Collins, 1988) and is therefore often referred to as turkey rhinotracheitis virus (TRTV). The disease is an upper respiratory tract infection of turkeys, resulting in high morbidity and variable, but often high, mortality. In turkey hens, the virus can also induce substantial reductions in egg production. The same virus can also infect chickens, but in this species, the role of the virus as a primary pathogen is less clearly defined, although it is commonly associated with swollen head syndrome (SHS) in breeder chicken (Cook, 2000). The virions are pleiomorphic, though mainly spherical, with sizes ranging from 70 to 600 nm and the nucleocapsid, containing the linear, non-segmented, negative-sense RNA genome, shows helical symmetry (Collins, 1986; Giraud, 1986). This morphology resembles that of members of the family Paramyxoviridae. Analyses of the APV-encoded proteins and RNAs suggested that of the two subfamilys of this family (Paramyxovirinae and Pneumovirinae), APV most closely resembled the Pneumovirinae (Collins, 1988; Ling, 1988; Cavanagh, 1988). APV has no non-structural proteins (NS1 and NS2) and the gene order (3′-N—P-M-F-M2-SH-G-L-5′) is different from that of mammalian pneumoviruses such as RSV. APV has therefore recently been classified as the type species for the new genus Metapneumovirus (Pringle, 1999). Differences in neutralisation patterns, ELISA and reactivity with monoclonal antibodies have revealed the existence of different antigenic types of APV. Nucleotide sequencing of the G gene led to the definition of two virus subtypes (A and B), which share only 38% amino acid homology (Collins, 1993; Juhasz, 1994). An APV isolated from Colorado, USA (Cook, 1999), was shown to cross-neutralize poorly with subtype A and B viruses and based on sequence information was designated to a novel subtype, C (Seal, 1998; Seal 2000). Two non-A/non-B APVs were isolated in France, and were shown to be antigenically distinct from subtypes A, B and C. Based on amino acid sequences of the F, L and G genes, these viruses were classified again as a novel subtype, D (Bayon-Auboyer, 2000). Diagnosis of APV infection can be achieved by virus isolation in chicken or turkey tracheal organ cultures (TOCs) or in Vero cell cultures. A cytopathic effect (CPE) is generally observed after one or two additional passages. This CPE is characterised by scattered focal areas of cell rounding leading to synctyial formation (Buys, 1989). A number of serology assays, including IF and virus neutralisation assays have been developed. Detection of antibodies to APV by ELISA is the most commonly used method (O'Loan, 1989; Gulati, 2000). Recently, the polymerase chain reaction (PCR) has been used to diagnose APV infections. Swabs taken from the oesophagus can be used as the starting material (Bayon-Auboyer, 1999; Shin, 2000) Alansari, H. and Potgieter, L. N. D. 1994. Nucleotide and predicted amino acid sequence analysis of the ovine respiratory syncytial virus non-structural 1C and 1B genes and the small hydrophobic protein gene. J. Gen. Virol. 75: 401-404. Alansari, H., Duncan R. B., Baker, J. C. and Potgieter, L. N. 1999. Analysis of ruminant respiratory syncytial virus isolates by RNAse protection of the G glycoprotein transcripts. J. Vet. Diagn. Invest. 11: 215-20 Anderson, L. J, Hierholzer, J. C., Tsou, C., Hendry, R. M., Fernic, B. F., Stone, Y. and McIntosh, K 1985. Antigenic characterisation of respiratory syncytial virus strains with monoclonal antibodies. J. Inf. Dis. 151: 626-633. Barr, J., Chambers, Pringle, C. R., Easton, A. J. 1991. Sequence of the major nucleocapsid protein gene of pneumonia virus of mice: sequence comparisons suggest structural homology between nucleocapsid proteins of pneumoviruses, paramyxoviruses, rhabdoviruses and filoviruses. J. Gen. Virol. 72: 677-685. Barr, J., Chambers, P., Harriott, P., Pringle, C. R. and Easton, A. J. 1994. Sequence of the phosphoprotein gene of pneumonia virus of mice: expression of multiple proteins from two overlapping rading frames. J. Virol. 68: 5330-5334. Bayon-Auboyer, M. H., Jestin, V., Toquin, D., Cherbonnel, M. and Eterradosi, N. 1999. Comparison of F-, G- and N-based RT-PCR protocols with conventional virological procedures for the detection and typing of turkey rhinotracheitis virus. Arch. Vir. 144: 1091-1109. Bayon-Auboyer, M. H., Arnauld, C., Toquin, D., and Eterradossi, N. 2000. Nucleotide sequences of the F, L and G protein genes of two non-A/non-B avian pneumoviruses (APV) reveal a novel APV subgroup. J. Gen. Virol. 81: 2723-2733. Buys, S. B., Du Preez, J. H. and Els, H. J. 1989. The isolation and attenuation of a virus causing rhinotracheitis in turkeys in South Africa. Onderstepoort J. Vet. Res. 56: 87-98. Cavanagh, D. and Barrett, T. 1988. Pneumovirus-like characteristics of the mRNA and proteins of turkey rhinotracheitis virus. Virus Res. 11: 241-256. Chambers, P., Pringle, C. R. and Easton, A. J. 1990a. Molecular cloning of pneumonia virus of mice. J. Virol. 64: 1869-1872. Chambers, P., Matthews, D. A, Pringle, C. R. and Easton, A. J. 1990b. The nucleotide sequences of intergenic regions between nine genes of pneumonia virus of mice establish the physical order of these genes in the viral genome. Virus Res. 18: 263-270. Chambers, P., Pringle, C. R., and Easton, A. J. 1991. Genes 1 and 2 of pneumonia virus of mice encode proteins which have little homology with the IC and 1B proteins of human respiratory syncytial virus. J. Gen. Vir. 72: 2545-2549. Chambers, P. Pringle CR, Easton A J. 1992. Sequence analysis of the gene encding the fusion glycoprotein of pneumonia virus of mice suggests possible conserved secondary structure elements in pramyxovirus fusion glycoproteins. J. Gen. Virol. 73: 1717-1724. Coggins, W. B., Lefkowitz, E. J. and Sullender, W. M. 1998. Genetic variability among group A and group B respiratory syncytial viruses in a children's hospital. J. Clin. Microbiol. 36: 3552-3557. Collins, M. S. and Gough, R. E., Lister, SA., Chettle, N. and Eddy, R. 1986. Further characterisation of a virus associated with turkey rhiotracheitis. Vet. Rec. 119: 606. Collins, M. S. and Gough, R. E. 1988. Characterisation of a virus associated with turkey rhinotracheitis. J. Gen. Virol. 69: 909-916. Collins, M. S., Gough, R. E., and Alexander, D. J. 1993. Antigenic differentiation of avian pneumovirus isolates using polyclonal antisera and mouse monoclonal antibodies. Avian Pathology 22: 469-479. Collins, P. L., McIntosh, K., Chanock, R. M. 1996. Respiratory syncytial virus. P. 1313-1351. In: B. N. Fields, D. M. Knipe, and P. M. Howley (ed.). Fields virology, 3rd ed., vol. 1 Lippincott-Raven, Philadelphia, Pa., USA Cook, J. K. A., Huggins, M. B., Orbell, S. J. and Senne, D. A. 1999. Preliminary antigenic characterization of an avian pneumovirus isolated from commercial turkeys in Colorado, USA. Avian pathol. 28: 607-617. Cook, J. K. A. 2000. Avian rhinotracheitis. Rev. Sci. tech. off int. Epiz. 19: 602-613. Dowell, S. F., Anderson, L. J., Gary, H. E., Erdman, D. D., Plouffe, J. F., File, T. M., Marston, B. J. and Breiman, R. F. 1996. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J. Infect. Dis. 174: 456-462. Elvander, M. 1996. Severe respiratory disease in dairy cows caused by infection with bovine respiratory syncytial virus. Vet. Rec. 138: 101-105. Elvander, M., Vilcek, S., Baule, C., Uttenthal, A., Ballagi-Pordany, A. and Belak, S. 1998. Genetic and antigenic analysis of the G attachment protein of bovine respiratory syncytial virus strains. J. Gen. Virol. 79: 2939-2946. Englund, JA., Anderson, L. J., and Rhame, F. S. 1991. Nosocomial transmission of respiratory syncytial virus in immunocompromised adults. J. Clin. Microbiol. 29: 115-119. Falsey, A. R. and Walsh, E. E. 2000. Respiratory syncytial virus infection in adults. Clin. Microb. Rev. 13: 371-84. Furze, J., Wertz, G., Lerch, R. and Taylor, G. 1994. Antigenic heterogeneity of the attachment protein of bovine respiratory syncytial virus. J. Gen. Virol. 75: 363-370. Gimenez, H. B., Cash, P. and Melvin, W. T. 1984. Monoclonal antibodies to human respiratory syncytial virus and their use in comparison of different virus isolates. J. Gen. Virol. 65: 963-971. Gulati, B. R., Cameron, K. T., Seal, B. S, Goyal, S. M., Halvorson, D. A. and Njenga, M. K 2000. Development of a highly sensitive and specific enzyme-linked immunosorbent assay based on recombinant matrix protein for detection of avian pneumovirus antibodies. J. Clin. Microbiol. 38: 4010-4. Johnson, P. R., Spriggs M. K, Olmsted, R. A. and Collins, P. L. 1987. The G glycoprotein of human respiratory syncytial virus subgroups A and B: extensive sequence divergence between antigenically related proteins. Proc. Natl. Acad. Sd. USA 84: 5625-5629. Juhasz, K. and Easton, A. J. 1994. Extensive sequence variation in the attachment (G) protein gene of avian pneumovirus: evidence for two distinct subgroups. J. Gen. Virol. 75: 2873-2880. LeaMaster, B. R., Evermann, J. F., Mueller, M. K., Prieur, M. K and Schlie, J. V. 1983. Serologic studies on naturally occurring respiratory syncytial virus and Haemophilus sommus infections in sheep. American Association of Veterinary Laboratory Diagnosticians 26: 265-276. Lehmkuhl, H. D., Smith, M. H., Cutlip, R. C. 1980. Morphogenesis and structure of caprine respiratory syncytial virus. Arch. Vir. 65: 269-76. Lerch, R. A., Anderson, K and Wertz, G. W. 1990. Nucleotide sequence analysis and expression from recombinant vectors demonstrate that the attachment protein G of bovine respiratory syncytial virus is distinct from that of human respiratory syncytial virus. J. Virol. 64: 5559-5569. Ling, R. and Pringle, C. R. 1988. Turkey rhinotracheitis virus: in vivo and in vitro polypeptide synthesis. J. Gen. Virol. 69: 917-923. Ling, R. and Pringle, C. R. 1989a. Polypeptides of pneumonia virus of mice. I. Immunological cross-reactions and post-translational modifications. J. Gen. Virol. 70: 1427-1440. Ling, R. and Pringle, C. R. 1989b. Polypeptides of pneumonia virus of mice. II. Characterization of the glycoproteins. J. Gen. Virol. 70: 1441-1452. McDougall, J. S. and Cook, J. K. A 1986. Turkey rhinotracheitis: preliminary investigations. Vet. Rec. 118: 206-207. Oberst, R. D., M. P. Hays, K. J. Hennessy, L. C. Stine, J. F. Evermann, and Kelling, C. L. 1993. Characteristic differences in reverse transcription polymerase chain reaction products of ovine, bovine and human respiratory syncytial viruses. J. Vet. Diagn. Investig. 5: 322-328. O'Loan, C. J., Allan, G., Baxter-Jones, C. and McNulty, M. S. 1989. An improved ELISA and serum neutralisation test for the detection of turkey rhinotracheitis virus antibodies. J. Virol. Meth. 25: 271-282. Paccaud, M. F. and Jacquier, C., 1970. A respiratory syncytial virus of bovine origin. Arch. Ges. Virusforsch. 30: 327-342. Pringle, C. R. 1999 Virus taxonomy at the Xith international congress of virology, Sydney, Australia 1999. Arch. Virol. 14412: 2065-2070. Prozzi, D., Walravens, K, Langedijk, J. P. M, Daus, F., Kramps, JA and Letesson, J. J. 1997. Antigenic and molecular analysis of the variability of bovine respiratory syncytial virus G glycoprotein. J. Gen. Virol. 78: 359-366. Randhawa, j. S., Marriott, AC., Pringle, C. R., and A. J. Easton 1997. Rescue of synthetic minireplicons establish the absence of the NS1 and NS2 genes from avian pneumoviruses. J. Virol. 71: 9849-9854. Richter, C. B., Thigpen, J. E., Richter, C. S. and Mackenzie, J. M. 1988. Fatal pneumonia with terminal emaciation in nude mice caused by pneumonia vrius of mice. Lab. Anim. Sci. 38: 255-261. Rothbarth, P. H., Habova, J. J. and Masurel, N. 1988. Rapid diagnosis of infections caused by respiratory syncytial virus. Infection 16:252. Seal, B. S. 1998. Matrix protein gene nucleotide and predicted amino acid sequence demonstrate that the first US avian pneumovirus isolate is distinct form European strans. Virus Res. 58, 45-52. Seal, B. S., Sellers, H. S., Meinersmann, R. J. 2000. Fusion protein predicted amino acid sequence of the first US avian pneumovirus isolate and lack of heterogeneity among other US isolates. Virus Res. 66: 139-147. Selwyn, B. J. 1990. The epidemiology of acute respiratory tract infection in young children: comparison findings from several developing countries. Rev. Infect. Dis. 12: S870-S888. Shin, H. J., Rajashekara, G., Jirjis, F. F., Shaw, D. P., Goyal, S. M., Halvorson, D. A. and Nagaraja, K. V 2000. Specific detection of avian pneumovirus (APV) US isolates by RT-PCR. Arch. Virol. 145: 1239-1246. Sullender, W. M. 2000. Respiratory syncytial virus genetic and antigenic diversity. Clin. Microb. Rev. 13: 1-15. Trudel, M., Nadon, F., Sinnard, C., Belanger, F., Alain, R., Seguin, C. and Lussier, G. 1989. Comparison of caprine, human and bovine strains of respiratory syncytial virus. Arch. Vir. 107: 141-149. Uttenthal, A., Jensen, N. P. B. and Blom, J. Y. 1996. Viral aetiology of enzootic pneumonia in Danish dairy herds, diagnostic tools and epidemiology. Vet. Rec. 139, 114-117. Valarcher, J., Bourhy, H., Gelfi, J. and Schelcher, F. 1999. Evaluation of a nested reverse transcription-PCR assay based on the nucleoprotein gene for diagnosis of spontaneous and experimental bovine respiratory syncytial virus infections. J. Clin. Microb. 37: 1858-1862 Van Milaan, A. J., Sprenger, J. J., Rothbarth, P. H., Brandenburg, A. H., Masurel, N. and Claas, E. C. 1994. Detection of respiratory syncytial virus by RNA-polymerase chain reaction and differentiation of subgroups with oligonucleotide probes. J. Med. Virol. 44:80-87. Vilcek, S, Elvander, M., Ballagi-Pordany, A., and Belak, S. 1994. Development of nested PCR assays for detection of bovine respiratory syncytial virus in clinical samples. J. Clin. Microb. 32: 2225-2231. Walravens, K, Kettmann, R., Collard, A., Coppe, P. and Burny, A., 1990. Sequence comparison between the fusion protein of human and bovine respiratory syncytial viruses. J. Gen. Virol. 71: 3009-3014. Weir, E. C., Brownstein, D. G., Smith, A L. and Johnson, E. A. 1988. Respiratory disease and wasting in athymic mice infected with pneumonia virus of mice. Lab. Anim. Sci. 34: 35-37.

20040304

20150106

20050602

57234.0

HILL, MYRON G

Virus causing respiratory tract illness in susceptible mammals

UNDISCOUNTED

ACCEPTED

ACCEPTED

Gssp4 polynucleotides and polypeptides and uses thereof

The present invention relates to the field of metabolic research. Metabolic disorders, such as obesity, are a public health problem that is serious and widespread. GSSP4 polypeptides have been identified that are believed to be beneficial in the treatment of metabolic disorders. These compounds should be effective for reducing cholesterol levels, body mass, body fat, and for treating metabolic-related diseases and disorders. The metabolic-related diseases or disorders envisioned to be treated by the methods of the invention include, but are not limited to: obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, diabetes, glucose intolerance, insulin resistance and hypertension.

1. A method of reducing circulating free fatty acid levels in an individual comprising administering to said individual a physiologically acceptable composition comprising a carrier and a polypeptide sequence comprising at least 6 consecutive amino acids of SEQ ID NO:3 with metabolic-related activity, wherein said method optionally reduces body mass. 2. A method of reducing circulating glucose levels in an individual comprising administering to said individual a physiologically acceptable composition comprising a carrier and a polypeptide sequence comprising at least 6 consecutive amino acids of SEQ ID NO:3 with metabolic-related activity, wherein said method optionally reduces body mass. 3. A method of reducing circulating triglyceride levels in an individual comprising administering to said individual a physiologically acceptable composition comprising a carrier and a polypeptide sequence comprising at least 6 consecutive amino acids of SEQ ID NO:3 with metabolic-related activity, wherein said method optionally reduces body mass. 4. A method of reducing circulating cholesterol levels in an individual comprising administering to said individual a physiologically acceptable composition comprising a carrier and a polypeptide sequence comprising at least 6 consecutive amino acids of SEQ ID NO:3 with metabolic-related activity, wherein said method optionally reduces body mass. 5. An isolated polypeptide comprising: a) an amino acid sequence at least 50% identical to the full length polypeptide of SEQ ID NO: 3; b) a polypeptide fragment of at least six consecutive amino acids of SEQ ID NO: 3; c) the polypeptide of SEQ ID NO: 3; d) homomultimers or heteromultimers of the polypeptide of SEQ ID NO: 3; e) a heterologous polypeptide fused to the polypeptide of a), b), c), or d); or f) a polypeptide according to a), b), c), d), or e) that has been differentially modified. 6. A composition comprising an isolated polypeptide according to claim 3 and a pharmaceutically or physiologically acceptable carrier. 7. An isolated or purified polynucleotide: a) encoding a polypeptide comprising an amino acid sequence at least 50% identical to the full length polypeptide of SEQ ID NO: 3; b) encoding a polypeptide comprising a fragment of at least six consecutive amino acids of SEQ ID NO: 3; c) encoding a polypeptide comprising SEQ ID NO: 3; d) encoding homomultimers or heteromultimers of the polypeptide of SEQ ID NO: 3; e) encoding a polypeptide comprising a heterologous polypeptide fused to the polypeptide of a), b), c), or d); f) encoding a polypeptide according to a), b), c), d), or e) that has been differentially modified; g) comprising a polynucleotide according to a), b), c), d), e), or f) operably linked to a promoter, other regulatory element, or selectable marker; or h) comprising a vector comprising a polynucleotide according to a), b), c), d), e), f), or g). 8. A recombinant cell comprising a polynucleotide according to claim 7. 9. An antibody that specifically binds to a polypeptide according to claim 5. 10. A method of producing a polypeptide comprising culturing a recombinant cell according to claim 8 under conditions that allow for the expression of said polypeptide. 11. The method according to claim 10, further comprising the isolation, recovery, or purification of said polypeptide. 12. A method of treating a obesity, a metabolic disease or a metabolic disorder comprising the administration of a therapeutically effective amount of a composition comprising: a) an isolated polypeptide comprising: 1) an amino acid sequence at least 50% identical to the full length polypeptide of SEQ ID NO: 3; 2) a polypeptide fragment of at least six consecutive amino acids of SEQ ID NO: 3; 3) the polypeptide of SEQ ID NO: 3; 4) homomultimers or heteromultimers of the polypeptide of SEQ ID NO: 3; 5) a heterologous polypeptide fused to the polypeptide of a(1), a(2), a(3), or a(4); or 6) a polypeptide according to a(1), a(2), a(3), a(4), or a(5) that has been differentially modified; b) an isolated or purified polynucleotide: 1) encoding a polypeptide comprising an amino acid sequence at least 50% identical to the full length polypeptide of SEQ ID NO: 3; 2) encoding a polypeptide comprising a fragment of at least six consecutive amino acids of SEQ ID NO: 3; 3) encoding a polypeptide comprising SEQ ID NO: 3; 4) encoding homomultimers or heteromultimers of the polypeptide of SEQ ID NO: 3; 5) encoding a polypeptide comprising a heterologous polypeptide fused to the polypeptide of b(1), b(2), b(3), or b(4); 6) encoding a polypeptide according to b(1), b(2), b(3), b(4), or b(5) that has been differentially modified; 7) comprising a polynucleotide according to b(1), b(2), b(3), b(4), b(5), or b(6) operably linked to a promoter, other regulatory element, or selectable marker; or 8) comprising a vector comprising a polynucleotide according to b(1), b(2), b(3), b(4), b(5), b(6), or b(7); or c) a recombinant cell comprising: 1) a polynucleotide encoding a polypeptide comprising an amino acid sequence at least 50% identical to the full length polypeptide of SEQ ID NO: 3; 2) a polynucleotide encoding a polypeptide comprising a fragment of at least six consecutive amino acids of SEQ ID NO: 3; 3) a polynucleotide encoding a polypeptide comprising SEQ ID NO: 3; 4) a polynucleotide encoding homomultimers or heteromultimers of the polypeptide of SEQ ID NO: 3; 5) a polynucleotide encoding a polypeptide comprising a heterologous polypeptide fused to the polypeptide of c(1), c(2), c(3), or c(4); 6) a polynucleotide encoding a polypeptide according to c(1), c(2), c(3), c(4), or c(5) that has been differentially modified; 7) a polynucleotide according to c(1), c(2), c(3), c(4), c(5), or c(6) operably linked to a promoter, other regulatory element, or selectable marker; or 8) comprising a vector comprising a polynucleotide according to c(1), c(2), c(3), c(4), c(5), c(6), or c(7). 13. A transgenic animal comprising a polynucleotide according to claim 7.

FIELD OF THE INVENTION The present invention relates to the field of metabolic research, in particular the discovery of compounds effective for reducing cholesterol levels, body fat, and body mass, and useful for treating metabolic-related diseases an disorders. The metabolic-related diseases or disorders envisioned to be treated by the methods of the invention include, but are not limited to, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, diabetes, glucose intolerance, insulin resistance and hypertension. BACKGROUND OF TH INVENTION The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention. Obesity is a public health problem that is serious, widespread, and increasing. In the United States, 20 percent of the population is obese; in Europe, a slightly lower percentage is obese (Friedman (2000) Nature 404:632-634). Obesity is associated with increased risk of hypertension, cardiovascular disease, diabetes, and cancer as well as respiratory complications and osteoarthritis (Kopelman (2000) Nature 404:635-643). Even modest weight loss ameliorates these associated conditions. While still acknowledging that lifestyle factors including environment, diet, age and exercise play a role in obesity, twin studies, analyses of familial aggregation, and adoption studies all indicate that obesity is largely the result of genetic factors (Barsh et al (2000) Nature 404:644-651). In agreement with these studies, is the fact that an increasing number of obesity-related genes are being identified. Some of the more extensively studied genes include those encoding leptin (ob) and its receptor (db), pro-opiomelanocortin (Pomc), melanocortin-4-receptor (Mc4r), agouti protein (Ay), carboxypeptidase E (fat), 5-hydroxytryptamine receptor 2C (Htr2c), nescient basic helix-loop-helix 2 (Nhlh2), prohormone convertase 1 IPCSK1), and tubby protein (tubby) (rev'd in Barsh et al (2000) Nature 404:644-651). SUMMARY OF THE INVENTION The instant invention is based on the discovery that GSSP4 polypeptides have unexpected effects in vitro and in vivo, including utility for weight reduction, prevention of weight gain, reduction of cholesterol levels, and control of blood glucose levels in humans and other mammals. These unexpected effects of administration of GSSP4 polypeptides in mammals also include reduction of elevated free fatty acid levels caused by administration of epinephrine, i.v. injection of “intralipid”, or administration of a high fat test meal, as well as increased fatty acid oxidation in muscle cells, reduction of circulating cholesterol levels, modulation of blood glucose and weight reduction in mammals, particularly those consuming a high fat/high carbohydrate diet. These effects are unexpected and surprising given that proteins of similar structure or homology (such as colipase and mamba intestinal toxin 1) have not been shown to have utility for weight reduction, prevention of weight gain, reduction of cholesterol levels, and control of blood glucose levels. However, the GSSP4 polypeptides of the invention are effective and can be provided at levels that are feasible for treatments in humans. Thus, the invention is drawn to GSSP4 polypeptides, polynucleotides encoding said polypeptides, vectors comprising said GSSP4 polynucleotides, and cells recombinant for said GSSP4 polynucleotides, as well as to pharmaceutical and physiologically acceptable compositions comprising said GSSP4 polypeptide and methods of administering said GSSP4 polypeptides or polynucleotides in a pharmaceutical and physiologically acceptable compositions in order to reduce body weight, cholesterol levels or glucose levels, or to treat metabolic-related diseases and disorders. Assays for identifying agonists and antagonists of metabolic-related activity are also part of the invention. In a first aspect, the invention features a purified, isolated, or recombinant GSSP4 polypeptides. In preferred embodiments, said polypeptides comprise, consist essentially of, or consist of, those having significant activity wherein the said activity is selected from the group consisiting of cholesterol reduction, cholesterol regulation, lipid partitioning, lipid metabolism, glucose control, and insulin-like activity. In preferred embodiments, said polypeptides comprise, consist essentially of, or consist of, the full length polypeptide of SEQ ID NO:3 or a fragment of consecutive amino acids of the full length polypeptide sequence of SEQ ID NO:3. In other preferred embodiments, said polypeptides comprise an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding consecutive amino acids of the polypeptide sequences identified in SEQ ID NO:3. In a further preferred embodiment, the GSSP4 polypeptide is able to lower circulating (either blood, serum or plasma) levels (concentration) of: (i) free fatty acids, (ii) glucose, and/or (iii) triglycerides. Further preferred GSSP4 polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GSSP4 polypeptides are those that cause C2C12 cells differentiated in the presence of said polypeptides to undergo at least 10%, 20%, 30%, 35%, or 40% more oleate oxidation as compared to untreated cells. Further preferred GSSP4 polypeptides are those that are at least 30% more efficient than untreated cells at increasing leptin uptake in a liver cell line (preferably BPRCL mouse liver cells (ATCC CRL-2217)). Further preferred GSSP4 polypeptides are those that significantly reduce the postprandial increase in plasma free fatty acids, particularly following a high fat meal. Further preferred GSSP4 polypeptides are those that significantly reduce or eliminate ketone body production, particularly following a high fat meal. Further preferred GSSP4 polypeptides are those that increase glucose uptake in skeletal muscle cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in adipose cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in neuronal cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in red blood cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in the brain. Further preferred GSSP4 polypeptides are those that significantly reduce the postprandial increase in plasma glucose following a meal, particularly a high carbohydrate meal. Further preferred GSSP4 polypeptides are those that significantly prevent the postprandial increase in plasma glucose following a meal, particularly a high fat or a high carbohydrate meal. Further preferred GSSP4 polypeptides are those that improve insulin sensitivity. Further preferred GSSP4 polypeptides are those that modulate food intake or food selection. Further preferred GSSP4 polypeptides are those that modulate satiety. Further preferred GSSP4 polypeptides are those that modulate fatty acid metabolism. Further preferred GSSP4 polypeptides are those that modulate cholesterol metabolism, particularly in steroidogenic tissues. Therefore, said polypeptides have a potential role in effecting, either directly or indirectly or both, levels of reproductive hormones (eg. estradiol, progesterone, testosterone). Further preferred GSSP4 polypeptides are those that modulate cortisol levels. Further preferred GSSP4 polypeptides are those that modulate aldosterone levels. Therefore, said polypeptides have a potential role in effecting, either directly or indirectly or both, levels of sodium and potassium. Further preferred GSSP4 polypeptides are those that modulate blood pressure preferably to normalize blood pressure within a normal range. Further preferred GSSP4 polypeptides are those that form multimers (e.g., heteromultimers or homomultimers) in vitro and/or in vivo. Preferred multimers are homodimers or homotrimers. Other preferred multimers are homomultimers comprising at least 4, 6, 8, 9, 10 or 12 GSSP4 polypeptides. Other preferred mulimers are hetero multimers comprising GSSP4 polypeptides of the invention. Further preferred embodiments include heterologous polypeptides comprising a GSSP4 polypeptide of the invention. In a second aspect, the invention features purified, isolated, or recombinant polynucleotides encoding said GSSP4 polypeptides described in the first aspect, or the complement thereof. A further preferred embodiment of the invention is a recombinant, purified or isolated polynucleotide comprising, or consisting of a mammalian genomic sequence, gene, cDNA, or fragments thereof. In one aspect the sequence is derived from a human, mouse or other mammal. In a preferred aspect, the genomic sequence includes isolated, purified, or recombinant polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 22, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000, 2000, 5000, 6000 or 7500 nucleotides of any one of the polynucleotide sequences described in SEQ ID NO:1, 2, or the complements thereof, wherein said contiguous span comprises a nucleotide sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding nucleotide sequence in SEQ ID NO: 1, 2, or 3. In further embodiments the polynucleotides are DNA, RNA, DNA/RNA hybrids, single-stranded, and double-stranded. Further preferred are GSSP4 polynucleotides and polypeptides that have cholesterol regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have body weight regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have body fat regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have glucose regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have lipid regulating activies. In a third aspect, the invention features a recombinant vector comprising, consisting essentially of, or consisting of, said polynucleotide described in the second aspect. In a fourth aspect, the invention features a recombinant cell comprising, consisting essentially of, or consisting of, said recombinant vector described in the third aspect. A further embodiment includes a host cell recombinant for a polynucleotide of the invention. In a fifth aspect, the invention features a pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of, said GSSP4 polypeptides described in the first aspect and, a pharmaceutical or physiologically acceptable diluent. In a sixth aspect, the invention features a method of controlling cholesterol levels comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering body weight comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering body fat comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering controlling blood glucose comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In a seventh aspect, the invention features a method of preventing or treating a metabolic-related disease or disorder comprising, providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. Preferably, said obesity-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a further preferred embodiment, a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect suggest that a compound may have utility in alleviating insulin resistance in individuals, particularly those that are obese or overweight. In a further preferred embodiment, the present invention may be used in complementary therapy in individuals to improve their cholesterol, weight or glucose level, comprising a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect in combination with known agents. The present invention further provides a method of improving the cholesterol levels, body weight or glucose control in individuals comprising the administration of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect alone, without known agents. In a further preferred embodiment, the present invention may be administered either concomitantly or concurrently, with known agents for example in the form of separate dosage units to be used simultaneously, separately or sequentially (either before or after the known agent). Accordingly, the present invention further provides a product containing a composition a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect and a known agent as a combined preparation for simultaneous, separate or sequential use for the improvement of cholesterol levels, body weight or glucose control in individuals, particularly those who are obese or overweight. The ratio of the present composition to known agent is such that the quantity of each active ingredient employed will be such as to provide a therapeutically effective level, but will not be larger than the quantity recommended as safe for administration. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect can be used as a method to improve insulin sensitivity in some persons, particularly those with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) or noninsulin dependent diabetics (Type II) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect can be used as a method to improve insulin sensitivity in some persons, particularly those with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) or noninsulin dependent diabetes mellitus (NIDDM, Type II) in combination with alternate therapies. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used as a method in prophylaxis of long-term detrimental effects caused by prolonged high dosage of insulin in humans having IDDM or NIDDM. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing hypersecretion of insulin and disorders or conditions resulting therefrom. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing obesity and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing hypercholesterolemia and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing NIDDM or IDDM and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing impaired glucose tolerance (IGT). Further preferred embodiment thus provides therapeutics and methods for normalizing insulin resistance. Further preferred embodiment thus provides therapeutics and methods for reducing, slowing or preventing the progression to NIDDM. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing the appearance of insulin-resistance syndrome. In further preferred embodiments, other conditions, particularly obesity, associated with insulin resistance are treated or prevented according to the methods of the invention. Thus, by preventing or treating obesity, the methods of the invention will allow an individual to have a more comfortable life and avoid the onset of various diseases triggered by obesity. In further preferred embodiments, the target of the methods according to the present invention includes individuals with normal glucose tolerance (NGT) who are obese or who have fasting hyperinsulinemia, or who have both. In an eighth aspect, the invention features a method of controlling blood free fatty acid (FFA) levels and lipid metabolism comprising, providing, or administering to individuals in need of increasing mobilization and utilization of fat stores and decreasing total fat stores with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In a further preferred embodiment, the identification of said individuals in need of increasing mobilization and utilization of fat stores and decreasing total fat stores to be treated with said pharmaceutical or physiologically acceptable composition comprises a person who is involved in physical activity which increases metabolic demand. Furthermore, increasing mobilization and utilization of fat stores and decreasing total fat stores would provide a means to decrease body weight, preventing weight gain, decrease body fat in overweight and obese individuals. Reduction in weight and obesity will thus decrease the risk of chronic disease associated with obesity such as but not limited to the onset of various lipid metabolism disorders, hypertension, Type II diabetes, atherosclerosis, cardiovascular disease and stroke. In related aspects, embodiments of the present invention includes methods of causing or inducing a desired biological response in an individual comprising the steps of: providing or administering to an individual a composition comprising a GSSP4 polypeptide, wherein said biological response is selected from the group consisting of: (a) lowering circulating (either blood, serum, or plasma) levels (concentration) of free fatty acids; (b) lowering circulating (either blood, serum or plasma) levels (concentration) of glucose; (c) lowering circulating (either blood, serum or plasma) levels (concentration) of triglycerides; (d) stimulating muscle lipid or free fatty acid oxidation; (e) increasing leptin uptake in the liver or liver cells; (f) reducing the postprandial increase in plasma free fatty acids, particularly following a high fat meal; and, (g) reducing or eliminating ketone body production, particularly following a high fat meal; (h) increasing tissue sensitivity to insulin, particularly muscle, adipose, liver or brain, (i) reducing cholesterol levels, particularly in those with elevated cholesterol (ie. greater than 200 mg/dl); (j) modulating circulating (either blood, serum or plasma) levels (concentration) of glucose within physiological range, preferably maintaining glucose between 60-190 mg/dl; (k) modulating circulating (either blood, serum or plasma) levels (concentration) of FFA within physiological range preferably maintaining FFA between 190-420 mg/dl; (l) modulating ketone body production as the result of a high fat meal, wherein said modulating is preferably reducing or eliminating; (m) reducing body weight particularly in individuals with a BMI of greater than 27. In a ninth aspect, the invention features a method of making the GSSP4 polypeptide described in the first aspect, wherein said method is selected from the group consisting of: proteolytic cleavage, recombinant methodology and artificial synthesis. In a tenth aspect, the present invention provides a method of making a recombinant GSSP4 polypeptides, the method comprising providing a transgenic, non-human mammal whose milk contains said recombinant GSSP4 polypeptides, and purifying said recombinant GSSP4 polypeptides from the milk of said non-human mammal. In one embodiment, said non-human mammal is a cow, goat, sheep, rabbit, or mouse. In another embodiment, the method comprises purifying a recombinant GSSP4 polypeptides from said milk, and further comprises cleaving said protein in vitro to obtain a desired GSSP4 polypeptides. In an eleventh aspect, the invention features a purified or isolated antibody capable of specifically binding to a protein comprising the sequence of one of the polypeptides of the present invention. In one aspect of this embodiment, the antibody is capable of binding to a polypeptide comprising at least 6 consecutive amino acids, at least 8 consecutive amino acids, or at least 10 consecutive amino acids of the sequence of one of the polypeptides of the present invention. In a twelfth aspect, the invention features a use of polypeptides described in the first aspect or polynucleotides described in the second aspect for treatment of metabolic-related diseases and disorders or reducing or increasing body mass. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a thirteenth aspect, the invention features a use of polypeptides described in the first aspect or polynucleotides described in the second aspect for the preparation of a medicament for the treatment of metabolic-related diseases and disorders or for reducing body mass. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a fourteenth aspect, the invention provides polypeptides of the first aspect of the invention or a composition of the fifth aspect for use in a method of treatment of the human or animal body. In a fifteenth aspect, the invention provides polynucleotides described in the second aspect or an acceptable composition thereof, for use in a method of treatment of the human or animal body. In a sixteenth aspect, the invention features methods of reducing body weight for cosmetic purposes comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect, or polypeptides described in the first aspect. Preferably, for said reducing body weight said individual has a BMI of at least 20, 25, 30, 35, or 40. In a seventeenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect or a polypeptide described in the first aspect for reducing body mass in said individuals with a BMI of at least 30, 35, 40, or 45 or for treatment or prevention of metabolic-related diseases or disorders. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In preferred embodiments, the identification of said individuals to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GSSP4 single nucleotide polymorphisms (SNPs) or measuring GSSP4 polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. In an eighteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect for reducing body weight for cosmetic reasons. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect for reducing glucose levels. In a nineteenth aspect, the invention features methods of treating insulin resistance comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect, or a polypeptide described in the first aspect. BRIEF DESCRIPTION OF THE SEQENCES SEQ ID NO:1 shows GSSP4 genomic sequence indicating regulatory regions, exons, polymorphic alleles and positions, and reverse and forward microsequencing primers for haplotyping. SEQ ID NO:2 shows GSSP4 polynucleotide sequence of cDNA SEQ ID NO:3 shows GSSP4 polypeptide sequence SEQ ID NO:4-18 shows GSSP4 47-mer nucleotide sequence comprising polymorphic allele at position 24. The corresponding alleles and primers indicated in SEQ ID NO:1 are as follows: VLP_1206_C_A, m=C or A SEQ ID NO:4 VLP_148_A_G, r=A or G SEQ ID NO:5 VLP_1851_T_C, y=T or C SEQ ID NO:6 VLP_2551_G_A, r=G or A SEQ ID NO:7 VLP_3124_C_T, y=C or T SEQ ID NO:8 VLP_3563_G_A, r=G or A SEQ ID NO:9 VLP_3792_G_A, r=G or A SEQ ID NO:10 VLP_4417_A_C, m=A or G SEQ ID NO:11 VLP_5757_T_C, y=T or C SEQ ID NO:12 VLP_6322_A_G, r=G or A SEQ ID NO:13 VLP_816_G_A, r=G or A SEQ ID NO:14 VLP_924_G_A, r=G or A SEQ ID NO:15 VLP_99-1_174_T_C, y=T or C SEQ ID NO:16 VLP_99-1_325_C_G, s=C or G SEQ ID NO:17 VLP_99-2_389_T_C, y=T or G SEQ ID NO:18 DETAILED DESCRIPTION OF THE INVENTION Before describing the invention in greater detail, the following definitions are set forth to illustrate and define the meaning and scope of the terms used to describe the invention herein. As used interchangeably herein, the terms “oligonucleotides”, and “polynucleotides” and nucleic acid include RNA, DNA, or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form. The terms encompass “modified nucleotides” which comprise at least one modification, including by way of example and not limitation: (a) an alternative linking group, (b) an analogous form of purine, (c) an analogous form of pyrimidine, or (d) an analogous sugar. For examples of analogous linking groups, purines, pyrimidines, and sugars see for example PCT publication No. WO 95/04064. The polynucleotide sequences of the invention may be prepared by any known method, including synthetic, recombinant, ex vivo generation, or a combination thereof, as well as utilizing any purification methods known in the art. The terms polynucleotide construct, recombinant polynucleotide and recombinant polypeptide are used herein consistently with their use in the art. The terms “upstream” and “downstream” are also used herein consistently with their use in the art. The terms “base paired” and “Watson & Crick base paired” are used interchangeably herein and consistently with their use in the art. Similarly, the terms “complementary”, “complement thereof”, “complement”, “complementary polynucleotide”, “complementary nucleic acid” and “complementary nucleotide sequence” are used interchangeably herein and consistently with their use in the art. The term “purified” is used herein to describe a polynucleotide or polynucleotide vector of the invention that has been separated from other compounds including, but not limited to, other nucleic acids, carbohydrates, lipids and proteins (such as the enzymes used in the synthesis of the polynucleotide). Purified can also refer to the separation of covalently closed polynucleotides from linear polynucleotides, or vice versa, for example. A polynucleotide is substantially pure when at least about 50%, 60%, 75%, or 90% of a sample contains a single polynucleotide sequence. In some cases this involves a determination between conformations (linear versus covalently closed). A substantially pure polynucleotide typically comprises about 50, 60, 70, 80, 90, 95, 99% weight/weight of a nucleic acid sample. Polynucleotide purity or homogeneity may be indicated by a number of means well known in the art, such as agarose or polyacrylamide gel electrophoresis of a sample, followed by visualizing a single polynucleotide band upon staining the gel. For certain purposes higher resolution can be provided by using HPLC or other means well known in the art. Similarly, the term “purified” is used herein to describe a polypeptide of the invention that has been separated from other compounds including, but not limited to, nucleic acids, lipids, carbohydrates and other proteins. In some preferred embodiments, a polypeptide is substantially pure when at least about 50%, 60%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% of the polypeptide molecules of a sample have a single amino acid sequence. In some preferred embodiments, a substantially pure polypeptide typically comprises about 50%, 60%, 70%, 80%, 90% 95%, 96%, 97%, 98%, 99% or 99.5% weight/weight of a protein sample. Polypeptide purity or homogeneity is indicated by a number of methods well known in the art, such as agarose or polyacrylamide gel electrophoresis of a sample, followed by visualizing a single polypeptide band upon staining the gel. For certain purposes higher resolution can be provided by using HPLC or other methods well known in the art. Further, as used herein, the term “purified” does not require absolute purity; rather, it is intended as a relative definition. Purification of starting material or natural material to at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. Alternatively, purification may be expressed as “at least” a percent purity relative to heterologous polynucleotides (DNA, RNA or both) or polypeptides. As a preferred embodiment, the polynucleotides or polypeptides of the present invention are at least; 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 96%, 98%, 99%, 99.5% or 100% pure relative to heterologous polynucleotides or polypeptides. As a further preferred embodiment the polynucleotides or polypeptides have an “at least” purity ranging from any number, to the thousandth position, between 90% and 100% (e.g., at least 99.995% pure) relative to heterologous polynucleotides or polypeptides. Additionally, purity of the polynucleotides or polypeptides may be expressed as a percentage (as descried above) relative to all materials and compounds other than the carrier solution. Each number, to the thousandth position, may be claimed as individual species of purity. The term “isolated” requires that the material be removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or DNA or polypeptide, separated from some or all of the coexisting materials in the natural system, is isolated. Such polynucleotide could be part of a vector and/or such polynucleotide or polypeptide could be part of a composition, and still be isolated in that the vector or composition is not part of its natural environment. Specifically excluded from the definition of “isolated” are: naturally occurring chromosomes (e.g., chromosome spreads), artificial chromosome libraries, genomic libraries, and cDNA libraries that exist either as an in vitro nucleic acid preparation or as a transfected/transformed host cell preparation, wherein the host cells are either an in vitro heterogeneous preparation or plated as a heterogeneous population of single colonies. Also specifically excluded are the above libraries wherein a 5′ EST makes up less than 5% (or alternatively 1%, 2%, 3%, 4%, 10%, 25%, 50%, 75%, or 90%, 95%, or 99%) of the number of nucleic acid inserts in the vector molecules. Further specifically excluded are whole cell genomic DNA or whole cell RNA preparations (including said whole cell preparations which are mechanically sheared or enzymatically digested). Further specifically excluded are the above whole cell preparations as either an in vitro preparation or as a heterogeneous mixture separated by electrophoresis (including blot transfers of the same) wherein the polynucleotide of the invention have not been further separated from the heterologous polynucleotides in the electrophoresis medium (e.g., further separating by excising a single band from a heterogeneous band population in an agarose gel or nylon blot). The term “primer” denotes a specific oligonucleotide sequence which is complementary to a target nucleotide sequence and used to hybridize to the target nucleotide sequence. A primer serves as an initiation point for nucleotide polymerization catalyzed by DNA polymerase, RNA polymerase, or reverse transcriptase. The term “probe” denotes a defined nucleic acid segment (or nucleotide analog segment, e.g., PNA as defined hereinbelow) which can be used to identify a specific polynucleotide sequence present in a sample, said nucleic acid segment comprising a nucleotide sequence complementary to the specific polynucleotide sequence to be identified. The term “polypeptide” refers to a polymer of amino acids without regard to the length of the polymer. Thus, peptides, oligopeptides, and proteins are included within the definition of polypeptide. This term also does not specify or exclude post-expression modifications of polypeptides. For example, polypeptides that include the covalent attachment of glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like are expressly encompassed by the term polypeptide. Also included within the definition are polypeptides which contain one or more analogs of an amino acid (including, for example, non-naturally occurring amino acids, amino acids which only occur naturally in an unrelated biological system, modified amino acids from mammalian systems etc.), polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring. The phrases “control of blood glucose”, “glucose regulation” “regulation of blood glucose”, “modulating blood glucose”, and “glucose control” refer to maintaining or regulating blood, serum, and plasma levels of glucose between 70-190 mg/dl. Without being limited by theory, the compounds/polypeptides of the invention feature a method of chronic control of blood glucose within a narrow and more physiological range compared to the control of blood glucose attained with current therapies which treat disorders of glucose metabolism or insulin action, including but not limited to hyperglycemia, insulin resistance, insulin dependent diabetes mellitus and noninsulin dependent diabetes mellitus. Without being limited by theory, the compounds/polypeptides of the invention are capable of modulating the control of blood glucose (as defined above), directing or partitioning glucose between the liver and the peripheral tissues, and are thus believed to treat “diseases involving the control of blood glucose between the liver and peripheral tissues”. The term “peripheral tissues” is meant to include the blood, brain, muscle and adipose tissue. In preferred embodiments, the compounds/polypeptides of the invention direct or partition glucose towards the liver, muscle and brain. In alternative preferred embodiments, glucose is directed or partitioned towards the adipose tissue. In other preferred embodiments, glucose is directed or partitioned towards the liver. In other preferred embodiments, glucose is directed or partitioned towards the brain. In other preferred embodiments, glucose is directed towards the blood. In yet other preferred embodiments, the compounds/polypeptides of the invention increase or decrease the oxidation of glucose, preferably by the muscle. Without being limited by theory, the compounds/polypeptides of the invention are capable of modulating the partitioning of dietary or endogenous lipids between the liver and peripheral tissues, and are thus believed to treat “diseases involving the partitioning of lipids between the liver and peripheral tissues.” The term “peripheral tissues” is meant to include the blood, muscle and adipose tissue. In preferred embodiments, the compounds/polypeptides of the invention partition the lipids toward the muscle. In alternative preferred embodiments, the lipids are partitioned toward the blood. In alternative preferred embodiments, the lipids are partitioned toward the adipose tissue. In other preferred embodiments, the lipids are partitioned toward the liver. In yet other preferred embodiments, the compounds/polypeptides of the invention increase or decrease the oxidation of dietary or endogenous lipids, preferably free fatty acids (FFA) by the muscle. Dietary and endogenous lipids include, but are not limited to triglycerides (TG) and FFA. “Preferred diseases” believed to involve the the control of cholesterol, body fat, lipid metabolism, blood glucose, partitioning of blood glucose, and partitioning of lipids include obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, reproductive cancers, hypercortisolism, aldosteronism, hyperandrogenism, hyperkalemia, hypernatremia, hyperlipoproteinemia, hyperinsulinemia, hyperglycemia, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (eg. ketosis), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be prevented or treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. The term “heterologous”, when used herein, is intended to designate any polypeptide or polynucleotide other than a GSSP4 polypeptide or a polynucleotide encoding a GSSP4 polypeptide of the present invention. The terms “comprising”, “consisting of” and “consisting essentially of” are defined according to their standard meaning. A defined meaning set forth in the M.P.E.P. controls over a defined meaning in the art and a defined meaning set forth in controlling Federal Circuit case law controls over a meaning set forth in the M.P.E.P. With this in mind, the terms may be substituted for one another throughout the instant application in order to attach the specific meaning associated with each term. The term “host cell recombinant for” a particular polynucleotide of the present invention, means a host cell that has been altered by the hands of man to contain said polynucleotide in a way not naturally found in said cell. For example, said host cell may be transiently or stably transfected or transduced with said polynucleotide of the present invention. The term “obesity” as used herein is defined by the National Heart, Lung and Blood Institute Expert Panel (J Amer Diet Assoc 98:1178-1191, 1998) based on Body Mass Index (BMI). BMI is calculated as body weight in kilograms divided by the square of height in meters, ie kg/m2. A BMI of less than 18.5 kg/m2 is considered “Underweight”; a BMI of 18.5-24.9 kg/m2 is considered “Normal” (healthy); a BMI of 25.0-29.9 kg/m2 is considered “Overweight”; a BMI of 30.0-34.9 kg/m2 is considered “Class I Obesity”; a BMI of 35.0-39.9 kg/m2 is considered “Class II Obesity”; a BMI of greater than 39.9 kg/m2 is considered “Class III Obesity”. Waist circumference can also be used to indicate a risk of metabolic complications where in men a circumference of greater than or equal to 94 cm indicates an increased risk, and greater than or equal to 102 cm indicates a substantially increased risk Similarly for women, greater than or equal to 88 cm indicates an increased risk, and greater than or equal to 88 cm indicates a substantially increased risk. The waist circumference is measured in cm at midpoint between lower border of ribs and upper border of the pelvis. Other measures of obesity include, but are not limited to, skinfold thickness which is a measurement in cm of skinfold thickness using calipers and bioimpedance which is based on the principle that lean mass and water will conduct electrical current and measurement of resistance to a weak current (impedance) applied across extremities provides an estimate of body fat using an empirically derived equation. The term “Insulin Dependent Diabetes Mellitus”, “IDDM”, “Type I Diabetes” and “Type I diabetics” are synomous, inclusive, or interchangable. The term “diabetes-related complications” refer to pathologic or physiologic states experienced by Type I diabetics (as defined previously) or Type II diabetics (as defined previously) or both. The term “Noninsulin Dependent Diabetes Mellitus”, “NIDDM”, “Type II Diabetes” and “Type II diabetics” are synomous, inclusive, or interchangable. The term “agent acting on the control of blood glucose, directing glucose between the liver and peripheral tissues” refers to a compound or polypeptide of the invention that modulates the control of blood glucose as previously described. Preferably, the agent increases or decreases the oxidation of glucose, preferably by the muscle. Preferably the agent decreases or increases the body weight of individuals or is used to treat or prevent an metabolic-related disease or disorder such as obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. The terms “response to an agent acting on the control of blood glucose, directing glucose between the liver and peripheral tissues” refer to drug efficacy, including but not limited to, ability to metabolize a compound, ability to convert a pro-drug to an active drug, and the pharmacokinetics (absorption, distribution, elimination) and the pharmacodynamics (receptor-related) of a drug in an individual. The terms “side effects to an agent acting on the control of blood glucose, directing glucose between the liver and peripheral tissues” refer to adverse effects of therapy resulting from extensions of the principal pharmacological action of the drug or to idiosyncratic adverse reactions resulting from an interaction of the drug with unique host factors. “Side effects to an agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” can include, but are not limited to, adverse reactions such as dermatologic, hematologic or hepatologic toxicities and further includes gastric and intestinal ulceration, disturbance in platelet function, renal injury, nephritis, vasomotor rhinitis with profuse watery secretions, angioneurotic edema, generalized urticaria, and bronchial asthma to laryngeal edema and bronchoconstriction, hypotension, and shock. The term “agent acting on the partitioning of glucose between the liver and peripheral tissues” refers to a compound or polypeptide of the invention that modulates the partitioning of glucose between the liver and the peripheral tissues as previously described. Preferably, the agent increases or decreases blood glucose levels. Preferably, the agent increases or decreases oxidation of glucose, preferably by the muscle. Preferably the agent decreases or increases the body weight of individuals or is used to treat or prevent an metabolic-related disease or disorder such as obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. The terms “response to an agent acting on the partitioning of glucose between the liver and peripheral tissues” refer to drug efficacy, including but not limited to, ability to metabolize a compound, ability to convert a pro-drug to an active drug, and the pharmacokinetics (absorption, distribution, elimination) and the pharmacodynamics (receptor-related) of a drug in an individual. The terms “side effects to an agent acting on the partitioning of glucose between the liver and peripheral tissues” refer to adverse effects of therapy resulting from extensions of the principal pharmacological action of the drug or to idiosyncratic adverse reactions resulting from an interaction of the drug with unique host factors. “Side effects to an agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” can include, but are not limited to, adverse reactions such as dermatologic, hematologic or hepatologic toxicities and further includes gastric and intestinal ulceration, disturbance in platelet function, renal injury, nephritis, vasomotor rhinitis with profuse watery secretions, angioneurotic edema, generalized urticaria, and bronchial asthma to laryngeal edema and bronchoconstriction, hypotension, and shock. The term “agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” refers to a compound or polypeptide of the invention that modulates the partitioning of dietary lipids between the liver and the peripheral tissues as previously described. Preferably, the agent increases or decreases the oxidation of dietary lipids, preferably free fatty acids (FFA) by the muscle. Preferably the agent decreases or increases the body weight of individuals or is used to treat or prevent an metabolic-related disease or disorder such as obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. The terms “response to an agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” refer to drug efficacy, including but not limited to, ability to metabolize a compound, ability to convert a pro-drug to an active drug, and the pharmacokinetics (absorption, distribution, elimination) and the pharmacodynamics (receptor-related) of a drug in an individual. The terms “side effects to an agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” refer to adverse effects of therapy resulting from extensions of the principal pharmacological action of the drug or to idiosyncratic adverse reactions resulting from an interaction of the drug with unique host factors. “Side effects to an agent acting on the partitioning of dietary lipids between the liver and peripheral tissues” can include, but are not limited to, adverse reactions such as dermatologic, hematologic or hepatologic toxicities and further includes gastric and intestinal ulceration, disturbance in platelet function, renal injury, nephritis, vasomotor rhinitis with profuse watery secretions, angioneurotic edema, generalized urticaria, and bronchial asthma to laryngeal edema and bronchoconstriction, hypotension, and shock. The term “agent acting on the partitioning of endogenous lipids between the liver and peripheral tissues” refers to a compound or polypeptide of the invention that modulates the partitioning of endogenous lipids between the liver and the peripheral tissues as previously described. Preferably, the agent increases or decreases the oxidation of endogenous lipids, preferably free fatty acids (FFA) by the muscle. Preferably the agent decreases or increases the body weight of individuals or is used to treat or prevent an metabolic-related disease or disorder such as obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. The terms “response to an agent acting on the partitioning of endogenous lipids between the liver and peripheral tissues” refer to drug efficacy, including but not limited to, ability to metabolize a compound, ability to convert a pro-drug to an active drug, and the pharmacokinetics (absorption, distribution, elimination) and the pharmacodynamics (receptor-related) of a drug in an individual. The terms “side effects to an agent acting on the partitioning of endogenous lipids between the liver and peripheral tissues” refer to adverse effects of therapy resulting from extensions of the principal pharmacological action of the drug or to idiosyncratic adverse reactions resulting from an interaction of the drug with unique host factors. “Side effects to an agent acting on the partitioning of endogenous lipids between the liver and peripheral tissues” can include, but are not limited to, adverse reactions such as dermatologic, hematologic or hepatologic toxicities and further includes gastric and intestinal ulceration, disturbance in platelet function, renal injury, nephritis, vasomotor rhinitis with profuse watery secretions, angioneurotic edema, generalized urticaria, and bronchial asthma to laryngeal edema and bronchoconstriction, hypotension, and shock. The term “GSSP4-related diseases and disorders” as used herein refers to any disease or disorder comprising an aberrant functioning of a GSSP4, or which could be treated or prevented by modulating GSSP4 levels or activity. “Aberrant functioning of a GSSP4” includes, but is not limited to, aberrant levels of expression of a GSSP4 polypeptide (either increased or decreased, but preferably decreased), aberrant activity of a GSSP4 polypeptide (either increased or decreased), and aberrant interactions with ligands or binding partners (either increased or decreased). By “aberrant” is meant a change from the type, or level of activity seen in normal cells, tissues, or patients, or seen previously in the cell, tissue, or patient prior to the onset of the illness. In preferred embodiments, these GSSP4-related diseases and disorders include obesity and the metabolic-related diseases and disorders described previously. The term “cosmetic treatments” is meant to include treatments with compounds or polypeptides of the invention that increase or decrease the body mass of an individual where the individual is not clinically obese or clinically underweight as defined previously. Thus, these individuals have a body mass index (BMI) below the cut-off for clinical obesity (e.g. below 30 kg/m2) and above the cut-off for clinical thinness (e.g. above 18.5 kg/m2). In addition, these individuals are preferably healthy (e.g. do not have an metabolic-related disease or disorder of the invention). “Cosmetic treatments” are also meant to encompass, in some circumstances, more localized increases in adipose tissue, for example, gains or losses specifically around the waist or hips, or around the hips and thighs, for example. These localized gains or losses of adipose tissue can be identified by increases or decreases in waist or hip size, for example. The term “prevent” or “preventing” as used herein refers to administering a compound prior to the onset of clinical symptoms of a disease or condition so as to prevent a physical manifestation of aberrations associated with obesity or insulin resistance to some extent. The term “prevent” or “preventing” does not mean the result is necessarily absolute, but rather effective for providing some degree of prevention or amelioration of the progression of the metabolic or GSSP4-related disorder (i.e., provide protective effects), amelioration of the symptoms of the disorder, and amelioration of the reoccurrence of the metabolic or GSSP4-related disorder. The term “treat” or “treating” as used herein refers to administering a compound after the onset of clinical symptoms. The term “treat” or “treating” means to ameliorate, alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition. The term “in need of treatment” as used herein refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that include the knowledge that the individual or animal is ill, or will be ill, as the result of a condition that is treatable by the compounds of the invention. The term “perceives a need for treatment” refers to a sub-clinical determination that an individual desires to reduce weight for cosmetic reasons as discussed under “cosmetic treatment” above. The term “perceives a need for treatment” in other embodiments can refer to the decision that an owner of an animal makes for cosmetic treatment of the animal. The term “patient” or “individual” as used herein refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The term may specify male or female or both, or exclude male or female. The term “non-human animal” refers to any non-human vertebrate, including birds and more usually mammals, preferably primates, animals such as swine, goats, sheep, donkeys, horses, cats, dogs, rabbits or rodents, more preferably rats or mice. Both the terms “animal” and “mammal” expressly embrace human subjects unless preceded with the term “non-human”. The inventors believe GSSP4 polypeptides are able to significantly reduce the postprandial response of glucose in an individual, particularly following a high fat/high carbohydrate meal, while not effecting the levels of insulin. Further, GSSP4 polypeptides of the invention are believed to modulate weight gain, particularly in individuals are fed a high fat/high carbohydrate diet. The instant invention encompasses the use of GSSP4 polypeptides in the modulation of glucose as an important new tool to control energy homeostasis and glucose regulation. The instant invention encompasses the use of GSSP4 polypeptides in the partitioning of glucose as an important new tool to control energy homeostasis and glucose regulation. The instant invention encompasses the use of GSSP4 polypeptides in the partitioning of lipids as an important new tool to control energy homeostasis and lipid regulation. The instant invention encompasses the use of GSSP4 polypeptides in the partitioning of dietary lipids as an important new tool to control energy homeostasis and lipid regulation. The instant invention encompasses the use of GSSP4 polypeptides in the partitioning of endogenous lipids as an important new tool to control energy homeostasis and lipid regulation. PREFERRED EMBODIMENTS OF THE INVENTION I. GSSP4 Polypeptides of the Invention GSSP4 polypeptides that have measurable activity in vitro and in vivo have been identified. These activities include, but are not limited to, reduction of the postprandial response of plasma free fatty acids, glucose, and triglycerides, particularly in mice fed a high fat/carbohydrate meal, increase in muscle free fatty acid oxidation in vitro and ex vivo, and sustained weight loss in mice on a high fat/carbohydrate diet. Other assays for GSSP4 polypeptide activity in vitro and in vivo are also provided (Examples 2-13, for example), and equivalent assays can be designed by those with skill in the art. The term “obesity-related” or “metabolic-related” activity as used herein refers to at least one, and preferably all, of the activities described herein for GSSP4 polypeptides. Assays for the determination of these activities are provided herein, and equivalent assays can be designed by those with ordinary skill in the art. The term “metabolic-related activity” as used herein refers to at least one, and preferably all, of the activities described herein for GSSP4 polypeptides. Assays for the determination of these activities are provided herein, known in the art, or can be designed by those with ordinary skill in the art. Optionally, “metabolic-related activity” can be selected from the group consisting of control of blood glucose, partitioning of glucose, glucose metabolism, lipid partitioning, lipid metabolism, and insulin-like activity, or an activity within one of these categories. Optionally, “obesity-related” activity can be selected from the group consisting of lipid partitioning, lipid metabolism, and insulin-like activity, or an activity within one of these categories. By “lipid partitioning” activity is meant the ability to effect the location of dietary lipids among the major tissue groups including, adipose tissue, liver, and muscle. The inventors have shown that GSSP4 polypeptides of the invention play a role in the partitioning of lipids to the muscle, liver or adipose tissue. By “lipid metabolism” activity is meant the ability to influence the metabolism of lipids. The inventors have shown that GSSP4 polypeptides of the invention have the ability to affect the level of free fatty acids in the plasma as well as to increase the metabolism of lipids in the muscle through free fatty acid oxidation experiments (Examples 4, 8, 10, 11, and 12) and to transiently affect the levels of triglycerides in the plasma and the muscle (Examples 7, 10, and 13). By “insulin-like” activity is meant the ability of GSSP4 polypeptides to modulate the levels of glucose in the plasma. The inventors have found that GSSP4 polypeptides do not significantly impact insulin levels but do impact glucose levels similarly to the effects of insulin (Examples 9 & 10). These effects are not seen in the presence of the intact (full-length) GSSP4 polypeptide or are significantly greater in the presence of the GSSP4 polypeptides compared with the full-length GSSP4 polypeptide. By “intact” or “full-length” GSSP4 polypeptide as used herein is meant the full length polypeptide sequence of the GSSP4 polypeptide of SEQ ID NO:3, from the N-terminal methionine to the C-terminal stop codon. Preferred GSSP4 polypeptides have a biological activity described herein, and as they would be useful in making antibodies, diagnostic assays, etc. As a further preferred embodiment, GSSP4 polypeptides which allow a rise in plasma glucose to not more than 190 mg/dl, particularly following consumption of food, or which prevent a drop in serum glucose to not less than 70 mg/dl, particularly following consumption of food. As a further preferred embodiment, GSSP4 polypeptides which allow a rise in plasma fatty acids to not more than 420 mg/dl, particularly following consumption of food, or which prevent a drop in serum fatty acids to not less than 190 mg/dl, particularly following consumption of food. By “significantly” as used herein is meant statistically significant as it is typically determined by those with ordinary skill in the art. For example, data are typically calculated as a mean±SEM, and a p-value≦0.05 is considered statistically significant. Statistical analysis is typically done using either the unpaired Student's t test or the paired Student's t test, as appropriate in each study. Representative “metabolic-related assays” are provided in Examples below. These assays include, but are not limited to, in vivo and in vitro methods of measuring the postprandial response, methods of measuring glucose uptake, glucose oxidation, glucose concentration, lipid concentration, free fatty acid levels, fatty acid oxidation and methods of measuring weight modulation. In preferred embodiments, the post-prandial response is measured in non-human animals, preferably rodents. In preferred embodiments physiologic parameters are measured including, but not limited to, levels of glucose, fatty acids, insulin, and leptin. In other preferred embodiments, free fatty acid oxidation is measured in cells in vitro or ex vivo, preferably in muscle cells or tissue of non-human animals, preferably rodents. In yet other preferred embodiments weight modulation is measured in human or non-human animals, preferably rodents (rats or mice), primates, canines, felines or procines on a high fat/carbohydrate diet. Optionally, “metabolic-related activity” includes other activities not specifically identified herein. In general, “measurable parameters” relating to obesity and the field of metabolic research can be selected from the group consisting of free fatty acid levels, free fatty acid oxidation, triglyceride levels, glucose levels, insulin levels, leptin levels, food intake, and body weight. In these metabolic-related assays, preferred GSSP4 polypeptides or polynucleotides or both would cause a significant change in at least one of the measurable parameters selected from the group consisting of post-prandial lipemia, free fatty acid levels, triglyceride levels, glucose levels, glucose oxidation, glucose uptake, free fatty acid oxidation, and weight. Alternatively, preferred GSSP4 polypeptides or polynucleotides or both would have a significant change in at least one of the measurable parameters selected from the group consisting of an increase in blood fatty acid levels (FFA), an decrease in blood glucose levels, a decrease in insulin levels, an increase in glucose oxidation and an increase in FFA oxidation. The invention is drawn, inter alia, to isolated, purified or recombinant GSSP4 polypeptides. GSSP4 polypeptides of the invention are useful for treating or preventing insulin resistance, and reducing body weight or increasing body weight (using antagonists of GSSP4 polypeptides) either as a cosmetic treatment or for treatment or prevention of metabolic-related diseases and disorders. GSSP4 polypeptides are also useful inter alia in screening assays for agonists or antagonists of GSSP4 polypeptide activity, for raising GSSP4 polypeptide-specific antibodies, and in diagnostic assays. The GSSP4 polypeptides of the present invention are preferably provided in an isolated form, and may be partially or substantially purified. A recombinantly produced version of any one of the GSSP4 polypeptides can be substantially purified by the one-step method described by Smith et al. ((1988) Gene 67(1):31-40) or by the methods described herein or known in the art. Polypeptides of the invention also can be purified from natural or recombinant sources using antibodies directed against the polypeptides of the invention by methods known in the art of protein purification. Preparations of GSSP4 polypeptides of the invention involving a partial purification of or selection for the GSSP4 polypeptides are also specifically contemplated. These crude preparations are envisioned to be the result of the concentration of cells expressing GSSP4 polypeptides with perhaps a few additional purification steps, but prior to complete purification of the polypeptides. The cells expressing GSSP4 polypeptides are present in a pellet, they are lysed, or the crude polypeptide is lyophilized, for example. GSSP4 polypeptides can be any integer in length from at least 6 consecutive amino acids to 1 amino acids less than a full length GSSP4 polypeptide of SEQ ID NO:4. Thus, for SEQ ID NO:4, a GSSP4 polypeptide can be: 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, or 105 consecutive amino acids. Each GSSP4 polypeptide as described above can be further specified in terms of its N-terminal and C-terminal positions. For example, every combination of a N-terminal and C-terminal position that polypeptides of from 6 contiguous amino acids to 1 amino acids less than the full length GSSP4 polypeptide could occupy, on any given intact and contiguous full length GSSP4 polypeptide sequence are included in the present invention. Thus, a 6 consecutive amino acid fragment could occupy positions selected from the group consisting of 1-6, 2-7, 3-8, 4-9, 5-10, 6-11, 7-12, 8-13, 9-14, 10-15, 11-16, 12-17, 13-18, 14-19, 15-20, 16-21, 17-22, 18-23, 19-24, 20-25, 21-26, 22-27, 23-28, 24-29, 25-30, 26-31, 27-32, 28-33, 29-34, 30-35, 31-36, 32-37, 33-38, 34-39, 35-40, 36-41, 37-42, 38-43, 39-44, 40-45, 41-46, 42-47, 43-48, 44-49, 45-50, 46-51, 47-52, 48-53, 49-54, 50-55, 51-56, 52-57, 53-58, 54-59, 55-60, 56-61, 57-62, 58-63, 59-64, 60-65, 61-66, 62-67, 63-68, 64-69, 65-70, 66-71, 67-72, 68-73, 69-74, 70-75, 71-76, 72-77, 73-78, 74-79, 75-80, 76-81, 77-82, 78-83, 79-84, 80-85, 81-86, 82-87, 83-88, 84-89, 85-90, 86-91, 87-92, 88-93, 89-94, 90-95, 91-96, 92-97, 93-98, 94-99, 95-100, 96-101, 97-102, 98-103, 99-104, and 100-105, of a 105 consecutive amino acid fragment. Similarly, the positions occupied by all the other fragments of sizes between 6 amino acids and 105 amino acids of SEQ ID NO:3 are included in the present invention and can also be immediately envisaged based on these two examples and therefore, are not individually listed solely for the purpose of not unnecessarily lengthening the specification. Furthermore, the positions occupied by fragments of 6 to 105 consecutive amino acids of SEQ ID NO:3 are included in the present invention and can also be immediately envisaged based on these two examples and therefore are not individually listed solely for the purpose of not unnecessarily lengthening the specification. In addition, the positions occupied by fragments of 6 consecutive amino acids to 1 amino acid less than any other full length GSSP4 polypeptide can also be envisaged based on these two examples and therefore are not individually listed solely for the purpose of not unnecessarily lengthening the specification. The GSSP4 polypeptides of the present invention may alternatively be described by the formula “n to c” (inclusive); where “n” equals the N-terminal most amino acid position (as defined by the sequence listing) and “c” equals the C-terminal most amino acid position (as defined by the sequence listing) of the polypeptide; and further where “n” equals an integer between 1 and 99; and where “c” equals an integer between 7 and 105, the number of amino acids of the full length polypeptide sequence; and where “n” is an integer smaller then “c” by at least 6. Therefore, for the sequences provided in SEQ ID NO:3, “n” is any integer selected from the list consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99; and “c” is any integer selected from the group consisting of: 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105. Every combination of “n” and “c” positions are included as specific embodiments of the invention. Moreover, the formula “n” to “c” may be modified as “n1-n2” to “c1-c2”, wherein “n1-n2” and “c1-c2” represent positional ranges selected from any two integers above which represent amino acid positions of the sequence listing. Alternative formulas include “n1-n2” to “c” and “n” to “c1-c2”. These specific embodiments, and other polypeptide and polynucleotide fragment embodiments described herein may be modified as being “at least”, “equal to”, “equal to or less than”, “less than”, “at least ______ but not greater than ______” or “from ______ to ______”. a specified size or specified N-terminal and/or C-terminal positions. It is noted that all ranges used to describe any embodiment of the present invention are inclusive unless specifically set forth otherwise. The present invention also provides for the exclusion of any individual fragment specified by N-terminal and C-terminal positions or of any fragment specified by size in amino acid residues as described above. In addition, any number of fragments specified by N-terminal and C-terminal positions or by size in amino acid residues as described above may be excluded as individual species. Further, any number of fragments specified by N-terminal and C-terminal positions or by size in amino acid residues as described above may make up a polypeptide fragment in any combination and may optionally include non-GSSP4 polypeptide sequence as well. The term “GSSP4 fragment” as used herein refers to fragments of a full-length GSSP4 polypeptides that comprise at least 6 and any other integer number of amino acids up to 104 of the full-length GSSP4 polypeptide (defined above). GSSP4 polypeptides of the invention include variants, fragments, analogs and derivatives of the GSSP4 polypeptides described above, including modified GSSP4 polypeptides. Variants It will be recognized by one of ordinary skill in the art that some amino acids of the GSSP4 polypeptide sequences of the present invention can be varied without significant effect on the structure or function of the proteins; there will be critical amino acids in the sequence that determine activity. Thus, the invention further includes variants of GSSP4 polypeptides that have metabolic-related activity as described above. Such variants include GSSP4 polypeptide sequences with one or more amino acid deletions, insertions, inversions, repeats, and substitutions either from natural mutations or human manipulation selected according to general rules known in the art so as to have little effect on activity. Guidance concerning how to make phenotypically silent amino acid substitutions is provided below. There are two main approaches for studying the tolerance of an amino acid sequence to change (see, Bowie, et al. (1990) Science, 247, 1306-10). The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or screens to identify sequences that maintain functionality. These studies have revealed that proteins are surprisingly tolerant of amino acid substitutions and indicate which amino acid changes are likely to be permissive at a certain position of the protein. For example, most buried amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Other such phenotypically silent substitutions are described by Bowie et al. (supra) and the references cited therein. In the case of an amino acid substitution in the amino acid sequence of a polypeptide according to the invention, one or several amino acids can be replaced by “equivalent” amino acids. The expression “equivalent” amino acid is used herein to designate any amino acid that may be substituted for one of the amino acids having similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. In particular embodiments, conservative substitutions of interest are shown in Table 1 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, or as further described below in reference to amino acid classes, are introduced and the products screened. TABLE 1 Original Residue Exemplary Substitutions Preferred Substitutions Ala (A) val; leu; ile val Arg (R) lys; gin; asn lys Asn (N) gin; his; lys; arg gin Asp (D) glu glu Cys (C) ser ser Gin (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His (H) asn; gin; lys; arg arg Ile (I) leu; val; met; ala; phe; norleucine leu Leu (L) norleucine; ile; val; met; ala; phe ile Lys (K) arg; gin; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; ala; norleucine leu Substantial modifications in function or immunological identity of the GSSP4 polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties: (1) hydrophobic: norleucine, met, ala, val, leu, ile; (2) neutral hydrophilic: cys, ser, thr; (3) acidic: asp, glu; (4) basic: asn, gln, his, lys, arg; (5) residues that influence chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe. Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites. The variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)], restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the GSSP4 variant DNA. Amino acids in the GSSP4 polypeptide sequences of the invention that are essential for function can also be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (see, e.g., Cunningham, et al. (1989) Science 244(4908):1081-5). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for metabolic-related activity using assays as described above. Of special interest are substitutions of charged amino acids with other charged or neutral amino acids that may produce proteins with highly desirable improved characteristics, such as less aggregation. Aggregation may not only reduce activity but also be problematic when preparing pharmaceutical or physiologically acceptable formulations, because aggregates can be immunogenic (see, e.g., Pinckard, et al., (1967) Clin. Exp. Immunol 2:331-340; Robbins, et al., (1987) Diabetes July;36(7):838-41; and Cleland, et al., (1993) Crit Rev Ther Drug Carrier Syst. 10(4):307-77). Thus, the fragment, derivative, analog, or homolog of the GSSP4 polypeptides of the present invention may be, for example: (i) one in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code (i.e. may be a non-naturally occurring amino acid); or (ii) one in which one or more of the amino acid residues includes a substituent group; or (iii) one in which the GSSP4 polypeptide is fused with another compound, such as a compound to increase the half-life of the fragment (for example, polyethylene glycol); or (iv) one in which the additional amino acids are fused to the above form of the fragment, such as an IgG Fc fusion region peptide or leader or secretory sequence or a sequence which is employed for purification of the above form of the fragment or a pro-protein sequence. Such fragments, derivatives and analogs are deemed to be within the scope of those skilled in the art from the teachings herein. A further embodiment of the invention relates to a polypeptide which comprises the amino acid sequence of GSSP4 polypeptide having an amino acid sequence which contains at least one conservative amino acid substitution, but not more than 50 conservative amino acid substitutions, not more than 40 conservative amino acid substitutions, not more than 30 conservative amino acid substitutions, and not more than 20 conservative amino acid substitutions. Also provided are polypeptides which comprise the amino acid sequence of a GSSP4 fragment, having at least one, but not more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 conservative amino acid substitutions. Another specific embodiment of a modified GSSP4 polypeptide of the invention is a polypeptide that is resistant to proteolysis, for example a GSSP4 polypeptide in which a —CONH— peptide bond is modified and replaced by one or more of the following: a (CH2NH) reduced bond; a (NHCO) retro inverso bond; a (CH2—O) methylene-oxy bond; a (CH2—S) thiomethylene bond; a (CH2CH2) carba bond; a (CO—CH2) cetomethylene bond; a (CHOH—CH2) hydroxyethylene bond); a (N—N) bound; a E-alcene bond; or a —CH═CH— bond. Thus, the invention also encompasses a GSSP4 polypeptide or a variant thereof in which at least one peptide bond has been modified as described above. In addition, amino acids have chirality within the body of either L or D. In some embodiments it is preferable to alter the chirality of the amino acids in the GSSP4 polypeptides of the invention in order to extend half-life within the body. Thus, in some embodiments, one or more of the amino acids are preferably in the L configuration. In other embodiments, one or more of the amino acids are preferably in the D configuration. Percent Identity The polypeptides of the present invention also include polypeptides having an amino acid sequence at least 50% identical, at least 60% identical, or 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a GSSP4 polypeptide as described above. By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a GSSP4 polypeptide amino acid sequence is meant that the amino acid sequence is identical to the GSSP4 polypeptide sequence except that it may include up to five amino acid alterations per each 100 amino acids of the GSSP4 polypeptide amino acid sequence. The reference sequence is the GSSP4 polypeptide with a sequence corresponding to the sequences provided in SEQ ID NO:3. Thus, to obtain a polypeptide having an amino acid sequence at least 95% identical to a GSSP4 polypeptide amino acid sequence, up to 5% (5 of 100) of the amino acid residues in the sequence may be inserted, deleted, or substituted with another amino acid compared with the GSSP4 polypeptide sequence. These alterations may occur at the amino or carboxy termini or anywhere between those terminal positions, interspersed either individually among residues in the sequence or in one or more contiguous groups within the sequence. As a practical matter, whether any particular polypeptide is a percentage identical to a GSSP4 polypeptide can be determined conventionally using known computer programs. Such algorithms and programs include, but are by no means limited to, TBLASTN, BLASTP, FASTA, TFASTA, and CLUSTALW (Pearson and Lipman, (1988) Proc Natl Acad Sci USA April;85(8):2444-8; Altschul et al., (1990) J. Mol. Biol. 215(3):403-410; Thompson et al., (1994) Nucleic Acids Res. 22(2):4673-4680; Higgins et al., (1996) Meth. Enzymol. 266:383-402; Altschul et al., (1997) Nuc. Acids Res. 25:3389-3402; Altschul et al., (1993) Nature Genetics 3:266-272). In a particularly preferred embodiment, protein and nucleic acid sequence homologies are evaluated using the Basic Local Alignment Search Tool (“BLAST”), which is well known in the art (See, e.g., Karlin and Altschul (1990) Proc Natl Acad Sci USA March;87(6):2264-8; Altschul et al., 1990, 1993, 1997, all supra). In particular, five specific BLAST programs are used to perform the following tasks: (1) BLASTP and BLAST3 compare an amino acid query sequence against a protein sequence database; (2) BLASTN compares a nucleotide query sequence against a nucleotide sequence database; (3) BLASTX compares the six-frame conceptual translation products of a query nucleotide sequence (both strands) against a protein sequence database; (4) TBLASTN compares a query protein sequence against a nucleotide sequence database translated in all six reading frames (both strands); and (5) TBLASTX compares the six-frame translations of a nucleotide query sequence against the six-frame translations of a nucleotide sequence database. The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as “high-scoring segment pairs,” between a query amino or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database. High-scoring segment pairs are preferably identified (i.e., aligned) by means of a scoring matrix, many of which are known in the art. Preferably, the scoring matrix used is the BLOSUM62 matrix (see, Gonnet et al., (1992) Science June 5;256(5062): 1443-5; Henikoff and Henikoff (1993) Proteins September;17(1):49-61). Less preferably, the PAM or PAM250 matrices may also be used (See, e.g., Schwartz and Dayhoff, eds, (1978) Matrices for Detecting Distance Relationships: Atlas of Protein Sequence and Structure, Washington: National Biomedical Research Foundation). The BLAST programs evaluate the statistical significance of all high-scoring segment pairs identified, and preferably selects those segments which satisfy a user-specified threshold of significance, such as a user-specified percent homology. Preferably, the statistical significance of a high-scoring segment pair is evaluated using the statistical significance formula of Karlin (See, e.g., Karlin and Altschul, (1990) Proc Natl Acad Sci USA March;87(6):2264-8). The BLAST programs may be used with the default parameters or with modified parameters provided by the user. Preferably, the parameters are default parameters. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (1990) Comp. App. Biosci. 6:237-245. In a sequence alignment the query and subject sequences are both amino acid sequences. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group=25 Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=247 or the length of the subject amino acid sequence, whichever is shorter. If the subject sequence is shorter than the query sequence due to N-or C-terminal deletions, not because of internal deletions, the results, in percent identity, must be manually corrected because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, that are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query amino acid residues outside the farthest N- and C-terminal residues of the subject sequence. For example, a 90 amino acid residue subject sequence is aligned with a 100-residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not match/align with the first residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues are perfectly matched the final percent identity would be 90%. In another example, a 90-residue subject sequence is compared with a 100-residue query sequence. This time the deletions are internal so there are no residues at the N- or C-termini of the subject sequence, which are not matched/aligned with the query. In this case, the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequence are manually corrected. No other manual corrections are made for the purposes of the present invention. Production Note, throughout the disclosure, wherever GSSP4 polypeptides are discussed, GSSP4 fragments are specifically intended to be included as a preferred subset of GSSP4 polypeptides. Specific production methods are addressed in detail in sections III, IV, V, and VI of the present specification. In brief, GSSP4 polypeptides are preferably isolated from mammalian tissue samples, preferably human samples, or expressed from mammalian genes, preferably human genes, in mammalian cells, preferably human cells. The GSSP4 polypeptides of the invention can be made using expression methods known in the art. The polynucleotides encoding the desired polypeptides of the invention, including fragments thereof, are ligated into an expression vector suitable for the particular host used. Both eukaryotic and prokaryotic host systems can be used in forming recombinant polypeptides. The polypeptides are isolated from lysed cells or from the culture medium and purified to the extent needed for its intended use. In addition, shorter protein fragments may be produced by chemical synthesis. Purification is by techniques known in the art, for example, differential extraction, salt fractionation, chromatography, centrifugation, and the like. Nucleotides comprising the coding sequence of the polynucleotides of the invention, or fragments thereof, are cloned into expression vectors by anyone skilled in the art. Preferred expression vectors include eukaryotic and prokaryotic expression vectors. Further preferred is the pGEX-3X expression vector. Purification of GSSP4 polypeptides may be facilitated by recombinant fusion of a heterologous peptide to the C-or N-terminus of the GSSP4 polypeptides. Preferred fusion polypeptides expressed include heterologous polypeptides containing a His-tag added to the C-terminus, a glutathione-S-transferase (GST) tag and a factor Xa protease digestion site. A preferred method of making the polypeptides of the invention includes a method comprising the following steps: Escherichia coli cells, preferably BL21, and preferably comprising the pGEX-3X vector containing polynucleotides of the invention containing a His tag added to the C-terminus, GST tag and Xa protease site, are grown to subconfluence, preferably absorbance of 0.8, and induced with isopropyl beta-D-thiogalactoside. Cells are pelleted, washed and lysed in buffer, preferably in buffer containing guanidine hydrochloride. Polypeptides are allowed to bind to nickel, preferably Ni-NTA containing beads, and are washed with buffers, preferably buffers containing urea. Polypeptide bound to nickel are equilibrated with buffer, preferably buffer containing sodium chloride and calcium chloride, preferably at pH 7.5. Polypeptides bound to Nickel are digested, ie. treated with buffer comprising protease, preferably protease factor Xa. Digestion is preferably carried out at room temperature for 12 to 20 hours. The cleaved GST tag, if any, is washed away with buffer, preferably buffer with urea, preferably at pH 5.9. Polypeptides of the invention are eluted with buffer, preferably buffer with urea, preferably at pH 4.5. Polypeptides of the invention are refolded, preferably by methods comprising the following steps: Polypeptides are diluted in buffer common in the art, preferably to a concentration of 100 microgram/ml, preferably in buffer containing urea at pH 4.5. Polypeptides are dialyzed against buffer, preferably dialysis buffer comprising 4M urea, 5 mM cysteine, 0.02% Tween-20, 10% glycerol, 10 mM Tris, 150 mM sodium chloride, and 100 mM NaH2PO4, preferably at pH 8.3. Dialysis buffer comprising 2 M urea is used to replace the initial dialysis buffer, and dialysis buffer is replaced at least 1, 2, or 3 times over at least 1, 2, 3, 4, 5, or 6 days. The refolded polypeptide is desalted by any method known in the art, preferably using a spin column. Polypeptides of the invention are further purified by methods known in the art. Preferably polpeptides are purified with reverse phase HPLC. Polypeptides are preferably eluted with 0.08% trifluoroacetic acid and a 10-50% acetonitrile gradient, and elution is monitored preferably at 206 nm. Acetonitrile and trifluoroacetic acid are removed for the compositions comprising the purified polypeptide, preferably by evaporation by lyophilization. Further examples of methods useful for the expression or purification of polypeptides of the invention are found described in Methods in Enzymology. The nucleic acid encoding a GSSP4 fragment can be obtained by PCR from a vector containing the GSSP4 nucleotide sequence using oligonucleotide primers complementary to the desired GSSP4 cDNA and containing restriction endonuclease sequences. Transfection of a GSSP4 fragment-expressing vector into mouse NIH 3T3 cells is one embodiment of introducing polynucleotides into host cells. Introduction of a polynucleotide encoding a polypeptide into a host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al. ((1986) Methods in Molecular Biology, Elsevier Science Publishing Co., Inc., Amsterdam). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector. A polypeptide of this invention (i.e. a GSSP4 fragment) can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification. Polypeptides of the present invention, and preferably the secreted form, can also be recovered from: products purified from natural sources, including bodily fluids, tissues and cells, whether directly isolated or cultured; products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. Preferably the polypeptides of the invention are non-glycosylated. In addition, polypeptides of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., coding sequence), and/or to include genetic material (e.g., heterologous polynucleotide sequences) that is operably associated with the polynucleotides of the invention, and which activates, alters, and/or amplifies endogenous polynucleotides. For example, techniques known in the art may be used to operably associate heterologous control regions (e.g., promoter and/or enhancer) and endogenous polynucleotide sequences via homologous recombination, see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication No. WO 96/29411, published Sep. 26, 1996; International Publication No. WO 94/12650, published Aug. 4, 1994; Koller et al., (1989) Proc Natl Acad Sci USA November;86(22):8932-5; Koller et al., (1989) Proc Natl Acad Sci USA November;86(22):8927-31; and Zijlstra et al. (1989) Nature November 23;342(6248):435-8; the disclosures of each of which are incorporated by reference in their entireties). Modifications In addition, polypeptides of the invention can be chemically synthesized using techniques known in the art (See, e.g., Creighton, 1983 Proteins. New York, N.Y.: W. H. Freeman and Company; and Hunkapiller et al., (1984) Nature July 12-18;310(5973): 105-11). For example, a relative short fragment of the invention can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the fragment sequence. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, a-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, b-alanine, fluoroamino acids, designer amino acids such as b-methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary). The invention encompasses polypeptide fragments which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH4; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc. Additional post-translational modifications encompassed by the invention include, for example, N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The polypeptide fragments may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the polypeptide. Also provided by the invention are chemically modified derivatives of the polypeptides of the invention that may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity. See U.S. Pat. No. 4,179,337. The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The polypeptides may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties. The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a therapeutic protein or analog). The polyethylene glycol molecules (or other chemical moieties) should be attached to the polypeptide with consideration of effects on functional or antigenic domains of the polypeptide. There are a number of attachment methods available to those skilled in the art, e.g., EP 0 401 384, herein incorporated by reference (coupling PEG to G-CSF), see also Malik et al. (1992) Exp Hematol. September;20(8):1028-35, reporting pegylation of GM-CSF using tresyl chloride). Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group. Multimers The polypeptide fragments of the invention may be in monomers or multimers (i.e., dimers, trimers, tetramers and higher multimers). Accordingly, the present invention relates to monomers and multimers of the polypeptide fragments of the invention, their preparation, and compositions (preferably, pharmaceutical or physiologically acceptable compositions) containing them. In specific embodiments, the polypeptides of the invention are monomers, dimers, trimers or tetramers. In additional embodiments, the multimers of the invention are at least dimers, at least trimers, or at least tetramers. Multimers encompassed by the invention may be homomers or heteromers. As used herein, the term homomer, refers to a multimer containing only polypeptides corresponding to the GSSP4 polypeptides of the invention (including polypeptide fragments, variants, splice variants, and fusion proteins corresponding to these polypeptide fragments as described herein). These homomers may contain polypeptide fragments having identical or different amino acid sequences. In a specific embodiment, a homomer of the invention is a multimer containing only polypeptide fragments having an identical amino acid sequence. In another specific embodiment, a homomer of the invention is a multimer containing polypeptide fragments having different amino acid sequences. In specific embodiments, the multimer of the invention is a homodimer (e.g., containing polypeptide fragments having identical or different amino acid sequences) or a homotrimer (e.g., containing polypeptide fragments having identical and/or different amino acid sequences). In additional embodiments, the homomeric multimer of the invention is at least a homodimer, at least a homotrimer, or at least a homotetramer. As used herein, the term heteromer refers to a multimer containing one or more heterologous polypeptides (i.e., corresponding to different proteins or polypeptide fragments thereof) in addition to the polypeptides of the invention. In a specific embodiment, the multimer of the invention is a heterodimer, a heterotrimer, or a heterotetramer. In additional embodiments, the heteromeric multimer of the invention is at least a heterodimer, at least a heterotrimer, or at least a heterotetramer. Multimers of the invention may be the result of hydrophobic, hydrophilic, ionic and/or covalent associations and/or may be indirectly linked, by for example, liposome formation. Thus, in one embodiment, multimers of the invention, such as, for example, homodimers or homotrimers, are formed when polypeptides of the invention contact one another in solution. In another embodiment, heteromultimers of the invention, such as, for example, heterotrimers or heterotetramers, are formed when polypeptides of the invention contact antibodies to the polypeptides of the invention (including antibodies to the heterologous polypeptide sequence in a fusion protein of the invention) in solution. In other embodiments, multimers of the invention are formed by covalent associations with and/or between the polypeptides of the invention. Such covalent associations may involve one or more amino acid residues contained in the polypeptide sequence (e.g., that recited in the sequence listing, or contained in the polypeptide encoded by a deposited clone). In one instance, the covalent associations are cross-linking between cysteine residues located within the polypeptide sequences, which interact in the native (i.e., naturally occurring) polypeptide. In another instance, the covalent associations are the consequence of chemical or recombinant manipulation. Alternatively, such covalent associations may involve one or more amino acid residues contained in the heterologous polypeptide sequence in a fusion protein of the invention. In one example, covalent associations are between the heterologous sequence contained in a fusion protein of the invention (see, e.g., U.S. Pat. No. 5,478,925). In a specific example, the covalent associations are between the heterologous sequence contained in an Fc fusion protein of the invention (as described herein). In another specific example, covalent associations of fusion proteins of the invention are between heterologous polypeptide sequence from another protein that is capable of forming covalently associated multimers, such as for example, oseteoprotegerin (see, e.g., International Publication NO: WO 98/49305, the contents of which are herein incorporated by reference in its entirety). In another embodiment, two or more polypeptides of the invention are joined through peptide linkers. Examples include those peptide linkers described in U.S. Pat. No. 5,073,627 (hereby incorporated by reference). Proteins comprising multiple polypeptides of the invention separated by peptide linkers may be produced using conventional recombinant DNA technology. Another method for preparing multimer polypeptides of the invention involves use of polypeptides of the invention fused to a leucine zipper or isoleucine zipper polypeptide sequence. Examples of leucine zipper domains suitable for producing soluble multimeric proteins of the invention are those described in PCT application WO 94/10308, hereby incorporated by reference. Recombinant fusion proteins comprising a polypeptide of the invention fused to a polypeptide sequence that dimerizes or trimerizes in solution are expressed in suitable host cells, and the resulting soluble multimeric fusion protein is recovered from the culture supernatant using techniques known in the art. Trimeric polypeptides of the invention may offer the advantage of enhanced biological activity. Preferred leucine zipper moieties and isoleucine moieties are those that preferentially form trimers. One example is a leucine zipper derived from lung surfactant protein D (SPD), as described in Hoppe et al. FEBS Letters (1994) May 16;344(2-3):191-5. and in U.S. patent application Ser. No. 08/446,922, hereby incorporated by reference. Other peptides derived from naturally occurring trimeric proteins may be employed in preparing trimeric polypeptides of the invention. In another example, proteins of the invention are associated by interactions between Flag® & polypeptide sequence contained in fusion proteins of the invention containing Flag® polypeptide sequence. In a further embodiment, proteins of the invention are associated by interactions between heterologous polypeptide sequence contained in Flag® fusion proteins of the invention and anti Flag® antibody. The multimers of the invention may be generated using chemical techniques known in the art. For example, polypeptides desired to be contained in the multimers of the invention may be chemically cross-linked using linker molecules and linker molecule length optimization techniques known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, multimers of the invention may be generated using techniques known in the art to form one or more inter-molecule cross-links between the cysteine residues located within the sequence of the polypeptides desired to be contained in the multimer (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Further, polypeptides of the invention may be routinely modified by the addition of cysteine or biotin to the C-terminus or N-terminus of the polypeptide and techniques known in the art may be applied to generate multimers containing one or more of these modified polypeptides (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Additionally, at least 30 techniques known in the art may be applied to generate liposomes containing the polypeptide components desired to be contained in the multimer of the invention (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). Alternatively, multimers of the invention may be generated using genetic engineering techniques known in the art. In one embodiment, polypeptides contained in multimers of the invention are produced recombinantly using fusion protein technology described herein or otherwise known in the art (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In a specific embodiment, polynucleotides coding for a homodimer of the invention are generated by ligating a polynucleotide sequence encoding a polypeptide of the invention to a sequence encoding a linker polypeptide and then further to a synthetic polynucleotide encoding the translated product of the polypeptide in the reverse orientation from the original C-terminus to the N-terminus (lacking the leader sequence) (see, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). In another embodiment, recombinant techniques described herein or otherwise known in the art are applied to generate recombinant polypeptides of the invention which contain a transmembrane domain (or hyrophobic or signal peptide) and which can be incorporated by membrane reconstitution techniques into liposomes (See, e.g., U.S. Pat. No. 5,478,925, which is herein incorporated by reference in its entirety). II. GSSP4 Polynucleotides of the Invention Preferred polynucleotides are those that encode GSSP4 polypeptides of the invention. The recombinant polynucleotides encoding GSSP4 polypeptides can be used in a variety of ways, including, but not limited to, expressing the polypeptides in recombinant cells for use in screening assays for antagonists and agonists of its activity as well as to facilitate its purification for use in a variety of ways including, but not limited to screening assays for agonists and antagonists of its activity, diagnostic screens, and raising antibodies, as well as treatment and/or prevention of metabolic-related diseases and disorders and/or to reduce body mass. The invention relates to the polynucleotides encoding GSSP4 polypeptides and variant polypeptide fragments thereof as described herein. These polynucleotides may be purified, isolated, and/or recombinant. In all cases, the desired GSSP4 polynucleotides of the invention are those that encode GSSP4 polypeptides of the invention having metabolic-related activity as described and discussed herein. Fragments A polynucleotide fragment is a polynucleotide having a sequence that entirely is the same as part, but not all, of the full length GSSP4 polypeptide or a specified GSSP4 polypeptide nucleotide sequence. Such fragments may be “free-standing”, i.e. not part of or fused to other polynucleotides, or they may be comprised within another non-GSSP4 (heterologous) polynucleotide of which they form a part or region. However, several GSSP4 polynucleotide fragments may be comprised within a single polynucleotide. The GSSP4 polynucleotides of the invention comprise from 18 consecutive bases to 18 consecutive bases less than the full length polynucleotide sequences encoding the intact GSSP4 polypeptides, for example the GSSP4 polynucleotide sequences in SEQ ID NO:1 or 2. In one aspect of this embodiment, the polynucleotide comprises at least 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, or 648 consecutive nucleotides of a polynucleotide of the present invention. In addition to the above preferred nucleic acid sizes, further preferred nucleic acids comprise at least 18 nucleotides, wherein “at least 18” is defined as any integer between 18 and the integer representing 18 nucleotides less than the 3′ most nucleotide position of the intact GSSP4 polypeptides cDNA as set forth in SEQ ID NO: 2, or elsewhere herein. Further included as preferred polynucleotides of the present invention are nucleic acid fragments at least 18 nucleotides in length, as described above, that are further specified in terms of their 5′ and 3′ position set forth in the sequence listing below. For allelic and degenerate and other variants, position 1 is defined as the 5′ most nucleotide of the ORF, i.e., the nucleotide “A” of the start codon (ATG) with the remaining nucleotides numbered consecutively. Therefore, every combination of a 5′ and 3′ nucleotide position that a polynucleotide fragment invention, at least 18 contiguous nucleotides in length, could occupy on an intact GSSP4 polypeptide polynucleotide of the present invention is included in the invention as an individual species. The polynucleotide fragments specified by 5′ and 3′ positions can be immediately envisaged and are therefore not individually listed solely for the purpose of not unnecessarily lengthening the specification. It is noted that the above species of polynucleotide fragments of the present invention may alternatively be described by the formula “x to y”; where “x” equals the 5′ most nucleotide position and “y” equals the 3′ most nucleotide position of the polynucleotide; and further where “x” equals an integer between 1 and the number of nucleotides of the polynucleotide sequence of the present invention minus 18, and where “y” equals an integer between 19 and the number of nucleotides of the polynucleotide sequence of the present invention minus 18 nucleotides; and where “x” is an integer smaller then “y” by at least 18. The GSSP4 polynucleotide fragments of the invention comprise from 18 consecutive bases to the full length polynucleotide sequence encoding the GSSP4 fragments described in Section II of the Preferred Embodiments of the Invention. In one aspect of this embodiment, the polynucleotide comprises at least 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 740, 770, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100 or 2200 consecutive nucleotides of a polynucleotide of the present invention. In addition to the above preferred nucleic acid sizes, further preferred nucleic acids comprise at least 18 nucleotides, wherein “at least 18” is defined as any integer between 18 and the integer corresponding to the 3′ most nucleotide position of a GSSP4 fragment cDNA herein. Further included as preferred polynucleotides of the present invention are nucleic acid fragments at least 18 nucleotides in length, as described above, that are further specified in terms of their 5′ and 3′ position. The 5′ and 3′ positions are represented by the position numbers set forth in the sequence listing below. For allelic and degenerate and other variants, position 1 is defined as the 5′ most nucleotide of the open reading frame (ORF), i.e., the nucleotide “A” of the start codon (ATG) with the remaining nucleotides numbered consecutively. Therefore, every combination of a 5′ and 3′ nucleotide position that a polynucleotide fragment invention, at least 18 contiguous nucleotides in length, could occupy on a GSSP4 fragment polynucleotide of the present invention is included in the invention as an individual species. The polynucleotide fragments specified by 5′ and 3′ positions can be immediately envisaged and are therefore not individually listed solely for the purpose of not unnecessarily lengthening the specification. It is noted that the above species of polynucleotide fragments of the present invention may alternatively be described by the formula “x to y”; where “x” equals the 5′ most nucleotide position and “y” equals the 3′ most nucleotide position of the polynucleotide; and further where “x” equals an integer between 1 and the number of nucleotides of the GSSP4 polynucleotide sequences of the present invention minus 18, and where “y” equals an integer between 9 and the number of nucleotides of the GSSP4 polynucleotide sequences of the present invention; and where “x” is an integer smaller than “y” by at least 18. Every combination of “x” and ‘y’ positions are included as specific embodiments of the invention. Moreover, the formula “x” to “y” may be modified as “‘x1-x2” to “y1-y2’”, wherein “x1-x2” and “y1-y2” represent positional ranges selected from any two nucleotide positions of the sequence listing. Alternative formulas include “‘x1-x2” to “y’” and “‘x” to “y1-y2’”. These specific embodiments, and other polynucleotide fragment embodiments described herein may be modified as being “at least”, “equal to”, “equal to or less than”, “less than”, “at least ______ but not greater than ______”or “from ______ to ______”. a specified size or specified 5′ and/or 3′ positions. The present invention also provides for the exclusion of any species of polynucleotide fragments of the present invention specified by 5′ and 3′ positions or polynucleotides specified by size in nucleotides as described above. Any number of fragments specified by 5′ and 3′ positions or by size in nucleotides, as described above, may be excluded. Variants In other preferred embodiments, variants of GSSP4 polynucleotides encoding GSSP4 polypeptides are envisioned. Variants of polynucleotides, as the term is used herein, are polynucleotides whose sequence differs from a reference polynucleotide. A variant of a polynucleotide may be a naturally occurring variant such as a naturally occurring allelic variant, or it may be a variant that is not known to occur naturally. Such non-naturally occurring variants of the polynucleotide may be made by mutagenesis techniques, including those applied to polynucleotides, cells or organisms. Generally, differences are limited so that the nucleotide sequences of the reference and the variant are closely similar overall and, in many regions, identical. Polynucleotide variants that comprise a sequence substantially different from those described above but that, due to the degeneracy of the genetic code, still encode GSSP4 polypeptides of the present invention are also specifically envisioned. It would also be routine for one skilled in the art to generate the degenerate variants described above, for instance, to optimize codon expression for a particular host (e.g., change codons in the human mRNA to those preferred by other mammalian or bacterial host cells). As stated above, variant polynucleotides may occur naturally, such as a natural allelic variant, or by recombinant methods. By an “allelic variant” is intended one of several alternate forms of a gene occupying a given locus on a chromosome of an organism (See, e.g., B. Lewin, (1990) Genes IV, Oxford University Press, New York). Non-naturally occurring variants may be produced using art-known mutagenesis techniques. Such nucleic acid variants include those produced by nucleotide substitutions, deletions, or additions. The substitutions, deletions, or additions may involve one or more nucleotides. Alterations in the coding regions may produce conservative or non-conservative amino acid substitutions, deletions or additions. Especially preferred among these are silent substitutions, additions and deletions, which do not alter the properties and activities of GSSP4 polypeptides of the invention. Also preferred in this regard are conservative substitutions. Nucleotide changes present in a variant polynucleotide are preferably silent, which means that they do not alter the amino acids encoded by the polynucleotide. However, nucleotide changes may also result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence. In cases where the nucleotide substitutions result in one or more amino acid changes, preferred GSSP4 polypeptides include those that retain one or more metabolic-related activity as described in Section I of the Preferred Embodiments of the Invention. By “retain the same activities” is meant that the activity measured using the polypeptide encoded by the variant GSSP4 polynucleotide in assays is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%, and not more than 101%, 102%, 103%, 104%, 105%, 110%, 115%, 120% or 125% of the activity measured using a GSSP4 polypeptide described in the Examples Section herein. By the activity being “increased” is meant that the activity measured using the polypeptide encoded by the variant GSSP4 polynucleotide in assays is at least 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 450%, or 500% of the activity measured using a GSSP4 polypeptide described in the Examples Section herein. By the activity being “decrease” is meant that the activity measured using the polypeptide encoded by the variant GSSP4 polynucleotide in assays is decreased by at least 25%, 30%, 35%, 40%, 45%, or 50% of the activity measured using a GSSP4 polypeptide described in the Examples Section herein. Percent Identity The present invention is further directed to nucleic acid molecules having sequences at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the polynucleotide sequences of SEQ ID NO:1, or 2 or fragments thereof that encode a polypeptide having metabolic-related activity as described in Section I of the Preferred Embodiments of the Invention. Of course, due to the degeneracy of the genetic code, one of ordinary skill in the art will immediately recognize that a large number of the nucleic acid molecules at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the nucleic acid sequences shown in SEQ ID NO:1, or 2 or fragments thereof will encode a polypeptide having biological activity. In fact, since degenerate variants of these nucleotide sequences all encode the same polypeptide, this will be clear to the skilled artisan even without performing the above described comparison assay. It will be further recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also encode a polypeptide having biological activity. This is because the skilled artisan is fully aware of amino acid substitutions that are either less likely or not likely to significantly affect protein function (e.g., replacing one aliphatic amino acid with a second aliphatic amino acid), as further described previously in Section I of the Preferred Embodiments of the Invention. By a polynucleotide having a nucleotide sequence at least, for example, 95% “identical” to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the GSSP4 polypeptide. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence may be deleted, inserted, or substituted with another nucleotide. The query sequence may be an entire sequence or any fragment specified as described herein. The methods of determining and defining whether any particular nucleic acid molecule or polypeptide is at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the present invention can be done by using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al., ((1990) Comput Appl Biosci. July;6(3):237-45). In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by first converting U's to T's. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identity are: Matrix=Unitary, k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the length of the subject nucleotide sequence, whichever is shorter. If the subject sequence is shorter than the query sequence because of 5′ or 3′ deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5′ and 3′ truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5′ or 3′ ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5′ and 3′ of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present invention. Only nucleotides outside the 5′ and 3′ nucleotides of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score. No other manual corrections are made for the purposes of the present invention. Fusions Further included in the present invention are polynucleotides encoding the polypeptides of the present invention that are fused in frame to the coding sequences for additional heterologous amino acid sequences. Also included in the present invention are nucleic acids encoding polypeptides of the present invention together with additional, non-coding sequences, including for example, but not limited to non-coding 5′ and 3′ sequences, vector sequence, sequences used for purification, probing, or priming. For example, heterologous sequences include transcribed, non-translated sequences that may play a role in transcription, and mRNA processing, for example, ribosome binding and stability of mRNA. The heterologous sequences may alternatively comprise additional coding sequences that provide additional functionalities. Thus, a nucleotide sequence encoding a polypeptide may be fused to a tag sequence, such as a sequence encoding a peptide that facilitates purification of the fused polypeptide. In certain preferred embodiments of this aspect of the invention, the tag amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. For instance, hexa-histidine provides for convenient purification of the fusion protein (See, Gentz et al., (1989) Proc Natl Acad Sci USA February;86(3):821-4). The “HA” tag is another peptide useful for purification which corresponds to an epitope derived from the influenza hemagglutinin protein (See, Wilson et al., (1984) Cell 37(3):767-78). As discussed above, other such fusion proteins include GSSP4 fragment cDNA fused to Fc at the N- or C-terminus. III. Recombinant Vectors of the Invention The term “vector” is used herein to designate either a circular or a linear DNA or RNA molecule, that is either double-stranded or single-stranded, and that comprises at least one polynucleotide of interest that is sought to be transferred in a cell host or in a unicellular or multicellular host organism. The present invention relates to recombinant vectors comprising any one of the polynucleotides described herein. The present invention encompasses a family of recombinant vectors that comprise polynucleotides encoding GSSP4 polypeptides of the invention. In a first preferred embodiment, a recombinant vector of the invention is used to amplify the inserted polynucleotide in a suitable cell host, this polynucleotide being amplified every time that the recombinant vector replicates. The inserted polynucleotide can be one that encodes GSSP4 polypeptides of the invention. A second preferred embodiment of the recombinant vectors according to the invention consists of expression vectors comprising polynucleotides encoding GSSP4 polypeptides of the invention. Within certain embodiments, expression vectors are employed to express a GSSP4 polypeptide of the invention, preferably a modified GSSP4 fragment described in the present invention, which can be then purified and, for example, be used as a treatment for metabolic-related diseases, or simply to reduce body mass of individuals. Expression requires that appropriate signals are provided in the vectors, said signals including various regulatory elements, such as enhancers/promoters from both viral and mammalian sources, that drive expression of the genes of interest in host cells. Dominant drug selection markers for establishing permanent, stable, cell clones expressing the products are generally included in the expression vectors of the invention, as they are elements that link expression of the drug selection markers to expression of the polypeptide. More particularly, the present invention relates to expression vectors which include nucleic acids encoding a GSSP4 polypeptide of the invention, or a modified GSSP4 fragment as described herein, or variants or fragments thereof, under the control of a regulatory sequence selected among GSSP4 polypeptides, or alternatively under the control of an exogenous regulatory sequence. Consequently, preferred expression vectors of the invention are selected from the group consisting of: (a) a GSSP4 fragmentregulatory sequence and driving the expression of a coding polynucleotide operably linked thereto; and (b) a GSSP4 fragment coding sequence of the invention, operably linked to regulatory sequences allowing its expression in a suitable cell host and/or host organism. Some of the elements which can be found in the vectors of the present invention are described in further detail in the following sections. 1) General Features of the Expression Vectors of the Invention: A recombinant vector according to the invention comprises, but is not limited to, a YAC (Yeast Artificial Chromosome), a BAC (Bacterial Artificial Chromosome), a phage, a phagemid, a cosmid, a plasmid, or even a linear DNA molecule which may consist of a chromosomal, non-chromosomal, semi-synthetic or synthetic DNA. Such a recombinant vector can comprise a transcriptional unit comprising an assembly of: (1) a genetic element or elements having a regulatory role in gene expression, for example promoters or enhancers. Enhancers are cis-acting elements of DNA, usually from about 10 to 300 bp in length that act on the promoter to increase the transcription; (2) a structural or coding sequence which is transcribed into mRNA and eventually translated into a polypeptide, said structural or coding sequence being operably linked to the regulatory elements described in (1); and (3) appropriate transcription initiation and termination sequences. Structural units intended for use in yeast or eukaryotic expression systems preferably include a leader sequence enabling extracellular secretion of translated protein by a host cell. Alternatively, when a recombinant protein is expressed without a leader or transport sequence, it may include a N-terminal residue. This residue may or may not be subsequently cleaved from the expressed recombinant protein to provide a final product. Generally, recombinant expression vectors will include origins of replication, selectable markers permitting transformation of the host cell, and a promoter derived from a highly expressed gene to direct transcription of a downstream structural sequence. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably a leader sequence capable of directing secretion of the translated protein into the periplasmic space or the extracellular medium. In a specific embodiment wherein the vector is adapted for transfecting and expressing desired sequences in mammalian host cells, preferred vectors will comprise an origin of replication in the desired host, a suitable promoter and enhancer, and also any necessary ribosome binding sites, polyadenylation sites, splice donor and acceptor sites, transcriptional termination sequences, and 5′-flanking non-transcribed sequences. DNA sequences derived from the SV40 viral genome, for example SV40 origin, early promoter, enhancer, splice and polyadenylation sites may be used to provide the required non-transcribed genetic elements. 2) Regulatory Elements Promoters The suitable promoter regions used in the expression vectors of the present invention are chosen taking into account the cell host in which the heterologous gene is expressed. The particular promoter employed to control the expression of a nucleic acid sequence of interest is not believed to be important, so long as it is capable of directing the expression of the nucleic acid in the targeted cell. Thus, where a human cell is targeted, it is preferable to position the nucleic acid coding region adjacent to and under the control of a promoter that is capable of being expressed in a human cell, such as, for example, a human or a viral promoter. A suitable promoter may be heterologous with respect to the nucleic acid for which it controls the expression or alternatively can be endogenous to the native polynucleotide containing the coding sequence to be expressed. Additionally, the promoter is generally heterologous with respect to the recombinant vector sequences within which the construct promoter/coding sequence has been inserted. Promoter regions can be selected from any desired gene using, for example, CAT (chloramphenicol transferase) vectors and more preferably pKK232-8 and pCM7 vectors. Preferred bacterial promoters are the LacI, LacZ, the T3 or T7 bacteriophage RNA polymerase promoters, the gpt, lambda PR, PL and trp promoters (EP 0036776), the polyhedrin promoter, or the p10 protein promoter from baculovirus (Kit Novagen) (Smith et al., (1983) Mol Cell Biol December;3(12):2156-65; O'Reilly et al., 1992), the lambda PR promoter or also the trc promoter. Eukaryotic promoters include CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-L. In addition, promoters specific for a particular cell type may be chosen, such as those facilitating expression in adipose tissue, muscle tissue, or liver. Selection of a convenient vector and promoter is well within the level of ordinary skill in the art. The choice of a promoter is well within the ability of a person skilled in the field of genetic engineering. For example, one may refer to Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY, Vol. 1, 2, 3 (1989), or also to the procedures described by Fuller et al. (1996) Immunology in Current Protocols in Molecular Biology. Other Regulatory Elements Where a cDNA insert is employed, one will typically desire to include a polyadenylation signal to effect proper polyadenylation of the gene transcript. The nature of the polyadenylation signal is not believed to be crucial to the successful practice of the invention, and any such sequence may be employed such as human growth hormone and SV40 polyadenylation signals. Also contemplated as an element of the expression cassette is a terminator. These elements can serve to enhance message levels and to minimize read through from the cassette into other sequences. 3) Selectable Markers Such markers would confer an identifiable change to the cell permitting easy identification of cells containing the expression construct. The selectable marker genes for selection of transformed host cells are preferably dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, TRP 1 for S. cerevisiae or tetracycline, rifampicin or ampicillin resistance in E. coli, or levan saccharase for mycobacteria, this latter marker being a negative selection marker. 4) Preferred Vectors Bacterial Vectors As a representative but non-limiting example, useful expression vectors for bacterial use can comprise a selectable marker and a bacterial origin of replication derived from commercially available plasmids comprising genetic elements of pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia, Uppsala, Sweden), and pGEM1 (Promega Biotec, Madison, Wis., USA). Large numbers of other suitable vectors are known to those of skill in the art, and are commercially available, such as the following bacterial vectors: pQE70, pQE60, pQE-9 (Qiagen), pbs, pD10, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNH16A, pNH18A, pNH46A (Stratagene); ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (Pharmacia); pWLNEO, pSV2CAT, pOG44, pXT1, pSG (Stratagene); pSVK3, pBPV, pMSG, pSVL (Pharmacia); pQE-30 (QIAexpress). Baculovirus Vectors A suitable vector for the expression of polypeptides of the invention is a baculovirus vector that can be propagated in insect cells and in insect cell lines. A specific suitable host vector system is the pVL1392/1393 baculovirus transfer vector (Pharmingen) that is used to transfect the SF9 cell line (ATCC NoCRL 1711) which is derived from Spodoptera frugiperda. Other suitable vectors for the expression of GSSP4 polypeptides in a baculovirus expression system include those described by Chai et al. (1993; Biotechnol Appl Biochem. December; 18 (Pt 3):259-73); Vlasak et al. (1983; Eur J Biochem September 1;135(1):123-6); and Lenhard et al. (1996; Gene March 9;169(2):187-90). Viral Vectors In one specific embodiment, the vector is derived from an adenovirus. Preferred adenovirus vectors according to the invention are those described by Feldman and Steg (1996; Semin Interv Cardiol September;1(3):203-8) or Ohno et al. (1994; Science August 5;265(5173):781-4). Another preferred recombinant adenovirus according to this specific embodiment of the present invention is the human adenovirus type 2 or 5 (Ad 2 or Ad 5) or an adenovirus of animal origin (French patent application No. FR-93.05954). Retrovirus vectors and adeno-associated virus vectors are generally understood to be the recombinant gene delivery systems of choice for the transfer of exogenous polynucleotides in vivo, particularly to mammals, including humans. These vectors provide efficient delivery of genes into cells, and the transferred nucleic acids are stably integrated into the chromosomal DNA of the host. Particularly preferred retroviruses for the preparation or construction of retroviral in vitro or in vivo gene delivery vehicles of the present invention include retroviruses selected from the group consisting of Mink-Cell Focus Inducing Virus, Murine Sarcoma Virus, Reticuloendotheliosis virus and Rous Sarcoma virus. Particularly preferred Murine Leukemia Viruses include the 4070A and the 1504A viruses, Abelson (ATCC No VR-999), Friend (ATCC No VR-245), Gross (ATCC No VR-590), Rauscher (ATCC No VR-998) and Moloney Murine Leukemia Virus (ATCC No VR-190; PCT Application No WO 94/24298). Particularly preferred Rous Sarcoma Viruses include Bryan high titer (ATCC Nos VR-334, VR-657, VR-726, VR-659 and VR-728). Other preferred retroviral vectors are those described in Roth et al. (1996), PCT Application No WO 93/25234, PCT Application No WO 94/06920, Roux et al., ((1989) Proc Natl Acad Sci USA December;86(23):9079-83), Julan et al., (1992) J. Gen. Virol. 3:3251-3255 and Neda et al., ((1991) J Biol Chem August 5;266(22):14143-6). Yet another viral vector system that is contemplated by the invention consists of the adeno-associated virus (AAV). The adeno-associated virus is a naturally occurring defective virus that requires another virus, such as an adenovirus or a herpes virus, as a helper virus for efficient replication and a productive life cycle (Muzyczka et al., (1992) Curr Top Microbiol Immunol;158:97-129). It is also one of the few viruses that may integrate its DNA into non-dividing cells, and exhibits a high frequency of stable integration (Flotte et al., (1992) Am J Respir Cell Mol Biol September;7(3):349-56; Samulski et al., (1989) J Virol September;63(9):3822-8; McLaughlin et al., (1989) Am. J. Hum. Genet. 59:561-569). One advantageous feature of AAV derives from its reduced efficacy for transducing primary cells relative to transformed cells. 5) Delivery of the Recombinant Vectors In order to effect expression of the polynucleotides of the invention, these constructs must be delivered into a cell. This delivery may be accomplished in vitro, as in laboratory procedures for transforming cell lines, or in vivo or ex vivo, as in the treatment of certain disease states. One mechanism is viral infection where the expression construct is encapsulated in an infectious viral particle. Several non-viral methods for the transfer of polynucleotides into cultured mammalian cells are also contemplated by the present invention, and include, without being limited to, calcium phosphate precipitation (Graham et al., (1973) Virology August;54(2):536-9; Chen et al., (1987) Mol Cell Biol August;7(8):2745-52), DEAE-dextran (Gopal, (1985) Mol Cell Biol May;5(5): 1188-90), electroporation (Tur-Kaspa et al., (1986) Mol Cell Biol February;6(2):716-8; Potter et al., (1984) Proc Natl Acad Sci USA November;81(22):7161-5.), direct microinjection (Harland et al., (1985) J Cell Biol September;101(3):1094-9), DNA-loaded liposomes (Nicolau et al., (1982) Biochim Biophys Acta October 11;721(2):185-90; Fraley et al., (1979) Proc Natl Acad Sci USA July;76(7):3348-52), and receptor-mediated transfection (Wu and Wu, (1987) J Biol Chem April 5;262(10):4429-32; Wu and Wu (1988) Biochemistry February 9;27(3):887-92). Some of these techniques may be successfully adapted for in vivo or ex vivo use. Once the expression polynucleotide has been delivered into the cell, it may be stably integrated into the genome of the recipient cell. This integration may be in the cognate location and orientation via homologous recombination (gene replacement) or it may be integrated in a random, non specific location (gene augmentation). In yet further embodiments, the nucleic acid may be stably maintained in the cell as a separate, episomal segment of DNA. Such nucleic acid segments or “episomes” encode sequences sufficient to permit maintenance and replication independent of or in synchronization with the host cell cycle. One specific embodiment for a method for delivering a protein or peptide to the interior of a cell of a vertebrate in vivo comprises the step of introducing a preparation comprising a physiologically acceptable carrier and a naked polynucleotide operatively coding for the polypeptide of interest into the interstitial space of a tissue comprising the cell, whereby the naked polynucleotide is taken up into the interior of the cell and has a physiological effect. This is particularly applicable for transfer in vitro but it may be applied to in vivo as well. Compositions for use in vitro and in vivo comprising a “naked” polynucleotide are described in PCT application No. WO 90/11092 (Vical Inc.) and also in PCT application No. WO 95/11307 (Institut Pasteur, INSERM, Universit{acute over (e )} d'Ottawa) as well as in the articles of Tascon et al. (1996) Nature Medicine. 2(8):888-892 and of Huygen et al. ((1996) Nat Med August;2(8):893-8). In still another embodiment of the invention, the transfer of a naked polynucleotide of the invention, including a polynucleotide construct of the invention, into cells may be proceeded with a particle bombardment (biolistic), said particles being DNA-coated microprojectiles accelerated to a high velocity allowing them to pierce cell membranes and enter cells without killing them, such as described by Klein et al. ((1990) Curr Genet February;17(2):97-103). In a further embodiment, the polynucleotide of the invention may be entrapped in a liposome (Ghosh and Bacchawat, (1991) Targeted Diagn Ther;4:87-103; Wong et al., (1980) Gene 10:87-94; Nicolau et al., (1987) Methods Enzymol.;149:157-76). These liposomes may further be targeted to cells expressing LSR by incorporating leptin, triglycerides, ACRP30, or other known LSR ligands into the liposome membrane. In a specific embodiment, the invention provides a composition for the in vivo production of an GSSP4 polypeptides described herein. It comprises a naked polynucleotide operatively coding for this polypeptide, in solution in a physiologically acceptable carrier, and suitable for introduction into a tissue to cause cells of the tissue to express the said polypeptide. The amount of vector to be injected to the desired host organism varies according to the site of injection. As an indicative dose, it will be injected between 0.1 and 100 μg of the vector in an animal body, preferably a mammal body, for example a mouse body. In another embodiment of the vector according to the invention, it may be introduced in vitro in a host cell, preferably in a host cell previously harvested from the animal to be treated and more preferably a somatic cell such as a muscle cell. In a subsequent step, the cell that has been transformed with the vector coding for the desired GSSP4 polypeptides or the desired fragment thereof is reintroduced into the animal body in order to deliver the recombinant protein within the body either locally or systemically. IV. Recombinant Cells of the Invention Another object of the invention consists of host cells recombinant for, i.e., that have been transformed or transfected with one of the polynucleotides described herein, and more precisely a polynucleotide comprising a polynucleotide encoding a GSSP4 polypeptide of the invention such as any one of those described in “Polynucleotides of the Invention”. These polynucleotides can be present in cells as a result of transient or stable transfection. The invention includes host cells that are transformed (prokaryotic cells) or that are transfected (eukaryotic cells) with a recombinant vector such as any one of those described in “Recombinant Vectors of the Invention”. Generally, a recombinant host cell of the invention comprises at least one of the polynucleotides or the recombinant vectors of the invention that are described herein. Preferred host cells used as recipients for the recombinant vectors of the invention are the following: a) Prokaryotic host cells: Escherichia coli strains (I.E. DH5-α strain), Bacillus subtilis, Salmonella typhimurium, and strains from species like Pseudomonas, Streptomyces and Staphylococcus, and b) Eukaryotic host cells: HeLa cells (ATCC NoCCL2; NoCCL2.1; NoCCL2.2), Cv 1 cells (ATCC NoCCL70), COS cells (ATCC NoCRL1650; NoCRL1651), Sf-9 cells (ATCC NoCRL1711), C127 cells (ATCC No CRL-1804), 3T3 (ATCC No CRL-6361), CHO (ATCC No CCL-61), human kidney 293 (ATCC No 45504; No CRL-1573), BHK (ECACC No 84100501; No 84111301), PLC cells, HepG2, and Hep3B. The constructs in the host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. Following transformation of a suitable host and growth of the host to an appropriate cell density, the selected promoter is induced by appropriate means, such as temperature shift or chemical induction, and cells are cultivated for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. Microbial cells employed in the expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents. Such methods are well known by the skilled artisan. Further, according to the invention, these recombinant cells can be created in vitro or in vivo in an animal, preferably a mammal, most preferably selected from the group consisting of mice, rats, dogs, pigs, sheep, cattle, and primates, not to include humans. Recombinant cells created in vitro can also be later surgically implanted in an animal, for example. Methods to create recombinant cells in vivo in animals are well-known in the art. The present invention also encompasses primary, secondary, and immortalized homologously recombinant host cells of vertebrate origin, preferably mammalian origin and particularly human origin, that have been engineered to: a) insert exogenous (heterologous) polynucleotides into the endogenous chromosomal DNA of a targeted gene, b) delete endogenous chromosomal DNA, and/or c) replace endogenous chromosomal DNA with exogenous polynucleotides. Insertions, deletions, and/or replacements of polynucleotide sequences may be to the coding sequences of the targeted gene and/or to regulatory regions, such as promoter and enhancer sequences, operably associated with the targeted gene. The present invention further relates to a method of making a homologously recombinant host cell in vitro or in vivo, wherein the expression of a targeted gene not normally expressed in the cell is altered. Preferably the alteration causes expression of the targeted gene under normal growth conditions or under conditions suitable for producing the polypeptide encoded by the targeted gene. The method comprises the steps of: (a) transfecting the cell in vitro or in vivo with a polynucleotide construct, the polynucleotide construct comprising; (i) a targeting sequence; (ii) a regulatory sequence and/or a coding sequence; and (iii) an unpaired splice donor site, if necessary, thereby producing a transfected cell; and (b) maintaining the transfected cell in vitro or in vivo under conditions appropriate for homologous recombination. The present invention further relates to a method of altering the expression of a targeted gene in a cell in vitro or in vivo wherein the gene is not normally expressed in the cell, comprising the steps of: (a) transfecting the cell in vitro or in vivo with a polynucleotide construct, the polynucleotide construct comprising: (i) a targeting sequence; (ii) a regulatory sequence and/or a coding sequence; and (iii) an unpaired splice donor site, if necessary, thereby producing a transfected cell; and (b) maintaining the transfected cell in vitro or in vivo under conditions appropriate for homologous recombination, thereby producing a homologously recombinant cell; and (c) maintaining the homologously recombinant cell in vitro or in vivo under conditions appropriate for expression of the gene. The present invention further relates to a method of making a polypeptide of the present invention by altering the expression of a targeted endogenous gene in a cell in vitro or in vivo wherein the gene is not normally expressed in the cell, comprising the steps of: a) transfecting the cell in vitro with a polynucleotide construct, the polynucleotide construct comprising: (i) a targeting sequence; (ii) a regulatory sequence and/or a coding sequence; and (iii) an unpaired splice donor site, if necessary, thereby producing a transfected cell; (b) maintaining the transfected cell in vitro or in vivo under conditions appropriate for homologous recombination, thereby producing a homologously recombinant cell; and c) maintaining the homologously recombinant cell in vitro or in vivo under conditions appropriate for expression of the gene thereby making the polypeptide. The present invention further relates to a polynucleotide construct that alters the expression of a targeted gene in a cell type in which the gene is not normally expressed. This occurs when a polynucleotide construct is inserted into the chromosomal DNA of the target cell, wherein the polynucleotide construct comprises: a) a targeting sequence; b) a regulatory sequence and/or coding sequence; and c) an unpaired splice-donor site, if necessary. Further included are polynucleotide constructs, as described above, wherein the construct further comprises a polynucleotide which encodes a polypeptide and is in-frame with the targeted endogenous gene after homologous recombination with chromosomal DNA. The compositions may be produced, and methods performed, by techniques known in the art, such as those described in U.S. Pat. Nos. 6,054,288; 6,048,729; 6,048,724; 6,048,524; 5,994,127; 5,968,502; 5,965,125; 5,869,239; 5,817,789; 5,783,385; 5,733,761; 5,641,670; 5,580,734; International Publication Nos:WO96/29411, WO 94/12650; and scientific articles described by Koller et al., (1994) Annu. Rev. Immunol. 10:705-730; the disclosures of each of which are incorporated by reference in their entireties). The expression of GSSP4s in mammalian, and typically human, cells may be rendered defective, or alternatively it may be enhanced, with the insertion of a GSSP4 genomic or cDNA sequence with the replacement of the GSSP4 gene counterpart in the genome of an animal cell by a GSSP4 polynucleotide according to the invention. These genetic alterations may be generated by homologous recombination events using specific DNA constructs that have been previously described. One kind of host cell that may be used are mammalian zygotes, such as murine zygotes. For example, murine zygotes may undergo microinjection with a purified DNA molecule of interest, for example a purified DNA molecule that has previously been adjusted to a concentration range from 1 ng/ml—for BAC inserts—3 ng/μl —for P1 bacteriophage inserts—in 10 mM Tris-HCl, pH 7.4, 250 μM EDTA containing 100 mM NaCl, 30 μM spermine, and 70 μM spermidine. When the DNA to be microinjected has a large size, polyamines and high salt concentrations can be used in order to avoid mechanical breakage of this DNA, as described by Schedl et al ((1993) Nature March 18;362(6417):258-61). Any one of the polynucleotides of the invention, including the DNA constructs described herein, may be introduced in an embryonic stem (ES) cell line, preferably a mouse ES cell line. ES cell lines are derived from pluripotent, uncommitted cells of the inner cell mass of pre-implantation blastocysts. Preferred ES cell lines are the following: ES-E14TG2a (ATCC No.CRL-1821), ES-D3 (ATCC No.CRL1934 and No. CRL-11632), YS001 (ATCC No. CRL-11776), 36.5 (ATCC No. CRL-11116). To maintain ES cells in an uncommitted state, they are cultured in the presence of growth inhibited feeder cells which provide the appropriate signals to preserve this embryonic phenotype and serve as a matrix for ES cell adherence. Preferred feeder cells are primary embryonic fibroblasts that are established from tissue of day 13-day 14 embryos of virtually any mouse strain, that are maintained in culture, such as described by Abbondanzo et al. (1993; Methods Enzymol;225:803-23) and are inhibited in growth by irradiation, such as described by Robertson ((1987) Embryo-derived stem cell lines. In: E. J. Robertson Ed. Teratocarcinomas and embrionic stem cells: a practical approach. IRL Press, Oxford), or by the presence of an inhibitory concentration of LIF, such as described by Pease and Williams (1990; Exp Cell Res. October;190(2):209-11). The constructs in the host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence. Following transformation of a suitable host and growth of the host to an appropriate cell density, the selected promoter is induced by appropriate means, such as temperature shift or chemical induction, and cells are cultivated for an additional period. Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. Microbial cells employed in the expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents. Such methods are well known by the skilled artisan. V. Transgenic Animals The present invention also provides methods and compositions for the generation of non-human animals and plants that express recombinant GSSP4 polypeptides, i.e. recombinant GSSP4 fragments or full-length GSSP4 polypeptides. The animals or plants can be transgenic, i.e. each of their cells contains a gene encoding a GSSP4 polypeptide, or, alternatively, a polynucleotide encoding a GSSP4 polypeptide can be introduced into somatic cells of the animal or plant, e.g. into mammary secretory epithelial cells of a mammal. In preferred embodiments, the non-human animal is a mammal such as a cow, sheep, goat, pig, or rabbit. Methods of making transgenic animals such as mammals are well known to those of skill in the art, and any such method can be used in the present invention. Briefly, transgenic mammals can be produced, e.g., by transfecting a pluripotential stem cell such as an ES cell with a polynucleotide encoding a polypeptide of interest. Successfully transformed ES cells can then be introduced into an early stage embryo which is then implanted into the uterus of a mammal of the same species. In certain cases, the transformed (“transgenic”) cells will comprise part of the germ line of the resulting animal, and adult animals comprising the transgenic cells in the germ line can then be mated to other animals, thereby eventually producing a population of transgenic animals that have the transgene in each of their cells, and which can stably transmit the transgene to each of their offspring. Other methods of introducing the polynucleotide can be used, for example introducing the polynucleotide encoding the polypeptide of interest into a fertilized egg or early stage embryo via microinjection. Alternatively, the transgene may be introduced into an animal by infection of zygotes with a retrovirus containing the transgene (Jaenisch, R. (1976) Proc. Natl. Acad. Sci. USA 73, 1260-1264). Methods of making transgenic mammals are described, e.g., in Wall et al. (1992) J Cell Biochem 1992 June;49(2): 113-20; Hogan, et al. (1986) in Manipulating the mouse embryo. A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; in WO 91/08216, or in U.S. Pat. No. 4,736,866. In a preferred method, the polynucleotides are microinjected into the fertilized oocyte. Typically, fertilized oocytes are microinjected using standard techniques, and then cultured in vitrountil a “pre-implantation embryo” is obtained. Such pre-implantation embryos preferably contain approximately 16 to 150 cells. Methods for culturing fertilized oocytes to the pre-implantation stage are described, e.g., by Gordon et al. ((1984) Methods in Enzymology, 101, 414); Hogan et al. ((1986) in Manipulating the mouse embryo. A Laboratory Manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y) (for the mouse embryo); Hammer et al. ((1985) Nature, 315, 680) (for rabbit and porcine embryos); Gandolfi et al. ((1987) J. Reprod. Fert. 81, 23-28); Rexroad et al. ((1988) J. Anim. Sci. 66, 947-953) (for ovine embryos); and Eyestone et al. ((1989) J. Reprod. Fert. 85, 715-720); Camous et al. ((1984) J. Reprod. Fert. 72, 779-785); and Heyman et al. ((1987) Theriogenology 27, 5968) (for bovine embryos); the disclosures of each of which are incorporated herein in their entireties. Pre-implantation embryos are then transferred to an appropriate female by standard methods to permit the birth of a transgenic or chimeric animal, depending upon the stage of development when the transgene is introduced. As the frequency of transgene incorporation is often low, the detection of transgene integration in pre-implantation embryos is often desirable using any of the herein-described methods. Any of a number of methods can be used to detect the presence of a transgene in a pre-implantation embryo. For example, one or more cells may be removed from the pre-implantation embryo, and the presence or absence of the transgene in the removed cell or cells can be detected using any standard method e.g. PCR. Alternatively, the presence of a transgene can be detected in utero or post partum using standard methods. In a particularly preferred embodiment of the present invention, transgenic mammals are generated that secrete recombinant GSSP4 polypeptides in their milk. As the mammary gland is a highly efficient protein-producing organ, such methods can be used to produce protein concentrations in the gram per liter range, and often significantly more. Preferably, expression in the mammary gland is accomplished by operably linking the polynucleotide encoding the GSSP4 polypeptide to a mammary gland specific promoter and, optionally, other regulatory elements. Suitable promoters and other elements include, but are not limited to, those derived from mammalian short and long WAP, alpha, beta, and kappa, casein, alpha and beta lactoglobulin, beta-CN 5′ genes, as well as the the mouse mammary tumor virus (MMTV) promoter. Such promoters and other elements may be derived from any mammal, including, but not limited to, cows, goats, sheep, pigs, mice, rabbits, and guinea pigs. Promoter and other regulatory sequences, vectors, and other relevant teachings are provided, e.g., by Clark (1998) J Mammary Gland Biol Neoplasia 3:337-50; Jost et al. (1999) Nat. Biotechnol 17:160-4; U.S. Pat. Nos. 5,994,616; 6,140,552; 6,013,857; Sohn et al. (1999) DNA Cell Biol. 18:845-52; Kim et al. (1999) J. Biochem. (Japan) 126:320-5; Soulier et al. (1999) Euro. J. Biochem. 260:533-9; Zhang et al. (1997) Chin. J. Biotech. 13:271-6; Rijnkels et al. (1998) Transgen. Res. 7:5-14; Korhonen et al. (1997) Euro. J. Biochem. 245:482-9; Uusi-Oukari et al. (1997) Transgen. Res. 6:75-84; Hitchin et al. (1996) Prot. Expr. Purif. 7:247-52; Platenburg et al. (1994) Transgen. Res. 3:99-108; Heng-Cherl et al. (1993) Animal Biotech 4:89-107; and Christa et al. (2000) Euro. J. Biochem. 267:1665-71; the entire disclosures of each of which is herein incorporated by reference. In another embodiment, the polypeptides of the invention can be produced in milk by introducing polynucleotides encoding the polypeptides into somatic cells of the mammary gland in vivo, e.g. mammary secreting epithelial cells. For example, plasmid DNA can be infused through the nipple canal, e.g. in association with DEAE-dextran (see, e.g., Hens et al. (2000) Biochim. Biophys. Acta 1523:161-171), in association with a ligand that can lead to receptor-mediated endocytosis of the construct (see, e.g., Sobolev et al. (1998) 273:7928-33), or in a viral vector such as a retroviral vector, e.g. the Gibbon ape leukemia virus (see, e.g., Archer et al. (1994) PNAS 91:6840-6844). In any of these embodiments, the polynucleotide may be operably linked to a mammary gland specific promoter, as described above, or, alternatively, any strongly expressing promoter such as CMV or MoMLV LTR. The suitability of any vector, promoter, regulatory element, etc. for use in the present invention can be assessed beforehand by transfecting cells such as mammary epithelial cells, e.g. MacT cells (bovine mammary epithelial cells) or GME cells (goat mammary epithelial cells), in vitro and assessing the efficiency of transfection and expression of the transgene in the cells. For in vivo administration, the polynucleotides can be administered in any suitable formulation, at any of a range of concentrations (e.g. 1-500 μg/ml, preferably 50-100 μg/ml), at any volume (e.g. 1-100 ml, preferably 1 to 20 ml), and can be administered any number of times (e.g. 1, 2, 3, 5, or 10 times), at any frequency (e.g. every 1, 2, 3, 5, 10, or any number of days). Suitable concentrations, frequencies, modes of administration, etc. will depend upon the particular polynucleotide, vector, animal, etc., and can readily be determined by one of skill in the art. In a preferred embodiment, a retroviral vector such as as Gibbon ape leukemia viral vector is used, as described in Archer et al. ((1994) PNAS 91:6840-6844). As retroviral infection typically requires cell division, cell division in the mammary glands can be stimulated in conjunction with the administration of the vector, e.g. using a factor such as estrodiol benzoate, progesterone, reserpine, or dexamethasone. Further, retroviral and other methods of infection can be facilitated using accessory compounds such as polybrene. In any of the herein-described methods for obtaining GSSP4 polypeptides from milk, the quantity of milk obtained, and thus the quantity of GSSP4 polypeptides produced, can be enhanced using any standard method of lactation induction, e.g. using hexestrol, estrogen, and/or progesterone. The polynucleotides used in such embodiments can either encode a full-length GSSP4 polypeptide or a GSSP4 fragment. Typically, the encoded polypeptide will include a signal sequence to ensure the secretion of the protein into the milk. Where a full length GSSP4 sequence is used, the full length protein can, e.g., be isolated from milk and cleaved in vitro using a suitable protease. Alternatively, a second, protease-encoding polynucleotide can be introduced into the animal or into the mammary gland cells, whereby expression of the protease results in the cleavage of the GSSP4 polypeptide in vivo, thereby allowing the direct isolation of GSSP4 fragments from milk. VI. Pharmaceutical or Physiologically Acceptable Compositions of the Invention The GSSP4 polypeptides of the invention can be administered to non-human animals and/or humans, alone or in pharmaceutical or physiologically acceptable compositions where they are mixed with suitable carriers or excipient(s). The pharmaceutical or physiologically acceptable composition is then provided at a therapeutically effective dose. A therapeutically effective dose refers to that amount of a GSSP4 polypeptide sufficient to result in prevention or amelioration of symptoms or physiological status of metabolic-related diseases or disorders as determined by the methods described herein. A therapeutically effective dose can also refer to the amount of a GSSP4 polypeptide necessary for a reduction in weight or a prevention of an increase in weight or prevention of an increase in the rate of weight gain in persons desiring this affect for cosmetic reasons. A therapeutically effective dosage of a GSSP4 polypeptide of the invention is that dosage that is adequate to promote weight loss or weight gain with continued periodic use or administration. Techniques for formulation and administration of GSSP4 polypeptides may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition. Other diseases or disorders that GSSP4 polypeptides of the invention could be used to treat or prevent include, but are not limited to, obesity and metabolic-related diseases and disorders such as obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. The GSSP4 polypeptides may also be used to enhance physical performance during work or exercise or enhance a feeling of general well-being. Physical performance activities include walking, running, jumping, lifting and/or climbing. The GSSP4 polypeptides or antagonists thereof may also be used to treat dyslexia, attention-deficit disorder (ADD), attention-deficit/hyperactivity disorder (ADHD), and psychiatric disorders such as schizophrenia by modulating fatty acid metabolism, more specifically, the production of certain long-chain polyunsaturated fatty acids. It is expressly considered that the GSSP4 polypeptides of the invention may be provided alone or in combination with other pharmaceutically or physiologically acceptable compounds. Other compounds useful for the treatment of obesity and other diseases and disorders are currently well-known in the art. In a preferred embodiment, the GSSP4 polypeptides are useful for, and used in, the treatment of insulin resistance and diabetes using methods described herein and known in the art. More particularly, a preferred embodiments relates to process for the therapeutic modification and regulation of glucose metabolism in an animal or human subject, which comprises administering to a subject in need of treatment (alternatively on a timed daily basis) GSSP4 polypeptide (or polynucleotide encoding said polypeptide) in dosage amount and for a period sufficient to reduce plasma glucose levels in said animal or human subject. Further preferred embodiments relate to methods for the prophylaxis or treatment of diabetes comprising administering to a subject in need of treatment (alternatively on a timed daily basis) a GSSP4 polypeptide (or polynucleotide encoding said polypeptide) in dosage amount and for a period sufficient to reduce plasma glucose levels in said animal or human subject. Routes of Administration. Suitable routes of administration include oral, nasal, rectal, transmucosal, or intestinal administration, parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intrapulmonary (inhaled) or intraocular injections using methods known in the art. A particularly useful method of administering compounds for promoting weight loss involves surgical implantation, for example into the abdominal cavity of the recipient, of a device for delivering GSSP4 polypeptidesover an extended period of time. Other particularly preferred routes of administration are aerosol and depot formulation. Sustained release formulations, particularly depot of the invented medicaments are expressly contemplated. Composition/Formulation Pharmaceutical or physiologically acceptable compositions and medicaments for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries. Proper formulation is dependent upon the route of administration chosen. Certain of the medicaments described herein will include a pharmaceutically or physiologically acceptable acceptable carrier and at least one polypeptide that is a GSSP4 polypeptide of the invention. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer such as a phosphate or bicarbonate buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Pharmaceutical or physiologically acceptable preparations that can be taken orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable gaseous propellant, e.g. carbon dioxide. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g. gelatin, for use in an inhaler or insufflator, may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical or physiologically acceptable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder or lyophilized form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical or physiologically acceptable compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Effective Dosage. Pharmaceutical or physiologically acceptable compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes or encompasses a concentration point or range shown to increase leptin or lipoprotein uptake or binding in an in vitro system. Such information can be used to more accurately determine useful doses in humans. A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50, (the dose lethal to 50% of the test population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD5O and ED5O. Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50, with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g., Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1). Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain or prevent weight loss or gain, depending on the particular situation. Dosages necessary to achieve these effects will depend on individual characteristics and route of administration. Dosage intervals can also be determined using the value for the minimum effective concentration. Compounds should be administered using a regimen that maintains plasma levels above the minimum effective concentration for 10-90% of the time, preferably between 30-90%; and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. A preferred dosage range for the amount of a GSSP4 polypeptide of the invention, which can be administered on a daily or regular basis to achieve desired results, including a reduction in levels of circulating plasma triglyceride-rich lipoproteins, range from 0.01-0.5 mg/kg body mass. A more preferred dosage range is from 0.05-0.1 mg/kg. Of course, these daily dosages can be delivered or administered in small amounts periodically during the course of a day. It is noted that these dosage ranges are only preferred ranges and are not meant to be limiting to the invention. VII. Methods of Treatment The invention is drawn inter alia to methods of preventing or treating metabolic-related diseases and disorders comprising providing an individual in need of such treatment with a GSSP4 polypeptide of the invention. Preferably, the GSSP4 polypeptide has metabolic-related activity either in vitro or in vivo. Preferably the GSSP4 polypeptide is provided to the individual in a pharmaceutical composition that is preferably taken orally. Preferably the individual is a mammal, and most preferably a human. In preferred embodiments, the metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In highly preferred embodiments, GSSP4 polypeptides in pharmaceutical compositions are used to modulate body weight in healthy individuals for cosmetic reasons. The invention also features a method of preventing or treating metabolic-related diseases and disorders comprising providing an individual in need of such treatment with a compound identified by assays of the invention (described in Section VI of the Preferred Embodiments of the Invention and in the Examples). Preferably these compounds antagonize or agonize effects of GSSP4 polypeptides in cells in vitro, muscles ex vivo, or in animal models. Alternatively, these compounds agonize or antagonize the effects of GSSP4 polypeptides on glucose metabolism, fatty acid metabolism, or lipid metabolism. Preferably, the compound is provided to the individual in a pharmaceutical composition that is preferably taken orally. Preferably the individual is a mammal, and most preferably a human. In preferred embodiments, the metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM, Type II diabetes), Insulin dependent diabetes mellitus (IDDM, Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In highly preferred embodiments, the pharmaceutical compositions are used to modulate glucose levels. In highly preferred embodiments, the pharmaceutical compositions are used to modulate body weight for cosmetic reasons. In a further preferred embodiment, NIDDM patients are often treated with oral insulin secretagogues, such as 1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate (BTS67582) or sulfonylureas including tolbutamide, tolazamide, chlorpropamide, glibendamide, glimepiride, glipizide and glidazide, or with insulin sensitising agents including metformin, ciglitazone, trogitazone and pioglitazone. A further use of the present invention is in therapy of NIDDM patients to improve their weight and glucose control, comprising a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect in combination with an oral insulin secretagogue or an insulin sensitising agent. Preferably, the oral insulin secretagogue is 1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. Preferably, the insulin sensitising agent is selected from metformin, ciglitazone, troglitazone and pioglitazone. The present invention further provides a method of improving the weight and glucose control of NIDDM patients comprising the administration of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect alone, without an oral insulin secretagogue or an insulin sensitising agent. In a further preferred embodiment, the present invention may be administered either concomitantly or concurrently, with the oral insulin secretagogue or insulin sensitising agent for example in the form of separate dosage units to be used simultaneously, separately or sequentially (either before or after the secretagogue or either before or after the sensitising agent). Accordingly, the present invention further provides a product containing a composition of said a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect and an oral insulin secretagogue or insulin sensitising agent as a combined preparation for simultaneous, separate or sequential use for the improvement of weight and glucose control in NIDDM patients. The ratio of the present composition to the oral insulin secretagogue or insulin sensitising agent is such that the quantity of each active ingredient employed will be such as to provide a therapeutically effective level, but will not be larger than the quantity recommended as safe for administration. The action of reducing insulin resistance by the present invention indicates that compounds of such invention may be useful in the manufacture of a medicament which can be used as an insulin sensitiser. Accordingly, the present invention further provides for the use in the manufacture of a medicament which is an insulin sensitiser. In further embodiments, some patients who are diagnosed with Insulin Dependent Diabetes Mellitus (IDDM, Type I) can also show a certain amount of insulin resistance. Therefore, there may be benefits in treating these patients with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect in order to reduce their insulin resistance. This would mean that these patients would require a lower dosage of insulin in order to maintain similar or better control of their diabetes since the insulin dose would be associated with a greater blood glucose lowering efficacy. Such therapy would provide long-term benefits in terms of reducing the detrimental effects which can be caused by prolonged high-dosage of insulin treatment. Additionally, some Noninsulin Dependent Diabetes Mellitus (NIDDM, Type II) patients are also treated with insulin and have insulin resistance. Accordingly the present invention further provides a method for, and the use thereof in the manufacture of the medicament for, reducing the amount of insulin required daily by a human having NIDDM. The present invention also provides a method for, and the use of the composition in the manufacture of a medicament for, the prophylaxis of long-term detrimental effects caused by prolonged high dosage of insulin in humans having IDDM. A consequence of the resistance is that glucose concentrations rise. This leads, in turn, to an increased release of insulin. Hyperinsulinemia, both in the fasting and postprandial states, is a hallmark of insulin resistance. Hyperinsulinemia is also caused by stimulation of gluconeogenesis. Epidemilogical studies have shown that hyperinsulinemia is a risk factor for morbidity and mortality in cardiovascular disease (Smith U. (1994) Am. J. Clin. Nutr. 59, suppl. 686S). Accordingly, the invention also provides therapeutics and methods for reducing or preventing hypersecretion of insulin and disorders or conditions resulting therefrom. NIDDM is associated with various complications. As defined herein, “complications of NIDDM” is referred to as cardiovascular complications or several of the metabolic and circulatory disturbances that are associated with hyperglycemia, e.g., insulin resistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulin release, dyslipidemia, retinopathy, peripheral neuropathy, hypertension, and other coronary artery diseases (CADs). CAD is a major cause of morbidity and mortality in patients with NIDDM. Thus, by providing therapeutics and methods for reducing glucose levels, the invention provides therapeutics and methods for treating and preventing NIDDM and consequences thereof. The invention also provides therapeutics and methods for treating and preventing having impaired glucose tolerance (IGT). The usual meaning of impaired glucose tolerance is that it is a condition associated with insulin-resistance which is intermediate between frank, NIDDM and normal glucose tolerance (NGT). A high percentage of the IGT population is known to progress to NIDDM relative to persons with normal glucose tolerance (Sad, et al., New Engl. J. Med. 1988; 319:1500-6). Thus, by providing therapeutics and methods for reducing or preventing IGT, i.e., for normalizing insulin resistance, the progression to NIDDM can be delayed or prevented. IGT is diagnosed by a procedure wherein an affected person's postprandial glucose response is determined to be abnormal as assessed by 2-hour postprandial plasma glucose levels. In this test, a measured amount of glucose is given to the patient and blood glucose levels measured regular intervals, usually every half hour for the first two hours and every hour thereafter. In a “normal” or non-IGT individual glucose levels rise during the first two hours to level less than 140 mg/dl and then drop rapidly. In an IGT individual, the blood glucose levels are higher and the drop-off level is at a slower rate. Resistance to insulin-stimulated glucose uptake in individuals who do not become frankly hyperglycemic nevertheless increases the likelihood of these individuals to develop numerous other diseases. In particular, an attempt to compensate for insulin resistance sets in motion a series of events that play an important role in the development of both hypertension and coronary artery disease (CAD), such as premature atherosclerotic vascular disease. This cluster of abnormalities is commonly called the “Metabolic Syndrome”, or the “Insulin-Resistance Syndrome” or “Syndrome X”. Increased plasma triglyceride and decreased HDL-cholesterol concentrations, conditions which are known to be associated with CAD, have also been reported to be associated with insulin resistance. Thus, by providing therapeutics and methods for reducing or preventing insulin resistance, the invention provides methods for reducing and/or preventing the appearance of insulin-resistance syndrome. Yet other diseases are associated with insulin resistance and, thus, be treated or prevented according to the methods of the invention. For example, obesity, which is the result of an imbalance between caloric intake and energy expenditure is highly correlated with insulin resistance and diabetes (Hotamisligil, Spiegelman et al., Science, 1993, 259:87-91). In humans obesity can be defined as a body weight exceeding 20% of the desirable body weight for individuals of the same sex, height and frame (Slans, L. B., in Endocrinology & Metabolism, 2d Ed., McGraw-Hill, New York 1987, pp. 1203-1244; see also, R H. Williams, Textbook of Endocrinology, 1974, pp. 904-916). In other animals (or also in humans) obesity can be determined by body weight patterns correlated with prolactin profiles given that members of a species that are young, lean and “healthy” (i.e., free of any disorders, not just metabolic disorders) have daily plasma prolactin level profiles that follow a regular pattern that is highly reproducible with a small standard deviation. Obesity, or excess fat deposits, correlate with and may trigger the onset of various lipid metabolism disorders, e.g. hypertension, Type II diabetes (NIDDM), atherosclerosis, cardiovascular disease, etc. Even in the absence of clinical obesity (according to the above definition) the reduction of body fat stores (notably visceral fat stores) in man especially on a long-term or permanent basis would be of significant benefit, both cosmetically and physiologically. Thus, by preventing or treating obesity, the methods of the invention will allow an individual to have a more comfortable life and avoid the onset of various diseases triggered by obesity. In yet another embodiment, the invention provides a method for treating a subject having polycystic ovary syndrome (PCOS). PCOS is among the most common disorders of premenopausal women, affecting 5-10% of this population. It is a syndrome of unknown Etiology characterized by hyperandrogenism, chronic anovulation, defects in insulin action, insulin secretion, ovarian steroidogenesis and fibrinolysis. Women with PCOS frequently are insulin resistant and at increased risk to develop glucose intolerance or NIDDM in the third and fourth decades of life (Dunaif et al. (1996) J. Clin. Endocrinol. Metab. 81:3299). Hyperandrogenism also is a feature of a variety of diverse insulin-resistant states, from the type A syndrome, through leprechaunism and lipoatrophic diabetes, to the type B syndrome, when these conditions occur in premenopausal women. It has been suggested that hyperinsulinemia per se causes hyperandrogenism. Insulin-sensitizing agents, e.g., troglitazone, have been shown to be effective in PCOS and that, in particular, the defects in insulin action, insulin secretion, ovarian steroidogenosis and fibrinolysis are improved (Ehrman et al. (1997) J. Clin. Invest. 100:1230), such as in insulin-resistant humans. Accordingly, the invention provides methods for reducing insulin resistance, normalizing blood glucose thus treating and/or preventing PCOS. Insulin resistance is also often associated with infections and cancer. Thus, prevention or reducing insulin resistance according to the methods of the invention may prevent or reduce infections and cancer. Insulin resistance can be diagnosed by various methods, such as by the intravenous glucose tolerance test or by measuring the fasting insulin level. It is well known that there is an excellent correlation between the height of the fasting insulin level and the degree of insulin resistance. Therefore, one could use elevated fasting insulin levels as a surrogate marker for insulin resistance for the purpose of identifying which normal glucose tolerance (NGT) individuals have insulin resistance. Another way to do this is to follow the approach as disclosed in The New England Journal of Medicine, No. 3, pp. 1188 (1995), i.e. to select obese subjects as an initial criteria for entry into the treatment group. Some obese subjects have impaired glucose tolerance (IGT) while others have normal glucose tolerance (NGT). Since essentially all obese subjects are insulin resistant, i.e. even the NGT obese subjects are insulin resistant, they have fasting hyperinsulinemia. Therefore, the target of the treatment according to the present invention can be defined as NGT individuals who are obese or who have fasting hyperinsulinemia, or who have both. Insulin resistance can also be diagnosed by the euglycemic glucose clamp test. This test involves the simultaneous administration of a constant insulin infusion and a variable rate glucose infusion. During the test, which lasts 3-4 hours, the plasma glucose concentration is kept constant at euglycemic levels by measuring the glucose level every 5-10 minutes and then adjusting the variable rate glucose infusion to keep the plasma glucose level unchanged. Under these circumstances, the rate of glucose entry into the bloodstream is equal to the overall rate of glucose disposal in the body. The difference between the rate of glucose disposal in the basal state (no insulin infusion) and the insulin infused state, represents insulin mediated glucose uptake. In normal individuals, insulin causes brisk and large increase in overall body glucose disposal, whereas in NIDDM subjects, this effect of insulin is greatly blunted, and is only 20-30% of normal. In insulin resistant subjects with either IGT or NGT, the rate of insulin stimulated glucose disposal is about half way between normal and NIDDM. For example, at a steady state plasma insulin concentration of about 100 uU/ml (a physiologic level) the glucose disposal rate in normal subjects is about 7 mg/kg/min. In NIDDM subjects, it is about 2.5 mg/.kg/min., and in patients with IGT (or insulin resistant subjects with NGT) it is about 4-5 mg/kg/min. This is a highly reproducible and precise test, and can distinguish patients within these categories. It is also known, that as subjects become more insulin resistant, the fasting insulin level rises. There is an excellent positive correlation between the height of the fasting insulin level and the magnitude of the insulin resistance as measured by euglycemic glucose clamp tests and, therefore, this provides the rationale for using fasting insulin levels as a surrogate measure of insulin resistance. Thus, any of the above-described tests or other tests known in the art can be used to determine that a subject is insulin-resistant, which patient can then be treated according to the methods of the invention to reduce or cure the insulin-resistance. Alternatively, the methods of the invention can also be used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance. More generally, the instant invention is drawn to treatment with GSSP4 polypeptides where an individual is shown to have a particular genotype for GSSP4 marker. Treatment comprises providing pharmaceutically acceptable GSSP4 polypeptides to the individual. The exact amount of GSSP4 polypeptide provided would be determined through clinical trials under the guidance of qualified physicians, but would be expected to be in the range of 5-7 mg per individual per day. In general, a preferred range would be from 0.5 to 14 mg per individual per day, with a highly preferred range being between 1 and 10 mg per individual per day. Individuals who could benefit from treatment with GSSP4 polypeptides could be identified through genotyping. GSSP4 Genotyping The methods treatment using genotyping to identify individuals that would benefit from treatments of the invention are based on the finding that single nucleotide polymorphisms (SNPs) in GSSP4 have been identified that show an association in obese adolescents with free fatty acid (FFA) and respiratory quotient levels, others that show an association with the relationship between BMI and leptin, and still others that show an association with glucose levels. Further, a combination of GSSP4 SNPs associated with FFA and leptin metabolism may also predict people who will be seriously overweight. Briefly, the term “genotype” as used herein refers to the identity of the alleles present in an individual or a sample. The term “genotyping” a sample or an individual for a biallelic marker consists of determining the specific allele or the specific nucleotide carried by an individual at a biallelic marker. Biallelic markers generally consist of a polymorphism at one single base position. Each biallelic marker therefore corresponds to two forms of a polynucleotide sequence which, when compared with one another, present a nucleotide modification at one position. Usually, the nucleotide modification involves the substitution of one nucleotide for another, optionally either the original or the alternative allele of the biallelic markers disclosed in SEQ ID NO:1. Optionally either the original or the alternative allele of these biallelic markers may be specified as being present. Preferred polynucleotides may consist of, consist essentially of, or comprise a contiguous span of nucleotides upstream and down-stream of the alternate allele position noted in SEQ ID No:1 as well as sequences which are complementary thereto. The “contiguous span” may be at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500 or 1000 nucleotides in length, to the extent that a contiguous span of these lengths is consistent with the lengths of the particular Sequence ID. Methods of genotyping comprise determining the identity of a nucleotide at GSSP4 biallelic marker site by any method known in the art. Preferably, microsequencing is used. The genotype is used to determine whether an individual should be treated with GSSP4 polypeptides. Thus, these genotyping methods are performed on nucleic acid samples derived from a single individual. These methods are well-known in the art, and discussed fully in the applications referenced briefly below. Any method known in the art can be used to identify the nucleotide present at a biallelic marker site. Since the biallelic marker allele to be detected has been identified and specified in the present invention, detection will prove simple for one of ordinary skill in the art by employing any of a number of techniques. Many genotyping methods require the previous amplification of the DNA region carrying the biallelic marker of interest. While the amplification of target or signal is often preferred at present, ultrasensitive detection methods that do not require amplification are also encompassed by the present genotyping methods. Methods well-known to those skilled in the art that can be used to detect biallelic polymorphisms include methods such as conventional dot blot analysis, single strand conformational polymorphism analysis (SSCP; Orita et al. (1989) Proc Natl Acad Sci USA April;86(8):2766-70), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, mismatch cleavage detection, and other conventional techniques as described in Sheffield et al. (1991; Am J Hum Genet October;49(4):699-706); White et al. (1992), Grompe et al. ((1989) Proc Natl Acad Sci USA August;86(15):5888-92; (1993) Nat Genet. October;5(2):111-7). Another method for determining the identity of the nucleotide present at a particular polymorphic site employs a specialized exonuclease-resistant nucleotide derivative as described in U.S. Pat. No. 4,656,127. Preferred methods involve directly determining the identity of the nucleotide present at a biallelic marker site by sequencing assay, allele-specific amplification assay, or hybridization assay. The following is a description of some preferred methods. A highly preferred method is the microsequencing technique. The term “sequencing” is used herein to refer to polymerase extension of duplex primer/template complexes and includes both traditional sequencing and microsequencing. Preferred biallelic markers, as shown in SEQ ID NO:1 and corresponding 47 mers as shown in SEQ ID NOs:4-18, include but are not limited to: 1. Biallelic marker 1: position base 148, alternate alleles A/G 2. Biallelic marker 2: position base 2551, alternate alleles G/A 3. Biallelic marker 3: position base 4417, alternate alleles A/C 4. Biallelic marker 4: position base 6322, alternate alleles A/G (amino acid change isoleucine to valine) 5. Biallelic marker 7: position base 816, alternate alleles G/A 6. Biallelic marker 8: position base 924, alternate alleles G/A 7. Biallelic marker 9: position base 1206, alternate alleles C/A 8. Biallelic marker 10: position base 1851, alternate alleles T/C 9. Biallelic marker 11: position base 3124, alternate alleles C/T 10. Biallelic marker 12: position base 3563, alternate alleles G/A 11. Biallelic marker 13: position base 3792, alternate alleles G/A 12. Biallelic marker 14: position base 5757, alternate alleles T/C 1) Sequencing Assays The nucleotide present at a polymorphic site can be determined by sequencing methods. In a preferred embodiment, DNA samples are subjected to PCR amplification before sequencing using any method known in the art. Preferably, the amplified DNA is subjected to automated dideoxy terminator sequencing reactions using a dye-primer cycle sequencing protocol. Sequence analysis allows the identification of the base present at the biallelic marker site. 2) Microsequencing Assays In microsequencing methods, the nucleotide at a polymorphic site in a target DNA is detected by a single nucleotide primer extension reaction. This method involves appropriate microsequencing primers that hybridize just upstream of the polymorphic base of interest in the target nucleic acid. A polymerase is used to specifically extend the 3′ end of the primer with one single ddNTP (chain terminator) complementary to the nucleotide at the polymorphic site. The identity of the incorporated nucleotide is then determined in any suitable way. Preferred microsequencing primers are described in SEQ ID NO:1. Typically, microsequencing reactions are carried out using fluorescent ddNTPs and the extended microsequencing primers are analyzed by electrophoresis on ABI 377 sequencing machines to determine the identity of the incorporated nucleotide as described in EP 412 883. Alternatively capillary electrophoresis can be used in order to process a higher number of assays simultaneously. Different approaches can be used for the labeling and detection of ddNTPs. A homogeneous phase detection method based on fluorescence resonance energy transfer has been described by Chen and Kwok ((1997) Nucleic Acids Res. January 15;25(2):347-53) and Chen et al. ((1997) Proc Natl Acad Sci USA September 30;94(20):10756-61). In this method, amplified genomic DNA fragments containing polymorphic sites are incubated with a 5′-fluorescein-labeled primer in the presence of allelic dye-labeled dideoxyribonucleoside triphosphates and a modified Taq polymerase. The dye-labeled primer is extended one base by the dye-terminator specific for the allele present on the template. At the end of the genotyping reaction, the fluorescence intensities of the two dyes in the reaction mixture are analyzed directly without separation or purification. All these steps can be performed in the same tube and the fluorescence changes can be monitored in real time. Alternatively, the extended primer may be analyzed by MALDI-TOF Mass Spectrometry. The base at the polymorphic site is identified by the mass added onto the microsequencing primer (see Haff and Smirnov, (1997) Nucleic Acids Res. September 15;25(18):3749-50; (1997) Genome Res. April;7(4):378-88). Microsequencing may be achieved by the established microsequencing method or by developments or derivatives thereof. Alternative methods include several solid-phase microsequencing techniques. The basic microsequencing protocol is the same as described previously, except that the method is conducted as a heterogeneous phase assay, in which the primer or the target molecule is immobilized or captured onto a solid support. To simplify the primer separation and the terminal nucleotide addition analysis, oligonucleotides are attached to solid supports or are modified in such ways that permit affinity separation as well as polymerase extension. The 5′ ends and internal nucleotides of synthetic oligonucleotides can be modified in a number of different ways to permit different affinity separation approaches, e.g., biotinylation. If a single affinity group is used on the oligonucleotides, the oligonucleotides can be separated from the incorporated terminator regent. This eliminates the need of physical or size separation. More than one oligonucleotide can be separated from the terminator reagent and analyzed simultaneously if more than one affinity group is used. This permits the analysis of several nucleic acid species or more nucleic acid sequence information per extension reaction. The affinity group need not be on the priming oligonucleotide but could alternatively be present on the template. For example, immobilization can be carried out via an interaction between biotinylated DNA and streptavidin-coated microtitration wells or avidin-coated polystyrene particles. In the same manner, oligonucleotides or templates may be attached to a solid support in a high-density format. In such solid phase microsequencing reactions, incorporated ddNTPs can be radiolabeled (Syvänen, (1994) Clin Chim Acta. May;226(2):225-36) or linked to fluorescein (Livak and Hainer, (1994) Hum Mutat.;3(4):379-85). The detection of radiolabeled ddNTPs can be achieved through scintillation-based techniques. The detection of fluorescein-linked ddNTPs can be based on the binding of antifluorescein antibody conjugated with alkaline phosphatase, followed by incubation with a chromogenic substrate (such as p-nitrophenyl phosphate). Other possible reporter-detection pairs include: ddNTP linked to dinitrophenyl (DNP) and anti-DNP alkaline phosphatase conjugate (Harju et al., (1993) Clin Chem. November;39(11 Pt 1):2282-7) or biotinylated ddNTP and horseradish peroxidase-conjugated streptavidin with o-phenylenediamine as a substrate (WO 92/15712). As yet another alternative solid-phase microsequencing procedure, Nyren et al. ((1993) Anal Biochem. January;208(1):171-5). described a method relying on the detection of DNA polymerase activity by an enzymatic luminometric inorganic pyrophosphate detection assay (ELIDA). Pastinen et al. ((1997) Genome Res. June;7(6):606-14) describe a method for multiplex detection of single nucleotide polymorphism in which the solid phase minisequencing principle is applied to an oligonucleotide array format. High-density arrays of DNA probes attached to a solid support (DNA chips) are further described below. It will be appreciated that any primer having a 3′ end immediately adjacent to the polymorphic nucleotide may be used. Similarly, it will be appreciated that microsequencing analysis may be performed for any biallelic marker or any combination of biallelic markers of the present invention. 3) Allele-Specific Amplification Assay Methods Discrimination between the two alleles of a biallelic marker can also be achieved by allele specific amplification, a selective strategy, whereby one of the alleles is amplified without, or at a much higher rate than, amplification of the other allele. This is accomplished by placing the polymorphic base at the 3′ end of one of the amplification primers. Because the extension forms from the 3′ end of the primer, a mismatch at or near this position has an inhibitory effect on amplification. Therefore, under appropriate amplification conditions, these primers only direct amplification on their complementary allele. Determining the precise location of the mismatch and the corresponding assay conditions are well with the ordinary skill in the art. The “Oligonucleotide Ligation Assay” (OLA) uses two oligonucleotides which are designed to be capable of hybridizing to abutting sequences of a single strand of a target molecules. One of the oligonucleotides is biotinylated, and the other is detectably labeled. If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate that can be captured and detected. OLA is capable of detecting single nucleotide polymorphisms and may be advantageously combined with PCR as described by Nickerson et al. ((1990) Proc Natl Acad Sci USA November;87(22):8923-7). In this method, PCR is used to achieve the exponential amplification of target DNA, which is then detected using OLA. Other amplification methods which are particularly suited for the detection of single nucleotide polymorphism include LCR (ligase chain reaction) and Gap LCR (GLCR). LCR uses two pairs of probes to exponentially amplify a specific target. The sequences of each pair of oligonucleotides are selected to permit the pair to hybridize to abutting sequences of the same strand of the target. Such hybridization forms a substrate for a template-dependant ligase. In accordance with the present invention, LCR can be performed with oligonucleotides having the proximal and distal sequences of the same strand of a biallelic marker site. In one embodiment, either oligonucleotide will be designed to include the biallelic marker site. In such an embodiment, the reaction conditions are selected such that the oligonucleotides can be ligated together only if the target molecule either contains or lacks the specific nucleotide that is complementary to the biallelic marker on the oligonucleotide. In an alternative embodiment, the oligonucleotides will not include the biallelic marker, such that when they hybridize to the target molecule, a “gap” is created as described in WO 90/01069. This gap is then “filled” with complementary dNTPs (as mediated by DNA polymerase), or by an additional pair of oligonucleotides. Thus at the end of each cycle, each single strand has a complement capable of serving as a target during the next cycle and exponential allele-specific amplification of the desired sequence is obtained. Ligase/Polymerase-mediated Genetic Bit Analysis™ is another method for determining the identity of a nucleotide at a preselected site in a nucleic acid molecule (WO 95/21271). This method involves the incorporation of a nucleoside triphosphate that is complementary to the nucleotide present at the preselected site onto the terminus of a primer molecule, and their subsequent ligation to a second oligonucleotide. The reaction is monitored by detecting a specific label attached to the reaction's solid phase or by detection in solution. 4) Hybridization Assay Methods A preferred method of determining the identity of the nucleotide present at a biallelic marker site involves nucleic acid hybridization. The hybridization probes, which can be conveniently used in such reactions, preferably include probes specific for GSSP4 cDNA surrounding GSSP4 biallelic markers. Any hybridization assay may be used including Southern hybridization, Northern hybridization, dot blot hybridization and solid-phase hybridization (see Sambrook et al., supra). Hybridization refers to the formation of a duplex structure by two single stranded nucleic acids due to complementary base pairing. Hybridization can occur between exactly complementary nucleic acid strands or between nucleic acid strands that contain minor regions of mismatch. Specific probes can be designed that hybridize to one form of a biallelic marker and not to the other and therefore are able to discriminate between different allelic forms. Allele-specific probes are often used in pairs, one member of a pair showing perfect match to a target sequence containing the original allele and the other showing a perfect match to the target sequence containing the alternative allele. Hybridization conditions should be sufficiently stringent that there is a significant difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles. Stringent, sequence specific hybridization conditions, under which a probe will hybridize only to the exactly complementary target sequence are well known in the art (Sambrook et al., supra). Stringent conditions are sequence dependent and will be different in different circumstances. Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. Although such hybridizations can be performed in solution, it is preferred to employ a solid-phase hybridization assay. The target DNA comprising a biallelic marker of the present invention may be amplified prior to the hybridization reaction. The presence of a specific allele in the sample is determined by detecting the presence or the absence of stable hybrid duplexes formed between the probe and the target DNA. The detection of hybrid duplexes can be carried out by a number of methods. Various detection assay formats are well known which utilize detectable labels bound to either the target or the probe to enable detection of the hybrid duplexes. Typically, hybridization duplexes are separated from unhybridized nucleic acids and the labels bound to the duplexes are then detected. Those skilled in the art will recognize that wash steps may be employed to wash away excess target DNA or probe as well as unbound conjugate. Further, standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the primers and probes. Two recently developed assays allow hybridization-based allele discrimination with no need for separations or washes (see Landegren U. et al., (1998) Genome Res. August;8(8):769-76). The TaqMan assay takes advantage of the 5′ nuclease activity of Taq DNA polymerase to digest a DNA probe annealed specifically to the accumulating amplification product. TaqMan probes are labeled with a donor-acceptor dye pair that interacts via fluorescence resonance energy transfer (FRET). Cleavage of the TaqMan probe by the advancing polymerase during amplification dissociates the donor dye from the quenching acceptor dye, greatly increasing the donor fluorescence. All reagents necessary to detect two allelic variants can be assembled at the beginning of the reaction and the results are monitored in real time (see Livak et al., 1995). In an alternative homogeneous hybridization based procedure, molecular beacons are used for allele discriminations. Molecular beacons are hairpin-shaped oligonucleotide probes that report the presence of specific nucleic acids in homogeneous solutions. When they bind to their targets they undergo a conformational reorganization that restores the fluorescence of an internally quenched fluorophore (Tyagi et al., (1998) Nat Biotechnol. January;16(1):49-53). The polynucleotides provided herein can be used to produce probes which can be used in hybridization assays for the detection of biallelic marker alleles in biological samples. These probes are characterized in that they preferably comprise between 8 and 50 nucleotides, and in that they are sufficiently complementary to a sequence comprising a biallelic marker of the present invention to hybridize thereto and preferably sufficiently specific to be able to discriminate the targeted sequence for only one nucleotide variation. A particularly preferred probe is 25 nucleotides in length. Preferably the biallelic marker is within 4 nucleotides of the center of the polynucleotide probe. In particularly preferred probes, the biallelic marker is at the center of said polynucleotide. In preferred embodiments the polymorphic base is within 5, 4, 3, 2, 1, nucleotides of the center of the said polynucleotide, more preferably at the center of said polynucleotide. Preferably the probes of the present invention are labeled or immobilized on a solid support. By assaying the hybridization to an allele specific probe, one can detect the presence or absence of a biallelic marker allele in a given sample. High-Throughput parallel hybridizations in array format are specifically encompassed within “hybridization assays” and are described below. 5) Hybridization To Addressable Arrays Of Oligonucleotides Hybridization assays based on oligonucleotide arrays rely on the differences in hybridization stability of short oligonucleotides to perfectly matched and mismatched target sequence variants. Efficient access to polymorphism information is obtained through a basic structure comprising high-density arrays of oligonucleotide probes attached to a solid support (e.g., the chip) at selected positions. Each DNA chip can contain thousands to millions of individual synthetic DNA probes arranged in a grid-like pattern and miniaturized to the size of a dime. The chip technology has already been applied with success in numerous cases. For example, the screening of mutations has been undertaken in the BRCA1 gene, in S. cerevisiae mutant strains, and in the protease gene of HIV-1 virus (Hacia et al., (1996) Nat Genet. December; 14(4):441-7; Shoemaker et al., (1996) Nat Genet December; 14(4):450-6; Kozal et al., (1996) Nat Med. July;2(7):753-9). Chips of various formats for use in detecting biallelic polymorphisms can be produced on a customized basis by Affymetrix (GeneChip™), Hyseq (HyChip and HyGnostics), and Protogene Laboratories. In general, these methods employ arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from an individual, which target sequences include a polymorphic marker. EP 785280 describes a tiling strategy for the detection of single nucleotide polymorphisms. Briefly, arrays may generally be “tiled” for a large number of specific polymorphisms. By “tiling” is generally meant the synthesis of a defined set of oligonucleotide probes which is made up of a sequence complementary to the target sequence of interest, as well as preselected variations of that sequence, e.g., substitution of one or more given positions with one or more members of the basis set of monomers, i.e. nucleotides. Tiling strategies are further described in PCT application No. WO 95/11995. In a particular aspect, arrays are tiled for a number of specific, identified biallelic marker sequences. In particular, the array is tiled to include a number of detection blocks, each detection block being specific for a specific biallelic marker or a set of biallelic markers. For example, a detection block may be tiled to include a number of probes, which span the sequence segment that includes a specific polymorphism. To ensure probes that are complementary to each allele, the probes are synthesized in pairs differing at the biallelic marker. In addition to the probes differing at the polymorphic base, monosubstituted probes are also generally tiled within the detection block. These monosubstituted probes have bases at and up to a certain number of bases in either direction from the polymorphism, substituted with the remaining nucleotides (selected from A, T, G, C and U). Typically the probes in a tiled detection block will include substitutions of the sequence positions up to and including those that are 5 bases away from the biallelic marker. The monosubstituted probes provide internal controls for the tiled array, to distinguish actual hybridization from artefactual cross-hybridization. Upon completion of hybridization with the target sequence and washing of the array, the array is scanned to determine the position on the array to which the target sequence hybridizes. The hybridization data from the scanned array is then analyzed to identify which allele or alleles of the biallelic marker are present in the sample. Hybridization and scanning may be carried out as described in PCT application No. WO 92/10092 and WO 95/11995 and U.S. Pat. No. 5,424,186. Thus, in some embodiments, the chips may comprise an array of nucleic acid sequences of fragments of about 15 nucleotides in length. In preferred embodiments the polymorphic base is within 5, 4, 3, 2, 1, nucleotides of the center of the said polynucleotide, more preferably at the center of said polynucleotide. In some embodiments, the chip may comprise an array of at least 2, 3, 4, 5, 6, 7, 8 or more of these polynucleotides. 6) Integrated Systems Another technique, which may be used to analyze polymorphisms, includes multicomponent integrated systems, which miniaturize and compartmentalize processes such as PCR and capillary electrophoresis reactions in a single functional device. An example of such technique is disclosed in U.S. Pat. No. 5,589,136, which describes the integration of PCR amplification and capillary electrophoresis in chips. Integrated systems can be envisaged mainly when microfluidic systems are used. These systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples are controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip to create functional microscopic valves and pumps with no moving parts. Varying the voltage controls the liquid flow at intersections between the micro-machined channels and changes the liquid flow rate for pumping across different sections of the microchip. For genotyping biallelic markers, the microfluidic system may integrate nucleic acid amplification, microsequencing, capillary electrophoresis and a detection method such as laser-induced fluorescence detection. In a first step, the DNA samples are amplified, preferably by PCR. Then, the amplification products are subjected to automated microsequencing reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide microsequencing primers which hybridize just upstream of the targeted polymorphic base. Once the extension at the 3′ end is completed, the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis. The separation medium used in capillary electrophoresis can for example be polyacrylamide, polyethyleneglycol or dextran. The incorporated ddNTPs in the single-nucleotide primer extension products are identified by fluorescence detection. This microchip can be used to process at least 96 to 384 samples in parallel. It can use the usual four color laser induced fluorescence detection of the ddNTPs. GSSP4 Association Studies Association studies focus on population frequencies and rely on the phenomenon of linkage disequilibrium. Linkage disequilibrium is the deviation from random of the occurrence of pairs of specific alleles at different loci on the same chromosome. If a specific allele in a given gene is directly associated with a particular trait, its frequency will be statistically increased in an affected (trait positive) population, when compared to the frequency in a trait negative population or in a random control population. As a consequence of the existence of linkage disequilibrium, the frequency of all other alleles present in the haplotype carrying the trait-causing allele will also be increased in trait positive individuals compared to trait negative individuals or random controls. Therefore, association between the trait and any allele (specifically a biallelic marker allele) in linkage disequilibrium with the trait-causing allele will suffice to suggest the presence of a trait-related gene in that particular region. Case-control populations can be genotyped for biallelic markers to identify associations that narrowly locate a trait causing allele, as any marker in linkage disequilibrium with one given marker associated with a trait will be associated with the trait. Linkage disequilibrium allows the relative frequencies in case-control populations of a limited number of genetic polymorphisms (specifically biallelic markers) to be analyzed as an alternative to screening all possible functional polymorphisms in order to find trait-causing alleles. Association studies compare the frequency of marker alleles in unrelated case-control populations, and represent powerful tools for the dissection of complex traits. Case-Control Populations (Inclusion Criteria) Population-based association studies do not concern familial inheritance, but compare the prevalence of a particular genetic marker, or a set of markers, in case-control populations. They are case-control studies based on comparison of unrelated case (affected or trait positive) individuals and unrelated control (unaffected, trait negative or random) individuals. Preferably, the control group is composed of unaffected or trait negative individuals. Further, the control group is ethnically matched to the case population. Moreover, the control group is preferably matched to the case-population for the main known confusion factor for the trait under study (for example age-matched for an age-dependent trait). Ideally, individuals in the two samples are paired in such a way that they are expected to differ only in their disease status. The terms “trait positive population”, “case population” and “affected population” are used interchangeably herein. An important step in the dissection of complex traits using association studies is the choice of case-control populations (see, Lander and Schork, (1994) Science, September 30;265(5181):2037-48). A major step in the choice of case-control populations is the clinical definition of a given trait or phenotype. Any genetic trait may be analyzed by the association method proposed here by carefully selecting the individuals to be included in the trait positive and trait negative phenotypic groups. Four criteria are often useful: clinical phenotype, age at onset, family history and severity. The selection procedure for continuous or quantitative traits (such as blood pressure for example) involves selecting individuals at opposite ends of the phenotype distribution of the trait under study, so as to include in these trait positive and trait negative populations individuals with non-overlapping phenotypes. Preferably, case-control populations consist of phenotypically homogeneous populations. Trait positive and trait negative populations consist of phenotypically uniform populations of individuals representing each between 1 and 98%, preferably between 1 and 80%, more preferably between 1 and 50%, and more preferably between 1 and 30%, most preferably between 1 and 20% of the total population under study, and preferably selected among individuals exhibiting non-overlapping phenotypes. The clearer the difference between the two trait phenotypes, the greater the probability of detecting an association with biallelic markers. The selection of those drastically different but relatively uniform phenotypes enables efficient comparisons in association studies and the possible detection of marked differences at the genetic level, provided that the sample sizes of the populations under study are significant enough. In preferred embodiments, a first group of between 50 and 300 trait positive individuals, preferably about 100 individuals, are recruited according to their phenotypes. A similar number of trait negative individuals are included in such studies. In the present invention, typical examples of inclusion criteria include obesity and disorders related to obesity as well as physiologic parameters associated with obesity, such as free fatty acid levels, glucose levels, insulin levels, leptin levels, triglyceride levels, free fatty acid oxidation levels, and weight loss. Association Analysis The general strategy to perform association studies using biallelic markers derived from a region carrying a candidate gene is to scan two groups of individuals (case-control populations) in order to measure and statistically compare the allele frequencies of the biallelic markers of the present invention in both groups. If a statistically significant association with a trait is identified for at least one or more of the analyzed biallelic markers, one can assume that: either the associated allele is directly responsible for causing the trait (i.e. the associated allele is the trait causing allele), or more likely the associated allele is in linkage disequilibrium with the trait causing allele. The specific characteristics of the associated allele with respect to the candidate gene function usually give further insight into the relationship between the associated allele and the trait (causal or in linkage disequilibrium). If the evidence indicates that the associated allele within the candidate gene is most probably not the trait-causing allele but is in linkage disequilibrium with the real trait-causing allele, then the trait-causing allele can be found by sequencing the vicinity of the associated marker, and performing further association studies with the polymorphisms that are revealed in an iterative manner. Association studies are usually run in two successive steps. In a first phase, the frequencies of a reduced number of biallelic markers from the candidate gene are determined in the trait positive and trait negative populations. In a second phase of the analysis, the position of the genetic loci responsible for the given trait is further refined using a higher density of markers from the relevant region. However, if the candidate gene under study is relatively small in length a single phase may be sufficient to establish significant associations. Haplotype Analysis As described above, when a chromosome carrying a disease allele first appears in a population as a result of either mutation or migration, the mutant allele necessarily resides on a chromosome having a set of linked markers: the ancestral haplotype. This haplotype can be tracked through populations and its statistical association with a given trait can be analyzed. Complementing single point (allelic) association studies with multi-point association studies also called haplotype studies increases the statistical power of association studies. Thus, a haplotype association study allows one to define the frequency and the type of the ancestral carrier haplotype. A haplotype analysis is important in that it increases the statistical power of an analysis involving individual markers. In a first stage of a haplotype frequency analysis, the frequency of the possible haplotypes based on various combinations of the identified biallelic markers of the invention is determined. The haplotype frequency is then compared for distinct populations of trait positive and control individuals. The number of trait positive individuals, which should be, subjected to this analysis to obtain statistically significant results usually ranges between 30 and 300, with a preferred number of individuals ranging between 50 and 150. The same considerations apply to the number of unaffected individuals (or random control) used in the study. The results of this first analysis provide haplotype frequencies in case-control populations, for each evaluated haplotype frequency a p-value and an odds ratio are calculated. If a statistically significant association is found the relative risk for an individual carrying the given haplotype of being affected with the trait under study can be approximated. Interaction Analysis The biallelic markers of the present invention may also be used to identify patterns of biallelic markers associated with detectable traits resulting from polygenic interactions. The analysis of genetic interaction between alleles at unlinked loci requires individual genotyping using the techniques described herein. The analysis of allelic interaction among a selected set of biallelic markers with appropriate level of statistical significance can be considered as a haplotype analysis. Interaction analysis consists in stratifying the case-control populations with respect to a given haplotype for the first loci and performing a haplotype analysis with the second loci with each subpopulation. VIII. Assays for Identifying Modulators of GSSP4 Polypeptide Activity The invention features methods of screening for one or more compounds that modulate the activity of GSSP4s in cells, which includes providing potential compounds to be tested to the cells. Exemplary assays that may be used are described in the Examples 2, 5-7,9-11. To these assays would be added compounds to be tested for their inhibitory or stimulatory activity as compared to the effects of GSSP4 polypeptides alone. Other assays in which an effect is observed based on the addition of GSSP4 polypeptides can also be used to screen for modulators of GSSP4 polypeptide activity or effects of the presence of GSSP4 polypeptides on cells. The essential step is to apply an unknown compound and then to monitor an assay for a change from what is seen when only GSSP4 polypeptides are applied to the cell. A change is defined as something that is significantly different in the presence of the compound plus GSSP4 polypeptide compared to GSSP4 polypeptide alone. In this case, significantly different would be an “increase” or a “decrease” in a measurable effect of at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. The term “modulation” as used herein refers to a measurable change in an activity. Examples include, but are not limited to, lipolysis stimulated receptor (LSR) modulation, leptin modulation, lipoprotein modulation, plasma FFA levels, FFA oxidation, TG levels, glucose levels, and weight. These effects can be in vitro or preferably in vivo. Modulation of an activity can be either an increase or a decrease in the activity. Thus, LSR activity can be increased or decreased, leptin activity can be increased or decreased, and lipoprotein activity can be increased or decreased. Similarly, FFA, TG, and glucose levels (and weight) can be increased or decreased in vivo Free Fatty Acid oxidation can be increased or decreased in vivo or ex vivo. By “LSR” activity is meant expression of LSR on the surface of the cell, or in a particular conformation, as well as its ability to bind, uptake, and degrade leptin and lipoprotein. By “leptin” activity is meant its binding, uptake and degradation by LSR, as well as its transport across a blood brain barrier, and potentially these occurrences where LSR is not necessarily the mediating factor or the only mediating factor. Similarly, by “lipoprotein” activity is meant its binding, uptake and degradation by LSR, as well as these occurrences where LSR is not necessarily the mediating factor or the only mediating factor. Exemplary assays are provided in Examples 2, 5-7,9-11. These assay and other comparable assays can be used to determine/identify compounds that modulate GSSP4 polypeptide activity. In some cases it may be important to identify compounds that modulate some but not all of the GSSP4 polypeptide activities, although preferably all activities are modified. The term “increasing” as used herein refers to the ability of a compound to increase the activity of GSSP4 polypeptides in some measurable way compared to the effect of GSSP4 polypeptides in its absence. As a result of the presence of the compound leptin binding and/or uptake might increase, for example, as compared to controls in the presence of the GSSP4 polypeptide alone. Preferably, an increase in activity is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% compared to the level of activity in the presence of the GSSP4 polypeptide. Similarly, the term “decreasing” as used herein refers to the ability of a compound to decrease an activity in some measurable way compared to the effect of a GSSP4 polypeptide in its absence. For example, the presence of the compound decreases the plasma concentrations of FFA, TG, and glucose in mice. Also as a result of the presence of a compound leptin binding and/or uptake might decrease, for example, as compared to controls in the presence of the GSSP4 polypeptide alone. Preferably, an decrease in activity is at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% as compared to the level of activity in the presence of the GSSP4 polypeptide alone. The invention features a method for identifying a potential compound to modulate body mass in individuals in need of modulating body mass comprising: a) contacting a cell with a GSSP4 polypeptide and a candidate compound; b) detecting a result selected from the group consisting of LSR modulation, leptin modulation, lipoprotein modulation; FFA oxidation modulation; and c) wherein said result identifies said potential compound if said result differs from said result when said cell is contacted with the GSSP4 polypeptide alone. In preferred embodiments, said contacting further comprises a ligand of said LSR. Preferably said ligand is selected from the group consisting of cytokine, lipoprotein, free fatty acids, and C1q, and more preferably said cytokine is leptin, and most preferably said leptin is a leptin polypeptide fragment as described in U.S. Provisional application No. 60/155,506 hereby incorporated by reference herein in its entirety including any figures, drawings, or tables. In other preferred embodiments, said GSSP4 polypeptide is mouse or is human. In other preferred embodiments, said cell is selected from the group consisting of PLC, CHO-K1, Hep3B, and HepG2. In yet other preferred embodiments, said lipoprotein modulation is selected from the group consisting of binding, uptake, and degradation. Preferably, said modulation is an increase in said binding, uptake, or degradation. Alternatively, said modulation is a decrease in said binding, uptake, or degradation. In other preferred embodiments, leptin modulation is selected from the group consisting of binding, uptake, degradation, and transport. Preferably, said modulation is an increase in said binding, uptake, degradation, or transport. Alternatively, said modulation is a decrease in said binding, uptake, degradation, or transport. Preferably, said transport is across a blood-brain barrier. In yet other preferred embodiments, said LSR modulation is expression on the surface of said cell. Preferably, said detecting comprises FACS, more preferably said detecting further comprises antibodies that bind specifically to said LSR, and most preferably said antibodies bind specifically to the carboxy terminus of said LSR. In still other preferred embodiments, said potential compound is selected from the group consisting of peptides, peptide libraries, non-peptide libraries, peptoids, fatty acids, lipoproteins, medicaments, antibodies, small molecules, and proteases. IX. Epitopes and Antibody Fusions A preferred embodiment of the present invention is directed to eiptope-bearing polypeptides and epitope-bearing polypeptide fragments. These epitopes may be “antigenic epitopes” or both an “antigenic epitope” and an “immunogenic epitope”. An “immunogenic epitope” is defined as a part of a protein that elicits an antibody response in vivo when the polypeptide is the immunogen. On the other hand, a region of polypeptide to which an antibody binds is defined as an “antigenic determinant” or “antigenic epitope.” The number of immunogenic epitopes of a protein generally is less than the number of antigenic epitopes. See, e.g., Geysen, et al. (1983) Proc. Natl. Acad. Sci. USA 81:39984002. It is particularly noted that although a particular epitope may not be immunogenic, it is nonetheless useful since antibodies can be made in vitro to any epitope. An epitope can comprise as few as 3 amino acids in a spatial conformation which is unique to the epitope. Generally an epitope consists of at least 6 such amino acids, and more often at least 8-10 such amino acids. In preferred embodiment, antigenic epitopes comprise a number of amino acids that is any integer between 3 and 50. Fragments which function as epitopes may be produced by any conventional means. See, e.g., Houghten, R. A., Proc. Natl. Acad. Sci. USA 82:5131-5135 (1985), further described in U.S. Pat. No. 4,631,211. Methods for determining the amino acids which make up an immunogenic epitope include x-ray crystallography, 2-dimensional nuclear magnetic resonance, and epitope mapping, e.g., the Pepscan method described by H. Mario Geysen et al. (1984); Proc. Natl. Acad. Sci. U.S.A. 81:3998-4002; PCT Publication No. WO 84/03564; and PCT Publication No. WO 84/03506. Another example is the algorithm of Jameson and Wolf, Comp. Appl. Biosci. 4:181-186 (1988) (said references incorporated by reference in their entireties). The Jameson-Wolf antigenic analysis, for example, may be performed using the computer program PROTEAN, using default parameters (Version 4.0 Windows, DNASTAR, Inc., 1228 South Park Street Madison, Wis.). The epitope-bearing fragments of the present invention preferably comprises 6 to 50 amino acids (i.e. any integer between 6 and 50, inclusive) of a polypeptide of the present invention. Also, included in the present invention are antigenic fragments between the integers of 6 and the full length sequence of the sequence listing. All combinations of sequences between the integers of 6 and the full-length sequence of a polypeptide of the present invention are included. The epitope-bearing fragments may be specified by either the number of contiguous amino acid residues (as a sub-genus) or by specific N-terminal and C-terminal positions (as species) as described above for the polypeptide fragments of the present invention. Any number of epitope-bearing fragments of the present invention may also be excluded in the same manner. Antigenic epitopes are useful, for example, to raise antibodies, including monoclonal antibodies that specifically bind the epitope (See, Wilson et al., 1984; and Sutcliffe, J. G. et al., 1983). The antibodies are then used in various techniques such as diagnostic and tissue/cell identification techniques, as described herein, and in purification methods. Similarly, immunogenic epitopes can be used to induce antibodies according to methods well known in the art (See, Sutcliffe et al., supra; Wilson et al., supra; Chow, M. et al.;(1985) and Bittle, F. J. et al., (1985). A preferred immunogenic epitope includes the polypeptides of the sequence listing. The immunogenic epitopes may be presented together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse) if nessary. Immunogenic epitopes comprising as few as 8 to 10 amino acids have been shown to be sufficient to raise antibodies capable of binding to, at the very least, linear epitopes in a denatured polypeptide (e.g., in Western blotting.). Epitope-bearing polypeptides of the present invention are used to induce antibodies according to methods well known in the art including, but not limited to, in vivo immunization, in vitro immunization, and phage display methods (See, e.g., Sutcliffe, et al., supra; Wilson, et al., supra, and Bittle, et al., 1985). If in vivo immunization is used, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling of the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine residues may be coupled to a carrier using a linker such as—maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carriers using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 μgs of peptide or carrier protein and Freund's adjuvant. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody, which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art. As one of skill in the art will appreciate, and discussed above, the polypeptides of the present invention including, but not limited to, polypeptides comprising an immunogenic or antigenic epitope can be fused to heterologous polypeptide sequences. For example, the polypeptides of the present invention may be fused with the constant region comprising portions of immunoglobulins (IgA, IgE, IgG, IgM), or portions of the constant region (CH1, CH2, CH3, any combination thereof including both entire domains and portions thereof) resulting in chimeric polypeptides. These fusion proteins facilitate purification, and show an increased half-life in vivo. This has been shown, e.g., for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins (See, e.g., EPA 0,394,827; and Traunecker et al., 1988). Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion can also be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone (See, e.g., Fountoulakis et al., 1995). Nucleic acids encoding the above epitopes can also be recombined with a gene of interest as an epitope tag to aid in detection and purification of the expressed polypeptide. Additonal fusion proteins of the invention may be generated through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to modulate the activities of polypeptides of the present invention thereby effectively generating agonists and antagonists of the polypeptides. See, for example, U.S. Pat. Nos. 5,605,793; 5,811,238; 5,834,252; 5,837,458; and Patten, P. A., et al., (1997); Harayama, S., (1998); Hansson, L. O., et al (1999); and Lorenzo, M. M. and Blasco, R., (1998). (Each of these documents are hereby incorporated by reference). In one embodiment, one or more components, motifs, sections, parts, domains, fragments, etc., of coding polynucleotides of the invention, or the polypeptides encoded thereby may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules. Antibodies: The present invention further relates to antibodies and T-cell antigen receptors (TCR), which specifically bind the polypeptides, and more specifically, the epitopes of the polyepeptides of the present invention. The antibodies of the present invention include IgG (including IgG1, IgG2, IgG3, and IgG4), IgA (including IgA1 and IgA2), IgD, IgE, or IgM, and IgY. As used herein, the term “antibody” (Ab) is meant to include whole antibodies, including single-chain whole antibodies, and antigen binding fragments thereof. In a preferred embodiment the antibodies are human antigen binding antibody fragments of the present invention include, but are not limited to, Fab, Fab′ F(ab)2 and F(ab)2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. The antibodies may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine, rabbit, goat, guinea pig, camel, horse, or chicken. Antigen-binding antibody fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entire or partial of the following: hinge region, CH1, CH2, and CH3 domains. Also included in the invention are any combinations of variable region(s) and hinge region, CH1, CH2, and CH3 domains. The present invention further includes chimeric, humanized, and human monoclonal and polyclonal antibodies, which specifically bind the polypeptides of the present invention. The present invention further includes antibodies that are anti-idiotypic to the antibodies of the present invention. The antibodies of the present invention may be monospecific, bispecific, and trispecific or have greater multispecificity. Multispecific antibodies may be specific for different epitopes of a polypeptide of the present invention or may be specific for both a polypeptide of the present invention as well as for heterologous compositions, such as a heterologous polypeptide or solid support material. See, e.g., WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, A. et al. (1991); U.S. Pat. Nos. 5,573,920, 4,474,893, 5,601,819, 4,714,681, 4,925,648; Kostelny, S. A. et al. (1992). Antibodies of the present invention may be described or specified in terms of the epitope(s) or epitope-bearing portion(s) of a polypeptide of the present invention, which are recognized or specifically bound by the antibody. In the case of proteins of the present invention secreted proteins, the antibodies may specifically bind a full-length protein encoded by a nucleic acid of the present invention, a mature protein (i.e., the protein generated by cleavage of the signal peptide) encoded by a nucleic acid of the present invention, a signal peptide encoded by a nucleic acid of the present invention, or any other polypeptide of the present invention. Therefore, the epitope(s) or epitope bearing polypeptide portion(s) may be specified as described herein, e.g., by N-terminal and C-terminal positions, by size in contiguous amino acid residues, or otherwise described herein (including the sequence listing). Antibodies which specifically bind any epitope or polypeptide of the present invention may also be excluded as individual species. Therefore, the present invention includes antibodies that specifically bind specified polypeptides of the present invention, and allows for the exclusion of the same. Antibodies of the present invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not specifically bind any other analog, ortholog, or homolog of the polypeptides of the present invention are included. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein, eg., using FASTDB and the parameters set forth herein) to a polypeptide of the present invention are also included in the present invention. Further included in the present invention are antibodies, which only bind polypeptides encoded by polynucleotides, which hybridize to a polynucleotide of the present invention under stringent hybridization conditions (as described herein). Antibodies of the present invention may also be described or specified in terms of their binding affinity. Preferred binding affinities include those with a dissociation constant or Kd value less than 5×10−6M, 10−6M, 5×10−7M, 10−7M, 5×10−8M, 10−8M, 5×10−9M, 10−9M, 5×10−10M, 10−10M, 5×10−11M, 10−11M, 5×10−12M, 10−12M, 5×10−13M, 10−13M, 5×10−14M, 10−14M, 5×10−15M, and 10−15M. Antibodies of the present invention have uses that include, but are not limited to, methods known in the art to purify, detect, and target the polypeptides of the present invention including both in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have use in immunoassays for qualitatively and quantitatively measuring levels of the polypeptides of the present invention in biological samples (See, e.g., Harlow et al., 1988). The antibodies of the present invention may be used either alone or in combination with other compositions. The antibodies may further be recombinantly fused to a heterologous polypeptide at the N- or C-terminus or chemically conjugated (including covalent and non-covalent conjugations) to polypeptides or other compositions. For example, antibodies of the present invention may be recombinantly fused or conjugated to molecules useful as labels in detection assays and effector molecules such as heterologous polypeptides, drugs, or toxins. See, e.g., WO 92/08495; WO 91/14438; WO 89/12624; U.S. Pat. No. 5,314,995; and EP 0 396 387. The antibodies of the present invention may be prepared by any suitable method known in the art. For example, a polypeptide of the present invention or an antigenic fragment thereof can be administered to an animal in order to induce the production of sera containing polyclonal antibodies. The term “monoclonal antibody” is not limited to antibodies produced through hybridoma technology. The term “antibody” refers to a polypeptide or group of polypeptides which are comprised of at least one binding domain, where a binding domain is formed from the folding of variable domains of an antibody molecule to form three-dimensional binding spaces with an internal surface shape and charge distribution complementary to the features of an antigenic determinant of an antigen, which allows an immunological reaction with the antigen. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced. Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technology. Hybridoma techniques include those known in the art (See, e.g., Harlow et al. 1988); Hammerling, et al, 1981). (Said references incorporated by reference in their entireties). Fab and F(ab′)2 fragments may be produced, for example, from hybridoma-produced antibodies by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab′)2 fragments). Alternatively, antibodies of the present invention can be produced through the application of recombinant DNA technology or through synthetic chemistry using methods known in the art. For example, the antibodies of the present invention can be prepared using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of a phage particle, which carries polynucleotide sequences encoding them. Phage with a desired binding property are selected from a repertoire or combinatorial antibody library (e.g. human or murine) by selecting directly with antigen, typically antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make the antibodies of the present invention include those disclosed in Brinkman U. et al. (1995); Ames, R. S. et al. (1995); Kettleborough, C. A. et al. (1994); Persic, L. et al. (1997); Burton, D. R. et al. (1994); PCT/GB91/01134; WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426, 5,223,409, 5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698, 5,427,908, 5,516,637, 5,780,225, 5,658,727 and 5,733,743. As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host including mammalian cells, insect cells, plant cells, yeast, and bacteria. For example, techniques to recombinantly produce Fab, Fab′ F(ab)2 and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in WO 92/22324; Mullinax, R. L. et al. (1992); and Sawai, H. et al. (1995); and Better, M. et al. (1988). Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al. (1991); Shu, L. et al. (1993); and Skerra, A. et al. (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, (1985); Oi et al., (1986); Gillies, S. D. et al. (1989); and U.S. Pat. No. 5,807,715. Antibodies can be humanized using a variety of techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101; and 5,585,089), veneering or resurfacing, (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991; Studnicka G. M. et al., 1994; Roguska M. A. et al., 1994), and chain shuffling (U.S. Pat. No. 5,565,332). Human antibodies can be made by a variety of methods known in the art including phage display methods described above. See also, U.S. Pat. Nos. 4,444,887,4,716,111, 5,545,806, and 5,814,318; WO 98/46645; WO 98/50433; WO 98/24893; WO 96/34096; WO 96/33735; and WO 91/10741. Further included in the present invention are antibodies recombinantly fused or chemically conjugated (including both covalently and non-covalently conjugations) to a polypeptide of the present invention. The antibodies may be specific for antigens other than polypeptides of the present invention. For example, antibodies may be used to target the polypeptides of the present invention to particular cell types, either in vitro or in vivo, by fusing or conjugating the polypeptides of the present invention to antibodies specific for particular cell surface receptors. Antibodies fused or conjugated to the polypeptides of the present invention may also be used in in vitro immunoassays and purification methods using methods known in the art (See e.g., Harbor et al. supra; WO 93/21232; EP 0 439 095; Naramura, M. et al. 1994; U.S. Pat. No. 5,474,981; Gillies, S. O. et al., 1992; Fell, H. P. et al., 1991). The present invention further includes compositions comprising the polypeptides of the present invention fused or conjugated to antibody domains other than the variable regions. For example, the polypeptides of the present invention may be fused or conjugated to an antibody Fc region, or portion thereof. The antibody portion fused to a polypeptide of the present invention may comprise the hinge region, CH1 domain, CH2 domain, and CH3 domain or any combination of whole domains or portions thereof. The polypeptides of the present invention may be fused or conjugated to the above antibody portions to increase the in vivo half-life of the polypeptides or for use in immunoassays using methods known in the art. The polypeptides may also be fused or conjugated to the above antibody portions to form multimers. For example, Fc portions fused to the polypeptides of the present invention can form dimers through disulfide bonding between the Fc portions. Higher multimeric forms can be made by fusing the polypeptides to portions of IgA and IgM. Methods for fusing or conjugating the polypeptides of the present invention to antibody portions are known in the art. See e.g., U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, 5,112,946; EP 0 307 434, EP 0 367 166; WO 96/04388, WO 91/06570; Ashkenazi, A. et al. (1991); Zheng, X. X. et al. (1995); and Vil, H. et al. (1992). The invention further relates to antibodies that act as agonists or antagonists of the polypeptides of the present invention. For example, the present invention includes antibodies that disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. Included are both receptor-specific antibodies and ligand-specific antibodies. Included are receptor-specific antibodies, which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. Also include are receptor-specific antibodies which both prevent ligand binding and receptor activation. Likewise, included are neutralizing antibodies that bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies that bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included are antibodies that activate the receptor. These antibodies may act as agonists for either all or less than all of the biological activities affected by ligand-mediated receptor activation. The antibodies may be specified as agonists or antagonists for biological activities comprising specific activities disclosed herein. The above antibody agonists can be made using methods known in the art. See e.g., WO 96/40281; U.S. Pat. No. 5,811,097; Deng, B. et al. (1998); Chen, Z. et al. (1998); Harrop, J. A. et al. (1998); Zhu, Z. et al. (1998); Yoon, D. Y. et al. (1998); Prat, M. et al. (1998) J.; Pitard, V. et al. (1997); Liautard, J. et al. (1997); Carlson, N. G. et al. (1997) J.; Taryman, R. E. et al. (1995); Muller, Y. A. et al. (1998); Bartunek, P. et al. (1996). As discussed above, antibodies of the polypeptides of the invention can, in turn, be utilized to generate anti-idiotypic antibodies that “mimic” polypeptides of the invention using techniques well known to those skilled in the art (See, e.g. Greenspan and Bona (1989); and Nissinoff (1991). For example, antibodies which bind to and competitively inhibit polypeptide multimerization or binding of a polypeptide of the invention to ligand can be used to generate anti-idiotypes that “mimic” the polypeptide multimerization or binding domain and, as a consequence, bind to and neutralize polypeptide or its ligand. Such neutralization anti-idiotypic antibodies can be used to bind a polypeptide of the invention or to bind its ligands/receptors, and therby block its biological activity, The invention also concerns a purified or isolated antibody capable of specifically binding to a mutated full length or mature polypeptide of the present invention or to a fragment or variant thereof comprising an epitope of the mutated polypeptide. In another preferred embodiment, the present invention concerns an antibody capable of binding to a polypeptide comprising at least 10 consecutive amino acids of a polypeptide of the present invention and including at least one of the amino acids which can be encoded by the trait causing mutations. Non-human animals or mammals, whether wild-type or transgenic, which express a different species of a polypeptide of the present invention than the one to which antibody binding is desired, and animals which do not express a polypeptide of the present invention (i.e. a knock out animal) are particularly useful for preparing antibodies. Gene knock out animals will recognize all or most of the exposed regions of a polypeptide of the present invention as foreign antigens, and therefore produce antibodies with a wider array of epitopes. Moreover, smaller polypeptides with only 10 to 30 amino acids may be useful in obtaining specific binding to any one of the polypeptides of the present invention. In addition, the humoral immune system of animals which produce a species of a polypeptide of the present invention that resembles the antigenic sequence will preferentially recognize the differences between the animal's native polypeptide species and the antigen sequence, and produce antibodies to these unique sites in the antigen sequence. Such a technique will be particularly useful in obtaining antibodies that specifically bind to any one of the polypeptides of the present invention. Antibody preparations prepared according to either protocol are useful in quantitative immunoassays which determine concentrations of antigen-bearing substances in biological samples; they are also used semi-quantitatively or qualitatively to identify the presence of antigen in a biological sample. The antibodies may also be used in therapeutic compositions for killing cells expressing the protein or reducing the levels of the protein in the body. The antibodies of the invention may be labeled by any one of the radioactive, fluorescent or enzymatic labels known in the art. Consequently, the invention is also directed to a method for detecting specifically the presence of a polypeptide of the present invention according to the invention in a biological sample, said method comprising the following steps: a) bringing into contact the biological sample with a polyclonal or monoclonal antibody that specifically binds a polypeptide of the present invention; and b) detecting the antigen-antibody complex formed. The invention also concerns a diagnostic kit for detecting in vitro the presence of a polypeptide of the present invention in a biological sample, wherein said kit comprises: a) a polyclonal or monoclonal antibody that specifically binds a polypeptide of the present invention, optionally labeled; b) a reagent allowing the detection of the antigen-antibody complexes formed, said reagent carrying optionally a label, or being able to be recognized itself by a labeled reagent, more particularly in the case when the above-mentioned monoclonal or polyclonal antibody is not labeled by itself. The antibodies of the invention may be labeled by any one of the radioactive, fluorescent or enzymatic labels known in the art. EXAMPLES The following Examples are provided for illustrative purposes and not as a means of limitation to support the finding that GSSP4 polypeptides have efficacy in reducing insulin resistance and improving glucose and lipid metabolism and may have an insulin sensitising action. One of ordinary skill in the art would be able to design equivalent assays and methods based on the disclosure herein all of which form part of the instant invention. Example 1 Northern Analysis of GSSP4 RNA Analysis of GSSP4 expression in different human tissues (adult and fetal) and cell lines, as well as mouse embryos in different stages of development, is accomplished by using poly A+ RNA blots purchased from Clontech (e.g. #7780-1, 7757-1, 7756-1, 7768-1and 7763-1). Labeling of RNA probes is performed using the RNA Strip-EZ kit from Ambion as per manufacture's instructions. Hybridization of RNA probes to RNA blots is performed Ultrahyb hybridization solution (Ambion). Briefly, blots are prehybridized for 30 min at 58° C. (low-strigency) or 65° C. (high stringency). After adding the labeled probe (2×106 cpm/ml), blots are hybridized overnight (14-24 hrs), and is washed 2×20 min at 50° C. with 2× SSC/0.1% SDS (low stringency), 2×20 min at 58° C. with 1× SSC/0.1% SDS (medium stringency) and 2×20 min at 65° C. with 1× SSC/0.1% SDS (high stringency). After washings are completed blots are exposed on the phosphoimager (Molecular Dynamics) for 1-3 days. Example 2 In Vitro Tests of Metabolic-Related Activity The activity of various preparations of GSSP4 polypeptides are assessed using various in vitro assays including those provided below. These assays are also exemplary of those that can be used to develop GSSP4 polypeptide antagonists and agonists. To do that, the effect of GSSP4 polypeptides in the above assays, e.g. on glucose uptake and fatty acid oxidation and partitioning in the presence of the candidate molecules would be compared with the effect of GSSP4 polypeptides in the assays in the absence of the candidate molecules. In Vitro Muscle Cells Glucose Uptake L6 Muscle cells are obtained from the European Culture Collection (Porton Down) and are used at passages 7-11. Cells are maintained in standard tissue culture medium DMEM, and glucose uptake is assessed using [.sup.3H]-2-deoxyglucose (2DG) with or without GSSP4 polypeptides in the presence or absence of insulin (10.sup.-8 M) as has been previously described (Walker P S et al, Glucose transport activity in L6 muscle cells is regulated by the coordinate control of subcellular glucose transporter distribution, biosynthesis, and mRNA transcription, JBC, 1990;265(3), 1516-1523, and Kilp A et al, Stimulation of hexose transport by metformin in L6 muscle cells in culture, Endocrinology,1992;130(5), 2535-2544). Uptake of 2DG is expressed as the percentage change compared with control (no added insulin or GSSP4). Values are presented as mean .+−.SEM of sets of 4 wells per experiment. Differences between sets of wells are evaluated by Student's t test, probability values p<0.05 are considered to be significant. Effect on Muscle Cell Fatty Acid Oxidation C2C12 cells are differentiated in the presence or absence of 2 μg/mL GSSP4 protein for 4 days. On day 4, oleate oxidation rates are determined by measuring conversion of 1-14C-oleate (0.2 mM) to 14CO2 for 90 min This experiment can be used to screen for active fragments and peptides as well as agonists and antagonists or activators and inhibitors of GSSP4 polypeptides. The effect of polypeptides on the rate of oleate oxidation can be compared in differentiated C2C12 cells (murine skeletal muscle cells; ATCC, Manassas, Va. CRL-1772) and in a hepatocyte cell line (Hepa1-6; ATCC, Manassas, Va. CRL-1830). Cultured cells are maintained according to manufacturer's instructions. The oleate oxidation assay is performed as previously described (Muoio et al (1999) Biochem J 338;783-791). Briefly, nearly confluent myocytes are kept in low serum differentiation media (DMEM, 2.5% Horse serum) for 4 days, at which time formation of myotubes became maximal. Hepatocytes are kept in the same DMEM medium supplemented with 10% FCS for 2 days. One hour prior to the experiment the media is removed and 1 mL of preincubation media (MEM, 2.5% Horse serum, 3 mM glucose, 4 mM Glutamine, 25 mM Hepes, 1% FFA free BSA, 0.25 mM Oleate, 5 μg/mL gentamycin) is added. At the start of the oxidation experiment 14C-Oleic acid (1 μCi/mL, American Radiolabeled Chemical Inc., St. Louis, Mo.) is added and cells are incubated for 90 min at 37° C. in the absence/presence of 2.5 μg/mL GSSP4 polypeptides. After the incubation period 0.75 mL of the media is removed and assayed for 14C-oxidation products as described below for the muscle FFA oxidation experiment. Triglyceride and Protein Partitioning following Oleate Oxidaiton in Cultured Cells Following transfer of media for oleate oxidation assay, cells are placed on ice. To determine triglyceride and protein content, cells are washed with 1 mL of 1×PBS to remove residual media. To each well 300 μL of cell dissociation solution (Sigma) is added and incubated at 37° C. for 10 min. Plates are tapped to loosen cells, and 0.5 mL of 1×PBS is added. The cell suspension is transferred to an eppendorf tube, each well is rinsed with an additional 0.5 mL of 1×PBS, and is transferred to appropriate eppendorf tube. Samples are centrifuged at 1000 rpm for 10 minutes at room temperature. Supernatant is discarded and 750 μL of 1×PBS/2% chaps is added to cell pellet. Cell suspension is vortexed and placed on ice for 1 hour. Samples are then centrifuged at 13000 rpm for 20 min at 4° C. Supernatants are transferred to new tube and frozen at −20° C. until analyzed. Quantitative measure of triglyceride level in each sample is determined using Sigma Diagnostics GPO-TRINDER enzymatic kit. The procedure outlined in the manual is adhered to, with the following exceptions: assay is performed in 48 well plate, 350 μL of sample volume is assayed, control blank consisted of 350 μL PBS/2% chaps, and standard contained 10 μL standard provide in kit plus 690 μL PBS/2% chaps. Analysis of samples is carried out on a Packard Spectra Count at a wavelength of 550 nm. Protein analysis is carried out on 25 μL of each supernatant sample using the BCA protein assay (Pierce) following manufacturer's instructions. Analysis of samples is carried out on a Packard Spectra Count at a wavelength of 550 nm. Cellular Binding and Uptake of GSSP4 Polypeptides as Detected by Fluorescence Microscopy Fluorecein isothiocyanate (FITC) conjugation of GSSP4 polypeptides: Purified GSSP4 proteins at 1 mg/mL concentration are labeled with FITC using Sigma's FluoroTag FITC conjugation kit (Stock No. FITC-1). Protocol outlined in the Sigma Handbook for small scale conjugation is followed for GSSP4 protein labeling. Cell Culture: C2C12 mouse skeletal muscle cells (ATCC, Manassas, Va. CRL-1772) and Hepa-1-6 mouse hepatocytes (ATCC, Manassas, Va. CRL-1830) are seeded into 6 well plates at a cell density of 2×105 cells per well. C2C12 and Hepa-1-6 cells are cultured according to repository's instructions for 24-48 hours prior to analysis. Assay is performed when cells are 80% confluent. FITC labeled GSSP4 proteincellular binding and uptake using microscopy: C2C12 and Hepa 1-6 cells are incubated in the presence/absence of antibody directed against human LSR (81B: N-terminal sequence of human LSR; does not cross react with mouse LSR and 93A: c-terminal sequence, cross reacts with mouse LSR) or an antiserum directed against gC1qr (953) for 1 hour at 37° C., 5% CO2. LSR antibodies are added to the media at a concentration of 2 μg/mL. The anti-gC1qr antiserum is added to the media at a volume of 2.5 μL undiluted serum (high concentration) or 1:100 dilution (low concentration). Following incubation with specified antibody, FITC-GSSP4 polypeptide (50 nM/mL) is added to each cell culture well. Cells are again incubated for 1 hour at 37° C., 5% CO2. Cells are washed 2× with PBS, cells are scraped from well into 1 mL of PBS. Cell suspension is transferred to an eppendorf tube and centrifuged at 1000 rpm for 2 minutes. Supernatant is removed and cells resuspended in 200 μL of PBS. Binding and uptake of FITC-GSSP4 polypeptide is analyzed by fluorescence microscopy under 40× magnification. This assay may be useful for identifying agents that facilitate or prevent the uptake and/or binding of GSSP4 polypeptides to cells. Example 3 In Vivo Tests for Metabolic-Related Activity in Rodent Diabetes Models As metabolic profiles differ among various animal models of obesity and diabetes, analysis of multiple models is undertaken to separate the effects GSSP4 polypeptides on hyperglycemia, hyperinsulinemia, hyperlipidemia and obesity. Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non-insulin dependent diabetes associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (See Diabetes, (1982) 31(1): 1-6) in mice and fa/fa in zucker rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838; Annu. Rep. Sankyo Res. Lab. (1994). 46: 1-57). The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85: 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention are tested for blood sugar and triglycerides lowering activities. Zucker (fa/fa) rats are severely obese, hyperinsulinemic, and insulin resistant (Coleman, Diabetes 31:1, 1982; E. Shafrir, in Diabetes Mellitus; H. Rifkin and D. Porte, Jr. Eds. (Elsevier Science Publishing Co., Inc., New York, ed. 4, 1990), pp. 299-340), and the fa/fa mutation may be the rat equivalent of the murine db mutation (Friedman et al., Cell 69:217-220, 1992; Truett et al., Proc. Natl. Acad. Sci. USA 88:7806, 1991). Tubby (tub/tub) mice are characterized by obesity, moderate insulin resistance and hyperinsulinemia without significant hyperglycemia (Coleman et al., J. Heredity 81:424, 1990). Previously, leptin was reported to reverse insulin resistance and diabetes mellitus in mice with congenital lipodystrophy (Shimomura et al. Nature 401: 73-76 (1999). Leptin is found to be less effective in a different lipodystrophic mouse model of lipoatrophic diabetes (Gavrilova et al Nature 403: 850 (2000); hereby incorporated herein in its entirety including any drawings, figures, or tables). The streptozotocin (STZ) model for chemically-induced diabetes is tested to examine the effects of hyperglycemia in the absence of obesity. STZ-treated animals are deficient in insulin and severely hyperglycemic (Coleman, Diabetes 31:1, 1982; E. Shafrir, in Diabetes Mellitus; H. Rifkin and D. Porte, Jr. Eds. (Elsevier Science Publishing Co., Inc., New York, ed. 4, 1990), pp. 299-340). The monosodium glutamate (MSG) model for chemically-induced obesity (Olney, Science 164:719, 1969; Cameron et al., Cli. Exp. Pharmacol. Physiol. 5:41, 1978), in which obesity is less severe than in the genetic models and develops without hyperphagia, hyperinsulinemia and insulin resistance, is also examined. Finally, a non-chemical, non-genetic model for induction of obesity includes feeding rodents a high fat/high carbohydrate (cafeteria diet) diet ad libitum. The instant invention encompasses the use of GSSP4 polypeptides for reducing the insulin resistance and hyperglycemia in any or all of the above rodent diabetes models or in humans with Type I or Type II diabetes or other prefered metabolic diseases described previously or models based on other mammals. In the compositions of the present invention the GSSP4 polypeptides may, if desired, be associated with other compatible pharmacologically-active antidiabetic agents such as insulin, leptin (U.S. provisional application No. 60/155,506), or troglitazone, either alone or in combination. Assays include that described previously in Gavrilova et al. ((2000) Diabetes November;49(11): 1910-6; (2000) Nature February 24;403(6772):850) using A-ZIP/F-1 mice, except that GSSP4 polypeptides are administered intraperotineally, subcutaneously, intramuscularly or intravenously. The glucose and insulin levels of the mice would be tested, and the food intake and liver weight monitored, as well as other factors, such as leptin, FFA, and TG levels, typically measured in our experiments. In Vivo Assay for Anti-Hyperglycemic Activity of GSSP4 Polypeptides Genetically altered obese diabetic mice (db/db) (male, 7-9 weeks old) are housed (7-9 mice/cage) under standard laboratory conditions at 22.degree. C. and 50% relative humidity, and maintained on a diet of Purina rodent chow and water ad libitum. Prior to treatment, blood is collected from the tail vein of each animal and blood glucose concentrations are determined using One Touch BasicGlucose Monitor System (Lifescan). Mice that have plasma glucose levels between 250 to 500 mg/dl are used. Each treatment group consists of seven mice that are distributed so that the mean glucose levels are equivalent in each group at the start of the study. db/db mice are dosed by micro-osmotic pumps, inserted using isoflurane anesthesia, to provide GSSP4 polypeptides, saline, and an irrelevant peptide to the mice subcutaneously (s.c.). Blood is sampled from the tail vein hourly for 4 hours and at 24, 30 h post-dosing and analyzed for blood glucose concentrations. Food is withdrawn from 0-4 h post dosing and reintroduced thereafter. Individual body weights and mean food consumption (each cage) are also measured after 24 h. Significant differences between groups (comparing GSSP4 treated to saline-treated) are evaluated using Student t-test. In Vivo Insulin Sensitivity Assay In vivo insulin sensitivity is examined by utilizing two-step hyperinsulinemic-euglycemic clamps according to the following protocol. Rodents from any or all of the various models described in Example 2 are housed for at least a week prior to experimental procedures. Surgeries for the placement of jugular vein and carotid artery catheters are performed under sterile conditions using ketamine and xylazine (i.m.) anesthesia. After surgery, all rodents are allowed to regain consciousness and placed in individual cages. GSSP4 polypeptides or vehicle is administered through the jugular vein after complete recovery and for the following two days. Sixteen hours after the last treatment, hyperinsulinemic-euglycemic clamps are performed. Rodents are placed in restrainers and a bolus of 4 .mu Ci [3-.sup.3 H] glucose (NEN) is administered, followed by a continuous infusion of the tracer at a dose of 0.2 mu.Ci/min (20 mu.1/min). Two hours after the start of the tracer infusion, 3 blood samples (0.3 ml each) are collected at 10 minute intervals (−20-0 min) for basal measurements. An insulin infusion is then started (5 mU/kg/min), and 100 .mu.1 blood samples are taken every 10 min. to monitor plasma glucose. A 30% glucose solution is infused using a second pump based on the plasma glucose levels in order to reach and maintain euglycemia. Once a steady state is established at 5 mU/kg/min insulin (stable glucose infusion rate and plasma glucose), 3 additional blood samples (0.3 ml each) are obtained for measurements of glucose, [3-.sup.3H] glucose and insulin (100-120 min.). A higher dose of insulin (25 mU/kg/min.) is then administered and glucose infusion rates are adjusted for the second euglycemic clamp and blood samples are taken at min. 220-240. Glucose specific activity is determined in deproteinized plasma and the calculations of Rd and hepatic glucose output (HGO) are made, as described (Lang et al., Endocrinology 130:43, 1992). Plasma insulin levels at basal period and after 5 and 25 mU/kg/min. infusions are then determined and compared between GSSP4 treated and vehicle treated rodents. Insulin regulation of glucose homeostasis has two major components; stimulation of peripheral glucose uptake and suppression of hepatic glucose output. Using tracer studies in the glucose clamps, it is possible to determine which portion of the insulin response is affected by the GSSP4 polypeptides. Example 4 Effect of GSSP4 Polypeptides on Mice Fed a High-Fat Diet Experiments are performed using approximately 6 week old C57B1/6 mice (8 per group). All mice are housed individually. The mice are maintained on a high fat diet throughout each experiment. The high fat diet (cafeteria diet; D12331 from Research Diets, Inc.) has the following composition: protein kcal % 16, carbohydrate kcal % 26, and fat kcal % 58. The fat is primarily composed of coconut oil, hydrogenated. After the mice are fed a high fat diet for 6 days, micro-osmotic pumps are inserted using isoflurane anesthesia, and are used to provide full-length GSSP4 polypeptides, GSSP4 polypeptide fragments, saline, and an irrelevant peptide to the mice subcutaneously (s.c.) for 18 days. GSSP4 polypeptides are provided at doses of 100, 50, 25, and 2.5 μg/day and the irrelevant peptide is provided at 10 μg/day. Body weight is measured on the first, third and fifth day of the high fat diet, and then daily after the start of treatment. Final body weight and final blood samples are taken by cardiac puncture and are used to determine triglyceride (TG), total cholesterol (TC), glucose, leptin, and insulin levels. The amount of food consumed per day is also determined for each group. Plasma glucose is determined by a glucose oxidase procedure (Analox GM7) and plasma insulin determined by radioimmunoassay (Amerlex, Amersham). Example 5 Effect of GSSP4 Polypeptides on Plasma Free Fatty Acid in C57 BL/6 Mice The effect of GSSP4 polypeptides on postprandial lipemia (PPL) in normal C57BL6/J mice is tested. The mice used in this experiment are fasted for 2 hours prior to the experiment after which a baseline blood sample is taken. All blood samples are taken from the tail using EDTA coated capillary tubes (50 μL each time point). At time 0 (8:30 AM), a standard high fat meal (6 g butter, 6 g sunflower oil, 10 g nonfat dry milk, 10 g sucrose, 12 mL distilled water prepared fresh following Nb#6, JF, pg.1) is given by gavage (vol.=1% of body weight) to all animals. Immediately following the high fat meal, 25 μg a GSSP4 polypeptide is injected i.p. in 100 μL saline. The same dose (25 μg/mL in 100 μL) is again injected at 45 min and at 1 hr 45 min. Control animals are injected with saline (3×100 μL). Untreated and treated animals are handled in an alternating mode. Blood samples are taken in hourly intervals, and are immediately put on ice. Plasma is prepared by centrifugation following each time point. Plasma is kept at −20° C. and free fatty acids (FFA), triglycerides (TG) and glucose are determined within 24 hours using standard test kits (Sigma and Wako). Due to the limited amount of plasma available, glucose is determined in duplicate using pooled samples. For each time point, equal volumes of plasma from all 8 animals per treatment group are pooled. Example 6 Effect of GSSP4 Polypeptides on Plasma Leptin and Insulin in C57 BL/6 Mice The effect of GSSP4 polypeptides on plasma leptin and insulin levels during postprandial lipemia (PPL) in normal C57BL6/J mice is tested. The experimental procedure is the same as previously described, except that blood is drawn only at 0, 2 and 4 hours to allow for greater blood samples needed for the determination of leptin and insulin by RIA. Briefly, 16 mice are fasted for 2 hours prior to the experiment after which a baseline blood sample is taken. All blood samples are taken from the tail using EDTA coated capillary tubes (100 μL each time point). At time 0 (9:00 AM), a standard high fat meal is given by gavage (vol.=1% of body weight) to all animals. Immediately following the high fat meal, 25 μg of a GSSP4 polypeptide is injected i.p. in 100 μL saline. The same dose (25 μg in 100 μL) is again injected at 45 min and at 1 hr 45 min (treated group). Control animals are injected with saline (3×100 μL). Untreated and treated animals are handled in an alternating mode. Blood samples are immediately put on ice and plasma is prepared by centrifugation following each time point. Plasma is kept at −20° C. and free fatty acids (FFA) are determined within 24 hours using a standard test kit (Wako). Leptin and Insulin are determined by RIA (ML-82K and SRI-13K, LINCO Research, Inc., St. Charles, Mo.) following the manufacturer's protocol. However, only 20 μL plasma is used. Each determination is done in duplicate. Due to the limited amount of plasma available, leptin and insulin are determined in 4 pools of 2 animals each in both treatment groups. Example 7 Effect of GSSP4 Polypeptides on Plasma FFA, TG and Glucose in C57 BL/6 Mice The effect of GSSP4 polypeptides on plasma FFA, TG, glucose, leptin and insulin levels during postprandial lipemia (PPL) in normal C57BL6/J mice has been described. Weight loss resulting from GSSP4 polypeptides (2.5 μg/day) given to normal C57BL6/J mice on a high fat diet is shown. The experimental procedure is similar to described previously. Briefly, 14 mice are fasted for 2 hours prior to the experiment after which a baseline blood sample is taken. All blood samples are taken from the tail using EDTA coated capillary tubes (50 μL each time point). At time 0 (9:00 AM), a standard high fat meal is given by gavage (vol.=1% of body weight) to all animals. Immediately following the high fat meal, 4 mice are injected 25 μg of a GSSP4 polypeptide i.p. in 100 μL saline. The same dose (25 μg in 100 μL) is again injected at 45 min and at 1 hr 45 min. A second treatment group receives 3 times 50 μg GSSP4 polypeptide at the same intervals. Control animals are injected with saline (3×100 μL). Untreated and treated animals are handled in an alternating mode. Blood samples are immediately put on ice. Plasma is prepared by centrifugation following each time point. Plasma is kept at −20° C. and free fatty acids (FFA), triglycerides (TG) and glucose are determined within 24 hours using standard test kits (Sigma and Wako). Example 8 Effect of GSSP4 Polypeptides on FFA Following Epinephrine Injection In mice, plasma free fatty acids increase after intragastric administration of a high fat/carbohydrate test meal. These free fatty acids are mostly produced by the activity of lipolytic enzymes i.e. lipoprotein lipase (LPL) and hepatic lipase (HL). In this species, these enzymes are found in significant amounts both bound to endothelium and freely circulating in plasma. Another source of plasma free fatty acids is hormone sensitive lipase (HSL) that releases free fatty acids from adipose tissue after β-adrenergic stimulation. To test whether GSSP4 polypeptides also regulate the metabolism of free fatty acid released by HSL, mice are injected with epinephrine. Two groups of mice are given epinephrine (5 μg) by intraperitoneal injection. A treated group is injected with a GSSP4 polypeptide (25 μg) one hour before and again together with epinephrine, while control animals receive saline. Plasma is isolated and free fatty acids and glucose are measured as described above. Example 9 Effect of GSSP4 Polypeptides on Muscle FFA Oxidation To investigate the effect of GSSP4 polypeptides on muscle free fatty acid oxidation, intact hind limb muscles from C57BL/6J mice are isolated and FFA oxidation is measured using oleate as substrate (Clee et al (2000) J Lipid Res 41:521-531; Muoio et al (1999) Am J Physiol 276:E913-921). Oleate oxidation in isolated muscle is measured as previously described (Cuendet et al (1976) J Clin Invest 58:1078-1088; Le Marchand-Brustel (1978) Am J Physiol 234:E348-E358). Briefly, mice are sacrificed by cervical dislocation and soleus and EDL muscles are rapidly isolated from the hind limbs. The distal tendon of each muscle is tied to a piece of suture to facilitate transfer among different media. All incubations are carried out at 30° C. in 1.5 mL of Krebs-Henseleit bicarbonate buffer (118.6 mM NaCl, 4.76 mM KCl, 1.19 mM KH2PO4, 1.19 mM MgSO4, 2.54 mM CaCl2, 25 mM NaHCO3, 10 mM Hepes, pH 7.4) supplemented with 4% FFA free bovine serum albumin (fraction V, RIA grade, Sigma) and 5 mM glucose (Sigma). The total concentration of oleate (Sigma) throughout the experiment is 0.25 mM. All media are oxygenated (95% O2; 5% CO2) prior to incubation. The gas mixture is hydrated throughout the experiment by bubbling through a gas washer (Kontes Inc., Vineland, N.J.). Muscles are rinsed for 30 min in incubation media with oxygenation. The muscles are then transferred to fresh media (1.5 mL) and incubated at 30° C. in the presence of 1 μCi/mL [1-14C] oleic acid (American Radiolabeled Chemicals). The incubation vials containing this media are sealed with a rubber septum from which a center well carrying a piece of Whatman paper (1.5 cm×11.5 cm) is suspended. After an initial incubation period of 10 min with constant oxygenation, gas circulation is removed to close the system to the outside environment and the muscles are incubated for 90 min at 30° C. At the end of this period, 0.45 mL of Solvable (Packard Instruments, Meriden, Conn.) is injected onto the Whatman paper in the center well and oleate oxidation by the muscle is stopped by transferring the vial onto ice. After 5 min, the muscle is removed from the medium, and an aliquot of 0.5 mL medium is also removed. The vials are closed again and 1 mL of 35% perchloric acid is injected with a syringe into the media by piercing through the rubber septum. The CO2 released from the acidified media is collected by the Solvable in the center well. After a 90 min collection period at 30° C., the Whatman paper is removed from the center well and placed in scintillation vials containing 15 mL of scintillation fluid (HionicFlour, Packard Instruments, Meriden, Conn.). The amount of 14C radioactivity is quantitated by liquid scintillation counting. The rate of oleate oxidation is expressed as nmol oleate produced in 90 min/g muscle. To test the effect of gACRP30 or ACRP30 on oleate oxidation, these proteins are added to the media at a final concentration of 2.5 μg/mL and maintained in the media throughout the procedure. Example 10 Effect of GSSP4 Polypeptides on Triglyceride in Muscle & Liver Isolated from Mice To determine whether the increased FFA oxidation induced by GSSP4 polypeptides is also accompanied by increased FFA delivery into muscle or liver, the hindlimb muscle and liver triglyceride content is measured after the GSSP4 polypeptide treatment of mice. Hind limb muscles as well as liver samples are removed from treated and untreated animals and the triglyceride and free fatty acid concentration is determined following a standard lipid extraction method (Shimabukuro et al (1997) Proc Natl Acad Sci USA 94:4637-4641) followed by TG and FFA analysis using standard test kits. Example 11 Effect of GSSP4 Polypeptides on FFA following Intralipid Injection Two groups of mice are intravenously (tail vein) injected with 30 μL bolus of Intralipid-20% (Clintec) to generate a sudden rise in plasma FFAs, thus by-passing intestinal absorption. (Intralipid is an intravenous fat emulsion used in nutritional therapy). A treated group (GSSP4 polypeptide-treated) is injected with a GSSP4 polypeptide (25 μg) at 30 and 60 minutes before Intralipid is given, while control animals (▴ control) received saline. Plasma is isolated and FFAs are measured as described previously. The effect of GSSP4 polypeptides on the decay in plasma FFAs following the peak induced by Intralipid injection is then monitored. Example 12 Tests of Obesity-Related Activity in Humans Tests of the efficacy of in humans are performed in accordance with a physician's recommendations and with established guidelines. The parameters tested in mice are also tested in humans (e.g. food intake, weight, TG, TC, glucose, insulin, leptin, FFA). It is expected that the physiological factors would show changes over the short term. Changes in weight gain might require a longer period of time. In addition, the diet is carefully monitored. GSSP4 is given in daily doses of about 6 mg protein per 70 kg person or about 10 mg per day. Other doses are tested, for instance 1 mg or 5 mg per day up to 20 mg, 50 mg, or 100 mg per day. Example 13 Tests of Obesity-Related Activity in a Murine Lipoatrophic Diabetes Model Leptin was reported to reverse insulin resistance and diabetes mellitus in mice with congenital lipodystrophy (Shimomura et al. Nature 401: 73-76 (1999). Leptin is found to be less effective in a different lipodystrophic mouse model of lipoatrophic diabetes (Gavrilova et al Nature 403: 850 (2000); hereby incorporated herein in its entirety including any drawings, figures, or tables). The instant invention encompasses the use of GSSP4 or polypeptide fragments for reducing the insulin resistance and hyperglycaemia in this model either alone or in combination with leptin, the leptin peptide (U.S. provisional application No. 60/155,506), or other compounds. Assays include that described previously in Gavrilova et al. ((2000) Diabetes November;49(11): 1910-6; (2000) Nature February 24;403(6772):850) using A-ZIP/F-1 mice, except that would be administered using the methods previously described in Example 5 (or Examples 8-10). The glucose and insulin levels of the mice would be tested, and the food intake and liver weight monitored, as well as other factors, such as leptin, FFA, and TG levels, typically measured in our experiments (see Example 5, above, or Examples 8-10).

<SOH> BACKGROUND OF TH INVENTION <EOH>The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention. Obesity is a public health problem that is serious, widespread, and increasing. In the United States, 20 percent of the population is obese; in Europe, a slightly lower percentage is obese (Friedman (2000) Nature 404:632-634). Obesity is associated with increased risk of hypertension, cardiovascular disease, diabetes, and cancer as well as respiratory complications and osteoarthritis (Kopelman (2000) Nature 404:635-643). Even modest weight loss ameliorates these associated conditions. While still acknowledging that lifestyle factors including environment, diet, age and exercise play a role in obesity, twin studies, analyses of familial aggregation, and adoption studies all indicate that obesity is largely the result of genetic factors (Barsh et al (2000) Nature 404:644-651). In agreement with these studies, is the fact that an increasing number of obesity-related genes are being identified. Some of the more extensively studied genes include those encoding leptin (ob) and its receptor (db), pro-opiomelanocortin (Pomc), melanocortin-4-receptor (Mc4r), agouti protein (A y ), carboxypeptidase E (fat), 5-hydroxytryptamine receptor 2C (Htr2c), nescient basic helix-loop-helix 2 (Nhlh2), prohormone convertase 1 IPCSK1), and tubby protein (tubby) (rev'd in Barsh et al (2000) Nature 404:644-651).

<SOH> SUMMARY OF THE INVENTION <EOH>The instant invention is based on the discovery that GSSP4 polypeptides have unexpected effects in vitro and in vivo, including utility for weight reduction, prevention of weight gain, reduction of cholesterol levels, and control of blood glucose levels in humans and other mammals. These unexpected effects of administration of GSSP4 polypeptides in mammals also include reduction of elevated free fatty acid levels caused by administration of epinephrine, i.v. injection of “intralipid”, or administration of a high fat test meal, as well as increased fatty acid oxidation in muscle cells, reduction of circulating cholesterol levels, modulation of blood glucose and weight reduction in mammals, particularly those consuming a high fat/high carbohydrate diet. These effects are unexpected and surprising given that proteins of similar structure or homology (such as colipase and mamba intestinal toxin 1) have not been shown to have utility for weight reduction, prevention of weight gain, reduction of cholesterol levels, and control of blood glucose levels. However, the GSSP4 polypeptides of the invention are effective and can be provided at levels that are feasible for treatments in humans. Thus, the invention is drawn to GSSP4 polypeptides, polynucleotides encoding said polypeptides, vectors comprising said GSSP4 polynucleotides, and cells recombinant for said GSSP4 polynucleotides, as well as to pharmaceutical and physiologically acceptable compositions comprising said GSSP4 polypeptide and methods of administering said GSSP4 polypeptides or polynucleotides in a pharmaceutical and physiologically acceptable compositions in order to reduce body weight, cholesterol levels or glucose levels, or to treat metabolic-related diseases and disorders. Assays for identifying agonists and antagonists of metabolic-related activity are also part of the invention. In a first aspect, the invention features a purified, isolated, or recombinant GSSP4 polypeptides. In preferred embodiments, said polypeptides comprise, consist essentially of, or consist of, those having significant activity wherein the said activity is selected from the group consisiting of cholesterol reduction, cholesterol regulation, lipid partitioning, lipid metabolism, glucose control, and insulin-like activity. In preferred embodiments, said polypeptides comprise, consist essentially of, or consist of, the full length polypeptide of SEQ ID NO:3 or a fragment of consecutive amino acids of the full length polypeptide sequence of SEQ ID NO:3. In other preferred embodiments, said polypeptides comprise an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding consecutive amino acids of the polypeptide sequences identified in SEQ ID NO:3. In a further preferred embodiment, the GSSP4 polypeptide is able to lower circulating (either blood, serum or plasma) levels (concentration) of: (i) free fatty acids, (ii) glucose, and/or (iii) triglycerides. Further preferred GSSP4 polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GSSP4 polypeptides are those that cause C2C12 cells differentiated in the presence of said polypeptides to undergo at least 10%, 20%, 30%, 35%, or 40% more oleate oxidation as compared to untreated cells. Further preferred GSSP4 polypeptides are those that are at least 30% more efficient than untreated cells at increasing leptin uptake in a liver cell line (preferably BPRCL mouse liver cells (ATCC CRL-2217)). Further preferred GSSP4 polypeptides are those that significantly reduce the postprandial increase in plasma free fatty acids, particularly following a high fat meal. Further preferred GSSP4 polypeptides are those that significantly reduce or eliminate ketone body production, particularly following a high fat meal. Further preferred GSSP4 polypeptides are those that increase glucose uptake in skeletal muscle cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in adipose cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in neuronal cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in red blood cells. Further preferred GSSP4 polypeptides are those that increase glucose uptake in the brain. Further preferred GSSP4 polypeptides are those that significantly reduce the postprandial increase in plasma glucose following a meal, particularly a high carbohydrate meal. Further preferred GSSP4 polypeptides are those that significantly prevent the postprandial increase in plasma glucose following a meal, particularly a high fat or a high carbohydrate meal. Further preferred GSSP4 polypeptides are those that improve insulin sensitivity. Further preferred GSSP4 polypeptides are those that modulate food intake or food selection. Further preferred GSSP4 polypeptides are those that modulate satiety. Further preferred GSSP4 polypeptides are those that modulate fatty acid metabolism. Further preferred GSSP4 polypeptides are those that modulate cholesterol metabolism, particularly in steroidogenic tissues. Therefore, said polypeptides have a potential role in effecting, either directly or indirectly or both, levels of reproductive hormones (eg. estradiol, progesterone, testosterone). Further preferred GSSP4 polypeptides are those that modulate cortisol levels. Further preferred GSSP4 polypeptides are those that modulate aldosterone levels. Therefore, said polypeptides have a potential role in effecting, either directly or indirectly or both, levels of sodium and potassium. Further preferred GSSP4 polypeptides are those that modulate blood pressure preferably to normalize blood pressure within a normal range. Further preferred GSSP4 polypeptides are those that form multimers (e.g., heteromultimers or homomultimers) in vitro and/or in vivo. Preferred multimers are homodimers or homotrimers. Other preferred multimers are homomultimers comprising at least 4, 6, 8, 9, 10 or 12 GSSP4 polypeptides. Other preferred mulimers are hetero multimers comprising GSSP4 polypeptides of the invention. Further preferred embodiments include heterologous polypeptides comprising a GSSP4 polypeptide of the invention. In a second aspect, the invention features purified, isolated, or recombinant polynucleotides encoding said GSSP4 polypeptides described in the first aspect, or the complement thereof. A further preferred embodiment of the invention is a recombinant, purified or isolated polynucleotide comprising, or consisting of a mammalian genomic sequence, gene, cDNA, or fragments thereof. In one aspect the sequence is derived from a human, mouse or other mammal. In a preferred aspect, the genomic sequence includes isolated, purified, or recombinant polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 22, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000, 2000, 5000, 6000 or 7500 nucleotides of any one of the polynucleotide sequences described in SEQ ID NO:1, 2, or the complements thereof, wherein said contiguous span comprises a nucleotide sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding nucleotide sequence in SEQ ID NO: 1, 2, or 3. In further embodiments the polynucleotides are DNA, RNA, DNA/RNA hybrids, single-stranded, and double-stranded. Further preferred are GSSP4 polynucleotides and polypeptides that have cholesterol regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have body weight regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have body fat regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have glucose regulating activies. Further preferred are GSSP4 polynucleotides and polypeptides that have lipid regulating activies. In a third aspect, the invention features a recombinant vector comprising, consisting essentially of, or consisting of, said polynucleotide described in the second aspect. In a fourth aspect, the invention features a recombinant cell comprising, consisting essentially of, or consisting of, said recombinant vector described in the third aspect. A further embodiment includes a host cell recombinant for a polynucleotide of the invention. In a fifth aspect, the invention features a pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of, said GSSP4 polypeptides described in the first aspect and, a pharmaceutical or physiologically acceptable diluent. In a sixth aspect, the invention features a method of controlling cholesterol levels comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering body weight comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering body fat comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In further preferred embodiments, the invention features a method of lowering controlling blood glucose comprising, providing, or administering to individuals with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In a seventh aspect, the invention features a method of preventing or treating a metabolic-related disease or disorder comprising, providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. Preferably, said obesity-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a further preferred embodiment, a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect suggest that a compound may have utility in alleviating insulin resistance in individuals, particularly those that are obese or overweight. In a further preferred embodiment, the present invention may be used in complementary therapy in individuals to improve their cholesterol, weight or glucose level, comprising a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect in combination with known agents. The present invention further provides a method of improving the cholesterol levels, body weight or glucose control in individuals comprising the administration of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect alone, without known agents. In a further preferred embodiment, the present invention may be administered either concomitantly or concurrently, with known agents for example in the form of separate dosage units to be used simultaneously, separately or sequentially (either before or after the known agent). Accordingly, the present invention further provides a product containing a composition a pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect and a known agent as a combined preparation for simultaneous, separate or sequential use for the improvement of cholesterol levels, body weight or glucose control in individuals, particularly those who are obese or overweight. The ratio of the present composition to known agent is such that the quantity of each active ingredient employed will be such as to provide a therapeutically effective level, but will not be larger than the quantity recommended as safe for administration. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect can be used as a method to improve insulin sensitivity in some persons, particularly those with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) or noninsulin dependent diabetics (Type II) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect can be used as a method to improve insulin sensitivity in some persons, particularly those with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) or noninsulin dependent diabetes mellitus (NIDDM, Type II) in combination with alternate therapies. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used as a method in prophylaxis of long-term detrimental effects caused by prolonged high dosage of insulin in humans having IDDM or NIDDM. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing hypersecretion of insulin and disorders or conditions resulting therefrom. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing obesity and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing hypercholesterolemia and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing NIDDM or IDDM and consequences or complications thereof. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing impaired glucose tolerance (IGT). Further preferred embodiment thus provides therapeutics and methods for normalizing insulin resistance. Further preferred embodiment thus provides therapeutics and methods for reducing, slowing or preventing the progression to NIDDM. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect is used in therapeutics or methods for reducing or preventing the appearance of insulin-resistance syndrome. In further preferred embodiments, other conditions, particularly obesity, associated with insulin resistance are treated or prevented according to the methods of the invention. Thus, by preventing or treating obesity, the methods of the invention will allow an individual to have a more comfortable life and avoid the onset of various diseases triggered by obesity. In further preferred embodiments, the target of the methods according to the present invention includes individuals with normal glucose tolerance (NGT) who are obese or who have fasting hyperinsulinemia, or who have both. In an eighth aspect, the invention features a method of controlling blood free fatty acid (FFA) levels and lipid metabolism comprising, providing, or administering to individuals in need of increasing mobilization and utilization of fat stores and decreasing total fat stores with said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect. In a further preferred embodiment, the identification of said individuals in need of increasing mobilization and utilization of fat stores and decreasing total fat stores to be treated with said pharmaceutical or physiologically acceptable composition comprises a person who is involved in physical activity which increases metabolic demand. Furthermore, increasing mobilization and utilization of fat stores and decreasing total fat stores would provide a means to decrease body weight, preventing weight gain, decrease body fat in overweight and obese individuals. Reduction in weight and obesity will thus decrease the risk of chronic disease associated with obesity such as but not limited to the onset of various lipid metabolism disorders, hypertension, Type II diabetes, atherosclerosis, cardiovascular disease and stroke. In related aspects, embodiments of the present invention includes methods of causing or inducing a desired biological response in an individual comprising the steps of: providing or administering to an individual a composition comprising a GSSP4 polypeptide, wherein said biological response is selected from the group consisting of: (a) lowering circulating (either blood, serum, or plasma) levels (concentration) of free fatty acids; (b) lowering circulating (either blood, serum or plasma) levels (concentration) of glucose; (c) lowering circulating (either blood, serum or plasma) levels (concentration) of triglycerides; (d) stimulating muscle lipid or free fatty acid oxidation; (e) increasing leptin uptake in the liver or liver cells; (f) reducing the postprandial increase in plasma free fatty acids, particularly following a high fat meal; and, (g) reducing or eliminating ketone body production, particularly following a high fat meal; (h) increasing tissue sensitivity to insulin, particularly muscle, adipose, liver or brain, (i) reducing cholesterol levels, particularly in those with elevated cholesterol (ie. greater than 200 mg/dl); (j) modulating circulating (either blood, serum or plasma) levels (concentration) of glucose within physiological range, preferably maintaining glucose between 60-190 mg/dl; (k) modulating circulating (either blood, serum or plasma) levels (concentration) of FFA within physiological range preferably maintaining FFA between 190-420 mg/dl; (l) modulating ketone body production as the result of a high fat meal, wherein said modulating is preferably reducing or eliminating; (m) reducing body weight particularly in individuals with a BMI of greater than 27. In a ninth aspect, the invention features a method of making the GSSP4 polypeptide described in the first aspect, wherein said method is selected from the group consisting of: proteolytic cleavage, recombinant methodology and artificial synthesis. In a tenth aspect, the present invention provides a method of making a recombinant GSSP4 polypeptides, the method comprising providing a transgenic, non-human mammal whose milk contains said recombinant GSSP4 polypeptides, and purifying said recombinant GSSP4 polypeptides from the milk of said non-human mammal. In one embodiment, said non-human mammal is a cow, goat, sheep, rabbit, or mouse. In another embodiment, the method comprises purifying a recombinant GSSP4 polypeptides from said milk, and further comprises cleaving said protein in vitro to obtain a desired GSSP4 polypeptides. In an eleventh aspect, the invention features a purified or isolated antibody capable of specifically binding to a protein comprising the sequence of one of the polypeptides of the present invention. In one aspect of this embodiment, the antibody is capable of binding to a polypeptide comprising at least 6 consecutive amino acids, at least 8 consecutive amino acids, or at least 10 consecutive amino acids of the sequence of one of the polypeptides of the present invention. In a twelfth aspect, the invention features a use of polypeptides described in the first aspect or polynucleotides described in the second aspect for treatment of metabolic-related diseases and disorders or reducing or increasing body mass. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a thirteenth aspect, the invention features a use of polypeptides described in the first aspect or polynucleotides described in the second aspect for the preparation of a medicament for the treatment of metabolic-related diseases and disorders or for reducing body mass. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In a fourteenth aspect, the invention provides polypeptides of the first aspect of the invention or a composition of the fifth aspect for use in a method of treatment of the human or animal body. In a fifteenth aspect, the invention provides polynucleotides described in the second aspect or an acceptable composition thereof, for use in a method of treatment of the human or animal body. In a sixteenth aspect, the invention features methods of reducing body weight for cosmetic purposes comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect, or polypeptides described in the first aspect. Preferably, for said reducing body weight said individual has a BMI of at least 20, 25, 30, 35, or 40. In a seventeenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect or a polypeptide described in the first aspect for reducing body mass in said individuals with a BMI of at least 30, 35, 40, or 45 or for treatment or prevention of metabolic-related diseases or disorders. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance (IGT), insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, Noninsulin dependent diabetes mellitus (NIDDM or Type II diabetes), Insulin dependent diabetes mellitus (IDDM or Type I diabetes), diabetes-related complications (such as elevated ketone bodies), microangiopathy, retinopathy, ocular lesions, neuropathy, nephropathy, polycystic ovarian syndrome (PCOS), and microangiopathic lesions, as well as syndromes such as acanthosis nigricans, leprechaunism, and lipoatrophy to be treated by the methods of the invention. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. In preferred embodiments, said individual is a mammal, preferably a human. In preferred embodiments, the identification of said individuals to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GSSP4 single nucleotide polymorphisms (SNPs) or measuring GSSP4 polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. In an eighteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect for reducing body weight for cosmetic reasons. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect for reducing glucose levels. In a nineteenth aspect, the invention features methods of treating insulin resistance comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect or polynucleotides described in the second aspect, or a polypeptide described in the first aspect.

20040916

20070529

20050407

78888.0

CHANDRA, GYAN

GSSP4 POLYNUCLEOTIDES AND POLYPEPTIDES AND USES THEREOF

UNDISCOUNTED

CONT-ACCEPTED

ACCEPTED

Packet data recording method and system

The present invention provides for a data recording system including data recording means having a plurality of network interface cards in which a plurality of network interface cards can be employed within a single recording mean and each card can be provided with a plurality of network connecting ports then, for example, for each RTP packet stream being recorded, the system can advantageously note the sequence number for the most recently accepted packet and any packet received with a lower sequence number can be readily discarded.

1. A data recording system including data recording means having a plurality of network interface cards. 2. A system as claimed in claim 1 and including a plurality of network interface cards within a single recording means. 3. A system as claimed in claim 2, wherein each Network interface card has multiple network connection ports. 4. A system as claimed in claim 1, 2 or 3, wherein each individual recording means is arranged for mutual communication so as to advise each other of the presence of particular packet streams. 5. A system as claimed in any one of claims 1 to 4, and arranged such that each recorder is advised of the addresses to be monitored; when a recorder identifies a packet with the required addresses it begins recording it and advises all other recorders to stand down; and other recorders are arranged to note these addresses as being recorded elsewhere. 6. A system as claimed in claim 5 and further arranged such that the notification sent to other recorders include within it the sequence number of an RTP packet that was first received and the IP address of the receiving recorder; that in the event that more than one recorder receives packets prior to hearing notification from another recorder that it has commenced recording, the recorder which received the earliest packet can maintain responsibility for recording and the other recorder shall cease recording; that should more than one recorder receive the same packet and send notification of this, then the recorder with highest IP address can maintain its recording and the other(s) will stand down; and that when recording begins, a recorder will not create a record in the database of recordings until a pre-defined time has elapsed in case it receives, during this period, a notification from another recorder that it too has started recording. Should it receive such notification and, according to the algorithms defined in (d) to (f) above, it is to stand down, it will abandon its recording without having altered the database of recordings. 7. A system as claimed in claim 6 and further arranged such that should a packet be lost an indication of the sequence number(s) of the lost packets can be maintained as part of the recording control structure for that IP address; and that when packets are received that are determined to be earlier than the most recently accepted packet for that address, their sequence number can subsequently be compared against the list of recently missed packets and, if found, can be stored at the appropriate offset within the recording buffer overwriting the padding that was inserted when the later packet was received and loss of packet(s) identified. 8. A method of recording a data employing a plurality of network interface cards and including the steps carried out by the system of any one or more of claims 2 to 7. 9. A data packet recording system arranged for determining an IP address of an application and including means for comparing at least a sample of received or transmitted packets with at least a set of pre-programmed signature packets. 10. A system as claimed in claim 9 and arranged for comparing all packets received from or sent to each destination against a set of pre-programmed signature packets. 11. A system as claimed in claim 9 and arranged such that the sustained absence of such packets is employed as an indicator of an error condition with the device that was previously active on that address. 12. A method of recording a data packet for determining an IP address of an application and including the step of comparing at least a sample of received or transmitted packets with at least a set of pre-programmed signature packets. 13. A data recording system arranged such that the data packets are arranged to be transmitted via a proxy server and further arranged such that the IP address of at least one party to the conversation is altered. 14. A system as claimed in claim 13, and arranged to determine the presence and IP address of the proxy servers, to allow for recorders passing their knowledge of current mappings to other recorders allowing them to refine their filtering algorithms; and to pass examples of specific packets identified as having been mapped by the proxy server to other recorders. 15. A data packet recording system including packet filtering means arranged for filtering on the basis of an IP address. 16. A data packet recording system as claimed in claim 15, and arranged for filtering on the basis of an IP port number of both source and/or destination address(es). 17. A system as claimed in claim 15 or 16, and arranged to analyse the sequence number and timestamp to determine the next packet in the expected sequence based on whether one or more packets have been missed such that performance counters can be incremented appropriately; inserting additional data in the recorded stream to pad-out the space that should have been taken up by the missing packet(s) and whether the payload of the RTP packet can be appended to a buffer and the remainder of the packet discarded. 18. A system as claimed in claim 15 or 16 and arranged such that a signature data pattern is appended to a data buffer collecting packets to/from the specific destination; a timestamp indicating the time at which the packet was received to the buffer; a length indicator specifying the number of bytes in the recorded packet is appended to the buffer; and that the contents of the packet are appended to the buffer. 19. A data recording system for IP telephones controlled by an IP-PBX application and wherein the controlling application is arranged to request that each phone advise it of the port number for which it can receive incoming audio data. 20. A system as claimed in claim 19, and arranged for the identification and storage of only the payloads of successive RTP messages. 21. A system as claimed in any one of the preceding claims, and arranged to compare the sequence number of the received packet with that of the previously received packet and to identify if a difference exists. 22. A data recording system as claimed in any one of the preceding claims and arranged such that recordings stored independently for each direction of transmission.

The present invention relates to a packet data recording method and related system. The integration of computers into office communication systems has enabled many functions previously performed by separate devices to be combined into a single management system. For example, computer-based voice logging systems enable a computer to: receive voice communication through a hardware connection to the regular telephony network; to record either a conversation, in which at least two parties converse, or a message from at least one party to one or more parties; and to replay such recorded conversations or messages upon request. It is therefore appreciated that commercial entities perform substantial amounts of business via telephone or Internet contact with their customers. The analysis of such contact can help businesses improve the quality and efficiency of their services, and assist with customer retention and, ultimately, profitability. Attempts have been made previously to achieve such analysis in a satisfactory manner and to a satisfactory degree. For example, many businesses have, for some time, recorded some of their staff/customer interactions. Traditionally this was done to satisfy regulatory requirements or to help resolve disputes. More recently, the emphasis has moved towards the reviewing of these interactions from a quality perspective. This is intended to identify good and bad aspects of particular interaction calls with a view to improving the level of customer service. Recently, for example, recording the activity on a PC screen has been undertaken to improve the completeness of the review procedure with the reviewer able to see how accurately staff are entering information received via the telephone. Also, it has been known to employ Call Detail Recording (CDR) systems to prevent perceived abuse of telephone systems and to apportion costs to the department or individual making the calls. Originally such records were printed out directly from the Private Automatic Branch Exchange (PABX) onto a line printer. Later, systems were designed to store this information in a database allowing more sophisticated reporting and searching fro calls on the basis of one or more of the stored call details. More recently, Computer Telephony Integration (CTI) interfaces have been provided that give this information in real-time, during the call. Further, several systems currently exist that use call recording in combination with CDR or CTI and a database application in order to perform routine monitoring of calls with the intention of identifying weaknesses in individual Customer Service Representatives (CSR). Typically a small percentage of the CSR calls are reviewed and “scored” against a set of predetermined criteria to give an indication of the quality of that particular member of staff. Within a call-centre environment, it should also be noted that rather than simply using standard PC office automation applications when dealing with customers, staff in most call centres use increasingly sophisticated applications that help them to handle the calls more efficiently and effectively. Help desk applications and telemarketing call scripting applications are examples of such applications. U.S. Pat. No. 6,122,665 discloses a method and a system for: the management of communication sessions for computer network-based telephone communication, and in particular for the identification of packets containing audio and/or video data; the storage of these packets; and for the reconstruction of selected communication sessions for audio and/or video display as needed. In particular, this document teaches the provision of a system and a method arranged to: record communication sessions performed over a computer network; to provide such a system and method for analysing data transmitted over the computer network in order to detect audio and video data transmitted over the computer network in order to detect audio and video data for recording; to provide such as system and method for displaying recorded video and audio data upon request; and to provide such a system and method for analysing, recording and displaying communication session conducted with a LAN-based telephone system. As will be appreciated, U.S. Pat. No. 6,122,665 serves to illustrate a general move towards Voice over IP (VoIP) Communications as bringing together voice and data environments. However, there remains a need to record interactions over data networks irrespective of whether these are voice communication sessions, video or data interaction between people and systems, systems and systems or people and people. While it is noted that systems produced by, e.g. Hewlett Packard, have long been able to monitor data networks and store details and contents of the packets they observe, the primary function of such devices has normally been for network performance analysis and diagnostics. Disadvantageously they do not provide for the management of large volumes of recordings, and related archival and indexing. Thus, such systems, and related methods, do exhibit limitations and disadvantages. As a further illustration U.S. Pat. No. 6,122,665 merely serves to address the recording of a single network segment. However, with the prevalence of Ethernet switches and routers, it is rare for a system of any size to be implemented as a single network segment. Whenever multiple segments are introduced, the packets are routed between these segments as required in order to reach their destination. There is therefore no single point at which all packets can be observed. It would therefore prove advantageous to provide a system which can be extended to tap into the network at however many points are needed to achieve the required coverage. Unfortunately, merely extending a simple system designed for a single tap-point will result in highly redundant recordings as many of the packets to be recorded will arise at more than one tap point. Further, known systems require knowledge of network addresses to operate properly. To determine what, and indeed how to record, some knowledge of the identity of specific IP addresses is often required. For example, knowing which IP address hosts an IP-PBX will allow better filtering of information and the analysis of call control packets involving that node. Unfortunately, many IP addresses are dynamically assigned, e.g. via DHCP. Also network configurations are regularly changed and updated as networks expand and evolve. Neither do known systems address the use of proxy addresses. In many IP networks, packets are readdressed en route by Proxy Servers. This makes it difficult for the controlling software to identify which packets should be recorded as a single IP address is often only appropriate for packets transmitted over the leg of the journey from which they emanate, or which they finally reach having regard to the network node having that IP address. The Known systems also do not support the recording of packet data streams along with voice/video. The system disclosed in U.S. Pat. No. 6,122,665 filters packets out that are not part of a voice or video stream. This prohibits its use in cases where the recording of a combination of data streams is required. With regard to packet filtering, known systems are far from optimal. It is important that a recording system is able to process all the packets it receives and eliminate those that are not required as efficiently as possible. Often only a small proportion of received traffic is to be recorded. The described system performs its filtering initially by determining the type of traffic contained within the packet, for example voice or video versus other. In a large voice/video system with many concurrent sessions occurring, there will be many thousands of packets per second being received at the network tap point. In many cases only a small proportion of these will be required. Known systems will not filter out any of these at the first level and will pass all packets on to the following stage. Such manner of operation proves to be sub-optimal. Disadvantageously, the integration of such a system with the systems controlling call placement is not generally achievable. Also, the determination of which IP ports to record on the basis of H323 signalling information also received via the network tap point is often superfluous. Rather, better information regarding the contacts and the requirement to record them can be obtained by interfacing to real-time event outputs, i.e. CTI ports, of the systems that are controlling the placement of calls. These ACDs or PABXs will often include additional information regarding the calls that cannot be deduced by observing the session control messages. For example, the linkage of one call to the next as calls are transferred between people is not always available from the session control protocol. Also, tolerance issues such as the loss of critical packets is not addressed in known systems. However, in situations where session control information can be gleaned from analysis of session control packets, it can be disadvantageously adversely affected by the loss of a single packet. This can readily lead to a call not being recorded. In many systems, there can prove to be multiple ways to deduce such information, thereby making the system tolerant to the loss of certain packets. As with filtering, known systems prove to be sub-optimal with regard to the storage of received packet data. The described system does not disclose in detail how the packets are stored and it appears that these are simply kept as raw, independent packets such that a significant potential for storage overhead has been found to arise. Importantly, the known systems do not integrate well with traditional (non VoIP) storage and replay mechanisms. Again, the described system appears to store the recorded packets as packets and replays these by retransmitting them to a device similar to that which would have received them originally. In many systems, however, only part of the voice system is packet-based and certainly the replay mechanisms are often not packet based. Hence there is a need to store, retrieve and replay conversations in a way that is both efficient and compatible with existing circuit-switched voice systems. Still further, such known systems do not address the specific requirements of testing and monitoring, nor do they attempt performance measure. In any packet system, there is the chance of the loss of a particular packet and the system described makes no reference to a determination of how well it is performing and whether any packets not recorded were lost by the network or at the recording device's network interface. It is now appreciated that with simple extensions, such recording systems can be used to record data steams in a form suitable for use in simulated loading tests. The capability for advanced recording options such as stereo and multi-party (conference call) recording are also disadvantageously absent from known systems. In particular, the system described does not address the added value that can be obtained by recording conversations so that they may be replayed in “stereo” with multiple tracks allowing the replayer to separate the audio travelling in each direction. Nor does it describe the extension of this technique into the recording of conference calls where the separation and identification of individual speakers is of great benefit in aiding the listener to follow the flow of conversation. The present invention seeks to provide for a data recording system and method and exhibiting an advantage over such known systems. According to one aspect of the present invention, there is provided a data recording system including data recording means having a plurality of network interface cards. Of course, alternatively, where more than one segment must be tapped in order to receive all required packets, this can be done either by providing multiple systems, each tapping a single segment but this can result in the same recordings being made by multiple recorders. A preferred embodiment is to use multiple network interface cards (NICs) within a single recorder. Advantageously, each NIC may have multiple network connection ports, such as typically are used to provide fault tolerant connection to multiple Ethernet switches. In this case, the filtering mechanism is enhanced to allow rapid elimination of duplicate packets. For each RTP packet stream being recorded, the system can advantageously note the sequence number of the most recently accepted packet. Any packet received with a lower sequence number (account being taken of sequence numbers wrapping as they overflow their assigned binary range) will immediately be discarded. In this way, the system advantageously need not actively keep track of network topology and will operate regardless of how many copies of each packet it receives. In larger or physically separated systems which require multiple recorders, it can prove impractical to bring all packets into a single recorder. In such cases, the individual recorders can be arranged to communicate with each other so as to advise each other of the presence of particular packet streams. In a prepared example, it is desired to record packets travelling between a specific pair of addresses: a) each recorder is advised of the addresses to be monitored; b) when a recorder identifies a packet with the required addresses it begins recording it and advises all other recorders to stand down; and c) other recorders are arranged to note these addresses as being recorded elsewhere. Further advantageous refinements to such a scheme can seek to ensure that only one recorder records each call or session in that: d) the notification sent to other recorders call include within it the sequence number (or timestamp) of the RTP packet that was first received and the IP address (or other identifier) of the receiving recorder; e) in the event that more than one recorder receives packets prior to hearing notification from another recorder that it has commenced recording, the recorder which received the earliest packet can maintain responsibility for recording and the other recorder shall cease recording; f) should more than one recorder receive the same packet and send notification of this, then the recorder with highest IP address (or other algorithm allowing unique determination of priority) can maintain its recording and the other(s) will stand down; g) when recording begins, a recorder will not create a record in the database of recordings until a pre-defined time has elapsed in case it receives, during this period, a notification from another recorder that it too has started recording. Should it receive such notification and, according to the algorithms defined in (d) to (f) above, it is to stand down, it will abandon its recording without having altered the database of recordings. The following further refinements can be employed to ensure that packet loss is minimized: h) should a packet be lost (as can be determined from a gap in the sequence number of received packets) an indication of the sequence number(s) of the lost packets can be maintained as part of the recording control structure for that IP address; and i) when packets are received that are determined to be earlier than the most recently accepted packet for that address, their sequence number can subsequently be compared against the list of recently missed packets and, if found, can be stored at the appropriate offset within the recording buffer overwriting the padding that was inserted when the later packet was received and loss of packet(s) identified. It should be appreciated that the invention also provides for a data recording method employing a plurality of network interface cards and as described above. According to another aspect of the present invention, there is provided a data packet recording system arranged for determining an IP address of an application and including means for comparing at least a sample of received or transmitted packets with at least a set of pre-programmed signature packets. The system can then advantageously determine the IP addresses of significant applications by comparing all packets received from or sent to each destination against a set of pre-programmed signature packets. These packets are preferably chosen to be examples of the traffic expected to involve the node being sought. For example, in many IP-PBX systems, each IP-phone regularly heartbeats by sending a simple packet to the IP-PBX control application every minute or so. By monitoring for these packets it is possible to determine the location of the IP-PBXes in the system being monitored. Preferably, the sustained absence of such packets can also be used as an indicator of an error condition with the device that was previously active on that address and can trigger an alarm condition and/or fallback mode of operation. It should be appreciated that the invention also provides for a data packet recording method including a comparison step as described above. According to yet another aspect of the present invention, a data recording system is provided wherein data packets are arranged to be transmitted via a Proxy server and further arranged such that the IP address of at least one party to the conversation is altered. This advantageously allows for security and re-use of address space although difficulties can be experienced in determining which packets should be recorded. The invention can preferably address this by being arranged to: a) determine the presence and IP address of such Proxy servers either by explicit configuration information or, preferably, by analysing the pattern of packets entering and leaving the IP node. This can be achieved for example by comparing the contents of packets transmitted by each node with the contents of those received by that node. Should it find packets that are identical bar the IP address, it can both deduce that this node is performing a Proxy function and determine the current mapping of IP addresses that it is performing; b) allow for recorders passing their knowledge of current mappings to other recorders allowing them to refine their filtering algorithms; and c) pass examples of specific packets identified as having been mapped by the Proxy server to other recorders. This advantageously allows recorders to differentiate between overlapping address ranges. For example, two different Proxy servers may both be mapping addresses in a given range. By passing occasional packets to each other, along with their pre-mapping addresses, recorders can determine whether the stream of data they are observing is indeed that for this address or a completely different stream mapped by a different Proxy server. As before, the invention also provides for a corresponding method including IP address alteration. According to still another aspect of the present invention, there is provided a data packet recording system including packet filtering means arranged to perform on the basis of an IP address and preferably, an IP port number of both source and/or destination address(es). Having determined that the packet is one that is to be recorded, the system can preferably then store the packet in the most appropriate way. For example, for RTP streaming data: a) The system is arranged to analyse the sequence number and timestamp to determine whether this is the next packet in the expected sequence; b) if one or more packets have been missed then performance counters can be incremented appropriately; c) additional data can preferably be inserted in the recorded stream to pad out the space that should have been taken up by the missing packet(s). This advantageously avoids gradual drift between the recording and real-time which would otherwise build up and result in the call being shorter when replayed than it had been originally; and d) the payload of the RTP packet can be appended to a buffer and the remainder of the packet discarded; and e) optionally, information can be flagged from the packet header so as to be retained where this is not the default header, i.e. it cannot be fully deduced from knowledge of the previous header. As an example for other packet oriented data: a) optionally, a signature data pattern (e.g. well known particular 4 byte value) can be appended to the data buffer collecting packets to/from the specific destination. This advantageously ensures that any application reading the recording subsequently can re-synch with these inter-packet boundaries should the recording become corrupted or the start of the recording cannot be accessed; b) a timestamp indicating the time at which the packet was received is appended to said buffer. This will typically be precise to at least millisecond and can often achieve micro-nanosecond precision; c) a length indicator specifying the number of bytes in the recorded packet is appended to said buffer; and d) finally, the contents of the packet can be appended to said buffer Again, the invention also provides for a related method. In an alternative data filtering arrangement and method filtering according solely to address data, or at least before looking at packet content type can be provided. In some cases a given IP port might only be transmitting one type of data and so filtering on its address alone can advantageously prove sufficient in whether or not to record the packet. A preferred arrangement can involve looking up the address of the IP destination of each packet, or equally source data, as the primary filter. A “map” of known addresses is maintained and each entry serves to identify whether data going to (or from) that address should be recorded. Advantageously, by utilizing the IP address as the primary key into this map, extremely fast look-up can be achieved. Further preferred refinements to this scheme include: a) the pre-filtering of packets on IP address so as to eliminate packets sent to or from the recorder itself. This allows the same network interface card to be used for normal IP communications (e.g. with clients searching and replaying previously recorded calls) whilst it is also being used a promiscuous mode tap. This simple filtering out on a single (32-bit) integer IP address avoids the need to look up the address map repeatedly for all packets that are directed at other sockets on this node. With the introduction of IP Version 6, this will become a 128-bit integer comparison; b) in preference to hashing or sorted table indexing, the map of required addresses can be implemented as a memory array. By using the fact that most IP addresses required will lie within a narrow range of possible values it is faster to compare the high order bytes of the IP address with the sub net or nets on which all the target nodes are located. The remainder of the address can then be used as an index into a (typically sparsely populated) memory map in which each address to be recorded is represented by a binary 1 and the remainder as 0. For a Class B address as described here, only 64K bits of information are required to achieve this though the use of 65,536×32 bit words allows for each entry in the map to be either null (0x00000000) or a pointer to the structure describing the known address and its recording details e.g. buffer storage location. It should be noted that a similar scheme can be used in IP Version 6 albeit with a much smaller portion of the overall numbering range being covered by such a table; c) in RTP based systems, many of the data streams being transmitted are constant bit rate. In these cases, many sessions will be transmitting packets at a regular rate resulting in a strong correlation between the order in which packets are received. This is especially true in cases where all transmitters are of the same type e.g. an IP-PBX with many identical IP-phones, all configured with the same packet interval. This can be used to advantage in filtering the incoming packets. If a record is maintained of the recently received packet addresses, the following optimized search algorithm can be deployed I. note the IP destination address of the first RTP packet received at the head of a list of such addresses. Look up the known destination for this address and include a pointer to it at the head of a list of such pointers, II. as subsequent packets are received, compare their address against the packet at the head of the list, III. if they are different, append their addresses to the list; look up their known destination descriptor and append it to the list of such pointers, IV. if it matches the address at the head of the list, use the pointer to the known destination at the head of such list. Note that the next packet should be compared to the following entry in the list, V. subsequent packets should be compared to the next entry in the list. If they match, repeat step IV, if not, insert them into the list at this point. d) The algorithm of c above can preferably be further refined to accommodate the cessation of transmission from any address as happens when a call terminates. By comparing the new packets address against the following item in the list, we can determine that the previous address has probably ceased transmitting and it can be removed from the list. e) To allow for the case where two streams cease in one cycle of the list, it is necessary to look two addresses ahead if the new packet s address is not found at the head or subsequent entries in the list. This is a common case as both directions of the call will typically terminate at or about the same time. However, given a typical interval between transmission of 50 ms it is rare that more than one call terminates in any given cycle of the list. As will be appreciated, traditional telephone recording systems are often controlled by or determine call details by interacting with the telephony switch via a Computer Telephony Integration (CTI) interface. Such an interface typically advises the recording system of call setup and teardown as well as associated details such as dialled digits, calling line identifier (CLI) etc. As such systems move to packet transmission of voice, many are doing so incrementally and hence supporting a mix of packet and traditional calls. Where such an interface exists, it is beneficial to retain the existing investment in its design and also to allow support of VoIP and traditional calls with a single interface rather than having to support a further interface. The present system and related method advantageously supports the use of existing interfaces, provided that where such interface previously provided call identification in the form of telecoms circuit and timeslot information allowing the matching of recorded data stream with call details, it is enhanced to provide equivalent information in the form of IP address and, preferably IP port number. Ideally the addresses of both parties to the conversation (be they IP phone and/or gateway) are provided. However, in some cases, the telephony system is only aware of the IP address of one or other party involved in the call. It is a preferred feature of the present invention that the instruction to record a specified address (source or destination) can optionally be extended with the instruction to automatically start recording of the counterpart with which that address starts to exchange data. In the case of an IP destination being recorded, this is achieved by noting the source of the packet that is recorded and creating a corresponding known destination record for that address. In this way, subsequent packets sent to the newly identified address will also be recorded. Obviously the converse applies should packet source be specified originally. Further, where call control packets are analysed to determine which addresses are to be recorded, there is a danger that the failure to receive such a packet could result in the subsequent failure to record the entire conversation e.g. if the packet lost contained the extension number of the IP phone and hence it was not recognized that a call to a recorded extension had started. Fortunately, many such protocols are redundant and the required information can be deduced from several of the packets. According to a further aspect of the present invention, the system can specifically address the case where IP telephones are controlled by an IP-PBX application. In such cases it is typically possible to deduce the IP port address to be used for transmission in multiple ways. In one case (Cisco CallManager) the controlling application requests that each phone advise it of the port number it can receive incoming audio data. It then advises the other phone in the call of that number. Hence the recorder can determine the port number to record should it receive either of these interactions. Should it receive both, the redundant information can easily be recognized as such and ignored. Yet further, when recording RTP streams, the header of these packets can be almost entirely derived from that of the previous packet and hence contains little of value. By advantageously arranging for the identification and storage of only the payloads of successive RTP messages, the storage requirements for recording a session are dramatically reduced. This is particularly so in the case of compressed audio transmission where the audio payload may be as little as twenty bytes in a packet of over one hundred bytes in total. An embodiment of the present invention also addresses the issue of packet loss by being arranged to compare the sequence number of the received packet with that of the previously received packet. Should these differ by more than one, packet loss can be deduced. In addition to noting the loss in system performance counters, the missing packets can be “padded” out in the buffer being used to receive the recording. Aspects of the present invention can also address the use of silence suppression which results in breaks in the transmission stream. In such cases, the timestamps of successive packets indicate the extent of the suppressed silence whilst the successive sequence numbers let us differentiate between deliberate silence suppression and the accidental loss of packets as described above. When packets are suppressed in this way, the present invention provides for either: the insertion of the appropriate amount of “padding” data which may be pure silence or “noise” derived according to a compression scheme; or the insertion of explicit indication of the silent period into the recorded stream. Such as scheme is described by Microsoft in the definition of the “.WAV” file format. This provides more efficient storage of such silence periods but unfortunately, most “.WAV” file players do not support this mechanism. The present invention can advantageously further optimize storage by supporting a range of compression formats and acting on the received data according to user defined rules. These can include: compressing data received in a specified format (e.g. G.711 mu-law) to a specified second format (e.g. G.726 16 kbps); leaving data received in a compressed format in that format (to avoid the inherent quality reduction associated with decompression and further compression; optionally mixing the two halves of a communication session into a single, mono, recording (preferably) prior to compression; or optionally saving to non-volatile storage (e.g. disk) a summary representation of the audio levels on each of the two channels prior to compression and/or mixing. This Energy Envelope representation allows a compact (20 samples per second, 2 byte values) representation that permits the graphical display of the call showing which party was speaking at what level even though the two halves of the call are subsequently mixed and only available as a mono rather than stereo signal. Within aspects of the present invention, by storing the packet payload in a standard .WAV file, the recorded audio can be replayed alongside traditional recordings using any existing replay mechanism. Also, given the ability of the system to record packet data with timestamps for each packet received, the system may be run in a special mode in which all packets recorded are processed and stored as described in above for the aforesaid other packet oriented data. By storing all packets, including RTP streams, in this way, the recordings made can subsequently be used advantageously as known test cases for exercising and testing the invention. By replaying recordings made in this way over the network, recorders under test will receive exactly the same packet stream as the recorder that made the original recording did. Hence known test cases can be run automatically and the output of the recorders compared with that of previous test runs. It is a further feature of the present invention that said recording files can be arranged to be processed offline, so as to multiply the traffic and hence simulate larger systems than were actually recorded. By replicating the packets in the recording file and, for example, incrementing the IP port numbers for each replication, large volumes of traffic can be simulated from a single recording. In another aspect of the invention, it is important that such recorders do not lose data packets as this will reflect in loss of audio and/or loss of control information and hence possibly missed calls. The present invention therefore can be arranged to monitor its performance in the following way: 1. the gaps in the received packet stream can be determined as described above; 2. by analysing the RTCP packets received alongside the RTP packet streams it is possible to see the loss statistics being experienced by the actual participants in the call; 3. by comparing the above two figures an estimate of the packet losses occurring somewhere other than en route between the end points can be determined. Some of this will be due to the recorder and can be used as an indication of the quality of the recording; In yet another aspect and as discussed above, recordings may advantageously be stored independently for each direction of transmission or combined into a single, mixed recording. The former is highly advantageous should analysis of who was talking be required e.g. to identify angry callers from high interruption levels or in performing speech recognition on the files. The latter however is both less accurate and less useful when performed on a mixed recording since a single speaker model cannot be used and it is not clear who said each word. On conference calls it is particularly beneficial to retain a recording of each party involved in the call since with many speakers, it can be difficult to differentiate between speakers with similar voices, and there is often background noise from one or more parties that makes it difficult to hear the principal speaker It is a preferred feature of the present invention that the recordings of a multiparty interaction can be kept as independent streams or mixed together to optimize storage space. As mentioned above, it is possible to retain a summary record of the level of audio from each speaker even though the actual audio signal has been mixed. It is a further preferred feature of the present invention that when such conferences are handled by a conference bridge, which mixes the signals, storage of the conversations can be limited to the minimum set of data streams needed to reconstruct the conference audio. This advantageous aspect is achieved as follows for a conference between parties A, B and C using conference bridge X A, B and C each transmit audio to X X transmits audio from (B+C) to A X transmits audio from (A+C) to B X transmits audio from (A+B) to C The recorder may simply be instructed not to record packet streams coming from the conference bridge X and hence only records the pure audio from each of the contributing parties. The required mixed signals can be reconstructed at replay time if required from these three streams. Of course, it should be appreciated that the invention can comprise any one or more of the aspects and embodiments described above in combination or alone. The invention is described further hereinafter, by way of example only, with reference to the accompanying drawings in which: FIG. 1 is a block diagram of a recording sub-system embodying the present invention; FIG. 2 is a schematic block diagram showing the operation of an IP address filter embodying an aspect of the present invention; FIG. 3 is a schematic block diagram showing the operation of a protocol filter embodying an aspect of the present invention; FIG. 4 is an illustration of packet data buffering as arising in an embodiment of the present invention; FIG. 5 is an illustration of RTP/PTCP Packet Buffering as arising in an embodiment of the present invention; and FIGS. 6A-6C illustrate the structure of IP packets, RTP packets and RTCP packets as arising within the present invention. Turning now to FIG. 1, there is illustrated a recording sub-system embodying the present invention and in which a recorder is connected to a network from which calls are to be recorded by connecting into allocated ports on one or network routers, switches or hubs such as the 10/100 Mbps Ethernet hubs [1], [2], [3]. In the case of intelligent switches, which only transmit data packets to those ports that need to receive the data, a “SPAN” setting is normally applied to the port used for the recorder. This setting is normally used for network diagnostics and forces the switch to copy packets destined for one or more of its other ports to this port as well. Each router/switch/hub is connected to an appropriate form of network interface card (NIC), for example 10/100 Mbps Ethernet, Token Ring, Gigabit Ethernet [4], [5]. The NIC [5] is an example of a multiport NIC which allows connection to more than one network access point. This allows efficient recording of larger networks where calls are spread across several network concentrator devices, without the need for a separate recorder for each of these. Within the operating system on the Recorder, such as Windows 2000 there will be installed one or more drivers that allow applications to communicate with the NIC(s) installed. A common NDIS driver (6) is illustrated. This typically allows other applications running on the same computer to share access to the NICs without having to be aware of each other. Hence this diagram only shows the recording sub-system. Note the archival, search and retrieval functions typical of a bulk voice recorder can still be hosted on the same PC providing of course that there are sufficient memory, processor and disk resources for these to co-exist. The system described communicates with the NDIS driver [6] and establishes a data channel which it places in promiscuous mode. This overrides the normal behaviour in which only data packets destined for this application will be delivered and instead requests that all data packets received via the network access point are passed through to an IP Address Filter mechanism [7]. The IP Address Filter mechanism [7] is described in more detail below with reference to FIG. 2. In summary, it compares the IP address and port number of each received IP packet against a list of known destinations. This could be equally well be applied to known sources rather than destinations. A rapid decision is made as to whether this packet is to be recorded or not. If the answer is yes, it will pass the packet on to a Protocol Filter [8]. This second stage filter [8] can therefore now use both knowledge of the destination to which the packet was sent and information from the IP packet itself to determine whether the packet contains RTP or RTCP data or other packet data. The filter [8] passes the packet on to either a Packet Data Buffering module [9] or a RTP Packet Buffering module [10]. Each of these two buffering modules [9], [10] applies schemes appropriate to the data type being recorded before passing on data, in relatively large, contiguous blocks, to the Record Thread Manager [14a] which, running at slightly lower priority than the previous components will write this data to the appropriate files on the hard disk. This results in efficient large data writes to the permanent storage such as a hard disk [11]. The end result is typically a pair of files one containing the actual content of the data stream, for example a .WAV audio file for RTP transmitted telephony, and the other containing details of the recording such as a .XML file containing start time, duration, IP address etc. Alternatively the details of the recordings may be inserted directly into a database. In buffering the RTP data streams, the RTP Packet Buffering module analyses the sequence numbers and timestamps of the received packets. It compares the packet loss rates it is experiencing against those reported by the participants in the streaming interaction and can hence deduce performance levels which it logs for example to a file [14]. It could equally well pass this information into a network management tool such as via Simple Network Management Protocol (SNMP). The set of known destinations that are to be recorded can be fixed in a variety of ways. For example, it could be achieved by direct, local configuration of the IP Address Filter [7], through blanket rules such as recording all streams; or it can be instructed explicitly by a component such as Unify [12] a CTI middleware platform which interfaces with a wide range of telephony and other customer contact service systems [13]. By observing activity on the external system and applying business rules, the addresses to be recorded can be readily identified. With reference to FIG. 2, once a packet is received and determined to be an IP packet it is examined by the IP Address Filter to determine whether or not it is to be recorded. It should be appreciated that, according to the network traffic patterns experienced and the proportion to be recorded, the order and/or presence of each of these filtering stages may be changed to deliver optimum performance typically measured by the packet rate that can be processed within a given proportion of the CPU time available. The IP packet [15] is normally first compared [17] with the IP address of the computer on which the recorder is hosted. This allows very rapid elimination of all packets that are intended for other processes on this computer and ensures that the hosting of, for example, a search and replay application on the same computer does not adversely impact the performance of the recording sub-system. The packets which were addressed to other IP addresses are then passed to a circular buffer lookup algorithm [21]. Recently received IP destination addresses including IP port number, are noted in a circular buffer [18]. When a packet is received, its IP address is compared with that of the entry at a Test Point [19] in the circular buffer [18]. If a match is identified, the Test Point [19] is advanced and the entry in the circular buffer is used as a pointer to the Known Destination Object [16] for this IP address. An entry in the Known Destination object's [16] data structure indicates whether or not the packet is to be recorded [25]. If it is, then it is passed through to the Protocol Filter (next section). If the packet's IP address does not match the next item in the Circular Buffer [18], it is compared against one or more subsequent entries and if a match is found, the test point [19] is advanced to this point. The entries that were tested and found not to match will be removed from the buffer as it can be deduced that they are no longer in the correct position or the stream to those addresses has terminated. If the packet's IP address does not match any of those within the lookahead window described above, it is passed to the following stage of the filter [22] in which the IP address is used to determine if there is an existing Known Destination record [16] for this IP address. The Known Destination list is typically held in memory in the form of a map with a fast indexing or hash function that allows rapid searching of many such records for the one with a specific address. However, the nature of IP addresses (e.g. 10.25.34.245) is deliberately hierarchical with the earlier numbers (when represented in text string form as here) representing the larger sub-networks. It is therefore very common for the vast majority of traffic observed on a single network segment to involve IP addresses from that sub-net i.e. the first 2 or even 3 of the numbers will be common. In such cases it is viable to maintain one or more look-up tables of Known Destination Maps [26] which simulate content addressable memory For example, such a table, with 65,536 entries can hold pointers to all the Known Destination records [16] relating to the block of IP addresses 10.10.xxx.yyy where xxx and yyy are any number from 0 to 255. It is therefore very easy and quick to compare the top (leftmost when written as text) two bytes of an IP address against the base address of such a lookup table and, if they match, use the lower (rightmost when written as text) bytes as an index into the table. A 0 (null) entry in the table infers that the destination does not yet have a Known Destination record associated with it whilst a non-zero entry can contain a pointer to the relevant Known Destination object. If the Destination is not within the range of any such rapid lookup maps [26], the normal hash table or other indexing method will be used to determine if a Known Destination Record exists. If it does, it will be inserted into the Circular Buffer [18] at the insertion point normally immediately prior to the test point [19]. If an existing Known Destination record is not found, then a new record will be created and the Record flag will be set to true or false according to the default recording rules [23]. Having found, or created, the appropriate Known Destination Record [16], the packet will at [25] either be discarded or passed to the Protocol Filter according to the Record flag within the Known Destination Record. It should be noted that the Known Destination Records can also be created, deleted and their recording flag set/reset by the Unify interface [12]. Also in order, to avoid long term build-up of redundant Known Destination Records [16], a background process can serve to periodically review the last time that a packet was observed being sent to that destination and will destroy the Known Destination Record should this exceed a pre-determined threshold. To enable this function, a data field within the Known Destination Record structure is updated to reflect the current system time whenever it is used to determine whether or not to record a packet. As illustrated in FIG. 3, the Protocol filter stage can be embodied very simply. It first examines the contents of the Known Destination Record [16] that is by now associated with the packet being processed. This record may contain information that allows the protocol filter to determine which protocol the packet should contain. This is particularly advantageous in the case of RTP data streams as there is no guaranteed method for determining that a packet is indeed an RTP packet. Such packets are identified as UDP protocol but there is no indication within the UDP packet that the payload is indeed RTP. Unless an external influence such as Unify [12] has deduced that RTP is to be expected on a given destination IP address, the only alternative is to determine if the first few bytes of the UDP packet's payload represent valid entries for an RTP packet header. This is time consuming and prone to occasional false detection. Hence, if the protocol being sent to a specific port is known already, this can be used to direct the packet at either the Packet Data Buffer [30] or the RTP/RTCP Buffer [31]. If the Known Destination Record [16] does not specify the protocol expected, the filter next examines the protocol type specified within the IP packet. A typical filter will simply check for TCP [28] and pass these packets to the Packet Data Buffer [30] then check for UDP packets [29] and pass these to the RTP/RTCP Packet Buffer [31]. According to pre-configured default behaviour [32], other protocol types may be either discarded [33] or sent to one or other of the two described buffering modules or to a new buffering module specifically optimized for storage of that protocol type such as ARP, ICMP or SNMP. Turning now to FIG. 4 there is illustrated the packet data buffering of the present invention. This can prove to be relatively straightforward with each packet simply being preceded by any or all of: A well-known synchronization value which will ensure eventual re-synchronization of a partially corrupt file; A precise time stamp; Offset of local time from Universal Co-ordinated Time (UTC); Daylight Savings Time offset; or Length of packet that follows. If this is the first packet being recorded for a given Known Destination [16] then the Known Destination record will not yet have had a buffer storage element [37] assigned. A start recording job is posted onto the queue [35] for the Record Thread Manager and a buffer [37] is assigned. These buffers are typically several Kbytes in length and can hence hold many individual packets. The packet to be stored and its associated data as listed above is appended to the buffer. When subsequent packets are received, these are appended to the buffer [37]. At the point where the buffer fills, it is moved to the FIFO queue [35] to await processing by the Record Thread Manager [39]. When the job reaches the head of the queue, it will be appended to the appropriate file on disk [34]. Meanwhile, a new buffer [37] will be allocated to the Known Destination Record [16] and any remnants of the packet which filled the previous buffer are appended to it. This process repeats until the recording is terminated at which point the partially filled buffer [37], if any, is appended to the job queue [35] and a Stop Recording job is then added to the job queue. When the Record Thread Manager reaches a Stop Recording job, it closes the file in question. Additional details about the call may be included within the Start and Stop Recording messages and these, along with other derived information, such as the total data volume stored are ultimately written to a call detail file, for example in .XML format or direct to a database. It should be appreciated that a lower priority thread high priority still being lower than Real-time priority—is used for writing data to disk than for capturing, filtering and buffering packets into memory. This allows RAM buffering to absorb short term peak load conditions which would otherwise cause bottlenecks and limit the peak throughput capacity of the recorder. FIG. 5 illustrates the RTP/RTCP Packet Buffering. This component can operate in the same way as the Packet Data Buffering component described above except for the way in which it handles the content of the data packet itself. Since RTP packets typically form a continuous stream of data, there is no need to store the RTP packet header information for all packets as it is only the payload of actual audio/video data that is required. When audio is compressed for transmission, the payload can be as little as 20 bytes (G.729A, 20 ms per packet) yet the total packet length, including Ethernet, IP, UDP and RTP headers, will typically exceed 100 bytes. Hence storing the whole packet is incredibly inefficient. In the simplest case, the payload of each RTP packet is appended to the buffer [37] and, when full, this is placed on the Record Job Queue [35]. Recording start and stop are exactly as per the Packet Data Buffering component and these two components share a common queue ensuring that data is written to disk in a FIFO manner regardless of which type of recording i.e. packet or stream, is being made. In the case of the RTP data, the files that are written by the Record Thread Manager are typically in Microsoft .WAV format and hence readable by any player device that supports this file format and the compression standard used within the file. The process is complicated somewhat by the need to allow for packet loss. This is achieved by maintaining in memory, details of the most recently received packet sequence number and timestamp. It is then possible to compare the currently available packet's sequence number and timestamp with that of the previous packet. A gap in sequence numbers can be noted and logged to a performance log file or similar [40A]. To avoid gradual buildup of error in the recorded file, any lost packet(s) can be compensated for by the automatic appending of the appropriate number of bytes of silence (or other pre-defined padding sound). Where a small number of bytes are missing (e.g. 1 or 2 packets) it is more efficient to simply add these to the buffer [37] as if they had been received. However, in the case of large gaps, it is more efficient to place the current buffer [37] on the Record Job Queue [35] for processing and then place a Padding job specifying the number of bytes of silence to be inserted. The Record Thread Manager can then append the appropriate number of bytes to the file without using excessive memory space on the Record Job Queue as would be the case if several buffers all full of silence were queued. This latter technique is particularly advantageous in systems that utilize silence suppression. In such cases, the RTP stream will stop until the audio level reaches a threshold. This can save significant bandwidth in voice communications as typically only one party is speaking at a time. In such cases, the packet sequence numbers in the RTP packet are contiguous but the timestamps are far apart. Again, this can be detected and the appropriate amount of silence indicated through the placement of a Padding job on the record job queue [35]. This then allows the Record Thread Manager to either pad the call with the appropriate amount of silence or to utilize a scheme such as the Wave List feature within the Microsoft .WAV format. This allows for the efficient storage of such audio as a sequence of sound, silence, sound, silence etc. A further refinement includes the processing of RTCP packets associated with the RTP streams being recorded. By examining the contents of these packets, one can determine the fraction and cumulative number of packets lost by each of the participants in the conversation. These details can be included with the loss rates experienced at the recorder and included in the Stop Recording job and/or entries to the log file [40A]. This allows subsequent analysis of the recorder's performance in comparison to that experienced by the participants on the call. To assist with the above description, reference is now made to the general structures of the packets arising in the aspects of the present invention. Turning now to FIG. 6A, a header 42 is shown as a plurality of boxes, each of which represents a portion or “field” of the header. The number of bytes occupied by each portion is also shown, it being understood that each layer consists of 32 bits. The first portion of the header, a “VERS” portion 44, is the protocol version number. Next, an “H.LEN” portion 46 indicates the number of 32-bit quantities in the header. A “SERVICE TYPE” portion 48 indicates whether the sender prefers the datagram to travel over a route with minimal delay or a route with maximal through-put. A “TOTAL LENGTH” portion 50 indicates the total number of octets in both the header and the data. In the next layer, an “IDENTIFICATION portion 52 identifies the packet itself. A “FLAGS” portion 54 indicates whether the datagram is a fragment or a complete datagram. A “FRAGMENT OFFSET” portion 56 specifies the location of this fragment in the original datagram, if the datagram is fragmented. In the next layer, a “TIME TO LIVE” portion 58 contains a positive integer between 1 and 255, which is progressively decremented at each route travelled. When the value becomes 0, the packet will no longer be passed and is returned to the sender. A “TYPE” portion 60 indicates the type of data being passed. A “HEADER CHECKSUM” portion 62 enables the integrity of the packet to be checked by comparing the actual checksum to the value recorded in portion 62. The next layer of header 42 contains the source IP address 64, after which the following layer contains the destination IP address 66. An optional IP OPTIONS portion 68 is present, after which there is padding (if necessary) and a data portion 70 of the packet containing the data begins. As shown in FIG. 6B, an RTP packet header 92 features several important fields: a timestamp field 94, a synchronization source (SSRC) identifiers field 96 and a contributing source (CSRC) identifiers field 98. SSRC field 96 is used to determine the source of the RTP packets (the sender), which has a unique identifying address (the SSRC identifier). The CSRC identifer in CSRC field 98 is used in a conference with multiple parties, and indicates the SSRC identifier of all parties. Timestamp field 94 is used by an RTP software module to determine the relative time at which the data in each packet should be displayed. Finally FIG. 6C shows the general structure of an RTCP packet.

20050610

20121009

20051027

90299.0

TODD, GREGORY G

PACKET DATA RECORDING METHOD AND SYSTEM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Methods and devices for treating and processing data

A data processing unit (VPU) is described, having a field of clocked logic cells (PAEs) which is operable in different configuration states and a clock preselecting means for preselecting logic cell clocking. It is provided here that the clock preselecting means is designed in such a way that, depending on the state, a first clock is preselected at least at a first cell (PAE) and an additional clock is preselected at least at an additional cell.

1. A data processing unit (VPU) comprising a field of clocked logic cells (PAES) which is operable in different configuration states and a clock preselecting means for preselecting logic cell clocking, wherein the clock preselecting means is designed in such a way that, depending on the state, a first clock is preselected at least at a first cell (PAE) and an additional clock is preselected at least at an additional cell. 2. The data processing unit as recited in the preceding claim, wherein the clock preselecting means is designed in such a way that it receives the setpoint clock for at least one first cell from a unit preselecting configuration states. 3. The data processing unit as recited in the preceding claim, wherein the unit preselecting the configuration states includes a compiling unit and/or a cell configuration preselecting unit. 4. The data processing unit as recited in one of the preceding claims, wherein the clock preselecting means is designed in such a way that it receives the setpoint clock from a logic cell. 5. The data processing unit as recited in one of the preceding claims, wherein the clock preselecting means includes at least one central clock preselecting unit and at least one local clock generating unit for generating the local clock from the preselected central clock, in particular one time synchronizing clock generating unit per cell. 6. The data processing unit as recited in one of the preceding claims, wherein at least a portion of the logic cells includes at last one ALU and/or is formed by such. 7. The data processing unit as recited in one of the preceding claims, wherein at least one memory and/or register is assigned to at least a portion of the logic cells. 8. The data processing unit as recited in one of the preceding claims, wherein a plurality of identical logic cells is provided. 9. The data processing unit as recited in one of the preceding claims, wherein all logic cells are identical. 10. A method for operating a field of clocked logic cells which are settable into different configuration states, wherein a first state is determined, at least temporarily, for at least one first cell, a clock which is to be assigned to the first cell being determined dependent on the first state and the cell being operated using this clock; a second state is determined for at least one additional cell, a second clock which is to be assigned to the second cell being determined dependent on the second state and the second cell being operated using this second clock, which differs from the first clock. 11. The method as recited in the preceding claim, wherein the clock is preselected for at least one first cell, either together with or determined by its configuration. 12. The method as recited in one of the preceding method claims, where a group of cells is jointly configured for executing algebraic and/or other operations which require a different number of clock cycles and where at least one cell, executing an operation which requires fewer clock cells than that operation requiring the most clock cycles within the group, is clocked slower than at least one other cell. 13. The method as recited in one of the preceding method claims, wherein cells of at least one group are configured for sequential data processing. 14. The method as recited in one of the preceding method claims, wherein the field in at least two cell groups is configured for executing at least two different tasks which are assigned different priorities, and the cell group appointed for executing the task having the lower priority is clocked using a lower clock frequency. 15. The method as recited in one of the preceding method claims, wherein the condition of a voltage supply source and/or a temperature is determined and the cell clock is determined as a function of the voltage and/or temperature condition thus determined. 16. A method for operating a system of reconfigurable logic elements which are operable in different configurations, wherein a still permissible frequency, in particular the still executable maximum frequency, is determined for a plurality of possible configurations, in particular such that are simultaneously configured into the field, a plurality of cells being operated using this frequency; the plurality of cells is larger than the plurality which is assigned for executing this so-called slowest configuration and the plurality is able, in particular, to include the entire field of the configurable elements. 17. The method for operating a system of reconfigurable logic elements which are operable in different configurations, wherein configurations are selected such that, by taking signal transmissions via bus lines into account, maximum frequencies are maintained during transmissions via bus systems.

The present invention relates to the definition of the species in the main claim and its object is to achieve an optimization of the hardware used in data processing. Data processing requires the optimization of the available resources, as well as the power consumption of the circuits involved in data processing. This is the case in particular when reconfigurable processors are used. Reconfigurable architecture is defined herein as modules (VPU) having a configurable function and/or interconnection, in particular integrated modules having a plurality of unidimensionally or multidimensionally positioned arithmetic and/or logic and/or analog and/or storage and/or internally/externally interconnecting modules, which are connected to one another either directly or via a bus system. These generic modules include in particular systolic arrays, neural networks, multiprocessor systems, processors having a plurality of arithmetic units and/or logic cells and/or communication/peripheral cells (IO), interconnecting and networking modules such as crossbar switches, as well as known modules of the type FPGA, DPGA, Chameleon, XPUTER, etc. Reference is also made in particular in this context to the following patents and patent applications of the same applicant: P 44 16 881.0-53, DE 197 81 412.3, DE 197 81 483.2, DE 196 54 846.2-53, DE 196 54 593.5-53, DE 197 04 044.6-53, DE 198 80 129.7, DE 198 61 088.2-53, DE 199 80 312.9, PCT/DE 00/01869, DE 100 36 627.9-33, DE 100 28 397.7, DE 101 10 530.4, DE 101 11 014.6, PCT/EP 00/10516, EP 01 102 674.7, PCT/DE 97/02949(PACT02/PCT), PCT/DE 97/02998 (PACT04/PCT), PCT/DE 97/02999 (PACT05/PCT), PCT/DE 98/00334 (PACT08/PCT), PCT/DE 99/00504 (PACT10b/PCT), PCT/DE 99/00505 (PACT10c/PCT), DE 101 39 170.6 (PACT11), DE 101 42 903.7 (PACT11a), DE 101 44 732.9 (PACT11b), DE 101 45 792.8, (PACT11c), DE 101 54 260.7 (PACT11d), DE 102 07 225.6 (PACT11e), PCT/DE 00/01869 (PACT13/PCT), DE 101 42 904.5 (PACT21), DE 101 44 733.7 (PACT21a), DE 101 54 259.3 (PACT21b), DE 102 07 226.4 (PACT21c), PCT/DE 00/01869 (PACT13/PCT), DE 101 10 530.4 (PACT18), DE 101 11 014.6 (PACT18a), DE 101 46 132.1 (PACT18II), DE 102 02 044.2 (PACT19), DE 102 02 175.9 (PACT19a), DE 101 35 210.7 (PACT25), DE 101 35 211.5 (PACT25a), DE 101 42 231.8 (PACT25II), (PACT25b). The entire contents of these documents are hereby included for the purpose of disclosure. The above-mentioned architecture is used as an example to illustrate the invention and is referred to hereinafter as VPU. The architecture includes an arbitrary number of arithmetic, logic (including memory) and/or memory cells and/or networking cells and/or communication/peripheral (IO) cells (PAEs—Processing Array Elements) which may be positioned to form a unidimensional or multidimensional matrix (PA); the matrix may have different cells of any desired configuration. Bus systems are also understood here as cells. A configuration unit (CT) which affects the interconnection and function of the PA through configuration is assigned to the entire matrix or parts thereof. The configuration of a VPU is determined by writing configuration words into configuration registers. Each configuration word determines a subfunction. PAEs may require a plurality of configuration words for their configuration, e.g., one/or more words for the interconnection of the PAE, one/or more words for the clock determination and one/or more words for the selection of an ALU function, etc. It is known that a processor which is operated at a higher clock frequency requires more power. Thus, the cooling requirements in modern processors increase substantially as the clock frequency increases. Moreover, additional power must be supplied which is critical in mobile applications in particular. To determine the clock frequency for a microprocessor based on the state is known. Such technologies are known from the area of mobile computers. However, problems arise in the overall speed with which certain applications are carried out. The object of the present invention is to provide a novel method for commercial application. The achievement of the object is claimed independently. The present invention thus shows how the power consumption may be reduced and/or optimized in VPU technology. As far as different methods are addressed in the following, it should be pointed out that they provide advantages, either individually or in combination. In a data processing unit (VPU) according to a first essential aspect of the present invention, by using a field of clocked logic cells (PAEs)-which is operable in different configuration states and a clock preselecting means for preselecting logic cell clocking, the clock preselecting means is designed in such a way that, depending on the state, a first clock is preselected at least at a first cell (PAE) and an additional clock is preselected at least at an additional cell (PAE). It is therefore suggested to operate different cells using different clocking. As a rule, the additional clock corresponds to the first clock; the former is thus situated in a defined phase angle to the latter. In order to achieve optimum data processing results, in particular with regard to the required data processing time, as well as the power consumption of the entire data processing unit, it is suggested that clocking takes place depending on the state, which means that no clock is preselected jointly for all cells based on a certain state, but rather an appropriate clock is assigned to each cell based on the state. Furthermore, it is suggested that the clocking be designed to be totally configurable, so that one calibration (configuration) mutually influences the clocking of the total number of cells. It is possible and desired that the clock preselecting means is designed in such a way that it receives the setpoint clock for at least one first cell from a unit which preselects configuration states. This makes it possible to select the clocking of the cell based on its configuration as soon as this configuration is determined. This has the advantage that configuration may take place free of problems. The unit preselecting configuration states may be a compiling unit, which means that required or desired clocking of the cell is already determined during the compiling of the program. If the compiling unit preselects the configuration states, then the cell configuration preselecting unit may convey clocking for cell configuration to a cell to be configured. This is advantageous since it is possible to merely add clock-determining information to the configuration word or the configuration instruction with which the configuration of a cell is determined, without additional measures being required such as the implementation of clock-assigning buses which separately transmit the clock-determining signals, or the like; it should be noted that this is possible in principle. It may also be provided that the clock preselecting means is designed in such a way that it receives the setpoint clock or a clock-influencing signal from one of the other logic cells, in particular a configurable logic cell. This is particularly advantageous if a first logic cell awaits an input signal from an external unit and not until arrival of such signals are the cells to be activated which process subsequently arriving signals. This makes it possible to implement a logic field sleeping mode in which only one or a plurality of cells are activated, if necessary, on a very low level, i.e., very slow clocking, and the remaining field is clocked extremely slowly. The clock frequencies required in the remaining field are dependent on physically necessary clocking which is required for the preservation of memory contents or the like. It is also advantageous to receive a clock-influencing signal from another logic cell if, using one logic cell, one or a series of a plurality of different arithmetic and/or logical operations may be executed which, at least in part, require a different number of clock cycles, but this may not be determined in advance by the compiling unit. Also in such a case, the subsequent cells do not need to be operated at a high clock frequency if they are appropriately clocked down by corresponding signals which indicate the state of the cell participating in a processing sequence. In a preferred variant, the clock preselecting means includes a central clock preselecting unit, e.g., a central clock generator, whose clock is transmitted to the individual cells via a clock line, as well as a local clock-generating unit for generating a local clock from and/or in response to the central clock transmitted via the clock line. In a possible embodiment, clocking of the central clock preselecting unit may be set or influenced by a configuration. The local clock-generating unit is preferably implemented by using a frequency divider and/or a frequency multiplier, and the frequency divider ratio is preferably determined by the preselections of the clock preselecting means according to the clock determination based on the state. In a preferred variant, the logic cells or at least some of the logic cells include at least one ALU and/or are formed by such. It is possible and preferred if some of the logic cells contain at least one memory unit and/or register unit which may be assigned to the remaining logic cells. In particular, this unit may be provided for data to be processed and/or for configurations of the cell. It is possible that a plurality of logic cells are identical and are operated using different clocking corresponding to their particular configuration. It is possible in particular that all logic cells are identical. A patent is also claimed for a method for operating a field of clocked logic cells which may be set into different configuration states, a first state being determined, at least temporarily, for at least one first cell, a clock which is to be assigned to the first cell being determined dependent on the first state and the cell being operated using this clock; a second state is determined for at least one additional cell, a second clock which is to be assigned to the second cell being determined dependent on the second state and the second cell being operated using the second clock which differs from the first clock. As mentioned above, clocking may be preselected together with the configuration. The state is then the configuration state and/or is at least determined by it. In known and configurable logic cells, cells are typically combined in groups for executing complex operations. If individual cells execute suboperations which run in fewer clock cycles as is the case with those cells which are [engaged] in particularly drawn-out suboperations of the complex total operations executed by the group, it is preferred if these cells are operated at different clock rates, namely in such a way that the cells for less complex operations, thus operations which run in fewer clock cycles, are clocked slower than the other cells; it is preferred in particular if the cells of one group are clocked collectively in such a way that the number of blank cycles within the group is minimized. An alternative and/or an addition to this lies in the fact of temporarily changing the use of cells burdened with less complex tasks for a certain number of clock cycles, thus changing the use during a fixed number of clock cycles. In particular, the case may occur that the maximum clock cycle rate of PAEs and/or PAE groups is limited by their function and in particular by their interconnection. The propagation time of signals via bus systems plays an increasingly frequency-limiting role, in particular in advancing semiconductor technology. Henceforth, the method allows slower clocking of such PAEs and/or PAE groups, while other PAEs and/or PAE groups operate at a different and, if needed, higher frequency. It is suggested in a simplified embodiment to make the clock rate of the entire reconfigurable module (VPU) dependent on the maximum clock rate of the slowest PAE and/or PAE group. In other words, the central clock preselecting unit may be configured in such a way that the highest mutual operating clock of all PAEs and/or PAE groups (in other words the smallest common denominator of all maximum clock rates) is globally generated for all PAEs. The above-described method is particularly advantageous if the cells of the group process data sequentially, i.e., the result determined by one cell is passed on to one or multiple cells which are subsequently processing data. It should be noted that in addition to prioritizing tasks within the cell field for clock preselection, the condition of a power source may also be included in cell clocking determination. Clocking may be reduced overall in the case of a drop in supply voltage, in particular in mobile applications. Clocking-down for preventing an overtemperature by responding to a temperature sensor signal or the like is equally possible. It is also possible for the user to preset the clock preselection. Different parameters may jointly establish the clock-determining state. It was mentioned above that it is possible to perform time division multiplexing for carrying out multiple configurations on the same PAE. A preferred and enhanced design makes particularly resource-saving time division multiplexing for carrying out multiple configurations on the same PAE possible; the design may have advantages independently from the different clocking of individual cells, e.g., when latencies have to be taken into account which occur in the signal transmission of digital data via a bus, such as configuration data, data to be processed, or the like. These problems are particularly serious when reconfigurable modules, having reconfigurable units which are located in part comparatively far apart from one another, are to be operated at high clock frequencies. The problem arises here that due to the special configuration of VPUs a plurality of arbitrary PAEs is connected via buses and considerable data transmission traffic exists via the buses. The switching frequency of transistors is expected to further increase in modern and above all in future silicon technologies, while the signal transmission via buses is to increasingly become a performance-limiting factor. It is therefore suggested to decouple the data rate or frequency on the buses vis-a-vis the operating frequency of the data-processing PAEs. A particularly simple embodiment, preferred for simple implementations, operates in such a way that the clock rate of a VPU is only globally settable. In other words, a settable clock may be preselected for all PAEs or it may be configured by a higher-level configuration unit (CT). All parameters which have an effect on clocking determine this one global clock. Such parameters may be, for example, a temperature determination, a power reserve measurement of batteries, etc. A determining parameter may be in particular the maximum operating frequency of the slowest configuration which results as a function of a PAE configuration or a configuration of a group of PAEs. Since different configurations may include different numbers of PAEs over stretches of bus connections of different lengths, it was realized, in particular in bus signal transmission-limiting applications, that configurations may have different maximum frequencies. Configurations may have different maximum frequencies, as is known from FPGAs, for example, which depend on the particular function of the PAEs and in particular on the lengths of bus connections. The slowest configuration then ensures that the proper operation of this configuration is also ensured, and simultaneously reduces the power demand of all other configurations which is advantageous in particular when different portions of the data processing such as through the other configurations, which would possibly run at higher clock frequencies, are not needed prior to the slowest configuration. Also in cases where it must be absolutely ensured that proper operation takes place, the possibly only negligible performance loss occurring by clocking-down other configurations, which could run faster per se, is often acceptable. In an optimized embodiment, the frequency is only adapted to the configurations which are currently carried out on a VPU, in other words, the global frequency may be reset/reconfigured with each configuration. In an enhanced embodiment, the clock may then be configured globally, as well as, as described above, individually for each configurable element. It should be noted that different variants are possible, individually or in combination. In order to show a detailed example, it is assumed in the following, without this necessarily being the case, that the clock may be controlled individually in each PAE. This offers the following possibilities, for example: a) Controlled Enabling and Disabling of the Clock It is preferred that the processing clock of PAEs is disabled, i.e., the PAEs operate only in case of need; clock enabling, i.e., activating the PAE, may take place, for example, under at least one of the following conditions, namely when valid data is present; when the result of the previous computation is approved; due to one or more trigger signals; due to an expected or valid timing mark, compare DE 101 10 530.4 (PACT18). In order to cause clock enabling, each individual condition may be used either individually or in combination with other conditions, clock enabling being computed based on the logical combination of conditions. It should be noted that it is possible to put the PAEs into a power-saving operating mode while a clock is disabled, for example, through additionally partly switched-off or reduced power supply, or, should it be necessary because of other reasons, through extremely reduced sleeping clocks. b) Different Frequencies per PAE Technologies for controlling sequences in VPUs are known from PCT/DE 97/02949 (PACT02/PCT), PCT/DE 97/02998 (PACT04/PCT), and PCT/DE 00/01869 (PACT13/PCT). Special sequencers (SWTs) which control a large number of PAEs and which are responsible for their (re)configuration are configured in PCT/DE 97/02998 (PACT04/PCT). The (re)configuration is controlled by using status signals which are generated by the PAEs (triggers) and passed on to the SWTs, namely in that the SWT responds to the triggers, making the particular continuation of a sequence dependent on the triggers. A small memory for their configuration is assigned to each individual PAE in PCT/DE 97/02949 (PACT02/PCT). A sequencer passes through the memory and addresses the individual configurations. The sequencer is controlled by triggers and/or by the status of its PAE (into which it may be integrated, for example). During data processing, it is now possible that different sequencers in different PAEs have to carry out a different number of operations per transmitted data packet (compare DE 101 39 170.6 (PACT11), DE 101 42 903.7 (PACT11a), DE 101 44 732.9 (PACT11b), DE 101 45 792.8 (PACT11c), DE 101 54 260.7 (PACT11d), DE 102 07 225.6 (PACT11e), PCT/DE 00/01869 (PACT13/PCT)). This is described using a configuration as an example in which 3 sequencers are involved in processing a data packet, requiring a different number of operations for data packet processing. Example: Sequencer 1 (Seq1) requires 10 operations for processing a data packet, Sequencer 2 (Seq2) requires 5 operations for processing a data packet, Sequencer 3 (Seq3) requires 20 operations for processing a data packet. In order to obtain an optimum operation/power consumption ratio, the individual sequencers would have to be clocked as follows: Fmax=FSeq2/4=FSeq1/2=FSeq3 or at a maximum operating frequency of, for example, 100 MHz: FSeq1=50 MHz, FSeq2=25 MHz, FSeq3=100 MHz. It is suggested in particular to use different clock sources for each PAE and/or group of PAEs. For example, different techniques may be used for this purpose, either individually or jointly: 1) Clock dividers, individually programmable per PAE, which enable an individually configurable divider ratio based on one or more mutual base clocks. 2) Clock multipliers (PLLs), individually programmable per PAE, which enable an individually configurable divider ratio based on one or more mutual base clocks. 3) Deriving the particular PAE clock from the data stream of the particular data to be processed, e.g., by oversampling. An exemplary embodiment having different algorithms is illustrated in FIG. 1. c) Configuration Clock Optimization of the power consumption is also favored in that the circuit components, necessary for executing a configuration, are clocked selectively, i.e., it is suggested to clock each PAE addressed and/or to completely disable the clock of those circuit components necessary for executing a configuration or a reconfiguration when no configuration or reconfiguration is being executed and/or to use static registers. In particular embodiments, the operating frequency of the PAEs or groups of PAEs may be made dependent on different and/or additional factors. The following is listed below as an example: 1. Temperature Measurement If the operating temperature reaches certain threshold values, the operating clock is reduced correspondingly. The reduction may take place selectively by initially operating those PAEs on a lower clock which represent the most irrelevant performance loss. In a particularly preferred embodiment, multiple temperature measurements may be performed in different regions and clocking may be adapted locally. 2. Buffer Filling Levels IO-FIFOs (input-output-first-in-first-out-circuits) which decouple peripheral data transmissions from data processing within a VPU are known from DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT15a), (PACT15b). One buffer for input data (input buffer) and/or one buffer for output data (output buffer) may be implemented, for example. A particularly efficient variable for determining the clock frequency may, for example, be determined from the filling level of the particular data buffers. The following effects and measures may occur, for example: a) An input buffer is largely full and/or the filling level rises abruptly: Clocking increase to accelerate processing. b) An input buffer is largely empty and/or the filling level drops abruptly: Clocking decrease to decelerate processing. c) An output buffer is largely full and/or the filling level rises abruptly: Clocking decrease to decelerate processing. d) An output buffer is largely empty and/or the filling level drops abruptly: Clocking increase to accelerate processing. Depending on the application and the system, suitable combinations may be implemented accordingly. It should be pointed out that such a clock frequency determination is implementable if a filling level determination means for a buffer, in particular an input and/or output buffer, alternatively also an intermediate buffer within a VPU array, is provided and if this filling level determination means is connected to a clock preselecting means for preselecting logic cell clocking so that this clock preselecting means is able to change the logic cell clocking in response to the buffer filling level. 3. Battery Charge State It is imperative to be careful with the power supply, e.g., a battery, for mobile units. Depending on the power reserve, which may be determined based on the existing methods according to the related art, the frequency of PAEs and/or groups of PAEs is determined and is reduced in particular when the power reserve is low. Besides or in addition to optimizing data processing clocking it is also possible to accomplish an optimization of the data transmission with respect to the relationship between data transmission and data processing. In a particular embodiment, the clock controls of PAEs described may be enhanced in such a way that, by using a sequencer-like activation and a suitable register set, for example, multiple, preferably different, configuration words may be executed successively in multiple clocks. A sequencer, sequentially processing a number of configuration inputs, may be additionally assigned to the configuration registers and/or to a configuration memory which is possibly also decoupled and implemented separately (compare DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT15a, PACT15b). The sequencer may be designed as a microcontroller. In particular, the sequencer may be programmable/configurable in its function such as Altera's module EPS448 (ALTERA Data Book 1993). Possible embodiments of such PAEs are described, for example, in the following patent applications which are included in their entirety for the purpose of disclosure: PCT/DE 97/02949 (PACT02/PCT), PCT/DE 97/02998 (PACT04/PCT), PCT/DE 00/01869 (PACT13/PCT), DE 101 10 530.4 (PACT18), DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT15a, PACT 15b). For the following, it is initially assumed that multiple configuration words are combined into one configuration (PAKKEDCONF) and are configured on a PAE. The PACKEDCONF is processed in such a way that the individual configuration words are executed in chronological succession. The data exchange and/or status exchange between the individual timed configurations takes place via a suitable data feedback in the PAES; for example by using a suitable register set and/or another data exchange and/or status exchange means such as suitable memories and the like. This method allows a different timing for PAEs and bus systems. While PAEs process data at very high clock rates, for example, operands and/or results are transmitted via a bus at only a fraction of the clock rate of the PAES. The transmission time via a bus may be correspondingly longer. It is preferred if not only the PAEs or other logic units in a configurable and/or reconfigurable module are clockable at a different rate, but also if different clocking is provided for parts of a bus system. It is possible here to provide multiple buses in parallel whose speed is clocked differently, i.e., a bus which is clocked particularly high for providing a high-performance connection, parallel to a bus which is clocked lower for providing a power-saving connection. The connection clocked high may be used when longer signal paths have to be compensated, or when PAES, positioned close together, operate at a high frequency and therefore also have to exchange data at a high frequency in order to provide a good transmission here over short distances in which the latency plays a minor role at best. Therefore, it is suggested in a possible embodiment that a number of PAEs, positioned together locally and combined in a group, operate at a high frequency and possibly also sequentially and that local and correspondingly short bus systems are clocked high corresponding to the data processing rate of the group, while the bus systems, inputting the operands and outputting the results, have slower clock and data transmission rates. For the purpose of optimizing the power consumption, it would be alternatively possible to implement slow clocking and to supply data at a high speed, e.g., when a large quantity of inflowing data may be processed with only a minor operational effort, thus at low clock rates. In addition to the possibility of providing bus systems which are clocked using different frequencies it is also possible to provide multiple bus systems which are operable independently from one another and to then apply the PAEs in a multiplex-like manner as required. This alone makes it possible to operate reconfigurable modules particularly efficiently in resource multiplexing, independently from the still existing possibility of differently clocking different bus systems or different bus system parts. It is possible here to assign different configurations to different resources according to different multiplexing methods. According to PCT/DE 00/01869 (PACT13/PCT), a group of PAEs may be designed as a processor in particular. In the following embodiments, for example, different configurations are assigned to data-processing PAEs using time-division multiplexing, while bus systems are assigned to the different configurations using space-division multiplexing. In the assignment of resources, i.e., the assignment of tasks to PAEs or a group of PAEs to be carried out by the compiler or a similar unit, the given field may then be considered as a field of the n-fold variable and code sections may be transferred to this field of resources, which is virtually scaled up by the factor n, without the occurrence of problems, particularly when code sections are transferred in such a way that no interdependent code sections have to be configured into a PAE which is used in a multiplex-like manner. In the previous approach, a PACKEDCONF was composed of at least one configuration word or a bundle of configuration words for PAEs which belong to one single application. In other words, only configuration words which belong together were combined in the PACKEDCONF. In an enhanced embodiment, at least one or more configuration words per each different configuration are entered into a PACKEDCONF in such a way that the configuration word or words which belong together in a configuration are combined in a configuration group and the configuration groups thus created are combined in the PACKEDCONF. The individual configuration groups may be executed in chronological succession, thus in time-division multiplexing by a timeslice-like assignment. This results in time division multiplexing of different configuration groups on one PAE. As described above, the configuration word or the configuration words within a configuration group may also be executed in chronological succession. Multiplexers which select one of the configuration groups are assigned to the configuration registers and/or to a configuration memory, which is possibly also decoupled and implemented separately (compare DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT15a, PACT 15b). In an enhanced embodiment, a sequencer (as described above) may be additionally assigned which makes the sequential processing of configuration words within configuration groups possible. Using the multiplexers and the optional sequencer, a resource (PAE) may be assigned to multiple different configurations in a time-division multiplex method. Among one another, different resources may synchronize the particular configuration group to be applied, for example by transmitting a configuration group number or a pointer. The execution of the configuration groups may take place linearly in succession and/or cyclically, with a priority being observed. It should be noted here in particular that different sequences may be processed in a single processor element and that different bus systems may be provided at the same time so that no time is wasted in establishing a bus connection which may take some time due to the long transmission paths. If a PAE assigns its first configuration to a first bus system and, on execution of the first configuration, couples the same to the bus system, then it may, in a second configuration, couple a different or partially different bus system to the former if spacial multiplexing for the bus system is possible. The execution of a configuration group, each configuration group being composed of one or more configuration words, may be made dependent on the reception of an execution release via data and/or triggers and/or an execution release condition. If the execute release (condition) for a configuration group is not given, the execute release (condition) may either be awaited, or the execution of a subsequent configuration group may be continued. The PAEs preferably go into a power-saving operating mode during the wait for an execute release (condition), for example with a disabled clock (gated clock) and/or partially disabled or reduced power supply. If a configuration group cannot be activated, then, as mentioned above, the PAEs preferably also go into a power-saving mode. The storage of the PACKEDCONF may take place by using a ring-type memory or other memory or register means, the use of a ring-type memory resulting in the fact that after the execution of the last input, the execution of the first input may be started again (compare PCT/DE 97/02998 (PACT04/PCT)). It should be noted that it is also possible to skip to a particular execution directly and/or indirectly and/or conditionally within the PACKEDCONF and/or a configuration group. In a preferred method, PAEs may be designed for processing of configurations in a corresponding time-division multiplexing method. The number of bus systems between the PAEs is increased such that sufficient resources are available for a sufficient number of configuration groups. In other words, the data-processing PAEs operate in a time-division multiplex method, while the data-transmitting and/or data-storing resources are adequately available. This represents a type of space division multiplexing, a first bus system being assigned to a first temporarily processed configuration, and a second bus system being assigned to an additional configuration; the second bus system runs or is routed spacially separated from the first bus system. It is possible at the same time and/or alternatively that the bus systems are also entirely or partially operated in time-division multiplexing and that multiple configuration groups share one bus system. It may be provided here that each configuration group transmits its data as a data packet, for example, a configuration group ID being assigned to the data packet (compare APID in DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT 15a, PACT 15b)). Subsequently it may be provided to store and sort the particular data packets transmitted based on their assigned identification data, namely between different buses if required and for coordinating the IDs. In an enhanced method, memory sources may also be run in a time-division multiplex, e.g:, by implementing multiple segments and/or, at a change of the configuration group, by writing the particular memory/memories according to PCT/DE 97/02998 (PACT04/PCT) and/or PCT/DE 00/01869 (PACT13/PCT) into a different or even external memory or by loading from the same. In particular the methods according to DE 102 06 653.1 (PACT15), DE 102 07 224.8 (PACT15a, PACT 15b) may be used (e.g., MMU paging and/or APID). The adaptation of the operating voltage to the clock should be noted as a further possibility for conserving resources. Semiconductor processes typically allow higher clock frequencies when they are operated at higher operating voltages. However, this causes substantially higher power consumption and may also reduce the service life of a semiconductor. An optimum compromise may be achieved in that the voltage supply is made dependent on the clock frequency. Low clock frequencies may be operated at a low supply voltage, for example. With increasing clock frequencies, the supply voltage is also increased (preferably up to a defined maximum). The present invention, as an example, is explained in greater detail below with reference to the enclosed drawing. It should be noted that this exemplary description is not limiting and that in isolated cases and in different figures identical or similar units may be denoted using different reference numbers. As an example, FIG. 1 shows a reconfigurable data processing unit (VPU) (0101). A configuration unit (CT, 0103) for the control and execution of the configuration and reconfiguration is superordinated to an array of PAEs (0102) which are configurable and reconfigurable independently from one another. In this connection, particular reference is made to the various applications of the applicant and the disclosure content of the patents and technologies mentioned in the introduction. In addition, a central clock generator (0104) is assigned to the data processing unit. In a possible embodiment, the clock rate of the central clock generator may be preselected by configuration unit 0103. In a possible embodiment, the clock rate of each PAE and/or groups of PAEs and their bus connections may also be preselected by configuration unit 0103. According to FIG. 2, configuration unit 0103 feeds configuring data via a configuration line 0103a into respective cells 2 of which only one is illustrated as an example. Furthermore, the clock signal of central clock generator 0104 is fed to cell 0102 via a clock line 0104a. Via a data bus input 0205a and a data bus output 0205b, reconfigurable cell 0102 communicates with other cells and additionally has a data processing unit, e.g., an arithmetic logic unit ALU 0206, and preferably an internal data memory 0207 and a configuration memory 0208 into which configuring instructions from configuration unit 0103 are fed via a configuration instruction extractor 0209 in order to configure the data processing unit, e.g., ALU 0206, as a response. In addition, configuration [instruction] extractor 0209 is connected to a frequency divider/multiplier factor preselecting input 0210a of a frequency divider/frequency multiplier 0210 which is designed to divide or multiply the clock signal of central clock generator 0104 on clock line 0104a according to a clock ratio preselected via input 0210a and to feed the clock signal to the data processing unit, e.g., arithmetic logic unit ALU 0206, and possibly other units of reconfigurable cell 0102 via a line 0211. Using an optional data bus monitoring circuit 0212, 0210 may be activated in such a way that the frequency is controlled depending on the data reception or the data transmission. Furthermore, a multiplexer 0213 for selecting different configurations and/or configuration groups may optionally be integrated dependent on 0212. Furthermore, the multiplexer may optionally be activated by a sequencer 0214 in order to make sequential data processing possible. In particular, intermediate results may be managed in data memory 0207. While the general configuration of the cell was described in part in the applicant's applications mentioned in the introduction, the presently described clock dividing system, the associated circuit, and the optimization of its operation are at least novel and it should be pointed out that these facts may and shall be associated with the required hardware changes. The entire system and in particular configuration unit 0103 is designed in such a way that, together with a configuring signal with which a configuration word is fed via configuration line 0103a via configuration word extractor 0209 to data processing unit 0206 or upstream and/or downstream and/or associated memory 0208, a clock dividing/multiplying signal may also be transmitted which is extracted by configuration word extractor 0209 and transmitted to frequency divider/multiplier 0210, so that, as a response, 0210 may clock data processing unit 0206 and possibly also other units. It should be pointed out that, as a response to an input signal to the cell, there are also other possibilities instead of unit 0209 to vary clocking of an individual data processing unit 0206 with reference to a central clock unit 0104, via data bus monitoring circuit 0212, for example. Described only as an example with reference to FIGS. 3 and 4, an entire field of all reconfigurable logic units 0102 may be operated using the above-described embodiment, but possibly also by implementing the units in a different way. For example, a 3×3 field of reconfigurable cells is configured in such a way, according to FIG. 3a, that a first cell 0102a is used for analyzing an input/output signal. Cells 0102b, 0102c are presently not needed and are therefore denoted as not configured (n. c.). Cells 0102d through 0102i together form a group which executes a complex arithmetic operation; an addition takes place in cell 0102d, a subtraction takes place in cell 0102e, a multiplication takes place in cell 0102f, a loop is run in cell 0102g, a multiple addition being executed within the loop, a division takes place in cell 0102h, and an addition in turn takes place in cell 0102i. Cells 0102d through 0102i are connected to one another in group 0301, indicated by dot and dash lines, in such a way that data is sequentially and pipeline-like processed by the cells. As is indicated in the second row of the table in FIG. 3b, the operations within cells 0102d and 0102e are executed in a different number of clock cycles. The number of clock cycles is denoted there and it is clear that an addition or a subtraction may be executed in one clock cycle; the division, however, requires 32 clock cycles. The third line of the table in FIG. 3b denotes which value is assigned to the frequency divider of each cell in order to achieve optimum power usage at a constant data throughput through the cell. Only the cell in which the division takes place is operated at the highest clock; the clock ratio here is 1. This cell requires the longest time for the operation assigned to it. Since a new result has to be delivered only every 32 clock pulses to cell 0102h executing the division, cells 0102d and 0102e are clocked slower by the appropriate factor of 32; the frequency divider ratio for these cells is therefore 32, as can be seen in FIG. 3b. Whereas, the multiplication running in two clock cycles has a frequency divider ratio of 16, and the more complex loop of cell 0102g running in 16 clock cycles is assigned a frequency divider ratio of only 2. These clock ratios are initially known at the configuration, in which the individual cells are compiled in groups and are assigned to each cell within the group since they were determined by the compiler at program compilation and may therefore be input into the cell at its configuration. It is denoted in the fourth row from the top which clock rate results from a central clock of 256 MHz. If the processor unit having the separately clockable reconfigurable logic cells is operated in an application where the voltage may drop, e.g., due to exhausting voltage supply capacities, it may be provided that, at a drop in the supply voltage, the entire frequency is reduced to a critical value U1; all cells are subsequently clocked slower by one half so that division cell 0102h too runs only at 128 MHz, while cell 0102d is clocked at 4 MHz. Cell 0102a, executing a query of the mouse pointer having a lower priority, is no longer clocked at 8 MHz as previously but rather at 2 MHz, i.e., depending on the prioritization, different slowdowns according to the importance of the task are assigned to the respective groups at a voltage drop or under other circumstances. If, for other reasons, the temperature still rises, the heat generation in the logic cell field may be further reduced by an additional clock rate reduction for the logic cells, as is indicated in the last row of FIG. 3b. It is understood that, for example, a particular individual sensor for determining the condition such as the supply voltage and/or the temperature may be provided whose sensor signal is fed to the cells in a conditioned manner; a corresponding sensor system may be assigned to each cell and/or the central clock is possibly modifiable. This makes it possible to optimally operate a processor field energy-efficiently; the cooling capacity required is reduced and it is clear that, since as a rule not all cells may and/or must be permanently operated at the highest clock frequency, heat sinks and the like may be dimensioned appropriately smaller which in turn offers additional cost advantages. It should be noted that in addition to the query regarding a supply voltage, a temperature, the prioritization of computations, and the like, other conditions may determine the clock. For example, a hardware switch or a software switch may be provided with which the user indicates that only low clocking or higher clocking is desired. This makes an even more economical and targeted handling of the available power possible. It may be provided in particular that, at the user's request or at an external request, the central clock rate in total may be reduced; the clock divider ratios within the cell array, however, are not changed in order to avoid the requirement of reconfiguring all cells, e.g., at an extreme temperature rise. Moreover, it should be pointed out that a hysteresis characteristic may be provided in determining the clock rates, when a temperature-sensitive change of the clock frequencies is to be performed, for example. FIG. 4 once more shows the data processing unit (VPU) according to FIG. 1. Different groups within the VPU are operated using different frequencies f which are derived from a frequency normal n generated by 0104. It should be expressly noted that multiple frequency normals (n1 . . . nn) may be generated by multiple 0104 and may be used within one VPU. FIG. 5 shows a simple exemplary embodiment for the operation of a PAE according to FIG. 2. A data bus (0205a) delivers operands ia1 and ia2 to an ALU (0206) which in turn delivers the result of the computation oa to 0205b. The PAE is only activated, i.e., clocked and/or supplied with current, when data bus monitoring circuit 0212 recognizes the acceptance of the previous result oa by the receiver and the arrival of operands ia1 and ia2 necessary for the operation. In other words, the PAE is only activated when all working conditions and requirements are met. The clock release is carried out by 0210, the clock source is 0104a. FIG. 6 corresponds to FIG. 5 with the exception that a sequencer (0214) is additionally activated which controls a multicyclical configuration (e.g., a complex computation such as a matrix multiplication or the like). The sequencer extracts the operations from the configuration memory or from a section of the configuration memory. In the example shown, operations op1, op2, op3, op4, op5 are carried out sequentially. Result oa is conveyed after completion and the PAE has to be activated again. The data transmission occurring on data bus 0205a/b is illustrated in FIG. 6a. It should be pointed out that the data routing via the bus may take place in a manner known per se as is known from other applications and/or publications of the present user, i.e., collision preventions and deadlock situations may be prevented for one configuration at a time in a manner known per se. In order to execute op1, operands ia must be available via 0205a (0601); the data transmissions for the remaining cycles may be undefined in principle. Thereafter, 0205a may preferably transmit the subsequent operands (0602) for which the execution time of op2, op3, op4, op5 is available, thus creating an essential temporal decoupling, allowing the use of slower and/or, in particular, longer bus systems. During the execution of op2, op3, op4, op5, data of other configurations may alternatively (0603) be transmitted via the same bus system 0205a using a time-division multiplex method. Following op5, result oa is applied to bus 0205b (0601); the data transmissions for the remaining cycles may be undefined in principle. The time prior to op5, i.e., during the execution of op1, op2, op3, op4, may be used for transmitting the previous result (0602). This again creates an essential temporal decoupling, allowing the use of slower and/or, in particular, longer bus systems. During the execution of op1, op2, op3, op4, data of other configurations may alternatively (0603) be transmitted via the same bus system 0205b using a time-division multiplex method. For clock multiplication, 0210 may use a PLL. A PLL may be used in particular in such a way that the operating clock of the PAE for executing op1, op2, op3, op4, op5 is five times that of the bus clock. In this case, the PAE may act as a PAE without a sequencer having only one (unicyclical) configuration and the same clock as the bus clock. FIG. 7 corresponds to FIG. 6 plus the addition that multiple configuration groups (ga, gb, gc) share the PAE in a time-division multiplexed manner and each group has connections to a separate (space-division multiplexed) bus system (ia/oa, ib/ob, ic/oc). A multiplexer in 0214 cyclically selects the groups ga, gb, gc. Provided the data monitoring circuit 0212 generates a valid execution release (condition) for a configuration group, the particular configuration group is executed; otherwise the execution release (condition) may be awaited or, preferably, a different subsequent configuration group may be selected. The configuration groups may be run through cyclically. One configuration group may contain multiple configuration words (ga={ka1, ka2}, gb={kb1}, gc={kc1, kc2, kc3}). The configuration words may be executed sequentially in 0214 using a sequencer. FIG. 7a shows the bus transmissions according to the example in FIG. 7. 0701 corresponds to 0601, 0702 corresponds to 0602, 0703 corresponds to 0603; a separate bus system is used thereby for each group ga, gb, gc. In addition, a possible bus transmission using a time-division multiplex for the bus systems is illustrated in 0704. The input data of all groups is transmitted via an input bus system and the output data of all groups is transmitted via an output bus system. The undefined intermediate cycles are either unused or are free for other data transmissions.

20040921

20081028

20050324

99608.0

ELAMIN, ABDELMONIEM I

METHODS AND DEVICES FOR TREATING AND PROCESSING DATA

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method of synchronizing fin fold-out on a fin-stabilized artillery shell, and an artillery shell designed in accordance therewith

The present invention relates to a method of as far as possible limiting the yawing motion on the trajectory of an artillery shell(1), provided during the firing phase with a sliding driving band and completely folded-in guide fins (3, 16), which shell, as soon as possible outside the mouth of the barrel of the firing piece, is converted, by fold-out of the guide fins (3, 16), into a fin-stabilized artillery shell, any form of non-uniform fin fold-out being avoided by virtue of all the guide fins (3, 16) being interconnected, by means (18, 19, 20) adapted thereto, to form a system which gives all the fins (3, 16) the same movement pattern and the same fold-out speed in each phase of fin fold-out. The invention also includes a shell (1) designed in accordance therewith, in which the means for synchronization of fin fold-out consists of a rotatable control ring (19) which is arranged around the axis of the shell and is connected to the rotation spindles (13) of all the fins.

1-10. (canceled) 11. A method for firing an artillery shell having a sliding driving band and completely folded-in and interconnected guide fins from a firing piece, the method comprising: firing the artillery shell; converting, as soon as possible outside a mouth of a barrel of the firing piece, the artillery shell by fold-out of the guide fins into a fin-stabilized artillery shell; avoiding any form of non-uniform fin fold-out by interconnecting all of the guide fins; and forming a system which gives all the guide fins a same movement pattern and a same fold-out speed during each of a plurality of fin fold-out phases. 12. The method of claim 1, further comprising: allowing moving of each of the interconnected fins around a respective rotation spindle arranged essentially in a longitudinal direction of the shell from a first, folded-in position in which an active area of a fin in a region of the rotation spindle lies essentially tangential to a shell body, to a second, folded-out position in which the active area is oriented essentially radially relative to the shell body; and interconnecting each of the fins to form a continuous system which assists with braking a fold-out of each of the fins according to a wind load acting on the active area of each fin. 13. The method of claim 1, further comprising: controlling an interaction of a relative fold-out of each of the fins by using a toothed ring connecting the fin spindles and a corresponding toothing on each fin spindle. 14. An artillery shell suitable for firing from a rifled barrel, the shell comprising: a sliding driving band; foldable stabilizing fins which are folded out after firing of the shell and which convert the shell into a fin-stabilized projectile, movement transmission means for interconnecting the foldable stabilizing fins and, when the fin-stabilized projectile is on a firing trajectory, synchronizing and making uniform fold-out movements of the foldable stabilizing fins. 15. The artillery shell of claim 14, wherein each of the fins have an associated active area which is rotatably mounted around an associated spindle arranged essentially in a longitudinal direction of the shell and around which the associated active area rotates from a first, folded-in position, in which said associated active area lies essentially tangential to a shell body and a free outer end thereof is curved in towards the shell body, to a second, folded-out position, in which the associated active area extends essentially radially out from a surface of the shell body, wherein the movement transmission means comprises at least one control ring arranged rotatably around the longitudinal axis of the shell and is connected to spindles of all of the fins so as to control the movement of each of the fins. 16. The artillery shell of claim 15, wherein the at least one control ring has an external toothing while the spindle of each fin has, at a respective place of connection to the control ring, corresponding toothing in engagement with the teeth of the control ring. 17. The artillery shell of claim 15, wherein the control ring comprises external knurling or another friction-increasing surface treatment, and wherein the rotation spindle of each fin has a corresponding friction-increasing surface treatment where the spindles make contact with the control ring. 18. The artillery shell of claim 14, wherein the movement transmission means is located around an exhaust opening of a base bleed unit which is arranged in a same part of the shell as the fins, said fins being mounted concentrically outside the base-bleed unit. 19. The artillery shell of claim 14, wherein an action of forces of air on the fins is augmented by the fins being given a relatively small angle of attack relative to the main axis of the shell. 20. The artillery shell of claim 19, wherein the angle of attack is brought about by the fin, in the folded-out position, being provided with a spiral or propeller twist. 21. The artillery shell of claim 19, wherein the angle of attack is brought about by the fin, in the folded-out position, being provided with a dog-ear design on at least a portion of an outer portion.

The present invention relates to a method of synchronizing fin fold-out on a long-range artillery shell which is fin-stabilized on its trajectory towards the target and is intended to be fired from a rifled barrel and is to this end provided with a sliding driving band as the main contact surface against the inside of the barrel and also with a number of stabilizing fins which can be folded out after the shell has left the barrel. The purpose of the sliding driving band is to allow the shell, in spite of the rifling of the barrel, to leave the latter with only low rotation or no rotation at all. It is particularly characteristic of the method and the shell according to the invention that the stabilizing fins of the shell are interconnected by specially designed movement transmission means which bring about uniform fold-out of all the fins irrespective of how these are loaded during the fold-out phase itself. Even if the shell should leave the barrel entirely without rotation, the fins arranged around the shell will nevertheless be loaded differently during the fold-out phase by the forces generated by the air flowing past. This is because it has proved to be impossible to avoid any type of shell being subjected to a certain conical yawing motion on its trajectory, and this yawing motion begins immediately after the shell has left the mouth of the barrel. The reason why an artillery shell is fin-stabilized instead of being rotation-stabilized may be, for example, that it is desirable to make it guidable on its way towards the target, and it is considerably easier to correct the course of a fin-stabilized shell than of a rotation-stabilized shell, and this is the case irrespective of whether the course correction concerned is intended to be performed by impulse motors, steering rudders or in another manner. It is a requirement of the shell according to the invention that it should be capable of being given an extra long range. A method used increasingly in recent years of achieving extremely long ranges even in older barrel-type artillery is the base-bleed technique, which is used in order to eliminate the turbulence and negative pressure which are formed behind the shells flying through the atmosphere and have a braking effect on the shells and shorten their flying distance. The base-bleed technique is based on arranging a combustion chamber in the rear part of the shell, which chamber is filled with a slow-burning pyrotechnic composition which, while it burns, produces combustion gases which are allowed, in a predetermined quantity, to flow out through an opening in the rear end wall of the shell and there eliminate and fill the abovementioned braking turbulence and negative pressure behind the shell. When a shell is to be provided with both a base-bleed unit and stabilizing fins, however, it is easy for positioning problems to arise, because the base-bleed unit definitely has to be arranged in the rear part of the shell with at least one gas outflow opening in the rear end wall of the shell, while the fins too ought to be positioned in the rear body of the shell as far away as possible from the centre of gravity of the shell, that is to say fins and base-bleed unit should preferably be arranged within the same part of the shell. An additional problem is that, in order to allow firing of the shell from a rifled barrel, the fins must be fully folded in inside the minimum diameter of the barrel during firing, at the same time as they must not occupy too great a volume either and thus prevent the use of this space for other purposes such as, therefore, the base-bleed unit or payload. In a known type of fold-in fin, which takes up little space and can be designed so that, in the folded-in position, the fins can share the rearmost part of the shell with a base-bleed unit, each fin consists of a plate which is fixed to a rotatable spindle arranged in the longitudinal direction of the shell and which, in the folded-out position, will constitute the active area of the fin and, in the folded-in position, is rotated in towards the shell body about its spindle, and is in this position curved in towards the shell body and, until the desired fold-out time, is retained in this position by a protective cover or equivalent. Previously, such fins were designed with a curved shape following the shell body and they retained this shape in the folded-out position as well, but, in recent years, elastically deformable materials have become available, which have such a good shape memory that it is now possible to produce fins which, even after years of incurvation in the folded-in position, essentially recover their original shape. It has therefore become possible to use these materials to produce fins which, as soon as they are given the opportunity, tend to recover the shape they were originally given, and this may have been entirely plane or slightly propeller-shaped or designed in another way so as to be provided with a limited angle of attack relative to the air rushing past. One way, which is relatively simple in terms of manufacture in this context, of giving the fins the desired angle of attack is to provide them with a sharp or gently curved dog-ear design or a few degrees of propeller twist. All these types of guide fins are presupposed at the same time to have a radial main direction seen in the cross-sectional direction of the shell. The angles of action relative to the air rushing past the shell which are chiefly of interest in the case of the guide fins for fin-stabilized shells are usually of the order of 1-2°, and corresponding angles of action can of course also be brought about by means of axes of rotation for folding in and folding out the fins which are inclined relative to the longitudinal axis of the shell, but this would as a rule involve more expensive overall solutions. As an example of the state of the art, WO 98/43037 may be mentioned, in which a fin-stabilized artillery shell with fold-out stabilizing fins of the type described above is disclosed. In the introduction, it was stated that every type of artillery shell is already subjected to a certain form of conical yawing motion on the trajectory immediately after it has left the mouth of the barrel and that this results in fold-out fins arranged on the shell being subjected to different degrees of loading by the relative wind of the surrounding air, which can moreover, to some extent, be from different directions. In brief, this means that the various fins on a fin-stabilized artillery shell will be loaded differently during the fold-out phase itself. In the case of shells provided with sliding driving bands, the centrifugal force acting on the fins is of little importance for fin fold-out. Instead, the majority of the fold-out force comes from the straightening force of the fin material, that is to say the force which is generated when the elastic deformation of the fin material returns to the original shape the fin was once given. In their folded-in position, elastically deformed fins of the type concerned here will quite simply spread out by virtue of their own built-in force but, in spite of this, the fold-out function cannot be left entirely to this mechanical energy development, inter alia because it is clearly most marked during the initial introductory phase of fold-out. For this reason, the fins are normally also provided in the previously indicated manner with a small angle of attack relative to the flying direction of the shell, so that the forces of the air will, above all in the final stage of fold-out, make their contribution to the requisite fin fold-out force. However, on account of the yawing motion of the shell, the air forces may vary quite considerably in strength and direction between the different sides of the shell because the relative wind against the shell is dependent on the yawing motion of the shell which begins directly outside the mouth of the barrel. A fin on one side of the shell could therefore, if it were able to define its own fold-out speed, have such a high fold-out speed that its strength is put at risk, while a fin on another side of the shell could at the same time have such a low fold-out speed that it does not completely reach its intended radial position. Accordingly, the object of the present invention is to eliminate, in a reliable manner, the effects of an otherwise readily occurring incomplete fin fold-out, and this is achieved by fold-out of the fins in relation to one another being synchronized using means adapted thereto. According to the invention, the fins are therefore to be interconnected in such a manner in relation to one another that they are folded out at the same speed. The invention therefore concerns a method of forcing the fins most heavily loaded in the fold-out direction to share the fold-out force acting on them with fins which are more lightly loaded in the fold-out direction at the same time as the latter are to force the more heavily loaded fins to slow down their fold-out speed and thus also to reduce the risk of them being overloaded. The basic principle of the invention is therefore that all the fins are to be connected by means of a common fin fold-out control or synchronizing arrangement which is to be designed in such a manner that it gives all the fins a simultaneously initiated uniform fold-out at the same speed from their initial folded-in position with that part of the fin blade or the active area of the fin which lies closest to the spindle extending tangentially to the immediately adjacent outer side of the shell into a folded-out position in which the fin blades are angled at in principle 90° relative to the folded-in position, in which position the fin blades or the active areas of the fins extend radially out from the shell body. The invention also includes the fact that the fins should, via the synchronizing arrangement, help one another with fold-out or alternatively brake one another as required. A direct drive function is therefore, at least in the first place, not intended to be included in the system. An essential part of fin fold-out is also that the fin plates which constitute the active areas of the fins recover elastically from their incurvation towards the shell body to the finally intended shape they were once given. Another advantage of the invention is that, in an especially preferred embodiment, it requires very limited extra space and by virtue of this makes it possible to arrange both the fold-out fins and a base-bleed unit within the same part of the shell. The invention therefore provides a method and an arrangement which guarantee that the fold-out fins on an artillery shell with a sliding driving band fired from a rifled barrel achieve their completely folded-out and locked end position. It is characteristic of the method and the arrangement according to the invention in this connection that any form of non-uniform fin fold-out and associated negative influence on the flight of the shell will be avoided by virtue of all the guide fins being interconnected by means adapted thereto to form a system which, during the fold-out phase, gives the fins a synchronized movement pattern with simultaneous and uniform fold-out movements. In order to make it possible to perform such a synchronized fin fold-out function, we have introduced a movement transmission means which connects all the rotation spindles around which the fins have, during the firing phase, been curved in towards the shell body, in which position they have been retained by a special protective cover from the completion of the shell during manufacture until it leaves the mouth of the barrel. When the shell leaves the mouth of the barrel, the protective cover is torn away from the shell by an inner powder gas pressure which, during the firing phase, is allowed to leak into the cover and which, inside the barrel, is balanced by the powder gas pressure behind the shell. This is because, when the shell leaves the barrel, this counterpressure ceases very rapidly and, by dimensioning the gas supply to the cover so that it is not possible for its inner overpressure to be eliminated at the same rate as the abrupt reduction in pressure behind the shell takes place, the cover will be thrown off. As soon as the protective cover has been removed, fin fold-out will begin and, as the method and the arrangement according to the invention are primarily intended for use on shells with sliding driving bands, there is only at the very most a weak centrifugal force available to assist fin fold-out. The majority of the force necessary for fin fold-out therefore has to be obtained, as already mentioned, from the straightening force built into the fins and also, to some extent, from the relative wind force against the fins of the passing air. The object of the method and the arrangement according to the invention is therefore to even out this non-uniformity and to give all the fins the same fold-out speed. According to an especially preferred embodiment, the main means of synchronizing the fin fold-out function consists of a control ring which is arranged concentrically around the longitudinal axis of the shell close to its outer wall, can rotate in a groove adapted thereto and connects the various fin spindles and gives these and the active areas of the fins identical movement patterns. In its most developed form, the outer surface of the control ring is designed as a toothed ring and each fin spindle is in turn provided with a corresponding toothed segment covering at least a quarter of a turn. Under certain circumstances, it would probably be possible to replace the toothing with low-cost variants in the form of knurling or another friction-increasing treatment of the outer surface of the control ring and the rotation spindles of the fins. Another possible but, because it would result in so many small parts, less practical solution would be to use a number of links which interconnect cranks rigidly connected to respective spindles. The invention is defined in greater detail in the patent claims below and will moreover be described in somewhat greater detail in connection with accompanying figures, in which FIG. 1 shows an oblique projection of an artillery shell while FIG. 2 shows a longitudinal section through the rear part of the shell, FIG. 3 shows the section III-III in FIG. 2 with the fins folded in and covered by a protective cover while FIG. 4 shows the section III-III in FIG. 2 but with the fins folded out, and FIG. 5 shows a detail from FIG. 4 while FIG. 6 shows the rear part of the shell according to FIG. 2 but in an oblique projection. The shell shown in an oblique projection in FIG. 1 represents an example of how a shell designed according to the invention may appear on its way towards the target. The shell in question consists of a shell body 1 provided with a groove for a sliding driving band 2 which has already been lost, a number of folded-out fins 3 which are attached to the rear portion 4 of the shell, the connection of which to the shell body 1 is indicated by the join 5. At the front end of the shell, there are four canard rudders 6a, 6b and 7a, 7b which can likewise be folded out and are moreover guidable. All the fins and rudders are designed in such a manner that they can be kept folded in during the firing phase. FIG. 2 shows in greater detail how the rear portion 4 is designed. This portion accordingly comprises an inner cavity 8, in which a base-bleed charge 9 is arranged. There is also an initiator 10 for the base-bleed charge and a support dome 12 arranged around the outlet 11 thereof. Each of the fins 3 is attached to a rotatable spindle 13 aligned essentially in the longitudinal direction of the shell. Each such spindle has a bearing point 14 and, respectively, 15 at each end. The active areas of the fins, which consist of plane plates as in FIGS. 2-6 in the folded-out position, have been given the general designation 16. In their folded-in position, the active areas 16 of the fins, which can be seen more clearly in FIG. 3, are on the one hand folded down a quarter of a turn around their respective spindles 13 towards the rear body 4 of the shell so that, in the region of their respective spindles 13, they extend essentially tangentially along the rear body 4, and on the other hand curved in at their respective free outer end along this body and moreover covered by a protective cover 17 which is removed as soon as the shell has left the mouth of the barrel. In order for it to be possible to bring about the synchronization of fold-out of the fins 16 which is characteristic of the invention, the spindles 13 of the fins are, somewhere along their length, in this case at one of their ends, designed with toothed arcs or toothed segments 18 which in turn are all in engagement with an externally toothed control ring 19 characteristic of the invention, which, in a groove 20 adapted thereto inside the rear body 4 close to its outer wall, runs concentrically around the central outlet 21 of the rear body 4 for the base-bleed charge. Until and when the shell leaves the barrel from which it is fired, the fins will therefore be covered by the cover 17 which, by interaction between powder gases penetrating into the cover and the vacuum directly outside the mouth of the barrel, is pulled off, whereupon fin fold-out begins immediately. By virtue of the fact that the spindles 13 of all the fins 16, via the toothed arcs 18 and then in turn by the externally toothed control ring or synchronizing means, are interconnected to form a continuous system, all the fins will be folded out at the same speed. As can be seen from FIGS. 3 and 5 in particular, we have, in the case illustrated, selected a tooth size which, with four teeth for each toothed arc 18 on the spindle 13 of each fin 16, gives a fold-out movement corresponding to a quarter of a turn for the active area 16 of the fin.

20050427

20060912

20051020

74147.0

HOLZEN, STEPHEN A

METHOD OF SYNCHRONIZING FIN FOLD-OUT ON A FIN-STABILIZED ARTILLERY SHELL, AND AN ARTILLERY SHELL DESIGNED IN ACCORDANCE THEREWITH

UNDISCOUNTED

ACCEPTED

ACCEPTED

Packaging machine for cigarettes

For the production of (cigarette) packs of different configurations, for example standard pack (13), round-edged pack (14) or octagonal pack (15), subassemblies and elements of the packaging machine are exchanged and/or uncoupled from the drive. For this purpose, a pack-specific operating element is provided with a drive which has a coupling and/or uncouplable gear-mechanism parts. These, in turn, are assigned operable handling elements which allow adjustment for coupling or uncoupling or removing sub-elements.

1. A packaging machine, in particular for producing cigarette packs, having folding subassemblies and elements for folding or shaping blanks (28) and having conveying elements for transporting packaging material and (partly) finished packs, characterized in that in the case of production changeover, in particular in respect of size and/or configuration of the (cigarette) pack, it is possible for folding subassemblies and/or elements and/or conveying elements to be wholly or partially exchanged or uncoupled from the drive. 2. The packaging machine as claimed in claim 1, characterized in that the correct exchange of folding subassemblies and/or shaping subassemblies and/or conveying elements can be checked by sensors, in particular by contactless initiators (23, 24), which respond to associated contact components on the elements which have been, or can be, exchanged. 3. The packaging machine as claimed in claim 2, characterized in that the sensors, in particular two initiators (23, 24) assigned to each adjustable subassembly which can be uncoupled or exchanged, are connected to a central control means (27), and in that production operation is only allowed when all the elements or subassemblies have been correctly exchanged and/or removed from the drive. 4. The packaging machine as claimed in claim 1, characterized in that a folding turret (17) can be removed as a whole from the drive and replaced by another folding turret (17), in particular a plate-like folding turret (17) which can be rotated about a vertical axis and is mounted in a releasable manner at a top end of an upright shaft (18), there being fitted on the folding turret, preferably on the underside, contact protrusions—contact rings (25, 26)—with which contact can be made by (two) initiators (23, 24) positioned beneath the same. 5. The packaging machine as claimed in claim 1, characterized in that processing elements, in particular shaping tools for producing or preparing round edges, have a gear mechanism (32, 56) for executing operating movements of the tools, and in that the tools, including the respectively associated gear mechanism (32, 56), can be uncoupled from the drive in order to stop operation of the tools. 6. The packaging machine as claimed in claim 5, characterized in that the gear mechanism (32, 56) for executing the movements of the elements, tools or the like is assigned a further gear mechanism, namely an intermediate gear mechanism (34) or a preliminary gear mechanism (58), which is connected in each case to the drive, and in that the drive can be uncoupled from the drive in the region of the intermediate gear mechanism (34) or of the preliminary gear mechanism (58). 7. The packaging machine as claimed in claim 1, characterized in that a drive shaft or actuating shaft (40) is connected to a driven element, in particular to a pivoting lever (41), via a coupling (48, 49) which can be actuated from the outside, and in that the driven element—pivoting lever (41)—can be uncoupled from the drive by virtue of the coupling being released. 8. The packaging machine as claimed in claim 7, characterized in that the driven element, in particular the pivoting lever (41), is mounted on the actuating shaft by way of an adjustable mount, in particular a sleeve (43), and in that the coupling (48, 49) can be actuated by axial displacement of the sleeve (43). 9. The packaging machine as claimed in claim 8, characterized in that the sleeve (43) or the like can be displaced in the axial direction by an adjusting wheel (44) which can be operated from the outside, and in that one coupling part (48) is connected to the sleeve and a corresponding coupling part (49) is connected to the actuating shaft (40). 10. The packaging machine as claimed in claim 5, characterized in that, in order to uncouple a subassembly or element from the drive, a drive wheel, in particular an intermediate wheel (60) designed as a gearwheel, can be disengaged from adjoining gearwheels, in particular disengaged from the gearwheel (59) assigned to the gear mechanism (56), by axial displacement. 11. The packaging machine as claimed in claim 10, characterized in that the gearwheel or intermediate wheel (60) can be adjusted in the axial direction by a tool which can be actuated from the outside, namely an actuating element (64). 12. The packaging machine as claimed in claim 1, characterized in that it is possible to remove elements or tools, in particular scoring rollers (72, 73) for stamping blanks (28) or material webs (71), preferably by virtue of a shaft or spindle (69, 70) which bears the scoring rollers (72, 73) being removed. 13. The packaging machine as claimed in claim 12, characterized in that the spindles (69, 70) which bear the elements, in particular scoring rollers (72, 73), have an uncouplable spindle component (77, 78), the spindle components (77, 78) being mounted, preferably by way of conical coupling ends (81, 82), in corresponding recesses of rotatable carrying components (79, 80), which are mounted in a stationary manner. 14. The packaging machine as claimed in claim 1, characterized in that the elements which can be exchanged or brought to a standstill have elevations (50), thickened portions (85) or the like adjacent to one or more initiators (23, 24), it being possible for one initiator (23) to be activated in one position and for the other initiator (24) to be activated in another position. 15. The packaging machine as claimed in claim 1, characterized in that, once uncoupled from the drive, rotatable elements can be fixed in a predetermined relative position, in particular by a fixing pin (68) entering into bores.

The invention relates to a packaging machine, in particular for producing cigarette packs, having folded subassemblies and elements for folding blanks and having conveying elements for transporting packaging material and (partly) finished packs. In the cigarette industry, there is increasing interest in producing cigarette packs of different configurations, in particular of different designs. On account of the variety of packs which can be produced, in some circumstances in limited quantities, there is a corresponding requirement for converting packaging machines from one type of pack to another. The object of the invention is to design packaging machines, in particular for producing cigarette packs, such that conversion from one type of pack to another can be reliably carried out within a short period of time. In order to achieve this object, the packaging machine according to the invention is characterized in that, in the case of production changeover, in particular in respect of size and/or configuration of the (cigarette) pack, folding subassemblies and/or elements and/or conveying elements can be wholly or partially exchanged or uncoupled from the drive. The correct and complete exchange or changeover of the elements and subassemblies concerning the relevant features of the packs is checked, according to the invention, by sensors, in particular by contactless initiators. These are connected to a central control unit. A signal for starting up the packaging machine for producing a new type of pack is given when the subassemblies and elements which can be exchanged or changed over or uncoupled from the drive are completely ready for the new type of pack. The invention concerns, in particular, a packaging machine for producing cigarette packs of the hinged-lid (-box) type). One special feature of the invention consists in converting the packaging machine alternatively to standard packs of this type, to packs with beveled pack edges (octagonal pack) or to packs of rounded pack edges (round corner pack). For this purpose, selected elements and subassemblies are exchanged, changed over or uncoupled from the drive. Details of the packaging machine according to the invention and of these specifically designed pack-specific elements and subassemblies are explained hereinbelow with reference to the patent drawings, in which: FIG. 1 shows a schematic side view of a packaging machine for producing hinged-lid boxes, FIG. 2 shows, in plan view or along a section plane II-II from FIG. 1, a detail of the packaging machine according to FIG. 1, namely a folding turret, FIG. 3 shows the detail according to FIG. 2 in cross section, namely along section III-III from FIG. 2, FIG. 4 shows a view, partly in section, of a subassembly for processing blanks, namely for preshaping folding tabs for round-edged packs, FIG. 5 shows a detail of the subassembly according to FIG. 4 with folding elements in different relative positions, FIG. 6 shows the subassembly according to FIG. 4 in a plan view or in a horizontal section along section plane VI-VI, FIG. 7 shows a further folding subassembly of the packaging machine, namely for shaping collar blanks, in elevation or along upright sectional plane VII-VII from FIG. 1, FIG. 8 shows a processing subassembly for blanks, namely a scoring subassembly, partly along axially running sectional plane VIII-VIII from FIG. 1, and FIG. 9 shows a diagram of a control system for a product changeover. The packaging machine discussed here (FIG. 1) serves for producing cigarette packs of the hinged-lid-box type. The use of this type of packet is particularly widespread throughout the world. The hinge-lid box is constructed from a blank made of thin cardboard for forming a bottom box part 10 and a lid 11, which is connected to the latter in a pivotable manner. A collar 12 arranged within the hinge-lid box comprises a separate blank. The packaging machine can be adjusted and/or converted for producing hinge-lid boxes or hinge-lid packs in different, in this case three, configurations (FIG. 9), specifically a standard pack 13 with cross-sectionally right-angled (upright) pack edges, a round-edged pack 14 with rounded pack edges and an octagonal pack with beveled pack edges. During the production of hinge-lid boxes, the packaging machine is supplied with prefabricated blanks in stacks. The stacks of blanks are held ready in a blank magazine 16. The blanks are removed individually from the underside of the latter and fed to a folding turret 17 via a blank path (EP 0 667 230). Said folding turret is of plate-like design (FIG. 2, FIG. 3) and is positioned at the top end of an upright, driven shaft 18. The folding turret 17 is provided, along the circumference, with a number of pockets 19 into which in each case one blank and, subsequently, the pack contents—cigarette blocks—are introduced. The pockets 19 are adapted to the shape of the hinge-lid boxes, that is to say are configured in a manner corresponding to the packs 13, 14, 15. In the case of this type of pack being changed over, the entire folding turret 17 is exchanged, that is to say replaced by a folding turret 17 with pockets 19 adapted to the respective type of pack. For this purpose, the folding turret 17 is fastened in a releasable manner on the shaft 18, that is to say by means of screws 20 in the region of a carrying flange 21. By virtue of the screws 20, which are arranged all the way round, being released, the folding turret 17 can be removed and a different folding turret can be fastened. For a precise adjustment of the relative position of the folding turret 17, use is made of an adjusting pin 22 on the shaft 18, or on the carrying flange 21, for entering into a precisely positioned bore of the folding turret 17. (Contactless) sensors, in the present case (two) initiators 23, 24, check as to whether the packaging machine has been correctly equipped with the necessary folding turret 17. Said initiators are assigned in each case to a contact protrusion, in the present case one of two contact rings 25, 26 on the underside of the folding turret 17. With the aid of this monitoring system, it is possible to detect and/or indicate centrally, that is to say via a central (machine) control means 27, whether the correct folding turret 17 for the respective type of pack has been installed. In the case of three different folding turrets, the arrangement may be selected such that either one or the other or both of the contact rings 25, 26 is/are fitted and a corresponding control signal can be derived therefrom. One special feature is brought to bear in respect of another subassembly for shaping or prefolding blanks 28. This is a blank or shaping subassembly (EP 0 667 230) for preshaping round edges during the production of round-edged packs 14 (FIG. 4, FIG. 5, FIG. 6). The subassembly is arranged as standard in the packaging machine, that is to say in the region of the blank path for feeding the blanks 28 from the blank magazine 16 to the folding turret 17. The blanks 28 are positioned, in the region of a shaping station, beneath a shaping body 29 with rounded (or beveled) longitudinal borders. Shaping tools, namely shaping rollers 30, 31, grip folding tabs of the blank 28 which project laterally beyond the shaping body 29, and shape the same by moving upward around the contour of the shaping body 29. The shaping rollers 30, 31 are moved by a specifically designed gear mechanism 32 (EP 0 667 230). The special feature, then, consists in uncoupling the gear mechanism 32 from its drive and thus bringing the shaping rollers 30, 31 to a standstill as the machine continues running. The arrangement is such that, during the production of standard packs 13 or octagonal packs 15, the shaping rollers 30, 31 remain in a position according to FIG. 5. The shaping rollers 30, 31, but also actuating arms and lateral aligning elements, are brought to a standstill in a position beneath the movement path of the blank 28. Accordingly, the planar, non-folded blank 28 runs through the shaping station without the processing elements, namely the shaping rollers 30, 31 becoming active. The gear mechanism 32 is connected to a drive via an actuating element, that is to say via a push rod 33, to be precise to a shaft 35 via a further intermediate gear mechanism 34. Said shaft is preferably connected to the central machine drive and circulates continuously. The intermediate gear mechanism 34 transmits drive movements, via the push rod 33, to the gear mechanism 32 of the shaping tools. If the latter are to be rendered inactive, disconnection takes place in the region of the intermediate gear mechanism 34. A cam plate 36 is mounted on the shaft 35. This cam plate actuates, via a cam roller 37, a pivoting arm 38 which, in turn, is connected to an actuating shaft 40 mounted in a housing component 39. The actuating shaft transmits the drive to a pivoting lever 41 which, for its part, is connected to the push rod 33 via a spherical head 42. The gear mechanism 32 is disconnected by virtue of the actuating shaft 40 being uncoupled from subsequent gear-mechanism parts. That end of the actuating shaft which is remote from the pivoting arm 38 is connected to the pivoting lever 41 via a coupling which can be operated from the outside. Said pivoting lever is fitted on an axially displaceable sleeve 43, which is displaced axially on the actuating shaft 40 for coupling and disconnection purposes. Provided for this purpose is an adjusting element, that is to say an adjusting wheel 44 that is fitted at the free end. This can be actuated by rotation from the outside, manually or using a suitable tool. The adjusting wheel 44 is mounted on a carrying part, that is to say on a threaded component 45 which is connected to the end of the actuating shaft 40. By virtue of rotation, the adjusting wheel 44 is thus adjusted out of one end position, that is to say the coupled position (FIG. 6, on the right) into the other, disconnection end position (FIG. 6, on the left). The adjusting wheel 44 is supported on an annular bearing 47 of the sleeve 43 via compression springs 46. The coupling which can be actuated by the adjusting wheel 44 comprises two coupling parts 48 and 49. The former is connected to the sleeve 43, and the latter coupling part is connected to the actuating shaft 40, to be precise at the end of the same. In the coupled position (FIG. 6, on the right), the coupling parts 48, 49 engage in a form-fitting manner one inside the other by way of protrusions and depressions. The rotary movement of the actuating shaft 40 is thus transmitted to the sleeve 43 and, from the latter, to the pivoting lever 41. For disconnection and coupling purposes, the sleeve 43 is thus displaced axially by the adjusting wheel 44. The actuating shaft 40 can continue running following disconnection (FIG. 6, on the left). It is also the case with this blank subassembly that a check is made of the operating position in respect of the pack which is to be produced. For this purpose, once again, two sensors, namely initiators 23, 24, are provided, a protrusion 50 on the sleeve 43 acting thereon. Depending on the position of this protrusion 50, one initiator 23, 24 or the other is activated. A corresponding signal is given to the central control means 27. FIG. 7 shows another processing subassembly, likewise for producing round-edged packs 14. It is also provided here that the subassembly is present as standard in the packaging machine and is set in operation or stopped independence on the pack which is to be produced. This subassembly is intended for preparing a blank for a collar 12. The blanks severed from a continuous web are fed to a collar subassembly corresponding to FIG. 7 and, in the region thereof, prepared in respect of the round edges which are to be produced, the round edges being provided between a collar front wall and corner side tabs. For this purpose, the collar subassembly has a stationary shaping body 51, which is positioned in the movement path of the collar 12 and has rounded contours on both sides. Projecting regions of the collar 12 for forming the collar side tabs are integrally formed by shaping tools, namely by rollers 52, 53, by virtue of the latter moving correspondingly on the lateral, rounded contours of the shaping body 51 (EP 0 667 232). The rollers 52, 53 are fitted on adjusting levers 54, 55. These are actuated in the manner described by a specific gear mechanism 56. The gear mechanism 56 contains a cam roller 57 which is driven in rotation. The latter, in turn, is moved via a further gear mechanism, namely a preliminary gear mechanism 58, by way of a central drive. During the production of a type of pack without round edges—the standard pack 13 or octagonal pack 15—the drive for the roller 52, 53 is brought to a standstill, to be precise with the rollers 52, 53 in a position beneath the shaping body 51 (dashed lines in FIG. 7). Disconnection takes place in the region of the preliminary gear mechanism 58. The cam roller 57 is driven by a gearwheel 59, which engages with an intermediate wheel 60. The latter, in turn, meshes with a drive wheel 61 of a central drive. The drive is disconnected by adjustment of the intermediate wheel 60, such that the latter disengages from the drive wheel 61. For this purpose, the intermediate wheel 60 is displaced axially into a position (dashed lines in FIG. 7) alongside the drive wheel 61. The connection to the gearwheel 59, which is dimensioned correspondingly in the axial direction, is maintained. In order to execute this displacement, the intermediate wheel 60 is fitted on a spindle, namely hollow spindle 62. The latter can be displaced axially in a carrying wall 63 of the machine framework. On one side, an actuating element 64 is connected to the hollow spindle 62. The actuating element 64 is adjusted axially by hand and is designed with a corresponding widened portion at the end. Connection between the actuating element 64 and the intermediate wheel 60 which is to be adjusted is such that rotary movements of the intermediate wheel 60 are not transmitted to the actuating element. For this purpose, the spindle of the intermediate wheel 60 is designed as hollow spindle 62, into which the actuating element 64 enters by way of a centering component 66. A claw-like connection 65 allows the transmission of axial forces, but permits relative rotary movements. Once again, two initiators 23, 24 are provided in order to check the correct position of the gear mechanism and/or of the coupling brought about by the pack which is to be produced. Said initiators are assigned to a thickened portion or a contact border 67 at the end of the hollow spindle 62. The latter has a corresponding length projecting through an opening in the carrying wall 63. Depending on the position of the hollow spindle 62, and thus of the intermediate wheel 60, the contact border 67 acts on one initiator 23, 24 or the other. The two examples according to FIGS. 4, 5 and 6, on the one hand, and according to FIG. 7, on the other hand, are provided with a securing means for the disconnected elements or gear-mechanism parts, with the result that these are locked in a certain position which is appropriate for operation of the packaging machine. In the case of the example of FIG. 6, the pivoting lever 41 is anchored in the inactive position by an arresting pin 68 in the housing component 39. In the case of the exemplary embodiment of FIG. 7, the arresting pin 68 is fitted on a housing wall and enters into a bore of the intermediate wheel 60 when the latter is located in the disconnected position. The elements or wheels which are to be fixed in certain relative positions are arrested by displacement relative to a stationary arresting pin 68 or the like. FIG. 8 shows a particular example in which it is necessary to remove elements arranged on a rotating shaft or spindle for certain types of packs. The procedure here is such that the relevant spindle 69, 70, with the element arranged thereon, is removed wholly or partially on account of a specifically designed coupling. The subassembly according to FIG. 8 is used in conjunction with the production of round-edged packs 14. A continuous material web 71 is processed by tools. In the case of the example shown, the material web 71 serves for producing the collars 12. Accordingly, the subassembly, in the production sequence, is arranged upstream of the collar subassembly shown in FIG. 7. The subassembly here is used for producing stamped scores in the region of the round edges which are to be produced. For this purpose, rotating scoring tools, namely corresponding scoring rollers 72, 73, are positioned on both sides in each case, that is to say beneath and above the material web 71. The scoring rollers 72, 73 are driven. The bottom spindle 70 is, in functional terms, a shaft which is driven by a driving gearwheel 74. Via the material web 71, the top scoring rollers 72 are likewise driven, with corresponding rotation of the top spindle 69. The ends of the spindles 69, 70 and/or of the (bottom) shaft are mounted for rotation in lateral housing walls 75, 76. A section of the spindles 69, 70 in which the two scoring rollers 72, 73 are fitted, namely a spindle component 77, 78, can be removed (with the scoring rollers 72, 73). For this purpose, the ends of the spindle components 77, 78 are seated in mounts or lateral carrying components 79, 80 as an extension of the spindles 69, 70. The carrying components 79, 80 are mounted in a rotatable manner in each case in the housing walls 75, 76 and have conical depressions on the sides which are directed toward the spindle components 77, 78. Correspondingly conically designed coupling ends 81, 82 of the spindle components 77, 78 enter in a form-fitting manner into said depressions. For coupling and uncoupling the spindle components 77, 78 in respect of the coupling ends 81, 82, the conical coupling ends 81 in each case can be displaced axially on one side of the spindle components 77, 78, to be precise counter to the loading of a spring 83. The displaceable coupling ends 81, 82 are secured against rotation by a slot guide. By virtue of being displaced from the position which is shown by solid lines in FIG. 8 into the position which is indicated by dashed lines, the conical coupling ends 81 pass out of the depressions of the carrying components 79, 80, with the result that the spindle components 77, 78 are freed. These may then be removed with the scoring rollers 72, 73. During operation, that is to say during use of the scoring rollers 72, 73, the spindle components 77, 78 are connected in a non-rotatable manner to the carrying components 79, 80, to be precise by a transversely directed carry-along pin 84. Initiators 23, 24 are provided in order to check the presence of the two spindle components 77, 78 (or the absence of these parts), the initiators interacting with a thickened portion 85 in each case on the outside of the spindle components 77, 78. In particular, the thickened portion 85 is provided at the displaceable coupling end 81. Using two initiators 23, 24 in conjunction with a single thickened portion 85 also ensures that an incorrect position of the displaceable coupling end 81 is established by the initiator 24. A functional diagram is illustrated schematically in FIG. 9. By way of the central control means 27, the operator can detect whether the machine has been converted completely to a new type of pack which is to be produced. For this purpose, the type of pack which is to be produced is input into the control means 27. Thereafter, the subassemblies are changed over and/or exchanged as necessary. In the case of the example of FIG. 9, three subassemblies or elements are shown by way of example, that is to say the folding turret 17, the shaping subassembly for round edges according to FIG. 4 and the shaping subassembly for collar blanks according to FIG. 7. The control means 27 signals to the operator when all the subassemblies which are to be exchanged or changed over have been set up for the respective type of pack. The schematic illustrations 86 give a symbolic illustration of the respectively associated functions. List of Designations 10 Box part 11 Lid 12 Collar 13 Standard pack 14 Round-edged pack 15 Octagonal pack 16 Blank magazine 17 Folding turret 18 Shaft 19 Pocket 20 Screw 21 Carrying flange mechanism 22 Adjusting pin 23 Initiator 24 Initiator 25 Contact ring 26 Contact ring 27 Control means 28 Blank 29 Shaping body 30 Shaping roller 31 Shaping roller 32 Gear mechanism 33 Push rod 34 Intermediate gear mechanism 35 Shaft 36 Cam plate 37 Cam roller 38 Pivoting arm 39 Housing component 40 Actuating shaft 41 Pivoting lever 42 Spherical head 43 Sleeve 44 Adjusting wheel 45 Threaded component 46 Compression spring 47 Annular bearing 48 Coupling part 49 Coupling part 50 Protrusion 51 Shaping body 52 Roller 53 Roller 54 Adjusting lever 55 Adjusting lever 56 Gear mechanism 57 Cam roller 58 Preliminary gear mechanism 59 Gear wheel 60 Intermediate wheel 61 Drive wheel 62 Hollow spindle 63 Carrying wall 64 Actuating element 65 Connection 66 Centering component 67 Contact border 68 Arresting pin 69 Spindle 70 Spindle 71 Material web 72 Scoring roller 73 Scoring roller 74 Driving gearwheel 75 Housing wall 76 Housing wall 77 Spindle component 78 Spindle component 79 Carrying component 80 Carrying component 81 Coupling end 82 Coupling end 83 Spring 84 Carry-along pin 85 Thickened portion 86 Illustration

20040609

20061212

20050728

66451.0

DESAI, HEMANT

PACKAGING MACHINE FOR CIGARETTES

UNDISCOUNTED

ACCEPTED

ACCEPTED

Gastrokines and derived peptides including inhibitors

A novel group of gastrokines called Gastric Antrum Mucosal Protein is characterized. A member of the group is designated AMP-18. AMP-18 genomic DNA, cDNA and the AMP-18 protein are sequenced for human, mouse and pig. The AMP-18 protein and active peptides derived from it are cellular growth factors. Surprisingly, peptides capable of inhibiting the effects of the complete protein, are also derived from the AMP-18 protein. Control of mammalian gastro-intestinal tissues growth and repair is facilitated by the use of the proteins, making the proteins candidates for therapies.

1. A group of isolated homologous cellular growth stimulating proteins designated gastrokines, said proteins produced by gastric epithelial cells and comprising an amino acid sequence selected from the group consisting of VKE(K/Q)KXXGKGPGG(P/A)PPK, (SEQ ID NO: 10) VKE(K/Q)KLQGKGPGG(P/A)PPK, (SEQ ID NO: 25) or VKE(K/Q)KGKGPGG(P/A)PPK. (SEQ ID NO: 26) 2. An isolated protein from the group of claim 1, said protein further characterized as comprising an amino acid sequence as in FIG. 8, present in pig gastric epithelia in a processed form lacking the 20 amino acids which constitute a signal peptide sequence, having 165 amino acids and an estimated molecular weight of approximately 18 kD as measured by polyacrylamide gel electophoresis, said protein capable of being secreted. 3. A protein from the group of claim 1, further characterized as comprising an amino acid sequence as in FIG. 3, said sequence deduced from a human cDNA. 4. A protein from the group of claim 1, further characterized as comprising an amino acid sequence as in FIG. 6, said sequence predicted from mouse RNA and DNA. 5. A growth stimulating peptide derived from a protein of claim 1. 6. A modified peptide produced by the method comprising the following steps: (a) eliminating major protease sites in an unmodified peptide amino acid sequence by amino acid substitution or deletion in the unmodified peptide derived from a protein of claim 1; and (b) optionally introducing amino acid analogs of amino acids in the unmodified peptide. 7. A synthetic growth stimulating peptide, having a sequence of amino acids from positions 78 to 119 as shown in FIG. 3. 8. The synthetic growth stimulating peptide of claim 7, said peptide having a 30 sequence of amino acids from position 97 to position 117 as shown in FIG. 3. 9. The synthetic growth stimulating peptide of claim 7, said peptide having a sequence of amino acids from position 97 to position 121 as shown in FIG. 3. 10. The synthetic growth stimulating peptide of claim 7, said peptide having a sequence of amino acids from position 104 to position 117 as shown in FIG. 3. 11. An isolated bioactive peptide comprising a sequence selected from the group consisting of KKLQGKGPGGPPPK, (SEQ ID NO: 11) LDALVKEKKLQGKGPGGPPPK, (SEQ ID NO: 12) or LDALVKEKKLQGKGPGGPPPKGLMY. (SEQ ID NO: 13) 12. An antibody to a protein of the group of claim 1, said antibody recognizing an epitope within a peptide of the protein that has an amino acid sequence from position 78 to position 119 as in FIG. 3. 13. An isolated genomic DNA molecule with the nucleotide sequence of a human as shown in FIG. 1. 14. An isolated cDNA molecule encoding a human protein, said protein having the amino acid sequence as shown in FIG. 3. 15. A method to stimulate growth of epithelial cells in the gastrointestinal tract of mammals, said method comprising: (a) contacting the epithelial cells with a composition comprising a protein from the group of claim 1 or a peptide derived from a protein of claim 1, and (b) providing environmental conditions for stimulating growth of the epithelial cells.

BACKGROUND A novel group of Gastric Antrum Mucosal Proteins that are gastrokines, is characterized. A member of the gastrokine group is designated AMP-18. AMP-18 genomic DNA, and cDNA molecules are sequenced for human and mouse, and the protein sequences are predicted from the nucleotide sequences. The cDNA molecule for pig AMP-18 is sequenced and confirmed by partial sequencing of the natural protein. The AMP-18 protein and active peptides derived from its sequence are cellular growth factors. Surprisingly, peptides capable of inhibiting the effects of the complete protein, are also derived from the AMP-18 protein sequence. Control of mammalian gastro-intestinal tissues growth and repair is facilitated by the use of the protein or peptides, making the protein and the derived peptides candidates for therapies. Searches for factors affecting the mammalian gastro-intestinal (GI) tract are motivated by need for diagnostic and therapeutic agents. A protein may remain part of the mucin layer, providing mechanical (e.g., lubricant or gel stabilizer) and chemical (e.g against stomach acid, perhaps helping to maintain the mucus pH gradient and/or hydrophobic barrier) protection for the underlying tissues. The trefoil peptide family has been suggested to have such general cytoprotectant roles (see Sands and Podolsky, 1996). Alternatively, a cytokine-like activity could help restore damaged epithelia. A suggestion that the trefoil peptides may act in concert with other factors to maintain and repair the epithelium, further underlines the complexity of interactions that take place in the gastrointestinal tract (Podolsky, 1997). The maintenance of the integrity of the GI epithelium is essential to the continued well-being of a mammal, and wound closing after damage normally occurs very rapidly (Lacy, 1988), followed by proliferation and differentiation soon thereafter to reestablish epithelial integrity (Nusrat et al., 1992). Thus protection and restitution are two critical features of the healthy gastrointestinal tract, and may be important in the relatively harsh extracellular environment of the stomach. Searches for GI proteins have met with some success. Complementary DNA (cDNA) sequences to messenger RNAs (mRNA) isolated from human and porcine stomach cells were described in the University of Chicago Ph.D. thesis “Characterization of a novel messenger RNA and immunochemical detection of its protein from porcine gastric mucosa,” December 1987, by one of the present inventors working with the other inventors. However, there were several cDNA sequencing errors that led to significant amino acid changes from the AMP-18 protein disclosed herein. The protein itself was isolated and purified only as an aspect of the present invention, and functional analyses were performed to determine utility. Nucleic acid sequences were sought. SUMMARY OF THE INVENTION A novel gene product designated Antrum Mucosal Protein 18 (“AMP-18”) is a gastrokine. The protein was discovered in cells of the stomach antrum mucosa by analysis of cDNA clones obtained from humans, pigs, and mice. The protein is a member of a group of cellular growth factors or cytokines, more specifically gastrokines. The AMP-18 cDNA sequences predict a protein 185 amino acids in length for both pig and man. The nucleotide sequences also predict a 20-amino acid N-terminal signal sequence for secreted proteins. The cleavage of this N-terminal peptide from the precursor (preAMP-18) was confirmed for the pig protein; this cleavage yields a secreted protein 165 amino acids in length and ca. 18,000 Daltons (18 kD) in size. Human and mouse genomic DNA sequences were also obtained and sequenced. A human genomic DNA was isolated in 4 overlapping fragments of sizes 1.6 kb, 3 kb, 3.3 kb and 1.1 kb respectively. The mouse genomic DNA sequence was isolated in a single BAC clone. The gastrokine designated AMP-18 protein is expressed at high levels in cells of the gastric antrum. The protein is barely detectable in the rest of the stomach or duodenum, and was not found, or was found in low levels, in other body tissues tested. AMP-18 is synthesized in lumenal surface mucosal cells, and is secreted together with mucin granules. Compositions of AMP-18 isolated from mouse and pig antrum tissue stimulate growth of confluent stomach, intestinal, and kidney epithelial cells in culture; human, monkey, dog and rat cells are also shown to respond. This mitogenic (growth stimulating) effect is inhibited by specific antisera (antibodies) to AMP-18, supporting the conclusion that AMP-18, or its products, e.g. peptides derived from the protein by isolation of segments of the protein or synthesis, is a growth factor. Indeed, certain synthetic peptides whose amino acid sequences represent a central region of the AMP-18 protein also have growth-factor activity. The peptides also speed wound repair in tissue culture assays, indicating a stimulatory effect on cell migration, the process which mediates restitution of stomach mucosal injury. Thus, the protein and its active peptides are motogens. Unexpectedly, peptides derived from sub-domains of the parent molecule can inhibit the mitogenic effect of bioactive synthetic peptides and of the intact, natural protein present in stomach extracts. There are 3 activities of the gastrokine proteins and peptides of the present invention. The proteins are motogens because they stimulate cells to migrate. They are mitogens because they stimulate cell division. They function as cytoprotective agents because they maintain the integrity of the epithelium (as shown by the protection conferred on electrically resistant epithelial cell layers in tissue culture treated with damaging agents such as oxidants or non-steroidal anti-inflammatory drugs NSAIDs). The synthesis of AMP-18 is confined to lumenal mucosal lining epithelial cells of the gastric antrum of humans and other mammals. Inside cells the protein is co-localized with mucins in secretion granules, and appears to be secreted into the mucus overlying the apical plasma membrane. Recombinant human AMP-18 in E. coli exerts its mitogenic effect at a concentration an order of magnitude lower than growth-promoting peptides derived from the center of the mature protein. Peptide 77-97, the most potent mitogenic peptide, is amino acid sequence-specific AMP peptides appears to be cell-type specific as it does not stimulate growth of fibroblasts or HeLa cells. Mitogenesis by specific AMP peptides appears to be mediated by a cell surface receptor because certain peptides that are not active mitogens can competitively inhibit, in a concentration-dependent manner, the growth-stimulating effects of peptide 58-99 and antrum cell extracts. AMP-18 and its derived peptides exhibit diverse effects on stomach and intestinal epithelial cells which suggest they could play a critical role in repair after gastric mucosal injury. These include cytoprotection, mitogenesis, restitution, and maturation of barrier function after oxidant-and/or indomethacin-mediated injury. Possible mechanisms by which AMP-18 or its peptide derivatives mediate their pleiotropic effects include stimulation of protein tyrosine kinase activity, prolongation of heat shock protein expression after cell stress, and enhanced accumulation of the tight junction-associated protein ZO-1 and occludin. Certain of these physiological effects can occur at concentrations that are relatively low for rhAMP-18 (<50 nM) compared to the concentrations of other gastric peptide mediators such as trefoil peptides or the α-defensin, cryptdin 3 (>100 μM). Immunoreactive AMP-18 is apparently released by cells of the mouse antrum after indomethacin gavage, and by canine antrum cells in primary culture exposed to forskolin, suggest that the protein is subject to regulation. These results imply that AMP-18 could play a role in physiological and pathological processes such as wound healing in the gastric mucosal epithelium in vivo. The invention relates a group of isolated homologous cellular growth stimulating proteins designated gastrokines, that are produced by gastric epithelial cells and include the consensus amino acid sequence VKE(K/Q)KXXGKGPGG(P/A)PPK (SEQ ID NO: 10) wherein XX can be LQ or absent (which results in SEQ ID NOS: 25 and 26, respectively). An isolated protein of the group has an amino acid sequence as shown in FIG. 8. The protein present in pig gastric epithelia in a processed form lacking the 20 amino acids which constitute a signal peptide sequence, has 165 amino acids and an estimated molecular weight of approximately 18 kD as measured by polyacrylamide gel electophoresis. Signal peptides are cleaved after passage through endoplasmic reticulum (ER). The protein is capable of being secreted. The amino acid sequence shown in FIG. 3 was deduced from a human cDNA sequence. An embodiment of the protein is shown with an amino acid sequence as in FIG. 6, a sequence predicted from mouse RNA and DNA. A growth stimulating (bioactive) peptide may be derived from a protein of the gastrokine group. Bioactive peptides rather than proteins are preferred for use because they are smaller, consequently the cost of synthesizing them is lower than for an entire protein. In addition, a modified peptide may be produced by the following method: (a) eliminating major protease sites in an unmodified peptide amino acid sequence by amino acid substitution or deletion; and/or (b) introducing into the modified amino acid analogs of amino acids in the unmodified peptide. An isolated protein of the present invention include an amino acid sequence as in FIG. 8, present in pig gastric epithelia in a processed form lacking the 20 amino acids which constitute a signal peptide sequence, having 165 amino acids and an estimated molecular weight of approximately 18 kD as measured by polyacrylamide gel electophoresis, said protein capable of being secreted. A protein of the present invention includes an amino acid sequence as in FIG. 3, a sequence deduced from a human cDNA. A protein of the present invention includes an amino acid sequence as in FIG. 6, a sequence predicted from mouse RNA and DNA. Embodiments of the present invention include a synthetic growth stimulating peptide, having a sequence of amino acids from positions 78 to 119 as shown in FIG. 3; having a sequence of amino acids from position 97 to position 117 as shown in FIG. 3, or a sequence of amino acids from position 97 to position 121 as shown in FIG. 3, or a sequence of amino acids from position 104 to position 117 as shown in FIG. 3. An antibody to a protein of the present invention recognizies an epitope within a peptide of the protein that has an amino acid sequence from position 78 to position 119 as in FIG. 3. An aspect of the invention also is an isolated genomic DNA molecule with the nucleotide sequence of a human as shown in FIG. 1 and an isolated cDNA molecule encoding a human protein with the amino acid sequence as shown in FIG. 3. The invention includes a method to stimulate growth of epithelial cells in the gastrointestinal tract of mammals including the steps of: (a) contacting the epithelial cells with a composition comprising a protein of the present invention or a peptide derived from the protein; and (b) providing environmental conditions for stimulating growth of the epithelial cells. An embodiment of an isolated bioactive peptide has one of the following sequences: KKLQGKGPGGPPPK, (SEQ ID NO: 11) LDALVKEKKLQGKGPGGPPPK, (SEQ ID NO: 12) LDALVKEKKLQGKGPGGPPPKGLMY. (SEQ ID NO: 13) Embodiments of inhibitors are KKTCIVHKMKK (SEQ ID NO: 14) or KKEVMPSIQSLDALVKEKK. (SEQ ID NO: 15) (see also Table 1) Antibodies to the protein product AMP-18 encoded by the human cDNA expressed in bacteria were produced in rabbits; these antibodies reacted with 18 kD antrum antigens of all mammalian species tested (human, pig, goat, sheep, rat and mouse), providing a useful method to detect gastrokines. An antibody to a protein of the group recognizes an epitope within a peptide of the protein that includes an amino acid sequence from position 78 to position 119 as in FIG. 3. The invention is also directed to an isolated genomic DNA molecule with the nucleotide sequence of a human as shown in FIG. 1 and an isolated cDNA molecule encoding a human protein, that the nucleotide sequence as shown in FIG. 2. Another aspect of the invention is an isolated DNA molecule having the genomic sequence found in DNA derived from a mouse, as shown in FIG. 4. Genomic DNA has value because it includes regulatory elements for gastric expression of genes, consequently, the regulatory elements can be isolated and used to express other gene sequences than gastrokines in gastric tissue. An aspect of the invention is a method to stimulate growth of epithelial cells in the gastrointestinal tract of mammals. The method includes the steps of: (a) contacting the epithelial cells with a composition comprising a gastrokine protein or a peptide derived from a protein of the group; and (b) providing environmental conditions for stimulating growth of the epithelial cells. A method to inhibit cellular growth stimulating activity of a protein of the group includes the steps of: (a) contacting the protein with an inhibitor; and (b) providing environmental conditions suitable for cellular growth stimulating activity of the protein. The inhibitor may be an antibody directed toward at least one epitope of the protein, e.g. an epitope with an amino acid sequence from position 78 to position 119 of the deduced amino acid sequence in FIG. 3 or an inhibitor peptide such as those in Table 1. A method of testing the effects of different levels of expression of a protein on mammalian gastrointestinal tract epithelia, includes the steps of: (a) obtaining a mouse with an inactive or absent gastrokine protein; (b) determining the effects of a lack of the protein in the mouse; (c) administering increasing levels of the protein to the mouse; and (d) correlating changes in the gastrointestinal tract epithelia with the levels of the protein in the epithelia. Kits are contemplated that will use antibodies to gastrokines to measure their levels by quantitative immunology. Levels may be correlated with disease states and treatment effects. A method to stimulate migration of epithelial cells after injury to the gastrointestinal tract of mammals, includes the steps of: (a) contacting the epithelial cells with a composition comprising a peptide derived from the protein; and (b) providing environmental conditions allowing migration of the epithelial cells. A method for cytoprotection of damaged epithelial cells in the gastrointestinal tract of mammals, includes the following steps: (a) contacting the damaged epithelial cells with a composition including a protein of the gastrokine group or a peptide derived from the protein; and (b) providing environmental conditions allowing repair of the epithelial cells. The damaged cells may form an ulcer. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a human genomic nucleotide sequence (SEQ ID NO: 1) of a pre-gastrokine; sequence features were determined from cDNA and PCR of human genomic DNA amph-ge8.seq Length: 7995 predicted promoter: 1405; exon 1: 1436-1490; exon 2: 4292-4345; exon 3: 4434-4571; exon 4: 5668-5778; exon 5: 6709-6856; exon 6: 7525-7770; polyA site: 7751. FIG. 2 is a human cDNA sequence (SEQ ID NO: 2); the DNA clone was obtained by differential expression cloning from human gastric cDNA libraries. FIG. 3 is a human preAMP-18 protein sequence (SEQ ID NO: 3) predicted from a cDNA clone based on Powell (1987) and revised by the present inventors; N-21 is the expected N-terminus of the mature protein. FIG. 4 is a mouse preAMP-18 sequence (SEQ ID NO: 4) determined from RT-PCR of mRNA and PCR of BAC-clones of mouse genomic DNA sequences: predicted promoter: 1874 experimental transcription start site: 1906 translation initiation site: 1945 CDS 1: 1906-1956; CDS 2: 3532-3582; CDS 3: 3673-3813; CDS 4: 4595-4705; CDS 5: 5608-5749; CDS 6: 6445-6542; polyA site: 6636. FIG. 5 is a mouse cDNA sequence (SEQ ID NO: 5) for preAMP-18. FIG. 6 is mouse preAMP-18 amino acid sequence (SEQ ID NO: 6); RT-PCR performed on RNA isolated from mouse stomach antrum: Y-21 is the predicted N-terminus of the mature protein; the spaces indicated by . . . mean there are no nucleotides there to align with other sequences in FIG. 11. FIG. 7 is a cDNA expressing porcine AMP-18 (SEQ ID NO: 7). FIG. 8 is pig pre-gastrokine (pre-AMP-18) protein sequence (SEQ ID NO: 8) predicted from a cDNA clone based on Powell (1987) D-21 is the N-terminus of the mature protein-confirmed by sequencing of the protein isolated from pig stomach. FIG. 9 is a comparison between the amino acid sequences of human (SEQ ID NO: 3) versus pig (SEQ ID NO: 8) pre-gastrokine. FIG. 10 shows a computer-generated alignment comparison of human (SEQ ID NO: 3), pig (SEQ ID NO: 8) and mouse (SEQ ID NO: 6) predicted protein sequences determined from sequencing of cDNA clones for human and pig AMP-18, and by polymerase chain reaction of mouse RNA and DNA using preAMP-18 specific oligonucleotide primers; in each case the first 20 amino acids constitute the signal peptide, cleaved after passage through the endoplasmic reticulum membrane. FIG. 11 shows the effect of porcine gastric antrum mucosal extract, human AMP peptide 77-97 (of the mature protein, same as peptide 97-117 of human precursor protein; Table 1), and EGF on growth of gastric epithelial cells; AGS cells were grown in DMEM containing fetal bovine serum (5%) in 60-mm dishes; different amounts of pig antrum extract, HPLC purified peptide 77-97, and/or EGF were added; four days later the cells were dispersed and counted with a hemocytometer; antrum extract and peptides each stimulated cell growth in a concentration-dependent manner; the bar graph shows that at saturating doses, peptide 77-97 (8 μg/ml) or EGF (50 ng/ml) was mitogenic; together they were additive suggesting that the two mitogens act using different receptors and/or signaling pathways; anti-AMP antibodies inhibited the antrum extract but did not inhibit peptide 77-97. FIG. 12 shows the structure of the human and mouse preAMP-18 genes; the number of base pairs in introns are shown above the bars; exons are indicated E1-E6 and introns 11-15; there are minor differences in intron length. FIG. 13 shows Left panel. Amino acid sequence of recombinant human AMP-18 (residues 21 to 185 of SEQ ID NO: 3) expressed in E. coli. Note the His6-tag (SEQ ID NO: 16) within a 12 amino acid domain (SEQ ID NO: 9) at the N-terminus that has replaced the putative hydrophobic signal peptide. Right panel. Effect of rhAMP-18 and AMP peptide 77-97 on growth of confluent cultures of IEC-18 cells. Although maximal growth stimulation is similar, the half-maximal concentration (K1/2) for rhAMP-18 (˜30 nM) is about an order of magnitude lower than for the peptide (˜300 nM). FIG. 14 shows Left Panel. Alignment of the open reading frames (ORF) derived from the cDNA clones for AMP-18 for the precursor proteins of human (SEQ ID NO: 3) and pig (SEQ ID NO: 8) antrum. Similarity was 78.50% and identity was 75.27%. Computer analysis was carried out using the GAP and PEPTIDESTRUCTURE programs of the Wisconsin Package (GCG). Right PaneL Model of the predicted secondary structure for the human preAMP ORF. Attention is drawn to the asparagine rich N-terminal domain, the short tryptohopan (W)-rich and glycine-proline (GP) regions, and the conserved positions of the four cysteine (C) residues. Possible amphipathic helices are indicated. DETAILED DESCRIPTION OF THE INVENTION 1. General A novel gene product, a member of a group of gastrokines, was detected in mammalian gastric antrum mucosal by a differential screen of cDNA libraries obtained from different regions of the pig stomach. The cDNA sequence predicted a protein of 185 amino acids including a signal peptide leader sequence. A cDNA was also isolated from a human library. The predicted amino acid sequence identity between pig and human in 76.3%. The sequences predicted a 20 amino acid signal peptide characteristic for secreted proteins. The cleavage of this N-terminal signal peptide was confirmed for the pig protein. Antibodies to the product of the human cDNA expressed in bacteria were raised in rabbits; these antibodies reacted with 18-20 kD antrum antigens of all mammalian species tested (pig, goat, sheep, rat and mouse). In agreement with mRNA levels, the AMP-18 protein is expressed at high levels only in the gastric antrum; it is barely detectable in the rest of the stomach or duodenum, and was not detected in a variety of other tissues tested. AMP-18 is synthesized in the lumenal surface mucosal cells; immuno-electron microscopy locates AMP-18 in the secretion granules of these cells. Partially purified AMP-18 preparations from mouse and pig antrum tissue are mitogenic to confluent stomach and kidney epithelial cells in culture; this effect is inhibited by the specific antisera, implying that AMP-18, or its products, is a growth factor. AMP-18 is likely secreted with the mucus and functions, perhaps as peptide derivatives, within the mucus gel to maintain epithelial integrity directly, and possibly to act against pathogens. In view of the growth factor activity observed on epithelial cell lines in culture, it is likely that AMP-18 or its peptide derivative(s) serves as an autocrine (and possible paracrine) factor for the gastric epithelium. The function of AMP-18 may not be simply as a mitogen, but in addition it may act as differentiation factor providing the signals for replenishment of the mature lumenal surface cells. The AMP-18 protein or its derivatives are likely important to the normal maintenance of the highly dynamic gastric mucosa, as well as playing a critical role in the restitution of the antrum epithelium following damage. This protein has not been characterized in any publication, however, related nucleic acid sequences have been reported as ESTs and as a similar full length gene. Limitations of EST data cannot yield information on starting sequences, signal peptides, or sequences in the protein responsible for bioactivity, as disclosed in the present invention. A number of these ESTs have been reported for mammalian stomach cDNAs, but related ESTs have also been reported or pancreas and also pregnant uterus libraries. Although expression of AMP-18 RNA in these other tissues appears to be low (as indicated for pancreas by PCR analysis), these results suggest that this growth factor may have broader developmental and physiological roles than that implied by the specific high levels of expression found for the stomach. The AMP-18 protein appears to be expressed at the surface of the cellular layers of the gastrointestinal (GI) tract. The expressing cells may be releasing stored growth factor where needed—in the crypts and crevices of the GI tract where cellular repair is needed due to surface damage. AMP-18 may act on the mucosal, apical surfaces of the epithelial cells, collaborating with prostaglandins and other growth factors that operate via basolateral cell surface receptors on the serosal side. The protein or its derivatives are likely important for the normal maintenance of the highly dynamic gastric mucosa, in face of the mechanical stress and high acidity of the stomach. AMP-18 may play a critical role in the repair of the stomach epithelium following damage by agents such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), or pathogens, in particular Heliobacter pylori, which predominantly infects the antrum and is a causative agent of gastric ulcers and possibly cancers. 2. Bioactivity A synthetic peptide (42 amino acids, a “42-mer”) representing a central region of the AMP-18 amino acid sequence also has growth factor activity, which is inhibited by specific antisera; some related shorter peptides also have stimulatory activity, while others can inhibit the activity of the 42-mer. This result suggests that a saturatable epithelial receptor exists for AMP-18, and opens direct avenues to analyzing the bioactive regions of the protein and identifying the putative receptor(s). Because AMP-18 does not resemble in structure any known cytokine or cytoprotectant protein (such as the trefoil peptides), the analysis of the interactions of the protein, and its active and inhibitory related peptides, with cells offers the opportunity to reveal novel molecular interactions involved in cell growth control. BSC-1 cell growth was stimulated by gel-fractionated porcine antrum extract; porcine extract protein (250 μg) was loaded into each of 2 lanes and subjected to electrophoresis in a polyacrylamide gel (12.5%); the 5 thin slices (2-3 mm) from each area between Mr 14 kDa and 21.5 kDa were cut from the experimental lanes. Each pair of slices was placed in a silanized microfuge tube with 2001 μl sterile PBS, 3% acetonitrule and 1% BSA, and macerated; proteins were eluted from the gel for 18 hr at 22° C. with vigorous shaking; the samples were then microcentrifuged and a sample of a supernatant was added to a confluent culture of BSC-1 cells; the number of cells was counted 4 days later; maximal growth stimulation was observed in cultures receiving extracts eluted from gel slices corresponding to a Mr of 18 kDa; antisera to recombinant human AMP-18 added to the culture medium completely inhibited growth stimulation by the 18 kDa fraction (+Ab); values are means of 2 cultures; SE is less than 10% of the mean. The biological activity (mitogenic for epithelial cells in the gastro-intestinal tract) of the AMP-18 is located in the C-terminal half of the protein. The epitopic sequence(s) appear(s) to be immediately N-terminal to the mitogenic sequence. The biological activity that is a growth factor, is exhibited by a peptide comprising at least 42 amino acids from positions 78 to 119 of the full-length protein sequence (see Table 1). An antibody to this region blocked mitogenic activity. Although a peptide having an amino acid sequence of 104 to 117 had mitogenic activity, an antibody to this region did not block (inhibit) the activity. A peptide with an amino acid sequence from positions 97-117 has the same mitogenic activity as a peptide with the 42 amino acid sequence, but is less expensive to produce as a synthetic peptide. 3. Inhibition of Bioactivity Epithelial cell growth that was stimulated by murine or porcine antrum cell extract was blocked by rabbit antiserum to a complete, recombinant human AMP-18 precursor protein; confluent cultures of BSC-1 cells were prepared; murine or porcine antrum cell extract was prepared and its protein concentration was measured; cell extracts alone and with different dilutions of the antiserum, or antiserum alone (1:100 dilution was added to the culture medium, and the number of cells was counted 4 days later). Growth stimulation by murine antrum gastrokines was maximally inhibited by the antiserum (93%) at a dilution of 1:400, whereas stimulation by the porcine antrum protein extract was totally inhibited at a dilution of 1:100. Scored values were means for 3 cultures; standard error of the mean (SE) was less than 10% of the mean. Antibodies to the AMP-18 protein have diagnostic uses to determine different levels of the protein in the gastro-intestinal tract in vivo. Ulcers are likely to develop if less than normal levels of AMP-18 protein are present. Normal values are determined by technologies known to those of skill in the art, that is, obtaining representative samples of persons to be tested (age, sex, clinical condition categories) and applying standard techniques of protein quantitation. The effects of aspirin and indamethacin on AMP-18 levels are also useful to monitor deleterious levels of the drugs including the non-steroidal anti-inflammatory drugs (NSAIDs). Stomach cancer cell lines do not express the AMP-18 proteins at least by detection methods disclosed herein. 4. Genomic DNA Genomic AMP-18 DNA sequences have been cloned for human and mouse as a prelude to the analysis of the gene regulatory elements, which presumably determine the great differences in the levels of expression of the gene in tissues where the gene may be active. Upstream and downstream flanking sequences have been isolated from mouse genomic DNA preparatory to a gene knockout. The flanking genomic sequences likely determine the very different levels of expression of the gene in the stomach and few other tissues where it may be expressed. With the involvement of different regulatory elements, gastrokine genes could be expressed as a growth factor in other tissues. 5. Uses of Gastrokines of the Present Invention Because the AMP-18 protein and certain peptides derived from it can stimulate growth and wound repair by stomach and intestinal epithelial cells (as well as kidney) these gastrokine molecules are candidates for therapeutic agents to speed recovery of the injured GI tract following pharmacological interventions, radiotherapy, or surgery. In addition, the antibodies developed to gastrokines may be used in kits to measure the levels of AMP-18 protein or peptide in tissue of blood in diverse pathological states. These novel molecules have great therapeutic potential in the treatment of gastric ulcers, and inflammatory bowel disease, whereas new agents that inhibit its function could prove useful in the treatment of cancers of the GI tract. The stomach is not a congenial location for many bacteria, and those that can survive the acidity do not establish themselves there (Rotimi et al., 1990). It is of interest therefore that the antrum region is the favored site for the attachment, penetration and cytolytic effects of Helicobaccter pylori, an agent which infects a major proportion of the human population (>60% by the seventh decade) and has been associated with gastritis, gastric and duodenal ulcers (Goodwin et al., 1986; Blaser, 1987) and gastric adenocarcinomas (Nomura et al., 1991; Parsonnet et al., 1991). Thus as an epithelial cell growth factor, AMP-18 may act to ameliorate the damage caused by bacterial infiltration and cytolysis. Given the conjunction of the specific antrum expression of AMP-18 and the preferred site of binding of H. pylori, it is possible that the bacteria use AMP-18 as a tropic factor. H pylori attaches to cells of the antrum having fucose-containing mucin granules (Falk et al., 1993; Baczako et al., 1995). These granules also may contain AMP-18. Anti-microbial peptides have been found in the stomach of the amphibian Xenopus laevis (Moore et al., 1991). Some domains of the AMP-18 structure resemble that of the magainins, and possibly AMP-18 interacts with enteric bacteria. 6. Isolation of Pig AMP-18 Antisera against human AMP-18 protein were used to assist in the purification of the protein from extracts of pig antrum mucosa. Immunoaffinity methods applied to total tissue extracts have not proven very effective, but by using immunoblots to monitor cell-fractionation, gradient centrifugation and gel electrophoresis sufficient amounts of the pig 18 kDa polypeptide was purified to confirm by sequencing that the native N-terminus is the one predicted by cleavage of 20 amino acids from the N-terminus of the ORF precisely at the alanine-aspartate site anticipated for signal peptide removal. Despite the abundance of asparagine residues in the mature protein, none fit the consensus context characteristic of glycosylation. Fairly extensive regions of the protein may possess amphipathic helix forming propensity. The latter may represent units within the protein yielding bioactive peptides after processing. Using circular dichroism the synthetic peptide representing amino acids 126-143 in the human preAMP sequence (FIG. 3) is readily induced to become helical in moderate concentrations of trifluoroethanol conditions used to assess helix propensity for some bioactive peptides, including anti-microbial peptides of the magainin type (see, for example, Park et al., 1997). 7. Preparation of active recombinant human AMP-18 in E. coli A cDNA encoding human AMP-18 was designed in which the 20-amino acid hydrophobic signal peptide sequence was replaced with an N-terminal 12-amino acid peptide that included a stretch of 6 histidine residues (FIG. 13, left panel). Expression of this modified cDNA sequence was predicted to yield a 177-amino acid protein product (Mr 19, 653) that could be readily purified using Ni—NTA resin to bind the His6-tag (SEQ ID NO: 16). The cDNA sequence lacking the region coding for the N-terminal signal peptide (see FIG. 14) was amplified by PCR using oligonucleotides that provided suitable linkers for inserting the product into the BamH1 site of a QE30 expression vector (QIAGEN); the sequence of the recombinant vector was confirmed. The recombinant human (rh) AMP-18 engineered with the His6-tag (SEQ ID NO: 16) was subsequently expressed in E. coli cells. To harvest it, the bacteria were lysed and alquots of the soluble and insoluble fractions were subjected to SDS-PAGE followed by immunoblotting using the specific rabbit antiserum to the rhAMP-18 precursor. Very little of the expressed protein was detected in the soluble fraction of the lysate. Urea (6 M) was employed to release proteins from the insoluble fraction solubilize rhAMP-18 containing the His6-tag (SEQ ID NO: 16), and make it available to bind to the Ni2+-charged resing from which it was subsequently eluted with a gradient of imidazole (0 to 200 mM). The amount of eluted rhAMP-18 was measured using the BCA assay, and the appearance of a single band at the predicted size of 19-20 kD was confirmed by SDS-PAGE followed by immunoblotting. To determine if eluted rhAMP-18 renatured to assume a structure that was mitogenic, aliquots of the eluate (following removal of urea and imidazole by dialysis) were added to cultures of IEC-18 cells and the number of cells was counted 4 days later. FIG. 13 (right panel) indicates that the recombinant protein stimulates cell proliferation to the same maximal extent as does mitogenic AMP peptide 77-97 (or soluble antrum tissue extracts from pig shown in FIG. 1), but that it does so at a half-maximal concentration an order of magnitude lower than for peptide 77-97. AMP peptide 77-97 refers to the mature protein; same as peptide 97-117 of human precursor protein in Table 1. These observations indicate that biologically active recombinant human AMP-18 that can be utilized in diverse clinical situations is available. The mitogenic potency of rhAMP-18 is in the nanomolar range which would be expected for a native gastric cell growth factor that participates in the maintenance and repair of the stomach in vivo. Materials and Methods 1. Isolation of Antrum-Specific cDNA Clones cDNA clones for the gastrointestinal (GI) peptide gastrin, which regulates gastric acid secretion as well as mucosal and pancreatic cell growth (Yoo et al., 1982) were isolated. From these screens several other mRNAs expressed relatively specifically in the antrum of the stomach were found. The open reading frame (ORF) in one of these RNAs was highly conserved between pig and man, and predicted a novel conserved protein of no immediately apparent function. Using specific antibodies, it was shown that similar protein species are present in the stomach antrum mucosa of all mammals tested. There is tissue specificity of expression of these sequences and they are apparently ubiquitously present in the antrum mucosa of mammalian species. 2. RNA Expression The isolation of the cDNA clones was predicted on a preferential expression in the mucosa of the stomach antrum and this has been confirmed initially by Northern blot hybridization of RNAs from various tissues probed with the cDNA sequences and subsequently by protein analysis. The Northern blots showed the specificity of mRNA expression within the gastrointestinal tract of the pig. Highest mRNA expression was in the antrum mucosa, variable amounts in the adjacent corpus mucosa and undetectable levels in fundus, esophagus and duodenum. The non-mucosal tissue of the antrum and corpus contained little RNA reacting with the cDNA probe. 3. Antibodies to Expressed Protein The open reading frames (ORFs) of the human and pig cDNA clones predict very similar relatively low molecular weight (MW) proteins, which have no close homologs to known proteins in the computer databases and therefore give little indication of possible function. As an approach to study the biological role of the presumptive proteins, the full cDNA sequences were expressed in E. coli, using a vector that also encoded an N-terminal His6-tag (SEQ ID NO: 16). Unfortunately, as expressed in bacteria the polypeptide products are insoluble and not readily amenable to biochemical studies. However, the bacterial product of the human cDNA was separated on sodium dodecyl sulfate (SDS) gels used as an immunogen in rabbits to elicit antisera. The sera were screened against protein extracts of antral tissue from a number of mammalian species. This procedure has successfully produced several high-titer, low background antisera capable of recognizing both the immunogen and proteins of about 18 kDa expressed in the antrum of the mammals tested. The bacterially-expressed protein migrates more slowly because it contains the signal peptide sequence was well as a His6-tag (SEQ ID NO: 16). The preimmune sera showed no significant 18 kDa reactivity. The cross-reactivity of the antisera raised against the protein expressed from the human cDNA clone with proteins of very similar MW in antrum extracts from a variety of mammals (pig, goat, sheep, rat and mouse; the last consistently migrates slightly more rapidly in SDS gels) supports the level of conservation of amino acid sequence predicted by comparison of the ORFs of the human and pig cDNAs (See FIG. 10). In subsequent experiments, human AMP-18 with a signal peptide was produced in bacteria. The preimmune sera give insignificant reactions on Western blots of all tissue extracts, while the two immune sera (at up to 1:50000 dilution) both give major bands of 18-20 kDa only, and those only in stomach antrum extracts, and to a lesser degree in the adjacent corpus extracts. The sera were raised against bacterially-expressed protein so there is no possibility of other exogenous immunogens of animal origin. As determined by immunoblots, the specificity of expression to the antrum is even greater than the Northern blots would suggest, and the strength of the signal from antrum extracts implies a relatively high abundance of the protein, although quantitative estimates were not made. Significant antigen was not detected in non-stomach tissues tested. The immunohistochemistry showed insignificant staining of antral tissue by both preimmune sera, while both immune sera stained the surface mucosal cells very strongly at considerable dilutions. The preimmune sera did not lead to immunogold staining in the immunoelectron microscope study. The growth factor activity of antrum extracts is inhibited by both immune, but not preimmune sera. Finally, the results with a synthetic peptide, which has growth factor activity, is inhibited by the immune but not the preimmune sera, and carries epitopes recognized by the immune but not the preimmune sera, further validate the specificity of these reagents. 4. Northern Blot Hybridization of RNAs From Pig Gut Mucosal Tissues Total RNA was electrophoresed, transferred to a membrane and hybridized with a labeled pig AMP-18 cDNA probe. The source of the RNA sample for each lane was: 1. Distal duodenum; 2. Proximal duodenum; 3. Antrum; 4. Adjacent corpus; 5. Fundus; 6. Esophagus. Equal amounts of RNA were loaded. The signal from RNA of the antrum adjacent corpus was variable. Size markers (nucleotides) were run on the same gel for comparison. 5. Immunoblots Using A Rabbit Antiserum Raised Against the Bacterial-Expressed Protein Directed By the Human Antrum-Specific cDNA Clone Whole tissue proteins were dissolved in SDS buffer, electrophoresed, and transferred to membranes that were reacted with immune serum (1:50000). Bound antibody molecules were detected using peroxidase-labeled anti-rabbit antibody. Preimmune serum gave no specific staining of parallel blots at 1:200 dilution. Lanes: 1,6,13,17 contained markers. 2 HeLa cells. 3 mouse TLT cells. 4 expressed human protein +HELA cells. 7 mouse corpus. 8 mouse antrum. 9 mouse duodenum. 10 mouse intestine. 11 mouse liver. 12 expressed human protein +TLT cells. 14 mouse antrum. 15 mouse brain. 16 mouse Kidney. 18 pig antrum. 19 mouse antrum. Immunoblots of high percentage acrylamide gels showed that the antisera recognized epitopes on the synthetic peptide 78-119. The reaction of peptide 78-119 with the antibodies was not unexpected because this region of the sequence was predicted to be exposed on the surface of the protein and to be antigenic. Not only does this further substantiate a belief that AMP-18 or its immediate precursor, is a growth factor, for epithelial cells, but also provides a basis for analysis of the bioactive (and antigenic) regions of AMP-18, and a tool for the assessment of cell receptor number and identity. Chemical synthesis of peptides also makes available a convenient and rapid source of considerable quantities of pure “wild-type” and “mutant” reagents for further cell studies. The synthetic peptide 78-119 apparently acts by the same mechanism as the antrum protein, because their maximal effects are not additive. 6. Sequence and Predicted Structure of the Pre-AMP Open Reading Frame The predicted amino acid sequences for human and pig are 76% identical. The predicted signal peptides are not bold; the N-terminus of native pig AMP has been shown to be aspartate (FIG. 10). 7. Structure of the Native Protein The ORF's of the human and pig cDNAs predicted polypeptides of similar general structure (FIG. 10). The predicted molecular weights for the otherwise unmodified human and pig proteins was 18.3 and 18.0 respectively; these values are in good agreement with electrophoretic mobility in SDS the of antrum proteins reacting with the antisera of the present invention. The antisera was used to assist in the purification of the protein from extracts of pig antrum mucosa. Immunoaffinity methods applied to total tissue extracts have not proven very effective, but by using immunoblots to monitor cell-fractionation, gradient centrifugation and gel electrophoresis sufficient amounts of the pig 18 kDa polypeptide was purified to confirm by sequencing that the native N-terminus is one predicted by cleavage of about 20 amino acids from the N-terminus of the ORF precisely at the alanine-aspartate site anticipated for signal peptide removal. Despite the abundance of asparagine residues, none fit the consensus context for glycosylation. Fairly extensive regions which may possess amphipathic helix forming propensity. The latter may represent units within the protein or as peptides after processing. Using circular dichroism the synthetic peptide representing amino acids 126-143 in the human preAMP sequence (FIG. 3) is readily induced to become helical in moderate concentrations of trifuoroethanol conditions used to assess helix propensity for some bioactive peptides, including anti-microbial peptides of the magainin type (see for example Park et al., 1997). 8. Localization of AMP-18 The antisera to AMP-18 have proven to be excellent histochemical probes, reacting strongly with sections of the mouse antrum region but not with the fundus, duodenum or intestine, confirming the results of the immunoblots. The preimmune sera give negligible reactions even at much higher concentration. The AMP-18 protein appears to be concentrated in mucosal epithelial cells lining the stomach lumen, although lesser signals in cells deeper in the tissue and along the upper crypt regions suggest that cells may begin to express the protein as they migrate toward the lumenal layer. Higher magnification of the histochemical preparations indicates only a general cytoplasmic staining at this level of resolution; there are some patches of intense staining that may be the light microscope equivalent of granule-packed regions of some lumenal surface cells seen by electron microscopy (EM). The localization of AMP-18 in the antrum mucosa is therefore very different from those cells synthesizing gastrin which are deep in the mucosal layer. 9. Immunoelectron microscope localization of the AMP-18 antigens in the mouse stomach antrum mucosal cells The tissue pieces were fixed in 4% formaldehyde and processed for embedding in Unicryl. Thin sections were reacted with rabbit anti-human AMP-18 antisera (1:200); bound antibodies detected by Protein-A conjugated to 10 nm colloidal gold. The reacted sections were stained with lead citrate before viewing (20,000×). The gold particles are visible over the semi-translucent secretion granules, which appear much more translucent here than in the standard glutaraldehyde-osmium-epon procedure (11,400×) because of the requirements for immuno-reactivity. Negligible background was seen on other cytoplasmic structures. The general structure of the protein implies a possible secretory role so a precise intracellular localization would be valuable. This requires EM immuno-cytochemical procedures. Standard embedding and staining methods reveal that, as previously reported by many others, the antrum region (e.g. Johnson and McMinn, 1970) contains mucosal epithelial cells which are very rich in secretory granules. Preliminary immuno-EM data show the immune sera used at 1:200-1:800 dilution react specifically with the secretion granules. The latter appear somewhat swollen and less electron opaque than in standard fixation conditions and the differences in density are harder to discern, but overall the cell structure is quite well-preserved for 30 stomach tissue fixed and embedded under the less stringent conditions required to preserve immuno-reactivity. At 1:100 dilution, the preimmune sera exhibited negligible backgrounds with no preference for the secretion granules. 10. Growth Factor Activity on Epithelial Cell Cultures. A possible function for AMP-18 is that it is a growth factor at least partly responsible for the maintenance of a functional mucosal epithelium in the pyloric antrum and possibly elsewhere in the stomach. Initially, stomach epithelial cell lines were not immediately available, but kidney epithelial cell systems (Kartha et al., 1992; Aithal et al., 1994; Lieske et al., 1994) were used. A fractionated antrum mucosal cell extract was used for these experiments. Using immunoblotting as a probe to follow fractionation, on lysis of the mucosal cells scraped from either pig or mouse antrum, the AMP-18 antigen was recovered in the 35S fraction on sucrose density gradients. Such high speed supernatant fractions served as the starting material for studies on cell growth. Unexpectedly, these extracts stimulated a 50% increase in confluent renal epithelial cells of monkey (BSC-1 cells), but had no effect on HeLa or WI-38 fibroblast cells. The stimulation of BSC-1 cells was at least as effective as that observed with diverse polypeptide mitogens, including EGF, IGF-I, aFGF, bFGF and vasopressin, assayed at their optimal concentrations. Comparable growth stimulation by the antrum extracts was observed when DNA synthesis was assessed by measuring [3H]thymidine incorporation into acid-insoluble material. The biological activity of the antrum extracts survived heating for 5 minutes at 65° C., and dialysis using a membrane with Mr cutoff of 10 kDa, which would eliminate most oligopeptides; this treatment removes 60-70% of polypeptide material, but spared AMP-18 as assayed by immunoblots. More importantly, mitogenic stimulation of BSC-1 cells by the mouse or pig antrum extract was inhibited when either of two different antisera to the human recombinant preAMP-18 (expressed in bacteria) was added to the culture medium. Preimmune sera (1:100 to 1:800) had no effect on cell growth, nor did they alter the mitogenic effect of the antrum extracts. These observations suggest that gastric mucosal cell AMP-18 functions as a potent mitogen for kidney epithelial cells, which do not normally express this protein. To gain further evidence that the growth-promoting activity in the partially fractionated antrum extracts was mediated by the AMP-18 protein, an aliquot of the mouse extract was subjected to SDS-polyacrylamide gel electrophoresis; the method used previously to determine the N-terminal sequence of the natural protein. The gel was cut into 2-mm slices and each slice was extracted with 3% acetonitrile in phosphate-buffered saline containing 1% BSA. The extract supernatants were assayed for mitogenic activity. The results indicated that one slice containing protein in the 16-19 kDa range possessed growth-promoting activity. Significantly, this growth response was blocked by the immune but not the pre-immune sera. Taken together with the relatively low sedimentation rate of the protein, these findings provide additional evidence to support the conclusion that AMP-18 is an epithelial cell mitogen and that it functions as a monomer or possibly a homotypic dimer. It also implies that the structure of the protein is such that it can readily reacquire a native conformation after the denaturing conditions of SDS-gel electrophoresis. To assess the interaction of the antrum growth factor activity with other cytokines, its activity was tested to determine if it was additive with EGF in epithelial cell cultures. EGF (50 ng/ml) added with untreated mouse antrum extract (10 μg/ml), or heated, dialyzed pig extract (10 μg/ml) exhibited additive stimulation of mitogenesis; up to 74% increase in cell number above the quiescent level; the greatest stimulation observed so far for any factor using the BSC-1 cell assay. An example of this additivity is shown for an AMP-peptide and EGF on AGS cells in FIG. 11. This observation suggests that AMP-18 and EGF initiate proliferation by acting on different cell surface receptors. It also implies that AMP-18 growth factor activity might normally collaborate with other autocrine and paracrine factors in the maintenance or restitution of the epithelium. In view of the results with EGF, it is likely that AMP-18 is secreted at and acts upon the apical face (i.e., stomach lumenal face) of the epithelial cell layer while other factors (for which EGF may serve as an example) act from the basal surface. 11. Bioactivity of Gastrokine (AMP-18) Related Peptides. The activities of synthetic peptides of the present invention are unexpected. Peptides based on the ORF of the human cDNA clone peptides were synthesized in the University of Chicago Cancer Center Peptide Core Facility, which checks the sequence and mass spectra of the products. The peptides were further purified by HPLC. Five relatively large oligopeptides (of about 40 amino acids each) approximately spanning the length of the protein without including the signal peptide, were analyzed. One peptide 42 amino acids long spanning amino acids lys-78 to leu-119 of the pre-AMP sequence (peptide 58-99 of the matured form of the protein; see Table 1), including a predicted helix and glycine-proline (GP) turns, gave good mitogenic activity. This response was blocked by the specific antiserum, but not by the preimmune sera. TABLE 1 BIOACTIVITY OF SYNTHETIC PEPTIDES BASED ON THE SEQUENCE OF PRE-GASTROKINE (PRE-AMP-18) Name of Peptide Sequence in # K½, Human AA AMINO ACID SEQUENCE μM 78-119 42 KKTCIVHKMKKEVMPSIQSLDALVKEKKLQGKGPGGPPPKGL 0.3 (SEQ ID NO: 17) 78-88 11 KKTCIVHKMKK Inactive (SEQ ID NO: 14) 87-105 19 KKEVMPSIQSLDALVKEKK Inactive (SEQ ID NO: 15) 104-117 14 KKLQGKGPGGPPPK 0.8 (SEQ ID NO: 11) 104-111 18 KKLQGKGPGGPPPKGLMY 1.0 (SEQ ID NO: 18) 97-117 21 LDALVKEKKLQGKGPGGPPPK 0.3 (SEQ ID NO: 12) 97-117** 21 GKPLGQPGKVPKLDGKEPLAK Inactive (SEQ ID NO: 19) 97-121 25 LDALVKEKKLQGKGPGGPPPKGLMY 0.2 (SEQ ID NO: 13) 109-117 9 KGPGGPPPK 2.5 (SEQ ID NO: 20) 104-109 6 KKLQGK 7.4 (SEQ ID NO: 21) 110-113 4 GPGG Inactive (SEQ ID NO: 22) mouse 97-119 23 LDTMVKEQK . . . GKGPGGAPPKDLMY 0.2 (SEQ ID NO: 23) **scrambled Table 1: Analysis of mitogenic peptides derived from the human and mouse pre-gastrokine (pre-AMP-18) sequence. A 14 amino acid mitogenic domain is in bold type. *Peptides are identified by their position in the amino acid sequence of the pre-gastrokine (preAMP-18). #AA; number of amino acids in a peptide. K1/2; concentration for half-maximal growth stimulation. Overlapping inactive peptides can inhibit the activity of the mitogenic peptides: that is, human peptides 78-88 and 87-105 block the activity of peptide 78-119, and while peptide 87-105 blocks the activity of peptide 104-117, the peptide 78-88 does not. Peptides 78-88 and 87-105 block the activity of the protein in stomach extracts. 12. The Growth Stimulatory Domain of Gastrokine (AMP-18). Finding that a 42-amino acid peptide representing a central region of the novel antrum mucosal cell protein AMP-18 had mitogenic activity similar in character to that of the intact protein in pig and mouse antrum extracts (Table 1), has facilitated the characterization of the bio-active region of the molecule. A peptide including amino acids at positions 78-119, gave similar maximal stimulation of growth of the BSC-1 epithelial cell line to that given by the tissue extracts and was similarly inhibited by several different antisera raised in rabbits to the bacterially-expressed complete antrum protein. The mitogenic activity of a number of synthetic “deletion” peptides related to peptide “78-119” are summarized in Table 1. Growth activity determinations have so far been accomplished with the kidney epithelial cell line as well as several gastric and intestinal lines. The original 42 amino acid sequence of peptide 78-119 was broken into three segments bounded by lysine (K) residues; N-terminal to C-terminal these are peptides with amino acids at positions 78-88, 87-105 and 104-117. Of these only peptide 104-117 possessed mitogenic activity giving a similar plateau of growth stimulation but requiring a higher molar concentration than the original peptide “78-119”; this is reflected in the higher K1/2 value, which suggests that 14-amino acid peptide has 30-40% of the activity of the 42-amino acid peptide. A conclusion from this is that the smaller peptide has less binding affinity for a cell receptor, perhaps due to a lessened ability to form the correct conformation, or alternatively because of the loss of ancillary binding regions. The latter notion is supported by the observations that peptides “78-88” and “87-105” can antagonize the activity of intact 42-mer peptide 78-119; these peptides also antagonize the activity of antrum extracts further supporting the validity of synthetic peptides as a means to analyze the biological function of the novel protein. An additional aspect of the invention is that peptide 87-105, but NOT 68-88, antagonizes the activity of peptide 104-117; note that peptide 87-105 overlaps the adjacent 104-117 sequence by two residues. Taken together these results suggest a relatively simple linear model for the growth-stimulatory region of AMP-18; viz, there is an N-terminal extended binding domain (predicted to be largely helix, the relative rigidity of which may explain the linear organization of the relevant sequences as determined in the cell growth studies), followed by a region high in glycine and proline with no predicted structure beyond the likelihood of turns. It is this latter region which contains the trigger for growth stimulation. The specificity of antagonism by peptides 78-88 and 87-105 may be based on whether they overlap or not the agonist peptides 78-119 and 104-117; for example 78-88 overlaps and inhibits 78-119, but does not overlap or inhibit 104-117. The specificity of competition by these peptides taken with the inactivity of the 78-119 scrambled peptide, strengthens a conclusion that AMP-18 interacts with specific cellular components. Further evidence that the receptor binding region extends N-terminally from peptide 104-117 is provided by the enhanced activity of peptide 97-117 which contains a seven amino acid N-terminal extension of 104-117. A peptide with a four amino acid extension in the C-terminal direction (peptide 104-121) appears to have slightly less activity to the parent 104-117, but does include a natural tyrosine, which makes possible labeling with radioactive iodine, which allows determination of the binding of AMP-related peptides to cells, initially by assessment of number of binding sites and subsequently detection of the receptor protein(s). The peptide 97-107 was used for most tests because of its activity (equal to the 42-mer) and its relative economy (21 amino acids in length). However, a C-terminal extension to the tyr-121 gives the most active peptide thus far, perhaps because it stabilizes secondary structure. Even though this peptide does not match the nanomolar activity of EGF, for example, it is much more potent than reported for trefoil peptides (Podolsky, 1997). An estimate for the activity the intact AMP protein is ca. 1-10 nM. 13. Expression of Recombinant Protein (a) E. coli. Recombinant constructs are generally engineered by polymerase-chain-reactions using synthetic oligonucleotides complementary to the appropriate regions of the full-length cDNA sequences within the PT/CEBP vector and extended by convenient restriction enzyme sites to enable ready insertion into standard vector polylinkers. The initial experiments with expression of the AMP ORF in bacterial systems employed an expression vector PT/CEBP, which included an N-terminal His6-tag (SEQ ID NO: 16) (Jeon et al., 1994), intended to facilitate the purification of the expressed protein on Ni—NTA resin (Qiagen). Expression of the full-length human cDNA within this vector in the host BL21 (DE3)pLyS gave good yields of insoluble protein, which after electrophoresis under denaturing conditions was suitable for use as an immunogen in rabbits to obtain specific high-titer antibodies, but which has not been useful for analysis of the protein's native structure and function. This insolubility is most probably due to the presence of an unnatural N-terminus, having a His6-tag (SEQ ID NO: 16) upstream of hydrophobic signal peptide, in the expressed protein. Engineering vectors which will express the ORF without the hydrophobic signal peptide sequence are also useful. These are constructed using bacterial expression vectors with and without N- or C-terminal His-tags. The human AMP-18 sequence lacking the 20 amino acid signal peptide and containing a His6-tag (SEQ ID NO: 16) was also expressed in bacteria. (b) Pichia pastoris. Among the simple eukaryotes, the budding yeast P. pastoris is gaining wide popularity as an expression system of choice for production and secretion of functional recombinant proteins (Romanos et al., 1992; Cregg et al., 1993). In this system, secretion of the foreign protein may utilize either its own signal peptide or the highly compatible yeast mating-type alpha signal. This organism will correctly process and secrete and at least partially modify the AMP-18 protein. Vectors for constitutive and regulated expression of foreign genes are developed in Pichia (Sears et al., 1998). In addition to a poly-linker cloning site, these vectors contain either the high expression constitutive glyceraldehyde-3-phosphate dehydrogenase (GAP) or the methanol-regulated alcohol oxidase promoter (AOX1). The latter is an extremely stringent promoter yielding insignificant product in normal culture conditions while giving the highest expression of the vectors tested in the presence of methanol, amounting to as much as 30% of the cell protein. The advantage that the yeast Pichia has over the mammalian and insect alternatives is that it is continuously grown in protein-free media, thus simplifying the purification of the expressed protein and eliminating extraneous bioactivities originating in the serum or the host animal cells. A pIB4 construct (inducible by methanol-containing medium) contains the complete human preAMP-18 cDNA sequence. (c) Baculovirus/Insect cells. An alternative, frequently successful, non-mammalian eukaryotic expression system is that using recombinant Baculovirus, such as Autographa californica, in an insect cell culture system. As with Pichia, a large repertoire of convenient vectors are available in this system, containing both glutathione S-transferase (GST)-and His6-tags (SEQ ID NO: 16) (Pharmingen). Transfections are carried out into Spodoptera frugiperda (Sf) cells; these cells can be slowly adapted to protein-free medium to favor the purification of secreted proteins. If an endogenous signal peptide does not function in these cells, secretion of foreign proteins can also be forced using vectors containing the viral gp67 secretion signal upstream of the cloning site. Recombinant proteins can be expressed at levels ranging from 0.1-50% total cell protein. Some protein modifications may be more favored in this insect cell system relative to yeast, but still may not duplicate the mammalian system. It appears that the insect expression system would be somewhat more onerous than Pichia, and not entirely substitute for expression in mammalian cells. The human AMP-18 sequence lacking the 20 amino acid signal peptide and containing a His6-tag (SEQ ID NO: 16) was expressed in Baculovirus. (d) Mammalian cells. Modifications not detectable by immunoblot analysis may take place in mammalian cells that are not duplicated in cells of other eukaryotes. Although not as convenient as prokaryotic and simple eukaryotic systems, mammalian cells are now frequently used for both transient and continuous expression of foreign proteins. Several growth factors have been expressed and secreted in significant amounts using these systems. The plasmid pcDNA3/human kidney 293 system: pcDNA3 contains a polylinker cloning site flanked by the strong constitutive cytomegalovirus (CMV) promoter and a SV40 polyA signal (Invitrogen). Laboratory experience is that 60-90% transient transfection levels can be achieved. To this end, PCR amplification of the human preAMP cDNA clone is performed with oligonucleotides that contain the initiation codon and native ribosome binding site (Kozak sequence) as well as suitable restriction enzyme linkers for correct orientation into pcDNA3. Favorable constructs were identified in the transient assay using the potent antibiotic blasticidin S and a vector containing the resistance gene, stable mammalian transfectant cell lines can be established “in less than one week” (Invitrogen). The available vectors also include the constitutive CMV promoter, a polylinker cloning site, an elective V5-epitope/His6-tag (SEQ ID NO: 16) and the SV40 poly(A) signal (PcDNA6/V5-His). 14. Expression and Analysis of Altered (Modified) Forms of AMP-18 Given an efficient expression system for the production of “wild-type” AMP-18, a series of mutant proteins, containing either deletions or substitutions may be created, which will permit analysis of the functional domains. The amphipathic helices, the conserved cystine (C) residues and the basic amino acids doublets, which may be cleavage sites, are attractive targets. Although not as simple as an enzyme assay, the mitogenesis assay is routine and replicable, and would enable “mutants” to be characterized as fast as they are constructed. Dominant negative (or positive) “mutants” will be as significant as mutations exhibiting simple loss of function, because these will imply interactions with other factors including possible cell receptors. 15. Biochemical and Immunoaffinity Fractionation of Expressed and Native Gastrokine Proteins In the case of some of the expressed forms of gastrokine AMP-18, the recombinant protein will contain peptide tags that will permit the rapid purification of soluble protein. The presence of these tags, if they do not severely interfere with the protein's normal functions, will also permit analysis of interactions with other relevant macromolecules. His6-tags (SEQ ID NO: 16) permit purification by binding the recombinant proteins to Ni—NTA resin beads (Janknecht et al., 1991; Ni—NTA resin from Qiagen). The tagged protein is bound with greater affinity than most antigen-antibody complexes and can be washed rigorously before the Ni2+-histidine chelation complex is disrupted by excess imidazole to release the purified protein. GST-tagged recombinant proteins are purified on glutathione-agarose, washed and then eluted with reduced glutathione (Smith and Johnson, 1988). As with all the proposed expression systems, each protein preparation may be tested at the earliest possible stage for its growth factor activity. Conventional fractionation procedures are used to achieve the desired purity, particularly in the case of the isolation of the natural protein from tissue. Pig antrum mucosa is a preferred starting point for the latter, using initial centrifugation and heat-treatment protocol, followed by a size-exclusion column: BioGel P60 is suitable, given the evidence that the 18 kDa protein exists, most probably as a monomer in the extracts. The eluant is loaded on an immunoaffinity matrix created by crosslinking anti-AMP antibodies purified on HiTrap Protein A to CNBr-activated Sepharose 4B (Pharmacia). Further modification of the immunoaffinity matrix may be helpful, either by extension of the linker to the matrix, which has proven useful in the past (Aithal et al., 1994), or by crosslinking the antibody to immobilized protein-A. Because active protein can be recovered by SDS-gel elution, active protein may also be recovered from the antigen-antibody complexes. Further fractionation could be achieved by C8 reversed-phase high-performance liquid chromatography (HPLC) column. A final step is the use of the SDS-gel elution technique with confirmation of identity by N-terminal sequencing. In all of these steps the immunodetectable AMP-18 and the growth factor activity should fractionate together. 16. AMP-18 Related Synthetic Peptides AMP-18 may be precursor to one or several bioactive peptides. Synthetic peptides provide a convenient avenue to explore the function of a protein; peptides may mimic aspects of the function or antagonize them. If a peptide either duplicates or inhibits the protein's activity, then it suggests the identity of functional domains of the intact protein, and also provides the possibility of synthesizing specifically tagged probes to explore protein-cell interactions. Finding that a synthetic 42 amino acid peptide, representing a middle region of the human protein, is capable of mimicking the growth factor activity of the partially fractionated antrum mucosal extracts has provided a short-cut to the analysis of AMP-18 function. This peptide (designated peptide 58-99; amino acids are at positions 58-99 of the mature protein after removal of the signal peptide) in addition to several possible protein processing sites at lysine pairs, contains one of the regions capable of extended helix formation as well as a glycine-proline loop. An added advantage of this peptide is that it contains epitopes recognized by both of the antisera disclosed herein. Some smaller peptides derived from this sequence were synthesized to focus on the bioactive regions. Initially sequences bounded by the lysine residues were studied because they may indicate distinct domains within the protein structure, by virtue of being exposed on the surface of the protein, as witnessed by the antigenicity of this region, and may be sites of cleavage in vivo to bioactive peptides. The glycine-proline region is important (see Table 1 illustrating the bioactive domains of AMP-18). Glycine-proline sequences are known to be involved in SH3 (src homology domain type 3) ligands (see Cohen et al., 1995; Nguyen et al., 1998); because SH domains are involved in protein-protein interactions that GP region of AMP-18 may be involved in the interaction of the protein with a cell surface receptor. The exact GPGGPPP (SEQ ID NO: 24) sequence found in AMP-18 has not been reported for the intracellular-acting SH3 domains, so the intriguing possibility exists that it represents a novel protein interaction domain for extracellular ligands. A 21-mer derived from amino acids at positions 97-117 of the mature sequence has activity similar to the 42-mer. This shorter peptide is useful for growth assays on various epithelial cell lines. This peptide does not express the epitope recognized by the antisera disclosed herein. All of the AMP-18 derived peptides were synthesized by the Cancer Center Peptide Core Facility of the University of Chicago, which also confirmed the molecular mass and amino acid sequence of the purified peptides that are isolated by HPLC. The biological activity of peptide 78-119 not only provides the basis for seeking smaller peptides with mitogenic activity, but permits amino acid substitutions that have positive or negative effects to be found rapidly. Inactive peptides were tested for their ability to block the function of active peptides or intact AMP-18. The possible inclusion of D-amino acids in the peptides (in normal or reverse order) may stabilize them to degradation while permitting retention of biological function. Further the ability to synthesize active peptides enables tags that facilitate studies of the nature, tissue distribution and number of cellular receptors. Such tags include His-6 biotin or iodinated tyrosine residues appended to the peptide sequence (several of the bioactive peptides have a naturally occurring tyrosine at the C-terminus). Synthetic peptides also permit assessment of the role of potential secondary structure on function. The finding that a 4 amino acid C-terminal extension of the active peptide 97-117, predicted to promote a helix similar to that for the intact AMP-18 sequence, led to a more active peptide 97-121, is interesting. The helix-propensity of these active peptides e.g. peptide 126-143, which resembles an anti-microbial magainin peptide, provides useful information. With respect to antimicrobial peptides, the function of the magain in class is related to their ability to form amphipathic helices (Boman, 1995). Synthetic peptides that can be locked in 30 the helical form by lactam bridges (Houston et al., 1996) enhanced biological activity; at least one pair of appropriate acidic and basic amino acid residues for lactam formation already exist in potential helix regions of AMP-18. Another equally significant aspect of the peptide studies is the potential availability of specific anti-AMP-18 peptides that antagonize its biological functions. Tissue culture studies show that sub-peptides of the growth-promoting peptide 78-119 can antagonize the activity of the intact peptide (see Table 1). Peptides that can occupy cellular binding sites but lack some essential residues for activity may block the action of AMP-18 and its active peptides. This makes available another set of reagents for the analysis of cellular receptors and for assessing receptor-ligand affinity constants. Availability of defined peptide antagonists is useful in whole animal studies, and may eventually serve to regulate the activity of the natural protein in humans. 17. Interactions of AMP-18 and Related Peptides with Cells: Assessment of Cell Growth Non-transformed monkey kidney epithelial cell line BSC-1 and other epithelial cell lines were used to assess effects on growth. In general, conditions were chosen for each line such that cells are grown to confluence in plastic dishes in supplemented growth medium with minimal calf (or fetal) serum for growth (Lieske et al., 1997); BSC-1 cells become confluent at 106/60 mm dish with 1% calf serum. At the start of the growth assay the medium on the confluent culture was aspirated and replaced with fresh medium with minimal serum to maintain viability (0.01% for BSC-1) cells. AMP-18 preparations were added to the culture medium and 4 days later the cell monolayer was rinsed, detached with trypsin, and the cells were counted using a hemocytometer. Determination of the capacity of AMP-18 to initiate DNA synthesis was measured by the incorporation of [3H]thymidine (Toback, 1980); to confirm the DNA synthesis assay, autoradiograms of leveled cells were counted (Kartha and Toback, 1985). The protein AMP-18 is expressed in the antrum mucosa and to a lesser extent in the adjacent corpus mucosa. However, both antrum extracts and the active synthetic peptides stimulate proliferation of most simple epithelial cell lines. The major criterion used, apart from cells which might be natural targets for AMP-18 or its peptides, was that of growth control, particularly cell-density restriction. Many transformed stomach lines derived from human cancer patients are available from various sources, but most of these do not exhibit growth control. For example, a gastric AGS adenocarcinoma cell subline from Dr. Duane Smoot (Howard University College of Medicine) showed a greater degree of contact inhibition, and responded well to AMP-18 and its derived peptides. These cells do not naturally synthesize AMP-18. Similar responses were observed with the non-transformed rat IEC intestinal epithelial cells (provided by Dr. Mark Musch, Dept. Medicine, University of Chicago); the latter show excellent epithelial cell characteristics in culture (Quaroni et al., 1979; Digass et al., 1998). 18. Receptors for AMP-18 on the Surface of Epithelial Cells Characterization of the target cell receptors of AMP-18 is intriguing because of the apparent existence of receptors on cells which are not expected ever to contact this protein. Initial growth response assays were performed on kidney-derived epithelial cell lines, which responded well to the stomach factor. Gastric cell lines, as well as the non-transformed rat intestinal epithelial IEC-6 cells, were used to address the receptors in cells that are likely the true physiological targets for the antrum factor. The specificity for the action of this protein in vivo likely arises from the extremely tissue specific nature of its expression, rather than that of its receptor. It is possible that AMP-18 may interact with receptors shared with other growth factors. However, the additive growth stimulus of EGF and the antrum extracts suggest that AMP-18 may have novel receptors. Protein molecules in cell membranes that interact with AMP-18 may be sought in several different ways. Pure AMP-18 or related peptides labeled, e.g. with biotin or radioactive iodine, are used to estimate the number of saturatable sites on the cell surface. Scatchard analysis of the binding values as used to determine the number and affinity of receptors. For quantitative studies, binding is measured at increasing AMP ligand concentrations, and non-specific components are identified by measuring binding in the presence of excess unlabeled factor. Iodinated growth factors have been cross-linked to cellular receptors enabling their identification (Segarini et al., 1987). Labeled AMP ligands are incubated with cells, and the bound ligand is cross-linked to the receptors by disuccinimidyl suberate. The labeled proteins are resolved by SDS-PAGE, and autodiography is used to visualize the cross-linked complex permitting an estimate of the MW of the receptor(s). Synthetic peptide mimics or antagonists permit studies of the cellular receptors, and their properties are reasonably inferred prior to future definitive identification, presumably by cloning techniques. In addition to crosslinking studies, antibodies, or his6-tagged (SEQ ID NO: 16) AMP-18 or peptides are used to isolate cellular or mucus proteins which bind to AMP-18. As an additional approach, an immobilized AMP-18 affinity matrix can be created by using CNMBr-activated Sepharose. As a simple beginning to the analysis of the signal transduction pathway mediated by any cell receptor, a test to assay protein tyrosine kinase activity in affinity isolates is available (Yarden and Ullrich, 1988; Schlessinger and Ullrich, 1992). 19. Is AMP-18 Processed to Bioactive Peptides? The functional molecular form(s) of AMP-18 is not known. Certainly, the ca. 18 kDa is the protein form which accumulates in antrum mucosal cells, and substantial amounts of polypeptides of lower MW are not detected with the antisera, even though they do react with pepsin fragments down to ca. 10 kDa and also with the bioactive peptide 78-119 (having only 42 amino acids). Having access to labeled or tagged AMP-18 enables a question of whether the protein is processed in antrum mucosal extracts, or by the epithelial cells which respond to it, to be explored. 20. Genes for AMP-18 in Man and Mouse Using PCR techniques employing primers based on the sequence of the human cDNA clone, genomic clones of human and mouse preAMP-18 were obtained. The exon/intron structure (FIG. 12) is complete. Mouse AMP exons are sufficiently similar to those of human and pig to allow a sequence of the mouse gene to be assembled. Human and mouse genes have very similar structures, the mouse gene being slightly smaller. The ORF contained in exons of the mouse gene predicts a protein having 65% identity to the human and pig proteins. A 2 kb of sequence is upstream of the human gene. 21. Knockout of the AMP-18 Gene in Mouse From the mouse map a targeting construct is designed. The construct preferably contains: [5′-TK (a functional thymidine kinase gene)-ca. 5 kb of the 5′ end of AMP-18 DNA-the neomycin phosph-transferase (neo) gene under the control of the phosphoglycerate kinase (PGK) promoter -ca. 3 kb of the 3′ end of the gene —3′]. A considerable length of homology of the construct with the resident AMP-18 gene is required for efficient targeting. Increasing the total homology from 1.7 to 6.8 kb increases the efficiency of homologous targeting into the hrpt gene about 200-fold (Hasty et al., 1991). Beyond that total length, the efficiency increases only slightly. To facilitate the detection of homologous intergrants by a PCR reaction, it is useful to have the neo gene close to one end of the vector. The resulting transfectants can be provided by PCR with two primers, one in the neo gene and the other in the AMP-18 locus just outside of the targeting vector. Flanks extending 4 kb 5′ and 4.5 kb 3′ of the mouse gene have been obtained. Through homologous recombination, the coding region will be replaced by the neo gene to ensure a complete knockout of the gene are already cloned. After trimming off the plasmid sequence, the targeting cassette will be transfected into ES cells and stable transfectants obtained by selection with G418, an analog of neomycin, and gancyclovir (Mansour et al., 1988). Southern blots with the probe from the flanking sequence will be used to screen for targeted homologous recombinants. Correctly targeted ES cell clones will be injected in blastocysts from C57BL/6 mice. Male offspring obtained from surrogate mothers that have at least 50% agouti coat (embryonic stem cell (ES) cell derived) are bred with C57BL/6 mice. Fl mice that are agouti have the paternal component derived from the ES cells (agouti is dominant over black). 50% of these mice should have the knockout preAMP-18 allele. These hemizygous mice are monitored for any effect of diminished gene dosage. Homozygous knockouts are preferable. If the sole function of AMP-18 is in the stomach following birth, then viable homozygotes are expected. If these cannot be obtained, a fetally lethal defect would be indicated, and the fetal stage of abortion would be ascertained. This result would suggest an unanticipated role of the protein in normal development. Homozygous AMP-18 knockout mice are useful for investigations of stomach morphology and function. It is expected that such knockouts will show if AMP-18 is essential, and at which stage of gastro-intestinal development it is bioactive. It is possible that the AMP-18 knockout hemizygous mice will already show a phenotype. This could occur if reduced dosage of the protein reduces or eliminates its function, or if parental imprinting or random mono-allelic expression has a significant influence. A range of possible outcomes of the AMP-18 knockout in mice include: i) no viable homozygotes, implying an essential unanticipated developmental role; ii) viable homozygotes, but with obviously impaired gastrointestinal functions; iii) no strong phenotype, i.e. the protein is not important to the development and life of the laboratory mouse. If appropriate, the generation of AMP-18 in overexpressing mice is pursued. A truncated AMP-18 protein produced in the mice could potentially create a dominant negative phenotype; knowledge gained from the experiments will further define the functional domains of the protein. Abbreviations for amino acids Three-letter One-letter Amino acid abbreviation symbol Alanine Ala A Arginine Arg R Asparagine Asn N Aspartic acid Asp D Asparagine or aspartic acid Asx B Cysteine Cys C Glutamine Gln Q Glutamic acid Glu E Glutamine or glutamic acid Glx Z Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V Documents Cited Aithal, N. H., et al. (1994) Am. J. Physiol. 266:F612-619. Altschul, S., (1997) et al. (1994) Nuc. Acids Res. 25:3389-3402. Baczako, K, et al. (1995) J Pathol. 176:77-86. Blaser, M. J. et al. (1987) Gastroenterol. 93:371-383 Boman, H. G. (1995) Ann. Rev. Immunol. 13:61-92. Cohen, G. B., et al. (1995) Cell 80:237-248. Cregg, J. M., et al. (1993) Bio/Technol. 11:905-910. Dignass, A. U., et al. (1998) Eur. J. clin. Invest. 28:554-561 Falk, P., et al. (1993) Proc. Nat. Acad. Sci. 90:2035-2039. Goodwin, C. S., et al., (1986) J. Clin. Microbiol. 39:353-356 Hasty, P., et al. (1991) Mol. Cell. Biol. 11:5586-5591. Houston, M. E., et al. (1996) Biochem. 35:10041-10050. Janknecht, R., et al. (1991) Proc. Nat. Acad. Sci. USA 88:8972-8976 Jeon, C. J., et al. (1994) Proc. Nat. Acad. Sci. USA 91:9106-9110 Johnson, F. R. and McMinn, R. M. H. (1970) J Anat. 107:67-86. Kartha, S. and Toback, F. G. (1985) Am. J. Physiol. 249: F967-F972 Kartha, S., et al. (1992) Exp. Cell Res. 200:219-226. Lacy, E. R. (1998) J. Clin. Gastroenterol. 10(Suppl 1):72-77. Lieske, J. C., et al. (1994) Proc. Natl. Acad. Sci. 91:6987-6991. Lieske, J. C., et al. (1997) Am. J. Physiol. F224-F233. Mansour, S., et al. (1988) Nature 336:348. Moore, K. S., et al. (1991) J. Biol. Chem. 266:19851-19857. Nguyen, J. T., et al. (1998) Science 282:2088-2092. Nomura, A., et al. (1991) N. engl. J. Med. 325-1132-1136. Nusrat, A., et al. (1992) J. Clin. Invest. 89:1501-1511. Park, C. B., et al. (1997) FEBS Lett. 411:173-178. Parsonnet, J., et al. (1991) N. Engl. J. Med. 325:1127-1131. Podolsky, D. K. (1997) J Gastroenterol. 32:122-126. Powell, C. J., (1987) Ph.D. Dissertation, University of Chicago. Quaroni, A., et al. (1979) J. Cell Biol. 80:248-265. Romanos, M. A., et al. (1992) Yeast 8:423-488. Rotimi, V. O., et al. (1990) Afr. J. Med. med. Sci. 19:275-280. Sands, B. E. and Podolsky, D. K. (1996) Ann. Rev. Physiol. 58:253. Schiessinger, J. and Ullrich, A. (1992) Neuron 9:383-391. Sears, I. B., et al. (1998) Yeast 14. Segarini, P. R., et al. (1987) J. Biol. Chem. 262:14655-14662. Smith, D. B. and Johnson, K. S. (1988) Gene 67:31-40. Toback, F. G. (1980) Proc. Nat. Acad. Sci. 77:6654-6656. Yarden et al. and Ullrich (1988) Biochemistry 27:3113-3119. Yoo, O. J. et al. (1982) PNAS 79:1049-1053. Yoshikawa, Y., et al. (2000) Jap. J, Cancer Res. 91:459-463.

<SOH> BACKGROUND <EOH>A novel group of Gastric Antrum Mucosal Proteins that are gastrokines, is characterized. A member of the gastrokine group is designated AMP-18. AMP-18 genomic DNA, and cDNA molecules are sequenced for human and mouse, and the protein sequences are predicted from the nucleotide sequences. The cDNA molecule for pig AMP-18 is sequenced and confirmed by partial sequencing of the natural protein. The AMP-18 protein and active peptides derived from its sequence are cellular growth factors. Surprisingly, peptides capable of inhibiting the effects of the complete protein, are also derived from the AMP-18 protein sequence. Control of mammalian gastro-intestinal tissues growth and repair is facilitated by the use of the protein or peptides, making the protein and the derived peptides candidates for therapies. Searches for factors affecting the mammalian gastro-intestinal (GI) tract are motivated by need for diagnostic and therapeutic agents. A protein may remain part of the mucin layer, providing mechanical (e.g., lubricant or gel stabilizer) and chemical (e.g against stomach acid, perhaps helping to maintain the mucus pH gradient and/or hydrophobic barrier) protection for the underlying tissues. The trefoil peptide family has been suggested to have such general cytoprotectant roles (see Sands and Podolsky, 1996). Alternatively, a cytokine-like activity could help restore damaged epithelia. A suggestion that the trefoil peptides may act in concert with other factors to maintain and repair the epithelium, further underlines the complexity of interactions that take place in the gastrointestinal tract (Podolsky, 1997). The maintenance of the integrity of the GI epithelium is essential to the continued well-being of a mammal, and wound closing after damage normally occurs very rapidly (Lacy, 1988), followed by proliferation and differentiation soon thereafter to reestablish epithelial integrity (Nusrat et al., 1992). Thus protection and restitution are two critical features of the healthy gastrointestinal tract, and may be important in the relatively harsh extracellular environment of the stomach. Searches for GI proteins have met with some success. Complementary DNA (cDNA) sequences to messenger RNAs (mRNA) isolated from human and porcine stomach cells were described in the University of Chicago Ph.D. thesis “Characterization of a novel messenger RNA and immunochemical detection of its protein from porcine gastric mucosa,” December 1987, by one of the present inventors working with the other inventors. However, there were several cDNA sequencing errors that led to significant amino acid changes from the AMP-18 protein disclosed herein. The protein itself was isolated and purified only as an aspect of the present invention, and functional analyses were performed to determine utility. Nucleic acid sequences were sought.

<SOH> SUMMARY OF THE INVENTION <EOH>A novel gene product designated Antrum Mucosal Protein 18 (“AMP-18”) is a gastrokine. The protein was discovered in cells of the stomach antrum mucosa by analysis of cDNA clones obtained from humans, pigs, and mice. The protein is a member of a group of cellular growth factors or cytokines, more specifically gastrokines. The AMP-18 cDNA sequences predict a protein 185 amino acids in length for both pig and man. The nucleotide sequences also predict a 20-amino acid N-terminal signal sequence for secreted proteins. The cleavage of this N-terminal peptide from the precursor (preAMP-18) was confirmed for the pig protein; this cleavage yields a secreted protein 165 amino acids in length and ca. 18,000 Daltons (18 kD) in size. Human and mouse genomic DNA sequences were also obtained and sequenced. A human genomic DNA was isolated in 4 overlapping fragments of sizes 1.6 kb, 3 kb, 3.3 kb and 1.1 kb respectively. The mouse genomic DNA sequence was isolated in a single BAC clone. The gastrokine designated AMP-18 protein is expressed at high levels in cells of the gastric antrum. The protein is barely detectable in the rest of the stomach or duodenum, and was not found, or was found in low levels, in other body tissues tested. AMP-18 is synthesized in lumenal surface mucosal cells, and is secreted together with mucin granules. Compositions of AMP-18 isolated from mouse and pig antrum tissue stimulate growth of confluent stomach, intestinal, and kidney epithelial cells in culture; human, monkey, dog and rat cells are also shown to respond. This mitogenic (growth stimulating) effect is inhibited by specific antisera (antibodies) to AMP-18, supporting the conclusion that AMP-18, or its products, e.g. peptides derived from the protein by isolation of segments of the protein or synthesis, is a growth factor. Indeed, certain synthetic peptides whose amino acid sequences represent a central region of the AMP-18 protein also have growth-factor activity. The peptides also speed wound repair in tissue culture assays, indicating a stimulatory effect on cell migration, the process which mediates restitution of stomach mucosal injury. Thus, the protein and its active peptides are motogens. Unexpectedly, peptides derived from sub-domains of the parent molecule can inhibit the mitogenic effect of bioactive synthetic peptides and of the intact, natural protein present in stomach extracts. There are 3 activities of the gastrokine proteins and peptides of the present invention. The proteins are motogens because they stimulate cells to migrate. They are mitogens because they stimulate cell division. They function as cytoprotective agents because they maintain the integrity of the epithelium (as shown by the protection conferred on electrically resistant epithelial cell layers in tissue culture treated with damaging agents such as oxidants or non-steroidal anti-inflammatory drugs NSAIDs). The synthesis of AMP-18 is confined to lumenal mucosal lining epithelial cells of the gastric antrum of humans and other mammals. Inside cells the protein is co-localized with mucins in secretion granules, and appears to be secreted into the mucus overlying the apical plasma membrane. Recombinant human AMP-18 in E. coli exerts its mitogenic effect at a concentration an order of magnitude lower than growth-promoting peptides derived from the center of the mature protein. Peptide 77-97, the most potent mitogenic peptide, is amino acid sequence-specific AMP peptides appears to be cell-type specific as it does not stimulate growth of fibroblasts or HeLa cells. Mitogenesis by specific AMP peptides appears to be mediated by a cell surface receptor because certain peptides that are not active mitogens can competitively inhibit, in a concentration-dependent manner, the growth-stimulating effects of peptide 58-99 and antrum cell extracts. AMP-18 and its derived peptides exhibit diverse effects on stomach and intestinal epithelial cells which suggest they could play a critical role in repair after gastric mucosal injury. These include cytoprotection, mitogenesis, restitution, and maturation of barrier function after oxidant-and/or indomethacin-mediated injury. Possible mechanisms by which AMP-18 or its peptide derivatives mediate their pleiotropic effects include stimulation of protein tyrosine kinase activity, prolongation of heat shock protein expression after cell stress, and enhanced accumulation of the tight junction-associated protein ZO-1 and occludin. Certain of these physiological effects can occur at concentrations that are relatively low for rhAMP-18 (<50 nM) compared to the concentrations of other gastric peptide mediators such as trefoil peptides or the α-defensin, cryptdin 3 (>100 μM). Immunoreactive AMP-18 is apparently released by cells of the mouse antrum after indomethacin gavage, and by canine antrum cells in primary culture exposed to forskolin, suggest that the protein is subject to regulation. These results imply that AMP-18 could play a role in physiological and pathological processes such as wound healing in the gastric mucosal epithelium in vivo. The invention relates a group of isolated homologous cellular growth stimulating proteins designated gastrokines, that are produced by gastric epithelial cells and include the consensus amino acid sequence VKE(K/Q)KXXGKGPGG(P/A)PPK (SEQ ID NO: 10) wherein XX can be LQ or absent (which results in SEQ ID NOS: 25 and 26, respectively). An isolated protein of the group has an amino acid sequence as shown in FIG. 8 . The protein present in pig gastric epithelia in a processed form lacking the 20 amino acids which constitute a signal peptide sequence, has 165 amino acids and an estimated molecular weight of approximately 18 kD as measured by polyacrylamide gel electophoresis. Signal peptides are cleaved after passage through endoplasmic reticulum (ER). The protein is capable of being secreted. The amino acid sequence shown in FIG. 3 was deduced from a human cDNA sequence. An embodiment of the protein is shown with an amino acid sequence as in FIG. 6 , a sequence predicted from mouse RNA and DNA. A growth stimulating (bioactive) peptide may be derived from a protein of the gastrokine group. Bioactive peptides rather than proteins are preferred for use because they are smaller, consequently the cost of synthesizing them is lower than for an entire protein. In addition, a modified peptide may be produced by the following method: (a) eliminating major protease sites in an unmodified peptide amino acid sequence by amino acid substitution or deletion; and/or (b) introducing into the modified amino acid analogs of amino acids in the unmodified peptide. An isolated protein of the present invention include an amino acid sequence as in FIG. 8 , present in pig gastric epithelia in a processed form lacking the 20 amino acids which constitute a signal peptide sequence, having 165 amino acids and an estimated molecular weight of approximately 18 kD as measured by polyacrylamide gel electophoresis, said protein capable of being secreted. A protein of the present invention includes an amino acid sequence as in FIG. 3 , a sequence deduced from a human cDNA. A protein of the present invention includes an amino acid sequence as in FIG. 6 , a sequence predicted from mouse RNA and DNA. Embodiments of the present invention include a synthetic growth stimulating peptide, having a sequence of amino acids from positions 78 to 119 as shown in FIG. 3 ; having a sequence of amino acids from position 97 to position 117 as shown in FIG. 3 , or a sequence of amino acids from position 97 to position 121 as shown in FIG. 3 , or a sequence of amino acids from position 104 to position 117 as shown in FIG. 3 . An antibody to a protein of the present invention recognizies an epitope within a peptide of the protein that has an amino acid sequence from position 78 to position 119 as in FIG. 3 . An aspect of the invention also is an isolated genomic DNA molecule with the nucleotide sequence of a human as shown in FIG. 1 and an isolated cDNA molecule encoding a human protein with the amino acid sequence as shown in FIG. 3 . The invention includes a method to stimulate growth of epithelial cells in the gastrointestinal tract of mammals including the steps of: (a) contacting the epithelial cells with a composition comprising a protein of the present invention or a peptide derived from the protein; and (b) providing environmental conditions for stimulating growth of the epithelial cells. An embodiment of an isolated bioactive peptide has one of the following sequences: KKLQGKGPGGPPPK, (SEQ ID NO: 11) LDALVKEKKLQGKGPGGPPPK, (SEQ ID NO: 12) LDALVKEKKLQGKGPGGPPPKGLMY. (SEQ ID NO: 13) Embodiments of inhibitors are KKTCIVHKMKK (SEQ ID NO: 14) or KKEVMPSIQSLDALVKEKK. (SEQ ID NO: 15) (see also Table 1) Antibodies to the protein product AMP-18 encoded by the human cDNA expressed in bacteria were produced in rabbits; these antibodies reacted with 18 kD antrum antigens of all mammalian species tested (human, pig, goat, sheep, rat and mouse), providing a useful method to detect gastrokines. An antibody to a protein of the group recognizes an epitope within a peptide of the protein that includes an amino acid sequence from position 78 to position 119 as in FIG. 3 . The invention is also directed to an isolated genomic DNA molecule with the nucleotide sequence of a human as shown in FIG. 1 and an isolated cDNA molecule encoding a human protein, that the nucleotide sequence as shown in FIG. 2 . Another aspect of the invention is an isolated DNA molecule having the genomic sequence found in DNA derived from a mouse, as shown in FIG. 4 . Genomic DNA has value because it includes regulatory elements for gastric expression of genes, consequently, the regulatory elements can be isolated and used to express other gene sequences than gastrokines in gastric tissue. An aspect of the invention is a method to stimulate growth of epithelial cells in the gastrointestinal tract of mammals. The method includes the steps of: (a) contacting the epithelial cells with a composition comprising a gastrokine protein or a peptide derived from a protein of the group; and (b) providing environmental conditions for stimulating growth of the epithelial cells. A method to inhibit cellular growth stimulating activity of a protein of the group includes the steps of: (a) contacting the protein with an inhibitor; and (b) providing environmental conditions suitable for cellular growth stimulating activity of the protein. The inhibitor may be an antibody directed toward at least one epitope of the protein, e.g. an epitope with an amino acid sequence from position 78 to position 119 of the deduced amino acid sequence in FIG. 3 or an inhibitor peptide such as those in Table 1. A method of testing the effects of different levels of expression of a protein on mammalian gastrointestinal tract epithelia, includes the steps of: (a) obtaining a mouse with an inactive or absent gastrokine protein; (b) determining the effects of a lack of the protein in the mouse; (c) administering increasing levels of the protein to the mouse; and (d) correlating changes in the gastrointestinal tract epithelia with the levels of the protein in the epithelia. Kits are contemplated that will use antibodies to gastrokines to measure their levels by quantitative immunology. Levels may be correlated with disease states and treatment effects. A method to stimulate migration of epithelial cells after injury to the gastrointestinal tract of mammals, includes the steps of: (a) contacting the epithelial cells with a composition comprising a peptide derived from the protein; and (b) providing environmental conditions allowing migration of the epithelial cells. A method for cytoprotection of damaged epithelial cells in the gastrointestinal tract of mammals, includes the following steps: (a) contacting the damaged epithelial cells with a composition including a protein of the gastrokine group or a peptide derived from the protein; and (b) providing environmental conditions allowing repair of the epithelial cells. The damaged cells may form an ulcer.

20041021

20090707

20050324

97100.0

DEBERRY, REGINA M

GASTROKINES AND DERIVED PEPTIDES INCLUDING INHIBITORS

SMALL

ACCEPTED

ACCEPTED

Shared water reservoir beverage system

An apparatus for making and dispensing a plurality of beverages, the dispensing apparatus comprising; a plurality of beverage dispensing modules (32), each beverage module having a container (68) and a brewing assembly (30) for making a respective beverage and delivering the respective beverage to the container, and a housing (34) associated with the plurality of beverage dispensing modules and defining a chamber containing a liquid for supply to the beverage making assemblies to make respective beverages.

1. An apparatus for brewing and dispensing a plurality of beverages, the dispensing apparatus comprising: (a) a plurality of beverage dispensing modules, each beverage dispensing module having a container and a brewing assembly for brewing a respective beverage and delivering the respective beverage to the container; and (b) a housing associated with and positioned externally of the plurality of beverage dispensing modules and defining a chamber containing a heated liquid for supply to the brewing assemblies to brew the respective beverages. 2. The apparatus of claim 1 wherein each beverage dispensing module includes a dispensing valve for dispensing the respective brewed beverage from the beverage dispensing module. 3. The apparatus of claim 1 further comprising a plurality of conduits, each conduit communicating with the chamber for supplying heated liquid from the chamber to the brewing assembly of a respective beverage dispensing module. 4. The apparatus of claim 1 wherein each of the beverage dispensing modules has a front and a back, the backs facing the housing. 5. The apparatus of claim 4 wherein the fronts of the beverage dispensing modules face the same direction generally outwardly away from the housing. 6. The apparatus of claim 1 wherein the housing is positioned behind the beverage dispensing modules. 7. The apparatus of claim 1 wherein the beverage dispensing modules have fronts and further comprising a plurality of second beverage dispensing modules having fronts, the fronts of the beverage dispensing modules and the fronts of the second beverage dispensing modules facing opposite directions. 8. The apparatus of claim 7 wherein the housing is positioned between the beverage dispensers and the second beverage dispensers. 9. The apparatus of claim 1 further including a heating element positioned at least one of proximate to and in the chamber for heating the liquid within the housing, a level sensor for sensing the level of the liquid within the housing, and a temperature sensor for sensing the temperature of the liquid within the housing. 10. The apparatus of claim 1 further including a controller for selectively activating the brewing of the respective beverages and a plurality of conduits for supplying liquid from the chamber to the brewing assemblies of the plurality of modules. 11. The apparatus of claim 10 further including a plurality of activation switches associated with the beverage dispensing modules, each activation switch adapted to send a switch signal to the controller to activate brewing of the respective beverage at the corresponding beverage dispensing module. 12. The apparatus of claim 11 further including a liquid sensor for sensing the level of the liquid in the housing and for sending a liquid level signal to the controller to activate brewing of the respective beverage. 13. The apparatus of claim 11 further including a temperature sensor for sensing the temperature of the liquid in the housing and for sending a temperature signal to the controller to activate brewing of the respective beverage. 14. The apparatus of claim 11 further including a heating element associated with the housing for receiving a heating signal from the controller to activate heating of the liquid within the chamber. 15. The apparatus of claim 11 further including an inlet valve for providing liquid to the housing in response to a valve signal from the controller. 16. The apparatus of claim 10 further including a plurality of activation switches associated with the plurality of beverage modules, a liquid level sensor for sensing the level of the liquid in the housing, a temperature sensor for sensing the temperature of the liquid in the housing, and a heating element for heating the liquid in the housing, the controller adapted to activate brewing of the respective beverage in response to activation of a respective activation switch, a liquid level signal from the liquid level sensor, and a temperature signal from the temperature sensor. 17. The apparatus of claim 1 further including a liquid flavor dispensing assembly for dispensing flavoring to the brewing assembly of at least one of the beverage dispensing modules to flavor the respective brewed beverage. 18. The apparatus of claim 1 further including a liquid flavor dispensing assembly for selectively dispensing a plurality of different flavorings to the brewing assemblies of at least some of the beverage dispensing modules so that at least some of the beverages have different flavors. 19. An apparatus for brewing and dispensing a plurality of beverages, the dispensing apparatus comprising: (a) a plurality of beverage dispensing modules, each beverage dispensing module having a container, a brewing assembly for brewing a respective beverage and delivering the respective beverage to the container, and a dispensing valve for dispensing the respective beverage from the beverage dispensing module; (b) a housing associated with the plurality of beverage dispensing machines and defining a chamber containing a heated liquid for supply to the brewing assemblies to brew the respective beverages; and (c) a plurality of conduits communicating with the chamber and with a corresponding making assembly for supplying heated liquid from the chamber to the brewing assemblies of the plurality of beverage dispensing modules. 20. The apparatus of claim 19 wherein the beverage dispensing modules face the same direction generally outwardly away from the housing and the housing is positioned behind the beverage dispensing modules. 21. The apparatus of claim 19 further including a controller for selectively activating the brewing of the respective beverages. 22. The apparatus of claim 21 further including a plurality of activation switches associated with the plurality of beverage modules, a liquid level sensor for sensing the level of the liquid in the housing, a temperature sensor for sensing the temperature of the liquid in the housing, and a heating element for heating the liquid in the housing, the controller adapted to activate brewing of the respective beverage by a respective beverage module in response to activation of a respective activation switch, a liquid level signal from the liquid level sensor, and a temperature signal from the temperature sensor. 23. An apparatus for brewing and dispensing a plurality of beverages, the dispensing apparatus comprising: (a) a plurality of beverage dispensing modules, each beverage dispensing module having a container and a brewing assembly for brewing a respective beverage and delivering the respective beverage to the container; (b) a housing associated with the plurality of beverage dispensing machines and defining a chamber containing a heated liquid for supply to the brewing assemblies to brew the respective beverages; (c) a plurality of conduits for supplying liquid from the chamber to the brewing assemblies of the plurality of beverage dispensing modules; and (d) a controller for selectively activating the brewing of the respective beverages. 24. The apparatus of claim 23 wherein each beverage dispensing module includes a dispensing valve for dispensing the respective brewed beverage.

BACKGROUND This disclosure relates to beverage systems and, more particularly, to a beverage apparatus for preparing, dispensing, monitoring, controlling and, if desired, flavoring beverages. Over the past 10 years, the coffee and beverage industry has experienced an evolution in connection with retail sales of fresh coffee. In particular, there is now a significant customer demand for individual servings of fresh coffee at, among other places, coffee shops, convenience stores, and fast food restaurants. Associated with the increase in demand for retail purchases of individual servings of fresh coffee are increases in demand for flavored coffee and for different types of flavored coffee as well as a variety of other beverages, such as teas, cocoas, etc. As a result of these significant changes in the coffee and beverage industry, the service market has changed drastically over the past 10 years. Coffee shops in which consumers can walk in and purchase a fresh cup of coffee have substantially increased in number. Convenience food stores, fast food restaurants and other retailers now devote substantial floor space to serving customer demand. Moreover, these changes place increasing demands on employees of retail outlets to monitor the coffee brewing and beverage preparation equipment to ensure that there is a constant supply of fresh coffee available to consumers and in many cases to also ensure that there is a sufficient number of different flavors of fresh coffee available. These changes in the coffee service industry have also created an increased need for efficiency in serving the consuming public. To be competitive in this expanding marketplace, efficiency in the brewing, storage, and dispensing of coffee is increasingly important. In particular, there is now a premium on being able to serve in an efficient manner the large demand for not only fresh coffee but also different flavors of coffee, in light of the substantial retail space needed for the coffee brewing and dispensing equipment and the continuous responsibilities in administering the brewing and dispensing process. SUMMARY The present disclosure relates to apparatus for making and dispensing beverages. The apparatus comprises a plurality of beverage dispensing modules, and a housing associated with the plurality of beverage dispensing modules and defining a chamber containing a liquid. Each beverage dispensing module has a container and an assembly for producing a respective beverage and delivering the respective beverage to the container. The liquid contained in the chamber is supplied to the assemblies to produce the respective beverages. In a preferred embodiment, each beverage dispensing module includes a dispensing valve for dispensing the respective brewed beverage from the beverage dispensing module. In a preferred embodiment, the apparatus may also include a controller for selectively activating the production of the respective beverages. The apparatus may also include a plurality of conduits for supplying liquid to the assembly. The dispensing modules and housing may have any suitable construction and desirably are oriented in a manner that is space efficient and facilitates easy administration and usage of the apparatus. Desirably, the beverage dispensing modules have a front and a back, the backs facing the housing, and the fronts may face the same direction. The housing may be positioned behind the beverage dispensing modules. In accordance with one embodiment, for example, the apparatus also includes a plurality of second beverage dispensing modules and the fronts of the beverage dispensing modules and the fronts of the second beverage dispensing modules face opposite directions. With this embodiment, desirably the housing is positioned behind the beverage dispensers and behind the second beverage dispensers. The apparatus may further include a heating element for heating the liquid within the housing, a level sensor for sensing the level of the liquid within the housing, and a temperature sensor for sensing the temperature of the liquid within the housing. A plurality of activation switches desirably are associated with the beverage dispensing modules, each activation switch is adapted to send a switch signal to the controller to activate production of the respective beverage. The controller preferably is adapted to activate production of the respective beverage in response to activation of the respective activation switch, a liquid level signal from the liquid level sensor, and a temperature signal from the temperature sensor. The apparatus also may include an inlet valve for providing liquid to the housing in response to a valve signal from the controller. In addition to being able to produce and serve a plurality of respective beverages, the apparatus desirably also includes a liquid flavor dispensing assembly for dispensing flavoring to the brewing assembly of at least one of the beverage dispensing modules to flavor the respective brewed beverage. In a preferred embodiment, for example, the liquid flavor dispensing assembly selectively dispenses a plurality of different flavorings to the assemblies of at least some of the beverage dispensing modules to provide beverages having different flavors. Additional features will become apparent to those skilled in the art upon consideration of the following detailed description of drawings exemplifying the best mode as presently perceived. BRIEF DESCRIPTION OF THE DRAWINGS The detailed description particularly refers to the accompanying figures in which: FIG. 1 is a partial fragmentary side elevational view of a modular beverage dispensing apparatus; FIG. 2 is a top plan view of the modular beverage dispensing apparatus of FIG. 1; FIG. 3 is a side elevational view of the modular beverage dispensing apparatus of FIGS. 1 and 2; FIG. 4 is a schematic illustration of the modular beverage dispensing apparatus; FIG. 5 is a schematic illustration of one module of the modular beverage dispensing apparatus; FIG. 6 is a diagrammatic illustration of a dispensing and disposal valve configuration; FIG. 7 is a partial fragmentary top plan view taken along 7-7 in FIG. 6; FIG. 8 is a diagrammatic illustration of a liquid flavor distributing system; FIGS. 9 and 10 are diagrammatic illustrations of the arrangement of liquid flavor distributing systems; FIG. 11 is a cross sectional view, schematic in nature, of a portion of a powdered beverage, soluble beverage dispensing system including connections to dispense liquid flavor to the soluble beverage production stream; FIGS. 12 and 13 are diagrammatic illustrations of the liquid flavor distributing system coupled to the soluble beverage dispensing system of FIG. 11; FIG. 14 is a perspective view of a soluble beverage dispenser having a slide-out assembly; FIG. 15 is an enlarged perspective view of the soluble beverage dispenser of FIG. 14 showing a user removing a container from the soluble beverage dispensing device using the slide-out assembly; FIGS. 16 and 17 are enlarged views of portions of the slide-out assembly of the soluble beverage dispenser of FIG. 14; FIG. 18 is a perspective view of a cable and spring leverage system which assists movement of the slide-out assembly relative to the beverage dispensing system; FIGS. 19 and 20 are schematic illustrations of a communication link between a base station and a beverage dispensing device; and FIGS. 21-28 are schematic illustrations of the circuitry associated with the communication system of FIGS. 19 and 20 AND INCLUDE FIG. 22A, FIGS. 22-22D, FIGS. 23-23D, FIG. 24, FIGS. 24A-24B, FIGS. 25A-25B, FIGS. 26A-26, FIG. 27, FIGS. 27A-27C, FIG. 28 and FIGS. 28A-28E. DESCRIPTION OF THE DRAWINGS While the present disclosure may be susceptible to embodiment in different forms, there is shown in the drawings, and herein will be described in detail, embodiments with the understanding that the present description is to be considered an exemplification of the principles of the disclosure and is not intended to limit the disclosure to the details of construction and the arrangements of components set forth in the following description or illustrated in the drawings. A beverage dispensing apparatus 30 illustrated generally in FIGS. 1-4 as comprising a plurality of beverage dispensing modules 32 and a housing 34 that defines a chamber 36 containing water or other liquid suitable for use in brewing. The housing 34 desirably acts as a central reservoir for a constant supply of heated water to be used by the beverage dispensing modules 32 to brew several different beverages. The beverage dispensing apparatus 30 may have any suitable construction and configuration. The beverage apparatus 30 may include any suitable number of beverage dispensing modules 32 oriented in any suitable manner, depending on various circumstances, such as, for example, customer demand, customer usage, available store space, and desired aesthetics. Similarly, the housing 34 may have any suitable construction and configuration that desirably is consistent with customer demand, customer usage, available store space and desired aesthetics. A plurality of conduits in the form of water lines 38 provide flow communication between the housing 34 and the beverage dispensing modules 32 to supply water for brewing. In a preferred embodiment, the housing 34 is positioned behind the beverage dispensing modules 32 and centrally located relative to the beverage dispensing modules 32 to minimize the distance between the housing and each of the beverage dispensing modules, thereby increasing operational efficiency and minimizing space. Terms including beverage and beverage making as used herein are intended to be broadly defined as including but not limited to the brewing of coffee, tea and any other brewed beverage, including a final beverage or food product as well as producing an intermediate product to be combined with a final beverage or food product. This broad interpretation is also intended to include, but is not limited to any process of infusing, steeping, reconstituting, diluting, dissolving, saturating or passing a liquid through or otherwise mixing or combining a beverage substance with a liquid such as water without a limitation to the temperature of such liquid unless specified. This broad interpretation is also intended to include, but is not limited to beverage substances such as ground coffee, tea, liquid beverage concentrate, powdered beverage concentrate, freeze dried coffee or other beverage concentrates, to obtain a desired beverage or other food. In the illustrated embodiment, for example, the beverage dispensing apparatus 30 comprises ten beverage dispensing modules 32 oriented in a generally U-shaped manner that substantially surrounds the housing 34. As illustrated, four of the beverage dispensing modules 32 face the same direction, four other beverage dispensing modules 32 face an opposite direction, and two of the beverage dispensing modules 32 are positioned in a space-efficient manner consistent with a desired orientation. A simplified form of the beverage apparatus 30 is shown in FIG. 4 which uses simplified block diagram illustrations to show multiple beverage dispensing modules 32 which are configured to provide a beverage brewing system. The beverage apparatus 30 shown in FIG. 4 is very similar to a soluble beverage apparatus 30a also shown in FIG. 4. The beverage apparatus 30, as will be described in greater detail herein below, relates to a beverage brewing or producing system whereas the soluble beverage apparatus 30a, as will be described in greater detail herein below, relates to a soluble or powdered beverage dispensing system. Both beverage apparatuses 30, 30a employ a common heated water reservoir contained in housing 34 to which the individual modules 32, 32a are connected. As shown in FIGS. 2-4, the housing 34 desirably is centrally located to serve multiple beverage modules 32, 32a. The benefit of a common housing 34 functioning as a common reservoir to supply water, instead of individual tanks for each module 32, 32a, is that it substantially reduces the cost and greatly increases the efficiency of the system. Also it reduces the redundancy of multiple heated water reservoirs, reduces the wattage required by the system and increases flexibility in the number of modules 32, 32a which might be included. The particular configuration with the housing 34 positioned in close proximity to or between several modules 32, 32a is beneficial in that it also minimizes the length of water lines 38 connecting the housing 34 to the modules 32, 32a. Additionally, a larger body of water in the housing 34 tends to help maintain the temperature and reduce temperature loss over time as well as maintaining a larger volume of brew water at a desired temperature. While the housing 34 retained within the beverage apparatus 30 is insulated to reduce heat loss and reduce heat load on the ambient environment, heat which may escape from the housing 34 will generally pass to the modules 32, thereby increasing the efficiency of maintaining the temperature of the beverages retained in the modules 32. Insulation desirably is provided to reduce heat loss to the ambient environment. This will also help reduce the exertion on the ambient air-conditioning system thereby further increasing efficiency of the present beverage apparatus 30, 30a. With reference to FIGS. 1-4, each module 32, 32a produces a separate brewed beverage. The centralization of a housing 34 helps reduce the individual cost associated with the module 32,32a and improves the ease of manufacturing of the modules. Also, there is increased commonality of parts associated with this type of system. The modular configuration of the beverage apparatus 30 using the modules 32, 32a increases the potential variability of the physical size and brewer configuration of the system. This is beneficial to accommodate the needs of a particular location. In other words, only a desired or required number of modules 32, 32a will be needed at any given time. If a location has an increase in demand for brewed or soluble beverages additional modules 32, 32a may be added as necessary for the particular change in demand. Additionally, with regard to repair and maintenance, the beverage apparatus 30, 30a can be designed such that individual modules 32, 32a can be removed for repair and maintenance as necessary with an identical module being inserted in the missing modules. In a preferred embodiment, (FIG. 5) the housing 34 includes a heating element 52, and one or more system sensors such as a level sensor 86 and a temperature sensor 84. Such components tend to be generally readily available and easily replaced and as such further enhance the reliability of the overall beverage apparatus 30, 30a. With reference to FIG. 3, the line 38 connecting each housing 34 to a brewing portion 40 of the module 32 is shown. Water 42 retained in the housing 34 can be readily dispensed. A water inlet line 44 is provided to introduce unheated water 50 to the housing 34. The inlet line 44 runs from an upper portion 46 of the housing 34 and directs the inward water downwardly towards a bottom portion 48 of the housing 34. Introducing the unheated water 50 towards the bottom of the reservoir introduces the unheated water 50 in close relation to a heated element 52 thereby accelerating the heating of the water. Additionally, the introduction of unheated water 50 in the bottom portion 48 tends to force heated water in the upper portion 46 upwardly. As such, the water 42 in the upper portion 46 tends to be the hottest water in the housing 34. Introducing unheated water 50 from the upper portion has the benefit of providing an entrance into the reservoir through a reservoir wall 56 with little or no pressure on the entry therethrough. This may result in an increase in the reliability of the entry therethrough. Additionally, a reinforcing or strengthening structure 58 is provided extending between opposed walls 60, 62 of the housing 34. This helps prevent bowing or stress on the walls 60, 62 which might otherwise result from the force of the water on the walls. Multiple reinforcing structures 58 may be provided throughout the housing 34 as necessary to provide support for the size and dimension of the housing required for a particular system. FIG. 5, for example, shows a diagrammatic illustration of an embodiment of the apparatus 30 shown in FIGS. 1-4. The beverage dispensing modules 32 can have any suitable construction desirably adapted to produce beverages, store beverages for ready consumption, and facilitate ready dispensing of the beverages. Each module 32 includes a brewing assembly 30 that may have any suitable construction that can be used to produce beverage such as brewing coffee or other beverages. The illustrated brewing assembly 30, for example, includes a brewing substance retainer or assembly 64 including a funnel 66. Such a retainer 64 may be well known in the art and may include a filter (not shown) retained in the funnel 66 for holding a charge of beverage substance. The funnel 66 may be positioned above a reservoir or container portion 68 of the dispensing module 32 which receives brewed beverage from the funnel. A dispensing assembly 70 in the form of a controllable valve may be associated with the container 68 for dispensing beverage from the module 32. With reference to FIG. 5 a simplified review of the beverage brewing process is described. A brew actuator switch 72 desirably is associated with each of the modules 32. To initiate a brew cycle for one of the modules 32 a respective brew activation switch 72 is operated. Operation of the switch 72 sends a signal over line 74 to controller 76. Controller 76 operates an inlet valve 78 over line 80 to introduce water to the housing 34. Also, heating element 52 is coupled to the controller 76 over line 82. The temperature sensor 84 and level sensor 86 are coupled to the controller over lines 88, 90 respectively. If the controller 76 detects proper level and temperature it will initiate a brew cycle thereby displacing water from the housing 34 through a sprayhead assembly 92. The sprayhead assembly 92 communicates with the substance retainer 64 and dispenses water into the funnel 66 for producing a beverage therein. The illustrated module 32 includes a level sensor 94 associated with the container 68 which is coupled to the control over line 96. The level sensor can detect a change in level in beverage retained in the container 68 which may be used to activate a brew cycle. Also, the level detector 94 may sense the level in the beverage container 68 thereby indicating if the container is full or above the desired level to prevent initiation of a brew cycle. This will prevent over flow of the beverage server 68. The beverage dispensing modules 32 can be constructed to dispense beverage in any suitable manner. In a preferred embodiment, for example, a dispenser or faucet switch 98 may be associated with the dispensing assembly 70 and coupled with a dispensing handle or control 100. Activation of the control 100 will activate the switch 98 over line 102 connected to the controller 76 thereby indicating that the controller 76 should operate a solenoid valve 104 (FIGS. 6 and 7), via line 106 to dispense beverage therefrom. As will be described in greater detail below with regard to FIGS. 6 and 7, a disposal or dump valve 108 is also coupled with the container 68 to facilitate controllable disposal, via line 110 coupled to the controller 76. With reference to FIGS. 6 and 7, the beverage container 68 may further include a manifold 114. The illustrated manifold 114 includes a primary passage 116 which communicates with an interior cavity or reservoir 118 of the container 68. Beverage flows from the cavity 118 through the primary passage 116. The solenoid valves 104, 108 communicate with the passage 116. A dispensing passage 120 and a disposal passage 122 communicate with the primary passage 116. Solenoid valve 104 and 108 desirably are normally closed and require specific activation in order to open the valves. During a dispense cycle the switch or control 100, for example a controllable faucet as shown in FIG. 5, is activated thereby activating solenoid valve 104. When the dispense solenoid valve 104 is opened beverage 124 will flow from the cavity through the solenoid valve 104. Under this condition disposal valve 108 is closed. When beverage must be disposed of, the disposal solenoid valve 108 is opened while maintaining the dispense solenoid valve 104 in a closed position. This will allow the disposal of beverage through a separate dispensing line. Disposal of beverage may occur as a result of a time lapsed period whereby after a specified period of time beverage should be disposed of. For example, if a beverage only maintains a desired flavor profile or other characteristics for a period of time, for example 2 hours, at the end of two hours after the beverage brewing cycle is initiated, the beverage may be disposed of through the disposal valve 108. Such disposal may also be used at the end of a service cycle such that at the end of the day all beverages may be disposed of at a predetermined time. The disposal valve may also be used in a manner to flush and cleanse the beverage brewing system. In this regard, at a predetermined period of time, the controller 76 may operate the disposal valve 108 to dispose of any beverage retained in the container 68. The disposal valve 108 and dispense valve 104 may be closed. The controller 76 may then dispense a quantity of water into the cavity 118 thereby flushing and sanitizing the reservoir. After holding the heated water for a predetermined period of time the water may be disposed through the disposal valve 108. Multiple rinsing or flushing cycles may be controlled by the controller 76. In this regard, both the cavity 118, the container 68 and the associated passages 116, 122, 120 and solenoid valve 104, 108 maybe cleansed and sanitize periodically and automatically. It will be appreciated that these automatic cycles will likely greatly increase the cleanliness, taste reliability and sanitation of such beverage dispensing systems as such procedures require considerable amount of time on the part of manual operators. The use of controllable solenoid valves 104, 108 also prevents dispensing of beverage during a brew cycle. For example, once a brew cycle is initiated the controller 76 can lock out the solenoid valves 104, 108. This will allow for the brewing cycle to complete and brewed beverage to mix within the container 68 to insure consistent flavor. The beverage dispensing modules 32 can be constructed in any other suitable manner to dispense brewed beverage in any suitable manner in accordance with various embodiments disclosed. If desired, for example, the beverage containers 68 of the beverage dispensing modules 32 can instead be in the form of carafes (not shown) or have any other suitable construction. In a preferred embodiment, during a brewing cycle, heated water 134 is dispensed from the housing 34 through the water dispensing system. Heated water 134 is used to infuse a beverage brewing substance 136 retained in the brewing assembly 64. An opening 138 is provided in the bottom of the funnel 66 to allow a brewed beverage 140 to flow therefrom. As shown, for example, in previous figures, a brewed beverage container 68 is provided to collect the beverage 140. The beverage container 68 may be of any suitable form. With reference to FIG. 8, a liquid flavor dispensing system 130 may be employed with the modular beverage dispensing system disclosed. The liquid flavor dispensing system 130 can have any suitable configuration and can be used to supply flavoring 132 to all or less than all of the beverage dispensing modules 32. The liquid dispensing system 130 may also be used to supply a different flavoring 132 to each of the different beverage dispensing modules 32. Additionally, the flavorings 132 can be supplied to the beverage dispensing modules by a single liquid flavor dispensing system 130 or several liquid flavor dispensing systems. Further, the flavoring 132 may in the form of the typical flavorings associated with brewed coffee or instead be in any other suitable form such as, for example, honey, peach, lemon, herbal flavors, or any other suitable flavoring which might be desired by a beverage consumer for any number of different beverages. In a preferred embodiment, a small quantity of flavoring 132 is introduced into the water which is dispensed to the beverage brewing substance 136. The beverage brewing substance may be in the form of decaff or regular ground coffee as well as tea substances or other substances which might be used in an infusion beverage brewing process. The objective in using the liquid flavoring material 132 is to introduce a small quantity of concentrated material or substance 132 during the brewing process so that the flavor becomes fully mixed with and saturated in the heated water 134. Introduction of the flavor 132 early in the brewing process will help assure that the flavor fully mixes with the water, is fully flushed through the beverage brewing substance to maximize the value of the flavor and is used to produce an aroma which might entice purchasers of the beverage as part of the beverage purchasing experience. The flavor could also be dispensed into the beverage brewing substance and subsequently mixed with the water and the resultant brew during the brewing process. A benefit of adding flavors at the time of brewing and/or mixing soluble beverages, over using pre-flavor beverage substances, is the increased effectiveness of the flavorings. The increased effectiveness of the flavorings reduces the amount of flavoring required to produce a desired taste profile. Under these circumstances, the flavorings are mixed with the beverage substance under optimal conditions to maximize the flavoring benefits of the flavorings. For example, the time prior to mixing the flavoring with the brewing substance is nominal thereby virtually eliminating any degradation of the flavoring which might occur if the flavoring was exposed to air. A liquid flavor dispensing system 130 is illustrated diagrammatically in FIG. 8. With this embodiment, the liquid flavor dispensing system dispenses a different liquid flavoring 132 in a controlled manner to several of the brewing assemblies of the beverage dispensing modules 32. The flavor can be dispensed to a water or liquid distribution system which controllably dispenses water to a beverage making substance, the beverage malting substance or both. With reference to FIGS. 8-10, the illustrated liquid flavor dispensing system 130 desirably includes a plurality of packages or containers 144a-144h, each of which retains a respective liquid flavor 132 therein. The containers 144 desirably are in controlled communication with respective beverage dispensing modules 32a-32d in any suitable manner. For example, a section of tubing or other passage 146 may connect each container 144 to a respective check valve 148. The check valve 148 is part of a respective solenoid or other form of pump device 150 coupled to the controller 76 via a respective line 152. A respective small diameter tube 154 extends from the solenoid pump 150 to a respective second check valve or flavor injection port 156 at a respective terminal end 158 of the tube 154. A respective sensor 160 can be coupled to the controller via a respective line 162 to monitor and detect a low level of the respective flavoring 132 in the respective container 144. As will be described in greater detail below with regard to sensing and monitoring, the status of the flavorings 132 can be reported by the controller 176. The check valves 148 and 156 at each end of each of the tubes 154 provide a sealed line to which the container 144 can be attached. Also, either alternatively or in addition to the use of the sensor 160, the flavor usage can be inferred based on information collected on a characteristic of the pump such as operation or usage for example, pump actuation. For example, a sensor may be associated with the pump and run time of the pump 150 could be monitored and a calculation made to infer the amount of flavorings remaining in a corresponding flavorings container 144. The system would provide a signal to the operator, such as “checlc-status” when the level of flavorings approaches, attains or drops below a predetermined level, for example 20% remaining. Such advance warning would give the operator the opportunity to change the flavorings container 144 before it runs out. The advance warning also helps assure that a reasonable margin of error in the inferred calculation is considered and accommodated for. In use, when a brewing cycle is initiated, the solenoid pump 150 can be activated simultaneous with the initiation of the brewing cycle of one of the beverage dispensing modules or shortly thereafter. A quantity, for example 9 ml for use in brewing ½ gallon of coffee, of liquid flavoring 132 is pumped from the container 144 through the tubing 154. The check valve or flavor injection port 156 is positioned in close proximity to a sprayhead 170 of the dispensing assembly 92. Dispensing of the flavor 132 into the water will allow the flavor to mix with the heated water for brewing substance during the saturation and extraction process. Generally, it is desirable to use the flavoring at the start of the cycle which will result in completely integrating the flavor during the brewing cycle. The process may be repeated with other beverage dispensing modules 32, 32a and, if desired, with other flavors. The flavor injection ports 156 may, for example, include a check valve of a type as produced by Smart Products. This is a positive pressure inverted check valve which requires positive pressure through the tube 154 to open the valve. Positioning of the injection port 156 in close proximity to the sprayhead 170 results in the benefit of clearing and rinsing the surface as a result of the water vapor and heat during a brewing cycle. Periodic manual cleaning of the sprayhead 170 and injection port 156 helps maintain a clean system. Desirably, because the injection port 156 is an inverted pressure check valve, physical contact with the tip of the injection port 156 through which the liquid 132 is dispensed does not result in dispensing of liquid 132. Rather, physical contact with the end of the injection port 156 causes the valve to close as opposed to open. The system also prevents the entry of atmosphere into the container 144 or line 154 thereby preventing contamination or degrading of the flavor or quality of the flavorings. This system provides a generally closed system which prevents the flavorings contact with the atmosphere and prevents contamination providing a generally aseptic environment. With reference to FIG. 11, the liquid flavor dispensing system 130 as described with regard to FIGS. 8-10 may be used with a soluble beverage system 176. In FIG. 11, the liquid dispensing system dispenses liquid flavor into a hot water path 174 of a soluble or powdered beverage dispensing system 176. The devices used to dispense the liquid flavor are the same as those describe above with regard to FIG. 8. As such, only the terminal ends 158a, 158b and 158c of multiple lines 154a, 154b, and 154c are shown. Similarly, the multiple injection ports 156a, 156b, and 156c are shown. The soluble beverage dispensing system 176 retains a quantity of powdered beverage mix (not shown) in a beverage dispensing container 178. The dispensing of soluble beverage material in powder form is generally known in the art. The container 178 includes a dispensing auger (not shown) which controllably dispenses powder by operation of a dispensing drive or motor 180 controlled by the controller 76a. Powdered beverage material is dispensed through the passage 182 into a mixing chamber 184. The hot water line 174 communicates with the mixing chamber 184 to combine with the powder. The combined powder and hot water flow into an agitating chamber 186 there below. A whipper motor 188 and agitating blade 190 further blend the powder and water combination for dispensing a beverage 192 through a nozzle 194. The flavor dispensing system 130 (see, FIG. 8) controllably dispenses liquid flavor 132 from respective containers 144 using corresponding pumps via the lines 154a, 154b, and 154c. Either individual flavors or combinations of flavors may be dispensed into the hot water line. Such dispensing may be programmed in the controller 76a. Positioning of the injection ports 156a, 156b, 156c in the heated water path helps to assure that the liquid flavors are rinsed from the injection ports during and at the conclusion of the heated water dispensing cycle during a beverage dispensing cycle. It should be noted that generally these powdered beverage dispensing systems have a momentary hot water overrun at the end of the cycle during which powdered beverages dispense from the container 178. The slight overrun of heated water helps to assure that the mixing chamber 184, whipping chamber 186, and nozzle 194 are rinsed clean at the end of the cycle. The injection ports 156a, 156b and 156c have been positioned in the hot water line to provide the rinsing characteristics and benefits of the overrun of hot water. Furthermore, it is commonly known to have at least one daily rinse cycle in which heated water is dispensed through the assembly 176 to maintain cleanliness and sanitation of the system. During a brew cycle as shown in FIG. 8, liquid flavor is generally preferably dispensed at the initiation of the brew cycle. As noted, this helps to ensure complete mixing and optimal extraction of the flavor from the beverage brewing substance 136. A predetermined volume of liquid flavor 132 can be dispensed into the brewing assembly 30 at the initiation of the brew cycle. In contrast, the soluble system 176 as shown in FIG. 11 may have a variable quantity of beverage 192 dispensed therefrom. It is anticipated that multiple beverage sizes may be dispensed from the soluble system 176. As a result, the liquid flavoring 132 must be dispensed at a rate consistent with the concentration flavor profile or recipe, and powder also dispensed by the system. For example, if a consumer wishes to obtain a 12 ounce beverage the proper amount of liquid flavoring must be dispensed for a 12 ounce beverage. However, the consumer may be allowed to control whether they wish to have a full 12 ounces of beverage or if they decide to short the beverage resulting in, perhaps, only 10 ounces being dispensed. As such, the pump associated with the powdered beverage system 176 must be calibrated to dispense small quantities of liquid flavoring 132 on a per unit time basis to assure a desirable and consistent mixing of flavor with the powder. This will help assure that the desired flavor is achieved regardless of the quantity of beverage dispensed. The solenoid pump 150 used with the liquid flavor dispensing system 130 is a precision controlled metering pump. It is anticipated that other forms of the metering pump may be used with this system. However, in the present embodiment, the metering pump is controllably operated to dispense very small quantities of the liquid flavor 132. The frequency of the plunger rate, the stroke of the plunger as well as the duration of plunger operation the solenoid pump 150 can be controlled by the controller 76, 76a. As a result, very small quantities of highly concentrated liquid flavor can be dispensed into the beverages 140, 192 during the corresponding beverage preparation process. As such, precise quantities can be added to provide flexibility and tailoring of the resultant beverages. The system 130 can be calibrated using volumetric guidelines associated with various beverage recipes and flavor materials to match particular flavor preferences, for example for various demographics. As such, a franchise operation can custom blend and configure the flavor of beverages dispensed by the beverage dispensing system to meet and satisfy regional preferences. Additionally, if preferences change over time the system can be modified and calibrated to match those preferences. This adds further flexibility to the beverage system disclosed. With reference to FIGS. 14-18, a powdered or soluble beverage dispensing system 199 is shown. While a soluable beverage system 199 has been shown and described as a powder dispensing system, it is envisioned that such a soluable system also includes a liquid concentrate system which dispenses a quality of liquid coffee concentrate for mixing with water or other dilution or reconsituting substance. Reference to a soluable beverage system is intended to be broadly interpreted. Such a beverage dispensing system has been generally and diagrammatically shown in FIG. 11. With further reference to FIG. 14, the container 178 is shown positioned inside a housing 200. The passage 182 coupled to the container 178 is shown positioned for dispensing into the mixing chamber 184 and communicating with the whipping chamber 186 and nozzle 194. A portion of the housing 200 in the form of a door 202 conceals the powdered beverage system 176 in the housing 200. Also, the liquid flavor dispensing system 130 as described hereinabove may be used with the powdered beverage or soluble beverage dispensing system 176 illustrated in FIGS. 14-18. One of the potential difficulties involved with a soluble beverage dispensing system is that the container 178 must be removed periodically for refilling with powdered or soluble beverage substance as well as regular maintenance and cleaning. The container 178 may not be very heavy when it is empty because it is generally formed of a plastic material. However, once filled, it may contain 5 to 10 pounds of powder material. With the container 178 being positioned in an elevated location and containing a quantity of material, it may be difficult to lift the container into a desired position in the housing 200. The container 178 is positioned in an upper position in the housing 200 in order to benefit from gravity assistance when dispensing powdered beverage therefrom to the mixing chamber 84. Additionally, it is important to align the dispensing passage 182 with the housing 184 to help assure that when powdered beverage material is dispensed from the container 178 it flows into the proper path for mixing with water. As such, it would be desirable to provide an apparatus and system for facilitating improved ease of removal and replacement of the powdered beverage container 178 relative to the housing 200. As shown in FIGS. 14-18, a container positioning assembly or container positioner 220 in the form of a slide-out support or shelf is provided. The container positioning assembly 220 includes a pair of handles 222 which can be grasped (see FIG. 15) by a user to extract the container 178 attached to the assembly 220 for removing it from the housing 200. As shown in FIG. 15, the assembly 220 allows the container 178 to be pulled straight out of the housing 200 thereby allowing disengagement of the passage 182 relative to the mixing chamber 184. Movement of the assembly 220 also replaces the container 178 in a desired position to align the dispensing passage 182 with the mixing chamber 184. As can be seen in FIGS. 15-17, the container 178 has been removed from the housing 200 in order to refill the container 178 but does not have to be removed from the shelf 250 of the assembly 220. Support rails 226 are positioned on each side of container 178 and are engaged with side walls 228 of the housing 200 (FIG. 15). Each of the guide rails 226 includes a pair of tracking slots 230, 232 which are engaged with corresponding upper 234 and lower 236 guide rollers. A support roller 240 is positioned along an exterior edge 242 of the guide 226 to further help facilitate smooth and controlled movement of the assembly 220. Support rollers 240 and guide rollers 234, 236 are mounted on the sidewalls of the housing 200. The guides 226 are connected by a cross extending shelf 250 on which the container 178 is positioned. The combination of the guide rails 226 and rollers help the assembly 220 slide outwardly and inwardly relative to the housing 200. FIG. 16 shows only the portion of the guide rails 226 extending past the edge of container 178. The guide rollers 240, 234, 236 associated with the guides 226 prevent tipping of the shelf 250 and associated container 178. When the assembly 220 is stowed in the housing 200 the shelf 250 rests on a corresponding surface 252 of the housing 200. As can be seen in FIGS. 15-17, the guides 226 include a generally horizontal portion 254 and a vertically oriented portion 256. The shelf 250 and container 178 are associated with the generally horizontal portion 254. The generally vertical portion 256 helps to allow forward movement as well as downward movement of the assembly 220 relative to the housing 200. The guide including the portion 254, 256 help facilitate movement of the container into and out of the housing 200 and forward and downward movement. In the embodiment as shown, the assembly facilitates positioning of the container 178 approximately 6-8 inches downwardly from its stored position in the housing 200. This lowering of the container 178 is beneficial in that it allows for easy filling of the container. Also, by fixing the container to the shelf 250 and the assembly 200 it prevents spilling or otherwise tipping of the container 178 during filling or other processes. This can result in savings in terms of lost beverage material as well as cleanup costs and associated complications. In the stored position, detents 260, 262 are provided on the guides 230, 232, respectively. The detents 260, 262 allow the rollers 234, 236 respectively, to be engaged therewith to prevent casual disengagement of the assembly 220 from the housing 200. This helps to lock or retain the assembly 220 in a desired stored or stowed position in the housing 200. As the assembly 220 is moved outwardly from the housing 200, the track guides 234, 236 track along the corresponding channels 230, 232 generally horizontally along the horizontal portion 254. As such, the container 278 attached to the shelf 250 sides forwardly and outwardly from the housing. At a position where the generally horizontal portion 254 transitions into the partially vertical portion 256 (elbow 270) the guides allow the assembly to slide downwardly and forwardly. In the extended most position the guides 234, 236 engage corresponding extended detents 272, 274, respectively. These detent positions 272, 274 help retain the assembly 220 in the outward or extended most position. The assembly 220 also includes an assist system 280 which includes cables 282 and biasing members to springs 284 forming a cable-biasing assembly help facilitate removal of and replacement of the container 178 relative to the housing 200. With reference to FIG. 18, the assist system 280 includes a spring 284 attached at one 286 to a back portion of the housing and at a second end to a first pulley 288. The cable 282 is attached at a first end 290 to a corresponding portion of the housing and extends through the first pulley 288 and up and around a second pulley 292. The second end 294 of the cable 282 attaches to a corresponding portion of the guides 226 at attachment point 296. Attachment of the cable 282 to the guide 226 is shown in FIG. 16. The assist assembly 288 helps further facilitate ease of removal and replacement of the container 178 relative to the housing 200. For example, when the container 178 is removed from the housing on the assembly 220 the spring 284 stores energy and is stretched as the cables 282 are extended. The cables 282 are extended as a result of the forward and downward movement of the guides 226. Extension of the springs 284 expends the stored energy and imparts a return force in the springs which helps reduce the force required to return the container 178 to the housing 200. This is particularly useful when an empty container is removed from the housing, filled with powdered material and then returned. Returning the filled container 178 normally would require additional effort on the part of the operator and as such the return forces in the assist system 280 help make the return easier. Turning now to FIGS. 19 and 20, the beverage system also includes a communications system or means 300 for communicating 302 between a corresponding beverage brewing, beverage making apparatus or beverage dispensing modules 32, 32a and a receiver or base station 304. Each of the modules 32, 32a includes a controller 76, 76a which is centralized for use with multiple modules or dedicated to an individual module. The controller collects information about the module or modules. For purposes of this present discussion, we will refer to the controller as being dedicated to multiple modules and receiving information from each individual module associated therewith. The many modules associated with a single control also provides the added benefit of the modular assembly as described hereinabove. It should also be noted that the details of the circuitry used to achieve the communication system are illustrated in the detailed schematics provided in FIGS. 21-28 and all corresponding sub-portions thereof. For example, FIG. 21 is a general schematic of the overall system. FIGS. 22-28 provide details about the general system shown in FIG. 21. FIG. 21 has been noted with cross reference to the other figures which provide details about the portions of the circuitry shown generally in FIG. 21. The controllers 76, 76a include the link 302 which connects the controller to the corresponding receiver or base station 304. In the present embodiment as diagrammatically illustrated in FIGS. 19 and 20, the controllers 76, 76a communicate with the receiver 304 by way of an RF link 302. Generally, the controllers are remote from the receiver and use the Link 302 and the associated means for linking to communicate the collected information about the beverage making apparatus. Antennae 306, 308 are provided on the controllers 76, 76a and the corresponding receivers 304 respectively. It should be noted that the communication link 302 may be in any one of a variety of forms such as hardwired physical point-to-point link, optical lines, light wave, ultrasonic, infrared or any other form of communication link between one or more devices. The receiver 304 receives information from the controller or various components of the modules 32, 32a to identify information relating to the modules and operation of the modules. The receiver 304 may be in the form of a monitoring unit positioned in an appropriate location relative to an operator or attendant who has responsibility for or otherwise maintains the modules 32, 32a. The receiver 304 includes a means for displaying display 305 and can provide visual auditor or other information about numerous conditions. The display 304 allows a form of the collected information about the beverage making apparatus to be displayed at the receiver. The visual display may include, but is not limited to lights, text, symbolic images (i.e., dispenser “full” showing a colored or shaded dispenser and a dispenser “empty” showing an unshaded dispenser), and mechanical devices that tare operated or other visual displays. An auditory display may include, but is not limited to speech information, alarms, tones or other signals that van be heard. Tactile displays are also contemplated in the form of a vibrating surface, vibrating device worn by the operator or other means for letting the operator or other means for letting the operator know about he collected information. For example, the following is a list of the messages or conditions which can be displayed: Receiver fault; Please wait attempting communication; Communication failure, coffee module #; Communication fault, soluble module #; Flavor [type] low, coffee module #; Flavor [type] low, soluble module #; Hopper low, soluble module #; Hopper empty, soluble module #; Coffee empty, coffee module #; Coffee low, coffee module #; Freshness expired, coffee module #; Dumping in ______ minutes, coffee unit #; Server removed, coffee module #; Refill too long; Temperature probe open; Temperature probe short; Heating too long; Over flow safety; Coffee stations all OK; and Soluble stations all OK For example, in an convenience store setting, multiple modules 32, 32a may be generally remotely positioned in one portion of the store, for example, a rearward location of the store, if desired. The operator of the beverage system may also be the same person responsible for stocking of the equipment, and register activities. As such, one person is required to operate and maintain many components of the convenience store facility. The receiver 304 may be positioned at the cash register so that while the attendant is operating the cash register he may also be notified of matters that require his attention at the modules 32, 32a. For example, if a module 32a indicates that a container 68 is empty the controller 76 will communicate with the receiver 304 to indicate this condition. The receiver may also be configured with audible alarms and visual displays to provide additional information. For example, a display may identify which module and the specific condition associated with the module which has provided a signal to the receiver 304. The operator can then make a decision how to use that information relative to his responsibilities at the cash register. If an emergency requires immediate attention he can secure the cash register and address the emergency while attending to the module 32. Alternatively, if it is a slow period in the store and a module is indicating that a container 68 is empty he can put off attending to this condition until he completes one or more transactions in queue. The signal communication between the controller 76 and the receiver 304 may be a single path signal or in the form of a multiple path verification signal. For example, as shown in FIGS. 19 and 20 a first signal 310 is transmitted from the controller 76 to the receiver 304. This initial communication may report the status of a condition at the module 32. The receiver 304 can then return a copy of the information 312 to the controller 76. If the controller confirms the information received (312) it can then send a return confirmation 314 that the information is correct. This is a useful communication link in the present situation due to the presence of electrical noise and other interference within other beverage system applications. For example, each of the components associated with the modules 32, 32a may provide some degree of electrical or other noise. Additionally, other systems within the beverage system setting may be producing RF or other signals which could create interference. As such, the present embodiment providing the verification communication links 310-314 helps facilitate and assure accurate and timely communication. In the event of excessive interference such as from patrons of the store using telephone or RF communication devices, the controller 76 can continue to periodically send a message 310 to the receiver 304 until the verification signal 312 is received. While preferred embodiments are disclosed, illustrated and described, it is envisioned that those skilled in the art may devise various modifications and equivalents without departing from the spirit and scope of the disclosure as recited in the following claims.

<SOH> BACKGROUND <EOH>This disclosure relates to beverage systems and, more particularly, to a beverage apparatus for preparing, dispensing, monitoring, controlling and, if desired, flavoring beverages. Over the past 10 years, the coffee and beverage industry has experienced an evolution in connection with retail sales of fresh coffee. In particular, there is now a significant customer demand for individual servings of fresh coffee at, among other places, coffee shops, convenience stores, and fast food restaurants. Associated with the increase in demand for retail purchases of individual servings of fresh coffee are increases in demand for flavored coffee and for different types of flavored coffee as well as a variety of other beverages, such as teas, cocoas, etc. As a result of these significant changes in the coffee and beverage industry, the service market has changed drastically over the past 10 years. Coffee shops in which consumers can walk in and purchase a fresh cup of coffee have substantially increased in number. Convenience food stores, fast food restaurants and other retailers now devote substantial floor space to serving customer demand. Moreover, these changes place increasing demands on employees of retail outlets to monitor the coffee brewing and beverage preparation equipment to ensure that there is a constant supply of fresh coffee available to consumers and in many cases to also ensure that there is a sufficient number of different flavors of fresh coffee available. These changes in the coffee service industry have also created an increased need for efficiency in serving the consuming public. To be competitive in this expanding marketplace, efficiency in the brewing, storage, and dispensing of coffee is increasingly important. In particular, there is now a premium on being able to serve in an efficient manner the large demand for not only fresh coffee but also different flavors of coffee, in light of the substantial retail space needed for the coffee brewing and dispensing equipment and the continuous responsibilities in administering the brewing and dispensing process.

<SOH> SUMMARY <EOH>The present disclosure relates to apparatus for making and dispensing beverages. The apparatus comprises a plurality of beverage dispensing modules, and a housing associated with the plurality of beverage dispensing modules and defining a chamber containing a liquid. Each beverage dispensing module has a container and an assembly for producing a respective beverage and delivering the respective beverage to the container. The liquid contained in the chamber is supplied to the assemblies to produce the respective beverages. In a preferred embodiment, each beverage dispensing module includes a dispensing valve for dispensing the respective brewed beverage from the beverage dispensing module. In a preferred embodiment, the apparatus may also include a controller for selectively activating the production of the respective beverages. The apparatus may also include a plurality of conduits for supplying liquid to the assembly. The dispensing modules and housing may have any suitable construction and desirably are oriented in a manner that is space efficient and facilitates easy administration and usage of the apparatus. Desirably, the beverage dispensing modules have a front and a back, the backs facing the housing, and the fronts may face the same direction. The housing may be positioned behind the beverage dispensing modules. In accordance with one embodiment, for example, the apparatus also includes a plurality of second beverage dispensing modules and the fronts of the beverage dispensing modules and the fronts of the second beverage dispensing modules face opposite directions. With this embodiment, desirably the housing is positioned behind the beverage dispensers and behind the second beverage dispensers. The apparatus may further include a heating element for heating the liquid within the housing, a level sensor for sensing the level of the liquid within the housing, and a temperature sensor for sensing the temperature of the liquid within the housing. A plurality of activation switches desirably are associated with the beverage dispensing modules, each activation switch is adapted to send a switch signal to the controller to activate production of the respective beverage. The controller preferably is adapted to activate production of the respective beverage in response to activation of the respective activation switch, a liquid level signal from the liquid level sensor, and a temperature signal from the temperature sensor. The apparatus also may include an inlet valve for providing liquid to the housing in response to a valve signal from the controller. In addition to being able to produce and serve a plurality of respective beverages, the apparatus desirably also includes a liquid flavor dispensing assembly for dispensing flavoring to the brewing assembly of at least one of the beverage dispensing modules to flavor the respective brewed beverage. In a preferred embodiment, for example, the liquid flavor dispensing assembly selectively dispenses a plurality of different flavorings to the assemblies of at least some of the beverage dispensing modules to provide beverages having different flavors. Additional features will become apparent to those skilled in the art upon consideration of the following detailed description of drawings exemplifying the best mode as presently perceived.

20041018

20100810

20050324

94388.0

ALEXANDER, REGINALD

SHARED WATER RESERVOIR BEVERAGE SYSTEM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method of building a tyre and tyre for a two-wheeled vehicle

A method of building a tyre includes forming a carcass structure comprising at least one carcass ply, applying a belt structure at a radially external position with respect to the at least one carcass ply, applying a pair of sidewalls at an axially external position with respect to side surfaces of the at least one carcass ply, applying a tread band to the belt structure at a radially external position of the belt structure, and applying annular stiffening inserts against the side surfaces of the at least one carcass ply before applying the sidewalls. Ends of the at least one carcass ply engage respective circumferentially inextensible annular anchoring structures. Each sidewall extends radially away from one of the annular anchoring structures. Each annular insert extends between one of the annular anchoring structures and a corresponding edge of the belt structure. A tyre for a two-wheeled vehicle is also disclosed.

1-30. (canceled) 31. A method of building a tyre, comprising: forming a carcass structure comprising at least one carcass ply; applying a belt structure at a radially external position with respect to the at least one carcass ply; applying a pair of sidewalls at an axially external position with respect to side surfaces of the at least one carcass ply; applying a tread band to the belt structure at a radially external position of the belt structure; and applying annular stiffening inserts against the side surfaces of the at least one carcass ply before applying the sidewalls; wherein ends of the at least one carcass ply engage respective circumferentially inextensible annular anchoring structures, wherein each sidewall extends radially away from one of the annular anchoring structures, and wherein each annular insert extends between one of the annular anchoring structures and a corresponding edge of the belt structure. 32. The method of claim 31, wherein each annular insert is formed by winding at least one continuous thread element into concentric coils. 33. The method of claim 31, wherein the annular inserts are made together with at least one belt layer of the belt structure by winding at least one continuous thread element into coils distributed between the annular anchoring structures. 34. The method of claim 31, wherein the annular inserts are applied before the belt structure is applied. 35. The method of claim 34, wherein during applying the belt structure, the edges of the belt structure are each superposed on a radially external edge of one of the annular inserts. 36. The method of claim 32, wherein the at least one thread element is wound with a substantially constant pitch, so that the coils are substantially spaced apart a same distance from each other. 37. The method of claim 32, wherein the at least one thread element is wound with a pitch that has a lower value close to the annular anchoring structures than close to the edges of the belt structure. 38. The method of claim 32, wherein the at least one thread element is wound with a pitch that has a higher value close to the annular anchoring structures than close to the edges of the belt structure. 39. The method of claim 32, wherein the at least one thread element is wound with a varying pitch between the annular anchoring structures and the edges of the belt structure. 40. The method of claim 31, wherein the annular inserts constitute part of the belt structure, and wherein the annular inserts extend continuously between the annular anchoring structures. 41. The method of claim 40, wherein the belt structure comprises spiraled coils of cord extending from a first annular anchoring structure to an axially opposite second annular anchoring structure. 42. The method of claim 40, wherein the belt structure consists of spiraled coils of cord extending from a first annular anchoring structure to an axially opposite second annular anchoring structure. 43. The method of claim 31, wherein applying the annular inserts is preceded by forming an intermediate elastomer substrate against an outer surface of the at least one carcass ply. 44. The method of claim 43, wherein the elastomer substrate is formed by winding at least one continuous elongated element of elastomer material into coils disposed in mutual side-by-side, superposed, or side-by-side and superposed relationship against the outer surface of the at least one carcass ply. 45. The method of claim 31, wherein forming the carcass structure comprises: preparing strip lengths; disposing the strip lengths, circumferentially distributed, on a toroidal support to form the at least one carcass ply; and applying the annular anchoring structures close to inner circumferential edges of the at least one carcass ply; wherein each strip length comprises longitudinal and parallel thread elements at least partly coated with at least one layer of elastomer material, and wherein each of the strip lengths extends in a substantially U-shaped configuration around a cross-section outline of the toroidal support to define two side portions, mutually spaced apart in an axial direction, and a crown portion, extending at a radially external position between the side portions. 46. The method of claim 45, wherein forming the at least one carcass ply comprises: disposing a first series of the strip lengths on the toroidal support; applying at least first annular anchoring inserts of the annular anchoring structures against end flaps of the strip lengths of the first series; and disposing a second series of the strip lengths on the toroidal support; wherein the first series of strip lengths are circumferentially distributed with a circumferential pitch corresponding to a multiple of a width of the strip lengths of the first series, wherein each strip length of the second series comprises end flaps that are superposed on respective first annular inserts at an axially opposite position relative to the end flaps of the strip lengths of the first series. 47. The method of claim 46, wherein the strip lengths of the first series are disposed in first deposition planes, wherein the strip lengths of the second series are disposed in second deposition planes, wherein the first deposition planes are offset in parallel from a plane radial to a rotation axis of the toroidal support, wherein the second deposition planes are offset in parallel from the plane radial to the rotation axis of the toroidal support, and wherein the first and second deposition planes are offset on opposite sides of the plane radial to the rotation axis of the toroidal support. 48. The method of claim 46, wherein the annular inserts are applied against the side portions of the strip lengths of the first series before disposing the second series of the strip lengths. 49. A tyre for a two-wheeled vehicle, comprising: a carcass structure comprising at least one carcass ply; a belt structure applied at a radially external position with respect to the at least one carcass ply; a pair of sidewalls applied at an axially external position with respect to side surfaces of the at least one carcass ply; a tread band applied to the belt structure at a radially external position of the belt structure; and annular stiffening inserts axially interposed between the side surfaces of the at least one carcass ply and the sidewalls; wherein ends of the at least one carcass ply engage respective circumferentially inextensible annular anchoring structures, wherein each sidewall extends radially away from one of the annular anchoring structures, and wherein each annular insert extends between one of the annular anchoring structures and a corresponding edge of the belt structure. 50. The tyre of claim 49, wherein each annular insert comprises at least one continuous thread element wound into concentric coils. 51. The tyre of claim 50, wherein the at least one thread element extends past the annular insert to form at least one belt layer of the belt structure. 52. The tyre of claim 49, wherein the belt structure comprises edges that are superposed on radially external edges of the annular inserts. 53. The tyre of claim 50, wherein the coils of the at least one thread element are substantially spaced apart a same distance from each other. 54. The tyre of claim 50, wherein the coils of the at least one thread element comprise a distribution pitch that has a lower value close to the annular anchoring structures than close to the edges of the belt structure. 55. The tyre of claim 50, wherein the coils of the at least one thread element comprise a distribution pitch that has a higher value close to the annular anchoring structures than close to the edges of the belt structure. 56. The tyre of claim 49, further comprising at least one intermediate elastomer substrate interposed between the at least one carcass ply and the annular inserts. 57. The tyre of claim 50, wherein the at least one thread element comprises at least one metal cord of a 3×3×0.175 HE HT type. 58. The tyre of claim 49, wherein the at least one carcass ply comprises: a plurality of strip lengths circumferentially distributed around a geometric axis of the tyre; wherein each strip length comprises longitudinal and parallel thread elements at least partly coated with at least one layer of elastomer material, and wherein each of the strip lengths extends in a substantially U-shaped configuration of a cross-section outline of the carcass structure to define two side portions, mutually spaced apart in an axial direction, and a crown portion, extending at a radially external position between the side portions. 59. The tyre of claim 58, comprising: a first series of the strip lengths; and a second series of the strip lengths; wherein each of the annular anchoring structures comprises at least one annular insert axially interposed between the strip lengths of the first series and the strip lengths of the second series. 60. The tyre of claim 59, wherein the strip lengths of the first series are disposed in first deposition planes, wherein the strip lengths of the second series are disposed in second deposition planes, wherein the first deposition planes are offset in parallel from a plane radial to the geometric rotation axis of the tyre, wherein the second deposition planes are offset in parallel from the plane radial to the geometric rotation axis of the tyre, and wherein the first and second deposition planes are offset on opposite sides of the plane radial to the geometric rotation axis of the tyre. 61. The tyre of claim 59, wherein the annular inserts are axially interposed between the side portions of the strip lengths of the first series and the side portions of the strip lengths of the second series.

The present invention relates to a method of building a tyre, in particular for two-wheeled vehicles, comprising the steps of: forming a carcass structure on a toroidal support which carcass structure comprises at least one carcass ply having its ends in engagement with respective circumferentially-inextensible annular anchoring structures; applying a belt structure at a radially external position with respect to the carcass ply; applying a pair of sidewalls at an axially external position relative to side surfaces of the carcass ply each extending radially away from one of the annular anchoring structures towards said belt structure; applying a tread band to the belt structure at a radially external position. The present invention also relates to a tyre, in particular for two-wheeled vehicles comprising: a carcass structure provided with at least one carcass ply having its ends in engagement with respective circumferentially-inextensible annular anchoring structures; a belt structure applied at a radially external position with respect to the carcass ply; a pair of sidewalls applied at an axially external position to side surfaces of the carcass ply each extending radially away from one of the annular anchoring structures towards said belt structure; a tread band applied to the belt structure at a radially external position. Building of tyres for two-wheeled vehicles in general involves formation of a carcass structure essentially made up of one or more carcass plies substantially shaped in a toroidal configuration and having their axially opposite side edges in engagement with respective annular reinforcing structures incorporating circumferentially inextensible annular elements, usually referred to as “rings”. Applied to the carcass structure, at a radially external position, is a belt structure comprising one or more belt strips in the form of a closed ring, essentially made up of textile or metallic cords which are suitably oriented with respect to each other and to the cords belonging to the adjacent carcass plies. In addition, a tread band is applied to the belt structure at a radially external position, said tread band being usually made up of a strip of elastomer material of appropriate thickness. To the aims of the present specification it should be pointed out that by the term “elastomer material” it is intended a rubber blend in its entirety, that is the combination of at least one base polymer suitably amalgamated with reinforcing fillers and process additives of various types. Finally, a pair of sidewalls is applied to the opposite sides of the tyre being formed, each of said sidewalls covering a side portion of the carcass structure included between a so-called shoulder region, located close to the corresponding edge of the tread band, and a so-called bead located at the corresponding annular reinforcing structure. While tyres for cars or trucks are characterised by a substantially flattened cross-section outline at the tread band, tyres for motorcycles are distinguishable due to their marked transverse curvature or bending, usually defined by the particular value of the ratio between the distance of the tread centre from the line passing through the opposite side extremities of the tread itself, measured at the equatorial plane of the tyre, and the distance measured along the tyre chord between said extremities. In tyres for two-wheeled vehicles the value of the bending ratio generally is at least as high as about 0.15 and it is usually in the order of 0.3 in the case of rear tyres, and even higher, until 0.45 in the case of front tyres, against a value usually smaller than 0.05 in tyres for motor-vehicles. Leaving the destination of use out of consideration, i.e. irrespective of its being used for motor-vehicles or motor-cycles, tyres are generally classified in at least two categories which are different from each other due to the orientation of the cords being part of the carcass plies. In particular, there are the so-called “radial tyres” in which each of the cords arranged in the carcass ply or plies lies in a plane substantially radial to the rotation axis of the tyre, i.e. it has an orientation substantially orthogonal to the circumferential extension direction. In addition, there are tyres of the so-called “traditional type” or “crossed-ply tires” the carcass structure of which generally comprises at least a first carcass ply having cords oriented obliquely to the circumferential extension direction of the tyre, and a second carcass ply the cords of which have an oblique orientation which is symmetrically crossed with respect to the cords of the first ply. As compared with tyres of the conventional type, radial tyres offer advantages in terms of lightness, ride comfort and structural strength at high speeds. Due to this circumstance, tyres of the conventional type practically fell in disuse in favour of tyres of the radial type, at least with reference to their use on cars and in the countries where a modern road network is present. With reference to motorcycles as well, use of tyres of the radial type has recently imposed itself, in particular on motorcycles of recent conception involving use of low-section tyres, i.e. tyres in which the ratio of the section height, measured between the bead base and the tread band centre, to the maximum tyre width is, by way of example, less than 0.7. There are however particular market sectors in which use of tyres of the radial type is presently precluded. This in particular occurs with reference to motorcycles mounting tyres with a rather high section ratio, by way of example greater than 0.7, as those of the so-called “custom” type in which the frame, suspensions and rims are inspired to technical and stylistic solutions going back to fifties and sixties. These motorcycles have recently awoken the interest of an important part of users, and today represent a non negligible portion of the circulating car pool. In terms of tyres, these vehicles both for aesthetic and functional reasons, require use of tyres having a high section ratio, which greatly conditions both the vehicle behaviour on the road and the tyre structure. In fact, these tyres, due to the important height of the sidewall, need carcass structures provided with rather stiff sidewalls to ensure the necessary vehicle steadiness in all use conditions, when running both on a straight stretch and on a bend. In all the above cases, resorting to tyres with a carcass structure of the conventional type, i.e. with several plies having mutually crossed cords that are inclined with respect to the circumferential direction, appears therefore necessary. The Applicant has now perceived that the above tyres for motorcycles with a high section ratio, traditionally obtained by means of production processes involving assembling of previously made and stored semi-finished products, do not lend themselves to be constructed following production methodologies of recent conception, aiming at eliminating or at least limiting the necessity to produce and store semi-finished products. An example of these production methodologies is described in document EP-A-0928680, in the name of the same Applicant, where each tyre component is directly made on a rigid toroidal support conforming in shape to the inner conformation of the tyre itself, using a semi-finished product continuously fed from an extruder or other appropriate devices. In more detail, one or more carcass plies are each obtained by laying down strip-like lengths in sequence and in mutual side by side relationship on the toroidal support, said strip-like lengths being obtained by cutting of a continuous semi-finished product directly coming from an extruder and comprising longitudinal cords incorporated in an elastomer layer. Other tyre components, such as the anchoring inserts incorporated in the annular reinforcing structures at the beads, are obtained by winding of a continuous thread-like element of metal material into radially superposed coils. Other components made of elastomer material such as the tread band, sidewalls and others, are obtained by winding up on the carcass structure, a continuous elongated element of elastomer material directly extruded from an extruder so as to form coils disposed in side by side and/or superposed relationship. By adopting the above production methods important advantages could be achieved both in terms of productivity and in terms of production flexibility of the plants. The Applicant has however perceived that, with use of such production methods, accomplishment of the traditional carcass structure with several plies having cords of crossed extension involves an important increase in the production times and costs, which neutralizes an important part of the advantages typically correlated with these production methodologies. The Applicant has also become aware of the fact that, in accordance with the present invention, it is surprisingly possible to simplify the carcass structure of the tyres having a high section ratio, until enabling use of a single carcass ply of the radial type, while maintaining the tyre taken as a whole in an excellent ride behaviour. So this fact enables use of production methodologies of the type disclosed in document EP-A-0928680, with consequent economical advantages on the production process and qualitative advantages as regards the finished product. In particular, it was surprisingly found that important advantages in terms of structural simplification and lightening of the tyres for motorcycles with a high section ratio could be achieved by arranging appropriate auxiliary stiffening inserts at the tyre sidewalls. The method in reference thus enables both low-section radial tyres intended for motorcycles of modern conception and radial tyres with a high section ratio intended for the so-called motorcycles of the custom type to be made on the same production line. In more detail, the invention relates to a method of building a tyre, in particular for two-wheeled vehicles, characterized in that it comprises the step of applying annular stiffening inserts against the side surfaces of the carcass ply, before application of the sidewalls, which inserts each extend between one of the annular reinforcing structures and a corresponding edge of the belt structure. The present invention also relates to a tyre, in particular for two-wheeled vehicles, characterized in that it further comprises annular stiffening inserts, each of which is axially interposed between the side surface of the carcass ply and one of said sidewalls, and extends between one of the annular reinforcing structures and a corresponding edge of the belt structure. Patent FR 2,055,988 discloses a tyre for motor-vehicles, specifically for heavy-duty use in transportation and on the stocks, the beads of which are reinforced with an element resisting to tensile stresses which is spirally wound on the turned-up end of the carcass ply, substantially at the bead, and radially extending until the sidewall half-height at most, for the purpose of giving the beads the maximum strength without impairing the sidewall flexibility. Likewise, U.S. Pat. No. 3,044,523 discloses the same type of reinforcement at the bead, indifferently located either at an axially external or an axially internal position with respect to the turned-up end of the carcass ply. Features and advantages of the method and the tyre in accordance with the invention will become more apparent from the detailed description of a preferred but not exclusive embodiment of a method of building a carcass structure for tyres, in particular for two-wheeled vehicles, and of a carcass structure obtainable by said method. This description will be set forth hereinafter with reference to the accompanying drawings, given by way of non-limiting example, in which: FIG. 1 is a fragmentary and cut-away perspective view of a tyre provided with a carcass structure obtained in accordance with the present invention; FIG. 2 is a diagrammatic fragmentary perspective view showing application of a first series of strip-like lengths for the purpose of forming a carcass ply of the tyre in accordance with the invention, with an annular reinforcing structure laterally applied to the end flaps of the strip-like lengths themselves; FIG. 3 is a fragmentary perspective view of a second series of strip-like lengths with the respective end flaps superposed on the annular reinforcing structure, and an annular stiffening insert laterally applied to the carcass ply, together with an auxiliary annular anchoring insert being part of the annular reinforcing structure; FIG. 4 is a fragmentary section taken along a plane radial to the rotation axis of the tyre, showing the cross-section outline of the tyre components. With reference to the drawings, a tyre, in particular for two-wheeled vehicles, built in accordance with the present invention has been generally identified by reference numeral 1. Tyre 1 has a right section (FIG. 4) denoted by a high transverse curvature or bending: in more detail, said tyre shows a section height H measured along the equatorial plane between the centre of the tread band and the fitting diameter identified by the reference line r passing through the tyre beads. In addition, tyre 1 has a width C defined by the distance between the laterally opposite ends E of the tread itself and a curvature defined by the particular value of the ratio between the distance f of the tread centre from the line passing through the tread ends, measured in the equatorial plane of the tyre, and width C. Preferably, the invention applies to tyres with a section ratio H/C equal to or higher than 0.70, designed for equipment of the above mentioned “custom” vehicles, and generally also identified by a bending ratio f/H higher than 0.30 in the rear tyres as well. Tyre 1 comprises a carcass structure 2 having at least one carcass ply 3 with a substantially toroidal conformation and engaged through its axially spaced apart circumferential edges, with a pair of annular reinforcing structures 4 (only one of which is shown in the drawings) each of which, when the tyre has been completed, is placed in the tyre region usually identified as “bead”. Applied to the carcass structure 2, at a circumferentially external position, is a belt structure 5 comprising at least one primary belt strip 6, formed of one or more continuous parallel cords or other appropriate thread-like elements, wound up into coils 6a which are disposed in axial side by side relationship and oriented with a substantially null angle relative to the equatorial plane of the tyre, as well as of possible auxiliary belt strips 7a, 7b (diagrammatically shown in chain line in FIG. 1) located at a radially internal position relative to the primary belt strip 6. Circumferentially superposed on the belt structure 5 is a tread band 8 in which, following a moulding operation carried out concurrently with tyre vulcanization, longitudinal and/or transverse grooves 8a can be formed and disposed to define a desired “tread pattern”. Tyre 1 also comprises a pair of so-called “sidewalls” 9 laterally applied to the carcass structure 2 on opposite sides thereof, and at least one pair of auxiliary stiffening inserts 10. Each auxiliary stiffening insert 10 is axially interposed between a respective side surface of the carcass ply 3 and one of the sidewalls 9, and preferably extends between one of the annular reinforcing structures 4 and a corresponding side edge of the belt structure 5. The carcass structure 2 can be optionally coated on its inner surface with a so-called “liner” 11 essentially consisting of a layer of air-tight elastomeric material adapted to ensure a hermetic seal to the tyre when inflated. The present invention is advantageously put into practice within the context of a building method according to which, except for that which is described in more detail in the following of the present specification, assembling of the above listed components as well as production of one or more of them, is preferably obtained following the teachings proposed for example in document EP-A-0976536 in the name of the same Applicant. As provided in the above mentioned document, the components of tyre 1 are each obtained by laying down on a toroidal support 1a (only diagrammatically shown) the shape of which matches that of the inner conformation of the tyre, one or more elements each obtained from an elongated semi-finished product continuously fed in the vicinity of the toroidal support itself. The toroidal support 1a, of a cross-section outline having a bending ratio at least as high as 0.15, in conformity with the bending ratio of tyre 1 to be made, can have reduced sizes with respect to those of the finished tyre, of a linear-measure value preferably included between 0.5% and 2%, taken by way of example along the circumferential extension of the support itself at an equatorial plane X-X thereof which is coincident with the equatorial plane of tyre 1. In more detail, liner 11 can be obtained by winding up a continuous strip-like element of appropriate elastomer material on the outer surface of the toroidal support 1a to form a plurality of coils 11a disposed in axial side by side relationship so as to follow the cross-section outline of the outer surface of the toroidal support 1a, and/or radially superposed so as to define a continuous layer adapted to integrally coat the inner surface of tyre 1. To the aims of the present description, by cross-section outline it is intended the configuration shown by the half-section of the toroidal support 1a and/or any annular component of tyre 1, sectioned along a plane radial to a geometric rotation axis (not shown) of the tyre itself. Each carcass ply 3 can be in turn made up of a plurality of strip-like lengths 12, 13 obtainable by cutting operations carried out on a narrow band or similar strip-like continuous element fed from a calender or an extruder and comprising longitudinal cords parallel to each other and incorporated in a layer of elastomer material. The strip-like lengths 12, 13 are circumferentially distributed around the geometric axis of tyre 1 and each extend in a U-shaped configuration to define two side portions 12a, 13a spaced apart from each other in an axial direction, and a crown portion 12b, 13b extending at a radially external position between the side portions 12a, 13a. In more detail, the presence of a first series of strip-like lengths 12 and a second series of strip-like lengths 13 is preferably provided and they are laid down on the toroidal support 11 in two successive steps and have the respective side portions 12a, 13a axially spaced apart from each other by interposition of one or more of the construction components belonging to the annular reinforcing structures 4. The strip-like lengths 12, 13 belonging to the first and second series respectively can be distributed with a circumferential pitch substantially corresponding to their width to form two separate carcass plies. For tyres intended for use in motorcycles although having a relatively high section ratio, higher than 0.70 by way of example, it is however preferably provided that, as shown in FIG. 1, the strip-like lengths 12, 13 of each series should be distributed according to a circumferential pitch corresponding to a multiple of their width, so that the crown portions 13b of lengths 13 belonging to the second series are each interposed between the crown portions 12b belonging to two consecutive lengths of the first series 12, to form a single carcass ply 3 altogether. Depending on requirements, the strip-like lengths 12, 13 belonging to the first and second series can be laid down in planes that are radial to the rotation axis of the toroidal support 1a, or offset in parallel relative to a radial plane, on opposite sides with respect to said plane, as described in document WO 00/38906 in the name of the same Applicant, to obtain a respectively crossed orientation of their side portions 12a, 13a, keeping the crown portions 12b, 13b oriented perpendicular to a circumferential direction. Deposition of the strip-like lengths 12, 13 belonging to the first and second series can be also carried out in inclined and mutually crossed orientations relative to the circumferential extension direction of the toroidal support 1a, to give the crown portions 12b, 13b a desired inclination, which however preferably must not exceed 20 degrees, with respect to said circumferential direction. Each of the annular reinforcing portions 5 preferably accomplished after deposition of at least the strip-like lengths 12 belonging to the first series, comprises at least one annular anchoring insert 14 which is substantially inextensible in a circumferential direction and is located close to the radially internal edge of the carcass structure 3, and a filling insert 15 of elastomer material tapering radially away from the anchoring insert 14. The first annular anchoring insert 14 is preferably obtained by winding of a continuous metallic cord or other suitable thread-like element directly against the side portions 12a of lengths 12 belonging to the first series, so as to form a plurality of coils 14a that are radially superposed in succession. The filling insert 15 can be in turn directly formed in contact with the annular anchoring insert 14, for instance by application of a continuous strip of suitable elastomer material coming out of an extruder located close to the toroidal support 1a. The continuous strip may have the final conformation in section of the filling body 15 already on coming out of the respective extruder. Alternatively, the continuous strip will have a reduced section as compared with that of the filling body 15, and the latter will be obtained by application of the strip itself in several coils disposed in side by side and/or superposed relationship, to define the filling body 15 in its final configuration. Each annular reinforcing structure 4 may further comprise an auxiliary annular anchoring insert 16, which is also obtainable by winding up a metallic cord or other appropriate continuous thread-like element, directly against the side portions 13a of the strip-like lengths 13 belonging to the second series, previously applied to the filling body 15 in superposed relationship therewith. The materials for producing the continuous thread-like element and the related structural configurations for said annular inserts 14 and 16 have been known for long to those skilled in the art and consequently they are not further described herein. Before or after deposition, as in the case herein illustrated, of the strip-like lengths 13 belonging to the second series, application of the stiffening inserts 10 against the side surfaces of the carcass ply 3 is carried out. In more detail, each stiffening insert 10 is preferably made by winding up at least one continuous thread-like element so as to form concentric coils 10a directly against the side portions 12a, 13a of the strip-like lengths 12, 13. These coils can be disposed radially close to each other or mutually spaced apart, by a constant or varying pitch, along the radial extension of the sidewall, depending on requirements. The thread-like element employed for making the annular stiffening inserts 10 may advantageously consist of a textile, metallic or other hybrid-type cord. The cord can be of the one-strand type, a 1×5 cord for example, or of the multi-strand type, a 3×3 cord for example. Preferred materials are steel for the metallic cords, polyamide fibres for the textile cords. In a preferred embodiment the cord is of the 3×3 type, i.e. it is made up of 3 strands each of 3 wires of high-carbon (>0.8%) steel, of the high-elongation (HE) Lang's lay type, i.e. it has the wires in the strands and the strands in the cord twisted in the same direction, with identical winding pitches or pitches that are different from each other. Preferably, the diameter of said wires is included between 0.12 and 0.38 mm inclusive. At all events the type of cord adopted must enable some expansion of the tyre sidewalls, in particular in a radial direction, without increasing yielding of same. Winding of the thread-like element for accomplishment of each stiffening insert can be conveniently carried out starting from a radially internal edge 17 of the stiffening insert itself, at the respective annular reinforcing structure 4, until a radially external edge 18 arranged at a corresponding side edge 5a of the belt structure 5, or in the opposite way. Afterwards the belt structure 5 is made, which comprises at least one primary strip made up of cords oriented circumferentially with respect to the tyre. In more detail, it is provided for the purpose that the primary belt strip 6 should be obtained by winding up into coils disposed mutually close on the carcass ply 3, at least one continuous thread-like element consisting of a steel cord for example, of the high-starting-elongation type, the tensile behaviour of which, represented on a load/elongation graph, is characterized by the presence of a starting stretch of a low slope which is an index of high extensibility for low loads, followed by an end stretch of a marked slope which is an index of high toughness for loads higher than a predetermined value. In particular, preferably used are cords in which the transition region (knee) between the starting stretch and the end stretch of the load/elongation curve extends in a range included between 0.7% and 3%: for instance, in cords of 3×3×0.175 size adopted in a preferred embodiment of the invention, this transition region extends around an elongation in the order of 0.7%. Advantageously, as viewed from the accompanying figures, during the step of accomplishing the primary belt strip 6, overlapping may be provided to be caused, of a measure included between 2 and 5 wires for example, between each of the edges 5a of the belt structure 5 and the radially external edge 18 of the respective auxiliary stiffening insert 10. Alternatively, the radially external edge 18 of the stiffening insert 10 may be spaced apart a measure included again by way of example between 2 and 5 wires, from the corresponding side edge 5a of the belt structure 5. According to a preferred embodiment of the invention, the radially external edge 18 of the stiffening insert 10 is disposed in side by side relationship with the corresponding side edge 5a of the belt structure 5, so as to constitute a continuous structure extending from bead to bead without gap. Still more preferably, such a continuous structure is made up of spiralled coils of one and the same cord from one bead to the other, passing through the tyre crown portion. The spiralling pitch of said cord can vary along the structure extension and in particular at the crown portion, so as to give origin to a belt strip with a differentiated density between the centre and shoulders of said crown portion. Prior to accomplishment of the annular stiffening inserts 10, as well as of the belt structure 5 and/or the auxiliary anchoring insert 16 belonging to the annular reinforcing structures 4, at least one elastomer substrate 19 of a thickness included, by way of example, between 0.2 mm and 1 mm, preferably equal to 0.7 mm, can be advantageously formed against the carcass ply 3, said substrate being formed by winding of at least one continuous elongated element of elastomer material into coils disposed mutually in side by side and/or superposition relationship against the outer surface of the carcass ply 3. With use of an elongated element of lenticular section and/or adoption of further suitable expedients, such as partial overlapping of the coils formed thereby, circumferential furrows can be generated in the elastomer substrate 19 that lend themselves to retain the coils formed by the annular stiffening inserts 10, the primary belt layer 6 and the possible auxiliary anchoring inserts 16, in order to stabilize positioning of same on the carcass ply 3. As shown in the drawings, winding of the cord or other continuous thread-like element designed to make each annular stiffening insert 10 is conveniently provided to be carried out according to a substantially constant pitch, to give origin to coils 10a substantially spaced apart the same distance from each other and preferably distributed with a density included between 2 and 7 threads per centimetre. Alternatively, winding can be carried out with a variable pitch in a continuous or discontinuous manner, for instance with a value close to the edges 5a of the belt structure 5 which is lower than the value measurable at the annular reinforcing structures 4, or vice versa. It may be also conveniently provided that the annular stiffening inserts 10 should be accomplished together with at least one of the belt layers 6, 7a, 7b being part of the belt structure 5, and/or together with the auxiliary anchoring inserts 16 being part of the annular reinforcing structures 4. In particular, for the purpose, the possible auxiliary anchoring inserts 16, primary belt layer 6 and annular stiffening inserts 10 may be provided to be formed of a single cord or several parallel cords wound up into coils distributed with a constant or a varying pitch depending on requirements, between one and the other annular reinforcing structure 4, along the whole cross-section outline of the carcass structure 2. Then sidewalls 9, obtainable in any manner convenient for a person skilled in the art are applied to the thread band 8. It will be now appreciated that the tyre structure simplified as above stated can also be obtained using the traditional building plants and following the traditional methodologies providing for use of a second-step shaping drum, of the expandable type, well known to those skilled in the art. Tyre 1 thus built now lends itself to be submitted, after possible removal from support 1a, to a vulcanization step that can be conducted in any known and conventional manner. The present invention achieves important advantages. In fact, it is to be noted that strengthening of the tyre sidewalls by the annular stiffening inserts 10 enables the expected qualities of dynamic rigidity of the sidewall to be achieved even on tyres with a high section ratio, without for the purpose requiring adoption of complicated construction solutions in the carcass plies. In particular, it is possible to drastically simplify the design schemes in the carcass structure, particularly in connection with the number and arrangement of the plies, until adopting, as provided in the above described embodiment, design schemes typical of the tyres of the radial type. This, on the one hand, enables the tyres for motorcycles with a high section ratio to be given all advantages typical of radial tyres, such as a greater lightness and better ride comfort, for instance. In addition, the possibility of using a radial carcass structure for building tyres with a high section ratio greatly facilitates adoption of production methodologies of the type described in said documents EP-A-0928680 and EP-A-0976536, in which working operations relating to construction of the carcass plies affect productivity and production costs to a relatively high degree. It should be also noted that the above described advantages are surprisingly achieved through the introduction of additional components in the carcass structure, in opposition to those that should be the normal expectations of a person skilled in the art resulting from the knowledge that generally the greater the number of components of a tyre structure is, the more said structure is complicated, delicate in its accomplishment and critical as regards control. It should be also noted that the invention, while particularly performing its beneficial effects in tyres with a high section ratio for motorcycles, is not limited to the latter but can be usefully adopted with all types of tyres.

20040913

20070703

20050324

60643.0

FISCHER, JUSTIN R

METHOD OF BUILDING A TYRE AND TYRE FOR A TWO-WHEELED VEHICLE

UNDISCOUNTED

ACCEPTED

ACCEPTED

Secure on-line payment system

The present invention relates to the field of e-commerce and in particular to making purchases on-line using payment card, for example debit, charge or credit cards. The concept of the present invention adopts an alternative approach to security methods presently employed to protect cardholders. The concept obviates the need for a cardholder to transmit Card Numbers along with other purchasing details at the time of purchase and couples this with the use of a password feature. This renders the transaction akin to a Bank Cash withdrawal that Bank/card Schemes are totally happy with from a security point of view but are reluctant to allow e-commerce and/or any others access to their “network” to ensure Security.

1-25. (Cancelled). 26. a computer data processing method for processing an on-line payment transaction, comprising the steps of: receiving a request from a payment card cardholder to connect to a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a payment request associated with the cardholder, said payment request identifying merchant information including a merchant code identifier and a transaction value, retrieving payment card details for the cardholder from a cardholder details database, submitting a payment authorisation request for the payment card details, the authorisation request including the merchant code and transaction value, to an authorisation host for authorising the transaction, and upon receipt of an authorisation, forwarding confirmation of the authorisation to the merchant. 27. The computer data processing method according to claim 26, further comprising the step of requesting a merchant code identifier from the merchant. 28. The computer data processing method for processing an on-line payment transaction of claim 26, further comprising the step of posting the payment request to a payment host for processing of the payment transaction. 29. The computer data processing method for processing an on-line payment transaction according to claim 28, further comprising the step of delaying posting the payment request until a confirmation of delivery has been received. 30. The computer data processing method of claim 26, further comprising the step of verifying to ensure that the cardholder information provided to a merchant matches cardholder information stored in the cardholder's details database. 31. A computer data processing method for processing an on-line payment transaction, comprising the steps of: receiving a request from a cardholder to connect to a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a first transaction request associated with a transaction between a merchant and the cardholder, retrieving payment card details for the cardholder from a database, submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value, to an authorisation host for authorising the transaction, and on receipt of an authorisation, forwarding a transaction request to the merchant, the request including a cardholder payment card code. 32. The computer data processing method according to claim 31, further comprising the step of requesting a merchant code identifier from the merchant. 33. The computer data processing method for processing an on-line payment transaction according to claim 31, further comprising the step of posting the payment request to a payment host for processing of the payment transaction. 34. The computer data processing method for processing an on-line payment transaction according to claim 33, further comprising the step of delaying posting the payment request until a confirmation of delivery has been received. 35. The computer data processing method for processing an on-line payment transaction according to claim 31, wherein a further verification is performed to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. 36. A system for processing an on-line payment transaction, the system having a connection to the Internet and a further connection via a local network to the terminal of a cardholder comprising: receiving means for receiving a request from a cardholder to connect to a network, said request including a cardholder password, authentication means for authenticating said cardholder request and providing access by said cardholder to the network, receiving means for retrieving payment card details for the cardholder from a database, authorising means for submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value to an authorisation host for authorising the transaction, and transaction means responsive to receipt of an authorisation from the authorisation host and adapted to forward a transaction request to the merchant, the request including a master cardholder account code. 37. The system of claim 36, further comprising merchant request means for requesting a merchant code identifier from the merchant. 38. The system of claim 36, further comprising a payment posting means for posting the payment request to a payment host for processing the payment transaction. 39. The system of claim 38, wherein the payment posting means delays posting the payment request until a confirmation of delivery has been received. 40. The system according to claim 36, wherein the verification means is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. 41. A payment processing system for processing an on-line payment transaction between a merchant and a cardholder comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder card details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, the merchant code of the payment request and the transaction value of the payment request to an authorisation host for authorising the transaction, and confirmation means which is adapted to forward confirmation of an authorisation received in response to a submitted authorisation request. 42. The system of claim 41, further comprising merchant request means for requesting a merchant code identifier from the merchant. 43. The system of claim 41, further comprising a payment posting means for posting the payment request to a payment host for processing of the payment transaction. 44. The system of claim 43, wherein the payment posting means delays posting the payment request until a confirmation of delivery has been received. 45. The system according to claim 41, wherein the verification means is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. 46. A payment processing system for processing an on-line payment transaction between a merchant and a cardholder, comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, a system merchant code and the transaction value of the payment request to an authorisation host for authorising the transaction, and response means responsive to receipt of an authorisation and adapted to forward a transaction request to the merchant, the request including a system cardholder account code. 47. The system of claim 46, further comprising merchant request means for requesting a merchant code identifier from the merchant. 48. The system of claim 46, further comprising a payment posting means for posting the payment request to a payment host for processing of the payment transaction. 49. The system of claim 48, wherein the payment posting means delays posting the payment request until a confirmation of delivery has been received. 50. The system according to claim 46, wherein the verification means is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database.

Field of the Invention The present invention relates to the field of e-commerce and in particular to making purchases on-line using payment cards, for example debit, charge or credit cards. Background to the Invention Significant research and resources have been applied in developing, implementing and maintaining secure payment systems which facilitate the use of credit/charge cards by cardholders in commercial transactions conducted over the Internet. All of these secure systems are based on cardholders having to “process” their card number each time, which leaves the “capturing” of card numbers and related information transmitted at time of purchase, open to hackers and/or other fraudsters who can gain access to card numbers and expiry dates. One solution is to use secure (encrypted) methods of communication in sending credit card details over the Internet to a merchant when making a purchase. Examples of such secure methods include Secure Socket Layer (SSL) and the Secure Electronic (SET) protocol. These methods have been developed by leading computer companies and businesses in the credit card industry specifically for the purposes of performing electronic transmission of credit card details on the Internet. However, there is no guarantee that the credit/charge card details whilst transmitted somewhat securely are not vulnerable to attack when stored on the merchant's system. It is a strong possibility that the card details could be hacked or used by a merchant or an employee of the merchant for fraudulent purposes. A further concern mitigating against on-line commerce, as perceived by cardholders, is the reliability of the e-commerce merchants and the lack of recourse available to card holders having made a purchase. The cardholder has no guarantee that items ordered will be delivered in a timely manner and be of an appropriate quality and/or quantity etc. It may be difficult, once card details have been supplied and appropriate funds debited to the cardholder's account, for a cardholder to obtain proper satisfaction from the merchant. A further concern is that there is no guarantee that a merchant, or associated personnel who may have access to the cardholders details, will not use the cardholders card details in subsequent unauthorised transactions, or pass the information onto third parties for criminal purposes. On the other hand, a significant concern for merchants is that items are definitely settled for before dispatch, i.e. that the card details and amount has been “approved” for settlement by the card scheme acquirer and that the card details and cardholder information is genuine. EP 0801479 discloses a secure communication mechanism for communicating credit card or other sensitive information between a cardholder terminal and a server which communicate over a data network (e.g. Internet). For secure or private communication of sensitive information over a data network, a telephone connection is established between the originating Internet Service Provider (ISP) server to which the cardholder is connected for access to the data network and the server provider to which the sensitive information is directed. Any communications or transactions to a terminating ISP server involving credit card or other sensitive information are effected, however, on a second connection through a telephone call placed to a telephone number of the terminating ISP server. After receiving a call, and by associating such call with the cardholder's request over the Internet for information and/or interactive services, and/or non-electronically deliverable goods or services, the ISP provides the cardholder with the requested information and/or service, or approves delivery of the non-electronically deliverable goods or services. With this arrangement, payment is effected without providing credit card information via the Internet routing servers and without establishing a financial relationship with the ISP. Preferably, the communication of information over the telephone line between the originating server and the terminating ISP server is also subject to encryption. The problem with this approach is that is essential for ISPs and merchants to sign up to the idea and to the installation of additional communications equipment to facilitate the secure communication on the secondary channel. Furthermore, the requirement for a separate telephone call adds additional cost to the process and there is still no guarantee from the cardholder's perspective. WO97/03410 discloses an Internet billing method comprising establishing an agreement between an Internet access provider and a customer, and an agreement between the Internet access provider and a vendor, wherein the Internet access provider agrees with the customer and the vendor to bill the customer and remit to the vendor for products and services purchased over the Internet by the customer from the vendor. The provider creates access to the Internet for the customer. When the customer orders a product or service over the Internet from a vendor, transactional information transmitted between the customer and the vendor is also transmitted to the provider. The provider then bills the transaction amount to the customer and remits a portion of the transaction amount to the vendor, keeping the differential as a fee for providing the service. As a result of this method, there is no need for any customer account numbers or vendor account numbers to be transmitted over the Internet, thereby maintaining the security of that information. An immense difficulty with this approach is that agreements are required between the ISP's and merchants before any transactions can take place. U.S. Pat. No. 5,905,736 discloses a method for performing centralised billing for transactions conducted over the Internet between a cardholder and an Internet Service Provider through an Internet Access Provider (IAP). Upon connection of the cardholder's terminal to the LAP, the IAP transmits to a billing platform a message that associates the cardholder's identity and the temporary Internet Protocol (EP) address -that is assigned by the IAP to the cardholder's session for use by to that cardholder's terminal. In response to a chargeable transaction with an ISP, the ISP transmits to the billing platform the IP address of the cardholder making the transaction and the charge for the transaction. The charges for all such transactions are accumulated by a transaction server and stored in an account on an associated database identified with the IP address of the requesting terminal. At the end of the cardholder's session, the charges for all the transactions during the session that are stored on the transaction server database in the account identified with the IP address, are charged to an account associated with the cardholder's identity that is stored on a database of a billing server by cross-referencing the IP address to the cardholder's identity from the previously received and stored message. In consideration of the prior art, it would be advantageous if a method of purchasing goods on-line could be provided which would permit a cardholder to have a simple and efficient recourse to the e-commerce merchant in the event of a complaint. It would further be desirable, if a method could be provided, which would allow a consumer to make a purchase on-line without disclosing their card details to third parties. SUMMARY OF THE INVENTION The concept of the present invention adopts an alternative approach to security methods presently employed to protect cardholders. The concept obviates the need for a cardholder to transmit card numbers along with other purchasing details at the time of purchase and couples this with the use of a password feature. This renders the transaction akin to a bank cash withdrawal that banks/card schemes are totally happy with from a security point of view but are reluctant to allow e-commerce and/or any others access to their “network” to ensure Security. In a first embodiment, a computer data processing method is provided for processing an on-line payment transaction, comprising the steps of: receiving a request from a cardholder to connect to a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a payment request associated with the cardholder, said payment request identifying merchant information including a merchant code identifier and a transaction value, retrieving payment card details for the cardholder from a cardholder details database, submitting a payment authorisation request for the payment card details, the authorisation request including the merchant code and transaction value to an authorisation host for authorising the transaction, and whereupon receipt of an authorisation forwarding confirmation of the authorisation to the merchant. The computer data processing method may further comprise the step of requesting a merchant code identifier from the merchant. The computer data processing method may include the step of posting the payment request to a payment host for processing of the payment transaction. Where posting is performed, the computer data processing method may further comprise the step of delaying posting the payment request until a confirmation of delivery has been received. Optionally, the computer data processing method may further comprise the step of verifying to ensure that the cardholder information provided to a merchant matches cardholder information stored in the cardholder's details database. In a second embodiment, a computer data processing method is provided for processing an on-line payment transaction, comprising the steps of: receiving a request from a cardholder to connect a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a first transaction request associated with a transaction between a merchant and the cardholder, retrieving payment card details for the cardholder from a database, submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value to an authorisation host for authorising the transaction, and on receipt of an authorisation forwarding a transation request to the merchant, the request including a cardholder payment card code. The computer data processing method may further comprise the step of requesting a merchant code identifier from the merchant. The computer data processing method may include the step of posting the payment request to a payment host for processing of the payment transaction. Where posting is performed, the computer data processing method may further comprise the step of delaying posting the payment request until a confirmation of delivery has been received. Optionally, the computer data processing method may further comprise the step of verifying to ensure that the cardholder information provided to a merchant matches cardholder information stored in the cardholder's details database. In a third embodiment, a system is provided for processing an on-line payment transaction, the system having a connection to the Internet and a further connection via a local network to the terminal of a cardholder comprising: receiving means for receiving a request from a cardholder to connect a network, said request including a cardholder password, authentication means for authenticating said cardholder request and providing access by said cardholder to the network, receiving means for receiving a first transaction request associated with a transaction between a merchant and the cardholder, retrieval means for retrieving payment card details for the cardholder from a database, authorising means for submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value to an authorisation host for authorising the transaction, and transaction means responsive to receipt of an authorisation from the authorisation host and adapted to forward a transaction request to the merchant, the request including a system cardholder account code. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant. The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In a fourth embodiment a payment processing system is provided for processing an on-line payment transaction between a merchant and a cardholder, comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder card details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, the merchant code of the payment request and the transaction value of the payment request to an authorisation host for authorising the transaction, confirmation means which is adapted to forward confirmation of an authorisation received in response to a submitted payment authorisation request. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant. The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In a fifth embodiment a payment processing system is provided for processing an on-line payment transaction between a merchant and a cardholder, comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder card details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, a system merchant code and the transaction value of the payment request to an authorisation host for authorising the transaction, response means responsive to receipt of an authorisation and adapted to forward a transaction request to the merchant, the request including a system cardholder account code. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In one embodiment, the first set of information identifying a cardholder and the second set of information identifying the merchant are received using an Internet submission protocol, for example the POST action associated with HTNL forms. These and other aspects of the invention will be apparent from, and elucidated with, reference to the embodiment(s) described hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be described in greater detail with reference to the accompanying drawings in which: FIG. 1 is a pictorial representation of the arrangement of a payment transaction scheme according to the invention, FIG. 2 is a more detailed representation of the arrangement of FIG. 1, FIG. 3 is a schema of an exemplary database for use with the present invention, FIG. 4 is a flowchart of a method according to a first aspect of the invention, FIG. 5 is a representation of a form intended for use with the invention, and FIG. 6 is a flowchart of a method according to a second aspect of the invention. DETAILED DESCRIPTION OF THE DRAWINGS An arrangement of the on-line transaction scheme according to the invention, shown in FIG. 1, involves a number of different parties at different nodes in a network. In particular, the process is concerned with an on-line (e-commerce) transaction conducted between a payment card (typically a debit, credit or charge card) cardholder 4 and a merchant 2. Communication between the merchant and cardholder is conducted over a network 3 (the Internet). The merchant, or more precisely the merchant's server 2, is, conventionally, continuously connected to the network so as to allow consumers unhindered access to the merchant's web site. The cardholder's computer may on the other hand be configured to connect to the Internet 3 only as required. Typically, the cardholder's computer connects to the Internet 3 via an Internet Service Provider (ISP) 5. The connection to the ISP may be made using a modem over a conventional or ISDN telephone line or by other suitable communication means. Upon connecting to the ISP 5, the cardholder may be required to enter a cardholder name and/or cardholder password. An authentication means, for example a security software module, performs a verification process typically comparing the cardholder name and password entered against a cardholder security database of valid cardholder names and passwords stored locally on the ISP server or an associated server or network of the ISP's server. Upon verification of the cardholder name and password, the cardholder's computer is granted access through the ISP network to the Internet. Typically, the ISP servers 5 may be connected to the Internet 3 using routers and other associated hardware devices. Security and protection for the ISP server and associated local network may be provided by firewall devices or software. This combination of router technology and security features allows ISP's to make services available on the ISP servers which may be accessed directly by cardholders connecting through the ISP without the necessity for transmission of cardholder requests and server responses over the Internet. In this way, communications between a server on the ISP network and a cardholder's computer connecting to the Internet through the ISP Network are not generally interceptable by third parties on the Internet. An exemplary structure for an ISP system for providing a cardholder access to the Internet and an associated payment/validation processing system for processing an on-line transaction between the cardholder and a merchant according to an embodiment of the invention is illustrated in FIG. 2. The associated payment processing system may be integrated within the ISP or maintained in a separate system in association with the ISP. In this exemplary structure, the cardholder database 100, 101 of the ISP described above is expanded to include further cardholder information, as illustrated in the exemplary database structure of FIG. 3, which may include the names 12, addresses 13 and payment card details of cardholders 14, 15, 16. The payment card key details may typically include details of the card payment scheme 14 (e.g. VISA™, AMERICAN EXPRESS™, DINERS CLUB™, MASTER CARD™etc.), card number 15 and expiry date 16 of the individual cardholders. These key payment card details could be established when the cardholder establishes their account with the ISP or at some subsequent time convenient to the cardholder and ISP. For reasons of security, it is proposed that the key details be supplied in a written application from the cardholder to the ISP. Alternatively, these key details may be provided by a telephone call to the ISP. Use of either of these methods would ensure that a cardholder's key details are not transmitted over the Internet. A less preferred embodiment, would allow a cardholder to enter their key details on-line. It will be appreciated that the database structure may be implemented using one or more tables 100, 101 in a relational database. Each cardholder account may have more than one associated set of key card details, i.e. where a cardholder has more than one credit card. In this scenario, it will be appreciated by those skilled in the art that a multiple table database would be appropriate having a first table identifying cardholders and their passwords, with a second table used to hold cardholder details. An additional field could be used to link the tables, e.g. a cardholder number which is created at the time of entry of the cardholder to the database and is unique to each cardholder. It will be appreciated further that the cardholder card details 101 may be stored in a separate system altogether to the cardholder security data store 100, in particular where the transaction processing system is distinct from the ISP. Generally, the methods of the invention commence with a cardholder establishing 20 a connection to the Internet via an ISP including the conventional steps of cardholder verification (authentication) 21. At the time of connection, the ISP may associate the connection ID (e.g. the assigned IP number) of the cardholder's computer with the cardholder. This may be used subsequently by the ISP to identify the cardholder in a transaction. Once a cardholder has established 22 a connection to the Internet through the ISP, the cardholder may use appropriate browser software e.g. NETSCAPE NAVIGATOR or MICROSOFT INTERNET EXPLORER to navigate the Internet and browse merchants'web sites. A first method of operation of the invention is shown in FIG. 4. In this embodiment, the merchant has established an agreement directly or indirectly with the ISP, which in the context of the present invention should be taken to mean an ISP with an associated payment processor, to use the transaction scheme of the present invention. It commences with a cardholder accessing a merchant's website. The cardholder may, depending on the configuration of the merchant's website, view descriptions of goods or services for sale, view pictures of these goods or services, and select items to purchase 23. Techniques for implementing these facilities on a website server are well known in the art. Upon receipt of a request to purchase an item from the cardholder, the merchant server may respond by forwarding a form for completion by the cardholder. The form may be a Hyper Text Mark-Up Language (HTML) document, with a small JAVASCRIPT program included to ensure that required fields are completed properly, although any browser readable form may be used. HTML forms which are well known in the art and permit the inclusion of a number of fields which indicate to the browser software what action to take with the form, how and where to send the information provided by a cardholder in a form. An example form 40 is shown in FIG. 4. The form allows the cardholder to enter some information, e.g. their name 44a, address 44b and phone number 44c, using their browser software. The form 40 may also contain information detailing the transaction including for example a description of the goods 43b, the quantities 43c, prices 43d and a merchant transaction reference number 43a. All of this information may be stored as fields in the form. Certain fields may be marked as hidden, e.g. the merchant transaction reference number. Once the cardholder has filled in the form 24 and clicked on an appropriate button 41 the form 40 is submitted by the browser software to a location defined in the form itself. A suitable script embedded in the HTML document may check the validity of fields and values entered. For example, a script might prompt the cardholder to re-enter their details if the name field had been left blank. The method of the invention may be configured to operate in a variety of different ways. In a first embodiment, in which the merchant's system is adapted to co-operate with the transaction system of the ISP, the merchant system provides the merchant's merchant code for a card scheme to the ISP. This may be implemented by the merchant providing a purchase payment option 45 corresponding to the ISP service. For example, the cardholder may be able to select the payment scheme of the ISP or an associate from a drop down list in a form, or using a check box. In one embodiment in which the cardholder selects the payment method prior to completing the above described form, upon selection of the option that the cardholder wishes to make a purchase using the cardholder's credit card details which are stored on their ISP or an associate, the form described above is forwarded to the cardholder by the merchant for completion. The form contains fields, which may be hidden, identifying merchant card information, e.g. the merchant's merchant code, an identifier of the card scheme. Upon completion of the form by the cardholder, the form is submitted 25 to the ISP server or an associated server hosting the transaction processor 102. The transaction processor 102, which includes a receiving means for receiving the form, extracts 26 information from the form including the the merchant's merchant code and the amount of the transaction. The transaction processor includes an association means which determines from which cardholder the form has been submitted, for example using the IP address of the computer from which the request was sent and associates the transaction with that cardholder. Once the transaction processor has determined the identity of the cardholder, the transaction processor using suitable retrieval means, retrieves 26 cardholder card details for the associated cardholder from the cardholder card information database. The transaction processor 102 (or an associated authorisation device) then establishes (if not already established) a connection to a card scheme authorisation host 7 and submits 27 the payment card details, the merchant code and the transaction value for approval. The connection to the authorisation host may for example be made over a dedicated security network or a telephone line. If the authorisation host rejects the transaction, the transaction processor responds by sending a suitable message to the cardholder and/or merchant and the transaction is cancelled. If the transaction is approved, the authorisation host provides the transaction processor 102 with a transaction authorisation number as per conventional payment transaction. The transaction processor using a confirmation means then forwards 28 confirmation of the authorisation, for example by insertion of the authorisation code as a field with the form details already completed by the cardholder, to the merchant server. The details of the transaction including the merchant information, cardholder information and transaction details may be stored by the transaction processor or in a transactions datastore either locally or on an associated server for subsequent processing 29 (e.g. by a posting means of the transaction processor posting the transaction information to a card payment scheme for processing of the transaction). Although, this step may be completed simultaneously with authorisation. Upon receipt of a confirmation, e.g. an authorisation code, with the transaction details, the merchant has an effective guarantee that the transaction will be valid and that the merchant will receive settlement in due course from the card scheme. With this guarantee, the merchant can allow the transaction, for example, the supplying the goods or services requested to proceed. It will be appreciated that in the entire transaction, the cardholder's card key details have never been revealed to the merchant. In a further embodiment, the transaction processor stores the details of the transaction but holds the transactions for posting until confirmation of processing of an order by a merchant or receipt of goods by a cardholder. For example, the transaction processor may hold the transaction until receipt of a message from the merchant detailing a delivery service company and their delivery transaction record. Upon receipt and possibly verification of such information, the transaction processor would release the transaction for processing by the appropriate card scheme. It will be apparent to those skilled in the art that a number of different methods and techniques may be used to allow the cardholder submit the information and for the transaction processor to obtain the merchant's card scheme details. For example, the merchant or the merchant's server software may simply identify the domain of the ISP gateway from the header information provided by the cardholder's browser software when connecting to the merchant. The merchant or the merchant's server software may forward a transaction request to a pre-designated sub-domain (previously indicated by the ISP to the merchant) or a pre-defined standard domain. For example, if the header information received from the cardholder indicated that it was sent from the domain TESTISP.COM, then the merchant software may select the standard sub domain of PAYMENT.TESTISP.COM to send the request to. In a second embodiment, the merchant may not have an agreement with the ISP or an associated transaction processor to facilitate use of the method described above. In this second embodiment, the transaction processor intercepts 31 the transaction form which has been completed 30 by the cardholder. This interception may for example be effected by the cardholder clicking a button on their graphical interface, the selection of which effects the running of a software module which directs the completed form to the ISP transaction processor. Upon receipt of the form, the transaction processor 102 may initially check to determine whether the merchant is approved for use with the ISP or associated transaction system either directly or via another party. The approval may also be in a negatively expressed way, in which merchants are banned from using the system, e.g. where the merchant has previously not performed satisfactorily in delivering goods or services. In this way, a reliability factor can be included when cardholders are dealing with merchants. A merchant could be placed on a banned list following a successful complaint by a cardholder. The transaction processor may also, using a merchant request means, attempt to submit a message to the merchant asking the merchant to provide their merchant details to allow processing of the transaction to proceed. For example, the message may be submitted by entering the message in fields of the transaction form and submitting these details to the merchant's server. This is particularly suited to situations where the transaction processing on the merchant's website is manually performed, i.e. in situations where a person manually re-keys submitted card information via a Point of Sale (POS) or virtual POS payment card device. In situations, where the payment transaction part of a website is automated, it is possible that the merchant's server would generate an error message. In the event that the merchant responds to such a request and provides their merchant card scheme details, the transaction may be processed as described above with respect to the processing of the transaction request in the first embodiment. In the event that a merchant responds negatively or fails to respond within a period of time, the method proceeds along the following lines: As described above with respect to the first embodiment, the transaction processor determines the identity of the cardholder and extracts 32 the cardholder information for the cardholder from the cardholder card key details datastore. Optionally, the transaction processor may include a verification means adapted to perform a check to ensure that the name and/or address etc. on the database matches that supplied by the cardholder in the transaction form. In this second embodiment, the transaction processor does not posess the merchant's merchant code information. As a result, it may not be possible to directly process the transaction as in the case of the first embodiment described. To overcome this, the payment processor employs a merchant code of its own, i.e. a merchant code associated with the transaction processor operator (e.g. the ISP), hereinafter refered to as the system_merchant code. The transaction processor then transmits 33 a payment authorisation request to an appropriate authorisation host, submitting the system_ merchant code, the amount of the transaction (extracted from the form) and the cardholder's payment card details (card number and expiry date). If the authorisation host rejects the transaction, then a suitable message is sent to the cardholder and the transaction is cancelled as described previously. If the authorisation host approves the transaction, it forwards an authorisation code to the transaction processor 102. Upon receipt of the authorisation code, the transaction processor stores it along with the other details of the transactions in the transactions datastore for further processing (e.g. payment) 35. It will be appreciated that once this transaction is processed for settlement with the card scheme, the amount of the transaction will be debited from the cardholder and credited to the system_merchant (transaction processor scheme operator) account corresponding to the system_merchant code. This first transaction does not involve the merchant, only the transaction processor scheme operator and the cardholder. In order to pass settlement (from the transaction processor scheme operator) to the merchant, the transaction processor provides cardholder information, card number and expiry date corresponding to an account of the transaction processor operator, hereinafter referred to as the system cardholder account, to the merchant. The merchant may process this system_cardholder information in the conventional way. In this second transaction, the transaction processor scheme operator system_cardholder account is debited and the merchant's account is credited. In combination with the first transaction, an effective debit is made from the cardholder's account and the merchant is credited for the transaction amount. The transaction processor segments of the two transactions effectively cancel. One method in which the transaction processor may provide its system_cardholder information to the merchant is by insertion 34 of the relevant system_cardholder card information in the appropriate fields of the form previously completed by the cardholder and submitted to the transaction processor and forwarding this revised form to the merchant's server. Upon receipt of the form, the merchant's server processes the form in a conventional manner. In this instance, however, the merchant's server submits a authorisation and (subsequent) payment request for the system_cardholder card number and not the cardholder's card number details. The transaction processor in turn forwards confirmation of acceptance of the transaction to the merchant along with the authorisation code. The merchant is not forwarded the payment card details of the cardholder. The transaction processor stores the details of the transaction subsequently posting the transaction (e.g. in a day end posting) for payment in accordance with conventional methods. Alternatively, the transaction could be posted at the time of authorisation. In this second embodiment, there are two transactions of equal value. The first transaction is between the transaction processor scheme operator and the cardholder. The second transaction is between the transaction processor scheme operator and the merchant. To prevent fraud, the transaction processor may be suitably adapted to perform reconciliations between the two sets of transactions, identifying transactions that are unusual. In a further embodiment, cardholders may have more than one card belonging to one or more card schemes. In this embodiment, the details of each individual card may be stored in the database. At the time of entering the cardholder name and password when connecting to the ISP or at some other appropriate time, the cardholder may be asked to identify which card they wish to use for that session. Alternatively, the cardholder may identify a particular card for a transaction at the time of submitting the form, e.g. be selection of an appropriate button. To ensure greater security, each card may be assigned a reference identifier by the cardholder at the time of submitting details to the ISP. For example, a cardholder may assign a name “VISA—household” to a VISA™ credit card used primarily for purchasing for the household or “AMEX—business” to identify an AMERICAN EXPRESS™ card used for business purposes. By providing the cardholder with a list of card identifiers to select from, the cardholder can identify the card they wish to use without the necessity for the cardholder or transaction processor to transmit data disclosing the card details to the cardholder. Frequently, a cardholder will have more than one address associated with one or more cards. For example, a cardholder may have a business address for a card associated with work and a home address for other cards. In addition, cardholder's frequently may wish to have goods delivered to an address, which is not the cardholder's actual address, e.g. a present to a loved one. In a further embodiment of the present system, the cardholder card key details database is structured so as to allow more than one address to be associated with a particular card or cardholder account. These addresses could be entered at the same time as a cardholder provides card details to the ISP or may be amended at a subsequent date to remove or add for addresses. At the time of conducting a validation check, the transaction processor could check to confirm that the address provided by the cardholder at the time of the transaction matched an address on the database for the particular card or cardholder. Although the present invention has been described in terms of HTML forms, it will be appreciated by the skilled person in the art that a variety of different methods could be used to implement the present invention that would not depart from the spirit or scope of the invention. For example, cardholders could download a specific add-in for their browsers that automatically operate upon detection of a selection by a cardholder or response from a merchant server, e.g. where the merchant server responds with a particular file format upon receipt of a purchase request from the cardholder. As herein described the present invention directed towards the routing of a payment transaction through an ISP and access only being permitted by a cardholder using a password, it includes the possibility of correlation/verification that cardholders database name/address etc. agrees with transaction order's name/address and permits the obtaining of payment authorisation independent, but on behalf, of a merchant. If declined, the declination is passed on to the cardholder and the transaction is not processed. If approved, then a confirmation is sent to the cardholder and the merchant. As a further separate confidence building measure, settlement of the transaction vis a vis the merchant can be delayed until independent confirmation of dispatch has been received. The words “comprises/comprising” and the words “having/including” when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

<SOH> Background to the Invention <EOH>Significant research and resources have been applied in developing, implementing and maintaining secure payment systems which facilitate the use of credit/charge cards by cardholders in commercial transactions conducted over the Internet. All of these secure systems are based on cardholders having to “process” their card number each time, which leaves the “capturing” of card numbers and related information transmitted at time of purchase, open to hackers and/or other fraudsters who can gain access to card numbers and expiry dates. One solution is to use secure (encrypted) methods of communication in sending credit card details over the Internet to a merchant when making a purchase. Examples of such secure methods include Secure Socket Layer (SSL) and the Secure Electronic (SET) protocol. These methods have been developed by leading computer companies and businesses in the credit card industry specifically for the purposes of performing electronic transmission of credit card details on the Internet. However, there is no guarantee that the credit/charge card details whilst transmitted somewhat securely are not vulnerable to attack when stored on the merchant's system. It is a strong possibility that the card details could be hacked or used by a merchant or an employee of the merchant for fraudulent purposes. A further concern mitigating against on-line commerce, as perceived by cardholders, is the reliability of the e-commerce merchants and the lack of recourse available to card holders having made a purchase. The cardholder has no guarantee that items ordered will be delivered in a timely manner and be of an appropriate quality and/or quantity etc. It may be difficult, once card details have been supplied and appropriate funds debited to the cardholder's account, for a cardholder to obtain proper satisfaction from the merchant. A further concern is that there is no guarantee that a merchant, or associated personnel who may have access to the cardholders details, will not use the cardholders card details in subsequent unauthorised transactions, or pass the information onto third parties for criminal purposes. On the other hand, a significant concern for merchants is that items are definitely settled for before dispatch, i.e. that the card details and amount has been “approved” for settlement by the card scheme acquirer and that the card details and cardholder information is genuine. EP 0801479 discloses a secure communication mechanism for communicating credit card or other sensitive information between a cardholder terminal and a server which communicate over a data network (e.g. Internet). For secure or private communication of sensitive information over a data network, a telephone connection is established between the originating Internet Service Provider (ISP) server to which the cardholder is connected for access to the data network and the server provider to which the sensitive information is directed. Any communications or transactions to a terminating ISP server involving credit card or other sensitive information are effected, however, on a second connection through a telephone call placed to a telephone number of the terminating ISP server. After receiving a call, and by associating such call with the cardholder's request over the Internet for information and/or interactive services, and/or non-electronically deliverable goods or services, the ISP provides the cardholder with the requested information and/or service, or approves delivery of the non-electronically deliverable goods or services. With this arrangement, payment is effected without providing credit card information via the Internet routing servers and without establishing a financial relationship with the ISP. Preferably, the communication of information over the telephone line between the originating server and the terminating ISP server is also subject to encryption. The problem with this approach is that is essential for ISPs and merchants to sign up to the idea and to the installation of additional communications equipment to facilitate the secure communication on the secondary channel. Furthermore, the requirement for a separate telephone call adds additional cost to the process and there is still no guarantee from the cardholder's perspective. WO97/03410 discloses an Internet billing method comprising establishing an agreement between an Internet access provider and a customer, and an agreement between the Internet access provider and a vendor, wherein the Internet access provider agrees with the customer and the vendor to bill the customer and remit to the vendor for products and services purchased over the Internet by the customer from the vendor. The provider creates access to the Internet for the customer. When the customer orders a product or service over the Internet from a vendor, transactional information transmitted between the customer and the vendor is also transmitted to the provider. The provider then bills the transaction amount to the customer and remits a portion of the transaction amount to the vendor, keeping the differential as a fee for providing the service. As a result of this method, there is no need for any customer account numbers or vendor account numbers to be transmitted over the Internet, thereby maintaining the security of that information. An immense difficulty with this approach is that agreements are required between the ISP's and merchants before any transactions can take place. U.S. Pat. No. 5,905,736 discloses a method for performing centralised billing for transactions conducted over the Internet between a cardholder and an Internet Service Provider through an Internet Access Provider (IAP). Upon connection of the cardholder's terminal to the LAP, the IAP transmits to a billing platform a message that associates the cardholder's identity and the temporary Internet Protocol (EP) address -that is assigned by the IAP to the cardholder's session for use by to that cardholder's terminal. In response to a chargeable transaction with an ISP, the ISP transmits to the billing platform the IP address of the cardholder making the transaction and the charge for the transaction. The charges for all such transactions are accumulated by a transaction server and stored in an account on an associated database identified with the IP address of the requesting terminal. At the end of the cardholder's session, the charges for all the transactions during the session that are stored on the transaction server database in the account identified with the IP address, are charged to an account associated with the cardholder's identity that is stored on a database of a billing server by cross-referencing the IP address to the cardholder's identity from the previously received and stored message. In consideration of the prior art, it would be advantageous if a method of purchasing goods on-line could be provided which would permit a cardholder to have a simple and efficient recourse to the e-commerce merchant in the event of a complaint. It would further be desirable, if a method could be provided, which would allow a consumer to make a purchase on-line without disclosing their card details to third parties.

<SOH> SUMMARY OF THE INVENTION <EOH>The concept of the present invention adopts an alternative approach to security methods presently employed to protect cardholders. The concept obviates the need for a cardholder to transmit card numbers along with other purchasing details at the time of purchase and couples this with the use of a password feature. This renders the transaction akin to a bank cash withdrawal that banks/card schemes are totally happy with from a security point of view but are reluctant to allow e-commerce and/or any others access to their “network” to ensure Security. In a first embodiment, a computer data processing method is provided for processing an on-line payment transaction, comprising the steps of: receiving a request from a cardholder to connect to a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a payment request associated with the cardholder, said payment request identifying merchant information including a merchant code identifier and a transaction value, retrieving payment card details for the cardholder from a cardholder details database, submitting a payment authorisation request for the payment card details, the authorisation request including the merchant code and transaction value to an authorisation host for authorising the transaction, and whereupon receipt of an authorisation forwarding confirmation of the authorisation to the merchant. The computer data processing method may further comprise the step of requesting a merchant code identifier from the merchant. The computer data processing method may include the step of posting the payment request to a payment host for processing of the payment transaction. Where posting is performed, the computer data processing method may further comprise the step of delaying posting the payment request until a confirmation of delivery has been received. Optionally, the computer data processing method may further comprise the step of verifying to ensure that the cardholder information provided to a merchant matches cardholder information stored in the cardholder's details database. In a second embodiment, a computer data processing method is provided for processing an on-line payment transaction, comprising the steps of: receiving a request from a cardholder to connect a network, said request including a cardholder password, authenticating said cardholder request and providing access by said cardholder to the network, receiving a first transaction request associated with a transaction between a merchant and the cardholder, retrieving payment card details for the cardholder from a database, submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value to an authorisation host for authorising the transaction, and on receipt of an authorisation forwarding a transation request to the merchant, the request including a cardholder payment card code. The computer data processing method may further comprise the step of requesting a merchant code identifier from the merchant. The computer data processing method may include the step of posting the payment request to a payment host for processing of the payment transaction. Where posting is performed, the computer data processing method may further comprise the step of delaying posting the payment request until a confirmation of delivery has been received. Optionally, the computer data processing method may further comprise the step of verifying to ensure that the cardholder information provided to a merchant matches cardholder information stored in the cardholder's details database. In a third embodiment, a system is provided for processing an on-line payment transaction, the system having a connection to the Internet and a further connection via a local network to the terminal of a cardholder comprising: receiving means for receiving a request from a cardholder to connect a network, said request including a cardholder password, authentication means for authenticating said cardholder request and providing access by said cardholder to the network, receiving means for receiving a first transaction request associated with a transaction between a merchant and the cardholder, retrieval means for retrieving payment card details for the cardholder from a database, authorising means for submitting a payment authorisation request for the payment card details, the authorisation request including a system merchant code and transaction value to an authorisation host for authorising the transaction, and transaction means responsive to receipt of an authorisation from the authorisation host and adapted to forward a transaction request to the merchant, the request including a system cardholder account code. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant. The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In a fourth embodiment a payment processing system is provided for processing an on-line payment transaction between a merchant and a cardholder, comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder card details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, the merchant code of the payment request and the transaction value of the payment request to an authorisation host for authorising the transaction, confirmation means which is adapted to forward confirmation of an authorisation received in response to a submitted payment authorisation request. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant. The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In a fifth embodiment a payment processing system is provided for processing an on-line payment transaction between a merchant and a cardholder, comprising: means for receiving a payment transaction request, said payment request identifying merchant information including a merchant code identifier and a transaction value, association means for associating a cardholder with the received payment request, means for retrieving payment card details for the cardholder from a datastore of cardholder card details, authorisation means for submitting a payment authorisation request for the retrieved payment card details, the payment authorisation request including the retrieved payment card details, a system merchant code and the transaction value of the payment request to an authorisation host for authorising the transaction, response means responsive to receipt of an authorisation and adapted to forward a transaction request to the merchant, the request including a system cardholder account code. In this embodiment, the system may further comprise a merchant request means for requesting a merchant code identifier from the merchant The system may include a payment posting means for posting the payment request to a payment host for processing of the payment transaction. In this option, the payment posting means delays posting the payment request until a confirmation of delivery has been received. Optionally, the system may include a verification means which is adapted to perform a second verification to ensure that the cardholder information provided to a merchant matches cardholder information stored in the database. In one embodiment, the first set of information identifying a cardholder and the second set of information identifying the merchant are received using an Internet submission protocol, for example the POST action associated with HTNL forms. These and other aspects of the invention will be apparent from, and elucidated with, reference to the embodiment(s) described hereinafter.

20041028

20120710

20050303

59106.0

JOHNSON, GREGORY L

SECURE PAYMENT SYSTEM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Field apparatus

A field apparatus (1a) comprises a diagnosis unit (11) diagnosing abnormality of oneself or a controlled element and a bidirectional digital communication means (22) to send a digital signal which shows a diagnosis result to outside and to receive the digital signal from outside in order to execute a control of controlled element and other predetermined functions based on a command signal received by a analog communications means (17) that can receive a analog signal from outside. A electric power for operation is supplied through a switching means (18, 53) that can switch either a electric power that is supplied by the analog communications means (17) or a electric power that is supplied by the bidirectional digital communication mean (22).

1. A field apparatus comprising: a analog communications means that can receive a analog signal from outside is comprised, and executing a control of controlled element and other predetermined functions based on a command signal received by the analog communications means; a diagnosis unit diagnosing abnormality of oneself or the controlled element; and a bidirectional digital communication means to send a digital signal which shows a diagnosis result to outside and to receive the digital signal fron outside. 2. The field apparatus according to claim 1, wherein a switching means can switch either a electric power that is supplied by the analog communications means or a electric power that is supplied by the bidirectional digital communication means as a electric power for operation. 3. The field apparatus according to claim 1, wherein an automatic switching means uses either a power supply from the analog communications means or a power supply from the bidirectional digital communication means as a elecic power for operation, and if a power supply in use runs out it can switch to the other power supply automatically.

FIELD OF THE INVENTION The present invention relates to a field apparatus of positioners having a communication function. BACKGROUND ART Generally in a control system operating a control apparatus of valves by remote control, a detection sign from the field apparatus measuring a quantity of physics such as flow quantity, pressure force and temperature are gathered to a controller as a superior apparatus, the controller operates opening and shutting of valves by remote control based on those detection signals. In such the control system, generally a communication cable of 4-20 mA is used as a transmission channel transmitting the detection signal from a detection port of feld apparatuses to the controller and transmitting a control signal from the controller to an operation port of valves. The controller receives an analog signal (following, “4-20 mA signal”) with an electric current of 4-20 mA normalized to 0-100% from the detection port by this communication cable. Further it establishes a PID parameter so that a detection data in the detection port will become a predetermined target value (set point) at every operation port. And it sends the 4-20 mA signal as the control signal normalized to 0-100% towards the operation port. In late years, the field apparatus comprising the function transmitting the diagnosis information of valve and oneself to the controller is developed in addition to the control function of the valve. As an example of such the field apparatus, there is the positioner disclosed by Japanese Patent Laid-Open No. 1-141202. According to this, because the diagnosis result of valve and oneself are informed to the controller via the transmission channel, the controller can analyze the diagnosis result and take the correspondence step. Therefore a bidirectional digital communication of field bus communications (following “FB communication”) is used and the control system by such the bidirectional digital communication will be replaced to the control system from the conventional analog communication. In such a digital control system, in addition to operating by remote control the operation port of valves as before, the controller instructs the diagnosis of the valve and own diagnosis of the field apparatus by remote control and it manages each field apparatus by acquiring the diagnosis information. In the control system that utilized such the FB communication, it is advantageous that setting and maintenance of the valve and the field apparatus are easy. However, it is needed to exchange the interface of all apparatuses to the interface for FB communication from the existing interface for 4-20 mA communication in order to change the existing control system using the communication cable of 4-20 mA to the control system by the FB communication. Moreover, very many costs are needed in a cage of such the system. Moreover in the control system which used the FB communication, because the control information that operate by remote control of the operation port and the diagnosis information of the apparatus intermingle, the inside of the transmission channel is crowded by the transmission information and may give bad influence to the control. SUMMARY OF THE INVENTION It is an object of the present invention to provide the field apparatus which can introduce the control system by the digital communication easily without wasting the control system by the existing 4-20 mA communication, and can transmit information between the outside device and the operation port precisely and speedily. The present invention is the field apparatus comprising the analog communications means that can receive the analog signal from outside, and executing the control of controlled element and other predetermined functions based on a command signal received by the analog communications means. The field apparatus of the present invention is characterized by comprising a diagnosis unit diagnosing abnormal of oneself or the controlled element and a bidirectional digital communication means to send a digital signal which shows the diagnosis result to outside and to receive the digital signal from outside. The embodiment of the present invention comprises a switching means for example, a power supply changeover unit 18 of FIG. 2) that can switch either a electric power that is supplied by the above analog communications means or a electric power that is supplied by the above bidirectional digital on means is used as the electric power for the field apparatus operation. The other embodiment uses either a power supply from the analog communications means or a power supply from the bidirectional digital communication means as the electric power for the field apparatus operation and if the power supply in use runs out, it comprises an automatic switching means (for example, an automatic changeover switch 53 of FIG. 5) that can switch to the other power supply automatically. According to the present invention, the existing equipment can be utilized usefully without setting up new communication equipment in order to control the controlled object of valves because communication with the existing control system is possible by the analog communications means. At the same tine an advantage of the bidirectional communication of the setting and the diagnosis of own diagnosis or the controlled object is provided by utilizing the digital communication with the outside by the bidirectional digital communication means. Moreover, because management/diagnosis information of the control information and the apparatus does not intermingle, congestion of the transmission channel is prevented and bad influence does not give to the control. According to the embodiment of the present invention, it can switch optionally either the electric power supplied by the analog communications means or the electric power supplied by the bidirectional digital communication means is used as the electric power for the field apparatus operation. Therefore, if the power supply by the FB communication is stopped, the electric power is secured by switch to the power supply by the analog communication, and influence to the control of the controlled object can be prevented. According to other embodiment, if the power supply in use runs out, it can be changed to the other power supply automatically. Therefore, even if either the power supply stops, the influence can be prevented. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows an embodiment of a control system constituted by using a positioner of the present invention. FIG. 2 shows a circuit composition of a positioner of an embodiment. FIG. 3 shows a circuit composition of an I/V block. FIG. 4 shows a circuit composition of a FB block. FIG. 5 shows another embodiment of a control system constituted by using a positioner of the present invention TNE BEST MODE FOR CARRYING OUT THE INVENTION FIG. 1 shows the control system constituted by using the positioner of embodiment of the present invention. The positioner 1a, 1b as the field apparatus have a positioning function to control a valve position of the valve 3a, 3b in response to the control signal from a controller 2. Each positioner 1a, 1b and the controller 2 are connected in the 4-20 mA communication cable 5a, 5b of two-line type respectively. Each positioner 1a, 1b controls the valve position of each valve 3a, 3b based on the control signal transmitted through the communication cable 5a, 5b from the controller 2 (following “4-20 mA signal”). The control signal transmitted from the controller 2 determines the PID parameter as opposed to each positioner 1a, 1b and is generated so that the detection data of the flow quantity transmitter 6 provided downstream of the valve 3a and 3b become a predetermined target value in the controller 2. Each positioner 1a, 1b move by electric power supplied through the 4-20 mA communication cable 5a, 5b from a stabilization power supply unit 7a connected to the controller 2. Each positioner 1a, 1b have also the function to diagnose operation circumstances of own operation circumstances and the valve 3a, 3b. Information of the diagnosis result (following “diagnosis information”) is transmitted through the FB communication cable 8a, 8b of two line type to the FB setting device 4 which does the setting and the management of each field apparatus. Moreover, each positioner 1a, 1b comprise the communication function that can receive the setting ation fom the FB setting device 4 via the FB communication cable 8a, 8b. The electric power to be necessary for movement of the above positioner 1a, 1b is supplied through the 4-20 mA communication cable 5a, 5b from the stabilization power supply with 7a of the controller 2 side. However even if this power supply was cut, the positioner 1a, 1b are composed to receive the power supply through the FB communication cable 8a, 8b. Concretely, the switch that can switch between the power supply via the 4-20 mA communication cable 5a, 5b and the power supply via the FB communication cable 8a, 8b are comprised inside the positioner 1a, 1b. The electric power via the FB communication cable 8a, 8b is supplied by the stabilization power supply unit 7b which is different from the stabilization power-supply unit 7a of the controller 2 side. FIG. 2 shows a circuit constitution of the positioner 1a. This circuit comprises the arithmetic a processing unit 10, a voltage conversion unit 20, a valve lift detection unit 21, a I/V block 17, YB block 22, the power supply changeover unit 18 as a main constitution element. The arithmetic processing unit 10 includes a CPU 11, a ROM 12, a RAM 13, a communication interface 14, a A/D converter 15 and a power supply unit 19 connected through a bus 16. The CPU 11 functions as the diagnosis unit generating the diagnosis information based on the input signal from various sensors (not shows) arranged for diagnoses. The diagnosis information is sent to the FB block 22 through the communication interface 14 and it is transmitted toward the FB setting device 4 via the FB communication cable 8a, 8b from the FB block 22. Various sensors arranged for diagnoses are such as an air pressure sensor, a supersonic wave sensor, a temperature sensor. The 4-20 mA signal sent via the communication cable 5a, 5b from the controller 2 is distributed to a 1-3V voltage signal or a power supply electric current in the I/V block 17 that is an example of the analog communications means. While the power supply electric current is supplied to the power supply unit 19 of the arithmetic processing unit 10 through the switch S1 of the power supply changeover unit 18, a voltage signal is converted into the digital signal at the A/D converter 15. In response to the CPU 11 getting a deviation between this digital signal and a later valve lift signal, the valve lift control signal which establishes a control quantity of the valve position of the valve 3a is generated and is output from the voltage conversion unit 20. The voltage conversion unit 20 consists of a well-known converter circuit that converts the valve lift control signal to an air pressure signal and the valve position of valve 3a is controlled by the air pressure signal after the conversion. The valve lift detection unit 21 consists of a well known detection circuit that converts stem displacement of the valve 3a to the voltage signal of 1-3V The detection signal is converted to the digital signal by the above A/D converter 15 and the above valve lift control signal is used for generation On the other hand, the digital signal sent via the FB communication cable 8a, 8b from the FB setting device 4 is distributed to the signal showing the setting information from the FB setting device 4 or the power supply electric current in FB block 22 that is an example of the bidirectional digital communication means. While the power supply electric current is supplied to the power supply unit 19 of an arithmetic processing unit 10 through the switch S1 of the power supply changeover unit 18, the setting information signal is inputted into the communication interface 14 after the noise removal in an isolator 24 through a channel 23. The CPU 11 executes various setting processing in response to the setting signal received through the communication interface 14. As shown in FIG. 2, the power supply changeover unit 18 of this positioner 1a includes usually a condition that the switch piece S1 connects to the I/V block 17 and the power supply electric current from the I/V block 17 is supplied to the power supply unit 19. But connection of this switch piece S1 consists of the manual switch that can be changed to the FB block 22 side by manual. Accordingly, even if the electric power from the contoller 2 is not supplied, it is changed to supply of the power supply from the FB setting device 4 by switching a condition of this switch. FIG. 3 shows circuit constitution of I/V block 17. Between the 4-20 mA communication cable 5a and 5b, this I/V block 17 connects a series circuit between the transistor as first variable impedance device Z1, and the resistor as impedance device RS for reception. And the transistor as second variable impedance device Z2 is connected to the series circuit of the resistor Rc in parallel with these. At the same time an arithmetic circuit 31 is connected in parallel with the device Z2 and was constituted to get the output from the both terminals of this arithmetic circuit 31. While the arithmetic circuit 31 controls the impedance of the device Z1 in the course for example, 10V) keeping the line voltage VL of the 4-20 mA communication cable 5a, 6b, the impedance of the device Z2 is controlled in the course (for example, 4 mA) keeping the electric current Ic flowing in the resistor Rc. If the electric current which is passed in the device Z2 is I1, the output electric current of the I/V block 17 becomes I2=Ic−I1. In the circuit of FIG. 3, if a track line electric current of the 4-20 mA communication cable 5a, 5b is IL, the electric current passing the series circuit between the first variable impedance device Z1 and the resistor Rs is Is=IL−Ic. Therefore, for example, IS becomes only a signal electric current of 0-16 mA by establishing kept Ic (for example, 4 mA) as a bias ingredient. Without giving influence on the reception of the signal shown by this IS, the power supply electric current I2 of maximum 4 mA can be supplied to the power supply unit 19 stably through the switch S1 of FIG. 2. On the other hand, for example, the terminal voltage VIN of the resistor Rs (=RsIs) is inputted into the A/D converter 15 as the voltage signal of 1-3V. FIG. 4 shows circuit constitution of the FB block 22. This FB block 22 comprises a MAU (Media Attachment Unit) 41, a CPU 42, a flash memory 43, a RAM 44 and a communication interface 45. MAU 41 distributes the transmission signal from the FB communication cable 8a, 8b to the power supply electric current or the digital signal as the setting information, and comprises a function to transmit the diagnosis information of the field apparatus (in this case, the positioner toward the FB setting device 4. The power supply electric current is supplied as the power supply for movement of this FB block 22, and when a condition of the switch S1 of FIG. 2 was switched from an as described before usual condition, the power supply electric current is supplied to the power supply unit 19. On the other hand, the digital signal as the setting information is processed in the CPU 42, it is transmitted through the transmission channel 23 from the communication interface 45 to the arithmetic processing unit 10. The CPU 11 inside the arithmetic processing unit 10 processes the monitoring and the adjustment of the output value of the field apparatus based on this setting information, various diagnosis information to be got on the basis of these is transmitted toward the FB setting device 4 through the FB block 22. The flash memory 43 stores a program about the FB communication, and the RAM 44 stores a variable about the FB communication. FIG. 5 shows the circuit constitution to switch the power supply from the I/V block 17 side and the power supply from the FB setting device 4 side in response to circumstances automatically in the positioner 1a. In this circuit constitution, the respective power supply monitor circuit 51a, 51b are connected to each output port of the I/V block 17 and the FB block 22 and it always watches the output electric current from the I/V block 17 and the FB block 22. The output showing monitor circumstances of the power supply monitor circuit 51a and 51b of these two becomes the input to the OR circuit 52, and the output of this OR circuit 52 becomes the setting signal of the automatic changeover switch 53. That is, the OR circuit 52 sends the in response to the monitor output from either power supply monitor circuit 6la or 51b to the automatic changeover switch 53. The automatic changeover switch 53 is set at the power supply condition from the I/V block 17 side or the power supply condition from the FB block 22 side by the input signal. Concretely, this automatic changeover switch 53 is usually set on the condition to supply the power supply electric current from the I/V block 17 for the power supply unit 19. If the output electric current runs out in the power supply monitor circuit 5la of the I/V block 17 side, the output from the OR circuit 52 changes. Therefore the automatic changeover switch 53 is switched to the condition that supplies the power supply electric current from the FB block 22 for the power supply unit 19. If the output runs out in the power supply monitor circuit 51b of the FB block 22 side in this condition, the output fox the OR circuit 52 changes. Therefore, the automatic changeover switch 53 returns to the usual condition that supplies the power supply electric current from the I/V block 17 for the power supply unit 19. In thee circumstances, though the positioner of embodiment was explored, the present invention is not limited to the positioner and can apply to other field apparatuses (for example, the measurement apparatus such as the differential pressure transmitter).

<SOH> BACKGROUND ART <EOH>Generally in a control system operating a control apparatus of valves by remote control, a detection sign from the field apparatus measuring a quantity of physics such as flow quantity, pressure force and temperature are gathered to a controller as a superior apparatus, the controller operates opening and shutting of valves by remote control based on those detection signals. In such the control system, generally a communication cable of 4-20 mA is used as a transmission channel transmitting the detection signal from a detection port of feld apparatuses to the controller and transmitting a control signal from the controller to an operation port of valves. The controller receives an analog signal (following, “4-20 mA signal”) with an electric current of 4-20 mA normalized to 0-100% from the detection port by this communication cable. Further it establishes a PID parameter so that a detection data in the detection port will become a predetermined target value (set point) at every operation port. And it sends the 4-20 mA signal as the control signal normalized to 0-100% towards the operation port. In late years, the field apparatus comprising the function transmitting the diagnosis information of valve and oneself to the controller is developed in addition to the control function of the valve. As an example of such the field apparatus, there is the positioner disclosed by Japanese Patent Laid-Open No. 1-141202. According to this, because the diagnosis result of valve and oneself are informed to the controller via the transmission channel, the controller can analyze the diagnosis result and take the correspondence step. Therefore a bidirectional digital communication of field bus communications (following “FB communication”) is used and the control system by such the bidirectional digital communication will be replaced to the control system from the conventional analog communication. In such a digital control system, in addition to operating by remote control the operation port of valves as before, the controller instructs the diagnosis of the valve and own diagnosis of the field apparatus by remote control and it manages each field apparatus by acquiring the diagnosis information. In the control system that utilized such the FB communication, it is advantageous that setting and maintenance of the valve and the field apparatus are easy. However, it is needed to exchange the interface of all apparatuses to the interface for FB communication from the existing interface for 4-20 mA communication in order to change the existing control system using the communication cable of 4-20 mA to the control system by the FB communication. Moreover, very many costs are needed in a cage of such the system. Moreover in the control system which used the FB communication, because the control information that operate by remote control of the operation port and the diagnosis information of the apparatus intermingle, the inside of the transmission channel is crowded by the transmission information and may give bad influence to the control.

<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide the field apparatus which can introduce the control system by the digital communication easily without wasting the control system by the existing 4-20 mA communication, and can transmit information between the outside device and the operation port precisely and speedily. The present invention is the field apparatus comprising the analog communications means that can receive the analog signal from outside, and executing the control of controlled element and other predetermined functions based on a command signal received by the analog communications means. The field apparatus of the present invention is characterized by comprising a diagnosis unit diagnosing abnormal of oneself or the controlled element and a bidirectional digital communication means to send a digital signal which shows the diagnosis result to outside and to receive the digital signal from outside. The embodiment of the present invention comprises a switching means for example, a power supply changeover unit 18 of FIG. 2 ) that can switch either a electric power that is supplied by the above analog communications means or a electric power that is supplied by the above bidirectional digital on means is used as the electric power for the field apparatus operation. The other embodiment uses either a power supply from the analog communications means or a power supply from the bidirectional digital communication means as the electric power for the field apparatus operation and if the power supply in use runs out, it comprises an automatic switching means (for example, an automatic changeover switch 53 of FIG. 5 ) that can switch to the other power supply automatically. According to the present invention, the existing equipment can be utilized usefully without setting up new communication equipment in order to control the controlled object of valves because communication with the existing control system is possible by the analog communications means. At the same tine an advantage of the bidirectional communication of the setting and the diagnosis of own diagnosis or the controlled object is provided by utilizing the digital communication with the outside by the bidirectional digital communication means. Moreover, because management/diagnosis information of the control information and the apparatus does not intermingle, congestion of the transmission channel is prevented and bad influence does not give to the control. According to the embodiment of the present invention, it can switch optionally either the electric power supplied by the analog communications means or the electric power supplied by the bidirectional digital communication means is used as the electric power for the field apparatus operation. Therefore, if the power supply by the FB communication is stopped, the electric power is secured by switch to the power supply by the analog communication, and influence to the control of the controlled object can be prevented. According to other embodiment, if the power supply in use runs out, it can be changed to the other power supply automatically. Therefore, even if either the power supply stops, the influence can be prevented.

20040823

20070717

20050120

96895.0

CHANG, SUNRAY

FIELD APPARATUS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Aircraft fluid cooling system and aircraft provided with said system

The aircraft (30) fluid coolint system has an air heat exchanger (40) passed by this fluid, said air heat exchanger (40) including a means for the introduction of air (52) and an air exhaust means (54). This air heat exchanger (40) is installed in a housing located in a flap (36) guide rail fairing (34) connected to one wing (32) of this aircraft, said means for the introduction of air (52) in the air heat exchanger (40) being connected to an air inlet means (42) crossing the outer surface (46) of the fairing (34) and said air exhaust means (54) of said air heat exchanger (40) being connected to an air output means (44) opening outside said outer surface (46) in order that the air outside the aircraft (30) passes this air heat exchanger (40) to cool said fluid.

1-25. (canceled) 26. An aircraft fluid cooling system, comprising: an air heat exchanger passed through by a fluid, said air heat exchanger including means for introducing air and an air exhaust, wherein said air heat exchanger is installed in a housing located in a flap guide rail fairing connected to one wing of the aircraft, said means for introducing air in the air heat exchanger being connected to an air inlet crossing an outer surface of the guide rail fairing and an air exhaust of this air heat exchanger being connected to an air output opening outside an outer surface in order that the air outside the aircraft passes through said air heat exchanger to cool said fluid. 27. A system according to claim 26, wherein said air inlet is connected to the means for introducing air of the air heat exchanger by a divergent duct whose section increases according to a direction of circulation of the air in said air inlet towards said means for introducing air of the air heat exchanger. 28. A system according to claim 26, wherein said air exhaust of the air heat exchanger is connected to said air output opening by a convergent duct whose section decreases according to a direction of circulation of the air in said air exhaust of the air heat exchanger towards said air output opening. 29. A system according to claim 26, wherein said air inlet includes a ram air intake. 30. A system according to claim 29, wherein said air inlet includes a Pitot tube air intake. 31. A system according to claim 29, wherein said air inlet includes a scoop air intake. 32. A system according to claim 29, wherein said air inlet includes an air intake embedded in the outer surface of the flap guide rail fairing. 33. A system according to claim 26, wherein said air inlet is located in a forward part of the flap guide rail fairing. 34. A system according to claim 26, wherein said air output opening is made up of at least one nozzle positioned in a thrust axis of the aircraft. 35. A system according to claim 34, wherein said nozzle is located on a lateral part of the flap guide rail fairing. 36. A system according to claim 34, further comprising at least two nozzles located on lateral parts of the flap guide rail fairing. 37. A system according to claim 27, wherein said divergent duct has a neck to limit throughput of air in said divergent duct in cruise flight phases. 38. A system according to claim 26, wherein dimensioning is provided to ensure the cooling of said fluid when the aircraft is flying under cruise conditions. 39. A system according to claim 26, further comprising at least one fan to ensure a minimal throughput of air in the air heat exchanger. 40. A system according to claim 26, further comprising a fan installed upstream of the air heat exchanger. 41. A system according to claim 26, further comprising a fan installed downstream of the air heat exchanger. 42. A system according to claim 39, further comprising control means for controlling said fan and which activates said fan when airspeed of the aircraft is below a predetermined value. 43. A system according to claim 39, further comprising control means for controlling said fan and which activates said fan when a temperature of the fluid to be cooled is greater than a predetermined value. 44. A system according to claim 39, further comprising control means for controlling said fan and which controls said fan with a variable speed that decreases when an airspeed of the aircraft increases. 45. A system according to claim 39, further comprising control means for controlling said fan and which controls said fan with a variable speed that decreases when a temperature of the fluid to be cooled decreases. 46. A system according to claim 39, further comprising plural fans arranged in parallel. 47. An aircraft including at least one fluid cooling system according to claim 26. 48. An aircraft including at least one fluid cooling system according to claim 26, with plural flap guide rail fairings connected to wings of the aircraft. 49. An aircraft according to claim 47, including at least one hydraulic fluid circuit in which hydraulic fluid is cooled by said at least one fluid cooling system. 50. An aircraft according to claim 49, wherein said hydraulic fluid passing through the air heat exchanger is from a drainage pipe of at least one hydraulic pump.

TECHNICAL DOMAIN The invention concerns a system for cooling an aircraft fluid, in particular, a hydraulic fluid circulating on board this aircraft, said hydraulic fluid being for supplying one or more hydraulic actuators. The invention also concerns an aircraft equipped with such a system for cooling a fluid, in particular, a hydraulic fluid circulating on board this aircraft. PRIOR ART In an aircraft, there are generally one or more hydraulic fluid circuits, for supplying one or more hydraulic actuators such as, for example, hydraulic motors, or servo-controle, or pistons, etc. In the description which follows, such a hydraulic actuator which is supplied with hydraulic fluid, or which “consumes” the energy from the hydraulic fluid, shall be called the “consumer mechanism” or simply, “consumer”. FIG. 1 shows a conventional hydraulic fluid circuit, identified by the reference number 2. It includes, as is known per se, a hydraulic fluid reservoir 10, one or more hydraulic pumps 12, and piping 14, 16, 18 and 20. The operating principle for such a circuit will be briefly summarised, in a particular case where the circuit is supplying a single consumer 22, it being understood that a circuit supplying several consumers 22 operates according to a similar principle. The hydraulic pump 12 is a high pressure pump which pumps or draws in hydraulic fluid from the reservoir 10 through a first pipe called the fluid suction pipe 14. The hydraulic fluid is then sent, under high pressure, to a consumer 22 by means of a second pipe, called the fluid supply pipe 16. The consumption of energy by said consumer 22 is shown by a reduction in hydraulic fluid pressure, which is at low pressure as it leaves the consumer, in a third pipe called the fluid return pipe 18, through which it is sent back to the hydraulic fluid reservoir 10. The hydraulic fluid circuit generally includes an additional pipe, called the drainage pipe 20, connected to the hydraulic pump. This allows for sending part of the hydraulic fluid coming from the hydraulic pump 12 and corresponding to internal leaks in this pump 12, directly back to the reservoir 10. Generally, it is estimated that approximately 10% to 15% of the total power available to the pumps is lost as a result of the existence of these internal leaks, and that this power fraction is turned into heat. This results in the heating of the hydraulic fluid that passes through the drainage pipe 20 towards the hydraulic fluid reservoir 10. The hydraulic fluid consumers may also heat said hydraulic fluid, generally to a lesser degree than the pumps. Such heating of the hydraulic fluid has a harmful effect on the functioning of the hydraulic circuit. In fact, this heating results in the degradation of the hydraulic fluid, and thus in a reduction in its performance. In particular, heating of the fluid may lead to an increase in the acidity of said fluid, which can cause deterioration of the consumer mechanisms of said hydraulic fluid. This heating may also lead to a deterioration of the joints in the hydraulic circuit, and consequently, external leaks on the hydraulic circuit. It is therefore necessary to keep the hydraulic fluid, circulating through ouch a hydraulic circuit for supplying one or more consumers, below a certain temperature, called the stability temperature, of said hydraulic fluid. A first solution consists in using the natural capacity of the hydraulic circuit to dissipate the heat by natural convection or by forced convection using the ambient air around the pipes. This first solution is satisfactory for aircraft whose hydraulic power requirements are sufficiently low so that such heat dissipation through the fluid supply pipes provides total or near-total dissipation of the hydraulic fluid heating. Dissipation is all the more efficient because the supply pipes are long. But for aircraft that are compact with regard to the hydraulic power installed, i.e. which have short supply pipes in comparison to the hydraulic power available, the natural dissipation of heat is still insufficient. A second solution for improving the cooling of the hydraulic fluid consists in adding a heat exchanger placed inside a fuel tank on the aircraft to the hydraulic circuit. The hydraulic fluid passes this heat exchanger, it is then cooled, and its heat is transferred to the fuel contained in the fuel tank housing the heat exchanger. This second solution was able to be used on old aircraft, but it has no longer been acceptable since new safety regulations came into effect, which stipulate minimising any heat transfers to fuel. A first condition required by the regulations recommends limiting the generation of fuel vapour within each fuel tank. This is achieved if the temperature of the fuel stays below its flammable temperature TF. A second condition required by the regulations stipulates that the temperature TM of the fuel as it enters the engines must not exceed a maximum value. Consequently, this second solution may no longer be used, as it does not allow for controlling the temperature of the fuel, whether inside the fuel tanks or as it enters the engines, and consequently, neither of the statutory conditions are respected. SUMMARY OF THE INVENTION The precise subject of the invention is an aircraft fluid cooling system which resolves the problems posed by systems of the prior art. In accordance with the invention, this system comprises an air heat exchanger, passed through by, the fluid to be cooled, said air heat exchanger including a means for air intake and an air exhaust means, characterised in that this air heat exchanger is installed in a housing located in a flap guide rail fairing connected to one of this aircraft's wings, said means for the introduction of air into the air heat exchanger being connected to an air inlet means passing the outer surface of the fairing and said air exhaust means for this air heat exchanger being connected to an air exhaust means opening outside said outer surface in such a way that the air outside the aircraft passes through this air exchanger to cool said fluid. This aircraft fluid cooling device allows for discharging the heat from the cooling of said fluid into the air outside this aircraft. In so doing, it benefits from the dynamic flow of air around the aircraft. In a preferred embodiment, said air inlet means passing the outer surface of the fairing corresponds to a ram air intake. The term “ram air intake” describes an air intake allowing at least some of the dynamic pressure resulting from the movement of the aircraft through the air to be captured. Advantageously, the aircraft fluid cooling system that is the subject of this invention has at least one fan for ensuring a minimum throughput of air in the air heat exchanger. This fan allows for ensuring and improving the cooling of said fluid by increasing the throughput of air through the air heat exchanger, in particular when the aircraft speed is nil (aircraft on the ground) or less than a predetermined value (e.g. during the take-off and landing phases). This fan can advantageously be installed upstream, depending on the direction of the air circulation, of the air heat exchanger or downstream of this air heat exchanger. The invention also concerns an aircraft equipped with such an aircraft fluid cooling system. BRIEF DESCRIPTION OF THE DRAWINGS Other features and advantages of the invention will become apparent upon reading the description which will follow of specific embodiments of the invention, with reference to the accompanying drawings, in which: FIG. 1, already described, illustrates a hydraulic circuit for supplying consumers, as well as its operating principle; FIG. 2 illustrates, from the outside, an aircraft likely to be fitted with a fluid cooling system in accordance with the invention; FIG. 3 is a cross-section of one wing of the aircraft of FIG. 2; FIG. 4 is a cross-section of an aircraft's wing which illustrates, on a larger scale, a flap guide rail fairing in which an air heat exchanger is installed in accordance with the invention; FIG. 5 is a similar view to that of FIG. 4, which illustrates a specific embodiment of the invention in which the cooling system has at least one fan; FIG. 6 is a schematic representation of a control system for the fan represented in FIG. 5; FIG. 7 is a cross-section, on an approximately horizontal plane when the aircraft is parked on the ground, of a guide rail fairing and a cooling system according to the invention which represents a specific embodiment of the air output means; FIGS. 8a, 8b, and 8c are cross-sections of ram air intakes; FIG. 9 is a cross-section of a divergent duct with a neck. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The aircraft fluid cooling system 30 in accordance with the invention, for which one embodiment is represented in FIG. 4, has an air heat exchanger 40 passed by said fluid to be cooled. This air heat exchanger 40 is installed in a housing located in a fairing 34 of the flap 36 guide rail connected to a wing 32 of this aircraft. Flap 36 guide rail fairings 34 connected to a wing 32 of an aircraft are represented from an exterior view in FIG. 2 and as a cross-section in FIG. 3. As is known, actuators, which are not shown, allow for moving these flaps 36 relative to the wing 32 of the aircraft 30 in such a way as to change the aerodynamic configuration of said aircraft. Said flap guide rails are generally located under the inner side 38 of the wing 32 and they are set to guide the movement of said flaps relative to this wing under the effect of said actuators. A fairing 34 is connected to each of said guide rails in such a way that these guide rails cause the minimum disruption possible to the aerodynamic characteristics of the wing 32 of the aircraft. In accordance with this embodiment of the invention, said housing in which the air heat exchanger 40 is installed is located in a free position within a flap guide rail fairing 34. A means for the introduction of air 52 into the air heat exchanger 40 is connected to an air inlet means 42 passing an external surface 46 of the fairing 34 in the forward part of the latter. Similarly, an air exhaust means 54 for the air heat exchanger 40 is connected to an air output means 44 which opens outside the outer surface 46 of the fairing 34, in a part of this fairing located behind said air inlet means 42 depending on the direction of advance of the aircraft in flight. The air inlet means 42 is a ram air intake. This may, for example, be a Pitot tube, as represented in FIG. 8a, which has the advantage of recovering the maximum dynamic pressure of the air entering through said air intake. Alternatively, depending on the characteristics required as to the throughput of air in the heat exchanger 40 and the options of integration in the fairing 34, this ram air intake may also be of a type that recovers less dynamic pressure than a Pitot-type air intake, e.g. of a scoop type as represented in FIG. 8b, or even of a type embedded in the outer surface 46 of the fairing 34 (e.g. NACA) as shown in FIG. 8c. Advantageously, the air inlet means 42 is connected to the means for the introduction of air 52 in the air heat exchanger 40 by a divergent duct 48, i.e., in which the section increases according to the direction of circulation of the air in said air inlet means 42 towards said means for the introduction of air 52 of the air heat exchanger 40. Conversely, the air exhaust means 54 of the air heat exchanger 40 is advantageously connected to the air output means 44 by a convergent duct 50, i.e. in which the section decreases according to the direction of circulation of the air in said air exhaust means, 54 of the air heat exchanger 40 towards said air output means 44. The divergent/convergent geometry of the air ducts 48, 50 on both sides of the heat exchanger 40 allow for reducing the speed of the air passing this heat exchanger in relation to the speed of the air entering the duct 48, and thus for reducing the losses in load when the air passes through this heat exchanger, which allows for recovering on leaving the convergent duct 50 an air speed close to that of the external air flow and consequently for reducing the interfering drag of the air output when the air passes through the heat exchanger 40, and more particularly an exchange matrix (not shown) in this heat exchanger, a transfer of heat is made from said fluid to be cooled to the air in question, the temperature of this latter (generally below 0° C. when the aircraft is flying under cruising conditions) being below the temperature of the fluid to be cooled (generally between 50 and 110° C., in the case of hydraulic fluid, when the aircraft is flying under cruising conditions). The heat transferred to the air when passing the heat exchanger 40 allows for supplying energy to the airflow, which contributes to reducing the device's drag. In the ideal scenario where the effect of this provision of energy is greater than the effect of the losses of load due to the airflow in ducts 48, 50 and in the heat exchanger 40, the device according to the invention even allows for contributing to increasing the aircraft's thrust. In an advantageous manner, the air inlet means 42 is located in the forward part, according to the aircraft's flight direction, of the flap 36 guide rail fairing 34. The fairing 34 forms a protrusion below the wing 32 of the aircraft, the distribution of air pressure on the surface of the fairing 34 is such that the air pressure is at its maximum on the forward part of the latter. This allows for benefiting from a higher air pressure at the air inlet means 42 than at the air output means 44 (located behind said air inlet mechanism 42), which contributes to the proper functioning of the cooling system. Advantageously, the air output means 44 comprises at least one nozzle positioned in the thrust axis of the aircraft 30. This allows, on the one hand, disruption to the aircraft's aerodynamics to be minimised and, on the other hand, best advantage to be taken of any contribution to this aircraft's thrust from said transfer of heat to the air passing through the heat exchanger 40. In an advantageous manner, this nozzle 44 is located on a lateral part of the flap guide rail fairing 34. In a preferred embodiment shown in FIG. 7, the convergent duct 50 has at least two parts 50a and 50b connected, respectively, to at least two nozzles 44a and 44b located on lateral parts of the flap guide rail fairing 34, these nozzles 44a and 44b being respectively located on each side of the longitudinal axis 66 (partially shown in FIG. 7) of said flap 36 guide rail fairing 34. The dimensions of the air inlet means 42, the air output means 44, the ducts 48, 50 and the heat exchanger 40 are determined, ordinarily, according to losses of load, desired air mass throughput and the dynamic speed of the flow in such a way that in the flight phases considered, the throughput of cool air passing through the heat exchanger 40 allows for ensuring the thermal exchange capacity required for the cooling of the fluid. In a preferred embodiment, said flight phases considered correspond to the aircraft cruising flight. In a preferred embodiment, the divergent duct 48 has a neck 49 as shown in FIG. 9. This neck 49 is located between the air inlet means 42 and the divergent part of the duct 48. It corresponds to a part of said duet 48 in which the section through which the air passes is minimal. This neck 49 allows for setting the air mass throughput in the divergent duct 48 by sound barrier; as is known, the speed of the air through the neck 49 is at most equal to the speed of sound. The result of this is that when the aircraft flies in the cruising phase, said airspeed in the neck 49 is equal to the speed of sound. The dimensioning of this neck 49 is calculated, ordinarily, to limit the throughput of air in the divergent duct 48 to a value which allows for respecting a maximum airspeed in the heat exchanger 40, determined according to losses of load which it is desired not to exceed. Another limitation on the air throughput may be determined in such a way as to limit the aerodynamic drag caused by said aircraft fluid cooling system to below a maximum predefined value. In a specific embodiment shown in FIG. 5, the cooling system subject of the invention has at least one fan 56. The operation of this fan 56 allows for ensuring and increasing the throughput of air in the heat exchanger 40, in particular when the aircraft's speed is nil (aircraft on the ground) or less than a predetermined value (e.g. in the take-off and landing phases). In this way, when the cooling system which is the subject of the invention is dimensioned to ensure the cooling of said fluid in the aircraft's cruising flight phases, the use of this fan allows for ensuring the cooling of said fluid in all the phases of use of the aircraft. Said cooling system comprising one fan 56 has the advantage of having a mass less than that of a cooling system which would be dimensioned to provide the cooling of this fluid without a fan in the aircraft's flight phases corresponding to a speed less than the cruising speed of this aircraft. It also has the advantage, in comparison to a system without a fan, of allowing for the cooling of said fluid even when the aircraft is running on the ground at nil speed. The fan 56 may be placed upstream, depending on the direction of the air circulation, of the heat exchanger 40 (FIG. 5), or downstream of this heat exchanger 40. It may be, in particular, electrically or hydraulically operated. In an advantageous manner, as shown in FIG. 6, this fan 56 is linked, by a connection 64, to control means 58 which have at least one input linked to a set 60 of sources of information S1, S2, . . . , Sn by at least one connection 62. These sources of information may in particular be from the aircraft's sensors or computers. Advantageously, the information provided by the sources of information S1, S2, . . . , Sn may in particular correspond to the temperature of the fluid to be cooled and/or the airspeed of the aircraft. In this case, the control means 58 stop the operation of the fan 56 when the temperature of the fluid is below a predetermined value Tmin so as not to cool this fluid excessively, or when the aircraft's airspeed is greater than a predetermined value Vmin so as not to race said fan. When the temperature of the fluid is greater than said predetermined value Tmin and/or when the aircraft's airspeed is less than said predetermined value Vmin, the control means 58 activate the fan 56 operation to force the circulation of the air in the heat exchanger 40. Such a mode of functioning offers the advantage of allowing for sufficient cooling of the fluid in flight phases other than those (corresponding for example to cruise flight phases) for which the dimensioning of the cooling system has been dimensioned. For example, a Vmin value may be chosen that is greater than the take-off speed and less than the cruising speed. As a variant of this embodiment, the control means 58 control the fan 56 with a variable decreasing speed when the aircraft's airspeed increases, so that the fan 56 is not controlled (nil speed) when the aircraft's airspeed is greater than Vmin. In another variant of this embodiment, the control means 58 control the fan 56 according to the temperature of the fluid to be cooled, either according to an on-off adjustment, or with a variable decreasing speed when the fluid temperature decreases. Both these embodiment variants may also be combined with each other. As an alternative, it is possible to have several fans 56 in parallel so as to increase the availability of the heat exchanger in the event of the breaking down of one of the fans 56. In the above-mentioned cage where the convergent duct 50 has two parts 50a and 50b connected, respectively to the two nozzles 44a and 44b, it is possible to have a fan 56 at the inlet of each of said parts 50a and 50b of said duct 50, the term inlet here being used in relation to the airflow direction when the aircraft 30 is in flight. The invention also concerns an aircraft 30 with at least one fluid cooling system as described previously. For example, the aircraft 30 may have at least one such cooling system in several flap 36 guide rail fairings 34 on this aircraft 30, so as to maximise the fluid cooling power of the aircraft 30 and/or to cover the fluid cooling requirements corresponding to the separate circuits of the aircraft 30. In one specific embodiment, the aircraft 30 has at least one hydraulic fluid circuit in which the hydraulic fluid is cooled by said cooling system or systems. Preferably, said hydraulic fluid passing through the air heat exchanger 40 is from the drainage pipe 20 of at least one hydraulic pump 12. This embodiment offers the advantage of only sending the part of the hydraulic fluid to the heat exchanger 40 that has been subjected to the most significant temperature rise, which provides greater efficiency of the cooling system.

<SOH> SUMMARY OF THE INVENTION <EOH>The precise subject of the invention is an aircraft fluid cooling system which resolves the problems posed by systems of the prior art. In accordance with the invention, this system comprises an air heat exchanger, passed through by, the fluid to be cooled, said air heat exchanger including a means for air intake and an air exhaust means, characterised in that this air heat exchanger is installed in a housing located in a flap guide rail fairing connected to one of this aircraft's wings, said means for the introduction of air into the air heat exchanger being connected to an air inlet means passing the outer surface of the fairing and said air exhaust means for this air heat exchanger being connected to an air exhaust means opening outside said outer surface in such a way that the air outside the aircraft passes through this air exchanger to cool said fluid. This aircraft fluid cooling device allows for discharging the heat from the cooling of said fluid into the air outside this aircraft. In so doing, it benefits from the dynamic flow of air around the aircraft. In a preferred embodiment, said air inlet means passing the outer surface of the fairing corresponds to a ram air intake. The term “ram air intake” describes an air intake allowing at least some of the dynamic pressure resulting from the movement of the aircraft through the air to be captured. Advantageously, the aircraft fluid cooling system that is the subject of this invention has at least one fan for ensuring a minimum throughput of air in the air heat exchanger. This fan allows for ensuring and improving the cooling of said fluid by increasing the throughput of air through the air heat exchanger, in particular when the aircraft speed is nil (aircraft on the ground) or less than a predetermined value (e.g. during the take-off and landing phases). This fan can advantageously be installed upstream, depending on the direction of the air circulation, of the air heat exchanger or downstream of this air heat exchanger. The invention also concerns an aircraft equipped with such an aircraft fluid cooling system.

20060206

20090421

20060907

92909.0

B60H100

GREEN, RICHARD R

AIRCRAFT FLUID COOLING SYSTEM AND AIRCRAFT PROVIDED WITH SAID SYSTEM

UNDISCOUNTED

ACCEPTED

B60H

ACCEPTED

Mycobacterial proteins as early antigens for serodiagnosis and vaccines

In view of the paucity of human material available to study the immunological events occurring after inhalation of virulent bacilli, but prior to development of clinical TB, the present invention is based in part on studies of aerosol infected rabbits. The present inventors reasoned that by 3-5 weeks post-infection, the sera from infected rabbits would contain antibodies to the antigens being expressed by the in vivo bacteria.

1. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of early antibodies specific for one or more early Mtb antigens which antigens are characterized as being surface or secreted proteins that are (i) reactive with antibodies found in tuberculosis patients who are in a stage of disease prior to the onset of (a) smear-positivity of sputum or other pulmonary associated fluid for acid-fast bacilli and (b) cavitary pulmonary lesions, and (ii) non-reactive with sera from healthy control subjects or healthy subjects with latent inactive tuberculosis wherein the presence of said early antibodies specific for said early antigens is indicative of the presence of said disease or infection. 2. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of antibodies or T lymphocytes specific for or reactive with an early Mtb antigen selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d). 3. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid or cell or tissue sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of one or more early M. tuberculosis early antigens selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810;, (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d), using an antiserum or a monoclonal antibody specific for an epitope of said an early antigen, wherein the presence of said one or more early antigens is indicative of the presence of said disease or infection. 4. A method for the early detection of mycobacterial disease or infection in a subject, comprising assaying a biological fluid sample from a subject having symptoms of active tuberculosis, but before the onset of symptoms identifiable as advanced tuberculosis for the presence of immune complexes consisting of one or more early M. tuberculosis antigens complexed with an antibody specific for said antigen selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); and (d) MtrA protein encoded by the Mtb gene Rv3246c, (e) an epitope of any of (a)-(d), wherein the presence of said immune complexes is indicative of the presence of said disease or infection. 5. The method of any one of claims 1-4 that further includes performance of a test that detects mycobacterial bacilli in a sample of sputum or other body fluid of said subject. 6. The method of any of claims 1-5 wherein said biological fluid sample is serum, urine or saliva. 7. The method of any of claims 1-6 comprising, prior to said assaying step, the step of removing from said sample antibodies specific for cross-reactive epitopes or antigens of proteins present in M. tuberculosis and in other bacterial genera. 8. The method of any of claims 1-7 wherein said removing is performed by immunoadsorption of said sample with E. coli antigens. 9. The method of any of claims 1-8, wherein said subject is a human. 10. The method of claim 9 wherein said subject is infected with HIV-1 or is at high risk for tuberculosis. 11. The method of any of claims 1-10 which includes assaying said sample for antibodies specific for one or more additional early antigens of M. tuberculosis selected from the group consisting of: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTV NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO: 14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; and (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. 12. A kit useful for early detection of M. tuberculosis disease comprising: (a) an antigenic composition comprising one or more proteins selected from the group consisting of (i) PirG protein encoded by the Mtb gene Rv3810; (ii) PE-PGRS protein encoded by the Mtb gene Rv3367; (iii) PTRP protein encoded by the Mtb gene Rv0538); and (iv) MtrA protein encoded by the Mtb gene Rv3246c, or an epitope of any of (i)-(iv), in combination with (b) reagents necessary for detection of antibodies which bind to said M. tuberculosis protein. 13. The kit of claim 12 further supplemented with one or more additional early antigens of M. tuberculosis selected from the group consisting of: (A) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (B) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA MNTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA LAAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW VHASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP ASGDNGWGSW APQLGAMSGD IVGAIR (C) a protein characterized as M. tuberculosis antigen 85C; or (D) a glycoprotein characterized as M. tuberculosis antigen MPT32. 14. The kit of claim 12 or claim 13 further supplemented with one or more of the following M. tuberculosis antigenic proteins having an approximate molecular weight as indicated: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref. No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% anpholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H3PO4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. 15. The kit of any of claims according of claim 12 wherein at least one of said early M. tuberculosis antigens is a recombinant protein or glycoprotein. 16. An antigenic composition useful for early detection of M. tuberculosis disease or infection comprising a onr or a mixture of two or more early M. tuberculosis antigens which antigens are selected from the group consisting of (a) PirG protein encoded by the Mtb gene Rv3810; (b) PE-PGRS protein encoded by the Mtb gene Rv3367; (c) PTRP protein encoded by the Mtb gene Rv0538); (d) MtrA protein encoded by the Mtb gene Rv3246c; and (e) an epitope of any of (a)-(d), said composition being substantially free of other M. tuberculosis proteins with which said early M. tuberculosis antigens are natively admixed in a culture of M. tuberculosis. 17. The antigenic composition of claim 16 wherein said other proteins are not early M. tuberculosis antigens. 18. The antigenic composition of claim 16 or 17, further comprising one or more of: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHVHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R; (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14 APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; or (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. 19. The antigenic composition of any of claims 16-18 further comprising one or more of the following M. tuberculosis antigenic proteins having an approximate molecular weight as indicated: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref. No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% ampholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H3PO4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention in the fields of microbiology and medicine relates to methods for rapid early detection of mycobacterial disease in humans based on the presence of antibodies to particular “early” mycobacterial antigens which have not been previously recognized for this purpose. Assay of such antibodies on select partially purified or purified mycobacterial preparations containing such early antigens permits diagnosis of TB earlier than has been heretofore possible. Also provided is a surrogate marker for screening populations at risk for TB, in particular subjects infected with human immunodeficiency virus (HIV). The invention is also directed to vaccine compositions and methods useful for preventing or treating TB. 2. Description of the Background Art The incidence of tuberculosis has shown a rapid increase in recent years, not only in the developing countries, but also in crowded urban settings in the US and in specific subsets of our society, including the homeless, IV drug users, HIV-infected individuals, immigrants and refugees from high prevalence endemic countries (Raviglione, M C et al., 1995. JAMA. 273:220-226). Studies show that these populations are at a significantly greater risk of developing tuberculosis, and also serve as the reservoir of infection for the community as a whole Raviglione, M C et al., 1992, Bull World Health Organization. 70:515-526; Raviglione, M C et al., 1995. JAMA. 273:220-226). None of the currently used methods for diagnosis of tuberculosis identify individuals with active but sub-clinical infection, and the disease is generally detected when the individuals are already infectious. Design of new diagnostic assays requires knowledge of antigens expressed by the bacteria during their in vivo survival. Most current studies of antigens of Mycobacterium tuberculosis (Mtb); also abbreviated herein are focused on antigens present in the culture filtrates of bacteria replicating actively in vitro, with the presumption that the same molecules are expressed by the in vivo bacteria. A vast majority of the Mtb infected individuals develop immune responses that arrest progression of infection to clinical TB, and also prevent the latent bacilli from reactivating to cause clinical disease, whereas about 10-15% of the infected individuals progress to developing primary or reactivation TB. Understanding the host-pathogen interactions that occur after infection, but prior to development of clinical TB (pre-clinical TB) is required both for the design of effective vaccines and for development of diagnosis of early disease. Several studies have shown that Mtb adapts to different environments in broth media (Garbe, T R et al., 1999, Infect. Immun. 67:460-465; Lee, B-Y et al., 1995, J. Clin. Invest. 96:245-249; Wong, D K et al., 1999, Infect. Immun. 67:327-336) and during intracellular residence by altering its gene expression (8, 22, 34). Clark-Curtiss, J E et al., 1999, p. 206-210. In Proceedings of Thirty-Fourth Tuberculosis-Leprosy Research Conference, San Francisco, Calif., Jun. 27-30. Lee et al., supra; Smith, I et al., 1998, Tuber. Lung Dis. 79:91-97). Earlier studies from the present inventors' laboratory with cavitary and non-cavitary TB patients have also shown that the in vivo environment in which the bacilli replicate affects the profile of the antigenic proteins expressed by Mtb (Samanich, K M et al., 1998, J. Infect. Dis. 178:1534-1538; Laal et al., U.S. Pat. No. 6,245,331 (2001)). One objective of the present invention was to identify the antigens expressed by inhaled Mtb during the pre-clinical stages of TB. There are no markers to identify non-diseased humans with an active infection with Mtb, but the rabbit model of TB closely resembles TB in immuno-competent humans in that both species are outbred, both are relatively resistant to Mtb, and in both the caseous lesions may liquify and form cavities (Converse, P J et al., 1996, Infect. Immun. 64:4776-4787). Studies have shown that on being inhaled, the bacilli are phagocytosed by (non specifically) activated alveolar macrophages (AM) which either destroy or allow them to multiply. If the bacilli multiply, the AM die and the released bacilli are phagocytosed by non activated monocyte/macrophages that emigrate from the bloodstream. Intracellular replication and host cell death continue for 3-5 weeks, when both cellular and humoral immune responses are elicited (Lurie, M B, 1964. Chapter VIII, p. 192-222, In M. B. Lurie (ed.) Resistance to tuberculosis: experimental studies in native and acquired defensive mechanisms. Harvard University Press, Cambridge, Mass.; Lurie, M B et al., 1965, Bact. Rev. 29:466-476; Dannenberg, A M., Jr., 1991, Immunol. Today. 12:228-233). Lymphocytes and macrophages enter the foci of infection, and if they become activated bacillary replication is controlled, if not, the infection progresses to clinical disease. During these initial stages of bacillary replication and immune stimulation, there are no outward signs of disease except the conversion of cutaneous reactivity to PPD. The antigens of Mtb expressed, and their interaction with the immune system during these pre-clinical stages of TB is not delineated. SUMMARY OF THE INVENTION In view of the paucity of human material available to study the immunological events occurring after inhalation of virulent bacilli, but prior to development of clinical TB, the present invention is based in part on studies of aerosol infected rabbits. The present inventors reasoned that by 3-5 weeks post-infection, the sera from infected rabbits would contain antibodies to the antigens being expressed by the in vivo bacteria. Four antigens of Mtb that are expressed in vivo after aerosol infection, but prior to development of clinical TB, in rabbits were identified by immunoscreening an expression library of Mtb genomic DNA with sera obtained 5 weeks post-infection. Three of the proteins identified, PirG (Rv3810) [SEQ ID NO:1 and 2; nucleotide and amino acid], PE-PGRS (Rv3367) [SEQ ID NO:3 and 4] and PTRP (Rv0538) [SEQ ID NO:5 and 6] have multiple tandem repeats of unique amino-acid sequences, and have characteristics of surface or secreted proteins. The fourth protein, MtrA (Rv3246c) [SEQ ID NO:7 and 8], is a response regulator of a putative two-component signal transduction system, mtrA-mtrB, of Mtb. All four antigens were recognized by pooled sera from TB patients and not from healthy controls, confirming their in vivo expression during active infection in humans. Three of the antigens, (PE-PGRS, PTRP and MtrA) were also recognized by retrospective, pre-clinical TB sera obtained from HIV-TB patients prior to the clinical manifestation of TB, suggesting their utility as diagnostics for active, pre-clinical (“early”) TB. The present invention provides methods, kits and compositions directed to the detection of antibodies or T cell reactivity to any of the above early antigens or to the detection of the antigens themselves in a body fluid of a subject as a means of detecting early mycobacterial disease in the subject. In other embodiments, the invention provides, methods, kits and compositions useful for detecting antibody or T cell reactivity to, in addition to one or more of the above early antigens, to one or more of the following early Mtb antigens: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; or (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. In yet another embodiment, the invention provides methods, kits and compositions useful for the detection of antibodies or T cell reactivity to any of the above early antigens or to one or more of the following early antigens: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% ampholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H3PO4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. In yet other embodiments, the present invention provides vaccines compositions and methods for treating or preventing mycobacterial disease in a subject. The vaccine composition may comprise any one or more of the early antigens noted above or an epitope thereof. Preferred vaccine epitopes are T helper epitopes, more preferably T helper epitopes that stimualte Th1 cells. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows reactilvit8y of guinea pig serum pool with antigen for Mtb (see description below figure) FIGS. 2a-2d show reactivity of fusion proteins from individual colonies of gsrI-3, I-6, II-1 and II-1 (see description below figure) FIG. 3a shows Western blots of fusion proteins with antibodies to β-galactosidase (see description below figure) FIG. 3b shows reactivity of sera from Mtb-infected guinea pigs and ant-β-gal antibody with fractionated lysates (see description below figure). FIG. 4a shows sequence alignment of clones gsr II-2 and I-6 with cosmid MTV004. FIG. 4b shows the amino acid sequence of protein encoded by MTV-=004.03. Peptides encoded by clones gsr I-6 and gsr II-2 are shown in bold. The 6 copies of the repeat motif in gsr I-6 are underlined. FIG. 5a shows sequence alignment of clone gsr II-1 with cosmid MTCY336. FIG. 5b shows amino acid sequence of MTCY336.28. Peptide encoded by clone gsr II-2 is shown in bold. FIGS. 6A, 6B and 6C shows reactivit8y of fusion proteins of gsrI-6, II-1 and II-1 with sera from individual guinea pigs (see description below figures). FIGS. 7A and 7B show a comparison of reactivity of Mtb infected guinea pig and human sera with culture filtrate proteins (7A) and SDS-soluble cell wall proteins (7B) of Mtb (see description below figure). FIGS. 8A and 8B shows reactivity of a pool of sera from PPD+ healthy individuals (8A) or from TB patients (8B) (see description below figure) FIG. 9 shows reactivity of sera from PPD+ individuals and TB patients with gsr I-6 lysates (see description below figure). FIG. 10 ( shows reactivity of HIV pre-TB serum pool with fusion proteins expressed by the various gsr clones (see description below figure). FIG. 11 shows a comparison of reactivity of TB sera with native and recombinant Mtb antigens (see description below figure). FIG. 12A shows expression of the 88 kDa seroreactive antigen in M. smegmatis (see description below figure). FIG. 12B shows reactivity of sera form a TB patient and a PPD+ healthy control with 30-fold concentrated culture filtrate of M. smegmatis (see description below figure). FIG. 13 Reactivity of Mtb antigens with pooled sera from rabbits. LFCFP (lanes 2 & 3 and SDS-CWP (lanes 4 & 5) proteins of Mtb were fractionated on 10% SDS-PA gels, and western blots probed with pooled sera from uninfected (lanes 2 & 4) and Mtb infected (lanes 3 & 5) rabbits. Lane 1 contains molecular weight markers. FIG. 14: Reactivity of β-gal fusion proteins of AD clones with anti β-gal antibody and sera from Mtb infected rabbits. Lysates of AD lysogens and λgt11 vector lysogen were separated on 10% SDS-PA gels and probed with anti-β-gal antibody (lanes 2-9), uninfected rabbit sera (lanes 11-18) and infected rabbit sera (lanes 19-27). Lanes; 1, 10 & 19 contain molecular weight markers; lanes 2, 11 & 20: lysates from clone AD 1; lanes 3, 12 & 21: clone AD2, lanes 4; 13 &22: clone AD4; lanes 5, 14 & 23: clone AD9; lanes 6, 15 & 24: clone AD10; lanes 7, 16 & 25: clone AD7; lanes 8, 17 & 26: clone AD16 and lanes 9, 18 & 27: λgt11 vector. FIG. 15: Schematic maps showing position of AD clones on cosmids of Mtb H37Rv. A: map of clones AD1 & AD2 on cosmid MTV026 and MTCY409. B: clone AD9 on cosmid MTV004. C: clone AD10 on cosmid MTY25D10. D: clone AD16 on cosmid MTY20B11. Black bar represents the gene on the cosmid. Hatched bar shows regions expressed as β-gal fusion protein in AD clones. Arrow indicates direction of translation. E denotes EcoRI site. FIG. 16: Nucleotide and deduced amino acid sequence of gene Rv3367 (PE_PGRS) (SEQ ID NO: 3 and 4, respectively). The signal peptide sequence is shown in italics, hollow arrow between aa 44 & 45 indicates signal peptidase cleavage site. The repetitive sequences are shown in boxes. The motif PE is underlined. Solid arrow at aa 230 indicates the start of fusion with β-gal in clone AD9. The transmembrane helices sequences are shown in bold. The asterisk indicates the termination codon. FIG. 17: Nucleotide and deduced amino acid sequence of gene Rv0538 (PTRP) (SEQ ID NO: 5 and 6, respectively). The repetitive motifs are shown in boxes. Arrow indicates the initiation of fusion with β-gal in clone AD10. The transmembrane helices sequences are shown in bold. The asterisk indicates the termination codon. FIG. 18: Reactivity of β-gal fusion proteins with human sera. Blot A: clone AD9 (PE_PGRS), B: clone AD10 (PTRP), C: clone AD2 (pirG) and D: clone AD16 (MtrA). Lanes 1, 4, 7, 10 & 13: molecular weight markers; lanes 2, 5, 8, 11 & 14: lysates form lysogens of respective AD clones; lanes 3, 6, 9, 12 & 15: lysogen of λgt11 vector. Lanes 2 & 3 probed with anti β-gal antibody, lanes 5 & 6 with pooled sera from PPD positive healthy individuals, lanes 8 & 9 with pooled sera from HIV pre-TB individuals, lanes 11 & 12 with pooled sera from non-cavitary TB individuals and lanes 14 & 15 with pooled sera from cavitary TB individuals. FIG. 19: Reactivity of β-gal fusion proteins of AD clones with sera from HIV pre-TB individuals. A: clone AD9 (PE_PGRS), B: clone AD10 (PTRP) and C: clone AD16 (MtrA). Lane 1; molecular weight marker; lanes 2-15: lysates from lysogens of respective AD clones. Lane 2 is probed with anti β-gal antibody in each case, lanes 3-5 with sera from three PPD positive healthy individuals and lanes 6-15 with sera from 10 HIV pre-TB individuals. DESCRIPTION OF THE PREFERRED EMBODIMENTS This Application incorporates by reference, in their entirety, U.S. Pat. No. 6,245,331 (12 Jun. 2001) and Laal et al., U.S. Ser. No. 9/396,347 (filed Sep. 14, 1999) 09/001,984, filed 31 Dec. 1997, which claims priority from U.S. Ser. No. 60/034,003, filed 31 Dec. 31, 1996). Also incorporated by reference are all references cited therein. In the following description, reference will be made to various methodologies known to those of skill in the art of immunology. Publications and other materials setting forth such known methodologies to which reference is made are incorporated herein by reference in their entireties as though set forth in full. Standard reference works setting forth the general principles of immunology include Roitt, I., Essential Immunology, 6th Ed., Blackwell Scientific Publications, Oxford (1988); Roitt, I. et al., Immunology, C. V. Mosby Co., St. Louis, Mo. (1985); Klein, J., Immunology, Blackwell Scientific Publications, Inc., Cambridge, Mass., (1990); Klein, J., Immunology: The Science of Self-Nonself Discrimination, John Wiley & Sons, New York, N.Y. (1982)); and Eisen, H. N., (In: Microbiology, 3rd Ed. (Davis, B. D., et al., Harper & Row, Philadelphia (1980)); A standard work setting forth details of mAb production and characterization, and immunoassay procedures, is Hartlow, E. et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988. As used herein, the term “early” and “late” in reference to (1) Mtb infection or disease, or the subject having the infection or disease, (2) the antibody response to an Mtb antigen, (3) an Mtb antigen itself or (4) a diagnostic assay, are defined in terms of the stage of development of TB. Early and late (or advanced) TB are defined in the table below. Thus, a subject with early TB is asymptomatic or, more typically, has one or more “constitutional symptoms” (e.g., fever, cough, weight loss). In early TB, Mtb bacilli are too few to be detectable as acid-fast bacilli in smears of sputum or other body fluid, primarily those fluids associated with the lungs (such as bronchial washings, bronchoalveolar lavage, pleural effusion). However, in these subjects, Mtb bacilli are present and culturable, i.e., can be grown in culture from the above body fluids. Finally, early TB subjects may have radiographically evident pulmonary lesions which may include infiltration but without cavitation. Any antibody present in such early stages is termed an “early antibody” and any Mtb antigen recognized by such antibodies is termed an “early antigen.” The fact that an antibody is characterized as “early” does not mean that this antibody is absent in advanced TB. Rather, such antibodies are expected to persist across the progression of early TB to the advanced stage. Early 1. Smear of sputum, bronchial washing, bronchoalveolar TB lavage or pleural effusion is negative for acid fast bacilli 2. Direct culture of sputum, bronchial washing, bronchoalveolar lavage or pleural effusion is positive for acid fast bacilli 3. Chest x-ray is normal or shows Infiltration in the lungs 4. Constitutional symptoms are present (fever, cough, appetite and weight loss) Late/ 1. Smear of sputum, bronchial washing, bronchoalveolar Advanced lavage or pleural effusion is positive TB (with possible hemoptysis) 2. Direct culture of sputum, bronchial washing, bronchoalveolar lavage or pleural effusion is positive 3. Chest x-ray shows cavitary lesions in the lungs 4. Constitutional symptoms are present (see above) Accordingly, the term “late” or “advanced” is characterized in that the subject has frank clinical disease and more advanced cavitary lesions in the lungs. In late TB, Mtb bacilli are not only culturable from smears of sputum and/or the other body fluids noted above, but also present in sufficient numbers to be detectable as acid-fast bacilli in smears of these fluids. Again, “late TB” or “late mycobacterial disease” is used interchangeably with “advanced TB” or “advanced mycobacterial disease.” An antibody that first appears after the onset of diagnostic clinical and other characterizing symptoms (including cavity pulmonary lesions) is a late antibody, and an antigen recognized by a late antibody (but not by an early antibody) is a late antigen. To be useful in accordance with this invention, an early diagnostic assay must permit rapid diagnosis of Mtb disease at a stage earlier than that which could have been diagnosed by conventional clinical diagnostic methods, namely, by radiologic examination and bacterial smear and culture or by other laboratory methods available prior to this invention. (Culture positivity is the final confirmatory test but takes two weeks and more) An objective of the invention is to define, obtain and characterize the antigens of Mtb expressed by the bacterium in vivo during early tuberculosis. These antigens are evaluated for their utility as markers of early disease that may be used to monitor suspected or high-risk individuals to identify those with active, subclinical infection. Mycobacterial Antigen Compositions The preferred mycobacterial antigen composition may be a substantially purified or recombinantly produced preparation of one or more Mtb proteins. Alternatively, the antigen composition may be a partially purified or substantially pure preparation containing one or more Mtb epitopes which are capable of being bound by antibodies or T lymphocytes of an infected subject Such epitopes may be in the form of peptide fragments of the early antigen proteins or other “functional derivatives” of Mtb proteins as described below. By “functional derivative” is meant a “fragment,” “variant,” “analogue,” or “chemical derivative” of an early antigen protein, which terms are defined below. A functional derivative retains at least a portion of the function of the protein which permits its utility in accordance with the present invention—primarily the capacity to bind to an early antibody. A “fragment” refers to any subset of the molecule, that is, a shorter peptide. A “variant” refers to a molecule substantially similar to either the entire protein or fragment thereof A variant peptide may be conveniently prepared by direct chemical synthesis or by recombinant means. An “analogue” of the protein or peptide refers to a non- natural molecule substantially similar to either the entire molecule or a fragment thereof. A “chemical derivative” of the antigenic protein or peptide contains additional chemical moieties not normally part of the peptide. Covalent modifications of the peptide are included within the scope of this invention. Such modifications may be introduced into the molecule by reacting targeted amino acid residues of the peptide with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues. Several proteins or glycoproteins, identified in culture filtrates of Mt, or on the surface of Mtb organisms are the preferred early Mtb antigens of the present invention. The secreted proteins may also be present in cellular preparations of the bacilli. Thus, these early antigens are not intended to be limited to the secreted protein form. The proteins are characterized at various places below. Preferred diagnostic epitopes are those recognized by antibodies or by T cells, preferably Th1 cells of “early” TB patients as defined above. This does not exclude the possibility that such epitopes are bound by antibodies or recognized by T cells present later in the infectious process. In fact, some of the present proteins or epitopes thereof my detect infection in subjects whose infectious state is not detected by antibodies against the 88 kDa protein (malate synthase) described in U.S. Pat. No. 6,245,331 and U.S. Ser. No. 9/396,347, and their respective file histories. Preferred vaccine epitopes (see below) are epitopes which stimulate naïve human Th1 cells or Th1 cells or infected subjects to proliferate or to secrete cytokines. Assays for Th1 cytokines, preferably interferon-γ (IFNγ). IL-12 and IL-18 are well-known in the art. The present immunoassay typically comprises incubating a biological fluid, preferably serum or urine, from a subject suspected of having TB, in the presence of an Mtb antigen-containing reagent which includes one or more Mtb early antigens, and detecting the binding of antibodies in the sample to the mycobacterial antigen(s). By the term “biological fluid” is intended any fluid derived from the body of a normal or diseased subject which may contain antibodies, such as blood, serum, plasma, lymph, urine, saliva, sputum, tears, cerebrospinal fluid, bronchioalveolar lavage fluid, pleural fluid, bile, ascites fluid, pus and the like. Also included within the meaning of this term as used herein is a tissue extract, or the culture fluid in which cells or tissue from the subject have been incubated. In a preferred embodiment, the mycobacterial antigen composition is brought in contact with, and allowed to bind to, a solid support or carrier, such as nitrocellulose or polystyrene, allowing the antigen composition to adsorb and become immobilized to the solid support. This immobilized antigen is then allowed to interact with the biological fluid sample which is being tested for the presence of anti-Mtb antibodies, such that any antibodies in the sample will bind to the immobilized antigen. The support to which the antibody is now bound may then be washed with suitable buffers after which a detectably labeled binding partner for the antibody is introduced. The binding partner binds to the immobilized antibody. Detection of the label is a measure of the immobilized antibody. A preferred binding partner for this assay is an anti-immunoglobulin antibody (“second antibody”) produced in a different species. Thus to detect a human antibody, a detectably labeled goat anti-human immunoglobulin “second” antibody may be used. The solid phase support may then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on the solid support may then be detected by conventional means appropriate to the type of label used (see below). Such a “second antibody” may be specific for epitopes characteristic of a particular human immunoglobulin isotype, for example IgM, IgG1, IgG2a, IgA and the like, thus permitting identification of the isotype or isotypes of antibodies in the sample which are specific for the mycobacterial antigen. Alternatively, the second antibody may be specific for an idiotype of the ant-Mtb antibody of the sample. As alternative binding partners for detection of the sample antibody, other known binding partners for human immunoglobulins may be used. Examples are the staphylococcal immunoglobulin binding proteins, the best know of which is protein A. Also intended is staphylococcal protein G, or a recombinant fusion protein between protein A and protein G. Protein G of group G and group C streptococci binds to the Fc portion of Ig molecules as well as to IgG Fab fragment at the VH3 domain. Protein C of Peptococcus magnus binds to the Fab region of the immunoglobulin molecule. Any other microbial immunoglobulin binding proteins, for example from Streptococci, are also intended (for example, Langone, J. J., Adv. Immunol. 32:157 (1982)). In another embodiment of this invention, a biological fluid suspected of containing antibodies specific for a Mtb antigen may be brought into contact with a solid support or carrier which is capable of immobilizing soluble proteins. The support may then be washed with suitable buffers followed by treatment with a mycobacterial antigen reagent, which may be detectably labeled. Bound antigen is then measured by measuring the immobilized detectable label. If the mycobacterial antigen reagent is not directly detectably labeled, a second reagent comprising a detectably labeled binding partner for the Mtb antigen, generally a second anti-Mtb antibody such as a murine mAb, is allowed to bind to any immobilized antigen. The solid phase support may then be washed with buffer a second time to remove unbound antibody. The amount of bound label on said solid support may then be detected by conventional means. By “solid phase support” is intended any support capable of binding a proteinaceous antigen or antibody molecules or other binding partners according to the present invention. Well-known supports, or carriers, include glass, polystyrene, polypropylene, polyethylene, polyvinylidene difluoride, dextran, nylon, magnetic beads, amylases, natural and modified celluloses, polyacrylamides, agaroses, and magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration so long as it is capable of binding to an antigen or antibody. Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads, 96-well polystyrene microplates and test strips, all well-known in the art. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation. Using any of the assays described herein, those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation. Furthermore, other steps as washing, stirring, shaking, filtering and the like may be added to the assays as is customary or necessary for the particular situation. A preferred type of immunoassay to detect an antibody specific for a mycobacterial antigen according to the present invention is an enzyme-linked immunosorbent assay (ELISA) or more generically termed an enzyme immunoassay (EIA). In such assays, a detectable label bound to either an antibody-binding or antigen-binding reagent is an enzyme. When exposed to its substrate, this enzyme will react in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorometric or visual means. Enzymes which can be used to detectably label the reagents useful in the present invention include, but are not limited to, horseradish peroxidase, alkaline phosphatase, glucose oxidase, β-galactosidase, ribonuclease, urease, catalase, malate dehydrogenase, staphylococcal nuclease, asparaginase, Δ-5-steroid isomerase, yeast alcohol dehydrogenase, α-glycerophosphate dehydrogenase, triose phosphate isomerase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. For descriptions of EIA procedures, see Voller, A. et al., J. Clin. Pathol. 31:507-520 (1978); Butler, J. E., Meth. Enzymol. 73:482-523 (1981); Maggio, E. (ed.), Enzyme Immunoassay, CRC Press, Boca Raton, 1980; Butler, J. E., In: Structure of Antigens, Vol. 1 (Van Regenmortel, M., CRC Press, Boca Raton, 1992, pp. 209-259; Butler, J. E., In: van Oss, C. J. et al., (eds), Immuniochemistry, Marcel Dekker, Inc., New York, 1994, pp. 759-803; Butler, J. E. (ed.), Immunochemistry of Solid-Phase Immunoassay, CRC Press, Boca Raton, 1991) In another embodiment, the detectable label may be a radiolabel, and the assay termed a radioimmunoassay (RIA), as is well known in the art. See, for example, Yalow, R. et al., Nature 184:1648 (1959); Work, T. S., et al., Laboratory Techniques and Biochemistry in Molecular Biology, North Holland Publishing Company, NY, 1978, incorporated by reference herein. The radioisotope can be detected by a gamma counter, a scintillation counter or by autoradiography. Isotopes which are particularly useful for the purpose of the present invention are 125I, 131I, 35S, 3H and 14C. It is also possible to label the antigen or antibody reagents with a fluorophore. When the fluorescently labeled antibody is exposed to light of the proper wave length, its presence can then be detected due to fluorescence of the fluorophore. Among the most commonly used fluorophores are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, fluorescamine or fluorescence-emitting metals such as 152Eu or other lanthanides. These metals are attached to antibodies using metal chelators. The antigen or antibody reagents useful in the present invention also can be detectably labeled by coupling to a chemiluminescent compound. The presence of a chemiluminescent-tagged antibody or antigen is then determined by detecting the luminescence that arises during the course of a chemical reaction. Examples of useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. Likewise, a bioluminescent compound such as a bioluminescent protein may be used to label the antigen or antibody reagent useful in the present invention. Binding is measured by detecting the luminescence. Useful bioluminescent compounds include luciferin, luciferase and aequorin. Detection of the detectably labeled reagent according to the present invention may be accomplished by a scintillation counter, for example, if the detectable label is a radioactive gamma emitter, or by a fluorometer, for example, if the label is a fluorophore. In the case of an enzyme label, the detection is accomplished by colorimetry to measure the colored product produced by conversion of a chromogenic substrate by the enzyme. Detection may also be accomplished by visual comparison of the colored product of the enzymatic reaction in comparison with appropriate standards or controls. The immunoassay of this invention may be a “two-site” or “sandwich” assay. The fluid containing the antibody being assayed is allowed to contact a solid support. After addition of the mycobacterial antigen(s), a quantity of detectably labeled soluble antibody is added to permit detection and/or quantitation of the ternary complex formed between solid-phase antibody, antigen, and labeled antibody. Sandwich assays are described by Wide, Radioimmune Assay Method, Kirkham et aL, Eds., E. & S. Livingstone, Edinburgh, 1970, pp 199-206. Alternatives to the RIA and EIA are various types of agglutination assays, both direct and indirect, which are well known in the art. In these assays, the agglutination of particles containing the antigen (either naturally or by chemical coupling) indicates the presence or absence of the corresponding antibody. Any of a variety of particles, including latex, charcoal, kaolinite, or bentonite, as well as microbial cells or red blood cells, may be used as agglutinable carriers (Mochida, U.S. Pat. No. 4,308,026; Gupta et al., J. Immunol. Meth. 80:177-187 (1985); Castelan et al., J. Clin. Pathol. 21:638 (1968); Singer et al., Amer. J. Med.(December 1956, 888; Molinaro, U.S. Pat. No. 4,130,634). Traditional particle agglutination or hemagglutination assays are generally faster, but much less sensitive than RIA or EIA. However, agglutination assays have advantages under field conditions and in less developed countries. In addition to detection of antibodies, the present invention provides methods to detect and enumerate cells secreting an antibody specific for a mycobacterial antigen. Thus, for example, any of a number of plaque or spot assays may be used wherein a sample containing lymphocytes, such as peripheral blood lymphocytes, is mixed with a reagent containing the antigen of interest. As the antibody secreting cells of the sample secrete their antibodies, the antibodies react with the antigen, and the reaction is visualized in such a way that the number of antibody secreting cells (or plaque forming cells) may be determined. The antigen may be coupled to indicator particles, such as erythrocytes, preferably sheep erytirocytes, arranged in a layer. As antibodies are secreted from a single cell, they attach to the surrounding antigen-bearing erythrocytes. By adding complement components, lysis of the erythrocytes to which the antibodies have attached is achieved, resulting in a “hole” or “plaque” in the erythrocyte layer. Each plaque corresponds to a single antibody-secreting cell. In a different embodiment, the sample containing antibody-secreting cells is added to a surface coated with an antigen-bearing reagent, for example, a mycobacterial antigen alone or conjugated to bovine serum albumin, attached to polystyrene. After the cells are allowed to secrete the antibody which binds to the immobilized antigen, the cells are gently washed away. The presence of a colored “spot” of bound antibody, surrounding the site where the cell had been, can be revealed using modified EIA or other staining methods well-known in the art. (See, for example, Sedgwick, J. D. et aL, J. Immunol. Meth. 57:301-309 (1983); Czerkinsky, C. C. et al., J. Immunol. Meth. 65:109-121 (1983); Logtenberg, T. et al., Immunol. Lett. 9:343-347 (1985); Walker, A. G. et al., J. Immunol. Meth. 104:281-283 (1987). The present invention is also directed to a kit or reagent system useful for practicing the methods described herein. Such a kit will contain a reagent combination comprising the essential elements required to conduct an assay according to the disclosed methods. The reagent system is presented in a commercially packaged form, as a composition or admixture (where the compatibility of the reagents allow), in a test device configuration, or more typically as a test kit. A test kit is a packaged combination of one or more containers, devices, or the like holding the necessary reagents, and usually including written instructions for the performance of assays. The kit may include containers to hold the materials during storage, use or both. The kit of the present invention may include any configurations and compositions for performing the various assay formats described herein. For example, a kit for determining the presence of anti-Mtb early antibodies may contain one or more early Mtb antigens, either in immobilizable form or already immobilized to a solid support, and a detectably labeled binding partner capable of recognizing the sample anti-Mtb early antibody to be detected, for example. a labeled anti-human Ig or anti-human Fab antibody. A kit for determining the presence of an early Mtb antigen may contain an immobilizable or immobilized “capture” antibody which reacts with one epitope of an early Mtb antigen, and a detectably labeled second (“detection”) antibody which reacts with a different epitope of the Mtb antigen than that recognized by the (capture) antibody. Any conventional tag or detectable label may be part of the kit, such as a radioisotope, an enzyme, a chromophore or a fluorophore. The kit may also contain a reagent capable of precipitating immune complexes. A kit according to the present invention can additionally include ancillary chemicals such as the buffers and components of the solution in which binding of antigen and antibody takes place. The present invention permits isolation of an Mtb early antigen which is then used to produce one or more epitope-specific mAbs, preferably in mice. Screening of these putative early Mtb-specific mAbs is done using known patient sera which have been characterized for their reactivity with the early antigen of interest. The murine mAbs produced in this way are then employed in a highly sensitive epitope-specific competition immunoassay for early detection of TB. Thus, a patient sample is tested for the presence of antibody specific for an early epitope of Mtb by its ability to compete with a known mAb for binding to a purified early antigen. For such an assay, the mycobacterial preparation may be less than pure because, under the competitive assay conditions, the mAb provides the requisite specificity for detection of patient antibodies to the epitope of choice (for which the mAb is specific). In addition to the detection of early Mtb antigens or early antibodies, the present invention provides a method to detect immune complexes containing early Mtb antigens in a subject using an EIA as described above. Circulating immune complexes have been suggested to be of diagnostic value in TB. (See, for example, Mehta, P. K. et al, 1989, Med. Microbiol. Immunol. 178:229-233; Radhakrishnan, V. V. et al., 1992, J. Med. Microbiol. 36:128-131). Methods for detection of immune complexes are well-known in the art. Complexes may be dissociated under acid conditions and the resultant antigens and antibodies detected by immunoassay. See, for example, Bollinger, R. C. et al, 1992, J. Infec. Dis. 165:913-916. Immune complexes may be precipitated for direct analysis or for dissociation using known methods such as polyethylene glycol precipitation. Purified Mtb early antigens as described herein are preferably produced using recombinant methods. See Examples. Conventional bacterial expression systems utilize Gram negative bacteria such as E. coli or Salmonella species. However, it is believed that such systems are not ideally suited for production of Mtb antigens (Burlein, J. E., In: Tuberculosis: Pathogenesis, Protection and Control, B. Bloom, ed., Amer. Soc. Microbiol., Washington, DC, 1994, pp. 239-252). Rather, it is preferred to utilize homologous mycobacterial hosts for recombinant production of early Mtb antigenic proteins or glycoproteins. Methods for such manipulation and gene expression are provided in Burlein, supra. Expression in mycobacterial hosts, in particular M. bovis (strain BCG) or M. smegmatis are well-known in the art. Two examples, one of mycobacterial genes (Rouse, D. A. et al., 1996, Mol. Microbiol. 22:583-592) and the other of non mycobacterial genes, such as HIV-1 genes (Winter, N. et al., 1992, Vaccines 92, Cold Spring Harbor Press, pp. 373-378) expressed in mycobacterial hosts are cited herein as an example of the state of the art. The foregoing three references are hereby incorporated by reference in their entirety. Urine-Based Antibody Assay The present invention also provides a urine based diagnostic method for TB that can be used either as a stand-alone test, or as an adjunct to the serodiagnostic methods described herein. Such a method enables the practitioner to (1) determine the presence of anti-mycobacterial antibodies in urine from TB patients with early disease (non-cavitary, smear negative TB patients) and from HIV-infected TB patients; (2) determine the profile of specific mycobacterial antigens, such as those in the culture filtrate, that are consistently and strongly reactive with the urine antibodies; and (3) obtain the antigens that are recognized by the urine antibodies. Smear positive (=late) cases constitute only about 50% of the TB cases, and patients with relatively early disease are generally defined as being smear negative. Moreover, as the HIV-epidemic spreads in developing countries, the numbers and proportions of HIV-infected TB patients increases. Serum and urine samples from non-cavitary and/or smear negative, culture positive TB patients and from HIV-infected TB patients are obtained Cohorts comprising PPD-positive and PPD-negative healthy individuals, non-tuberculous HIV-infected individuals, or close contacts of TB patients can serve as negative controls. The reactivity of the serum samples with culture filtrate proteins of Mtb, and the purified antigens (as described herein) is preferably determined by ELISA as described herein. All sera are preferably depleted of cross-reactive antibodies prior to use in ELISA. The following description is of a preferred assay method and approach, and is not intended to be limiting to the particular steps (or their sequence), conditions, reagents and amounts of materials. Briefly, 200 μl of E. coli lysates (suspended at 500 μg/ml) are coated onto wells of ELISA plates (Immulon 2, Dynex, Chantilly, Va.) and the wells are blocked with 5% bovine serum albumin (BSA). The serum samples (diluted 1:10 in PBS-Tween-20) are exposed to 8 cycles of absorption against the E. coli lysates. The adsorbed sera are then used in the ELISA assays. Fifty μl of the individual antigens, suspended at 2 μg/ml in coating buffer (except for the total culture filtrate proteins which is used at 5 μg/ml), are allowed to bind overnight to wells of ELISA plates. After 3 washes with PBS (phosphate buffered saline), the wells are blocked with 7.5% FBS (fetal bovine serum, Hyclone, Logan, Utah) and 2.5% BSA in PBS for 2.5 hr at 37° C. Fifty μl of each serum sample are added per well at predetermined optimal dilutions (e.g., dilutions of about 1:50-1:200). The antigen-antibody binding is allowed to proceed for 90 min at 37° C. The plates are washed 6 times with PBS-Tween 20 (0.05%) and 50 μl/well of alkaline phosphatase-conjugated goat anti-human IgG (Zymed, Calif.), diluted 1:2000 in PBS/Tween 20 is added. After 60 min the plates are washed 6 times with Tris buffered saline (50 mM Tris, 150 mM NaCl) and the Gibco BRL Amplification System (Life Technologies, Gaithersburg, Md.) used for development of color. The absorbance is read at 490 nm after stopping the reaction with 50 μl of 0.3M H2SO4. The cutoff in all ELISA assays is determined by using mean absorbance (=Optical Density O.D.) +3 standard deviations (SD) of the negative control group comprising PPD positive and PPD negative healthy individuals. The reactivity of the urine samples with the various antigens is determined initially with undiluted urine samples as described above. For the urine ELISA, results obtained by the present inventors showed that the optimal concentration of the culture filtrate protein preparation is about 125 μl/well of 4 μg/ml suspension, and for certain proteins, 125 μl/well of about 2 μg/ml. Also, the urine is left overnight in the antigen coated wells. However, if urine antibody titers of smear-negative and HIV-infected patients are lower than those observed in smear positive patients, it may be necessary to first concentrate the urine samples. For concentration, Amicon concentrators with a molecular weight cut off of 30 kDa is preferred. Concentrated urine samples are evaluated for the presence of antibodies to the above mentioned antigens. Optimal conditions for these assays are determined readily. The sensitivity and specificity of antibody detection by use of one or more of the antigens, with both urine and serum samples is also readily determined. Vaccines The present disclosure and Examples prove that human subjects infected with Mtb indeed do respond immunologically to early Mtb antigens, including the four surface proteins described more thoroughly herein. Thus the antigens are available to the immune system and are immunogenic. It is believed that these are stage-specific proteins that play some critical role in the microorganisms life cycle at relatively early stages of the infectious process. Hence, the vaccine compositions and methods described herein are designed to augment this immunity, and preferably, to induce it a stage wherein the bacterial infection can be prevented or curtailed. The vaccine compositions are particularly useful in preventing Mtb infection in subjects at high risk for such an infection, as discussed above. The vaccine compositions and methods are also applicable to veterinary uses for infections with other mycobacterial species such as M. bovis which infects cattle, particularly because these proteins are conserved among mycobacterial species. Thus, this invention includes a vaccine composition for immunizing a subject against Mtb infection. An Mtb early antigen preferably one of the proteins described herein in more detail, is prepared as the active ingredient in a vaccine composition. The vaccine may also comprises one or more of the proteins described herein, peptides thereof or functional derivatives as described, or DNA encoding the protein, and a pharmaceutically acceptable vehicle or carrier. In one embodiment, the vaccine comprises a fusion protein which includes an Mtb early antigen. The vaccine composition may further comprise an adjuvant or other immune stimulating agent. For use in vaccines, the Mtb early antigen protein or epitope-bearing peptide thereof is preferably produced recombinantly, preferably in prokaryotic cells. Full length proteins or longer epitope-bearing fragments of the Mtb early antigen proteins are preferred immunogens, in particular, those reactive with early antibodies or T cells. If a shorter epitope-bearing fragment, for example containing 20 amino acids or less, is the active ingredient of the vaccine, it is advantageous to couple the peptide to an immunogenic carrier to enhance its immunogenicity. Such coupling techniques are well known in the art, and include standard chemical coupling techniques using linker moieties such as those available from Pierce Chemical Company, Rockford, Ill. Suitable carriers are proteins such as keyhole limpet hemocyanin (KLH), E. coli pilin protein k99, BSA, or rotavirus VP6 protein. Another embodiment is a fusion protein which comprise the Mtb early antigen protein or epitope-bearing peptide region fused linearly to an additional amino acid sequence. Because of the ease with which recombinant materials can be manipulated, multiple copies a selected epitope-bearing region may be included in a single fusion protein molecule. Alternatively, several different epitope-bearing regions can be “mixed and matched” in a single fusion protein. The active ingredient such, preferably a recombinant product, is preferably administered as a protein or peptide vaccine. The vaccine composition may also comprise a DNA vaccine (e.g., Hoffman, S L et al., 1995, Ann N Y Acad Sci 772:88-94; Donnelly, J J et al., 1997, Annu Rev Immunol 15:617-48; Robinson, H L, 1997, Vaccine. 15: 785-787, 1997; Wang, R et al., 1998, Science. 282: 476-480, 1998; Gurunathan, S et al., 2000, Annu Rev Immunol 18:927-74; Restifo, N P et al., 2000, Gene Ther. 7: 89-92). The DNA preferably encodes the protein or epitope(s), optionally linked to a protein that promotes expression of the Mtb protein in the host after immunization. Examples known in the art include heat shock protein 70 (HSP70) (Srivastava, P K et al., 1994. Immunogenetics 39:93-8;Suto, R et al., 1995, Science 269:1585-8; Arnold-Schild, D et al., 1999, J Immunol 162:3757-60; Binder, R J et al., 2000, Nature Immunology 2:151-155; Chen, C H et al., 2000, Cancer Res 60:1035-42) or translocation proteins such herpesvirus protein VP22 (Elliott, G, and O'Hare, P., 1997. Cell 88:223-33; Phelan, A et al., 1998, Nat Biotechnol 16:440-3; Dilber, M S et al., 1999. Gene Ther 6:12-21) or domain II of Pseudomonas aeruginosa exotoxin A (ETA) (Jinno, Y et aL, J Biol Chem. 264: 15953-15959, 1989; Siegall, C B et al., Biochemistry. 30: 7154-7159, 1991; Prior, T I et al., Biochemistry. 31: 3555-3559, 1992; Fominaya, J et al., J Biol Chem. 271: 10560-10568, 1996; Fominaya, J et al., Gene Ther. 5: 521-530, 1998; Goletz, T J et al., Hum Immunol. 54: 129-136, 1997). In another embodiment, the vaccine is in the form of a strain of bacteria (preferably a known “vaccine strain”) which has been genetically transformed to express the protein or epitope-bearing peptide. Some known vaccine strains of Salmonella are described below. Salmonella dublin live vaccine strain SL5928 aroA148 fliC(i)::Tn10 and S. typhimurium LB5000 hsdSB121 leu-3121 (Newton S. M. et al., Science 1989, 244: 70 A Salmonella strain expressing the Mtb protein or fragment of this invention may be constructed using known methods. Thus, a plasmid encoding the protein or peptide. The plasmid may first be selected in an appropriate host, e.g., E. coli strain MC1061. The purified plasmid is then introduced into S. typhimurium strain LB5000 so that the plasmid DNA is be properly modified for introduction into Salmonella vaccine strains. Plasmid DNA isolated from LB5000 is introduced into, e.g., S. dublin strain SL5928 by electroporation. Expression of the Mtb protein or fragment encoded by the plasmid in SL5928 can be verified by Western blots of bacterial lysates and antibodies specific for the relevant antigen or epitope. The active ingredient, or mixture of active ingredients, in protein or peptide vaccine composition is formulated conventionally using methods well-known for formulation of such vaccines. The active ingredient is generally dissolved or suspended in an acceptable carrier such as phosphate buffered saline. Vaccine compositions may include an immunostimulant or adjuvant such as complete or incomplete Freund's adjuvant, aluminum hydroxide, liposomes, beads such as latex or gold beads, ISCOMs, and the like. For example, 0.5 ml of Freund's complete adjuvant or a synthetic adjuvant with less undesirable side effects is used for intramuscular or subcutaneous injections, preferably for all initial immunizations; this can be followed with Freund's incomplete adjuvant for booster injections. General methods to prepare vaccines are described in Remington's Pharmaceutical Science; Mack Publishing Company Easton, Pa. (latest edition). Liposomes are pharmaceutical compositions in which the active protein is contained either dispersed or variously present in corpuscles consisting of aqueous concentric layers adherent to lipidic layers. The active protein is preferably present in the aqueous layer and in the lipidic layer, inside or outside, or, in any event, in the non-homogeneous system generally known as a liposomic suspension. The hydrophobic layer, or lipidic layer, generally, but not exclusively, comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surface active substances such as dicetylphosphate, stearylamine or phosphatidic acid, and/or other materials of a hydrophobic nature. Adjuvants, including liposomes, are discussed in the following references, incorporated herein by reference: Gregoriades, G. et al., Immunological Adjuvants and Vaccines, Plenum Press, New York, 1989 Michalek, S. M. et al., “Liposomes as Oral Adjuvants,” Curr. Top. Microbiol. Immunol. 146:51-58 (1989). The vaccine compositions preferably contain (1) an effective amount of the active ingredient, that is, the protein or peptide together with (2) a suitable amount of a carrier molecule or, optionally a carrier vehicle, and, if desired, (3) preservatives, buffers, and the like. Descriptions of vaccine formulations are found in Voller, A. et al., New Trends and Developments in Vaccines, University Park Press, Baltimore, Md. (1978). As with all immunogenic compositions for eliciting antibodies or cell-mediated immunity, the immunogenically effective amounts of the proteins or peptides or other vaccine compositions of the invention must be determined empirically. Factors to be considered include the immunogenicity of the native peptide, whether or not the peptide will be complexed with or covalently attached to an adjuvant or carrier protein or other carrier and the route of administration for the composition, i.e., intravenous, intramuscular, subcutaneous, etc., and the number of immunizing doses to be administered. Such factors are known in the vaccine art, and it is well within the skill of the immunologists to make such determinations without undue experimentation. The vaccines are administered as is generally understood in the art. Ordinarily, systemic administration is by injection; however, other effective means of administration are known. With suitable formulation, peptide vaccines may be administered across the mucus membrane using penetrants such as bile salts or fusidic acids in combination, usually, with a surfactant. Transcutaneous administration of peptides is also known. Oral formulations can also be used. Dosage levels depend on the mode of administration, the nature of the subject, and the nature of carrier/adjuvant formulation. Preferably, an effective amount of the protein or peptide is between about 0.01 μg/kg-1 mg/kg body weight. Subjects may be immunized systemically by injection or orally by feeding, e.g., in the case of vaccine strains of bacteria, 108-1010 bacteria on one or multiple occasions. In general, multiple administrations of the vaccine in a standard immunization protocol are used, as is standard in the art. For example, the vaccines can be administered at approximately two to six week intervals, preferably monthly, for a period of from one to four inoculations in order to provide protection. Vaccination with the vaccine composition will result in an immune response, either or both of an antibody response and a cell-mediated response, , which will block one or more steps in the Mtb bacterium's infective cycle, preferably the steps of binding to and entry into host cells in which it grows. T Cell Responses Human (or animal model) peripheral blood lymphocytes (PBL) or lymphocytes from another source (e.g., lymph node) are incubated in complete culture medium (as are well known in the art) at appropriate cell concentrations. A preferred medium is RPMI 1640, supplemented with 10% (vol/vol) fetal bovine serum, 50 units/ml penicillin/ streptomycin, 2 mM L-glutamine, 1 mM sodium pyruvate, 2 mM nonessential amino acids) Cells are stimulated for an appropriate period, e.g., 2-4 days with an Mtb protein or peptide fragment thereof antigen at concentrations readily ascertainable by those of skill in the art. Interleukin 2 (IL-2) can be added to promote expansion of antigen-specific cells if it is desired to generate antigen-specific lines or clones. T cells from a PPD+ normal individual or from a patient being tested are cultured with varying concentrations of an Mtb protein or peptide being evaluated for its T cell stimulatory capacity. T cell reactivity is measured in any of a number of conventional assays, for example T cell proliferation which can be measured by radiolabeled thymidine or iododeoxyuridine, or by colorimetric assay of cell number. Alternatively, stimulation of T cell activity can be measured by secretion of cytokines or by ELISPOT assays that enumerate cytokine secreting cells. The enzyme-linked immunospot (ELISPOT) assay described (e.g. Miyahira, Y et al., J Immunol Methods. 181: 45-54, 1995) utilizes 96-well filtration plates (Millipore, Bedford, Mass.) coated with about 10 μg/ml of an antibody (commercially available) specific for a cytokine being assayed in 50 μl PBS. After overnight incubation at 4° C., the wells are washed and blocked with culture medium containing 10% fetal bovine serum. Different concentrations of fresh isolated lymphocytes being assayed starting from 1×106/well, are added to the well along with 15 international units/ml interleukin-2 (IL-2). Cells are incubated at 37° C. for 24 hours either with or without a stimulatory amount of the Mtb protein or peptide thereof. After culture, the plate is washed and then followed by incubation with 5 μg/ml biotinylated antibody specific for the cytokine being assayed (e.g., IFN-γ) in 50 μl in PBS at 4° C. overnight. After washing six times, 1.25 μg/ml avidin-alkaline phosphatase (Sigma, St. Louis, Mo.) in 50 μl PBS are added and incubated for 2 hours at room temperature. After washing, spots are developed by adding 50 μl BCIP/NBT solution (Boehringer Mannheim, Indianapolis, Ind.) and incubated at room temperature for 1 hr. The spots are counted using a dissecting microscope. Intracytoplasmic Cytokine Staining and Flow Cytometry Analysis Lymphocytes are incubated either with the Mtb protein or peptide at an appropriate concentration for about 20 hours. Golgistop (Pharmingen, San Diego, Calif.) is added 6 hours before harvesting the cells from the culture. Cells are then washed once in an appropriate buffer for flow cytometry and stained with appropriately labeled (e.g., phycoerythrin-conjugated) anti CD8 or anti-CD4 antibody. Cells are subjected to intracellular cytokine staining using the Cytofix/Cytoperm kit according to the manufacturer's instructions (e.g., from Pharmingen). FITC-conjugated anti-cytokine antibodies and the immunoglobulin isotype control antibody are used. Analysis was done on a flow cytometer ELISA for Cytokines Lymphocytes (e.g., 4×106) are obtained from subjects or from culture and are incubated in culture medium with Mtb protein or peptide in a total volume of 2 ml of medium in a 24-well tissue culture plate for 72 hours. The supernatants are harvested and assayed for the presence of cytokine, e.g., IFN-γ or IL12 or IL18 using commercial ELISA kits according to manufacturer's protocol. Antibody Responses to Mt The humoral responses to Mtb in TB patients have been the subject of investigation for several decades, primarily for the purpose of devising serodiagnosis for TB (reviewed in Grange, J M, 1984, Adv Tuberc Res. 21:1-78). The earlier studies of humoral responses in TB patients were mostly based on use of crude mixtures of antigens like PPD, bacterial sonicates, Ag A60 etc. These antigen preparations provided unsatisfactory results, because although a majority of TB patients were antibody positive, often-healthy individuals also had antibodies that showed cross-reactivity with these preparations. A variety of approaches, both biochemical and recombinant, were then used by different labs to obtain individual, purified antigens of Mtb (Young, D B et al., Mol. Microbiol. 6:133-145). Studies of purified antigens showed that many of the Mtb antigens are conserved, prokaryotic proteins which have significant homology with analogous proteins in other mycobacterial and non-mycobacterial organisms (the 65 kDa GroEL, 70 kDa DNA K, 47 kDa elongation factor Tu, 44 kDa Pst A homolog, 40 kDa L-alanine dehydrogenase, 23 kDa superoxide dismutase, 23 kDa outer membrane protein, 14 kDa GroES, enzymes of metabolic pathways etc (Young et al., supra). Studies also showed that healthy individuals often have antibodies to epitopes on conserved regions of such ubiquitous prokaryotic proteins, resulting in the observed cross-reactivity of the healthy sera with mycobacterial antigens. Some of the purified mycobacterial antigens were evaluated for their use in serodiagnosis of TB, and one of them, a 38-kDa protein provided promising results. This antigen provided very high specificity (>98%). However, extensive studies with the 38 kDa protein in different populations showed that anti-38 kDa antibodies are present only in individuals with chronic, recurrent, cavitary TB, limiting its utility in diagnosis of TB (Bothamley, G H et al., 1992, Thorax. 47:270-275; Daniels, T M, 1996, p. 223-231. In W. R. Rom and S. Garay (ed.), In: Tuberculosis. Little, Brown and Company, Inc, Boston, Mass.). Most of the purified antigens that were evaluated for their utility for serodiagnosis were either proteins that were immunodominant in mice that were immunized with killed preparations/sonicates of Mtb or BCG for the purpose of producing monoclonal antibodies (Engers, H D et al., 1986, Infect. Immun. 51:718-720), or were antigens that were relatively easy to purify by biochemical procedures (Sada, E et al., 1990, J. Clin Microbiol. 28:2587-2590; Sada, E et al., 1990, J. Infec. Dis. 162:928-931). Based on the rationale that there may be differences in antigens expressed by in vivo replicating bacteria, and inactivated antigen preparations, our approach was to perform a direct analysis of antibody responses in patients with active TB. We developed a unique approach to address the issue of cross-reactivity described above, and have provided evidence that adsorption of sera with lysates of E. coli, which contain many of the ubiquitous prokaryotic proteins, results in significant depletion of the cross-reactive antibodies. Using cross-reactive antibody depleted sera, we have systematically dissected the antibody responses of both HIV-infected and non-HIV TB patients at different stages of disease progression. Our studies show that the culture filtrate antigens are targets of humoral responses during active infection in humans, and that antibodies to the culture filtrate proteins are present in individuals with active TB, and not in PPD positive healthy individuals. We have defined the repertoire of antigens in culture filtrates of Mtb that elicit antibodies in TB patients by using 2-D fractionated proteins and immunoblotting. Our studies show that of the >100 different proteins released by extracellularly growing Mtb, antibodies to only a small number of proteins (18 antigens) are present in non-HIV TB patients with non-cavitary disease. HIV-infected TB patients, a majority of whom also has non-cavitary disease, have antibodies to the same small subset of culture filtrate antigens. In contrast, a majority of the advanced cavitary TB patients have antibodies to the above 18 antigens, and several additional antigens. These studies make several important points. First, the reactivity of TB sera with the culture filtrate proteins, and the lack of reactivity of sera from PPD positive healthy individuals with the same antigens suggest that antibodies to these antigens are associated with active TB infection. Second, the sera from TB patients with only a minority of the culture filtrate proteins of Mtb suggests that many of the culture filtrate proteins may not be expressed in significant amounts by the in vivo replicating bacteria. Third, the differences in the antigen profiles recognized by the non-cavitary and cavitary TB patients suggests that the local milieu (intracellular vs. extracellular, extent of liquification, cavitation, etc.) in which the in vivo bacteria exist affects the antigen profiles expressed. We also showed that 3 of these 26 culture filtrate proteins, identified on the basis of their reactivity with TB sera, are useful for serodiagnosis for pulmonary TB. Although the culture filtrates have yielded important molecules for diagnosis of TB, they would only contain antigens that are expressed by Mtb replicating in vitro in bacteriological media. Other antigens that are expressed by the bacteria during in vivo growth may be poorly expressed or even absent in these preparations. Recently at least 3 antigens of Mtb that are expressed/upregulated in intracellular conditions, or in vivo, or in granulomas have been reported. In fact, the ability of bacteria to respond to environmental changes is a key feature in their ability to survive, and differential expression of proteins in vivo and in vitro, and of different proteins during different stages of disease progression has been reported for several pathogens. The importance of the effect of the immune system components on bacterial survival and growth is also emphasized by the opportunistic pathogens that cause disease only in individuals with compromised immune systems. A multitude of factors—cytokine levels, iron availability, pH, osmolarity etc can affect the gene expression, and therefore the gene products, expressed by the bacteria in vivo. The search for molecules that may be useful for early diagnosis of TB should ideally be focused on antigens expressed by the in vivo bacteria during the earliest stages of infection. Yet, most current studies have focused either on antigens expressed by the bacteria growing in vitro in bacteriological media or on antigens recognized by sera of patients with clinical disease. Recent experiments with increasing doses of BCG as a vaccine in mice showed that regardless of the route of immunization, high doses of BCG activated Th2 responses (Power, C A et al.., 1998, Infect. Immun. 66:5743-5750). Other studies in which humoral, cellular and protective immune responses were monitored in individual animals immunized with DNA vaccines encoding several different Mtb antigens have shown that antibody concentrations reflected the levels of antigenic expression (Li, Z et al., 1999, Infect. Immun. 67:4780-4786). These studies suggested that the presence of antibodies to any protein can serve as an excellent marker of expression of high levels of that protein in vivo. Since the exact in vivo environment is impossible to replicate in vitro or in culture, the studies described herein are based on using antibodies as tools to identify antigens that are expressed by Mtb in vivo during the early stages of disease progression. Other investigators (Amara, R R et al., 1996, Infect. Immun. 64:3765-3771) used antibodies from TB patients to identify antigens of Mtb expressed in vivo and have identified several novel antigens. However, these antigens are those that were recognized by sera from patients with chronic, culture-positive TB, and represent antigens expressed in an environment where there is marked caseous necrosis, liquification of caseous material and cavity formation—an environment that allows extensive extracellular replication of the in vivo bacteria. In contrast, prior to the development of extensive pulmonary lesions, the bacteria are believed to be primarily intracellular, an environment that is different from the cavity environment. Whether the same antigens are expressed by the in vivo Mtb during the early and the late stages of active disease is not known. Our own studies with non-cavitary and cavitary TB patients have shown that cavitary patients have antibodies to several antigens that are not recognized in non-cavitary patients, suggesting that the antigen profile expressed in vivo is altered with disease progression as the environment in which the bacteria survive changes. Thus, sera from advanced TB patients are likely to be enriched for antibodies to antigens expressed by the bacteria replicating extracellularly in cavitary lesions. The present invention focuses on identifying and obtaining antigens of Mtb that are expressed in vivo, and elicit immune responses during the early, pre-clinical stages of an active infection with Mtb. Sera from patients with active, early TB cannot be obtained from humans because the lifetime risk of a latently infected individual (PPD positive) developing active clinical TB is so small that the size of the cohort of PPD positive individuals that would have to be studied for their lifetimes, to identify some individuals who may develop disease is not possible at the practical level. Yet, the antigens expressed during the early stages of disease may play an important role in determining the outcome of infection and may prove useful in serodiagnostic assays for diagnosis of early, active infection with Mtb. To identify the antigens expressed by in vivo replicating Mtb during the early stages of disease progression, studies were done with antibodies from guinea pigs infected by virulent airborne organisms. The guinea pig model is considered especially relevant to humans, clinically, immunologically and pathologically (Smith, D W et al., 1989. Reviews of Infect. Dis. 2:s385-s393). In contrast to the mouse and rat, but like the humans, guinea pigs are susceptible to low doses of airborne Mtb, have a strong cutaneous DTH to tuberculin, and display langans giant cells and caseation in pulmonary lesions. Earlier studies of the course of infection in guinea pigs following low dose, pulmonary infection with Mtb have revealed that the mycobacteria replicate exponentially in the lungs during the first 3-21 days post-infection in the lungs (Smith, D W et al., 1970, Am Rev. Respir Dis 102:937-949). Dissemination via the lymphatics to the lymph nodes draining the lung fields occurs at about 8-10 days post-infection, with organisms reaching the spleen via the bloodstream between 14 and 20 days. Within 4 weeks following initiation of the pulmonary infection, there is seeding of mycobacteria into so-called secondary foci throughout the lungs via hematogenous dissemination. Clinical signs of TB in these guinea pigs, such as weight loss and respiratory distress, usually occur at 8-10 weeks post-infection, with mortality observed at 14-18 weeks (Wiegeshaus, E H et al., 1970, Am. Rev. Respir. Dis. 102:422-429). For studies of antigens that are expressed during the early stages of bacterial replication and dissemination by in vivo growing bacteria, serum samples were obtained from guinea pigs infected with airborne virulent Mtb. These sera, obtained at 1, 3, 4, 5 and 6 weeks post infection were provided by Dr. David McMurray, Texas A & M University. One serum sample, obtained from a guinea pig 8 weeks post infection was obtained from Dr. John Belisle, Colorado State University. Thus, the period of time during which the sera used in this study were collected reflects the early post-infection period during which rapid bacillary multiplication and dissemination is known to occur in the lung and elsewhere. These sera would contain antibodies directed against antigens expressed by the bacteria replicating and disseminating in vivo and were therefore used to screen a λgt11 expression library of Mtb to obtain the clones expressing these antigens (Young, R A et al., 1985, Proc. Natl. Acad. Sci. USA. 82:2583-2587). These are the proteins expressed during the early stages of disease progression by in vivo growing bacteria. Our initial studies showed that these antigens were also recognized during infection with Mtb in humans. These antigens, therefore, are useful as diagnostic reagents The following examples are directed to the discovery of four novel repetitive proteins that are immunodominant as Mtb antigens during early tuberculosis To identify antigens of Mtb expressed during early TB, rabbits were infected by aerosols of Mtb H37Rv or a clinical isolate CDC1551, and bled 5 weeks post-infection. These sera were used to immunoscreen a λgt11 genomic DNA expression library of Mtb. Seven positive clones were obtained, five of which were sequenced. Clones AD1 and AD2 express overlapping portions of C-terminal of the protein PirG (Rv 3810). The product of the PirG has previously been shown to be a cell surface exposed protein associated with virulence of Mtb (Berthet, F.-X. et al., 1998, Science. 282:759-762). Clones AD9, AD10 and AD16 express the C-terminal portion of a PE_PGRS (Rv3367) glycine rich protein; a proline and threonine rich protein PTRP (Rv 0538) and the protein MtrA (Rv 3246c) respectively. Three of the proteins, PirG, PE_PGRS and PTRP are repetitive proteins, and have multiple tandem repeats of unique amino acid motifs while the fourth protein, MtrA is a response regulator of a putative two component signal transduction system mtrA-mtrB of Mtb, which has been shown to be upregulated on intracellular entry and residence of Mtb in macrophages (44). All four antigens were recognized by pooled sera from cavitary TB patients confirming their in vivo expression in human TB. Three of the antigens, (PE_PGRS, PTRP and MtrA) were also reactive with sera from non-cavitary TB and HIV pre-TB individuals suggesting that these proteins are expressed in vivo early during an active infection. Studies performed by the present inventors' laboratory identifying the antigens in culture filtrates of Mtb recognized by antibodies from non-cavitary and/or cavitary TB patients are published (described supra). Studies with sera from the aerosol-infected guinea pigs are presented below in Examples I-V. A list of references following Examples I-V contains the references cited by parenthetical number in these Examples. Subsequent Examples VI-XIII are directed to the discovery of four novel repetitive proteins that are immunodominant as Mtb antigens during early tuberculosis To identify antigens of Mtb expressed during early TB, rabbits were infected by aerosols of Mtb H37Rv or a clinical isolate CDC1551, and bled 5 weeks post-infection. These sera were used to immunoscreen a λgt11 genomic DNA expression library of Mtb. Seven positive clones were obtained, five of which were sequenced. Clones AD1 and AD2 express overlapping portions of C-terminal of the protein PirG (Rv 3810). The product of the PirG has previously been shown to be a cell surface exposed protein associated with virulence of Mtb (Berthet, F.-X. et al., 1998, Science. 282:759-762). Clones AD9, AD10 and AD16 express the C-terminal portion of a PE_PGRS (Rv3367) glycine rich protein; a proline and threonine rich protein PTRP (Rv 0538) and the protein MtrA (Rv 3246c) respectively. Three of the proteins, PirG, PE_PGRS and PTRP are repetitive proteins, and have multiple tandem repeats of unique amino acid motifs while the fourth protein, MtrA is a response regulator of a putative two component signal transduction system mtrA-mtrB of Mtb, which has been shown to be upregulated on intracellular entry and residence of Mtb in macrophages (Via, L et al., 1996, J. Bacteriology. 178:3314-21). All four antigens were recognized by pooled sera from cavitary TB patients confirming their in vivo expression in human TB. Three of the antigens, (PE_PGRS, PTRP and MtrA) were also reactive with sera from non-cavitary TB and HIV pre-TB individuals suggesting that these proteins are expressed in vivo early during an active infection. EXAMPLE I Examination of Sera of Infected Guinea Pigs Serum samples: Sera obtained from 2 uninfected guinea pigs and 20 guinea pigs infected with 4-10 cfu, airborne, virulent Mtb H37Rv, and bled at 1,3,4,5, and 6 weeks post-infection, were provided by Dr. David McMurray. Serum from one guinea pig infected for 8 weeks was obtained from Dr. John Belisle. A serum pool containing one serum each from guinea pigs bled 1, 3-6 weeks post-infection and 8 weeks post infection sample was absorbed against an E. coli lysate and used at a dilution of 1:100 for probing the western blots (described below) and for immunoscreening the expression library. Reactivity of guinea-pig serum pool with antigens of Mtb: The reactivity of the above serum pool was assessed with the following antigen preparations of Mtb (provided by Dr. John Belisle, Colorado State University) by western blot analyses: a) Bacterial cell sonicate (CS): the cell pellet of organisms harvested by centrifugation, sonicated extensively, and subjected to high speed centrifugation to get rid of the cell-wall fragments. This preparation contains primarily cytoplasmic proteins of Mtb. b) SDS-soluble cell-wall proteins (SDS-CW): the proteins associated with the bacterial cell wall, extracted as described in (Laal, S et al., 1997, J. Infect. Dis. 176:133-143). c) Lipoarabinomannan-free culture filtrate proteins (LAM-free CFP) from log phase Mtb: This preparation contains the proteins secreted by bacteria replicating in vitro (in bacteriological media) (Sonnenberg, M G et al., 1997, Infect. Immun. 65:4515-4524). The preparation of these antigens has been described before (Laal et al., supra). Western blots prepared after SDS-PA gel fractionation of these antigens were probed with the guinea-pig serum pool at a dilution of 1:100. The filters were washed, exposed to 1:1000 dilution of alkaline phosphatase conjugated anti-guinea-pig IgG, washed and developed with BCIP-NBT substrate. Only the serum pool from Mtb infected guinea pigs reacted strongly with a 40 kDa protein present in the total CS of Mtb (FIG. 1, lane 3). Weaker reactivity was also seen with a doublet at 50-52 kDa (lane 3). Several other proteins reacted strongly with the infected guinea pig serum pool (lane 3) and weakly with the uninfected guinea pig serum pool (lane 2). A 40 kDa protein was also identified only by the serum pool from infected animals in the SDS-CW preparation, as were several weakly reactive bands ranging from 48-103 kDa (lane 5). None of the antigens in the LAM-free CFP preparation showed any specific reactivity with the serum pool from the infected animals. Screening of the Mtb λgt11 expression library with guinea pig sera: To obtain the antigens recognized by the sera from the aerosol infected guinea-pigs, the above serum pool was used to screen a λgt11 expression library of Mtb DNA (World Health Organization (Young, R A et al., 1985, Proc. Natl. Acad. Sci. USA. 82:2583-2587). The details of the library and the methods for screening are described in the Experimental Design section. Several recombinant phages, 10 of which could be cloned by several rounds of screening, were obtained. These are referred to as gsr I-3, and I-6, which were obtained during preliminary screening, and gsr II-1, II-2, II-3, II-4, II-6, II-14, II-15 and II-20 which were obtained during the second round of screening. Characterization of the recombinant proteins: Lysogens of the gsr-clones were established in E. coli Y1089. Single colonies from lysogens were used to obtain the recombinant proteins (35). The E. coli lysates containing the recombinant proteins were fractionated on 10% SDS-PA gels and electroblotted onto nitrocellulose membranes. Lysates from several individual colonies from each of the lysogens were tested. The blots were probed with the guinea-pig serum pool and separate blots were also probed with a commercially available murine mAb against β-galactosidase. Lysates from E. coli Y1089 alone were used as controls. FIGS. 2a-d and 3a show the results of these experiments. β-gal-fusion proteins were present in the lysates of lysogens from all the 10 recombinant phages obtained from the library. Further studies were performed to confirm that the reactivity of the sera from the infected animals with the fusion proteins was with the mycobacterial fragment, and not the β-galactosidase portion of the fusion protein (FIG. 3b). E coli Y 1089 was lysogenized with the empty λgt11 vector, induced to express the β-galactosidase, and the blots probed with the anti-β-gal antibody, or the guinea-pig serum pool. Only the former antibody showed significant reactivity with the β-galactosidase band in the induced lysate (FIG. 3b). Cross hybridization between the 10 clones: DNA from {fraction (9/10)} gsr clones was isolated by the commercial Wizard L Preps DNA Purification system (Promega), and digested with EcoR1 to determine the insert size. To determine if some of the gsr clones were related to the others, the insert DNA from {fraction (9/10)} clones was isolated, and labeled with 32P by a random priming DNA labeling. The DNA from all the gsr clones (except gsr II-14 and II-20) was digested with EcoR1, transferred from the agarose gels to a Nytran Plus filters (Schleicher & Schuell, Keene, N.H.) and the filters subjected to Southern blot analysis using the labeled insert DNA from the gsr clones. The hybridization pattern revealed that insert DNA from clones gsr I-3, II-3 and II-6 cross hybridized, while inserts of gsr I-6, II-1, II-2, II-4 and II-15 hybridized only with the parent clone. The status of clones gsr II-14 and gsr II-20 remains to be determined. Thus, at least six of the eight clones are independent clones. Clones gsr I-6, gsr II-1 and gsr II-2 were randomly selected for initial studies. DNA Sequence Analyses: λDNA from clones gsr I-6, II-1 and II-2 was digested with EcoR1 and the insert subcloned into vector pGEMEX-1 (Promega) whose reading frame at the EcoR1 cloning site is identical to λgt11. Competent E. coli JM 109 cells were transformed with the recombinant plasmid (pGEMEX plus insert from gsr clones). Plasmid DNA was isolated using Wizard Plus Minipreps (Promega), and used for automated sequencing with SP6 and T3 promoter specific primers flanking the multiple cloning site in the pGEMEX-1 followed by primer walking. The sequencing was performed by the NYU Medical Center core sequencing facility. The nucleotide sequences obtained were used in homology searches using the NCBI BLAST search (1). Nucleotide sequences for all 3 clones shared homology to known Mtb sequences. DNA sequence analyses of clones gsr I-6 (0.7 kb) and gsr II-2 (2.1 kb) showed 98% and 99% homology respectively to different regions of the same gene (Mtb cosmid MTV004.03c: nu 4314-13787, FIG. 4a). Clone gsr I-6 (nu 1-720) and gsr II-2 (nu 1-1903) showed homology to nu 5870-6590 and nu 2573-4476 of MTV004 respectively. A DNA fragment (152 bp) at the 3′ end of gsr II-2 showed only 60% homology to MTV004 (and several other regions on the mycobacterial genome) indicating that scrambling might have occurred during construction of the library. The gene product of MTV004.03 is a 3175 aa (309 kDa) member of the recently described PPE family of Gly-, Ala-, Asn-rich proteins (FIG. 4b). The peptides expressed in gsr I-6 and gsr II-2 represent aa 2400-2639 and 3104-3157 respectively in the C-terminal half of the MTV004.03 gene product (FIG. 4b). The PPE family of acidic proteins was described recently when the genome sequence of Mtb was analyzed (5). This family of proteins has 68 members, all of who possess a conserved N-terminal domain of 180 aa, and a ProProGlu (PPE) motif at positions 7,8 and 9. Based on the characteristics of the C-terminal portion, the PPE proteins fall into 3 groups, one of which (MPTR family) is characterized by the presence of multiple copies of the AsnXGlyXGlyXAsnXGly motif (5). Analyses of the protein encoded by MTV004.03 by FINDPATTERN revealed the presence of 65 tandem copies of this motif spanning the entire length of the protein in 5 clusters. The motif is repeated 6 times in the region encoded by clone gsr I-6. The sequence of gsr II-2 did not contain this motif (FIG. 4b). Clone gsr II-1 (2.14 kb) nucleotide sequence showed homology to Mtb cosmid Y336 (A# Z95586) region 22232-24371. Nucleotides 1-819 (273 aa) of gsr II-1 showed 96% homology to nu 22232-23050 (ORF MTCY336.28) of MTCY336 (FIG. 5a). This clone also showed homology to the RD3 region of M. bovis (24) which is represented by sequences with accession numbers U35017 (MBDR3S1) and U35018 (MBDR3S2). Nucleotides 1-819 of gsr II-1 showed 99% homology to nu 8370-9189 (ORF 3H) of MBDR3S1. The orientation of the sequence was established by restriction analysis. The gene product of MTCY336.28 is a 50 kDa protein with unknown function (FIG. 5b). The RD3 region has been described to be present in Mtb Erdman and M. bovis, but absent from BCG and BCG substrains Connaught, Pasteur and Brazil. Reactivity of the fusion proteins with sera from guinea-pigs with early TB: To determine the earliest time point post-infection at which these antigens are recognized by the infected animals, reactivity of the recombinant proteins of clones gsr I-6, II-1 and II-2 with individual guinea pig sera were tested. Western blots prepared from lysate from clone gsr I-6 were probed with the individual sera that were included in the pool used for immunoscreening of the library. The fusion protein band was strongly reactive with the sera obtained 1,3 and 4 weeks post-infection, and weakly reactive with the sera obtained 5 and 6 weeks post-infection. A pool of these sera failed to identify a corresponding sized protein in the control E. coli lysate. (FIG. 6a). The reactivity of lysate from clone gsr II-1 was evaluated with serum samples from 4 animals each, obtained at 1 and 3 weeks post-infection. (FIG. 6b). Three of the 4 sera at 1 week post-infection and 3 of the 4 sera at 4 weeks post-infection (total 6 out of 8 animals) showed reactivity with the fusion protein in the gsr II-1 lysate. The same sera were also tested for reactivity with the lysate of clone gsr II-2 (FIG. 6c). Three of the 4 sera obtained 1 week post-infection and all 4 samples at weeks 3 post-infection (total 7 out of 8 animals) showed reactivity with the fusion protein. Sera from 2 uninfected guinea pigs showed no corresponding reactivity with either of the lysates. Thus, the antigens encoded by all 3 clones tested showed reactivity with serum samples from animals bled during the early stages of disease progression (1-3 weeks post-infection). The same 8 sera from weeks 1 and 3 post infection were evaluated for reactivity with the 3 antigen preparations: (CS, SDS-CW and LAM-free CFP). In contrast to the results obtained with the serum pool comprising of sera from animals bled 1-8 weeks post-infection (used for library screening, FIG. 1), all 8 sera from animals bled 1 and 3 weeks post-infection failed to show reactivity with any antigen in the above preparations. However, some of the sera obtained 4-6 weeks post-infection, and the serum obtained 8 weeks post-infection showed reactivity with the three antigen preparations (data not shown). Validation of use the of guinea pig as model system for human TB: There are no markers to identify humans who have an active but subclinical infection with Mtb, which may be considered equivalent to the first few weeks post-infection stage of aerosol infected guinea pigs. Therefore, in order to validate the use of these proteins in studies of human immune responses, the following studies have been done: a. Comparison of antibody reactivity of tuberculous guinea pigs and pulmonary TB patients: Sera from 2 guinea pigs who were infected with aerosolized, virulent Mtb, and bled at 15 weeks post-infection, when they have advanced TB, were obtained from Dr. McMurray. The reactivity of these sera with the culture filtrate and cell-wall associated proteins of Mtb was assessed, and compared to reactivity of sera from 4 patients with confirmed pulmonary TB. Culture filtrate proteins and cell-wall associated proteins of Mtb were fractionated on SDS-PA gels, and the western blots probed with the human TB and guinea pig TB sera at a dilution of 1:100. As seen in FIG. 7, the protein bands in the two antigen preparations recognized by the human and animal TB sera were remarkably similar. Thus, at the advanced stage of active infection, tuberculous humans and guinea pigs have antibodies to the same antigens. While sera from only four TB patients have been studied to date, the finding that 4/4 patients showed similar reactivity to the reactivity observed with sera from tuberculous guinea pigs suggests that our hypothesis that the guinea pig is adequate as a model system relevant to human TB is tenable and worthy of further studies. b. Reactivity of human TB sera with gsr recombinant proteins: The reactivity of the fusion proteins from seven gsr clones with a pool of sera from 6 PPD positive, healthy individuals, and a pool from 6 TB patients was evaluated. (FIG. 8). Fusion proteins expressed in 5/7 clones were reactive with the pooled TB sera, but not the PPD pool. These results suggest that human TB patients have antibodies to the fusion proteins recognized by the guinea-pig sera. Individual sera from various cohorts have not been evaluated for reactivity with the fusion proteins because each of these β-gal-fusion proteins contains only a small fragment of the original mycobacterial protein, and these small fragments may not account for the immune response to this protein in every diseased individual. For example, the mycobacterial DNA fragment in gsr I-6 expresses only 240 aa of the total 3147 aa long PPE protein, and gsr II-2 expressed only 74 aa of the same protein. Thus, the two clones express ˜7.5% and 1.7% respectively, of the parent molecule. Positive reactivity of any fusion protein with human TB sera would indicate that the antigen is relevant to human TB. However, the small fragment of the mycobacterial antigen in the fusion protein lacks most of the regions/epitopes/conformations expressed by the parent molecules, and to which the patients are exposed. The absence of a significant portion of the original protein could provide false negative results when studying individual sera. Moreover, serum samples, especially the pre-clinical TB sera, are available in small amounts (100-200 μl). Thus, it would be unwise and premature to use these valuable sera to test reactivity with the fusion proteins. These sera are being saved for testing with the complete recombinant proteins once they are produced (EXAMPLE 3). This is the reason that more preliminary data with the serum panels available has not been generated. Nevertheless, the reactivity of the fusion protein in gsr1-6 was tested with individual sera from 3 PPD positive individuals, and 4 TB patients. Although the number of individuals tested is small, the reactivity of sera from several TB patients confirms that this protein is recognized during TB in humans (FIG. 9). In order to determine if these fusion proteins are also recognized during the early stages of disease progression, the reactivity of the fusion proteins from seven gsr clones with a pool of sera from 6 PPD positive, healthy individuals, and a pool from 6 HIV-pre TB sera was also evaluated. These pre-TB sera are retrospective, stored serum samples that were obtained from HIV-infected individuals prior to their developing clinical TB (cohort described in EXAMPLE 4) and represent the earliest stage of TB that can be diagnosed in humans. Fusion proteins from 2 clones (PPE protein encoded by gsr II-2 and the fusion protein encoded by clone gsrII-4) showed reactivity with the pool of the pre-TB sera, and not the pool of PPD control sera Whether the protein expressed by the remaining clones are genuinely not recognized by the pre-TB sera remains to be confirmed since this experiment was done at one serum dilution (1:200) (HIV-infected patients may have lower titers of antibodies) and will be repeated with more concenrated sera, and with complete proteins to confirm the negative results. The volumes of pre-TB sera available are very small (100-200 μl), and studies with individual pre-TB sera are performed only after the full-length proteins are expressed and purified. Such well defined sera are difficult to obtain, and we know of no other cohort that exists. Ongoing studies with the PPE protein: In order to determine the distribution of the PPE protein encoded by gsr I-6, genomic DNA from Mtb H37Rv, Mtb H37Ra, Mtb Erdman, clinical isolates CSU 11, CSU 17, CSU 19, CSU 22, CSU 25, CSU 26 and CSU 27, M. bovis, M. bovis BCG, M. africanum, M. microti, M. smegmatis, M. vaccae, M. phlei, M. chelonae, and M. xenopii was digested with Eco R1 and southern blofted. A PCR product corresponding to a 481 bp sequence of gene MTV004.03c was used to probe the southern blot. The gene for this PPE protein is present in all members of the TB complex, and all the clinical isolates tested but not in the non-TB mycobacterial species tested (FIG. 10). Currently more clinical isolates and non-TB mycobacterial species are being evaluated to confirm the specificity of this gene. This is continued and expanded as part of EXAMPLE 2. Several unsuccessful efforts have been made to detect the 309 kDa protein in the culture filtrates or cell wall preparations or sonicates of Mtb. Either this protein is not expressed/very poorly expressed during in vitro growth of Mtb, or is expressed by the bacteria but destroyed by the purification procedures used. Thus, in the case of the PPE protein, the hydrophobic nature (30% LVIFM) of the total protein could result in its being insoluble in aqueous solvents leading to its loss during antigen preparations. To localize the protein in the bacterial cell, high titer antibodies directed against the PPE protein are obtained. For this, the amino-acid sequence of the peptide from gsr I-6 and gsr II-2 has been subjected to Kyte and Doolittle analyses and two amino acid sequences with a high antigenic index identified. Summary of results: Sera from guinea pigs infected with airborne, virulent Mtb H37Rv, and bled within the first few weeks post-infection have been used to screen an expression library of Mtb DNA. Eight clones have been obtained by the immunoscreening. Of the 3 clones sequenced, two (gsr I-6 and gsr II-1) code for different portions of the same PPE protein, and clone gsr II-2 codes for a protein on the RD3 region of Mtb H37Rv. Thus, we have identified at-least 2 novel antigens that are expressed by the bacteria in vivo during the time when bacterial replication and dissemination is known to occur in this animal model. Preliminary studies suggest that sera from human TB patients have antibodies against the fusion proteins expressed by a majority of these clones. EXAMPLE II Identification of Mtb Antigens that are Expressed in vivo During Early Stages of the Disease In guinea pigs infected by aerosolized virulent Mtb, the in vivo replicating organisms express molecules which are recognized by the humoral immune system of the animals, resulting in antibody production. These antibodies, present in the sera of aerosol infected guinea pigs can be used to identify and obtain the antigens from the expression library. The approach was to obtain antigens expressed during the early stages of disease progression, sera from Mtb infected guinea pigs, obtained prior to the development of clinical disease. These sera are expectf provide information on the GC content, presence of leader peptides (peptides with high content of hydrophobic amino acids that are often associated with secreted proteins), organization of the genetic loci, etc and will enable the identification of at least some of the genes being expressed. EXAMPLE III Confirmation that Antigens Identified in Example II are Specific to Mtb, or Mtb Complex, and are Widely Present in Clinical Isolates The antigens identified by the immunoscreening may be specific to Mtb, to all members of the Mtb complex, to mycobacteria, or may be products of genes conserved in prokaryotes. Mtb possesses genes encoding proteins involved in house-keeping fimctions like general metabolism, signal transduction, enzymes, heat shock proteins etc that are conserved in prokaryotes. Mtb will also have genes encoding proteins that are also present in other mycobacteria, for example those involved in novel biosynthetic pathways that generate mycobacterial cell-wall components like mycolic acids (Ag 85 complex), lipoarabinomannans, mycocerosic acid etc. In addition the presence of genes encoding proteins specific to Mtb is likely. The sequencing of the Mtb H37Rv genome has revealed that of the ˜4000 open reading frames present, 20% of the encoded proteins resemble no other known proteins (5). Such specific antigens are likely to be important for diagnostic assays. Recent studies have reported that there can be genetic differences between clinical isolates of Mtb. Thus, the gene for mtp40 protein of Mtb was recently reported to be present in only some of the clinical isolates tested (42). Similarly, the gene encoding the antigen expressed by the clone gsr II-1 in the studies presented in the progress report has been reported to be present in only 16% of the clinical isolates of Mtb tested (24). Only antigens that are specific to Mtb or Mtb complex, yet are widely present in clinical isolates, are likely to be useful for diagnostic or vaccination purposes. It is therefore important to confirm that the gene for any immunogenic protein identified in EXAMPLE II is a) specific to Mtb or Mtb complex, and b) conserved in Mtb isolates from different geographical isolates. These studies are done by 2 approaches: a) Genomic DNA from members of the Mtb complex, clinical isolates of Mtb from different geographical locations, and other mycobacterial species are probed with genes identified in EXAMPLE II. Materials and Methods: Clinical isolates of Mtb from 25 patients from the V.A. Medical Center, Manhattan, 10 patients from the Lala Ram Sarup TB Hospital, New Delhi, India, and 15 patients from the Laboratoire De Sante Hygiene Mobile, Yaounde, Cameroon, Africa have been obtained. Efforts to obtain clinical isolates from patients in additional countries are on going. Thus, isolates from several different geographical regions are used in our studies. Other mycobacterial species (M. smegmatis, M. gordonae, M. chelonie, M. bovis BCG, M. xenopi, M. kansasi, M. fortuitum, M. africanum, M. microti etc.) have been obtained from the ATCC. 15-20 patient isolates of MAIS are obtained from the mycobacteriology laboratory at the VAMC, Manhattan. Non mycobacterial prokaryotes (E. coli, staphylococcus, streptococci, nocardia etc) are obtained either from the clinical microbiology laboratory at the VAMC, or from the ATCC. Genomic DNA from non-mycobacterial species are isolated by routine methods (35). For isolation of genomic DNA from mycobacterial species, standardized, published methods are used (3). Mycobacteria grown in Middlebrook 7H9 broth are harvested from cultures (2-3 days old for fast growers, 14-21 days for slow growers) and the pellet frozen overnight at −20° C., then thawed and suspended in TE buffer. An equal volume of chloroform/methanol (2:1) are added to the bacterial pellet for 5 min. to remove the cell wall lipids. The suspension is centrifuged, and the bacteria at the organic-aqueous interphase collected. These bacteria are then suspended in TE buffer, followed by 1M Tris-HCl to raise the pH before addition of lysozyme and incubation overnight. This is followed by addition of an appropriate amount of 10% SDS and proteinase K to the cell lysate. The proteins are extracted by Phenol/chloroform/Isoamyl alcohol extraction, the phenol removed by chloroform/isoamyl alcohol extraction, and the DNA precipitated by use of sodium acetate and Isopropanol. Hybridization and detection methods as per the ‘DIG System User's Guide for Filter Hybridization’ (Boehringer Manheim) are currently in use in the lab. The genomic DNA is digested with an appropriate restriction enzyme to completion and electrophoresed on agarose gels. The separated DNA fragments are transferred to Hybond-N positively charged membrane (Amersham) and the DNA crosslinked to the membrane by U.V. Specific fragments are obtained from the sequence of the relevant genes (from the Mtb genomic database) from genomic DNA of H37Rv by PCR, labeled with DIG and used to probe the blots prepared from the genomic DNA. Hybridization and washing conditions are optimized for each probe, and the chemiluminescent substrate CSPD used to detect hybridization. b) Antibodies raised against the mycobacterial peptides from antigens identified in EXAMPLE II are used to probe lysates of the same strains of bacteria by western blotting since it is possible that although the homology at the DNA level is not strong, the expressed proteins may be cross-reactive. To confirm that further studies are performed only with proteins that are specific to Mtb (or M. tb complex), and are conserved amongst clinical isolates of Mtb, the amino-acid sequence of the mycobacterial fragment in the β-gal fusion protein(s) are analyzed for regions that have high antigenicity. A mixture of chemically synthesized peptides representing 2-4 epitopes on each fusion protein are used obtain anti-peptide antibodies from rabbits (commercially). Anti-peptide antibodies are purified from the polyclonal rabbit serum by affinity purification and the antibodies tested to ensure that they recognize the parent fusion protein. Lysates of bacterial strains that were included in the DNA hybridization studies are fractionated by SDS-PAG electrophoresis and western blots probed with the anti-peptide antibodies. These experiments enable us to confirm that there are no cross-reactive proteins in the other bacterial species. These studies will enable us to identify the antigens of Mtb or Mtb complex, that are conserved in clinical isolates from different sources. As mentioned in the progress report, the methods involved in the completion of this aim are already being used in the lab and no problems are expected. The inclusion of M. smegnatis in the studies in EXAMPLE III is crucial because we intend to use this as the host for expression of the full genes of proteins of interest (see EXAMPLE 3) EXAMPLE IV Expression in a Mycobacterial Host of the Antigens Identified in the Screening of Examples II & III Expression cloning of the complete genes will provide the proteins that can be used for immunological studies. The recombinant clones obtained in EXAMPLE II all express β-gal fusion proteins (FIG. 2 and 3) which contain only a fragment of the original mycobacterial protein. For immunological studies, complete genes of these proteins will have to be expressed. There is increasing evidence that proteins of Mtb expressed in the E. coli host may show differences from the native counterparts. Thus, Mtb super-oxide dismutase expressed in E. coli was enzymatically inactive, whereas the same molecule expressed in M. smegnatis was enzymatically active (12). Reduced reactivity of human antibodies with recombinant 38 kDa protein, and 10 and 16 kDa proteins has been observed (41). We compared the reactivity of sera from the same TB patients with native Ag 85C and MPT 32 purified from culture filtrates of Mtb, and with the corresponding recombinant molecules expressed in the E. coli host (FIG. 11). Our studies showed that human antibodies to MPT 32 and Ag 85C, that were elicited by native antigens during natural disease show lower reactivity with the same proteins expressed in E. coli host (FIG. 11). Recent studies have shown that deglycosylation of MPT 32 decreases its capacity to elicit in vitro or in vivo cellular immune responses (32). That glycosylation has a role in proteolytic cleavage of proteins has also been shown for the 19 kDa antigen of Mtb, (17). Also, rMBP 64, expressed in E. coli was unable to elicit DTH in sensitized animals whereas the same protein expressed in M. smegmatis mimicked the native protein (31). The reasons underlying the differences in the immunological reactivity of native Mtb, and E. coli expressed recombinant molecules are not understood, but experience from several labs shows that mycobacterium proteins expressed in a mycobacterial host are immunologically more competent, probably because proteins expressed in E. coli lack the post-translational modifications often present on native Mtb antigens (15). Since vectors for efficient expression in M. smegmatis or M. vaccae have now been constructed and used successfully (11, 12, 15), and since the recombinant proteins obtained in EXAMPLE II are to be used for immunological studies with human sera, the antigens identified by the screening of the library are expressed in mycobacterial hosts to enhance the probability of obtaining proteins that are immunologically similar to the native antigens. Since we intend to express only those antigens that are specific to Mtb, the studies in EXAMPLE III will ensure that M. smegmatis does not have cross-reactive proteins or genes, the use of this organism as a host will not be a problem. Materials and Methods: Two vectors that have been used successfully to express Mtb proteins successfully in M. smegmatis have been obtained. Vector pVV16 has been obtained from Dr. John Belisle, CSU. This vector has the origin of replication from pAL5000, the hygromycin resistance gene, the hsp60 promoter, and, in addition, has 6 His-tag sequences at the C terminal end of the expressed protein. The 88 kDa protein, identified in our lab to be a potential candidate for serodiagnosis of TB has successfully been cloned into pVV16 and expressed in M. smegmatis (FIG. 12 A). The advantage with this vector is that the hsp60 promoter is a strong promoter resulting in high level constitutive expression of the cloned gene. Also, the His-tag allows the use of commercially available Nickel-Agarose columns (Qiagen) for purification of the cloned protein. The basic method for cloning specific genes into any expression vector is described (11). Briefly, PCR amplification of the target gene are performed using primers that contain restriction sites to generate in-frame fusions. The PCR product are purified and digested with the appropriate restriction enzymes and purified again. The vector DNA will also be cut with the appropriate restriction enzymes and purified. The PCR product and the vector are ligated, electroporated into DH5 and plated onto hygromycin containing plates overnight. Several antibiotic resistant colonies are grown in small volumes of medium, and the plasmid DNA isolated by miniprep. The size of the insert is checked in these colonies. Inserts from one or more colonies are sequenced to ensure fidelity of the amplified gene. For electroporation into M. smegmatis, the bacteria are grown shaking in 7H9 medium till an OD of 0.8-1.0 is obtained. The bacteria are harvested, washed twice with water, once with 10% glycerol and suspended in the same. An aliquot of the M. smegmatis cells is electroporated with the plasmid DNA from the colony whose insert was sequenced. The electroporated cells are grown for 34 hrs in 7H9, and plated on antibiotic containing plates. Several resistant colonies are grown in minimal media for 48-72 hrs. The bacterial cells are collected, frozen in liquid nitrogen overnight, thawed, suspended in PBS containing protease inhibitors, and sonicated in ice for 5 mins. After centrifuging the lysate for 30 mins at 5000 rpm, the supernatants are aliquoted and frozen. Five-10 ul of the lysate is fractionated on 10% SDS-PA gels, and western blots prepared from these gels are probed with anti-His antibodies to confirm the expression of the protein. The protein(s) are purified from the lysates by use of commercial Nickel-chelate-nitrilotriacetic acid (Ni-NTA) columns (Quiagen, Inc) (19). These columns allow the purification of proteins constituting <1% of the total cellular protein to >95% homogeneity in one step. Briefly, the M. smegmatis containing the cloned genes are grown in Middlebrook 7H9 medium for 72 hrs, after which the bacteria are pelleted by centrifugation and resuspended (1/100 volume) in PBS containing protease inhibitors (PMSF, DTT, EDTA). The bacterial cell pellet is frozen overnight in liquid nitrogen overnight, thawed and exposed to 1 mg/ml lysozyme for 30 mins (in ice). The pellet will then be sonicated and the lysate treated with RNase and DNase for 30 mins. The lysate will then be subjected to high speed centrifugation (>10, 000 g for 20 mins) and the supernatant mixed with an equal volume of slurry of Ni-NTA agarose in the appropriate buffer. The His-tagged protein is allowed to bind to the agarose for 60-90 mins in ice, the mix is loaded onto a column, and washed 2-3 times with buffer to get rid of unbound material. The bound protein will then be eluted by use of appropriate elution buffer. The purification procedures for His-tagged proteins may need to be modified for different proteins (19, 20), and the specific conditions for each protein is developed and optimized in consultation with Dr. John Belisle. As mentioned above, the 88 kDa protein of Mtb has been successfully cloned into this vector (FIG. 12A). Lysates of M. smegmatis mc2 alone and mc2 with the 88 kDa-pVV16 (10 μg/lane) were fractionated by SDS-PAGE and western blots probed with anti-His antibodies. The His-tagged 88 kDa recombinant protein is well expressed and easily detectable. One possible problem that may be encountered with one or more of the proteins cloned in this vector is that accumulation of foreign proteins can sometimes lead to toxicity to the host cell, or the recombinant protein forms inclusion bodies which necessitates denaturation of the protein for purification. An alternative vector, pDE 22 has been obtained from Dr. Douglas Young, imperial college, London. This vector is derived from a vector pSMT3 which has been used successfully for expression of 4 different Mtb proteins (11, 15), and also contains the pAL5000 origin of replication, the gene for hygromycin resistance, the hsp60 promoter and has the signal sequence from BCG alpha gene. In this case, the recombinant protein is secreted out of the host, and so toxicity to the host or inclusion body formation is not a problem. Moreover, this vector can also be used for expression in M. vaccae if required. The proteins cloned into pDE 22 are secreted out of the host, and the recombinant protein is present in the culture supernatants. One problem that may be encountered in the use of this plasmid is that the M. smegmatis host itself may express proteins that cross-react with the Mtb protein. To determine if cross-reacting extracellular antigens are present in culture filtrates of M. smegmatis, the organisms were grown in minimal media. The culture supernatants obtained after 24, 48 and 72 hrs of growth were concentrated 30-fold by Amicon filtration (10 kDa cut-off), 10 μgs fractionated on a 10% SDS-PA gel and 2 identical blots containing fractionated, concentrated culture filtrate proteins and LAM-free CFP (as positive control) probed with TB sera or healthy control sera. The TB sera recognized several proteins in the LAM-free CFP preparation, but no specific bands in the concentrated M. smegmatis culture filtrate (FIG. 12B). The healthy control sera showed no reactivity with either of the antigen preparations. These results show that M. smegmatis itself does not produce any extracellular proteins that cross-react with sera from TB patients. EXAMPLE V Assessing the Role of the Recombinant Proteins in Humoral Responses Antibodies to the recombinant antigens identified in EXAMPLES II and III are present in the sera of individuals with clinical and/or subclinical active TB. Scant information is available on the Mtb antigens that are expressed by the in vivo bacteria and are recognized by the human immune system during the early stages of disease progression. The guinea-pig sera used to obtain the antigens was from animals that had been infected with aerosolized, virulent, Mtb and bled before they developed the disease. The antibodies in the sera of the animals at this stage are directed against antigens that are expressed by the bacteria during this pre-clinical period of bacterial replication and dissemination. The profile of antigens of Mtb recognized by tuberculous guinea pigs and humans is very similar (FIG. 7). Moreover, human TB serum pools show reactivity with fusion proteins from several clones (FIG. 8). The fusion protein encoded by clone gsr 1-6 is recognized by sera from TB patients but not by sera from healthy controls (FIG. 9). The HIV-pre TB serum pool recognizes at least 2 of the antigens (FIG. 10). Together these results support the hypothesis that the antigens identified by guinea pig sera will also be recognized by the human TB sera. Evaluation of reactivity of proteins identified in this study with sera from patients at different stages of disease will enable us to determine which of these antigens is recognized by humans during early TB. Materials and methods: In order to determine the stage of TB infection at which antibodies to these antigens are present in humans, and their utility in serving as markers of active infection, antibodies to them are assessed in serum samples in the already existing cohorts in the lab. Sera from the following cohorts are available in the PI's laboratory. Sera from non-TB controls: Sera from 40 PPD positive and 60 PPD negative healthy controls are available in the laboratory. These sera are used as negative controls for assessment of antibodies to the recombinant antigens in the sera from TB patients at different stages of disease progression. Sera from ˜50 HIV-infected, asymptomatic individuals are also available, and are included as additional controls. Pre-TB and TB sera from HIV-infected individuals: We currently have sera from >50 HIV-infected patients who developed clinical TB {and >200 serum specimens from the same subjects that were obtainedprior to their developing TB (pre-clinical TB)}. These are HIV-infected individuals who were being regularly monitored for their T cell profiles, and developed clinical TB during the course of the HIV disease progression. Serum/plasma samples from each time when the T cell profiles were evaluated was saved, providing us with retrospective sera that were obtained prior to clinical manifestations of TB, that is, during pre-clinical disease (21). Chest X-ray reports, and microbiological data from these patients are also available]. This is the earliest stage of active infection that can be recognized in humans. Since these sera are from pre-clinical stages of tuberculosis, they should contain antibodies to the antigens expressed during early stages of tuberculosis disease progression. This is a unique, well-characterized and extremely valuable set of specimens which, to the best of our knowledge, does not exist anywhere else. Only with such a specimen bank could these studies be undertaken Sera from minimal TB patients: Serum samples from 20 patients with non-cavitary TB are available in the laboratory. A majority of these patients are also smear negative for Acid Fast Bacilli. These patients are at a relatively early stage of disease progression, defined as “early TB” or “early infection.” These patients are from the Manhattan VA Medical Center. Sera from additional patients with a similar clinical profile are obtained with informed consent, during the course of the studies. Sera from advanced TB patients: Serum samples from 60 cavitary, smear positive patients have been obtained from India and from about 20 similar patients from the Manhattan VA medical center. These sera represent samples obtained at an advanced stage of disease progression. Sera from HIV-infected individuals with M. avium bacteremia: The pre-TB sera are derived from HIV-infected patients. These patients are also at high risk for having M. avium infection. To further ensure the specificity of the antibody responses to the recombinant antigens, sera from 20 HIV-infected individuals who developed M. avium bacteremia, obtained at the time of disease manifestation, and in the months or years prior to the bacteremia (equivalent to the pre-TB and at-TB sera from HIV-TB patients) have also been obtained. These sera will also be used as negative controls. The sera in the above cohorts represent sera obtained at different stages of disease progression in humans. Reactivity of these sera with the purified proteins are assessed by ELISA. The method used is the same as described in our previous publications. Briefly, the recombinant antigens purified from M. smegmatis supernatants or lysates are used to coat the ELISA plates at a predetermined optimal antigen concentration overnight. Next morning, the plates are washed, blocked with PBS containing 5%BSA and 2.5% FCS for 2.5 hrs. This is followed by the addition of a predetermined optimal dilution(s) of the serum samples to the antigen-coated wells. After incubating the antigen coated wells with antibody containing sera for 90 mins, the plates are washed with PBS containing 0.05% Triton-X and then exposed to alkaline phosphatase-conjugated anti-human IgG, followed by the substrate for the enzyme. We routinely use the GIBCO-BRL amplification system as the substrate since it increases the sensitivity of antibody detection. Checker-board titration is used to determine the optimal antigen concentration, and serum dilution for each antigen. For MPT 32 and Ag 85C, as little as 50 μls per well of a 2 μg/ml suspension of the purified protein was required for optimal results. Mean optical density plus 2.5-3 SD with the sera from the healthy individuals is used as the cut-off to determine positive reactivity of patients. Reactivity with the guinea pig sera which were used for the initial immunoscreening of the λgt11 library is included as positive control. Studies with the above cohorts of sera will help to identify the antigens that are expressed by the in vivo M. tb, and recognized by the immune system during different stages of disease progression in humans. We expect that some antigens (that are expressed by the in vivo bacteria at all stages of disease progression) are reactive with antibodies from patients at all different stages of TB described in the cohorts above. Antibodies to these antigens are absent in various groups of negative controls (including the PPD+ healthy individuals). Such antigens are very useful for devising diagnostic tests since a single test could then be used to diagnose TB at any stage of the disease progression. However, the in vivo bacteria may express some antigens only during early stages of TB, and not during advanced TB. Such antigens would be recognized only by antibodies obtained during early TB, for example by the pre-TB sera from the HIV-infected individuals. Such antigens are useful for devising tests for identification of individuals who are at high risk of developing infectious TB. Reactivity of sera from a cohort of individuals at high risk of developing TB: Dr. J. J. Ellner, TB Research Unit (TBRU), Case Western Reserve University, had initiated studies with a cohort comprising of families with one or more index cases of confirmed TB during the last 2 years in Uganda. Three hundred and two families with at least one smear positive TB case are included in the study, with approximately 1200 household contacts. All contacts were evaluated for clinical TB, TB infection and underlying diseases that may predispose to TB at the time of inclusion into the study. Over the past year, 14 of the household contacts who did not initially have any signs and symptoms of TB have developed TB during follow up. Baseline sera (obtained at the time of inclusion into the study), and sera obtained during follow up from contacts who developed TB during the course of the study are evaluated for reactivity with the antigens obtained in EXAMPLE IV. An equal number of household contacts who did not develop TB, and are members of the same families are included in this testing as negative controls. Any additional contacts who develop TB during the course of the study will also be included in these studies. This longitudinal study is designed to determine which antigens can be used as surrogate markers for identification of individuals who are at a risk of developing TB in high-risk populations. The selection of the individuals and the sera, the number and appropriateness of the controls and the analysis of the data is done in consultation with Dr. Christopher Whalen, Epidemiology leader for the TB Research Unit. Cohort of recent converters of PPD reactivity: The VA assesses the PPD skin test reactivity of all employees and volunteers (1500 individuals) on an annual basis. Of these, ˜500 are baseline positive. All individuals working in the emergency room, medical intensive care unit and those involved in taling care of the TB patients are tested every six months. About 5-10 individuals convert to positive reactivity every year. The testing is done with 5 US units/test, of tuberculin obtained from Pasteur-Meriuex Corporation, and 10 mm or greater induration is considered positive. Sera from recent converters of PPD skin test are obtained with their informed consent. The reactivity of the sera obtained from recent converters with the recombinant antigens is determined by the above described methods, and compared to the reactivity with an equal number of long term PPD positive individuals. Since these individuals are employees of the hospital, both male and female individuals are included in the cohort. Summary: This study focuses on identifying, obtaining and studying the antigens of Mtb which are expressed by the bacterium during in vivo replication. No such antigens that are associated with early TB have been described before. The fact that one of the antigens we identified is a PPE protein is interesting, since other pathogens have similar proteins, which elicit cellular and humoral immune responses in their hosts, and also contribute to immune evasion by antigenic variation The studies of humoral responses elicited by these antigens contribute to the development of diagnostic assays. If, as in guinea-pigs, humans also recognize one or more of these proteins prior to clinical manifestation of TB, these antigens can be included in tests that can be used to screen large numbers of suspect individuals quickly. The detection of individuals with early, subclinical disease will enable clinicians to institute treatment to patients before they develop disease and become infectious. This will benefit not only the individuals themselves, but also contribute significantly to decreasing the transmission of the infection in the community. Literature References Cited in Examples I-V 1 Altschul, S. F., W. Gish, W. Miller, E. W. Myers, and D. J. Lipman. 1990. Basic Local Alignment Search Tool. J. Molecular Biology. 215:403-410. 2 Amara, R. R., and V. Satchidanadam 1996. Analysis of a genomic DNA expression library of mycobacterium tuberculosis using tuberculosis patient sera: evidence for modulation of host immune response. Infect. Immun. 64:3765-3771. 3 Belisle, J., and M. Sonnenberg. 1999. Isolation of genomic DNA from Mycobacteria, p. 31-44. In T. Parish and N. Stoker (ed.), Methods in Molecular Biology: Mycobacteria Protocols, vol. 101. Humana Press, London, UK. 4 Bothamley, G. H., R. Rudd, F. Festenstein, and J. Ivanyi. 1992. Clinical value of the measurement of Mycobacterium tuberculosis specific antibody in pulmonary tuberculosis. Thorax. 47:270-275. 5 Cole, S. T., R. Brosch, J. Parkhill, T. Garnier, C. Churcher, D. Harris, S. V. Gordon, K. Eiglneier, S. Gas, C. E. Barry III, F. Tekaia, K. Badcock, D. Basham, D. Brown, T. Chillingworth, R. Connor, R. Davies, K. Devlin, T. Feltwell, S. Gentles, N. Hamlin, S. Holroyd, T. Hornsby, K. Jagels, A. Krogh, J. McLean, S. Moule, L. Murphy, K. Oliver, J. Osborne, M. A. Quail, M. A. Rajandream, J. Rogers, S. Rutter, K. Seegar, J. Skelton, R. Squares, S. squares, J. E. Sulston, K. Taylor, S. Whitehead, and B. G. Barell. 1998. 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The humoral immune response in tuberculosis: its nature, biological role and diagnostic usefulness. Adv Tuberc Res. 21:1-78. 14 Grange, J. M. 1996. The natural history of tuberculosis, Mycobacteria and Human Disease, Second Edition ed. Oxford University Press, New York. 15 Harth, G., B.-Y. Lee, and M. A. Horwitz. 1997. High-Level Heterologous Expression and Secretion in Rapidly Growing Nonpathogenic Mycobacteria of Four Major Mycobacterium tuberculosis Extracellular Proteins Considered To Be Leading Vaccine Candidates and Drug Targets. Infect Immun. 65:2321-28. 16 Headley, V. L., and S. H. Payne. 1990. Differential protein expression by Shigella flexneri in intracellular and extracellular environments. Proc Natl Acad Sci USA. 87:4179-4183. 17 Herrmann, J., P. O'Gaora, A. Gallagher, J. Thole, and D. Young. 1996. Bacterial glycoproteins: a link between glycosylation and proteoltic cleavage of a 19 kDa antigen from Mycobacterium tuberculosis. EMBO J. 15:3547-3554. 18 Ho, R. S., J. S. Fok, G. E. Harding, and D. W. Smith. 1978. Host-parasite relationships in experimental airborne tuberculosis. VII. Fate of Mycobacterium tuberculosis in primary lung lesions and in primary lesion-free lung tissue infected as a result of bacillemia. J. Infect. Dis. 138:237-241. 19 Kneusel, R. E., J. Crowe, M. Wulbeck, and J. Ribbe. 1999. Procedures for the Analysis and Purification of His-Tagged Proteins. Methods in Molecular medicine. 13:293-308. 20 Kneusel, R. E., M. Wulbeck, and J. Ribbe. 1999. Detection and Immobilization of Proteins Containing the 6xHis Tag. methods in Molecular medicine. 13:309-321. 21 Laal, S., K. M. Samanich, M. G. Sonnenberg, J. T. Belisle, J. O'Leary, M. S. Simberkoff, and S. Zolla-Pazner. 1997. Surrogate marker of preclinical tuberculosis in human immunodeficiency virus infection: antibodies to an 88 kDa secreted antigen of Mycobacterium tuberculosis. J. Infect. Dis. 176:133-143. 22 Laal, S., K. M. Samanich, M. G. Sonnenberg, S. Zolla-Pazner, J. M. Phadtare, and J. T. Belisle. 1996. Human humoral responses to antigens of Mycobacterium tuberculosis:immunodominance of high molecular weight antigens. Clin. Diag. Lab. Immunnol. 4:49-56. 23 Li, Z., A. Howard, C. Kelley, G. Delogu, F. Collins, and S. Morris. 1999. Immunogenicity of DNA vaccines expressing tuberculosis proteins fused to tissue plasminogen activator signal sequences. Infect. Immun. 67:4780-4786. 24 Mahairas, G. G., P. J. SAbo, M. J. Hickey, D. C. Singh, and C. K. Stover. 1996. Molecular Analysis of genetic differences between Mycobacterium bovis BCG and Virulent M. bovis. J. Bacteriol. 178:1274-1282. 25 Mekalanos, J. J. 1992. Environmental signals controlling expression of virulence deterninants in bacteria. J. Bacteriol. 174:1-7. 26 Modun, B., P. Williams, W. J. Pike, A. Cockayne, J. P. Arbuthnott, R. Finch, and S. P. Denyer. 1992. Cell envelope proteins of Staphylococcus epidermis grown in vivo in a peritoneal chamber implant Infect Immun. 60:2551-2553. 27 Power, C. A., G. Wei, and P. A. Bretscher. 1998. Mycobacterial dose defines the Th1/Th2 nature of the immune response independently of whether immunization is administered by the intravenous, subcutaneous, or intradermal route. Infect. Immun. 66:5743-5750. 28 Ramakrishnan, L., N. A. Federspiel, and S. Falkow. 2000. Granuloma-Specific Expression of Mycobacterium Virulence proteins from the glycine-rich PE-PGRS family. Science. 288:1436-1439. 29 Raviglione, M. C., J. P. Narain, and A. Kochi. 1992. HIV-associated tuberculosis in developing countries: clinical features, diagnosis, and treatment. Bull World Health Organization. 70:515-526. 30 Raviglione, M. C., D. E. Snider, and A. Kochi. 1995. Global epidemiology of Tuberculosis: Morbidity and mortality of a worldwide epidemic. Jama. 273:220-226. 31 Roche, P. W., N. Winter, J. A. Triccas, C. G. Feng, and W. J. Britton. 1996. Expression of Mycobacterium tuberculosis MPT64 in recombinant Mycobacterium smegmatis: purification, immunogenicity and application of skin tests for tuberculosis. Clin. Exp. Imunnol. 103:226-232. 32 Romain, F., C. Horn, P. Pescher, A. Namane, M. Riviere, G. Puzo, 0. Barzu, and G. Marchal. 1999. Deglycosylation of the 45/47-Kilodalton Antigen Complex of mycobacterium tuberculosis Decreases It;s capacity To Elicit In Vivo or in Vitro Cellular Inimunce Responses. Infect. Immun. 67:5567-5572. 33 Sada, E., P. J. Brennan, T. Herrera, and M. Torres. 1990. Evaluation of lipoarabinomannan for the serological diagnosis of tuberculosis. J. Clin Microbiol. 28:2587-2590. 34 Sada, E., L. E. Ferguson, and T. M. Daniel. 1990. An ELISA for the serodiagnosis of tuberculosis using a 30,000-Da native antigen of Mycobacterium tuberculosis. J. Inf Dis. 162:928-931. 35 Sambrook, J., E. F. Fritsch, and T. Maniatis. 1989. Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 36 Skurnik, M., and P. Toivanen. 1993. Yersinia entercolitica lipopolysaccharide: genetics and virulence. Trends Microbiol. 1:148-152. 37 Smith, D. W., D. N. McMurray, E. H. Wiegeshaus, A. A. Grover, and G. E. Harding. 1970. Host parasite relationships in experimental airborne tuberculosis IV. Early events in the course of infection in vaccinated and nonvaccinated guinea pigs. American Rev. of Respiratory Disease. 102:937-949. 38 Smith, D. W., and E. H. Wiegenshaus. 1989. What Animal Models Can Teach Us About the Pathogenesis of Tuberculosis in Humans. Reviews of Infect. Dis. 2:s385-s393. 39 Sonnenberg, M. G., and J. T. Belisle. 1997. Definition of Mycobacterium tuberculosis culture filtrate proteins by two-dimensional polyacrylarnide gel electrophoresis, N-terminal amino acid sequencing and electrospray mass spectrometry. Infect. Immun. 65:4515-4524. 40 Triccas, J. A., F.-X. Berthet, V. Pelicic, and B. Gicquel. 199. Use of fluorescence induction and sucrose counterselection to identify Mycobacterium tuberculosis genes expressed within host cells. Microbiology. 145:2923-2930. 41 Verbon, A. 1994. Development of a serological test for tuberculosis. Trop Geo Med. 46:275-279. 42 Weil, A., B. Pikaytis, W. Butler, C. Woodley, and T. Shinnick. 1996. The mtp40 gene is not present in all strains of Mycobacterium tuberculosis. J. Clin. Microbiol.:2309-2311. 43 Wiegeshaus, E. H., D. N. McMurray, A. A. Grover, G. E. Harding, and D. W. Smith. 1970. Host-parasite relationships in experimental airborne tuberculosis III. Revelance of microbial enumeration to acquired resistance in guinea pigs. Am. Rev. Respir. Dis. 102:422-429. 44 Young, D. B., S. H. E. Kaufinann, P. W. M. Hermans, and J. E. R. Thole. 1992. Mycobacterial protein antigens: a compilation. Mol. Microbiol. 6:133-145. 45 Young, R. A., B. R. Bloom, C. M. Grosskinsky, J. Ivannyi, D. Thomas, and R. W. Davis. 1985. Dissection of Mycobacterium tuberculosis antigens using recombinant DNA. Proc. Natl. Acad. Sci. USA. 82:2583-2587. EAMPLES VI-XIII Parts of the studies described in Examples VI-XIII below were also published in K. K. Singh, X. Zhang, A. Sai Patibandla, P. Chien and S. Laal: Antigens of Mtb Expressed During Pre-Clinical TB: Serological Immunodominance of Proteins with Repetitive Amino Acid Sequences, Infec. Immun. 69:4185-4191 (1991), which is incorporated by reference in its entirety. References cited in these Examples as numbers in parentheses are listed following Example XIII. EXAMPLE VI Materials and Methods Serum samples from rabbits: Six pathogen-free rabbits (2.5 to 2.7 kg, Covance Research Products, Inc., Denver, Pa.) were infected by aerosols of Mtb H37Rv and another six were similarly infected by aerosol of Mtb CDC 1551 at the US Army Medical Research Institute of infectious Diseases, F. Detrick, Frederick, Md. (10). After infection, the rabbits were maintained in the BL3 facility at George Washington University, Washington, DC. The infected rabbits were bled 5 weeks post-infection when they were euthanized for determination of tubercles in their lungs (6). All 12 rabbits showed the presence of tubercles, confirming that all animals had been successfully infected. Also, there was no significant difference in the numbers of tubercles, or in the bacterial loads in the tubercles, between the rabbits infected by the H37Rv or CDC1551 strains(6). Sera from 3 normal (uninfected) rabbits was obtained as controls. Serum samples from Humans: Sera were obtained from the following groups of individuals: a) 5 PPD sldn test positive, healthy individuals. Three of the 5 individuals were BCG vaccinated, and all 5 would also be potentially exposed to the bacteria since they were individuals working in the laboratory or were clinicians working in the VA Infectious Disease Clinic. b) 10 HIV-infected patients: This patient cohort has been described earlier (24). Briefly, these were HIV-infected individuals who were routinely being monitored for their CD4 numbers, and developed TB during the course of HIV disease progression. At each time point when they were bled for evaluation of the T cell numbers, plasma from these patients had been saved and frozen. Thus, when they developed TB, it was possible to identify and obtain the retrospective, pre-TB sera. Multiple samples from each individual are available, but for the current study, one randomly chosen pre-TB serum obtained around 6 months prior to clinical TB was used for each individual. c) 2 TB patients with early disease: These were smear negative, culture positive TB patients with infiltration in their lungs but no radiological evidence of cavitary lesions. d) 5 TB patients with advanced disease: These were smear positive TB patients with extensive cavitary lesions. Mtb H37Rv antigen preparations : Two antigen preparations of Mtb H37Rv, lipoarabinomannan (LAM)-free culture filtrate proteins (LFCFP), and SDS-soluble cell-wall proteins (SDS-CWP) were tested in the study. The preparation of these antigens has been described previously (25). The former antigen preparation contains >100 different proteins, some of which (˜30%) have been mapped on the basis of reactivity with murine monoclonal antibodies or peptide sequencing (41). The latter preparation contains˜estimate different proteins but these have not been mapped as yet. Immunoscreening of Mtb λgt11 library: Mtb λgt11 expression library was obtained from the World Health Organization (47). The library contains random sheared fragments of Mtb H37Rv DNA cloned into gt11 phage that expresses the foreign insert DNA as E. coli β-galactosidase (β-gal) fusion protein. Immunoscreening of expression library was performed by standard methods (47). Briefly, E. coli Y1090 was infected with phage from the library and plated in top agar on LB plates. After 2.5 h incubation at 42° C., expression of recombinant proteins was induced by overlaying the plates with Isopropyl β-D thiogalactoside (IPTG, Sigma) saturated nitrocellulose filters for 2.5 h at 37° C. The filters were removed, washed and probed with 1:50 dilution of a serum pool from the above described 12 infected rabbits. The serum pool was absorbed extensively with an E. coli lysate before use. The recombinant phages producing positive signals were cloned and designated as AD clones. Western Blot analysis: This was used both for evaluating reactivity of the rabbit sera with the LFCFP and the SDS-CWP preparations, as well as characterization of the recombinant proteins expressed by the AD clones. Briefly, the Mtb antigen preparations were fractionated on 10% SDS-PA gels, and the western blots probed with serum pools from Mtb infected or uninfected rabbits. The blots were washed with PBS, and blocked with PBS containing 3% BSA for 2 h. After washing the blots with PBS-2% Tween 20 (PBST), they were incubated overnight with the rabbit pools described at a dilution of 1:60 in PBST-1% BSA at 4° C. after which they were washed with PBST and exposed to 1:2000 dilution of alkaline phosphatase-conjugated goat anti-rabbit IgG (Sigma, St Louis, Mo.) for 1.5 h. Extensively washed blots were developed with BCIP-NBT substrate (Kirkegard & Perry Labs, Gaithersburg, Md.). For the recombinant protein studies, lysogenic strains were prepared from phage clones in E. coli Y1089 (37). Single colonies from lysogens were grown in LB medium at 32° C. till midlog (optical density of 0.5 at 600 nm), induced at 45° C. for 20 min and followed by addition of IPTG (10 mM) and further incubation at 37° C. for 1 h. The bacterial pellets obtained were sonicated in a small volume of PBS containing 1 mM of DTT, EDTA and PMSF, and the lysates fractionated on 10% SDS-PAGE gels. The western blots were probed as described above with the serum pool from infected rabbits (1:200), or with a pool of sera from uninfected rabbits (1:200) or with murine anti-β-gal monoclonal antibody (1:10,000) (Promega), or with human sera (1:100-1:700) and the appropriate alkaline phosphatase-conjugated IgG secondary antibody. Lysates from E. coli Y1089 lysogenized with λgt11 phage without insert were included as controls. Isolation, sequencing and computer analysis of DNA from recombinant λgt11 clones: DNA from recombinant λgt11 clones was isolated by using Qiagen λ DNA purification kit (Qiagen, Valencia, Calif.), digested with EcoRI for release of mycobacterial DNA insert, and the insert DNA purified by extracting from low melting agarose gel with QIAquick gel extraction kit (Qiagen,). The purified EcoRI insert DNA was subcloned into vector pGEMEX-1 (Promega, Madison, Wis.) at the EcoRI site and the recombinant plasmid transformed into JM 109 competent cells. The recombinant plasmid DNA was isolated using Wizard plus minipreps kit (Promega), and used for sequencing with SP6 and T3 promoter primers flanking the multiple cloning site in pGEMEX-1. The sequence similarity analysis of the DNA sequences was performed by BLAST using the National Center for Biotechnology Information site (NCBL USA). The repetitive structures in the protein were analyzed by using Statistical Analyses of Protein sequences (SAPS). Prediction of trans-membrane helices was performed by TMpred software using ISREC server at European Molecular Biology Research network-Swiss node site. The prediction of signal peptide and signal peptidase cleavage sites were performed by the SignalP V2.0 software using neural networks (NN) and hidden Markov models (HMM) trained on gram positive bacteria, available from Center for Biological Sequence Analyses (CBSA, Denmark). The glycosylation sites were predicted by using the NetOGlyc 2.0 software also available from the CBSA. The Kyte & Doolittle hydrophobicity plot and theoretical molecular weight and pI of the proteins were performed by using software from ExPASy site. Prosite profile scan was performed by ISREC server at Swiss Institute for Bioinformatics (SIB). EXAMPLE VII Reactivity of Mtb Infected Rabbit Serum Pool with LFCFP and the SDS-CWP Preparations Studies with other intracellular bacterial pathogens suggest that the first crucial steps towards establishment of the infecting organism, adhesion and invasion, are likely to be mediated by extracellularly expressed or cell surface associated proteins of the pathogen (21, 22, 32). To determine if any antigens in the culture filtrates or cell-wall preparations of Mtb are recognized by antibodies from the infected rabbits at 5 weeks post-infection, a pool of sera from all 12 rabbits was used to probe the LFCFP and SDS-CWP preparations (FIG. 13), and the reactivity compared with a pool of sera from 3 uninfected rabbits. Three bands corresponding to ˜27.5 kDa, 35.5 kDa and 56 kDa in LFCFP preparation were reactive only with the serum pool from the infected rabbits, as were two bands corresponding to 27.5 kDa and 43 kDa in the SDS-CWP preparation (FIG. 13, lane 3 and 5). The serum pool from the infected rabbits was absorbed extensively against a lysate of E. coli Y1090 and used to screen the λgt11 expression library of Mtb H37Rv genomic DNA (47). EXAMPLE VIII Screening of the λgt11 Library and Characterization of the Recombinant Proteins To obtain the antigenic proteins that are recognized by antibodies in the sera from the Mtb infected rabbits, ˜1.2×105 pfu from the library were screened with the serum pool. Seven clones were plaque purified, and designated AD1, AD2, AD4, AD7, AD9, AD10, and AD16. Lysates prepared from cultures of single colonies of lysogens of all 7 AD clones were fractionated on 10% SDS-PAGE, and the western blots probed with the rabbit serum pools from infected or uninfected rabbits, or mouse anti-β-gal monoclonal antibody. As shown in FIG. 14, all 7 recombinant clones produced β-gal fusion proteins, with sizes ranging from 125 kDa to 170 kDa, which were recognized both the anti-β-gal mAb (FIG. 14 lanes 2-8) and with the rabbit serum pool from the infected rabbits (FIG. 14, lanes 20-26). The recombinant fusion proteins failed to react with the serum pool prepared from uninfected rabbits (FIG. 14, lanes 11-17). DNA Sequence and Protein Analyses Restriction digestion 5 of the 7 clones with EcoRI yielded single insert ranging from 3.7 kb to 5.6 kb. The remaining clones had multiple inserts. This manuscript reports the results obtained with the five clones with single EcoR1 inserts. Sequencing of the EcoRl inserts of the 5 clones after subcloning into PGEMEX-1 resulted in sequencing of about 450-700 bp nucleotides from each end. Orientation of the insert in the AD clones were determined by restriction map analysis (data not shown). EXAMPLE IX Sequence Analyses of Clones AD1 and AD2 DNA sequence analyses of both ends of EcoR1 insert of clones AD1 (5.1 kb) and AD2 (4.6 kb) showed 98% identities to different regions of two overlapping cosmids MTV026 and MTCY409. One end of the insert of clone AD1 (nu 1-440) showed homology to nu 23458-23740 of cosmid MTV026 and nu 1-207 of overlapping cosmid MTCY409 while the other end (nu 4530-5154) showed homology to nu 4297-4921 of cosmid MTCY409 (FIG. 15A). Similarly, one end of the insert of clone AD2 (nu 1-610) showed homology to nu 23227-23740 of cosmid MTV026 and nu 1-146 of cosmid MTCY409 while the other end (nu 3958-4620) showed homology to nu 3494-4156 of cosmid MTCY 409 (FIG. 15A). Restriction map analysis showed that the ends of the inserts of clones AD1 and AD2 which showed homology with cosmid MTV026 was in correct reading frame with β-gal. The peptide expressed in clones AD1 (nu 1-123) and AD-2 (nu 1-354) represents amino acids 245-284 and 168-284 respectively in the C-terminal region of Rv3810 (pirG) gene product. The protein encoded by the Rv3810 (pirG) is a 284 amino acid cell surface protein precursor, which is almost identical (99.3% identity in 284 aa overlap) to previously described cell surface protein ERP (exported repetitive protein) of Mtb (4) and secreted antigen p36/p34 (5) of M. bovis. This gene also shows 53.4% identity to a M. leprae gene for a 28 kDa protein (7). As reported earlier, the ERP protein has 12 tandem repeats of five amino acid PGLTS in the central region from position 92 to 173. The theoretical molecular weight and pI of the protein are 27.6 kDa and 4.34 respectively, although the molecular weight of the native molecule was reported to be 36 kDa (3). The protein has a typical N-terminal signal sequence with a possible signal peptidase cleavage site at position 22. The Kyte-Dolittle plot demonstrated hydrophobic regions in the N-terminal and C-terminal portion of the protein which have no repeat motifs and a hydrophilic central portion which contains all the repeat motifs. EXAMPLE X Sequence Analyses of Clone AD9 DNA sequence analyses of both ends of EcoR1 insert of clone AD9 (4.9 kb) showed 94% identities to different regions of cosmid MTV004. One end of the insert (nu 1-540) showed homology to nu 36201-36740 and other end (nu 4364-4921) to nu 40564-41121of the cosmid (FIG. 15B). Restriction map analysis showed that the end of the insert of clone AD9 which is in correct reading frame with β-gal, starts within the gene Rv 3367 (PE-PGRS). The peptide expressed in clone AD9 (nu 1-1080) represents amino acids 230-588 in the C-terminal region of Rv3367 (PE-PGRS) gene product (FIG. 16). The protein encoded by the Rv3367 (PE_PGRS) is a 588 amino acid protein, which is a member of recently described PE-PGRS family of glycine-rich Mtb proteins (9). This protein possesses the highly conserved N-terminal domain of ˜110 residues and Pro-Glu (PE) motif near the N-terminus described to be characteristic of the PE protein family (9). The gene product of Rv3367 showed the presence of 39 tandem copies of motif Gly-Gly-Ala/Asn and 43 tandem copies of motif Gly-Gly-X (total 82 repeats) spanning the entire protein except the conserved N-terminal region (FIG. 16). The deduced amino acid sequence encoded by clone AD9 contains 61 repeats of the motifs. Amino acid analysis of Rv3367 by SAPS predicted five other possible repetitive motifs, Gly-Asn-Gly-Gly-Asn-Gly-Gly, Gly-Asn-Gly-Gly-Ala-Gly-Gly, Asn-Gly-Gly-Ala-Gly-Gla-Asn,Gly-Gly-Ala-Gly-Gly-Ala and Gly-Ala-Gly-Gly-Asn-Gly-Gly in the region extending from aa 137-542. The theoretical molecular weight and pI of the protein are 49.7 kDa and 4.05 respectively. This protein has a high content of Gly (38.32%), Ala (16.26%) and Asn (8.97%). The homology search showed 50-55% homology to most of the members of PE-PGRS family of Mycobacterium tuberculosis H37Rv. This protein also displayed homology with a glycine rich cell-wall structural protein of Phasiolus Vulgaris (42% identity in 483 aa overlap). The Kyte-Dolittle plot demonstrated a hydrophobic region in N-terminal portion of the protein with no repeat motif clusters, and a hydrophilic C-terminal which has the majority of the repeat motifs. A N-terminal signal peptide with a putative signal peptidase cleavage site between aa 44 and 45, and two putative O-glycosylation sites at positions 221 and 438 are predicted to be present in the protein. TMpred analysis predicted five transmembrane helices at aapositions 24-43, 166-186, 194-218, 351-368 and 431-451. EXAMPLE XI Sequence Analyses of Clone AD10 DNA sequence analyses of both ends of EcoR1 insert of clone AD10 (3.7 kb) showed 94% identities to different regions of cosmid MTY25D10. One end of the insert of clone AD10 (nu 1-623) showed homology to nu 17037-17659 and other end (nu 3147-3742) to nu 20183-20778 of cosmid MTY25D10 (FIG. 15C). Restriction map analysis showed that the end of the insert of clone AD10 which is in correct reading frame with β-gal, starts within the gene Rv0538. The peptide expressed in clone AD10 (nu 1-636) represents amino acids 338-548 in the C-terninal region of Rv0538 gene product (FIG. 17). The protein encoded by Rv0538 is a 548 amino acid hypothetical protein with a repetitive proline and threonine-rich region at C-terminal (proline threonine repetitive protein, PTRP). Amino acid analysis of Rv0538 (PTRP) gene product showed the presence of 23 tandem repeats of motif Pro-Pro-Thr-Thr in C-terminal region from position 415 to 495, with positions 2, 3 and 4 being better conserved as compared to position 1. The deduced amino acid sequences encoded by clone AD10 contains all 23 repeats of the motif (FIG. 17). SAPS amino acid analysis of Rv 0538 (PTRP) gene revealed 7 tandem repeats of motif Thr-Thr-Pro-Pro-Thr-Thr-Pro-Pro-Thr-Thr-Pro-Val from aa 413 to 489. The theoretical molecular weight and pI of the protein are 55 kDa and 4.44 respectively. This protein has a high content of Proline (15.63%), Alanine (15.23%), Threonine (12.83%) and valine (11.42%) with two proline rich regions at aa positions 334-340 and 387-464. No signal peptide appears to be present but four transmembrane helices at aa positions 97-114, 198-218, 278-299 and 379-398 and 50 putative O-glycosylation sites, mostly at C-terminal, are predicted. The Kyte and Doolittle plot shows the presence of seven short hydrophobic regions in the protein. Homology searches showed 100% identity in C-terminal region to a 295 aa (29.4 kD) hypothetical Mycobacterium bovis protein and 40% identity in 226 aa overlap to a probable cell wall-plasma membrane linker protein of Brassica napus. EXAMPLE XII Sequence Analyses of Clone AD16 DNA sequence analyses of both ends of EcoR1 insert of clone AD16 (5.6 kb) showed 98% identities to different regions of cosmid MTY20B11. One end of the insert of clone AD16 (nu 1-628) showed homology to nu 24404-23777 and other end (nu5028-5646) showed homology to nu 19377-18759 of cosmid MTY20B11 (FIG. 15D). Restriction map analysis showed that the end of the insert of clone AD16 which is in correct reading frame with β-gal, starts within the gene Rv3246c (mtrA). The peptide expressed in clone AD16 (nu 1-216) represents amino acids 157-228 in the C-terminal region of Rv3246c (mtrA) gene product. The protein encoded by the Rv 3246c is a 228 amino acid MtrA response regulator protein, a putative transcriptional activator, which is identical (100% identity in 225 aa overlap) to previously described response regulator protein MtrA of a putative two-component system, mtrA-mtrB of Mtb H37Rv (44) and similar (55.2% identity in 221aa overlap) to M. bovis regX3 [#1838). A homolog of the Mtb MtrA protein was also identified in cell wall fraction of M. leprae (30). The theoretical molecular weight and pI of the protein are 25.2 kDa and 5.34 respectively. The Kyte and Doolittle plot showed presence of hydrophobic region in the N-terminal of the protein. EXAMPLE XIII Reactivity of Recombinant Proteins with Sera from Individuals with TB at Different Stages of Disease Progression In order to determine if the antigens identified by sera from aerosol infected rabbits were expressed during human infection with Mtb, their reactivity with sera from TB patients was evaluated. Initially pooled sera from individuals at different stages of disease progression were used. The fusion proteins of PE-PGRS protein (FIG. 18A), the PTRP (FIG. 18B) and the MtrA (FIG. 18C) were strongly reactive with pooled sera from the pre-TB patients. The PE-PGRS protein was also well recognized by the serum pools from non cavitary and the cavitary TB patients (FIG. 18A), but the PTRP and the MtrA fusion proteins showed poorer reactivity with these serum pools (FIG. 18B and D). In contrast, the pirG (ERP) fusion protein reacted only with the serum pool from the cavitary TB patients (FIG. 18C). Since the pre-TB serum pools showed reactivity with fusion proteins of three of the four antigens, reactivity with pre-TB sera from 10 individual patients and 3 PPD positive controls was assessed. All 10 pre-TB sera recognized the PE-PGRS (FIG. 19A) and PTRP (FIG. 19B) fusion proteins, whereas 6 of the 10 patients had antibodies to the MtrA fusion protein (FIG. 19C). None of 10 patients showed reactivity with the pirG (ERP) fusion protein when tested individually (data not shown). DISCUSSION OF EXAMPLES VI-XIII The rabbit model of TB closely resembles TB in immuno-competent humans in that both species are outbred, both are relatively resistant to Mtb, and in both the infection may or may not progress to form liquified foci and cavities(6). The paucity of human material available for study of immunological events occurring after inhalation of virulent bacilli necessitates the use of animal models for these studies. The sera used in this study was obtained from rabbits at 5 weeks post-infection because earlier studies have shown that the logarithmic multiplication of inhaled Mtb within the lungs of infected rabbits slows down at about 3 weeks post-infection, and the 4th week onwards, the numbers of cultiviable bacilli decrease (11). Thus, immune responses that can inhibit the intracellular multiplication of inhaled Mtb are first recognized at 4-5 weeks post-infection. Using antibodies in these sera as markers of antigens expressed in vivo, 4 antigens from the Mtb expression library were recognized. Two of these are novel proteins, one is a member of PE-PGRS family of proteins and the other is a protein with proline threonine repeats (PTRP). The other proteins identified in this study, the pirg (ERP), and the MtrA were previously identified by other methodologies, although their role in natural infection and disease progression has not been explored (4, 44). Interestingly, all four proteins identified by the use of early post-infection sera are either known to be, or have signatures of, surface or secreted proteins of Mtb. Thus, the pirG (ERP) protein has been shown to be a cell surface-exposed protein that is expressed by the bacteria during residence in the phagosomes of in vitro maintained macrophages (3). The cellular location of the Mtb MtrA is not known, but the homolog of MtrA was isolated from cell walls of M. leprae (30). This cell surface location of the Mtb MtrA is consistent with its proposed role as response regulator of a putative two component system mtrA-mtrB (44). The PE-PGRS protein has a hydrophobic N terminal, a putative N-terninal signal peptide and 5 transmembrane regions, suggesting that the protein is either secreted or cell surface associated. The prediction of four transmembrane domains and seven short hydrophobic regions suggests that the PTRP protein is also likely to be a cell surface protein. Recent analysis of ˜4000 open reading frames from the genome sequence to predict their subcellular location showed that in contrast to B. subtilis, Mtb has 4-fold more proteins with extremely basic pIs (42). In contrast, all 4 proteins identified in this study have acidic pIs ranging between 4-5. Since the ERP and the MtrA are known to be expressed during intracellular residence (3, 44), these observations raise the possibility that the PTRP and the PE-PGRS protein identified in this study may also be expressed (or upregulated) under similar conditions. This hypothesis is further strengthened by the observation that pre-TB sera had antibodies to both the proteins. Since the pre-TB sera were obtained from the patients 6 months prior to clinical manifestation of TB, and since none of these patients had cavitary lesions even at the time of clinical confirmation of TB, the bacteria replication would be intracellular during the pre-TB stage in these patients. It is also interesting that 3 of the 4 antigens identified in this study are repetitive proteins. Proteins with tandem repetitive motifs are found in several eukaryotic (1, 20, 23, 27, 35) and prokaryotic organisms (13, 16, 17). In fact, a vast majority of gram-positive cell wall associated proteins have tandem repeats of amino acid sequences, which are associated with binding domains for host cell ligands. In many instances, the ability to alter the numbers of the repetitive domains contributes to antigenic variation and to adapting to environmental changes (22). Many of the repetitive proteins are anchored on the cell-wall by the C terminal region containing the LPXTGX motif, but others that may be anchored by charge and/or hydrophobic interactions have been reported (15). The C-terminal portion of another member of the PE-PGRS family (Rv1759c) of Mtb has recently been shown to bind fibronectin (14), and an M. leprae 21 kD surface protein with 11 repeats of XKKX motif at the C-terminal has been shown to bind the laminin-2 of peripheral nerves, thus facilitating the entry of the bacilli into Schwann cells. (38). In addition, the heparin binding hemagglutinin (HBHA) of Mtb that has been shown to be an adhesin which binds to epithelial cells via the Pro/lys repeats in the C-terminal region (31, 33). The PTRP (Rv 0538) is structurally similar to these proteins in having the repetitive regions clustered in the C-terminal region, suggesting that it may have a similar fUnction. The PE-PGRS (Rv3367) protein belongs to the PE family of proteins which is one of the two large, clustered multigene families of glycine-rich acidic proteins discovered when the genome sequence of Mtb was determined (9). Some information is now available regarding expression, subcellular location and function of the PE_PGRS family proteins (14, 34). Thus, the fibronectin-binding PE-PGRS protein encoded by Rv 1759c (described above) has been reported to be absent from antigen preparations made from bacteria grown in bacteriological media (14), although the presence of antibodies in patient sera confirm its in vivo expression. Also, PE-PGRS proteins of M. marinum, homologous to Mtb PE-PGRS proteins (Rv3812 and Rv1651c) have been shown to be induced in cultured macrophages as well as in frog granulomas (34). Although, no protein band of the molecular weight corresponding to the PE-PGRS (Rv3367) protein (49 kDa) was observed in the LFCFP and SDS-CW (FIG. 13), whether this protein is really not expressed during in vitro growth, or is expressed very poorly, or is destroyed during the preparation of the LFCFP and the SDS-CWP remains to be determined. The presence of antibodies in sera from TB patients to all the four proteins identified, and their absence in the sera from PPD positive healthy individuals shows that these proteins are expressed by the in vivo Mtb only during active infection in humans. The mtrA promoter has earlier been shown to be upregulated/activated upon entry and incubation of Mtb in macrophages (44) and the presence of anti MtrA antibodies in pre-TB and non-cavitary TB sera suggests that it is expressed in vivo during intracellular bacterial replication. The β-gal fusion proteins of PE_PGRS and PTRP were also well recognized by the pre-TB sera. We have earlier shown that an 88 kDa culture filtrate protein is recognized by antibodies in the pre-TB sera of about 75% of the HIV-infected TB patients (24). Thus, along with the 88 kDa protein, these 3 proteins may be useful for developing surrogate markers for identifying HIV and Mtb co-infected individuals who are at a high risk of reactivating latent TB. Such markers have the potential to make significant contribution to tuberculosis control in countries with high incidence of co-infection. Earlier studies have shown that antibodies to the ERP homologs are present in M. bovis infected cattle, and in leprosy patients (5). Our results show that cavitary TB patients have antibodies to β-gal fusion protein of the ERP, but the sera from non-cavitary TB patients and the pre-TB sera did not show reactivity even when individual patients were tested (data not shown). It is possible that in the human tissue environment, this protein is not well-expressed, and therefore is immunogenic only when the bacterial load is high. In summary, we have identified 4 antigenic proteins of Mtb that are immunodominant during the early phase of an active Mtb infection. All the antigens appear to be surface proteins, and their involvement in bacillary adhesion and/or invasion is currently under investigation. Three of the 4 antigens are potential candidates for devising immunodiagnostic tests for identification of individuals with active, sub-clinical TB. Since many antigens of Mtb, including those that have provided some degree of protection in animal models, have been reported to elicit both cellular and humoral immune responses (2, 12, 19, 43), and since these antigens are expressed in rabbits at the time when cellular immune responses that restrict bacterial growth of the inhaled bacteria are elicited, they are also being studied for their inclusion as components of a subunit vaccine for TB. References Cited in Examples VI-XIII 1 Allred, D. R., T. C. Mcguire, G. H. Palmer, S. R. Leib, T. M. Harkins, T. F. McElwain, and A. F. Barbet. 1990. Molecular basis for surface antigen size polymorphisms and conservation of a neutralization-sensitive epitope in Anaplasma marginale. Proc. Natl. Acad. Sci. 87:3220-3224. 2 Baldwin, S. L., C. d'Souza, A. D. Roberts, B. P. Kelly, A. A. Frank, M. A. Lui, J. B. Ulmer, K. Huygen, D. M. McMurray, and I. M. Orme. 1998. Evaluation of new vaccines in the mouse and guinea pig model of tuberculosis. Infect. Immun. 66:2951-2959. 3 Berthet, F.-X., M. Lagranderie, P. Gounon, C. Laurent-Winter, D. Ensergueix, P. Chavarot, F. Thouron, E. Maranghi, V. Pelicic, D. Portnoi, G. Marchal, and B. Gicquel. 1998. Attenuation of Virulence by Disuption of the Mycobacterium tuberculosis erp Gene. Science. 282:759-762. 4 Berthet, F.-X., J. Rauzier, E. M. Lim, W. Philipp, B. Gicquel, and D. Portnoi. 1995. Characterization of the mycobacterium tuberculosis erp gene encoding a potential cell surface protein with repetitive structures. Microbiology. 141:2123-2130. 5 Bigi, F., A. Alito, J. C. Fisanotti, M. I. Rornano, and A. Cataldi. 1995. Characterization of a novel Mycobacterium bovis secreted antigen containing PGLTS repeats. Infect. Immun. 63:2581-2586. 6 Bishai, W. R., A. M. Dannenberg Jr, N. Parrish, R. Ruiz, P. Chen, B. C. Zook, W. Johnson, J. W. Boles, and M. L. M. Pitt. 1999. Virulence of Mycobacterium tuberculosis CDC 1551 and H37RV in Rabbits Evaluated by Lurie's Pulmonary Tubercle Count Method. 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M., J. T. Belisle, M. G. Sonnenberg, M. A. Keen, S. Zolla-Pazner, and S. Laal. 1998. Delineation of human antibody responses to culture filtrate antigens of Mycobacterium tuberculosis. J. Infect. Dis. 178:1534-1538. 37 Sambrook, J., E. F. Fritsch, and T. Maniatis. 1989. Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 38 Shimoji, Y., V. Ng, K. Matsumura, V. A. Fischetti, and A. Rambukkana. 1999. A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proc. Natl. Acad. Sci. 96:9857-9862. 39 Smith, I., J. Dubnau, R. Manganelli, G. M. Rodriguez, B. Gold, S. Walters, J. Chan, and W. Rom. 1999. Identification and Characterization of Potential Virulence genes of Mycobacterium tuberculosis, p. 108-112. US-Japan Cooperative Medical Science Program-Thirty-Fourth Tuberculosis-Leprosy Research Conference, San Francisco-Calif. 40 Smith, I., O. Duserget, M. Rodriquez, J. Timm, M. 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EXAMPLE XIV Definition of M. tuberculosis Culture Filtrate Proteins by 2-Dimensional Polyacrylamide Gel Electrophoresis Mapping, N-terminal Amino Acid Sequencing and Electrospray Mass Spectrometry This Example that describes various individual culture filtrate proteins of Mtb is taken from U.S. Pat. No. 6,245,331 (12 Jun. 2001) which, as indicated, is incorporated by reference in its entirety. (See Example V therein) The combination of 2-D PAGE, western blot analysis, N-terminal amino acid sequencing and liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) was used to develop a detailed map of culture filtrate proteins and to obtained partial amino acid sequences for five previously undefined, relatively abundant proteins within this fraction which are found to be useful as early antigens for serodiagnosis of TB. These proteins were shown to be early antigens of TB recognized by circulating antibodies in TB patients early in the disease process. SDS-PAGE and 2-D PAGE of Culture Filtrate Proteins SDS-PAGE was performed under reducing conditions by the method of Laemmli with gels (7.5×10 cm×0.75 mm) containing a 6% stack over a 15% resolving gel. Each gel was run at 10 mA for 15 min followed by 15 mA for 1.5 h. 2-D PAGE separation of proteins was achieved by the method of O'Farrell with minor modifications. Specifically, 70 μg of CFP was dried and suspended in 30 μl of isoelectric focusing (IEF) sample buffer [9 M urea, 2% Nonidet P-40, 5% βmercaptoethanol, and 5% ampholytes pH 3-10 (Pharmalytes; Pharmacia Biotech, Piscataway, N.J.)], and incubated for 3 h at 20° C. An aliquot of 25 μg of protein was applied to a 6% polyacrylamide IEF tube gel (1.5 mm by 6.5 cm) containing 5% Pharmalytes pH 3-10 and 4-6.5 in a ratio of 1:4. The proteins were focused for 3 h at 1 kV using 10 mM H3PO4 and 20 mM NaOH as the catholyte and anolyte, respectively. The tube gels were subsequently imbibed in sample transfer buffer for 30 min and placed on a preparative SDS-polyacrylamide gel (7.5×10 cm×1.5 mm) containing a 6% stack over a 15% resolving gel. Electrophoresis in the second dimension was carried out at 20 mA per gel for 0.3 h followed by 30 mA per gel for 1.8 h. Proteins were visualized by staining with silver nitrate. Silver stained 2-D PAGE gels were imaged using a cooled CCD digitizing camera and analyzed with MicroScan 1000 2-D Gel Analysis Software for Windows 3.x (Technology Resources, Inc., Nashville, Tenn.). Protein peak localization and analysis was conducted with the spot filter on, a minimum allowable peak height of 1.0, and minimum allowable peak area of 2.0. Proteins, subjected to 2-D or SDS-PAGE, were transferred to nitrocellulose membranes (Schleicher and Schuell, Keene, N.H.) which were blocked with 0.1% bovine serum albumin in 0.05 M Tris-HCl, pH 7.5, 0.15 M NaCl, and 0.05% Tween 80 (TBST). These membranes were incubated for 2 h with specific antibodies diluted with TBST to the proper working concentrations. After washing, the membranes were incubated for 1 h with goat anti-mouse or -rabbit alkaline phosphatase-conjugated antibody (Sigma) diluted in TBST. The substrates nitro-blue-tetrazolium and 5-bromo-4-chloro-3-indoyl phosphate (BCIP) were used for color development. Mapping of proteins reactive to specific antibodies within the 2-D PAGE gel was accomplished using 0.1% India ink as a secondary stain for the total protein population after detection by immunoblotting. Alternatively, the Digoxigenin (DIG) Total Protein/Antigen Double Staining Kit (Boehringer Mannheim, Indianapolis, Ind.) was employed for those antibody-reactive proteins that could not be mapped using India ink as the secondary stain. Briefly, after electroblotting, the membranes were washed three times in 0.05 M K2HPO4, pH 8.5. The total protein population was conjugated to digoxigenin by incubating the membrane for one hour at room temperature in a solution of 0.05 M K2HPO4, pH 8.5 containing 0.3 ng/ml digoxigenin-3-0-methylcarbonyl-ε-amino-caproic acid N-hydroxysuccinimide ester and 0.01% Nonidet-P40. The membranes were subsequently blocked with a solution of 3% bovine serum albumin in 0.05 M Tris-HCl, pH 7.5, 0.15 M NaCl (TBS) for 1 h followed by washing with TBS. Incubation with specific antibodies was performed as described, followed by incubation of the membranes with mouse anti-DIG-Fab fragments conjugated to alkaline phosphatase diluted 1:2000 in TBS, for 1 h. The membranes were washed three times with TBS and probed with goat anti-mouse or -rabbit horse radish peroxidase-conjugated antibody. Color development for the proteins reacting to the specific anti-Mtb protein antibodies was obtained with the substrates 4-(1,4,7,10-tetraoxadecyl)-1-naphthol and 1.8% H2O2. Secondary color development of the total protein population labeled with digoxigenin utilized BCIP and [2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl-tetrazolium chloride] as the substrates. To obtain N-terminal amino acid sequence for selected proteins, CFPs (200 μg) were resolved by 2-D PAGE and transferred to polyvinylidene difluoride membrane (Millipore, Milford, Mass.) by electroblotting at 50 V for 1 h, using CAPS buffer with 10% methanol. The membrane was stained with 0.1% Coomassie brilliant blue in 10% acetic acid and destained with a solution of 50% methanol and 10% acetic acid. Immobilized proteins were subjected to automated Edman degradation on a gas phase sequencer equipped with a continuous-flow reactor. The phenylthiohydantoin amino acid derivatives were identified by on-line reversed-phase chromatography as described previously. Selected CFP were subjected to LC-MS-MS to determine the sequence of internal peptide fragments. CFPs (200 mg) were resolved by 2-D PAGE and the gel stained with 0.1% Coomassie brilliant blue and destained as described for proteins immobilized to PVDF membranes. The protein of interest was excised from the gel, washed several times with distilled water to remove residual acetic acid and subjected to in-gel proteolytic digestion with trypsin. Peptides were eluted from the acrylamide and separated by C18 capillary RP-HPLC. The microcapillary RP-HPLC effluent was introduced directly into a Finnigan-MAT (San Jose, Calif.) TSQ-700 triple sector quadrupole mass spectrometer. Mass spectrometry and analysis of the data was performed as described by Blyn et al.. C. Results 1. Definition of Proteins Present in the Culture Filtrate of Mtb H37Rv. Through the efforts of the World Health Organization (WHO) Scientific Working Groups (SWGs) on the Immunology of Leprosy (IMMLEP) and Immunology of Tuberculosis (IMMTUB) an extensive collection of mAbs against mycobacterial proteins has been established. This library as well as mAbs and polyclonal sera not included in these collections allowed for the identification of known mycobacterial proteins in the culture filtrate of Mt. A detailed search of the literature identified mAbs and/or polyclonal sera reactive against 35 individual Mtb CFP (Table 1). Initially, the presence or absence of these proteins in the culture filtrate of Mtb H37Rv, prepared for these studies, was determined by Western blot analyses. Of the antibodies and sera tested, all but one (IT-56) demonstrated reactivity to specific proteins of this preparation (Table 1). The mAb IT-56 is specific for the 65 kDa Mtb GroEL homologue; a protein primarily associated with the cytosol. Additionally the mAb IT-7 reacted with a 14 kDa and not a 40 kDa CFP. 2. 2-D PAGE Mapping of Known CFP of Mtb H37Rv Using 2-D western blot analysis coupled with secondary staining (either India ink or Dig total protein/antigen double staining) the proteins reactive to specific mAbs or polyclonal sera were mapped within the 2-D PAGE profile of CFP of Mtb H37Rv. In all, 32 of the reactive antibodies detected specific proteins resolved by 2-D PAGE (Table 1). However, two antibodies (IT-1 and IT-46), that were reactive by conventional western blot analysis, failed to detect any protein within the 2-D profile (not shown; summarized in Tables). This lack of reactivity by 2-D western analysis, presumably, was due to the absence of linear epitopes exposed by the denaturing conditions used to resolve molecules for conventional Western blot analyses. The majority of the antibodies recognized a single protein spot. However, several (IT-3, IT-4, IT-7, IT-20, IT-23, IT-41, IT-42, IT-44, IT-49, IT-57, IT-58, IT-61 and MPT 32) reacted with multiple proteins. Five of these, IT-23, IT-42, IT-44, IT-57 and IT-58 reacted with protein clusters centered at 36 kDa, 85 kDa, 31 kDa, 85 kDa and 50 kDa, respectively. Additionally the proteins in each of these clusters migrated within a narrow pI range; suggesting that the antibodies were reacting with multiple isoforms of their respective proteins. In the case of the protein cluster at 85 kDa (which is the “88 kDa” identified as malate synthase) detected by IT-57, the most dominant component of this cluster was also recognized by IT-42. Polyclonal sera against MPT 32 recognized a 45 and 42 kDa protein of relatively similar pI. While defining sites of glycosylation on MPT 32 (see above) we observed that this protein was prone to autoproteolysis and formed a 42 kDa product. Thus, the 42 kDa protein detected with the anti-MPT 32 sera was a breakdown product of the 45 kDa MPT 32 glycoprotein. The mAb (T-49 specific for the Antigen 85 (Ag85) complex clearly identified the three gene products (Ag85A, B and C) of this complex. The greatest region of antibody cross-reactivity was at molecular masses below 16 kDa. The most prominent protein in this region reacted with niAb IT-3 specific for the 14 kDa GroES homolog. This mAb also recognized several adjacent proteins at approximately 14 kDa. Interestingly, various members of this same protein cluster reacted with anti-MPT 57 and anti-MPT 46 polyclonal sera, and the mAbs IT-4, IT-7, and IT-20. 3. N-terminal Amino Acid Sequencing of Selected CFPs The N-terminal amino acid sequences or complete gene sequences and functions of several of the CFPs of Mt, mapped with the available antibodies, are known. However, such information is lacking for the proteins that reacted with IT-42 IT-43, IT-44, IT-45, IT-51, IT-52, IT-53, IT-57, IT-59 and IT-69, as well as several dominant proteins not identified by these means. Of these, the most abundant proteins (IT-52, IT-57, IT 42, IT-58 and proteins labeled A-K) were selected and subjected to N-terminal amino acid sequencing. TABLE 1 Reactivity of CFPs of M. tuberculosis H37Rv to reported specific mAbs and polyclonal antisera Dilution REACTIVITY Antibody1 MW (kDa) Used 1-D 2-D IT-1 (F23-49-7) 16 kDa 1:2000 + − IT-3 (SA-12) 12 kDa 1:8000 + + IT-4 (F24-2-3) 16 kDa 1:2000 + + IT-7 (F29-29-7) 40 kDa 1:1000 + + IT-10 (F29-47-3) 21 kDa 1:1000 + + IT-12 (HYT6) 17-19 kDa 1:50 + + IT-17 (D2D) 23 kDa 1:8000 + + IT-20 (WTB68-A1) 14 kDa 1:250 + + IT-23 (WTB71-H3) 38 kDa 1:250 + + IT-40 (HAT1) 71 kDa 1:50 + + IT-41 (HAT3) 71 kDa 1:50 + + IT-42 (HBT1) 82 kDa 1:50 + + IT-43 (HBT3) 56 kDa 1:50 + + IT-44 (HBT7) 32 kDa 1:50 + + IT-45 (HBT8) 96 kDa 1:50 + + IT-46 (HBT10) 40 kDa 1:50 + − IT-49 (HYT27) 32-33 kDa 1:50 + + IT-51 (HBT2) 17 kDa 1:50 + + IT-52 (HBT4) 25 kDa 1:50 + + IT-53 (HBT5) 96 kDa 1:50 + + IT-56 (CBA1) 65 kDa 1:50 − ND* IT-57 (CBA4) 82 kDa 1:50 + + IT-58 (CBA5) 47 kDa 1:50 + + IT-59 (F67-1) 33 kDa 1:100 + + IT-61 (F116-5) 30 (24) kDa 1:100 + + IT-67 (L24.b4) 24 kDa 1:50 + + IT-69 (HBT 11) 20 kDa 1:6 + + F126-2 30 kDa 1:100 + + A3h4 27 kDa 1:50 + + HYB 76-8 6 kDa 1:100 + + anti-MPT 32 50 kDa 1:100 + + anti-MPT 46 10 kDa 1:100 + + anti-MPT 53 15 kDa 1:100 + + anti-MPT 57 12 kDa 1:100 + + anti-MPT 63 - K64 18 kDa 1:200 + + *ND: Not done 1Original designations for the World Health Organization cataloged Mab are given in parentheses. Three of these proteins were found to correspond to previously defined products. The N-terminal amino acid sequence of the protein labeled D was identical to that of Ag85 B and C. This result was unexpected given that the IT-49 mAb failed to detect this protein and N-terminal amino acid analysis confirmed that those proteins reacting with IT-49 were members of the Ag85 complex. Second, the protein labeled E had an N-terninal sequence identical to that of glutamine synthetase. A third protein which reacted with IT-52 was found to be identical to MPT 51. However, five of the proteins analyzed appeared to be novel. Three of these, those labeled B, C and IT-58 did not demonstrate significant homology to any known mycobacterial or prokaryotic sequences. The protein labeled I possessed an N-terminal sequence with 72% identity to the amino terminus of an α-hydroxysteroid dehydrogenase from a Eubacterium species, and the protein labeled F was homologous to a deduced amino acid sequence for an open reading frame identified in the Mtb cosmid MTCY1A11. Repeated attempts to sequence those proteins labeled as A, G, H, J, K, IT-43, IT-44, IT-49 and IT-57 were unsuccessful. Reactivity of Tuberculosis Sera with the M. tuberculosis 88 kDa Antigen A high molecular weight fraction of CFP of Mtb reacted with a preponderance of sera from TB patients and that this fraction was distinguished from other native fractions in that it possessed the product initially thought to be reactive to mAb IT-57. In view of this, the protein cluster (the 88 kDa protein) initially thought to be defined by IT-42 and IT-57 was excised from a 2-D polyacrylamide gel, digested with trypsin and the resulting peptides analyzed by LC-MS-MS. In order to confirm that M. tuberculosis also contains a seroreactive 88 kDa antigen which is not the catalase/peroxidase, a katG-negative strain of M. tuberculosis (ATCC 35822) was tested. Lysates from this strain failed to react with any of the anti-catalase/peroxidase antibodies However, when individual sera from healthy controls and TB patients of all three groups were tested with the same lysates, all the group III and group IV sera reacted with the 88 kDa protein Identification of the Amino Acid Sequence of the Sero-Reactive 88 kDa Protein The culture filtrate protein from a katG-negative strain of M tuberculosis (ATCC 35822) was resolved as above by 2-D PAGE. The protein spot corresponding to the sero-reactive 88 kDa protein was cut out of the gel and subject to an in-gel digestion with trypsin. The resulting tryptic peptides were exteracted, applied to a C18 RP-HPLC column, and eluted with an increasing concentration of acetonitrile. The peptides eluted in this manner were introduced directly into a Finnigan LCQ Electrospray mass spectrometer. The molecular mass of each peptide was determined, as was the charge state, with a zoom-scan program. Identification of the 88 kDa protein was achieved by entering the mass spectroscopy date obtained above into the MS-Fit computer program and searching it against the M. tuberculosis database. The protein was identified as GlcB (Z78020) of M. tuberculosis, which is believed to be the enzyme malate synthase based on sequence homology to known proteins of other bacteria This protein has the Accession number CAB01465 on the NCBI Genbank database (based on Cole, S. T. et al., Nature 393:537-544 (1998), which describes the complete genome sequence of M. tuberculosis). The sequence of this protein, SEQ ID NO: 13 is presented below. C. Discussion In contrast to Mtb cell wall, cell membrane and cytoplasmic proteins, the CFPs are well defined in terms of function, immunogenicity and composition. However, a detailed analysis of the total proteins, and the molecular definition and 2-D PAGE mapping of the majority of these CFPs has not been performed. Nagai and colleagues identified and mapped by 2-D PAGE the most abundant proteins filtrate harvested after five weeks of culture in Sauton medium. The present study used culture filtrates from mid- to late-logarithmic cultures of three Mtb type strains H37Ra, H37Rv, and Erdman to provide for the first time a detailed analysis understanding of this widely studied fraction. Computer analysis of the 2-D gels of CFP resolved 205, 203 and 206 individual protein spots from filtrates of strains H37Rv, H37Ra and Erdman, respectively. Of the total spots, 37 were identified using a collection of mAb and polyclonal sera against CFPs. Several of these antibodies recognized more than one spot; several are believed to react with multiple isoforms of the same protein or were previously shown to recognize more then a single gene product. In all, partial or complete amino acid sequences have been reported for 17 of the proteins mapped with the available antibodies. For greater molecular definition, a number of abundant products observed in the 2-D PAGE were subjected to N-terminal sequence analysis. One such protein that migrated between Ag85B and Ag85C was found to have 16 residues (FSRPGLPVEYLQVPSP, [SEQ ID NO:12]) identical to the N-terminus of mature Ag85A and Ag85B, and different from Ag85C by a single residue (position 15). This protein spot was apparently merely a homologue of Ag85A or B. However, its complete lack of reactivity with an Ag85-specific mAb (IT-49), its weight greater than that of Ag85B and its shift in pI in relation to Ag85A suggested that this product may have resulted from post translational modifications. Alternatively, this protein may be a yet unrecognized fourth member of the Ag85 complex. However, members of the Ag85 complex appear to lack post-translational modifications in some reports whereas others report several bands corresponding to Ag85C after isoelectric focusing. However, no direct evidence supports the existence of a fourth Ag85 product. A second product sequenced was a 25 kDa protein with a pI of 5.34. Its N-terminal sequence (XPVM/LVXPGXEXXQDN, [SEQ ID NO:15]) showed homology to an internal fragment (DPVLVFPGMEIRQDN, [SEQ ID NO: 16]) corresponding to open reading frame 28c of the Mtb cosmid MTCY1A11. Analysis of that deduced sequence revealed a signal peptidase I consensus sequence (Ala-Xaa-Ala) and an apparent signal peptide preceding the N-terminus of the 25 kDa protein sequenced above N-terminal sequencing of selected CFPs identified three novel products: (I) protein with 72% identity to the N-terminus of a 42 kDa α-hydroxysteroid dehydrogenase of Eubacterium sp. VPI 12708; (2) 27 kDa protein previously defined as MPT-51; and (3) 56 kDa protein previously identified as glutamine synthetase. Three proteins showed no significant homology between their N-termini and any known peptides. For these proteins and for others that were refractory to N-group analysis, more advanced methods of protein sequencing (e.g., LC-MS-MS) will permit acquisition of extended sequence information. This type of broad survey of virulent Mtb strains has led to, and will continue to allow, the identification of immunologically important proteins and will lead to identification of novel virulence factors leading to improved approaches to chemotherapy. Thus, not only does the present invention enhance the overall knowledge in the art of the physiology of Mt, but it also provides immediate tools for early serodiagnosis. TABLE 2 Summary of certain protein spots detected by computer aided analysis of silver nitrate stained 2-D gels. Antibody Function/ N-terminal Ref #. H37Rv H37Ra Erdman MW(kDa) pI Reactivity Designation Sequence SEQ ID NO 11 11 11 11 38.90 4.31 anti-MPT 32 MPT 32 DPAPAPPVPT 9 14 14 14 14 42.17 4.51 anti-MPT 32 MPT 32 DPAPAPPVPT 9 24 24 24 24 48.70 4.79 59 59 59 59 29.68 5.08 66 66 66 66 35.69 5.09 IT-23 PstS CGSKPPSPET 10 68 68 68 68 42.41 5.10 69 69 69 69 30.20 5.10 77 77 77 77 28.18 5.10 80 80 80 80 42.17 5.10 C XXAVXVT 11 103 103 103 103 31.08 5.12 D: Antigen 85 FSRPGLPVEYLQVPSP 12 Homolog? 111 111 111 111 104.71 5.13 124 124 124 124 85.11 (88) 5.19 Malate synthase See below for full 13 sequencel 170 170 170 170 26.92 5.91 IT-52 MPT 51 See below for full 14 sequence Amino Acid Sequence of 88 kDa Malate Synthase (SEQ ID NO: 13): MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R Amino Acid Sequence of Secreted Form of MPT 51 (SEQ ID NO:14): APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR. The references cited above are all incorporated by reference herein, whether specifically incorporated or not. Having now fully described this invention, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While this invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth as follows in the scope of the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention in the fields of microbiology and medicine relates to methods for rapid early detection of mycobacterial disease in humans based on the presence of antibodies to particular “early” mycobacterial antigens which have not been previously recognized for this purpose. Assay of such antibodies on select partially purified or purified mycobacterial preparations containing such early antigens permits diagnosis of TB earlier than has been heretofore possible. Also provided is a surrogate marker for screening populations at risk for TB, in particular subjects infected with human immunodeficiency virus (HIV). The invention is also directed to vaccine compositions and methods useful for preventing or treating TB. 2. Description of the Background Art The incidence of tuberculosis has shown a rapid increase in recent years, not only in the developing countries, but also in crowded urban settings in the US and in specific subsets of our society, including the homeless, IV drug users, HIV-infected individuals, immigrants and refugees from high prevalence endemic countries (Raviglione, M C et al., 1995. JAMA. 273:220-226). Studies show that these populations are at a significantly greater risk of developing tuberculosis, and also serve as the reservoir of infection for the community as a whole Raviglione, M C et al., 1992, Bull World Health Organization. 70:515-526; Raviglione, M C et al., 1995. JAMA. 273:220-226). None of the currently used methods for diagnosis of tuberculosis identify individuals with active but sub-clinical infection, and the disease is generally detected when the individuals are already infectious. Design of new diagnostic assays requires knowledge of antigens expressed by the bacteria during their in vivo survival. Most current studies of antigens of Mycobacterium tuberculosis (Mtb); also abbreviated herein are focused on antigens present in the culture filtrates of bacteria replicating actively in vitro, with the presumption that the same molecules are expressed by the in vivo bacteria. A vast majority of the Mtb infected individuals develop immune responses that arrest progression of infection to clinical TB, and also prevent the latent bacilli from reactivating to cause clinical disease, whereas about 10-15% of the infected individuals progress to developing primary or reactivation TB. Understanding the host-pathogen interactions that occur after infection, but prior to development of clinical TB (pre-clinical TB) is required both for the design of effective vaccines and for development of diagnosis of early disease. Several studies have shown that Mtb adapts to different environments in broth media (Garbe, T R et al., 1999, Infect. Immun. 67:460-465; Lee, B-Y et al., 1995, J. Clin. Invest. 96:245-249; Wong, D K et al., 1999, Infect. Immun. 67:327-336) and during intracellular residence by altering its gene expression (8, 22, 34). Clark-Curtiss, J E et al., 1999, p. 206-210. In Proceedings of Thirty-Fourth Tuberculosis-Leprosy Research Conference, San Francisco, Calif., Jun. 27-30. Lee et al., supra; Smith, I et al., 1998, Tuber. Lung Dis. 79:91-97). Earlier studies from the present inventors' laboratory with cavitary and non-cavitary TB patients have also shown that the in vivo environment in which the bacilli replicate affects the profile of the antigenic proteins expressed by Mtb (Samanich, K M et al., 1998, J. Infect. Dis. 178:1534-1538; Laal et al., U.S. Pat. No. 6,245,331 (2001)). One objective of the present invention was to identify the antigens expressed by inhaled Mtb during the pre-clinical stages of TB. There are no markers to identify non-diseased humans with an active infection with Mtb, but the rabbit model of TB closely resembles TB in immuno-competent humans in that both species are outbred, both are relatively resistant to Mtb, and in both the caseous lesions may liquify and form cavities (Converse, P J et al., 1996, Infect. Immun. 64:4776-4787). Studies have shown that on being inhaled, the bacilli are phagocytosed by (non specifically) activated alveolar macrophages (AM) which either destroy or allow them to multiply. If the bacilli multiply, the AM die and the released bacilli are phagocytosed by non activated monocyte/macrophages that emigrate from the bloodstream. Intracellular replication and host cell death continue for 3-5 weeks, when both cellular and humoral immune responses are elicited (Lurie, M B, 1964. Chapter VIII, p. 192-222, In M. B. Lurie (ed.) Resistance to tuberculosis: experimental studies in native and acquired defensive mechanisms. Harvard University Press, Cambridge, Mass.; Lurie, M B et al., 1965, Bact. Rev. 29:466-476; Dannenberg, A M., Jr., 1991, Immunol. Today. 12:228-233). Lymphocytes and macrophages enter the foci of infection, and if they become activated bacillary replication is controlled, if not, the infection progresses to clinical disease. During these initial stages of bacillary replication and immune stimulation, there are no outward signs of disease except the conversion of cutaneous reactivity to PPD. The antigens of Mtb expressed, and their interaction with the immune system during these pre-clinical stages of TB is not delineated.

<SOH> SUMMARY OF THE INVENTION <EOH>In view of the paucity of human material available to study the immunological events occurring after inhalation of virulent bacilli, but prior to development of clinical TB, the present invention is based in part on studies of aerosol infected rabbits. The present inventors reasoned that by 3-5 weeks post-infection, the sera from infected rabbits would contain antibodies to the antigens being expressed by the in vivo bacteria. Four antigens of Mtb that are expressed in vivo after aerosol infection, but prior to development of clinical TB, in rabbits were identified by immunoscreening an expression library of Mtb genomic DNA with sera obtained 5 weeks post-infection. Three of the proteins identified, PirG (Rv3810) [SEQ ID NO:1 and 2; nucleotide and amino acid], PE-PGRS (Rv3367) [SEQ ID NO:3 and 4] and PTRP (Rv0538) [SEQ ID NO:5 and 6] have multiple tandem repeats of unique amino-acid sequences, and have characteristics of surface or secreted proteins. The fourth protein, MtrA (Rv3246c) [SEQ ID NO:7 and 8], is a response regulator of a putative two-component signal transduction system, mtrA-mtrB, of Mtb. All four antigens were recognized by pooled sera from TB patients and not from healthy controls, confirming their in vivo expression during active infection in humans. Three of the antigens, (PE-PGRS, PTRP and MtrA) were also recognized by retrospective, pre-clinical TB sera obtained from HIV-TB patients prior to the clinical manifestation of TB, suggesting their utility as diagnostics for active, pre-clinical (“early”) TB. The present invention provides methods, kits and compositions directed to the detection of antibodies or T cell reactivity to any of the above early antigens or to the detection of the antigens themselves in a body fluid of a subject as a means of detecting early mycobacterial disease in the subject. In other embodiments, the invention provides, methods, kits and compositions useful for detecting antibody or T cell reactivity to, in addition to one or more of the above early antigens, to one or more of the following early Mtb antigens: (a) an 88 kDa M. tuberculosis protein having the an amino acid sequence SEQ ID NO:13: MTDRVSVGNL RIARVLYDFV NNEALPGTDI DPDSFWAGVD KVVADLTPQN QALLNARDEL QAQIDKWHRR RVIEPIDMDA YRQFLTEIGY LLPEPDDFTI TTSGVDAEIT TTAGPQLVVP VLNARFALNA ANARWGSLYD ALYGTDVIPE TDGAEKGPTY NKVRGDKVIA YARKFLDDSV PLSSGSFGDA TGFTVQDGQL VVALPDKSTG LANPGQFAGY TGAAESPTSV LLINHGLHIE ILIDPESQVG TTDRAGVKDV ILESAITTIM DFEDSVAAVD AADKVLGYRN WLGLNKGDLA AAVDKDGTAF LRVLNRDRNY TAPGGGQFTL PGRSLMFVRN VGHLMTNDAI VDTDGSEVFE GIMDALFTGL IAIHGLKASD VNGPLINSRT GSIYIVKPKM HGPAEVAFTC ELFSRVEDVL GLPQNTMKIG IMDEERRTTV NLKACIKAAA DRVVFINTGF LDRTGDEIHT SMEAGPMVRK GTMKSQPWIL AYEDHNVDAG LAAGFSGRAQ VGKGMWTMTE LMADMVETKI AQPRAGASTA WVPSPTAATL HALHYHQVDV AAVQQGLAGK RRATIEQLLT IPLAKELAWA PDEIREEVDN NCQSILGYVV RWVDQGVGCS KVPDIHDVAL MEDRATLRIS SQLLANWLRH GVITSADVRA SLERMAPLVD RQNAGDVAYR PMAPNFDDSI AFLAAQELIL SGAQQPNGYT EPILHRRRRE FKARAAEKPA PSDRAGDDAA R (b) a 27 kDa M. tuberculosis protein named MPT51 having the amino acid sequence SEQ ID NO:14: APYENLMVPS PSMGRDIPVA FLAGGPHAVY LLDAFNAGPD VSNWVTAGNA NTLAGKGIS VVAPAGGAYS MYTNWEQDGS KQWDTFLSAE LPDWLAANRG AAQGGYGAMA AAFHPDRFG FAGSMSGFLY PSNTTTNGAI AAGMQQFGGV DTNGMWGAPQ LGRWKWHDPW HASLLAQNN TRVWVWSPTN PGASDPAAMI GQTAEAMGNS RMFYNQYRSV GGHNGHFDFP SGDNGWGSW APQLGAMSGD IVGAIR; (c) a protein characterized as M. tuberculosis antigen 85C; or (d) a glycoprotein characterized as M. tuberculosis antigen MPT32. In yet another embodiment, the invention provides methods, kits and compositions useful for the detection of antibodies or T cell reactivity to any of the above early antigens or to one or more of the following early antigens: (i) a 28 kDa protein corresponding to the spot identified as Ref. No. 77 in Table 2. (ii) a 29/30 kDa protein corresponding to the spot identified as Ref No. 69 or 59 in Table 2; (iii) a 31 kDa protein corresponding to the spot identified as Ref. No. 103 in Table 2; (iv) a 35 kDa protein corresponding to the spot identified as Ref. No. 66 in Table 2 and reacting with monoclonal antibody IT-23; (v) a 42 kDa protein corresponding to the spot identified as Ref. No. 68 or 80 in Table 2; (vi) a 48 kDa protein corresponding to the spot identified as Ref. No. 24 in Table 2; and (vii) a 104 kDa protein corresponding to the spot identified as Ref. No. 111 in Table 2, which spots are obtained by 2-dimensional electrophoretic separation of M. tuberculosis lipoarabinomannan-free culture filtrate proteins as follows: (A) incubating 3 hours at 20° C. in 9M urea, 2% Nonidet P-40, 5% β-mercaptoethanol, and 5% ampholytes at pH 3-10; (B) isoelectric focusing on 6% polyacrylamide isoelectric focusing tube gel of 1.5 mm×6.5 cm, said gel containing 5% ampholytes in a 1:4 ratio of pH 3-10 ampholytes to pH 4-6.5 ampholytes for 3 hours at 1 kV using 10 mM H 3 PO 4 as catholyte and 20 mM NaOH as anolyte, to obtain a focused gel; (C) subjecting the focused gel to SDS PAGE in the second dimension by placement on a preparative SDS-polyacrylamide gel of 7.5×10 cm×1.5 mm containing a 6% stack over a 15% resolving gel and electrophoresing at 20 mA per gel for 0.3 hours followed by 30 mA per gel for 1.8 hours. In yet other embodiments, the present invention provides vaccines compositions and methods for treating or preventing mycobacterial disease in a subject. The vaccine composition may comprise any one or more of the early antigens noted above or an epitope thereof. Preferred vaccine epitopes are T helper epitopes, more preferably T helper epitopes that stimualte Th1 cells.

20041108

20100629

20050421

79139.0

SWARTZ, RODNEY P

MYCOBACTERIAL PROTEINS AS EARLY ANTIGENS FOR SERODIAGNOSIS AND VACCINES

SMALL

ACCEPTED

ACCEPTED

Novel human hepatoma lines, methods for obtaining same and uses thereof

The invention concerns human hepatoma cell lines, characterized in that they are capable of being naturally infected by parasites and/or viruses; said parasites can be hepatotropic or not, such as Plasmodium or parasites of the genus leishmania and express receptors of the family of Flaviviridae and Ilepadnaviridae viruses, preferably HBV and HCV. The invention has diagnostic, therapeutic and prophylactic applications.

1. Human hepatoma cell lines, said cell lines capable of being infected naturally by parasites and/or viruses; said parasites optionally being hepatotropes and being capable of expressing receptors of the family of the Flaviviridae and Hepadnaviridae viruses. 2. Human hepatoma cell lines, wherein their cells can reach a stage of hepatic differentiation. 3. Human hepatoma cell lines, wherein said cell lines express the characteristic functions of a hepatocyte comprising: production of plasmatic proteins and transferrin, detoxification, and energy. 4. Human hepatoma cell lines, wherein the cells in the proliferation phase possess pluripotent cell properties, wherein the properties are the property of differentiating towards the hepatocyte, biliary, pancreatic and intestinal route. 5. Hepatoma cell lines according to claim 1, wherein in the proliferation phase, their population doubles in approximately 24 hours. 6. Hepatoma cell line as deposited on 5 Apr. 2001 at CNCM, under No. I-2652. 7. Cells or elements of cells originating from the lines according to claim 1. 8. A process for selecting human hepatoma cell lines according to claim 1, comprising: a phase of cell proliferation in a culture medium comprising continuously at least one cortico-steroid at a non-toxic concentration which promotes the differentiation of normal human hepatocytes, then, upon reaching confluence, a phase of cell differentiation in this same medium, by adding DMSO, in a quantity sufficient to induce differentiation, and repeating said phases of cell proliferation and cell differentiation at least once. 9. A process for obtaining human hepatoma cell lines comprising a stage of biopsy of a solid tumor of hepatocarcinoma type, a stage of isolation of the cell population using a proteolytic enzyme and a stage of selection of the lines according to the process of claim 8. 10. A process for infecting hepatic cells with a hepatotropic parasite and/or a virus comprising: a selection phase according to claim 8, a differentiation phase allowing the cells to reach a morphology close to the hepatocyte using culture medium comprising at least one cortico-steroid at a non-toxic concentration which promotes differentiation of normal human hepatocytes, with DMSO added to it in a quantity sufficient to induce differentiation, and an infection phase with incubation of the hepatic cells with a hepatotropic parasite and/or a virus in a culture medium comprising at least one cortico-steroid at a non-toxic concentration which promotes differentiation of normal human hepatocytes, to which the infectious source is added. 11. The process according to claim 8, wherein the media used contains insulin in a quantity sufficient to promote the survival of normal human hepatocytes. 12. The process according to claim 8, wherein the cortico-steroid of the culture medium is chosen from the group consisting of hydrocortisone hemisuccinate, dexamethasone, and/or another differentiation factor selected from the group consisting of retinoic acid and/or its synthetic analogues, oestrogens, and thyroid hormones. 13. The process according to claim 12, wherein the concentration of hydrocortisone hemisuccinate is from 10−7 M to 10−4 M, and approximately 10−6 M for dexamethasone. 14. The process according to claim 8, wherein the DMSO concentration is from 1% to 4%. 15. A process for transfection of the lines according to claim 1 or cells or elements of cells originating therefrom using a vector comprising the complete sequence and/or part of the genetic material of the HBV and/or HCV virus. 16. A process for high flow rate screening of differentially expressed genes using a chip-type tool produced from the lines according to claim 1 and/or cells and/or parts of cells originating therefrom. 17. A method for maintaining stability of cell lines according to claim 1 or cells originating therefrom, comprising continuously adding at least one cortico-steroid at a non-toxic concentration which promotes the differentiation of normal human hepatocytes. 18. A method for inducing differentiation of cell lines according to claim 1 or cells originating therefrom, comprising continuously adding at least one cortico-steroid, at a non-toxic concentration which promotes the differentiation of normal human hepatocytes together with DMSO, said corticosteroid and DMSO being added in a quantity sufficient to induce differentiation of the cells originating from the lines. 19. The method according to claim 17, wherein said medium further comprises sodium butyrate at a concentration sufficient to induce a biliary-type differentiation. 20. A method for evaluating new medicaments and/or nutritional constituents and/or environmental pollutants comprising adding the medicament, nutritional constituent and/or environmental pollutant to be evaluated to the lines according to claim 2 and/or cells originating therefrom, for metabolic and/or toxicity tests intended for the evaluation of new medicaments and/or nutritional constituents and/or environmental pollutants. 21. An extracorporeal bioreactor for the transient treatment of acute hepatocellular insufficiencies comprising at least one line according to claim 2 or cell originating therefrom. 22. A method for screening and/or manufacturing new vaccines and/or antiviral molecules comprising adding said vaccine and/or antiviral molecule to the lines according to claim 1 and/or cells originating therefrom, for the screening and/or manufacture of new vaccines and/or antiviral molecules. 23. Antibodies directed against a virus belonging to the Flaviviridae and Hepadnaviridae family obtained from the lines according to claim 1 and/or cells originating therefrom. 24. Viral neutralization test, wherein said test comprises the following stages: incubating virions with variable concentrations of antibodies to be tested and/or of antibodies according to claim 23, then, bringing the medium incubated into contact with human hepatoma cell lines, wherein said cell lines are capable of being infected naturally by parasites and/or viruses; said parasites being able to be hepatotropes or not; and express receptors of the family of the Flaviviridae and Hepadnaviridae viruses, and measuring the secretion of HBs antigen in the supernatant of the infected cells to determine the residual infection. 25. Vaccinal composition comprising at least viral particles and/or polypeptides obtained after infection and/or transfection of the lines according to claim 1 and/or cells originating therefrom, combined with a pharmaceutically acceptable vehicle and/or excipient and/or adjuvant. 26. (Cancelled). 27. A method for evaluating the virucidal capacity of a disinfectant chemical product for cleaning equipment, premises and/or surfaces comprising: bringing at least one virus into contact with said equipment, premises and/or surfaces, disinfecting said equipment, premises and/or surfaces with said disinfectant chemical product, and contaminating the cells according to claim 7, by any viruses having survived the disinfecting. 28. The human hepatoma cell lines according to claim 1, wherein said parasites is selected from the group consisting of Plasmodium and parasites of the genus leishmania; and said Hepadnaviridae virus is selected from the group consisting of HBV and HCV. 29. The human hepatoma cell lines according to claim 3, wherein the P450 cytochromes are selected from the group consisting of CYP2E1, CYP1A and CYP3A. 30. The human hepatoma cell lines according to claim 4, wherein the pluripotent cell properties are properties of resident and/or oval stem cells, wherein said cells are capable of differentiating towards the hepatocyte, biliary, pancreatic and intestinal route. 31. Cells or elements of cells according to claim 7, wherein said cells originate from membranes, receptors and/or antigens originating from the membrane, cytoplasm, nucleus, genes and/or products of genes, DNA, mRNA, cDNA, proteins, and/or peptides. 32. The process according to claim 8, wherein said process is repeated three times. 33. The process according to claim 11, wherein the media contains from 2.5 μg/ml to 10 μg/ml insulin. 34. The process according to claim 33, wherein the media contains 5 μg/ml insulin. 35. The process according to claim 13, wherein the concentration of hydrocortisone hemisuccinate is approximately 5.10−5 M and approximately 10−6 M for dexamethasone. 36. The process according to claim 14, wherein the DMSO concentration is approximately 2%. 37. The method according to claim 19, wherein said medium contains sodium butyrate at a concentration of 2.5 to 5 mM. 38. The method according to claim 37, wherein said medium contains sodium butyrate at a concentration of 3.75 mM. 39. The method according to claim 22, wherein the vaccines and/or antiviral molecules are screened to determine whether they are active vis-à-vis one of the viral cycle stages. 40. Antibodies according to claim 23, wherein said antibodies are directed against the HBV and HCV and/or their cell membrane receptors. 41. The human hepatoma cell lines according to claim 3, wherein said at least one detoxification function is selected from the group consisting of: (a) the expression of various forms of P450 cytochromes, (b) the expression of various forms of phase II detoxification enzymes, (c) the conjugation of biliary salts, and (d) the elimination of urea. 42. The human hepatoma cell lines according to claim 41, wherein said various forms of P450 cytochromes is CYP2E1, CYP1A, and/or CYP3A, and further wherein said various forms of phase II detoxification enzymes is GSTα. 43. The human hepatoma cell lines according to claim 3, wherein said at least one energy function is selected from the group consisting of: (a) storage of sugar in the form of glycogen, (b) production of glucose by glycolysis, (c) neoglucogenesis, and (d) metabolism of lipids.

The invention relates to novel human hepatoma lines. It also relates to methods for obtaining same and their uses in diagnostic, therapeutic and prophylactic applications. Hepatitis B is an infectious disease which is widespread throughout the world. Its virus (abbreviated to HBV) is a small virus with DNA possessing a high host specificity. In fact, only humans and the higher primates are infected by this virus, which strongly limits the in vivo study models of this infection. However, a “duck” model exists which allows the study of an entire replication cycle of a hepadnavirus (in vitro and in vivo). This hepadnavirus, although close to the HBV virus, however has a somewhat different biology. Moreover, the metabolic behaviour of the duck cannot be simply compared to that of humans. HBV moreover shows a strong tropism for the liver and preferentially targets the parenchymatous cells. Also, unlike other viruses, only the differentiated hepatic cells can be infected. A cell line derived from hepatomas has allowed rapid progress in the understanding of the replication mechanisms. This line, which is widely used, is referenced under the name HepG2. A derived clone HepG2 2.2.15 has the advantage of possessing a considerable ability to proliferate and actively replicate the virus. However, this replication is possible only after the introduction of the viral DNA into the cells, by transfection. Natural infection of this line by the HBV has proved impossible. Moreover, due to the age of this line, the karyotype of its cells is broadly modified, which makes it an imperfect model for mimicking human hepatocytes. Finally, the differentiation capacity of these cells remains fairly limited. Other more or less differentiated cell lines have been proposed. In particular the line Hep3B, which is slightly different from the line HepG2, and which has the same limits as the latter can be mentioned. All the line infection tests have proved negative or disappointing in terms of effectiveness. In order to study the mechanisms of HBV infection, a model of human hepatocytes in primary culture has been developed. This model is very useful in involving human hepatocytes and allowing access to the whole viral cycle. However, it is difficult and tedious to manipulate, and obtaining bioptic fragments is increasingly difficult and random. The inventors' work in this field has led them to record that human hepatoma lines, actively multiplying whilst being capable of being infected by parasites and/or viruses, in particular HBV, could be obtained by carrying out a cell selection under specific conditions. The invention therefore aims to provide new human hepatoma lines capable of being infected by parasites and/or viruses, and the cells or elements of these cells originating from these lines. It also relates to a process for selecting such lines. A subject of the invention is also the uses of these lines in diagnostic, therapeutic and prophylactic applications. According to the present invention, the human hepatoma cell lines are characterized in that they are capable of being infected naturally by parasites and/or viruses; said parasites may or may not be hepatotropic, such as Plasmodium or parasites of the genus leishmania; and express receptors of the family of the Flaviviridae and Hepadnaviridae viruses, preferably HBV and HCV. These new lines thus allow complete study of the cycle of the parasites and/or viruses in particular the viral cycle of the HBV, from the natural infection stage to the replication and/or propagation of the virus. It will be observed in this respect that no human hepatoma cell line is at present capable of being infected by Plasmodium falciparum, i.e. that no human hepatoma cell line is capable of supporting the development of mature forms of this hepatotropic parasite (schizonts). Moreover, due to its ability to proliferate, these lines are very easy to manipulate. According to another aspect of the invention, these lines are capable of reaching an advanced level of differentiation. In particular, the cells resulting from the lines according to the invention make it possible to reach a stage of hepatic differentiation, i.e. a morphology close to cells constituting the liver, such as the hepatocytes and/or the biliary cells with in particular: the formation of trabeculae of parenchymatous cells, the formation of functional biliary canaliculi, with at cell level, the reconstitution of a biliary pole. Throughout the Application, reference is made to typical notions of the structural organization of the liver cells. These notions, in particular the biliary pole, are explained in the preamble to the “Results” paragraph of Example 1 hereafter. It is surprising to note that the cells originating from the lines according to the invention are capable of practically identically mimicking the structural organization of the liver cells and of reproducing its functions: in fact, the biliary canaliculi formed by the cells of the lines according to the invention are functional, i.e. capable of playing their detoxification role. This functional differentiation is moreover highly advanced: the cells of the human hepatoma cell lines according to the invention can express the functions characteristic of the hepatocyte, namely: the production of plasmatic proteins, in particular albumin, and transferrin, the detoxification function, in particular: the expression of various forms of P450 cytochromes, such as CYP2E1, CYP3A and/or CYP1A, the expression of various forms of detoxification phase II enzymes in particular GSTα, the conjugation of biliary salts, the elimination of urea. the energy regulation function: the storage of sugar in the form of glycogen and the production of glucose by glycolysis, in particular, the expression of aldolase B, and/or neoglucogenesis, metabolism of lipids. It will be noted with interest that no human hepatoma cell line was capable of producing cells which could reach a level of differentiation such that these cells could express practically all of the functions of the normal human hepatocyte, in particular, the detoxification functions of phases I and II (CYP2E1, CYP3A, CYP1A and GSTa). According to an unexpected aspect, the cells originating from the lines according to the invention possess properties of pluripotent cells, in particular properties of resident and/or oval stem cells, i.e. capable of differentiating towards the hepatocyte, biliary, pancreatic and/or intestinal route. The resident stem cells are liver cells, capable, during a massive destruction of the liver, of actively multiplying in order to regenerate the part destroyed. These cells can evolve towards a hepatocyte or biliary lineage (FIG. 1). Moreover, these resident stem cells, sometimes also designated oval cells, have the ability to differentiate into different cell types such as pancreatic, intestinal and/or hepatic cells. Another advantage of the lines according to the invention lies in their ability to proliferate actively. Thus, in the proliferation phase, the cell population doubles in approximately 24 hours. The invention relates in particular to the cell line filed on 5 Apr. 2001 at the Collection Nationale de Cultures de Microorganismes, Institut Pasteur, 25 rue du Docteur Roux, F-75724 Paris Cedex 15, under No. I-2652. This line, called HepaRG, is an example of a cell line having all the characteristics of the lines according to the invention at the same time: it can be infected naturally by parasites, viruses, it has the morphological characteristics set forth above, and possesses all the biological functions of a hepatic cell. It appears to be a virtually perfect model of the hepatic cells. Also included within the scope of the invention are cells or elements of cells originating from the lines according to the invention and in particular, membranes, receptors and/or antigens originating from this membrane, cytoplasm, nucleus, genes and/or gene products, DNA, mRNA, cDNA, proteins, peptides. Moreover, the invention aims to provide methods for obtaining and selecting such lines. This involves in particular a process for selecting human hepatoma cell lines comprising: a phase of cell proliferation in a culture medium comprising continuously at least one cortico-steroid at a non-toxic concentration which promotes the differentiation of normal human hepatocytes, and in particular their optimum differentiation. then, having reached confluence, a phase of cell differentiation in this same medium, by the addition of DMSO, in a quantity sufficient to induce differentiation, this process being repeated several times, preferentially 3 times, if desired. This cell selection process is indispensable for maintaining the properties of the lines according to the invention. In fact, this selection process induces high cell mortality. Example 3 below demonstrates the necessary cooperation between the cortico-steroid and the DMSO. The phrase “non-toxic concentration which promotes the differentiation of normal human hepatocytes”, is used to refer to the cortico-steroid concentration promoting, during its addition to a culture of normal human hepatocytes, the differentiation of the cells towards a morphology and a functional state described in the preamble to the “Results” paragraph of Example 1. This concentration is non-toxic, i.e. its addition does not lead to a cell mortality rate greater than approximately 10%. Moreover, the term “quantity sufficient to induce the differentiation” is used to refer to the quantity of DMSO necessary to induce the differentiation of a culture of normal human hepatocytes. It will be noted with interest that a preferential process comprises a cortico-steroid present at a high concentration, continuously in the medium, in contrast to the processes usually used in hepatoma culture. Surprisingly, the presence of this cortico-steroid in no way prevents the lines from proliferating. This selection process has made it possible to develop a process for obtaining the lines according to the invention comprising a stage of biopsy of a solid tumor of hepatocarcinoma type, a stage of isolation of the cell population using a proteolytic enzyme and a stage of selection of the lines using the selection process detailed above. The proteolytic enzyme preferentially used is trypsin and/or collagenase. The invention also proposes a process for infecting hepatic cells with a hepatotropic parasite and/or a virus comprising: a selection phase using the abovementioned selection process, a differentiation phase allowing the cells to reach a morphology close to the hepatocyte using culture medium comprising at least one cortico-steroid at a non-toxic concentration which promotes optimum differentiation of normal human hepatocytes, with DMSO added to it, in a quantity sufficient to induce differentiation, an infection phase with incubation of the hepatic cells in a culture medium comprising at least one cortico-steroid at a non-toxic concentration which promotes optimum differentiation of normal human hepatocytes, to which the infectious source is added. The hepatotropic parasite can be a Plasmodium and the virus, HBV or HCV. A possible infectious source is the supernatant of HepG2 cells and/or a patient's serum. The culture media used for the selection, obtaining and infection processes preferably contain insulin in a quantity sufficient to promote the survival of normal human hepatocytes, preferentially from 2.5 μg/ml to 10 μg/ml, in particular of the order of 5 μg/ml. The insulin makes it possible to considerably improve the viability of the cells. Moreover, the cortico-steroids of these culture media are preferably hydrocortisone hemisuccinate and dexamethasone. Other inducers of differentiation can be used, in particular retinoic acid and/or its synthetic analogues, oestrogens and thyroid hormones. The term “synthetic analogues” is used to refer to the analogues of said cortico-steroids and retinoids of non-natural origin. The corticoid concentration is from 10−7 M to 10−4 M, preferentially approximately 5.10−5 M for the hydrocortisone hemisuccinate and approximately 10−5 M for the dexamethasone. Finally, the DMSO concentration, when the latter is added to the culture media, is from 1% to 4%, preferentially approximately 2%. The invention also relates to a process for transfection of the lines according to the invention using a vector comprising the complete sequence and/or part of genetic material from the HBV and/or HCV viruses. It also relates to a high-flow-rate screening process of differentially expressed genes using a chip-type tool produced from the lines and/or cells and/or parts of cells according to the invention, preferably, these genes being differentially expressed under the effect of culture conditions, exposure to a molecule and/or virus and/or a parasite. An example of a chip-type tool is given in Example 7 hereafter. It is a cDNA chip the construction of which allows high-flow-rate screening of differentially expressed genes. The invention finally covers the use of the different culture media allowing the obtaining, maintaining, proliferation, selection, differentiation, transfection, infection of the lines according to the invention. It involves in particular the use of a culture medium comprising continuously at least one cortico-steroid, preferentially hydrocortisone hemisuccinate at a non-toxic concentration which promotes optimum differentiation of normal human hepatocytes, in order to maintain the stability of the cell population lines and/or of the cells according to the invention; as well as the use of a culture medium continuously comprising at least one cortico-steroid, preferentially hydrocortisone hemisuccinate at a non-toxic concentration which promotes optimum differentiation of normal human hepatocytes, with DMSO added in a quantity sufficient to induce differentiation of the cells originating from the lines according to the invention; and use of the culture medium continuously comprising at least one cortico-steroid at the above-mentioned concentration as well as sodium butyrate at a concentration sufficient to induce a biliary-type differentiation, preferably a concentration of 2.5 to 5 mM, in particular approximately 3.75 nM. As already indicated, the lines according to the invention are capable of evolving towards distinct differentiation routes. The differentiation route is strongly influenced by the choice of culture medium. Evolution towards the hepatic, biliary and pancreatic routes are illustrated by Example 4. Human hepatoma lines according to the invention are the subject of a numerous applications, given their high differentiation capacity, their considerable functionality and their ease of manipulation. A first useful application corresponds to the use of the lines and/or cells originating from the lines according to the invention, for metabolic and/or toxicity tests intended for the evaluation of new medicaments and/or nutritional constituents and/or environmental pollutants. In fact, the lines according to the invention are at present the best model mimicking normal human hepatocytes, in particular in terms of detoxification. In particular the lines according to the invention allow the manufacture of an extracorporeal bioreactor for the transient treatment of acute hepatocellular insufficiencies. The invention also covers the use of the lines according to the invention for the screening and/or manufacture of new vaccines and/or antiviral molecules, in particular for the screening of molecules active vis-à-vis one of the viral cycle stages; for the manufacture of antibodies directed against a virus belonging to the Flaviviridae and Hepadnaviridae family, in particular directed against the HBV and HCV and/or their cell membrane receptors; for carrying out viral neutralization and/or vaccinal composition tests comprising at least viral particles and/or polypeptides obtained after infection and/or transfection of the lines according to the invention, combined with a pharmaceutically acceptable vehicle and/or excipient and/or adjuvant. The lines according to the invention are advantageously used for the purposes of validating the virucidal capacity of disinfectant chemical products. The invention also proposes a new method for evaluating the virucidal capacity of a disinfectant chemical product for cleaning equipment, premises and/or surfaces comprising: bringing the viruses into contact with said equipment, premises and/or surfaces, the disinfecting of said equipment, premises and/or surfaces with said disinfectant chemical product, then the contamination of cells according to the invention, by the viruses having survived the disinfecting. Other characteristics and advantages of the invention are given in the examples which follow. They relate, for illustration purposes, to the line I-2652 deposited at the CNCM, called HepaRG. In these examples, reference is made to FIGS. 1 to 13, which represent respectively: FIG. 1, a diagrammatic representation of the different cell types participating in the homeostasis of the liver, FIG. 2, a diagrammatic cross-section of the liver, clearly showing the structural organization of the different cells constituting the liver, FIG. 3, the growth curve of the HepaRG line, FIG. 4, phase contrast microphotographs of HepaRG cells at different stages of differentiation. FIG. 5, electron micrographs of HepaRG cells FIG. 6, the karyotype, with RHG-type staining, of a pseudodiploid metaphase representative of the HepaRG line, FIG. 7, a Northern blot analysis of the expression of the mRNAs in 2 liver biopsies, HepG2 cells and HepaRG cells, FIG. 8, the effects of activity inducers CYP1A (phenacetin deethylase) and CYP3A4 (nifedipine oxidase), FIG. 9, the influence of corticoids and DMSO on the level of hepatic mRNAs in the HepaRG cells, FIG. 10, the effects of different factors influencing the infectability of the cells, and FIG. 11, the results of infection of the HepaRG cells with HBV. FIGS. 12 and 13, biliary and pancreatic differentiations, FIGS. 14 and 15, the infectability of HepaRG cells with the serum of patients carrying HCV, in the presence or absence of interferon α, FIG. 16, the kinetics of replication or inhibition of HCV, by interferon α, FIG. 17, the kinetics of infection by parasites of the genus Leishmania, and, FIGS. 18 and 19, optimizations of the protocol of infection by parasites of the genus Leishmania. EXAMPLE 1 Isolation of Hepatoma Cell Line 1. Materials and Methods Cells were isolated from a liver tumor taken from a patient suffering from a hepatocarcinoma and viral hepatitis C. The whole procedure was carried out in accordance with French law and regulations and approved by the Comite National d'Ethique, and confidentially. The samples were cut into fine sheets, then rinsed with a HEPES-based buffer solution [(pH 7.7; 140 mM NaCl, 2.68 mM KCl, 0.2 mM Na3HPO4 and 10 mM HEPES], and digested with 0.025% of collagenase D (Boehringer Mannheim) diluted in the same buffer solution with 0.075% of CaCl2 added (addition under gentle stirring at 37° C.). After two washings with the HEPES buffer solution, the cells are resuspended in a Williams' medium E, supplemented with 10% of foetal calf serum (FCS), 100 U/ml of penicillin, 100 μg/ml of streptomycin, 5 μg/ml of insulin, 2 mM/ml of L-glutamine and 5.10−7 M of hydrocortisone hemisuccinate. The cell suspension is then distributed into different wells on a plastic support. After several weeks, the cell growth is sufficient to produce a culture. Its population is heterogenous, but the cells are highly differentiated and have a hepatocyte-type morphology. The wells having the most homogenous cell populations are separated with trypsin, then redistributed. After 3 passages, the cells are aliquoted, then frozen in the culture medium with 10% of DMSO added, and preserved in liquid nitrogen. After thawing, the well having the greatest proportion of cells having a hepatocyte-type morphology is selected. The cells are cultured in the culture media used for their isolation and/or in the differentiation medium used to complete the cell selection. In order to obtain a more frequent hepatocyte differentiation in the line, the HepaRG cells originating from the first selection are cultured in a Williams' medium E, with 5 μg/ml of insulin, 100 U/ml of penicillin, 100 μg/ml of streptomycin, 5.10−7 M of hydrocortisone hemisuccinate, 2 mM/ml of L-glutamine and 10% of FCS added. The cells are subjected to a passage every 10-15 days, at a ⅕ dilution. The differentiation phase takes place in two stages: the cells are maintained in their growth medium for two weeks, confluence being reached at the end of one week, they are then maintained in a differentiation medium (corresponding to the preceding culture medium, with 2% of DMSO added) for another two weeks, the medium being replenished every 2 or 3 days. Cytogenetic Analysis The karyotype of the HepaRG cells was analyzed after 8 passages. The cells were first maintained for 24 to 48 hours in RPMI 1640 with 10% of FCS added, then blocked in metaphasis by exposure to Colcemide (10 μg/mL) for 45 minutes. The cells were then treated with a hypotonic solution (0.1 M of MgCl2), fixed with Carnoy's acetic solution and the chromosomes revealed by RHG staining. 2. Results Preamble FIG. 2 shows a diagrammatic cross-section of the liver clearly showing the structural organization of the liver cells. In particular, a normal human hepatocyte has the following morphological characteristics: These are cells with a granular cytoplasm due to the fact that they are rich in organites such as mitochondria and rough endoplasmic reticulum vesicles, and a round and regular central nucleus with a very dense nucleolus. These cells become grouped and organized into typical trabecula, most often formed from cords of 2 to 4 cells, interlinked by joining structures of desmosome type, and communicating structures of “Gap”-type, and bordered on either side by sinusoids in which the blood circulates. This organization into trabeculae determines the double polarity which characterizes the hepatocyte: a sinusoidal pole on the side of the sinusoids and a biliary pole at the interface of the hepatocytes. The biliary pole is associated with the detoxification function and more particularly with the elimination of biliary salts. It is a dilated intercellular space, closed by characteristic complex junctions (tight junctions plus desmosomes) which delimit for each cell a specialized membrane zone on the one hand, at the functional level by the expression of specific proteins, and on the other hand, at the morphological level by the formation of numerous villi. Moreover, the term biliary cells refers to cells constituting the biliary canals and canaliculi. The latter make it possible to evacuate into the bile, the biliary salts originating from the hepatocytes and having circulated along the trabecula of parenchymatous cells via the biliary pole. Selection of Cells Having a Hepatocyte Morphology The cells originating from the wells initially selected for their high proportion of hepatocyte-type cells are maintained in a culture medium containing 5.10−7 M of hydrocortisone hemisuccinate. It is noted that their morphology becomes more and more heterogenous and removed from that of a hepatocyte. In order to find a hepatocyte-type cell population, in accordance with the invention the following selection method is then used: a differentiation medium is used, formed from a basic medium containing only 5 mg/L of insulin and 10% of FCS to which 2% of DMSO and 5.10-5 M of hydrocortisone hemisuccinate are added. Once confluence is well established, the HepaRG cells are cultured in this medium. In the following 2 to 4 days, the medium, which is highly toxic, causes the death of more than 90% of the cells. In parallel, the morphology of certain surviving cells changes considerably. After two weeks of this treatment, the mortality rate of the cells appears to be zero, and certain surviving cells have the same morphology as normal human hepatocytes, cultured under the same conditions. It is therefore established that the differentiated cells are more resistant to DMSO than the others. The cells, once replaced in the medium without DMSO, return to an active proliferation phase. The selection process is continued. After 3 selection stages in this differentiation medium, most of the cells become resistant to DMSO and capable of re-differentiating, once confluence is reached. The homogeneity of the population is further increased by means of two other selection protocols. We observed and took advantage of the fact that treatment with trypsin tends to separate the most differentiated cells in the form of multi-cell clusters whilst the less differentiated cells are isolated. The purification of the large aggregates makes it possible to enrich the population with cells capable of differentiating. The use of collagenase is based on a very different principle: the treatment carried out with the collagenase involves selective separation of the most differentiated cells which can be recovered and reseeded. Finally, the stability of the phenotype of the line is considerably promoted by the continuous use of a high concentration of hydrocortisone hemisuccinate (5.10-5 M). Morphological Modifications: from Proliferation to Differentiation An unexpected characteristic of the cells selected concerns their ability to proliferate in the presence of strong corticoid concentrations. After separation, most of the cells attach to the support in two hours and begin to proliferate. During the exponential proliferation phase, the population doubles in 24 hours then, when the cells reach confluence, growth slows down. The latter reaches a plateau in the 10 days following the passage, after which the cells can no longer divide, but stay alive for several weeks. In FIG. 3, the cells cultivated in the absence—▪—or in the presence of hydrocortisone (5.10−5 M)—♦—for 10 passages were seeded at a density of 40,000 cells per 4 cm2 well and maintained in the same culture medium. The cells were collected by trypsinization and counted manually. During the proliferation phase, the HepaRG cells form a homogenous population of epithelial phenotype (absence of regular structural organization) and shapes different from that of the hepatocytes (FIG. 4A, HepaRG cells under proliferation conditions). Once confluence is reached, the cells undergo considerable morphological modifications. In four weeks, a number of colonies of granular hepatocyte-type cells appear, whilst at the periphery, epithelial cells can be distinctly seen (FIG. 4B, HepaRG cells maintained at confluence for 20 days). The addition of DMSO two weeks after the passage induces a very complete morphological differentiation: organization of the cells into trabeculae comparable to those obtained in primary culture of normal hepatocytes, in which canaliculus-type structures can be recognized (indicated by a black arrow in FIG. F4). FIGS. 4C and 4D show HepaRG cells maintained at confluence for 5 days, then treated with 2% of DMSO for 15 days (scale=100 μm). Some epithelial cells occupy the free spaces (flat, regular cells, written in full in FIG. 4C and annotated by the letter E in FIG. 4D). The characteristic hepatocyte morphology is also translated at the level of the organization into trabeculae of the hepatocyte cords. It is obtained at the end of two weeks of exposure to DMSO, the granular cells then very strongly resembling hepatocytes (FIG. 4C, cells annotated by the letter H in FIG. 4D). At the end of these two weeks, no further significant modifications are noted. The conditions making it possible to obtain complete hepatocyte differentiation are therefore defined by: one week of confluence in the presence of corticoid (5.105 M of hydrocortisone), then two weeks of differentiation in the presence of hydrocortisone and 2% of DMSO. Surprisingly, it was observed that by selectively collecting the granular cell population from the trabeculae, the latter was capable, even after a long period of quiescence, of returning to the active proliferation phase and once again giving rise to two hepatocyte and epithelial cell types, when confluence is reached. An electron microscope study revealed the structural organization of the cells: two adjacent cells are strongly attached to each other by desmosomes (FIG. 5A, view with low magnification), with structures strongly resembling biliary caniculi, and surrounded by complexes typical of junctions (“tight” junctions+desmosomes). FIGS. 5B and 5C show views with a greater magnification, showing a typical accumulation of collagen granules and a biliary canaliculus-type structure. (Scale=2 μm). In FIG. 5A, characteristic regular, round nuclei can be seen, comprising one or two nucleoli. The large number of mitochondria in the cytoplasm are slightly domed in shape, showing a few peaks. It is also possible to observe a number of cytoplasmic granules, which are in fact an accumulation of glycogen particles organized into a “rosette” as described in the normal liver in vivo (FIG. 5B). Finally, unexpectedly, the karyotype of the cells of the line is subdiploid. The following karotype formula was deduced: 46 <2n>, XX, +del (7) (q11-q21) inv? (7) (q21 q36), -der (22) t (12; 22) (p11; q11). Determination of the deletion and translocation points was carried out by hybridization in situ. Out of 40 mitoses studied, 65% contain 46 chromosomes. 100% of the cells have the following anomalies (FIG. 6): a supernumerary and modified chromosome 7 leading to a trisomy 7, and a translocation t (12.22) with a loss of the fragment 12p leading to a monosomy 12p (FIG. 6). Other isolated anomalies were detected and are reported in Table I below: TABLE 1 Cytogenetic Characteristics of the HepaRG Line CHROMOSOMES WITH ANOMALIES FREQUENCY (% OF CHROMOSOME ANOMALIES MITOSES) 7 ?inv(7)(q21q36) Partial trisomy 100 del(q11-q21) supernumerary 12 Unbalanced Monosomy 12p 100 translocation 22 t(12; 22)(p11; q11) Monosomy 22p 100 2 supernumerary Trisomy 15 4 supernumerary Trisomy 7.5 8 i(8)(q10) Monosomy 8p 5 Monosomy 8q EXAMPLE 2 Functional Ability of the Line 1. Materials and Methods Extraction of the RNA and Analyses THE total cell RNA is extracted using the Total SV RNA® kit; (Promega, France), separated on 1.5% agarose gel and analyzed by Northern blot. A check on the quantity of RNA transferred to the filters is carried out after staining with methylene blue. The hybridization is carried out according to the protocol of Gripon et al. (1993, Virology, 192: 534-540). Enzyme Activities Associated with the Detoxification Function The enzyme activities were established by means of the protocols developed by Guillouzo et al. (1993, Hepatology 18: 406-414). The following were studied: the deethylation of phenacetin to paracetamol, the oxidation of nifedipine to 3,5-dimethoxy-carbonyl-2,6-dimethyl-4-(2-nitro-phenyl) pyridine, the demethylation of dextromethorphan to dextrorphan tartrate, the hydroxylation of tolbutamide to hydroxytolbutamide, the hydroxylation of 4-mephenyloin to 4-hydroxymephenyloin. For comparison, enzyme activities were also determined on cultures of normal human hepatocytes incubated for 2 to 16 hours in the presence of the following substrates: 2.10−4 mol/L of phenacetin 2.10−4 mol/L of nifedipine 2.10−4 mol/L of dextromethorphan and mephenyloin 1 mmol/L of tolbutamide. The assays are carried out by high performance liquid chromatography (HPLC). The results are expressed in picomoles of metabolites formed per hour and per μg of DNA. The activity of the glutathion-S-transferase (GST) is estimated using 1-chloro-2,4-dinitro-benzene (CDNB) (Merck) as substrate, at pH 6.5 and at ambient temperature. 2. Results The level of differentiation of the cells was checked by analysis of the quantities of different mRNAs specific to the liver, in particular the mRNAs of the proteins of the functions specific to the liver, such as the proteins of the serum (albumin, transferrin), a hepatic enzyme involved in glycolysis (aldolase B) and 3 specific enzymes involved in detoxification (CYP2E1, CYP3A etGSTa). All these RNAs are expressed by adult hepatocytes. Their expression levels in the proliferation and differentiation phases were compared. Moreover, a comparison was established with the corresponding expression levels in human hepatocytes and the HepG2 cells. FIG. 7 is a Northern blot analysis of the expression of the messenger RNAs in 2 liver biopsies, HepG2 cells and HepaRG cells. The cells were maintained either under proliferation conditions (prolif) or at confluence for 1 month. Treatment of the cells with 2% of DMSO for the last 15 days of culture is indicated as follows: +D. Little or no specific hepatic mRNAs were detected in the cells during proliferation. In contrast, these can be detected in the cells at confluence, maintained for 2 weeks in the presence of a high corticoid concentration. Those of albumin and aldolase B are strongly expressed, whereas CYP2E1 and CYP3A4 remain weakly expressed. It is also observed that in the cells having acquired the typical organization into trabeculae, exposure to DMSO causes an increase in the transcripts corresponding to the increased expression of the latter two enzymes, making their expression level practically equal to that observed in cells originating from biopsies. The study carried out in parallel on cells of the HepG2 line used as a reference reveals that 3 of the 5 specific functions studied are only slightly expressed or not expressed in these cells. Moreover, the action of the DMSO on the HepG2s seems to inhibit the expression of certain of these functions, in particular CYP2E1 and CYP3A. These analyses demonstrate the original character of the HepaRG line. The activity of these different enzymes corresponding to detoxification phases I and II was then measured. The other cell lines weakly express these enzymes, often late, or also do not respond to specific inducers. The activity of these different enzymes was measured on confluent HepaRG cells treated with DMSO. This activity was compared to that of primary cultures of human hepatocytes, as well as to that of the HepG2 lines and the BC2 clone of the HBG line. The results are given in Table II below: TABLE II Activity of the Enzymes of Phases I And II HUMAN PRIMARY CULTURE HEPATOMA OF HUMAN LINE HEPATOCYTES ENZYME ACTIVITY HepaRG HBG BC2 HEPG2 Min/Max Average n Phenacetin deethylase* 0.33 0.1 0.3 0.1-25 3.9 47 Tolbutamide hydroxylase 0.51 0.03 <0.2 0.2-2.1 0.9 8 S-mephenytoin hydroxylase* 0.45 <0.1 ND 0.1-2 0.7 10 Dextromethorphan demethylase* 0.06 0.02 <0.1 0.1-2 0.5 10 Nifedipine oxydase* 1 1 <0.5 0.5-30 5.7 34 Paracetamol glucuronyl transferase* 3.7 1.5 <0.3 0.3-16 4.1 26 Paracetamol sulphoconjugation* 0.7 0.16 0.3 0.1-14 3.6 27 Glutathion S-transferase+ 0.04 0.008 ND 0.03-0.5 0.12 27 (substrate: chlorodinitrobenzene) *activity expressed in nanomoles of metabolites produced/h/mg of proteins +activity expressed in units/mg of proteins Examination of this table shows that the HepaRG cells possess the enzyme activities associated with the detoxification function at levels practically equivalent to those expressed by normal human hepatocytes, except for dextromethorphan demethylase, the activity of which is slightly less. Activation of the phenacetin deethylase and nifedipine oxydase is greater than that obtained with the other lines. This activation is lower than that observed in normal human hepatocytes, whilst remaining within the same order of magnitude (FIG. 8, the activities were measured after 72 hours of treatment and are expressed as a ratio of the cells treated to the cells not treated corresponding to the control cells). EXAMPLE 3 Cooperation Necessary Between the Corticoid and DMSO for Complete Differentiation Experiments were carried out in order to verify whether both agents were necessary to induce complete differentiation. 1. Effect on the Differentiation A first series of experiments was carried out in order to study the effects of the absence of the corticoid on cells having always been maintained in its presence. In FIG. 9A, the HepaRG cells at passage 13, were kept for 2 additional passages either in the continuous presence of hydrocortisone (growth: HN), or in the absence of hydrocortisone (growth: HO). They were then induced to differentiate (diff.) for 3 weeks in the absence of hydrocortisone (HO) or in the presence of hydrocortisone 5×10−5 M (HN), and in the presence of different concentrations of DMSO. The withdrawal of the corticoid was carried out at confluence, i.e. at the time when the cells begin their differentiation. After culture for 2 weeks, in the absence of DMSO, no specific liver function (no transcript), except albumin, is detected. The addition of 2% of DMSO is so toxic that its use is impossible. The addition of 1% of DMSO, less toxic, does not induce any more advanced differentiation. A second series of experiments made it possible to study the effects due to the absence of DMSO. When the cells are exposed only to corticoid, the presence of a few transcripts (of albumin, transferrin and aldolase B) is detected at very low levels. The addition of 1 to 2% of DMSO to the culture medium causes a rapid accumulation of a number of transcripts, in particular those already mentioned and those of CYP2E1 and CYP3A. This demonstrates that the cooperation between the corticoid and the DMSO is indispensable in order to reach maximum differentiation. Finally, the stability of the cultures was established over at least 6 weeks. 2. Effect on Proliferation: Continuous Use of Corticoid The cells are kept in a culture medium without corticoid and their ability to carry out differentiation is tested after 2 (FIG. 9A) and 10 passages (FIG. 9B). In both cases, no differentiation is observed and only the mRNA of the albumin is detected. The addition of 2% of DMSO proves highly toxic and the addition of 1% of DMSO causes no perceptible changes. The addition of corticoid only at confluence, on the other hand, causes an accumulation of the different transcripts specific to the liver. But this differentiation is incomplete as the CYP2E1 and CYP3A transcripts are difficult to detect, even after the addition of 1 or 2% of DMSO, the latter dosage proving to be highly toxic after 10 weeks without corticoid. Finally, the cells without corticoid gradually undergo growth modifications: contact inhibition is delayed to the extent that the confluence plateau has a cell density twice that noted with cells continuously maintained in the presence of corticoid (FIG. 3). This study clearly shows the importance of the cooperation between the DMSO and the corticoid, both in the proliferation phase (the corticoid making it possible to reduce the toxicity of DMSO) and in the differentiation phase (where the action of the two agents is complementary). EXAMPLE 4 Abilities of the HepaRG Cells to Evolve Towards the Biliary and Pancreatic Differentiation Routes 1. Materials and Methods HepaRG cells were separated, diluted to ⅕ in Williams' E medium to which 5 μg/ml of insulin, 100 U/ml of penicillin, 100 μg/ml of streptomycin, 510-5M of hydrocortisone hemisuccinate, 2 mM of L-glutamine and 10% FCS were added, then redistributed into wells with a plastic support. Four culture conditions were produced: HepaRG cells were treated with 3.75 mM sodium butyrate in the maintenance medium as from the day following subculture according to the protocol described by Blouin et al. (1995, Specialization switch in differentiating embryonic rat liver progenitor cells in response to sodium butyrate, Exp. cell res., 217: 22-33). The medium is then replenished every 2-3 days, the HepaRG cells were treated 5 days after subculture by 3.75 mM sodium butyrate or 2% DMSO. The medium was replenished every day for 5 days, the HepaRG cells were treated at strong confluence by 3.75 mM sodium butyrate; the medium was replenished every 2-3 days, the HepaRG cells were seeded on a plastic support or monolayer of rat primitive biliary epithelial cells in MEM alpha medium complemented with L-glutamine (2 mM), i-inositol (0.2 mM), folic acid (20 mM), β-mercaptoethanol (10−4 M), transferrin 200 μg/ml, 12.5% FCS and 12.5% horse serum. In certain situations, cytokines such as LIF, IL-3, SCF or G-CSF were added to the medium. This medium was replenished every 2-3 days. Indirect Immunohistochemistry The cells after washing with PBS are fixed by a solution of 4% paraformaldehyde buffered by 0.1 M sodium cacodylate at pH 7.4 for 20 minutes at 4° C. They are then preserved in a PBS buffer until the time of the analysis. The specific sites are saturated for 45 minutes with PBS containing 10% FCS. The samples are then treated with primary antibodies for an hour at ordinary temperature in PBS containing 0.05% saponin. After 3 washings in PBS containing 0.05% saponin, the samples are incubated with the second antibody coupled to peroxydase. Two washings are then carried out, then the peroxydase activity is revealed by incubation with 0.4 mg/ml of 3,3′-diaminobenzidine in a solution of 0.05M Tris at pH 7.6, 0.01% H2O2 at 110 volumes. 2. Results a/ Differentiation Towards the Biliary Route (FIG. 12) Morphological Modification Before any treatment and at confluence, the HepaRG cells constitute a population which is not very homogenous, where polygonal cells and elongate cells are found (FIG. 12). Under all the conditions of treatment at confluence of the HepaRG cells by the sodium butyrate, the cells have the particular morphology of biliary cells in culture (FIG. 12). The cells spread out and increase in size, they have a clear cytoplasm with an ovoid nucleus containing several nucleoli. The contour of the cells is generally poorly defined. Sometimes, lipid droplets are observed. When the cells are treated at very strong confluence, certain of the cells die. These cells probably correspond to the cells already committed towards the hepatocyte route. The effect of the butyrate was also tested on HepaRG cells at a low density and in active proliferation phase. A characteristic of these cells is their ability to proliferate in the presence of a high dose of sodium butyrate (FIG. 13A). During the proliferation phase, the HepaRG cells form a homogenous population of epitheloid-type cells, at confluence they have the appearance of biliary epithelial cells. Phenotypical Changes The morphological modifications observed in the presence of sodium butyrate are correlated to phenotypical changes (Blouin et al. 1995). We used four markers of differentiation towards the biliary route, γ-glutamyl transferase, the α6 chain of integrins and the cytokeratins 7 and 19 which normally disappear when the cells are directed towards the hepatocyte route. For differentiation towards the hepatocyte route, we looked for an increase in the expression of albumin and a reduction in the expression of the al chain of the integrins. In the first instance we characterized the non-differentiated proliferating cells. The cells of the HepaRG line have the following phenotype: expression of the c-kit, cytokeratins 7 and 19, α1 and α6 chains of the integrins, γ-glutamyl transferase and albumin suggesting that these cells are oval cells and/or stem cells (see diagram FIG. 1). When the cells are cultured in the presence of sodium butyrate, they express γ-glutamyl transferase more strongly, preserve the expression of the α6 chain of the integrins, and the cytokeratins 7 and 19 attesting to their commitment towards the biliary route. When they are cultured in the presence of DMSO, which induces hepatocyte differentiation, we observe a disappearance of the expression of the cytokeratins 7 and 19, α6 chain of the integrins. They express the α1 chain of the integrins at a lesser level and albumin very strongly, confirming their hepatocyte differentiation. The cell populations being heterogeneous in the cultures, these highly characteristic phenotypes are found only in the plaques differentiating towards one or other of the routes. The results obtained after in situ marking of the cells treated or not treated by sodium butyrate are summarized in Table III below. TABLE III Biliary/Hepatocyte Route Differentiation HepaRG HepaRG cells cells HepaRG 2% DMSO Sodium cells Differentiation butyrate before hepatocyte Differentiation treatment route biliary route γ-glutamyl + −/+ ++ transferase α6 chain + − + Cytokeratin 7 + − + Cytokeratin 19 ++ − ++ Albumin −/+ ++ −/+ α1 chain ++ + −/+ −/+: weakly positive; + positive; ++: highly positive b/ Differentiation Towards the Pancreatic Route (FIG. 13B) As illustrated by the diagram in FIG. 1, the “oval” stem cells of the liver are pluripotent. Apart from being able to differentiate into hepatic cells, which is demonstrated above, they have the ability to differentiate into other cell types, including the pancreatic cell of the acini. We researched whether this differentiation potential was one of the characteristics of the HepaRG line. When the cells are seeded and cultured in MEM alpha culture medium, the cells adhere, then retract in order to former spheroid structures suggesting the formation of complex canalicular networks, morphologically similar to the three-dimensional cultures of pancreatic epithelial cells (Keer-Conte et al., 1996, Ductal cyst formation in collagen-embedded adult human islet preparations: a means to the reproduction of nesidioblastosis in vitro, Diabetes, 45:1108-1114). EXEMPLE 5 Infection of the Line by the HBV 1. Materials and Methods Infection The infectious source is preferentially constituted by the supernatant of HepG2 cells of the clone 2.2.15, concentrated 100 times. In fact, this infectious source has the double advantage of being inexhaustible and of constant quality. The cells used for the infection are cells having been cultured according to the conditions defined in Example 1 (permanent presence of 5.10−5M of hydrocortisone hemisuccinate) and having been maintained for a week at confluence, then for 2 weeks in the same medium with 2% of DMSO added. These cells are incubated with the infectious source, diluted 10 times, in the culture medium with 4% of PEG 8000 (Sigma) added, for 20 hours at 37° C. The second part of this HBV infection protocol was established by Gripon et al., 1993, Virology, 192: 534-540. The control cultures were incubated with 4% of PEG and 25% of FCS diluted in a solution of phosphate buffer saline (PBS). At the end of the incubation, the cells are washed three times with culture medium and maintained in the presence of 2% of DMSO and 5.10−5 M of hydrocortisone hemisuccinate until they are used. Neutralization tests were carried out before infection by incubating the virus with hepatitis B surface monoclonal antibodies (S39-10) for 1 hour at ambient temperature. Detection of the Hepatitis B Virus Surface Antigen (HbsAg) The HBs antigen was detected in the medium using the ELISA kit (Monalisa AgHBs plus®) from Biorad Laboratories. The results are expressed in pg/ml of supernatant. Extraction of Viral DNA and Analyses Viral DNA replication intermediates were isolated in all the cell lysates. The cells are recovered after separation with trypsin, then lysed at 37° C. with a lysis buffer (10 mM of Tris-HCl pH 7.4, 0.5% of SDS, 10 ml of EDTA pH 7.4, 10 ml of NaCl) with proteinase K (200 μg/ml) added. The cell DNA is precipitated over 12 hours, at 4° C. with 1M NaCl. The supernatant containing the viral DNA is then extracted. The complete viral particles are isolated from the cell supernatant by immunoprecipitation with an anti-HBs polyclonal antibody (Dako, France). The nucleic acids are finally extracted after 12 hours of lysis at 37° C., in a lysis buffer with tRNA (40 μg/ml) and proteinase K (200 μg/ml) added. In all the above protocol, the DNA is extracted using phenol-chloroform and precipitated by isopropanol. The nucleic acids are analyzed by Southern blot on a 1.5% agarose gel. The molecular weight markers are restriction fragments of the DNA of the hepatitis B virus (3182 and 1504 bp). The hybridization is carried out according to the protocol of Gripon et al. above. 2. Results Evidence of the Infection The intracellular viral DNA is analyzed over the 10 days following the infection. FIG. 10A shows the effects of PEG on the infectability of the cells. It is a Southern blot analysis of the kinetics of appearance of the intracellular viral DNA after infection of the HepaRG cells in the presence of 5% of PEG (+PEG), or in the absence of PEG (−PEG). The position of the relaxed circular (RC) DNA and covalently closed circular (CCC) DNA forms are indicated to the right of the figure. The migration position of the molecular weight markers (fragments of the genome of the hepatitis B virus) is indicated to the left of the figure. In the absence of PEG, the DNA profile observed is identical to that revealed for the viral particles present in the inoculum. However, this signal gradually disappears until becoming practically undetectable 10 days after the infection. Moreover, no intermediate form of viral replication is detected under these conditions. On the other hand, the latter are clearly present when the cells are infected in the presence of PEG. A strong signal is observed immediately after the infection, with a profile similar to that observed in the absence of PEG. This proves that the penetration of the viral particles into the cells is effective. On the second day, the signal is sharply reduced due to the elimination of numerous viral particles, but a fine band positioned towards 2 kb can be observed. This band corresponds to CCC DNA (covalently closed circular DNA). The signals detected at intermediate positions correspond to nascent viral DNA, gradually increasing until the 10th day. In parallel, the kinetics of viral RNA accumulation is established. FIG. 10B is a Northern blot analysis of this kinetics after infection of the HepaRG cells, the HepG2 cells are used as a negative control of the viral infection. The size of the RNAs is indicated to the left of the figure. The signals at 2.4 and 3.5 kb, corresponding to the main species of RNA specific to the HBV, appear after two days of infection and accumulate only in the infected cells. In order to verify the specificity of the HepaRG cells to be infected, infection of two other hepatoma lines, HepG2 and BC2, was carried out under identical conditions. These two lines were selected because they are capable of differentiating. They were cultured under conditions allowing them to reach a maximum differentiation stage, as well as under the same conditions as those used for the HepaRG cells. After approximately 12 hours of incubation with the viral particles and 5% of PEG, the intracellular viral DNA and the viral RNA produced are analyzed. Immediately after infection, a large quantity of viral DNA is detected in all the lines, and above all in HepaRG and BC2. To the extent that the trypsin/EDTA treatment eliminates the viral particles adsorbed at the surface of the cells, the DNA observed must correspond to viral particles having penetrated to the interior of the cells. The signal decreases considerably in the two days following the infection. On the other hand, 18 days after the infection, only the HepaRG line has forms corresponding to viral replication intermediates i.e. the ccc DNA and the viral RNA forms. This shows that only the HepaRG line is capable of being infected and initiating the replication of the virus. The production of viral particles was sought in the supernatant of the infected HepaRG cells. The HBs antigen was assayed by radioimmunology. FIG. 11A represents a kinetics of AgHBs secretion in the supernatant of the cells infected. The supernatants were collected for 15 days after the infection of the HepaRG cells (▪), HBG BC2 () and HepG2 (□). A high HBs antigen concentration was detected in the supernatant. The antigen concentration increased during the 9 days following the infection, and was then maintained at a high level. On the other hand, in the supernatant of the HepG2 et BC2 cells, the antigen was only detected in the two days following the infection, which shows that the viral particles were adsorbed by the cells, then gradually released into the medium. Moreover, the complete viral particles present in the medium were estimated by immunoprecipitation with an anti-HBs antibody, followed by a Southern blot analysis of the DNA present in the precipitate. FIG. 11B shows this Southern blot analysis of the appearance kinetics of the extracellular viral DNA in the supernatant of the HepaRG cells infected by the HBV. After immunoprecipitation of the complete viral particles with an anti-HBs antibody, the viral DNA is extracted, then analyzed. The migration position of the molecular weight markers (fragments of the genome of the hepatitis B virus) is indicated to the right of the figure. A strong signal is observed two days after the infection. On the 4th day, it has decreased considerably but it gradually increases again until the 8th day and is maintained throughout the culture period. This kinetics analysis is suitable for the method of replication of the virus: after a period of release of the viral particles having penetrated the cell (for 2 to 4 days), the virus begins to replicate actively. The profile observed differs slightly from that obtained on the 2nd day. In Vitro Neutralization of the Infection In order to determiner whether a specific anti-S monoclonal antibody is capable of neutralizing the infection of the cells, virions are incubated with variable concentrations of antibodies, then brought into contact with the cells. The residual infection is estimated as a function of the long-term secretion of HBs antigen. FIG. 11C shows this viral neutralization test in vitro. The viral particles are incubated with seriated dilutions of a monoclonal antibody directed against the Hbs antigen (antibody S 39-10) () or of a non-relevant antibody (▪) and their infectivity evaluated on the HepaRG cells. The level of infection of these cells is estimated by measuring the secretion of HBs antigen in the supernatant of the cells infected, 10 days after the infection. In this figure, it can be seen that concentrations of 10 and 1 μg/mL block the viral infection, whilst lower concentrations only induce partial inhibition. A 50% inhibition corresponds to a concentration of 0.03 μg/mL. Influence of the Degree of Differentiation on the Infection The ability of the HepaRG cells to be infected was studied as a function of their degree of differentiation. Using the methods described in Examples 1 and 2, the cell differentiation programme was modified. A first series of infection was carried out on cells continually maintained in the presence of corticoid only, then in the presence of corticoid and different concentrations of DMSO, in order to induce different stages of differentiation. The analyses carried out 2 weeks later on the viral RNA show a correlation between the accumulation of the two main viral transcripts and the level of differentiation. FIG. 10C shows the effects of hepatocellular differentiation on infection by HBV. It is a Northern blot analysis of the intracellular viral RNAs after infection of the HepaRG cells in the presence of increasing concentrations of DMSO. This correlation was confirmed by a series of experiments carried out on cells infected at confluence (before their differentiation) then placed under optimum conditions in order to induce their differentiation. The results are given in Table IV below: TABLE IV Effect of Hydrocortisone Hemisuccinate and Cell Proliferation on the Infectability of HepaRG Cells Culture HbsAg secretion (pg/ml)# conditions HN Differentiation HO HN with 2% conditions HO after HO after HN after of DMSO after Infection 17th day 17th day 17th day 17th day D3 (growth) <20 <20 33 41 D5 (growth) <20 <20 37 84 D10 (confluence) <20 <20 93 171 #HbsAg secretion measured in the supernatant of the cells 47 days after seeding Examination of this table shows that these quantities of HBs antigen measured are low when the cells are infected before treatment by DMSO, which means that an infection carried out on slightly differentiated cells is not very effective compared with that carried out on strongly differentiated cells. Similarly, an infection carried out on cells maintained in a medium without corticoid (for 10 passages), then cultured for two weeks in the presence or absence of DMSO, also proves to be ineffective, in particular, for cells not having benefited from the action of the DMSO. Finally, the effectiveness of an infection carried out on undifferentiated cells multiplying actively was compared with that on cells with arrested growth and well-differentiated. The results are given in Table V below: TABLE V Effect of Cell Differentiation on the Infectability of HepaRG cells HbsAg secretion (pg/ml)# Differentiation Infection on day Infection on day medium 15 day after 28 after (after day 17) differentiation differentiation DMSO 0% <20 31 DMSO 1% 70 214 DMSO 2% 79 >2000 #HbsAg secretion measured in the supernatant of the cells 47 days after seeding The results show that an infection carried out on cells in the proliferation phase is ineffective, even in the presence of corticoid and of DMSO. EXAMPLE 6 Use of the HepaRG Line for the Evaluation of the Antiviral Activity of Chemical or Biological Molecules 1. Materials and Methods The cells are maintained and infected according to the protocols of Examples 1 and 5. The antiviral treatment by 3TC is administered from the 8th day to the 15th day following the infection of the HepaRG cells, at final concentrations of 0.1 and 10 μM in the culture medium. A complete replenishment of the medium is carried out every two days. The supernatants are stored at −20° C. and the cell pellets at −80° C. The viral antigen (HBs) was detected in the culture supernatant using the commercial ELISA test ETI-MAK-3® (SORIN). The viral DNA present in the culture supernatant could be detected and quantified by the Amplicor-Monitor test (ROCHE). The results are expressed as number of viral particles/ml. For the analysis of intracellular viral DNA, the cells were separated with trypsin and stored at −80° C. The total DNA was isolated according to the protocol described previously (Zoulim et al., 1998, Drug therapy for chronic hepatitis B virus replication. J. Hepatol. 29:151-168). 2. Results The HBs antigen is detected in the culture supernatant after 8 days of treatment by 3TC, the value remaining constant whatever the dose and equal to the non-treated control. The Amplicor-Monitor® test demonstrates a dose-dependent reduction in the quantity of viral DNA present in the HepaRG cells infected by the HBV after 8 days of treatment by 3TC, with respect to the control cells infected by the HBV and not treated, as shown by the results of Table VI below. TABLE VI Antiviral Activity of 3TC 3TC Concentration μM Inhibition 10 100 1 98 0.1 69 EXAMPLE 7 Use of the HepaRG Line for the Evaluation of the Antiseptic Power of Products Capable of Inactivating the HBV, for Example Javel Water 1. Materials and Methods 2. 1.1. The HepaRG cells are maintained according to the protocols of Example 1. 1.2. The infection is carried out in parallel: a) either with a native inoculum obtained as previously described from the HepG2 2.2.15 cells, the infectivity of which is documented according to the operating protocol of Example 5, b) or with the same inoculum brought into contact with the inactivating solution to be tested, here Javel water. The antiseptic power will depend on the concentration and period of contact of the product with the inoculum. We tested the Javel water in 2 concentrations: 12° et 24° and two exposure periods: 15 s and 30 s as detailed in the following paragraph. Exposure of the HBV of the inoculum to Javel water. series 1: Javel 12° for 15 seconds ″ 2: Javel 12° for 30 seconds ″ 3: Javel 240 for 15 seconds ″ 4: Javel 240 for 30 seconds ″ 5: distilled H2O used for diluting the virus: control virus 200 μl of pure virus stock then 200 μl of Javel water are poured into 4 ml tubes. The reaction is stopped by adding 1.6 ml of PBS (dilution {fraction (1/10)}). Elimination of Excess Javel. The above viral preparation is decanted into special tubes (2 tubes per series) and ultracentrifuged at 4° C. in order that the HBV is precipitated in the pellet. The supernatant containing the Javel water is gently drawn off. The small residual volume of the 2 tubes for each dilution is mixed and the virus pellets recovered by homogenization. The more or less inactivated viral suspension of each series is inoculated into HepaRG cell cultures according to operating conditions identical to Example 5. 1.3. In order to reveal the infection, both the proteins and the viral DNA will be measured. The viral Ag (Ag Hbs) is sought by a commercial ELISA test (for example. ETI-MAK-3® from Sorin or also Monolisa Ag HBsplus® from Biorad) as detailed in Examples 5 and 6. The viral DNA is sought using PCR in the culture supernatant and can be also be quantified by the Amplicor-Monitor® test (ROCHE). The results are expressed in viral genome/ml equivalents. In order to analyze the intracellular viral DNA, the cells are separated with trypsin and stored at −80° C. The total DNA is isolated and the search for DNA specific to HBV is carried out according to the protocol described previously (Zoulim, 1998). 2. Results 2.1. The control inoculum without Javel water makes it possible to obtain production of Ag Hbs and viral DNA in the supernatant as well as the characteristic profiles of the DNA of HBV in the cells, as detailed in Example 5. This infection was obtained with the pure virus and diluted to {fraction (1/10)}. 2.2. With the inoculum exposed to different concentrations of Javel water as described above, it appears that, after contact for 15 or 30 seconds with 12° Javel water, no infection takes place. The same applies to the 24° Javel water (15, 305), for a {fraction (1/10)} dilution of the virus. 3. Conclusions The test on HepaRG cells therefore makes it possible for the first time to offer an in vitro infection cell model of the HBV capable of validating physical (heating, irradiation) or chemical procedures (detergent/antiseptic solutions or gases: peroxides, ozone etc.) capable of inactivating this major contaminant virus involved in nosocomial infections via medico-surgical devices and instruments. In this example, a single dilution was tested. Experiments in progress will specify the sensitivity of the model and the number of logs of infectious doses (expressed as a logarithm to the base 10) that it is possible of evaluate including the capacities of concentrations of the virus by ultracentrifuging/filtration/precipitation. EXAMPLE 8 Construction of a “cDNA Chip” from the HepaRG Line This construction comprises the following stages Preparation of two total RNA pools, then purification of poly A RNA on the one hand, from cells originating from the differentiated HepaRG line after culture in a medium containing 10−5 M of hydrocortisone hemissuccinate then 2% of DMSO, and on the other hand of non-differentiated cells taken 5 days after subculture. Preparation of complementary DNAs, by reverse transcriptase. Carrying out suppressive subtractive hybridization using a commercial kit. Cloning of the cDNAs present in the subtractive library. Test of the representativeness of the library by sequencing of a limited number of cDNAs. PCR amplification of the cDNA products of interest using the universal primers present in the vector. “Spotting” of the PCR products according to one of the “microarray”-type processes. Thus the expression of 1000 to 2000 genes representative of functional states of the expression of hepatic cells can be studied in various situations of interest. EXEMPLE 9 Inoculation and Culture of the Hepatic Forms of Plasmodium falciparum in the HepaRG Line A few years ago, it was demonstrated that normal human hepatocytes in primary culture represented a system favourable to the survival of Plasmodium falciparum and that the latter could support the complete hepatic cycle of the parasite. In contrast, replication models in the hepatoma cells have to date been lacking. The novel HepaRG hepatoma line may represent an important advance, due to observation in a test involving infestation of these cells by the parasite, of a complete cycle with formation of schizonts. Materials and Methods P-falciparum sporozoites are prepared from Anopheles stephensi mosquitoes infected by ingestion of blood cells, themselves infected by the erythroid forms of the parasite, the gametocytes. Approximately two weeks after the infectious meal, the infected salivary glands are dissected under aseptic conditions and collected in culture medium. These suspensions, i.e. 10 pairs of salivary glands per 100 ml of medium, are added to the cultures of HepaRG cells. The cells used for the infestation were cultured according to the conditions defined in Example 1 (permanent presence of 5.10−5 M of hydrocortisone hemisuccinate) and maintained for a week at confluence, then for 2 weeks in the same medium with 2% of DMSO added. At the time of the infestation, they are confluent and completely differentiated by the corticoid/DMSO treatment described in Examples 1 to 4. The exposure or inoculation period is approximately 3-4 hours and is carried out in the same medium deficient in DMSO. Then, medium is added to the cultures and replenished every 2-3 days. Detection of the Parasites The preparations are washed in PBS then fixed and stained by May-Grunwald Giemsa staining. The intra-cellular parasites have a cytoplasmic localization. The characteristic formation of schizonts appears clearly. These schizonts firstly have a small number of nuclei, then they grow larger, with a considerably increased number of nuclei, attesting to the realization of a complete replication process. Optimization of the Infestation Protocol Plasmodium falciparum, a very fragile parasite, has appeared highly sensitive to DMSO. The results, showing a greater effectiveness, were obtained by removing the DMSO from the culture medium during the inoculation period. EXAMPLE 10 Injection of hepaRG Cells into a Mouse It is possible to inject hepaRG cells into an immunodeficient laboratory animal such as a nude mouse in order to obtain an in vivo study model. This injection into the mouse allows the hepaRG cells to find an environment favourable to their proliferation and their differentiation, leading to the formation of a large mass of differentiated cells. Given the pluripotent character of the hepaRG cells, these cells will undergo different differentiations depending on the cell implantation site (hepatic, pancreatic cells etc.). This injection thus makes it possible to reconstruct an organ of hepatic or pancreatic type in an animal, having an alteration of said organ (see article of M. Dandry et al., 2001, 33: 981-988, Hepatology, Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus). This model not only allows the study of the functions of the human hepatocyte in a whole animal organism but also the study of the infection of human hepatic cells by hepatotropic viruses and/or parasites in an animal model. EXAMPLE 11 Infection of the Line by the HCV 1. Materials and Methods Infection The infectious sources originate from serums of patients infected by the HCV. At present this is the only source of virus available, knowing that to date it has not been possible to develop any virus production model. Five serums were tested. The viruses from two serums (Nos. 2 and 4) have a genotype lb and that of serum No. 3 is a virus of genotype 3. The genotyping was not carried out on the two serums used, it concerns serums No. 1 and No. 5. The cells used for the infection were cultured according to the conditions defined in Example 1 (permanent presence of 5.10−5 M of hydrocortisone hemisuccinate) and maintained for a week at confluence, then for 2 weeks in the same medium with 2% of DMSO added. These cells are incubated for 48 hours at 37° C. with the infectious source, diluted 10 times, in the culture medium devoid of FCS and optionally with PEG 8000 (Sigma) added. For controls, cultures were incubated under identical conditions but the serum used this time originates from a patient not infected by the HCV. At the end of the incubation, the cells are washed three times with culture medium and maintained in the presence of 2% of DMSO and 5.10−5 M of hydrocortisone hemisuccinate until they are used. Extraction of the Intra and Extracellular Viral RNAs and Analyses The replicative forms of the intracellular viral RNAs were isolated in all the cell lysates. The cells are recovered after separation with trypsin, then the total RNA is extracted using the High Pure RNA Isolation kit (Roche). The quantity of total RNA extracted is estimated by optical density in order to standardize the different samples. The quality and homogeneity of the RNAs are examined by visualizing the ribosomic RNAs (rRNA: 28S and 18S) on a 1% agarose gel stained with ethidium bromide. The RNAs of the viral particles are extracted from the culture supernatant using the High Pure viral RNA kit (Roche). By retrotranscription (RT), the complementary DNA (cDNA) of the viral RNAs of positive polarity is synthesized from a specific primer hybridizing at 5′ of the region which codes for the viral capsid protein. This oligonucleotide (5′-TTTGAGGTTTAGGATTYGTGCTCAT-3′) derived from that described by Martell et al., 1999, Journal of Clinical Microbiology, 37: 327-332, designated C-342. The cDNA is then amplified by the “Polymerase Chain Reaction” (PCR) technique using two primers hybridizing in the 5′ non-translated region of the viral genome. The primers used are as follows: the sense oligonucleotide (5′-TGAGTGTCGTRCAGCCTCC-3′), and the antisense oligonucleotide (5′-ACCACAAGGCCTTTCGCRACCCAC-3′) which corresponds to that conceived by Mercier et al., 1999, Journal of Virological Methods, 77 1-9, designated NCR-3. The amplification product (amplicon of 190 pb) is visualized on a 2% agarose gel stained with ethidium bromide. A marker of molecular weight of DNA (M) is also deposited in order to verify the identity of the amplicon by its size. The effectiveness of the different stages is always controlled by detecting the viral RNA present in a standard (T+), which corresponds to a diluted serum, originating from an infected patient. The absence of any contamination is also systematically verified in the retrotranscription (RT) and amplification (PCR) stages by substituting water (T−) for the samples. 2. Results Evidence of the Infection FIG. 14 shows the analysis of the infectability of the HepaRG cells by viruses originating from the five serums tested. This involves looking for the presence of the viral RNA both in the extracellular and intracellular compartments by RT-PCR after infection of the cells in the presence of PEG 8000. The viral RNA is sought on the 12th day following the infection. The position of the amplicon is indicated to the right of the figure. The rRNAs are shown after homogenization of the samples in the lower part of the figure where the position of the 28S and 18S RNAs is indicated on the right. During the use of a inoculum without any virus (HCV-serum), no viral RNA is detected either in the culture supernatants or in the cells. Despite the origin of the line which was selected from a liver tumor taken from a female patient suffering from viral hepatitis C, no residual viral replication is detectable in the HepaRGs. The semi-quantitative technique of detection by RT-PCR makes it possible to reveal the presence of signals not only in the intracellular compartment but also in the culture supernatants whatever the serum used (serums No. 1 to No. 5). These results explain the establishment of an HCV replication in the HepaRG cells which leads to an effective secretion of virions by the cells. In order to confirm that a viral replication is established in the HepaRG cells after their infection, the sensitivity of the HCV replication to an antiviral, interferon α, was studied. The cells were inoculated over 48 hours in the presence of PEG 8000 by the virus-containing serum No. 4. A serum without any HCV is used as a negative control of the viral infection. Cytokine (Introna®, Schering-Plough, France) is added to the culture medium from the end of the 6th day to the 12th day following the infection of the cells, at final concentrations of 5, 50 or 500 U.I./ml. Complete replenishment of the medium is carried out every two days. The supernatants are stored at −80° C. for kinetics analysis. FIG. 15 shows the incidence of the presence of the interferon α on the 12th day following the exposure of the cells to the infectious source, with respect to the quantity of viral RNA detectable in the cells and in the supernatants. The position of the amplicon is indicated to the right of the figure. The rRNAs are shown after homogenization of the samples in the lower part of the figure where the position of the 28S and 18S RNAs is indicated on the right. Starting from the lower dose (5 U.I./ml), a drop of more than 60% of the intracellular signal is detected after the six days of treatment and complete disappearance of the signal is obtained in the extracellular medium. Kinetics of HCV Replication and Its Inhibition by Interferon α A kinetics of HCV replication and of its inhibition by interferon α was established and is shown in FIG. 16. The presence of the viral RNA in the supernatants was sought in parallel in a non-treated reference culture (ν) and in a culture where the cytokine is present in the medium at 5 U.I./ml a concentration the effectiveness of which was previously verified (FIG. 15), from the end of the 6th day following the infection, until the 12th day after exposure to the infectious source (ο). Analysis of the sample taken at the end of the 2nd day following the infection (ν, Day 2) reveals a strong signal. This phenomenon must correspond to a release from the inoculum of the viruses which were initially adsorbed onto, or internalized in, the cells. Then, the constant signal detected from the 4th day post-infection (ν, Day 4 to Day 12) translates an active replication of the virus which leads to a constant secretion of virions over the period studied. The first part of the kinetics carried out on the cultures incubated in the presence of interferon α is identical to that carried out in the absence of the antiviral (compare ν and ο from Day 2 to Day 8). This makes it possible to affirm that a replication was well established in the HepaRG cells before the treatment. In contrast, after four days of incubation with cytokine, no extracellular viral RNA is detected, until the end of the treatment (ο, Day 10 to Day 12). The inhibitory action of interferon α observed in vivo is therefore well reproduced in the HepaRG cells infected by the HCV, after a minimum treatment period of 2 days. EXAMPLE 12 Infection of the Line by Parasites of the Genus Leishmania The leishmaniases are diseases subsequent to infection by a parasite of the genus leishmania. The clinical presentation of these infections ranges from localized cutaneous infection, to a disseminated infection during which the main organs infected are the lymph glands, bone marrow, spleen and liver. The leishmania are transmitted in flagellate promastigote form by a hematophagous diptrous insect, the phlebotomine sand fly, and rapidly become intracellular in their host. The cells currently described as permissive to the leishmanias are the cells of the mononuclear phagocyte system. However, a hepatocyte infection test recently demonstrated the permissiveness of this cell type, opening up research perspectives in order to better understand the physiopathology of the infection and to evaluate new therapeutic targets. 1. Materials and Methods Infection The Leishmania major, L. donovani, L. infantum, L. tropica, L. braziliensis and L. guyanensis promastigotes used are strains isolated from patients, identified by the reference isoenzymatic method and cryopreserved in liquid nitrogen. Obtaining an inoculum requires at least 2 successive amplification phases in Novy-McNeal-Nicolle gelose medium with rabbit blood added, then in Schneider medium with 10% of FCS added. The cells used for the infection were cultured according to the conditions defined in Example 1 (permanent presence of 5.10−5 M of hydrocortisone hemisuccinate) and maintained for a week at confluence, then for 2 weeks in the same medium with 2% of DMSO added. These cells are incubated for 18 hours at 37° C. with leishmania promastigotes, then washed 3 times with culture medium and maintained in the presence of 2% of DMSO and 5 M hydrocortisone hemisuccinate. Detection of Intracellular Parasites The checking and quantification of the infection are carried out by optical microscopy. The cells are recovered after trypsinization of the wells and 2 washings in PBS, cytocentrifuqed for 10 minutes at 9000 rpm, then fixed and stained by May-Grunwald Giemsa stain. The intracellular parasites in amastigote form have cytoplasmic localization, measure 3×6 micrometres and are easily locatable thanks to their structure comprising a bluish cytoplasm, and a violet nucleus and kinetoplast. The number of cells infected and the total number of parasites found are calculated for an average number of 4000 hepatocytes read. 2. Results Evidence of the Infection FIG. 17 shows the kinetics of infection observed with an L. donovani strain and an L. major strain for infection ratios of 25 parasites per cell. The cells can therefore be infected with a hepatotropic strain (L. donovani) but also a dermatropic strain (L. major). The number of amastigotes of L. donovani per 100 cells is comprised between 7 and 45 for 4000 cells read (0.175% to 1.125%), corresponding to a percentage of infected cells comprised between 0.1 to 0.55%. The number of amastigotes of L. major is comprised between and 6 and 38 for 4000 cells read (0.15 and 0.725%), corresponding to a percentage of cells infected comprised between 0.1 to 0, 375%. Optimization of the Infection Protocol A first experiment studied the “culture duration” effect on the total number of parasites and the number of cells infected. The results of this work carried out with cells infected by L. major (infection ratio=25 parasites per cell) are shown in FIG. 18. A second experiment aimed at studying the “inoculum” effect on the level of infection of the cells. L. major was successively inoculated in the cells with ratios of 6, 12, 25, 50, 100 and 200 parasites per cell. The results of the cultures on Day 7 are shown in FIG. 19 and show that the number of parasites per 100 cells varied from 2 to 218 for 4000 cells read (0.05% to 5.45%), corresponding to a percentage of cells infected ranging from 0.05% to 1.6%. In total, it appears that the ideal infection ratio by L. major is 100 parasites per cell, and the parasite infection quantification is optimum between Day 4 and Day 7.

20041008

20081125

20050324

69244.0

MOSHER, MARY

NOVEL HUMAN HEPATOMA LINES, METHODS FOR OBTAINING SAME AND USES THEREOF

UNDISCOUNTED

ACCEPTED

ACCEPTED

Manufacturing device

The present invention relates to a configurator and a method of configuring articles. A configurator regarded as a device of the type in question is a configurator comprising a processor having associated therewith a type-of-article memory, which has stored therein at least one data record representative of the outward appearance of a type of article, and an article design memory having stored therein data representative of a plurality of different article designs related with one type of article, an input unit for selecting a type of article and/or an article design, and a screen for displaying a predetermined, selected type of article with the selected article design. A configurator which is easier to construct and which allows the selected article design to be experienced directly is provided by the present invention in that a recognition means for recognizing a sample of the selectable article designs is provided, said recognition means detecting an article design signal which is representative of the article design and by means of which a specific article design is selected from the article design memory.

1. A configurator for configuring articles, comprising a processor having associated therewith a type-of-article memory, which has stored therein at least one data record representative of the outward appearance of a type of article, and an article design memory having stored therein data representative of a plurality of different article designs related with one type of article, an input unit for selecting a type of article and/or an article design; a screen for displaying a predetermined or a selected type of article with the selected article design, and a recognition means for recognizing a selected sample of the selectable article designs, said recognition means detecting an article design signal which is representative of the article design and by means of which a specific article design corresponding to the sample is selected from the article design memory, characterized in that the recognition means comprises a receiver unit which is adapted to receive the article design signal of a transmitting unit associated with the selected sample, and that the transmitting unit and the receiver unit are adapted to one another in such a way that the article design signal of the sample selected from a plurality of samples presented to the user of the configurator will not be detected by the receiver unit until the selected sample has been transferred to a predetermined local area that is within reach of the user. 2. A configurator according to claim 1, characterized in that the receiver unit comprises a receiver plate, and that the transmitting unit is defined by a transponder which transmits the article design signal through energy supplied by said receiver plate. 3. A configurator according to claim 1, characterized in that the transmitting unit is adapted to be programmed. 4. A configurator according to claim 1, comprising a design element memory, which is associated with the processor and which has stored therein various selectable design elements, each of said design elements having associated therewith various designs in the article design memory, characterized in that the sample has associated therewith an element signal which is representative of the design element and by means of which a specific design element is selected from the design element memory.

The invention relates to a configurator for configuring articles. Certain articles, such as kitchen furniture or appointments, articles of clothing or automobiles, can be configured as desired by the individual customer. It is, for example, common practice that a buyer of a new motor vehicle determines first the type of article, i.e. he selects the type and the model at the respective car dealer. The thus determined article is then configured by the customer. The customer has the possibility of freely selecting various article designs. The term article design can stand for technical features, such as the type of engine provided and technical options. Article design in the sense of the present invention is, however, especially the design of the article appealing to the aesthetic sense, i.e. the colour of the outer paint finish, the colour of the upholstery, the type of upholstery, the colour of trim strips, the colour of keters, the type of wood or the grain of wood inlays, etc. Renowned car manufacturers offer nowadays the possibility of configuring a vehicle over the Internet, via terminals or via CD-Roms made available to the customer. On the respective page of the enterprise, the potential buyer is first requested to select a type of article, i.e. a specific model of the car manufacturer. Subsequently, the article is designed as desired by the individual customer, guided by a menu. The customer is conducted through various selection areas in which he has to select first e.g. the desired engine, a design package, then the colour of the vehicle, the type of upholstery, etc. In the case of this menu guidance, all the fields must be worked through in the predetermined sequence. The selection of a specific article design has the effect that the initially selected type of article displayed in the form in question on the screen will be represented in accordance with the selected article design. For example, the article design selection “colour of the outer paint finish” will, after selection of a desired colour by the customer, be realized by a processor, which is associated with the screen, and the type of article displayed on the screen will be shown with the desired colour. A corresponding to realization is imaginable for the selection of the wheel rims, the selection of the colour of the upholstery, perhaps the selection of the type of upholstery, etc. When vehicles are being configured, data originating from the engineering departments of the respective car manufacturers are often used for graphically representing the type of article. These data allow arbitrary three-dimensional views of the type of article selected. When a motor vehicle is being configured, it is therefore known to show to the user the motor vehicle that it just being configured in any three-dimensional representation desired. For example, enlarged details can be zoomed in; the vehicle to be configured can be rotated. A view into the passenger compartment of the vehicle can be shown as well. The representation of these various, preferably three-dimensionally represented views normally takes place on a stationary screen. In the prior art, the selection of a type of article, and especially of the respective article designs, is carried out via an input unit. This input unit can be defined by a keyboard or a mouse operating device. Frequently, so-called touch screens are used for inputting data, since a touch screen can be handled easier and more playfully by the user. Nevertheless, also the user using a touch screen has to work through the predetermined areas in the given sequence so as to take all the decisions for configuring his vehicle. The known systems are therefore inflexible. In addition, they require a certain amount of practice in handling a computer, at least via the touch screen. The handling of the programs for carrying out the configuring necessitates familiarization at least to a certain degree. In addition, it should be taken into consideration that the age of persons who buy most frequently a new car is approx. 46. Such persons cannot be expected to deal with a computer quite naturally. Irrespectively of his age, the user of a configurator will feel himself restricted with regard to his freedom of design by the given menu, and this will definitely have a negative effect on the fun of configuring an article to be ordered. Finally, mere representations on a screen do not provide the possibility of sufficiently experiencing the effect of the selected designs and of their interplay when the configuring process has been finished. This applies in particular to cases where design elements having a texture and specific haptic properties are to be selected and combined with one another. Taking this as a basis, the technical problem underlying the present invention is to provide a configurator of the type referred at the beginning, which can be handled more easily and which provides the possibility of experiencing the effect of the individual article design selected and, in particular, the combinatorial effect of various article designs selected. In addition, it is the object of the present invention to provide a method for configuring articles, which can be handled more easily and which provides the possibility of experiencing the effect of the article designs selected. As far as the device is concerned, the present invention discloses a configurator having the features of claim 1 for solving the above problem. This configurator differs from the prior art according to the generic clause insofar as a recognition means is provided with the aid of which a sample of the selectable article design can be recognized. This recognition means is implemented such that it detects an article design signal which is representative of the article design. The article design signal is associated with the sample. When the sample is being selected, the article design signal is determined simultaneously. Via the recognition means, this article design signal is advanced to the processor, which will select a specific article design from the article design memory and display said article design on the screen. It follows that, in contrast to the prior art, the configurator according to the present invention offers the advantage that individual article designs exist in the form of real samples, which are combined when the article is being configured. Each individual sample allows the effect of the respective selected article design to be experienced. Taking still a motor vehicle as an example, the paint finish, e.g. a metallic finish with its light reflections and its metallic gleam, appears as a real image much more attractive than in the case of a mere representation on a screen. The screen takes over the article design signal representative of the paint finish selected and displays the type of article on the screen in a three-dimensional configuration with the paint finish selected. The paint finish detail can, however, be experienced on the basis of the sample. In addition, the present invention offers the possibility of genuinely experiencing the inter-play of the individual article designs selected. For example, a respective sample can be selected for various article designs and the samples in question can be arranged side by side or on top of one another. The article design signals taken from the individual samples are detected by the recognition means for producing an overall image, and advanced to the processor for the purpose of representation. On the basis of the representation on the screen, the interplay of the colours and the total three-dimensional effect produced can be conveyed. A genuine experience of the interplay of the individual article designs is, however, realized via the interplay of the really existing samples. On the basis of the recognition means for recognizing a sample, the configurator according to the present invention allows the effect of the genuine article design to be experienced directly. This direct experience is much more intensive than any representation on a screen. This is even more relevant in cases where various article designs, e.g. for the passenger compartment of a motor vehicle, are combined with one another (colour of the upholstery, type of upholstery, colour of keters, perhaps the type of wood and the grain of wood inlays). In contrast to the prior art according to the generic clause, the configurator according to the present invention also offers a haptic impression of the respective article designs to be selected, since the samples exist in reality. It follows that the configurator according to the present invention provides an almost real image of the article which will be produced later on according to the customer's wishes. The configurator according to the present invention emotionalizes, on the basis of the actually existing samples and their noble effect, the selection decision that has to be taken for each article design. This selection decision can be taken without the necessity of interacting directly with the processor via the screen, but for representing the article in the selected article design, it will suffice to select the sample in question, to take hold of it and to transfer it to the recognition means. Handling the configurator according to the present invention is therefore very easy. Any imaginable means which has been prepared such that it is able to recognize, on the basis of specific information carriers, an unequivocally defined article design can be used as a recognition means. It is, for example, imaginable to provide a barcode recognition means and to provide corresponding and individual barcodes on the respective samples. From the viewpoint of sales psychology, it should, however, be preferred to use recognition means which do not necessitate special handling for reading in the article design signal. The recognition means is therefore preferably provided with a receiver unit which is adapted to receive the article design signal of a transmitting unit associated with the sample. In a sales talk, a large number of samples for an article design will be offered for selection. By coordinating the transmitting units and the receiver units in a suitable manner, it should be guaranteed that the article design signal associated with the sample will be ascertained by the receiver unit only after the selection of a specific sample and the transfer of said sample to a predetermined local area. The preferred embodiment of the device according to claim 3 offers the advantage that the transmitting unit provided on the sample is capable of functioning without having a power source of its own. The transmitting unit can thus preferably be incorporated into the sample, a solution which should be preferred because the aesthetic impression will thus be impaired as little as possible. When the transmitting unit is defined by a transponder in accordance with a further development according to the present invention, maintenance and repair work will not be necessary for the transponder. According to a further preferred development of the present invention, the transmitting unit is programmable. This offers the advantage that the transmitting unit can first be connected to the respective sample, preferably incorporated in the sample, without the necessity of taking into consideration what kind of information the transmitting unit carries. Furthermore, it is possible to program the transmitting unit with additional information which turns out to be necessary only when the configurator is in use. Another preferred embodiment of the configurator according to the present invention is provided with a design element memory, which is known per se and which is associated with the processor; in said design element memory, various selectable design elements are stored. Each of these various design elements is associated with different designs in the article design memory. For a motor vehicle, which is the example referred in the present connection, the design element is e.g. the outer paint finish. This design element has associated therewith various colours as variable article design. The design element memory has stored therein a plurality of different design elements, which are, taking still an automobile as an example: colour of the vehicle, upholstery, existence of trim strips, steering wheel design and the like. In the case of the configurator according to the present invention, also this design element memory is addressed by the sample selected. For this purpose, the sample selected has associated therewith an element signal through which a specific design element is selected from the design element memory. In other words, the element signal indicates the “function” and the “location” of a sample, whereas the article design signal indicates the “outward appearance” of a sample. Due to the combinatorial form of the article design memory and of the design element memory, which are each addressed by the sample selected, it is possible to select several samples simultaneously and to read them in via the recognition means. On the basis of each individual sample, the function of the respective sample (element signal) and the outward appearance of said sample (article design signal) will then be detected. Taking still a motor vehicle as an example, an almost complete image of the interior trim of the vehicle will be obtained when the following is selected: a sample for the upholstery (texture and colour); a sample for a trim strip; a sample for a keter as well as a sample for an inlay. Within the framework of a sales talk, it will not be necessary to assign the function to the respective samples. The sample carries both the information “outward appearance” as well as the information “function”. From the above, it can be seen that the present invention provides a configurator which, making use of configurator elements that are known per se, establishes a direct relationship with the article designs to be selected. The quality of the material, the precise effect and especially the texture and the haptic properties of the article design can be experienced genuinely. The overall optical impression is—just as in the prior art—created via one or a plurality of screens when the selected article designs are being realized. The customer and orderer of an article who makes use of the configurator is not compelled to communicate with the processor via a screen and/or a keyboard. This communication can take place exclusively through the sample selected. The configurator according to the present invention allows the configuring of an article, e.g. of a motor vehicle, to be experienced in an hitherto unknown manner. The customer only concerns himself with the selection of the materials and experiences an interplay of the materials in the real world. The customer has a complete freedom of design, and he is not restricted with respect to the input of his selection and the temporal sequence of his selection steps. The customer experiences the configuring of the article as an event free from any direct interaction with the processor. Also a salesman assisting the customer can fully concentrate his attention on the customer and the sales talk and does not have to concentrate on the input of data into the processor. In addition, the configurator is completely intuitive. The customer only has to take hold of the sample and arrange the sample in a predetermined area. He can combine an arbitrary number of different article designs, each in the form of a sample, and obtain any article design in this way. Especially when a design element memory is realized, the customer is absolutely free in sequentially selecting each individual article design. The configurator according to the present invention may, of course, also comprise a type-of-article memory which is addressed by a sample which is representative of the type of article and which is recognized by the recognition means. It is easily imaginable to control the configurator through samples alone, to such an extent that e.g. even a very complex article, such as an automobile, will be configured up to an including the last freely selectable equipment feature. For solving the method aspect of the above-mentioned problem, the present invention suggests, accordingly, a configuring method for configuring articles, comprising the steps of representing, in a manner known per se, a known type of article on a screen, and selecting at least one article design, as well as displaying on the screen the represented type of article with the selected article design. The method according to the present invention differs, however, from the prior art insofar as the article design is determined via a signal processed in a processor, said signal being associated with a selected real sample of the article design in question.

20040507

20080805

20050519

98084.0

ALLEN, WILLIAM J

A CONFIGURATOR FOR CONFIGURING AND DISPLAYING THE APPEARANCE OF AN ARTICLE TO BE CONFIGURED

UNDISCOUNTED

ACCEPTED

ACCEPTED

Chain transport system with add-on components

The invention relates to a chain-transport system containing chain links (10, 20, 30, 40, 50, . . . ) which are strung together and adjacent chain links (10-20, 20-30, 30-40, 40-50, . . . ) being rotatably joined together about an axis of rotation (11, 21, 31, 41, 51) common to one of the two chain links and all of the axes of rotation (11, 21, 31, 41, 51, . . . ) in the chain-transport system running parallel to each other. At least some of the chain links (10, 50, 90, . . . ) are adapted (10-12, 50-52, 90-92, . . . ) in such a way that respectively one add-on component (13, 53, 93) can be attached thereto. According to the invention, attachment of the respective component (13, 53, 93, . . . ) to the respective adapted chain link (10-12, 50-52, 90-92, . . . ) occurs in the form of a positive fit connection between a connecting area (13a, 13b, 13c, . . . ) of the add-on component (13, . . . ) and a connecting area (12a, 12b, 12c, . . . ) of the adapted chain link (10-12, . . . ). The invention also relates to a system for securing add-on components to a transport chain, whereby an add-on component (13, 53, 93, . . . ) is secured to each respectively selected chain link (10, 50, 90, . . . ). According to the invention, the respective add-on component (13, 53, 93, . . . ) is secured to the respective selected chain link (10, 50, 90, . . . ) with the aid of an adapter (12, 52, 92, . . . ).

1. A chain transporter system which includes sequentially arranged chain links (10, 20, 30, 40, 50, . . . ) and in which adjacent chain links (10-20, 20-30, 30-40, 40-50, . . . ) are rotatably attached to one another about a rotational axis common to both chain links (11, 21, 31, 41, 51, . . . ), and all rotational axes (11, 21, 31, 41, 51) of the chain transporter system are extend parallel to one other, wherein at least some of the chain links (10, 50, 90, . . . ) are adapted (10-12, 50-52, 90-92, . . . ) in such manner that a mounting part (13, 53, 93) is attachable to each, characterised in that the attachment of the respective mounting part (13, 53, 93, . . . ) to the respective adapted chain link (10-12, 50-52, 90-92, . . . ) is created by means of a positive locking connection between a connection area (13a, 13b, 13c, . . . ) of mounting part (13, . . . ) and a connection area (12a, 12b, 12c, . . . ) of the adapted chain link (10-12, . . . ). 2. The chain transporter system according to claim 1, characterised in that one mounting part is attached to each of the at least some chain links (10, 50, 90). 3. The chain transporter system according to claim 1 or 2, characterised in that the connection area (12a, 12b, 12c, . . . ) of the adapted chain link (10-12, . . . ) is a counterpart recess for the connection area (13a, 13b, 13c, . . . ) of the mounting part (13, . . . ). 4. The chain transporter system according to any of claims 1 to 3, characterised in that the recess is a groove-type depression in the surface (12d, 12e) of the adapted chain link (10-12, . . . ) along a groove direction (N), wherein opposing walls of the groove, each furnished with an undercut (12a, 12b, . . . ) parallel to the surface (12d, 12e) of the adapted chain link (10-12, . . . ) and having a depth (t) perpendicular to the groove direction (N), extend in complementary fashion into the corresponding socket-like extensions (13a, 13b, . . . ) in the connection area of the mounting part (13, . . . ). 5. The chain transporter system according to claim 4, characterised in that at least one of the two undercuts (12a) has a undercut depth (t) perpendicular to the groove direction (N) that is less than the maximum flaring (Δa) of the groove's clearance (a) that can be attained by elastic distortion of the groove perpendicular to the groove direction (N). 6. The chain transporter system according to claim 4 or 5, characterised in that at least one of the undercuts (12a) has the form of a concave rounding (12a) in a section perpendicular to the groove direction (N) and the surface area of the adapted chain link (10-12) has the form of a convex rounding (12f) above the undercut (12a) in a section perpendicular to the groove direction (N), wherein the transition area (12g) between the convex rounding (12f) and the concave rounding (12a) is the area of the groove wall projecting farthest into the groove opening perpendicularly to the groove direction (N). 7. The chain transporter system according to claims 4 to 6, characterised in that at least one knob-like projection (12c) and/or depression is provided in the floor of the recess that fits into and/or into which a corresponding counterpart depression (13c) and/or stop boss fits in the connection area of the mounting piece (13). 8. The chain transporter system according to claims 4 to 7, characterised in that at least one bulging projection and/or one depression is provided in the floor of the recess which extends in a direction not parallel to the groove direction (N). 9. The chain transporter system according to any of the preceding claims, characterised in that the adapted chain links (10-12, 50-52, 90-92, . . . ) each consist of a regular chain link (10, 50, 90) and an adapter element (12, 52, 92, . . . ) positively engaged therewith, which adapter element is conformed such that the mounting part (13, 53, 93) is attachable thereto. 10. The chain transporter system according to claim 9, characterised in that the adapter element (12, 52, 92, . . . ) is positively engaged with pins (14, 15) projecting on both sides of the respective adapted chain link (10-12, 50-52, 90-92, . . . ) of the chain. 11. The chain transporter system according to claim 10, characterised in that perpendicularly to the longitudinal direction (K) of the chain, the adapter element (12) has an essentially U-shaped cross-section with a crosspiece (12h) and two legs (12i, 12j) angled essentially perpendicularly therefrom, wherein the U-shaped adapter element (12) clasps the respective chain link (10) in positive locking engagement. 12. The chain transporter system according to claim 11, characterised in that the legs (12i, 12j) have at least one recess or hole (12k) on the insides thereof facing the chain link (10), in which the at least one projecting pin (14, 15) of the respective chain link is form-fitted. 13. The chain transporter system according to claim 12, characterised in that the end area of the legs (12i, 12j) of the adapter element (12) are tapered on the inside facing the chain link by a surface (12l) inclined towards the leg extremity. 14. The chain transporter system according to any of the preceding claims, characterised in that the mounting part (13) is an angle element in which the first angled leg includes the connection area (13a, 13b, 13c) of the mounting part (13), and the second angled leg (13d) extends at an angle (γ) to the first angled leg. 15. The chain transporter system according to claim 14, characterised in that the first angled leg engages positively with the adapted chain link (10-12) in such manner that the inside surface (13e) of the first angled leg is flush with the surface (12d, 12e) of the adapted chain link (10-12). 16. A system for securing mounting parts to a transporter chain, wherein one mounting part (13, 53, 93, . . . ) each is attached to a selected chain link (10, 50, 90, . . . ), characterised in that each mounting part (13, 53, 93, . . . ) is attached to the respective selected chain link (10, 50, 90, . . . ) using an adapter element (12, 52, 92, . . . ). 17. The system according to claim 16, characterised in that the mounting part (13, 53, 93, . . . ) is in positive engagement with pins (14, 15) projecting on both sides of the respective chain link (10, 50, 90, . . . ). 18. The system according to claim 16 or 17, characterised in that the adapter element (12, 52, 92) has an essentially U-shaped cross-section perpendicularly to the chain's longitudinal direction (K), with a crosspiece (12h) and two legs (12i, 12j) angled essentially perpendicularly to the crosspiece, wherein the U-shaped adapter element (12, 52, 92) clasps the respective chain link (10, 50, 90) in positive engagement. 19. The system according to any of claims 16 to 18, characterised in that the legs (12i, 12j) have at least one recess or hole (12k) on the insides thereof facing the chain link (10), in which the at least one projecting pin (14, 15) of the respective chain link (10) is form-fitted. 20. The system according to any of claims 16 to 19, characterised in that at the end area thereof, the legs (12i, 12j) are tapered on an inside surface facing the chain link by a surface (12l) inclined towards the leg extremity. 21. The system according to any of claims 16 to 20, characterised in that the mounting part (13) is connected to adapter element (12) via a positive locking engagement between a connection area (13a, 13b, 13c) of the mounting part (13) and a connection area (12a, 12b, 12c) of the adapter element (12). 22. The system according to claims 16 to 21, characterised in that the connection area (12a, 12b, 12c) of the adapter element (12) has a recess matching the connection area (13a, 13b, 13c) of the mounting part (13). 23. The system according to any of claims 16 to 22, characterised in that the recess is a groove type depression in the surface (12d, 12e), of the adapter element (12) along a groove direction (N), wherein opposing groove walls are each furnished with an undercut (12a, 12b) parallel to the surface (12d, 12e) of the adapter element (12) and having a depth (t) perpendicular to the groove direction (N), in which corresponding socket-type enlargements (13a, 13b) in the connection area of the mounting part (13) engage mutually. 24. The system according to any of claims 16 to 23, characterised in that at least one of the two undercuts (12a) has an undercut depth (t) perpendicular to the groove direction (N) that is less than the maximum flaring (Δa) of the groove's clearance (a) that can be attained by elastic distortion of the groove perpendicular to the groove direction (N). 25. The system according to any of claims 16 to 24, characterised in that at least one of the undercuts (12a) has the form of a concave rounding (12a) in a section perpendicular to the groove direction (N) and the surface area of the adapter element (12) above the undercut (12a) has a convex rounding (12f) in a section perpendicular to the groove direction (N), wherein the transition area (g) between the convex rounding (f) and the concave rounding (a) is the area of the groove wall projecting farthest into the groove opening perpendicularly to the groove direction (N). 26. The system according to any of claims 16 to 25, characterised in that at least one projection (12c) and/or one depression is provided in the floor of the recess of the adapter element (12), which fits into or is fitted by a corresponding matching depression (13c) or projection and in the connection area of the mounting part (13). 27. The system according to any of claims 16 to 25, characterised in that at least one knob-type projection and/or a depression is provided in the floor of the recess of the adapter element (12), which extends in a direction not parallel to the groove direction (N). 28. The system according to any of the preceding claims, characterised in that the mounting part (13) is an angled element, in which the first angled leg is the connection area (13a, 13b, 13c) of the mounting part (13) and the second angled leg (13d) extends at an angle (γ) to the first angled leg (13a, 13b, 13c). 29. The system according to claim 28, characterised in that the first angled leg engages positively with the adapter element (12), such that the inside surface (13e) of the first angled leg is flush with the upper surface (12d, 12e) of the adapter element (12). 30. The chain transporter system according to any of claims 1 to 15, characterised in that it is usable in chocolate processing, particularly in the area of cooling lines and/or heating lines. 31. The system for securing mounting parts to a transporter chain according to any of claims 16 to 29, characterised in that it is usable in chocolate-processing, particularly in the area of cooling lines and/or heating lines.

The invention relates to a chain transporter system with mounting parts in accordance with the preamble of claim 1, and to a system for securing mounting parts to a transporter chain in accordance with the preamble of claim 16. Chain transporter systems of such kind, having specially conformed mounting parts are used in industry in many production processes. Such a system is used particularly with vertical chain transporters for shells filled with chocolate or similar fillings. The specially designed mounting parts may be, for example, angle elements made from aluminium that are attached to selected chain links of a roller chain. FIGS. 1A and 1B show a known system for attaching mounting parts to a transporter chain, particularly for attaching aluminium angle elements 13′, 53′, 93′ to selected chain links 10, 50, 90 of a transporter chain. In this arrangement, aluminium angle elements 13′ are screwed to the roller chain, i.e. to link plates 12a′ and 12b′ on either side thereof using countersunk screws 16, 17. For the screwed connection of angle elements 13′, 53′, 93′, these had to be marked, drilled and then countersunk at each screwing position. These processing steps are very time consuming and thus also costly. The object was therefore defined to provide a system of attaching mounting parts to a transporter chain, particularly for securing aluminium angle elements to a roller chain, which permits the rapid and thus cost-saving attachment of the mounting parts to the chain links of a transporter chain. This task is solved by the chain transporter system in accordance with claim 1 and by the system for securing mounting parts to a transporter chain in accordance with claim 16. The chain transporter system according to the invention includes specially adapted chain links and link pins, wherein a positive connection is enabled between a connection area of the mounting part and a connection area of the adapted chain link and link pin. The system according to the invention for securing mounting parts to a transporter chain uses specially conformed adapter elements, by means of which the respective mounting parts are attached to the respective selected chain link. Further advantageous embodiments of the chain transporter system according to the invention and the system for securing mounting parts to a transporter chain according to the invention are described in subordinate claims 2 to 15 and subordinate claims 17 to 29 respectively. Further advantages, features and application possibilities of the invention will become evident from the following description of a particularly preferred embodiment of the invention, in which: FIGS. 1A and 1B are a side view and a plan view respectively of a known chain transporter system. FIGS. 2A and 2B are a side view and a plan view respectively of the chain transporter system according to the invention with the system for securing mounting parts to a transporter chain according to the invention; FIG. 3 is a side view of the adapter element according to the invention; FIG. 4 is a front view of the adapter element according to the invention of FIG. 3 in the direction of arrow A; FIG. 5 is a side view showing the attachment according to the invention of the adapter element to the mounting part; FIG. 6 is a front view showing the attachment according to the invention of a selected chain link to the adapter element according to the invention. FIG. 1A shows a section of a conventional transporter chain with chain links 10, 20, 30, . . . , 90, which extend along a chain's longitudinal direction K. Some selected chain links 10, 50, 90 from the chain section represented are furnished with adapter elements 12′, 52′ and 92′, to each of which a mounting part 13′, 53′ and 93′ is attached. FIG. 1B shows a plan view of the chain section of FIG. 1A. Adapter elements 12′, 52′ and 92′ of selected chain links 10, 50 and 90 are each furnished with a pair of link plates 12a′, 12b′, 52a′, 52b′ and 92a′, 92b′, which extend away from the transporter chain on either side thereof. Each of mounting parts 13′, 53′ and 93′ (FIG. 1A), is secured to the corresponding adapter element 12′, 52′ and 92′ using countersunk screws 16 and 17. FIG. 2A, is a side view of a section of the chain transporter system according to the invention, equipped with the system according to the invention for securing mounting parts to the transporter chain. The section shown includes chain links 10, 20, 30, . . . , 90, wherein for example chain links 10, 50 and 90 are specially conformed chain links in that they are connected to an adapter element 12, 52 and 92. The chain is preferably constructed with extended pins in its entirety, i.e. on all chain links, so that the adapter element may be inserted at any position. Adapter element 12, 52 and 92 is attached to the associated chain link 10, 50 and 90 via a latching or clamping connection (see FIG. 6). The corresponding mounting part 13, 53 and 93 is also attached to the corresponding adapter element 12, 52 and 92 via a latching or clamping connection (see FIG. 5), wherein a connection area of each mounting part 13, 53, 93 engages both positively and negatively with a connection area conformed as a counterpart recess of corresponding adapter element 12, 52 and 92. FIG. 2B is a plan view the section of the transporter chain of FIG. 2A. The three mounting parts 13, 53 and 93 shown, which are fitted into the corresponding recess of the respective adapter element 12, 52 and 92 with both and negative engagement, are aluminium angle elements. The material from which adapter elements 12, 52 and 92 are made is preferably an elastic plastic. It is important that the material of the adapter element is elastically deformable when mounting parts 13, 53 and 93 are pressed into the respective adapter elements 12, 52 and 92, so that above a given pressure point the mounting parts can be pressed into the recess of the adapter element, whereupon the positively and negatively engaged connection is created between mounting parts 13, 53 and 93 and the corresponding adapter elements 12, 52 and 92. The same material deformation of adapter elements 12, 52 and 92 is also essential for producing the positively and negatively engaged connection between chain links 10, 50 and 90 and the corresponding adapter elements 12, 52 and 92. FIG. 3 is a side view of the adapter element 12 according to the invention. It serves as an adapter between a selected chain link 10 and a mounting part 13 to be attached to chain link 10. The upper area of adapter element 12 is attachment area 12a, 12b, 12c, which is conformed as a recess to accommodate the corresponding counterpart attachment area of mounting part 13 (FIG. 5). The attachment area is a groove-type recess in the upper part of adapter element 12, wherein the groove has a clearance ‘a’. On one wall of the groove is an undercut 12a, which is conformed as a concave rounding having undercut depth ‘t’. In the middle of the floor of the recess is a prominence 12c, and on the other wall of the groove is an undercut 12b opposite to undercut 12a. Similarly, a borehole may also be provided, which serves to accommodate a stop boss in mounting part 13. Surfaces 12d and 12e on both sides of the recess lie on the same plane. The surface above undercut 12a is furnished with a convex rounding 12f. A transition area 12g is configured between the concave rounding serving as undercut 12a and the convex rounding 12f, which transition area protrudes farthest into the groove. Adapter element 12 further includes recesses and boreholes 12k, which are provided on the inside of legs 12i and 12j (FIG. 4, FIG. 6) of adapter element 12. FIG. 4 is a view of adapter element 12 of FIG. 3 along arrow A. The cross-section of adapter element 12 perpendicular to direction A is essentially U-shaped with a crosspiece 12a and two legs 12i and 12j, which extend parallel to each other and perpendicularly to the crosspiece 12a. The two recesses or holes 12k on the insides of legs 12i and 12j in the positive locking engagement with the corresponding selected chain link 10 (see FIG. 6). FIGS. 5 and 6 show the process of connecting a mounting part 13 according to the invention with an adapter element 12 according to the invention and thus also to a chain link 10 fitted with the adapter element 12 according to the invention. FIG. 5 shows the mounting part 13 according to the invention, which includes a first angled leg with a first extension 13a, a second extension 13b and a depression 13c, and a second angled leg 13d. Instead of depression 13c, a stop boss may also be provided. Angle γ between the first angled leg and the second angled leg is 90°. If the first angled leg of mounting part 13 according to the invention is now twisted from above into the recess in adapter element 12 as indicated by arrow A, convex rounding 13a of mounting part 13 slides along convex rounding 12f of the adapter element, which causes increasing elastic deformation of adapter element 12. It is crucial that clearance ‘a’ (see FIG. 3) in the groove-type depression of adapter element 12 is flared progressively, such that the contact point with convex rounding 13a of mounting part 13 is displaced downward as mounting parts 13, 53 and 93 are pushed into respective adapter elements 12, 52 and 92, so that the mounting parts may be pressed into the recess of the adapter elements above a given pressure point. The groove is flared because convex rounding 13a of mounting part 13 slides along convex rounding 12f of adapter element 12 as mounting part 13 is pressed into adapter element 12, and the line of contact between convex rounding 13a and convex rounding 12f is displaced downwards until it is located in transition area 12g between convex rounding 12f and concave rounding 12a of adapter element 12. Now the maximum pressure point has been reached. With further insertion pressure the elastically flared groove snaps together above extensions 13a and 13b, which causes mounting part 13 to be slid into the positively locking position by the elastic potential energy. For an especially secure positive lock between mounting part 13 and adapter element 12, it is particularly important that mounting part 13 have a much greater modulus of elasticity than the adapter element 12 designed to accommodate it. In other words, mounting part 13 should be essentially rigid for all practical purposes, whereas the reception part is less rigid and more easily elastically deformable. Then as soon as the rigid mounting part 13 is locked into the recess of the adapter element 12, the elastic deformation thereof is prevented due to blocking by the floor surface of the groove-type recess in the adapter element, and consequently much greater force is required to disengage the mounting part from adapter element 12 than the pressure used to insert it. In order to prevent mounting part 13 from slipping sideways out of the groove in adapter element 12, a projection 12c is provided on the floor of the groove and is engaged in a counterpart depression 13c on the first angled leg of mounting part 13. Instead of the projection 12c, a hole may also be provided with which a boss stop may create a positive locking arrangement. The recess in adapter element 12 designed to seat the first angled leg is preferably constructed somewhat smaller than the precise counterpart form of the first angled leg of mounting part 13, so that a slight elastic flaring of the groove is still possible even after engagement, as a result of which a significant frictional engagement is present between mounting part 13 and adapter element 12 in addition to the purely positive locking engagement. FIG. 6 shows a situation similar to FIG. 5. Adapter element 12 is displaced in the direction of arrow A over chain link 10, and laterally projecting pins 14 and 15 of chain link 10 are flush with inclined surfaces 12l on the inside of legs 12i and 12j. If adapter element 12 is now pushed further onto chain link 10, the two legs 12i and 12j are flared progressively due to the projecting pins 14 and 15 being forced against inclined surfaces 12l, which in turn exerts increasing pressure on adapter element 12 until a maximum pressure point is reached. This pressure point is then exceeded when the two projecting pins 14 and 15 of chain link 10 engage with the recesses or holes 12k on the inside of legs 12i and 12j, thereby creating a positively fitted connection between adapter element 12 and chain link 10. Here too, it is advantageous if the U-shape consisting of legs 12i and 12j designed to accommodate chain link 10 with its two projecting pins 14 and 15 is dimensioned somewhat smaller than would create an exact form fit, so that here too a friction lock is created between adapter element 12 and chain link 10 in addition to the purely positive locking engagement. Of course the invention is not limited to the embodiment described. Thus, for example, latching areas might also be conformed at the ends of legs 12i, 12j of adapter element 12, so that after the positively and negatively locking engagement has been established with chain link 10, as retaining clip (not shown) might be applied between the two legs 12i and 12j, with corresponding means of engagement with the ends of the legs, thereby providing additional stabilisation of the U-shaped adapter element 12, thus also ensuring extra protection for the connection between adapter element 12 and chain link 10. In addition, a specially adapted one-piece chain link may be used instead of the locking connection between chain link 10 and adapter element 12, and which may be integrated therewith when the roller chain is assembled.

20040722

20110913

20050414

60100.0

DEUBLE, MARK A

CHAIN TRANSPORT SYSTEM WITH ADD-ON COMPONENTS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Efficient and scalable parametric stereo coding for low bitrate applications

The present invention provides improvements to prior art audio codecs that generate a stereo-illusion through post-processing of a received mono signal. These improvements are accomplished by extraction of stereo-image describing parameters at the encoder side, which are transmitted and subsequently used for control of a stereo generator at the decoder side. Furthermore, the invention bridges the gap between simple pseudo-stereo methods, and current methods of true stereo-coding, by using a new form of parametric stereo coding. A stereo-balance parameter is introduced, which enables more advanced stereo modes, and in addition forms the basis of a new method of stereo-coding of spectral envelopes, of particular use in systems where guided HFR (High Frequency Reconstruction) is employed. As a special case, the application of this stereo-coding scheme in scalable HFR-based codecs is described.

1. A method for coding of stereo properties of an input signal, characterised by: at an encoder, calculate a width-parameter that signals a stereo-width of said input signal, and at a decoder, generate a stereo output signal, using said width-parameter to control a stereo-width of said output signal. 2. A method according to claim 1, characterised by: at said encoder, form a mono signal from said input signal, and at said decoder, said generation implies a pseudo-stereo method operating on said mono signal. 3. A method according to claim 2, characterised in that said pseudo-stereo method implies splitting of said mono signal into two signals as well as addition of delayed version(s) of said mono signal to said two signals, at level(s) controlled by said width-parameter. 4. A method according to claim 3, characterised in that said delayed version(s) are high-pass filtered and progressively attenuated at higher frequencies prior to being added to said two signals. 5. A method according to claim 1, characterised in that said width-parameter is a vector, and the elements of said vector correspond to separate frequency bands. 6. A method according to claims 1-5, characterised in that if said input signal is of type dual mono, said output signal is also of type dual mono. 7. A method for coding of stereo properties of an input signal, characterised by: at an encoder, calculate a balance-parameter that signals a stereo-balance of said input signal, and at a decoder, generate a stereo output signal, using said balance-parameter to control a stereo-balance of said output signal. 8. A method according to claim 7, characterised by: at said encoder, form a mono signal from said input signal, and at said decoder, said generation implies splitting of said mono signal into two signals, and said control implies adjustment of levels of said two signals. 9. A method according to claim 7, characterised in that a power for each channel of said input signal is calculated, and said balance-parameter is calculated from a quotient between said powers. 10. A method according to claim 9, characterised in that said powers and said balance-parameter are vectors where every element corresponds to a specific frequency band. 11. A method according to claim 7, characterised in at said decoder interpolating between two in time consequtive values of said balance-parameters in a way that the momentary value of the corresponding power of said mono signal controls how steep the momentary interpolation should be. 12. A method according to claim 11, characterised in that said interpolation method is performed on balance values represented as logarithmic values. 13. A method according to claim 7, characterised in that said values of balance-parameters are limited to a range between a previous balance value, and a balance value extracted from other balance values by a median filter or other filter process, where said range can be further extended by moving the borders of said range by a certain factor. 14. A method according to claim 13, characterised in that said method of extracting limiting borders for balance values, is, for a multiband system, frequency dependent. 15. A method according to claim 10, characterised in that an additional level-parameter is calculated as a vector sum of said powers and sent to said decoder, thereby providing said decoder a representation of a spectral envelope of said input signal. 16. A method according to claim 15, characterised in that said level-parameter and said balance-parameter adaptively are replaced by said powers. 17. A method according to claim 16, characterised in that said spectral envelope is used to control a HFR-process in a decoder. 18. A method according to claim 15, characterised in that said level-parameter is fed into a primary bitstream of a scalable HFR-based stereo codec, and said balance-parameter is fed into a secondary bitstream of said codec. 19. A method according to claims 2 and 18, characterised in that said mono signal and said width-parameter are fed into said primary bitstream. 20. A method according to claims 5 and 16, characterised in that said width-parameters are processed by a function that gives smaller values for a balance value that corresponds to a balance position further from the center position. 21. A method according to any of claims 7-18, characterised in that a quantization of said balance-parameter employs smaller quantization steps around a center position and larger steps towards outer positions. 22. A method according to claims 5 and 21, characterised in that said width-parameters and said balance-parameters are quantized using a quantization method in terms of resolution and range which, for a multiband system, is frequency dependent. 23. A method according to any of claims 10-18, characterised in that said balance-parameter adaptively is delta-coded either in time or in frequency. 24. A method according to any of claims 2 and 8, characterised in that said input signal is passed though a Hilbert transformer prior to forming said mono signal. 25. An apparatus for parametric stereo coding, characterised by: at an encoder, means for calculation of a width-parameter that signals a stereo-width of an input signal, and means for forming a mono signal from said input signal, at a decoder, means for generating a stereo output signal from said mono signal, using said width-parameter to control a stereo-width of said output signal.

TECHNICAL FIELD The present invention relates to low bitrate audio source coding systems. Different parametric representations of stereo properties of an input signal are introduced, and the application thereof at the decoder side is explained, ranging from pseudo-stereo to full stereo coding of spectral envelopes, the latter of which is especially suited for HFR based codecs. BACKGROUND OF THE INVENTION Audio source coding techniques can be divided into two classes: natural audio coding and speech coding. At medium to high bitrates, natural audio coding is commonly used for speech and music signals, and stereo transmission and reproduction is possible. In applications where only low bitrates are available, e.g. Internet streaming audio targeted at users with slow telephone modem connections, or in the emerging digital AM broadcasting systems, mono coding of the audio program material is unavoidable. However, a stereo impression is still desirable, in particular when listening with headphones, in which case a pure mono signal is perceived as originating from “within the head”, which can be an unpleasant experience. One approach to address this problem is to synthesize a stereo signal at the decoder side from a received pure mono signal. Throughout the years, several different “pseudo-stereo” generators have been proposed. For example in [U.S. Pat. No. 5,883,962], enhancement of mono signals by means of adding delayed/phase shifted versions of a signal to the unprocessed signal, thereby creating a stereo illusion, is described. Hereby the processed signal is added to the original signal for each of the two outputs at equal levels but with opposite signs, ensuring that the enhancement signals cancel if the two channels are added later on in the signal path. In [PCT WO 98/57436] a similar system is shown, albeit without the above mono-compatibility of the enhanced signal. Prior art methods have in common that they are applied as pure post-processes. In other words, no information on the degree of stereo-width, let alone position in the stereo sound stage, is available to the decoder. Thus, the pseudo-stereo signal may or may not have a resemblance of the stereo character of the original signal. A particular situation where prior art systems fall short, is when the original signal is a pure mono signal, which often is the case for speech recordings. This mono signal is blindly converted to a synthetic stereo signal at the decoder, which in the speech case often causes annoying artifacts, and may reduce the clarity and speech intelligibility. Other prior art systems, aiming at true stereo transmission at low bitrates, typically employ a sum and difference coding scheme. Thus, the original left (L) and right (R) signals are converted to a sum signal, S=(L+R)/2, and a difference signal, D=(L−R)/2, and subsequently encoded and transmitted. The receiver decodes the S and D signals, whereupon the original L/R-signal is recreated through the operations L=S+D, and R=S−D. The advantage of this, is that very often a redundancy between L and R is at hand, whereby the information in D to be encoded is less, requiring fewer bits, than in S. Clearly, the extreme case is a pure mono signal, i.e. L and R are identical. A traditional UR-codec encodes this mono signal twice, whereas a S/D codec detects this redundancy, and the D signal does (ideally) not require any bits at all. Another extreme is represented by the situation where R=−L, corresponding to “out of phase” signals. Now, the S signal is zero, whereas the D signal computes to L. Again, the S/D-scheme has a clear advantage to standard L/R-coding. However, consider the situation where e.g. R=0 during a passage, which was not uncommon in the early days of stereo recordings. Both S and D equal L/2, and the S/D-scheme does not offer any advantage. On the contrary, L/R-coding handles this very well: The R signal does not require any bits. For this reason, prior art codecs employ adaptive switching between those two coding schemes, depending on what method that is most beneficial to use at a given moment. The above examples are merely theoretical (except for the dual mono case, which is common in speech only programs). Thus, real world stereo program material contains significant amounts of stereo information, and even if the above switching is implemented, the resulting bitrate is often still too high for many applications. Furthermore, as can be seen from the resynthesis relations above, very coarse quantization of the D signal in an attempt to further reduce the bitrate is not feasible, since the quantization errors translate to non-neglectable level errors in the L and R signals. SUMMARY OF THE INVENTION The present invention employs detection of signal stereo properties prior to coding and transmission. In the simplest form, a detector measures the amount of stereo perspective that is present in the input stereo signal. This amount is then transmitted as a stereo width parameter, together with an encoded mono sum of the original signal. The receiver decodes the mono signal, and applies the proper amount of stereo-width, using a pseudo-stereo generator, which is controlled by said parameter. As a special case, a mono input signal is signaled as zero stereo width, and correspondingly no stereo synthesis is applied in the decoder. According to the invention, useful measures of the stereo-width can be derived e.g. from the difference signal or from the cross-correlation of the original left and right channel. The value of such computations can be mapped to a small number of states, which are transmitted at an appropriate fixed rate in time, or on an as-needed basis. The invention also teaches how to filter the synthesized stereo components, in order to reduce the risk of unmasking coding artifacts which typically are associated with low bitrate coded signals. Alternatively, the overall stereo-balance or localization in the stereo field is detected in the encoder. This information, optionally together with the above width-parameter, is efficiently transmitted as a balance-parameter, along with the encoded mono signal. Thus, displacements to either side of the sound stage can be recreated at the decoder, by correspondingly altering the gains of the two output channels. According to the invention, this stereo-balance parameter can be derived from the quotient of the left and right signal powers. The transmission of both types of parameters requires very few bits compared to full stereo coding, whereby the total bitrate demand is kept low. In a more elaborate version of the invention, which offers a more accurate parametric stereo depiction, several balance and stereo-width parameters are used, each one representing separate frequency bands. The balance-parameter generalized to a per frequency-band operation, together with a corresponding per band operation of a level-parameter, calculated as the sum of the left and right signal powers, enables a new, arbitrary detailed, representation of the power spectral density of a stereo signal. A particular benefit of this representation, in addition to the benefits from stereo redundancy that also S/D-systems take advantage of, is that the balance-signal can be quantized with less precision than the level ditto, since the quantization error, when converting back to a stereo spectral envelope, causes an “error in space”, i.e. perceived localization in the stereo panorama, rather than an error in level. Analogous to a traditional switched L/R- and S/D-system, the level/balance-scheme can be adaptively switched off, in favor of a levelL/levelR-signal, which is more efficient when the overall signal is heavily offset towards either channel. The above spectral envelope coding scheme can be used whenever an efficient coding of power spectral envelopes is required, and can be incorporated as a tool in new stereo source codecs. A particularly interesting application is in HFR systems that are guided by information about the original signal highband envelope. In such a system, the lowband is coded and decoded by means of an arbitrary codec, and the highband is regenerated at the decoder using the decoded lowband signal and the transmitted highband envelope information [PCT WO 98/57436]. Furthermore, the possibility to build a scalable HFR-based stereo codec is offered, by locking the envelope coding to level/balance operation. Hereby the level values are fed into the primary bitstream, which, depending on the implementation, typically decodes to a mono signal. The balance values are fed into the secondary bitstream, which in addition to the primary bitstream is available to receivers close to the transmitter, taking an IBOC (In-Band On-Channel) digital AM-broadcasting system as an example. When the two bitstreams are combined, the decoder produces a stereo output signal. In addition to the level values, the primary bitstream can contain stereo parameters, e.g. a width parameter. Thus, decoding of this bitstream alone already yields a stereo output, which is improved when both bitstreams are available. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will now be described by way of illustrative examples, not limiting the scope or spirit of the invention, with reference to the accompanying drawings, in which: FIG. 1 illustrates a source coding system containing an encoder enhanced by a parametric stereo encoder module, and a decoder enhanced by a parametric stereo decoder module. FIG. 2a is a block schematic of a parametric stereo decoder module, FIG. 2b is a block schematic of a pseudo-stereo generator with control parameter inputs, FIG. 2c is a block schematic of a balance adjuster with control parameter inputs, FIG. 3 is a block schematic of a parametric stereo decoder module using multiband pseudo-stereo generation combined with multiband balance adjustment, FIG. 4a is a block schematic of the encoder side of a scalable HFR-based stereo codec, employing level/balance-coding of the spectral envelope, FIG. 4b is a block schematic of the corresponding decoder side. DESCRIPTION OF PREFERRED EMBODIMENTS The below-described embodiments are merely illustrative for the principles of the present invention. It is understood that modifications and variations of the arrangements and the details described herein will be apparent to others skilled in the art. It is the intent therefore, to be limited only by the scope of the impending patent claims, and not by the specific details presented by way of description and explanation of the embodiments herein. For the sake of clarity, all below examples assume two channel systems, but apparent to others skilled in the art, the methods can be applied to multichannel systems, such as a 5.1 system. FIG. 1 shows how an arbitrary source coding system comprising of an encoder, 107, and a decoder, 115, where encoder and decoder operate in monaural mode, can be enhanced by parametric stereo coding according to the invention. Let L and R denote the left and right analog input signals, which are fed to an AD-converter, 101. The output from the AD-converter is converted to mono, 105, and the mono signal is encoded, 107. In addition, the stereo signal is routed to a parametric stereo encoder, 103, which calculates one or several stereo parameters to be described below. Those parameters are combined with the encoded mono signal by means of a multiplexer, 109, forming a bitstream, 111. The bitstream is stored or transmitted, and subsequently extracted at the decoder side by means of a demultiplexer, 113. The mono signal is decoded, 115, and converted to a stereo signal by a parametric stereo decoder, 119, which uses the stereo parameter(s), 117, as control signal(s). Finally, the stereo signal is routed to the DA-converter, 121, which feeds the analog outputs, L′ and R′. The topology according to FIG. 1 is common to a set of parametric stereo coding methods which will be described in detail, starting with the less complex versions. One method of parameterization of stereo properties according to the present invention, is to determine the original signal stereo-width at the encoder side. A first approximation of the stereo-width is the difference signal, D=L−R, since, roughly put, a high degree of similarity between L and R computes to a small value of D, and vice versa. A special case is dual mono, where L=R and thus D=0. Thus, even this simple algorithm is capable of detecting the type of mono input signal commonly associated with news broadcasts, in which case pseudo-stereo is not desired. However, a mono signal that is fed to L and R at different levels does not yield a zero D signal, even though the perceived width is zero. Thus, in practice more elaborate detectors might be required, employing for example cross-correlation methods. One should make sure that the value describing the left-right difference or correlation in some way is normalized with the total signal level, in order to achieve a level independent detector. A problem with the aforementioned detector is the case when mono speech is mixed with a much weaker stereo signal e.g. stereo noise or background music during speech-to-music/music-to-speech transitions. At the speech pauses the detector will then indicate a wide stereo signal. This is solved by normalizing the stereo-width value with a signal containing information of previous total energy level e.g., a peak decay signal of the total energy. Furthermore, to prevent the stereo-width detector from being trigged by high frequency noise or channel different high frequency distortion, the detector signals should be pre-filtered by a low-pass filter, typically with a cutoff frequency somewhere above a voice's second formant, and optionally also by a high-pass filter to avoid unbalanced signal-offsets or hum. Regardless of detector type, the calculated stereo-width is mapped to a finite set of values, covering the entire range, from mono to wide stereo. FIG. 2a gives an example of the contents of the parametric stereo decoder introduced in FIG. 1. The block denoted ‘balance’, 211, controlled by parameter B, will be described later, and should be regarded as bypassed for now. The block denoted ‘width’, 205, takes a mono input signal, and synthetically recreates the impression of stereo width, where the amount of width is controlled by the parameter W. The optional parameters S and D will be described later. According to the invention, a subjectively better sound quality can often be achieved by incorporating a crossover filter comprising of a low-pass filter, 203, and a high-pass filter, 201, in order to keep the low frequency range “tight” and unaffected. Hereby only the output from the high-pass filter is routed to the width block. The stereo output from the width block is added to the mono output from the low-pass filter by means of 207 and 209, forming the stereo output signal. Any prior art pseudo-stereo generator can be used for the width block, such as those mentioned in the background section, or a Schroeder-type early reflection simulating unit (multitap delay) or reverberator. FIG. 2b gives an example of a pseudo-stereo generator, fed by a mono signal M. The amount of stereo-width is determined by the gain of 215, and this gain is a function of the stereo-width parameter, W. The higher the gain, the wider the stereo-impression, a zero gain corresponds to pure mono reproduction. The output from 215 is delayed, 221, and added, 223 and 225, to the two direct signal instances, using opposite signs. In order not to significantly alter the overall reproduction level when changing the stereo-width, a compensating attenuation of the direct signal can be incorporated, 213. For example, if the gain of the delayed signal is G, the gain of the direct signal can be selected as sqrt(1−G2). According to the invention, a high frequency roll-off can be incorporated in the delay signal path, 217, which helps avoiding pseudo-stereo caused unmasking of coding artifacts. Optionally, crossover filter, roll-off filter and delay parameters can be sent in the bitstream, offering more possibilities to mimic the stereo properties of the original signal, as also shown in FIGS. 2a and 2b as the signals X, S and D. If a reverberation unit is used for generating a stereo signal, the reverberation decay might sometimes be unwanted after the very end of a sound. These unwanted reverb-tails can however easily be attenuated or completely removed by just altering the gain of the reverb signal. A detector designed for finding sound endings can be used for that purpose. If the reverberation unit generates artifacts at some specific signals e.g., transients, a detector for those signals can also be used for attenuating the same. An alternative method of detecting stereo-properties according to the invention, is described as follows. Again, let L and R denote the left and right input signals. The corresponding signal powers are then given by PL˜L2 and PR˜R2. Now, a measure of the stereo-balance can be calculated as the quotient of the two signal powers, or more specifically as B=(PL+e)/(PR+e), where e is an arbitrary, very small number, which eliminates division by zero. The balance parameter, B, can be expressed in dB given by the relation BdB==10 log10(B). As an example, the three cases PL=10PR, PL=PR, and PL=0.1PR correspond to balance values of +10 dB, 0 dB, and −10 dB respectively. Clearly, those values map to the locations “left”, “center”, and “right”. Experiments have shown that the span of the balance parameter can be limited to for example +/−40 dB, since those extreme values are already perceived as if the sound originates entirely from one of the two loudspeakers or headphone drivers. This limitation reduces the signal space to cover in the transmission, thus offering bitrate reduction. Furthermore, a progressive quantization scheme can be used, whereby smaller quantization steps are used around zero, and larger steps towards the outer limits, which further reduces the bitrate. Often the balance is constant over time for extended passages. Thus, a last step to significantly reduce the number of average bits needed can be taken: After transmission of an initial balance value, only the differences between consecutive balance values are transmitted, whereby entropy coding is employed. Very commonly, this difference is zero, which thus is signaled by the shortest possible codeword. Clearly, in applications where bit errors are possible, this delta coding must be reset at an appropriate time interval, in order to eliminate uncontrolled error propagation. The most rudimental decoder usage of the balance parameter, is simply to offset the mono signal towards either of the two reproduction channels, by feeding the mono signal to both outputs and adjusting the gains correspondingly, as illustrated in FIG. 2c, blocks 227 and 229, with the control signal B. This is analogous to turning the “panorama” knob on a mixing desk, synthetically “moving” a mono signal between the two stereo speakers. The balance parameter can be sent in addition to the above described width parameter, offering the possibility to both position and spread the sound image in the sound-stage in a controlled manner, offering flexibility when mimicking the original stereo impression. One problem with combining pseudo stereo generation, as mentioned in a previous section, and parameter controlled balance, is unwanted signal contribution from the pseudo stereo generator at balance positions far from center position. This is solved by applying a mono favoring function on the stereo-width value, resulting in a greater attenuation of the stereo-width value at balance positions at extreme side position and less or no attenuation at balance positions close to the center position. The methods described so far, are intended for very low bitrate applications. In applications where higher bitrates are available, it is possible to use more elaborate versions of the above width and balance methods. Stereo-width detection can be made in several frequency bands, resulting in individual stereo-width values for each frequency band. Similarly, balance calculation can operate in a multiband fashion, which is equivalent to applying different filter-curves to two channels that are fed by a mono signal. FIG. 3 shows an example of a parametric stereo decoder using a set of N pseudo-stereo generators according to FIG. 2b, represented by blocks 307, 317 and 327, combined with multiband balance adjustment, represented by blocks 309, 319 and 329, as described in FIG. 2c. The individual passbands are obtained by feeding the mono input signal, M, to a set of bandpass filters, 305, 315 and 325. The bandpass stereo outputs from the balance adjusters are added, 311, 321, 313, 323, forming the stereo output signal, L and R. The formerly scalar width- and balance parameters are now replaced by the arrays W(k) and B(k). In FIG. 3, every pseudo-stereo generator and balance adjuster has unique stereo parameters. However, in order to reduce the total amount of data to be transmitted or stored, parameters from several frequency bands can be averaged in groups at the encoder, and this smaller number of parameters be mapped to the corresponding groups of width and balance blocks at the decoder. Clearly, different grouping schemes and lengths can be used for the arrays W(k) and B(k). S(k) represents the gains of the delay signal paths in the width blocks, and D(k) represents the delay parameters. Again, S(k) and D(k) are optional in the bitstream. The parametric balance coding method can, especially for lower frequency bands, give a somewhat unstable behavior, due to lack of frequency resolution, or due to too many sound events occurring in one frequency band at the same time but at different balance positions. Those balance-glitches are usually characterized by a deviant balance value during just a short period of time, typically one or a few consecutive values calculated, dependent on the update rate. In order to avoid disturbing balance-glitches, a stabilization process can be applied on the balance data. This process may use a number of balance values before and after current time position, to calculate the median value of those. The median value can subsequently be used as a limiter value for the current balance value i.e., the current balance value should not be allowed to go beyond the median value. The current value is then limited by the range between the last value and the median value. Optionally, the current balance value can be allowed to pass the limited values by a certain overshoot factor. Furthermore, the overshoot factor, as well as the number of balance values used for calculating the median, should be seen as frequency dependent properties and hence be individual for each frequency band. At low update ratios of the balance information, the lack of time resolution can cause failure in synchronization between motions of the stereo image and the actual sound events. To improve this behavior in terms of synchronization, an interpolation scheme based on identifying sound events can be used. Interpolation here refers to interpolations between two, in time consecutive balance values. By studying the mono signal at the receiver side, information about beginnings and ends of different sound events can be obtained. One way is to detect a sudden increase or decrease of signal energy in a particular frequency band. The interpolation should after guidance from that energy envelope in time make sure that the changes in balance position should be performed preferably during time segments containing little signal energy. Since human ear is more sensitive to entries than trailing parts of a sound, the interpolation scheme benefits from finding the beginning of a sound by e.g., applying peak-hold to the energy and then let the balance value increments be a function of the peak-holded energy, where a small energy value gives a large increment and vice versa. For time segments containing uniformly distributed energy in time i.e., as for some stationary signals, this interpolation method equals linear interpolation between the two balance values. If the balance values are quotients of left and right energies, logarithmic balance values are preferred, for left-right symmetry reasons. Another advantage of applying the whole interpolation algorithm in the logarithmic domain is the human ear's tendency of relating levels to a logarithmic scale. Also, for low update ratios of the stereo-width gain values, interpolation can be applied to the same. A simple way is to interpolate linearly between two in time consecutive stereo-width values. More stable behavior of the stereo-width can be achieved by smoothing the stereo-width gain values over a longer time segment containing several stereo-width parameters. By utilizing smoothing with different attack and release time constants, a system well suited for program material containing mixed or interleaved speech and music is achieved. An appropriate design of such smoothing filter is made using a short attack time constant, to get a short rise-time and hence an immediate response to music entries in stereo, and a long release time, to get a long fall-time. To be able to fast switch from a wide stereo mode to mono, which can be desirable for sudden speech entries, there is a possibility to bypass or reset the smoothing filter by signaling this event. Furthermore, attack time constants, release time constants and other smoothing filter characteristics can also be signaled by an encoder. For signals containing masked distortion from a psycho-acoustical codec, one common problem with introducing stereo information based on the coded mono signal is an unmasking effect of the distortion. This phenomenon usually referred as “stereo-unmasking” is the result of non-centered sounds that do not fulfill the masking criterion. The problem with stereo-unmasking might be solved or partly solved by, at the decoder side, introducing a detector aimed for such situations. Known technologies for measuring signal to mask ratios can be used to detect potential stereo-unmasking. Once detected, it can be explicitly signaled or the stereo parameters can just simply be decreased. At the encoder side, one option, as taught by the invention, is to employ a Hilbert transformer to the input signal, i.e. a 90 degree phase shift between the two channels is introduced. When subsequently forming the mono signal by addition of the two signals, a better balance between a center-panned mono signal and “true” stereo signals is achieved, since the Hilbert transformation introduces a 3 dB attenuation for center information. In practice, this improves mono coding of e.g. contemporary pop music, where for instance the lead vocals and the bass guitar commonly is recorded using a single mono source. The multiband balance-parameter method is not limited to the type of application described in FIG. 1. It can be advantageously used whenever the objective is to efficiently encode the power spectral envelope of a stereo signal. Thus, it can be used as tool in stereo codecs, where in addition to the stereo spectral envelope a corresponding stereo residual is coded. Let the total power P, be defined by P=PL+PR, where PL and PR are signal powers as described above. Note that this definition does not take left to right phase relations into account. (E.g. identical left and right signals but of opposite signs, does not yield a zero total power.) Analogous to B, P can be expressed in dB as PdB=10 log10(P/Pref), where Pref is an arbitrary reference power, and the delta values be entropy coded. As opposed to the balance case, no progressive quantization is employed for P. In order to represent the spectral envelope of a stereo signal, P and B are calculated for a set of frequency bands, typically, but not necessarily, with bandwidths that are related to the critical bands of human hearing. For example those bands may be formed by grouping of channels in a constant bandwidth filterbank, whereby PL and PR are calculated as the time and frequency averages of the squares of the subband samples corresponding to respective band and period in time. The sets P0, P1, P2, . . . , PN−1 and B0, B1, B2, . . . , B N−1, where the subscripts denote the frequency band in an N band representation, are delta and Huffman coded, transmitted or stored, and finally decoded into the quantized values that were calculated in the encoder. The last step is to convert P and B back to PL and PR. As easily seen form the definitions of P and B, the reverse relations are (when neglecting e in the definition of B) PL=BP/(B+1), and PR=P/(B+1). One particularly interesting application of the above envelope coding method is coding of highband spectral envelopes for HFR-based codecs. In this case no highband residual signal is transmitted. Instead this residual is derived from the lowband. Thus, there is no strict relation between residual and envelope representation, and envelope quantization is more crucial. In order to study the effects of quantization, let Pq and Bq denote the quantized values of P and B respectively. Pq and Bq are then inserted into the above relations, and the sum is formed: PLq+PRq=BqPq/(Bq+1)+Pq/(Bq+1)=Pq(Bq+1)/(Bq+1)=Pq. The interesting feature here is that Bq is eliminated, and the error in total power is solely determined by the quantization error in P. This implies that even though B is heavily quantized, the perceived level is correct, assuming that sufficient precision in the quantization of P is used. In other words, distortion in B maps to distortion in space, rather than in level. As long as the sound sources are stationary in the space over time, this distortion in the stereo perspective is also stationary, and hard to notice. As already stated, the quantization of the stereo-balance can also be coarser towards the outer extremes, since a given error in dB corresponds to a smaller error in perceived angle when the angle to the centerline is large, due to properties of human hearing. When quantizing frequency dependent data e.g., multi band stereo-width gain values or multi band balance values, resolution and range of the quantization method can advantageously be selected to match the properties of a perceptual scale. If such scale is made frequency dependent, different quantization methods, or so called quantization classes, can be chosen for the different frequency bands. The encoded parameter values representing the different frequency bands, should then in some cases, even if having identical values, be interpreted in different ways i.e., be decoded into different values. Analogous to a switched L/R- to S/D-coding scheme, the P and B signals may be adaptively substituted by the PL and PR signals, in order to better cope with extreme signals. As taught by [PCT/SE00/00158], delta coding of envelope samples can be switched from delta-in-time to delta-in-frequency, depending on what direction is most efficient in terms of number of bits at a particular moment. The balance parameter can also take advantage of this scheme: Consider for example a source that moves in stereo field over time. Clearly, this corresponds to a successive change of balance values over time, which depending on the speed of the source versus the update rate of the parameters, may correspond to large delta-in-time values, corresponding to large codewords when employing entropy coding. However, assuming that the source has uniform sound radiation versus frequency, the delta-in-frequency values of the balance parameter are zero at every point in time, again corresponding to small codewords. Thus, a lower bitrate is achieved in this case, when using the frequency delta coding direction. Another example is a source that is stationary in the room, but has a non-uniform radiation. Now the delta-in-frequency values are large, and delta-in-time is the preferred choice. The P/B-coding scheme offers the possibility to build a scalable HFR-codec, see FIG. 4. A scalable codec is characterized in that the bitstream is split into two or more parts, where the reception and decoding of higher order parts is optional. The example assumes two bitstream parts, hereinafter referred to as primary, 419, and secondary, 417, but extension to a higher number of parts is clearly possible. The encoder side, FIG. 4a, comprises of an arbitrary stereo lowband encoder, 403, which operates on the stereo input signal, IN (the trivial steps of AD-respective DA-conversion are not shown in the figure), a parametric stereo encoder, which estimates the highband spectral envelope, and optionally additional stereo parameters, 401, which also operates on the stereo input signal, and two multiplexers, 415 and 413, for the primary and secondary bitstreams respectively. In this application, the highband envelope coding is locked to P/B-operation, and the P signal, 407, is sent to the primary bitstream by means of 415, whereas the B signal, 405, is sent to the secondary bitstream, by means of 413. For the lowband codec different possibilities exist: It may constantly operate in S/D-mode, and the S and D signals be sent to primary and secondary bitstreams respectively. In this case, a decoding of the primary bitstream results in a full band mono signal. Of course, this mono signal can be enhanced by parametric stereo methods according to the invention, in which case the stereo-parameter(s) also must be located in the primary bitstream. Another possibility is to feed a stereo coded lowband signal to the primary bitstream, optionally together with highband width- and balance-parameters. Now decoding of the primary bitstream results in true stereo for the lowband, and very realistic pseudo-stereo for the highband, since the stereo properties of the lowband are reflected in the high frequency reconstruction. Stated in another way: Even though the available highband envelope representation or spectral coarse structure is in mono, the synthesized highband residual or spectral fine structure is not. In this type of implementation, the secondary bitstream may contain more lowband information, which when combined with that of the primary bitstream, yields a higher quality lowband reproduction. The topology of FIG. 4 illustrates both cases, since the primary and secondary lowband encoder output signals, 411, and 409, connected to 415 and 417 respectively, may contain either of the above described signal types. The bitstreams are transmitted or stored, and either only 419 or both 419 and 417 are fed to the decoder, FIG. 4b. The primary bitstream is demultiplexed by 423, into the lowband core decoder primary signal, 429 and the P signal, 431. Similarly, the secondary bitstream is demultiplexed by 421, into the lowband core decoder secondary signal, 427, and the B signal, 425. The lowband signal(s) is(are) routed to the lowband decoder, 433, which produces an output, 435, which again, in case of decoding of the primary bitstream only, may be of either type described above (mono or stereo). The signal 435 feeds the HFR-unit, 437, wherein a synthetic highband is generated, and adjusted according to P, which also is connected to the HFR-unit. The decoded lowband is combined with the highband in the HFR-unit, and the lowband and/or highband is optionally enhanced by a pseudo-stereo generator (also situated in the HFR-unit), before finally being fed to the system outputs, forming the output signal, OUT. When the secondary bitstream, 417, is present, the HFR-unit also gets the B signal as an input signal, 425, and 435 is in stereo, whereby the system produces a full stereo output signal, and pseudo-stereo generators if any, are bypassed.

<SOH> BACKGROUND OF THE INVENTION <EOH>Audio source coding techniques can be divided into two classes: natural audio coding and speech coding. At medium to high bitrates, natural audio coding is commonly used for speech and music signals, and stereo transmission and reproduction is possible. In applications where only low bitrates are available, e.g. Internet streaming audio targeted at users with slow telephone modem connections, or in the emerging digital AM broadcasting systems, mono coding of the audio program material is unavoidable. However, a stereo impression is still desirable, in particular when listening with headphones, in which case a pure mono signal is perceived as originating from “within the head”, which can be an unpleasant experience. One approach to address this problem is to synthesize a stereo signal at the decoder side from a received pure mono signal. Throughout the years, several different “pseudo-stereo” generators have been proposed. For example in [U.S. Pat. No. 5,883,962], enhancement of mono signals by means of adding delayed/phase shifted versions of a signal to the unprocessed signal, thereby creating a stereo illusion, is described. Hereby the processed signal is added to the original signal for each of the two outputs at equal levels but with opposite signs, ensuring that the enhancement signals cancel if the two channels are added later on in the signal path. In [PCT WO 98/57436] a similar system is shown, albeit without the above mono-compatibility of the enhanced signal. Prior art methods have in common that they are applied as pure post-processes. In other words, no information on the degree of stereo-width, let alone position in the stereo sound stage, is available to the decoder. Thus, the pseudo-stereo signal may or may not have a resemblance of the stereo character of the original signal. A particular situation where prior art systems fall short, is when the original signal is a pure mono signal, which often is the case for speech recordings. This mono signal is blindly converted to a synthetic stereo signal at the decoder, which in the speech case often causes annoying artifacts, and may reduce the clarity and speech intelligibility. Other prior art systems, aiming at true stereo transmission at low bitrates, typically employ a sum and difference coding scheme. Thus, the original left (L) and right (R) signals are converted to a sum signal, S=(L+R)/2, and a difference signal, D=(L−R)/2, and subsequently encoded and transmitted. The receiver decodes the S and D signals, whereupon the original L/R-signal is recreated through the operations L=S+D, and R=S−D. The advantage of this, is that very often a redundancy between L and R is at hand, whereby the information in D to be encoded is less, requiring fewer bits, than in S. Clearly, the extreme case is a pure mono signal, i.e. L and R are identical. A traditional UR-codec encodes this mono signal twice, whereas a S/D codec detects this redundancy, and the D signal does (ideally) not require any bits at all. Another extreme is represented by the situation where R=−L, corresponding to “out of phase” signals. Now, the S signal is zero, whereas the D signal computes to L. Again, the S/D-scheme has a clear advantage to standard L/R-coding. However, consider the situation where e.g. R=0 during a passage, which was not uncommon in the early days of stereo recordings. Both S and D equal L/2, and the S/D-scheme does not offer any advantage. On the contrary, L/R-coding handles this very well: The R signal does not require any bits. For this reason, prior art codecs employ adaptive switching between those two coding schemes, depending on what method that is most beneficial to use at a given moment. The above examples are merely theoretical (except for the dual mono case, which is common in speech only programs). Thus, real world stereo program material contains significant amounts of stereo information, and even if the above switching is implemented, the resulting bitrate is often still too high for many applications. Furthermore, as can be seen from the resynthesis relations above, very coarse quantization of the D signal in an attempt to further reduce the bitrate is not feasible, since the quantization errors translate to non-neglectable level errors in the L and R signals.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention employs detection of signal stereo properties prior to coding and transmission. In the simplest form, a detector measures the amount of stereo perspective that is present in the input stereo signal. This amount is then transmitted as a stereo width parameter, together with an encoded mono sum of the original signal. The receiver decodes the mono signal, and applies the proper amount of stereo-width, using a pseudo-stereo generator, which is controlled by said parameter. As a special case, a mono input signal is signaled as zero stereo width, and correspondingly no stereo synthesis is applied in the decoder. According to the invention, useful measures of the stereo-width can be derived e.g. from the difference signal or from the cross-correlation of the original left and right channel. The value of such computations can be mapped to a small number of states, which are transmitted at an appropriate fixed rate in time, or on an as-needed basis. The invention also teaches how to filter the synthesized stereo components, in order to reduce the risk of unmasking coding artifacts which typically are associated with low bitrate coded signals. Alternatively, the overall stereo-balance or localization in the stereo field is detected in the encoder. This information, optionally together with the above width-parameter, is efficiently transmitted as a balance-parameter, along with the encoded mono signal. Thus, displacements to either side of the sound stage can be recreated at the decoder, by correspondingly altering the gains of the two output channels. According to the invention, this stereo-balance parameter can be derived from the quotient of the left and right signal powers. The transmission of both types of parameters requires very few bits compared to full stereo coding, whereby the total bitrate demand is kept low. In a more elaborate version of the invention, which offers a more accurate parametric stereo depiction, several balance and stereo-width parameters are used, each one representing separate frequency bands. The balance-parameter generalized to a per frequency-band operation, together with a corresponding per band operation of a level-parameter, calculated as the sum of the left and right signal powers, enables a new, arbitrary detailed, representation of the power spectral density of a stereo signal. A particular benefit of this representation, in addition to the benefits from stereo redundancy that also S/D-systems take advantage of, is that the balance-signal can be quantized with less precision than the level ditto, since the quantization error, when converting back to a stereo spectral envelope, causes an “error in space”, i.e. perceived localization in the stereo panorama, rather than an error in level. Analogous to a traditional switched L/R- and S/D-system, the level/balance-scheme can be adaptively switched off, in favor of a levelL/levelR-signal, which is more efficient when the overall signal is heavily offset towards either channel. The above spectral envelope coding scheme can be used whenever an efficient coding of power spectral envelopes is required, and can be incorporated as a tool in new stereo source codecs. A particularly interesting application is in HFR systems that are guided by information about the original signal highband envelope. In such a system, the lowband is coded and decoded by means of an arbitrary codec, and the highband is regenerated at the decoder using the decoded lowband signal and the transmitted highband envelope information [PCT WO 98/57436]. Furthermore, the possibility to build a scalable HFR-based stereo codec is offered, by locking the envelope coding to level/balance operation. Hereby the level values are fed into the primary bitstream, which, depending on the implementation, typically decodes to a mono signal. The balance values are fed into the secondary bitstream, which in addition to the primary bitstream is available to receivers close to the transmitter, taking an IBOC (In-Band On-Channel) digital AM-broadcasting system as an example. When the two bitstreams are combined, the decoder produces a stereo output signal. In addition to the level values, the primary bitstream can contain stereo parameters, e.g. a width parameter. Thus, decoding of this bitstream alone already yields a stereo output, which is improved when both bitstreams are available.

20040108

20080603

20050310

80374.0

SUTHERS, DOUGLAS JOHN

EFFICIENT AND SCALABLE PARAMETRIC STEREO CODING FOR LOW BITRATE AUDIO CODING APPLICATIONS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Production of soluble keratin derivaties

A process for the preparation of soluble proteins of high molecular weight with little or no damage to the structural integrity of the proteins. The process is economically and environmentally acceptable by virtue of the cost of reagents that are used, and the recycling of some of those reagents, and is suitable for the production of soluble proteins on a large scale. The process includes a first stage using oxidative sulfitolysis followed by a second stage using mild conditions to extract the soluble protein. In the case of wool as the protein source the process leads to the production of soluble keratin proteins fractionated into the classes S-sulfonated keratin intermediate filament proteins and S-sulfonated keratin high sulfur proteins.

1. A process for the preparation of keratin derivatives of high molecular weight, the process including a first stage digestion step of sulfonating a keratin source by oxidative sulfitolysis followed by a second stage repetitive aqueous extraction involving separation of soluble and insoluble keratin and subsequent re-extraction of the insoluble keratin to thereby produce a highly S-sulfonated keratin derivative. 2. A process according to claim 1 wherein the first stage is carried out without the use of a chaotropic agent. 3. A process according to claim 1 wherein the first stage is carried out under conditions of pH that maintains structural integrity of the protein. 4. A process according to claim 1 in which the oxidative sulfitolysis uses cuprammonium hydroxide, or a thionate, as the oxidant, and sulfite. 5. A process as according to claim 1 wherein the two stages use surfactants, heat, agitation and homogenization to control the rate of digestion in the first stage and extraction in the second stage. 6. A process as recited in claim 4 using surfactants, heat agitation and homogenization to control the rate of release of residual reagents and soluble protein, thereby allowing separation of the highly S-sulfonated keratin derivative. 7. A process for the separation of a gelatinous keratin substrate from the solution of S-sulfonated keratin produced by the process as recited in claim 1 wherein the S-sulfonated keratin derivative solution is treated by the use of a gentle, gravity fed filtration system followed by centrifugal separation. 8. A process as recited claim 1 that uses a combination of engineering solutions to allow continuous preparation of S-sulfonated keratin derivatives. 9. A process as recited in claim 1 wherein the solution of S-sulfonated keratin is purified using chelating agents, such as EDTA, to sequester metal ions, such as copper. 10. A process as recited in claim 1 wherein the solution containing S-sulfonated keratin derivatives is purified using ion exchange media to remove residual reagents, including metals such as copper. 11. A process as recited in claim 10 wherein the solution is concentrated prior to an ion exchange treatment through the use of ultrafiltration membranes, or similar. 12. A process as recited in claim 11 in which reagents such as copper are isolated and reused in subsequent processes. 13. A highly S-sulfonated solution of keratin derivatives produced by the process of claim 1. 14. A process or isolation of highly S-sulfonated keratin intermediate filament proteins from the solution of keratin claimed in claim 13 wherein the highly S-sulfonated keratin intermediate filament protein is isolated by isoelectric precipitation at acidic pH. 15. A highly purified proteinaceous product produced by the process of claim 14. 16. A proteinacious product as recited in claim 15 which is purified by the dissolution of the S-sulfonated keratin intermediate filament proteins in base in the presence of EDTA, and subsequently precipitated at acidic pH. 17. A water soluble form of S-sulfonated keratin intermediate filament protein produced by spray drying an aqueous solution of the polymeric product as recited in claim 15. 18. A process for the production of highly S-sulfonated keratin high sulphur proteins, produced by spray drying the solution of S-sulfonated keratin derivatives purified as claimed in claim 9, and after having had the intermediate filament proteins removed. 19. A proteinaceous product produced by the process of claim 18. 20. A process for the production of soluble keratin peptides through the action of hydrogen peroxide solutions on the gelatinous residue produced by the process as recited in claim 1. 21. A proteinaceous product produced by the process recited in claim 20. 22. A process for the production of soluble keratin peptides through the action of sodium sulfide solution on the gelatinous residue produced by the process as recited in claim 1. 23. A proteinaceous product produced by the process recited in claim 22. 24. A process for the production of soluble keratin peptides through the action of proteolytic enzymes, such as those from the subtilisin, papain or trypsin families, on the gelatinous residue produced by the process as recited in claim 1. 25. The proteinaceous product produced by the process recited in claim 24. 26. A process for the treatment of copper-rich solutions produced by the process as recited in claim 4, in which wool is used as a filter media to bind copper and remove it from the solution. 27. A subsequent protein extraction process for the treatment of the copper-laden wool produced by the process recited in claim 26.

FIELD OF THE INVENTION This invention relates to a process for the preparation of derivatives of keratin from animal sources such as wool, hair, horns, hooves, feathers and scales by an economic and environmentally acceptable process, and to a series of keratin derivative products produced thereby. Some of the keratin derivatives are soluble and can be used in the production of a range of biopolymer materials. BACKGROUND OF THE INVENTION Keratins are a class of structural proteins widely represented in biological structures, especially in epithelial tissues of higher vertebrates. Keratins may be divided into two major classes, the soft keratins (occurring in skin and a few other tissues) and the hard keratins, forming the material of nails, claws, hair, horn, feathers and scales. The toughness and insolubility of hard keratins, which allow them to perform a fundamental structural role in many biological systems, are also desirable characteristics in many of the industrial and consumer materials currently derived from synthetic polymers. In addition to possessing excellent physical properties, keratin, as a protein, is a material with a high degree of chemical functionality and, consequently, exhibits many properties that synthetic materials cannot achieve. Keratin is, therefore, well suited to the development of products with high-value, niche-market applications. Keratin is also an environmentally acceptable polymer produced from a sustainable resource and therefore has environmental benefits over synthetic materials. Following the global trend of developing materials from renewable sources produced in a sustainable process, a range of materials has been produced from keratin, most commonly in the form of keratin films. At the core of a new industry producing biopolymer materials from keratin it is essential to have a process for extracting keratin from its source that is economically viable, sustainable from an environmental perspective, and produces a stable and versatile product. Methods used to date for the extraction of keratin that maintain the integrity of the individual proteins have been designed for the purpose of protein analysis and characterisation and consequently are not viable on an industrial scale, from an economic and environmental viewpoint. Methods used to date for the economic dissolution of keratin have significantly degrading effects on the protein, and consequently the dissolved protein retains few of the physicochemical properties that lead to the desirability of keratin as a biopolymer, such as the ability to reconstitute into tough materials. It is an object of the invention to go some way in overcoming the disadvantages with known processes or at least provide the public with a useful choice. In at least one embodiment the invention strives to provide an economic and environmentally acceptable process for the dissolution of keratin proteins that maintains the structural integrity and chemical functionality of the proteins during the dissolution process and leads to a stable and versatile keratin derivative product for the development of biopolymer materials. SUMMARY OF THE INVENTION According to a first aspect the invention provides a dissolution process for producing a range of stable, soluble keratin derivatives of high molecular weight, the molecular weight being similar to or greater than that of proteins originally expressed in the keratin source, with little or no damage to the structural integrity of the constituent proteins. The dissolution occurs in a two-stage process. According to a preferred aspect the invention provides a process for the preparation of keratin derivatives of high molecular weight, the process including a first stage digestion step of S-sulfonating a keratin source by oxidative sulfitolysis followed by a second stage extraction step using controlled washing with water to thereby obtain a highly S-sulfonated keratin derivative. The conversion of highly S-sulfonated keratin from a solid state into solution is without the use of chaotropic agents, by controlled, gradual washing of the sulfonated keratin with water in order to wash out the residual chemical reagents from the extraction procedure and alter the ionic strength of the extraction solution. The first stage involves oxidative sulfitolysis to convert cystine groups present in the protein to S-sulfocysteine, using industrially acceptable concentrations of inexpensive reagents for the purpose of sulfonation (eg. sodium sulfite) and oxidation (eg. cupraammonium hydroxide). According to another aspect, the invention provides a process for the separation of a gelatinous keratin product from a solution of S-sulfonated keratin produced by the above process, wherein the S-sulfonated keratin derivative solution is treated by the use of a gentle, gravity fed filtration system followed by separation. Preferably the separation is centrifugal. According to another aspect of the invention, a liquid stream remaining after the gelatinous keratin is removed is processed by passing over scoured wool, thereby removing residual chemicals from the solution and preparing the wool for subsequent protein extraction processes. Following conversion of the cystine groups, the second stage of the process is one in which the highly S-sulfonted keratin derivative is brought from a solid or gelatinous state into solution by extensive dilution with water. The rate and extent of dissolution can be controlled by the use of heat, surfactants, gentle agitation and vigorous chopping or homogenisation. By controlling the rate of dissolution, reaction solutions can be isolated, for example if a copper oxidant is used a reaction solution rich in copper is produced but it contains little or no dissolved protein, or are rich in protein but contain little or no copper. According to another aspect of the invention, a liquid stream resulting from the second stage of the process, which contains residual chemicals such as copper sulfate and sulfite, as well as S-sulfonated keratin derivatives, is processed using any one or more of a variety of methods that allow the recycling of reagents from the solution and the separate isolation of purified S-sulfonated Keratin Intermediate Filament Protein(s) (SIFP) and S-sulfonated Keratin High Sulfur Protein(s) (SHSP). This is achieved through the use of chelating agents, such as ethylenediamine tetraacetic acid, or chelating ion exchange resins, such as those containing the iminodiacetic functional group, and the use of isoelectric precipitation to separate protein types. Ultrafiltration can be used at several stages in the process to improve the efficiency of reagent removal or protein separation. Metallic impurities in the protein products can be further reduced by the washing of the protein derivative(s) following precipitation with dilute acids, water or chelating agents. Once separated, the protein products can be dried by a range of methods such as fluid bed, spray or freeze drying. Another aspect of the invention is the further processing of residual keratin not dissolved by the two stage sulfitolysis process, through the use of other reagents, such as hydrogen peroxide, sodium sulfide or proteolytic enzymes, to produce keratin peptides. Another aspect of the invention is the provision of a method for large scale recovery of proteins from a natural source, including subjecting said natural protein source to a treatment sufficient to render at least some of the protein(s) water soluble, and subsequently separating the water soluble protein(s). Another aspect of the invention is the provision of an installation for large scale recovery of proteins from a natural source, a treatment vessel to contain and subject a large quantity of natural protein source to a treatment sufficient to render at least some of the protein(s) contained in said feed, water soluble, and a separation apparatus to subsequently separate the water soluble protein(s). Another aspect of the invention is a method of selectively solubilising a protein having plurality of disulfide bonds from a mixture of proteins including subjecting said mixture of proteins to oxidative sulfitolysis to produce a soluble S-sulfonated protein fraction. The oxidative sulfitolysis is preferably effected in the absence of chaotropic agents with little or no damage to the structural integrity of the protein. Another aspect of the invention is method for obtaining a purified protein from an impure protein source with little or no damage to the structural integrity of the protein including subjecting said protein source to a treatment sufficient to render at least some of the protein(s) water soluble, and subsequently separating the water soluble protein(s) in the absence of chaotropic agents. DESCRIPTION OF PREFERRED EXAMPLES OF THE INVENTION The combination of aspects that make up the process as a whole are summarized diagrammatically in attached FIG. 1. This process method is for the preparation of highly sulfonated keratin derivatives and can be applied to any keratin source, such as animal wool, hair, horns, hooves, feathers or scales. Whilst the application of the method to different keratin sources can give soluble keratins with different structure and properties, the fundamental step of the dissolution process, in which cystine is converted to s-sulfocysteine, applies equally well to all keratin-containing materials. The process can be conceived as occurring in two stages. Stage one, which involves the conversion of cystine to S-sulfocysteine, occurs through a procedure of oxidative sulfitolysis. This can be achieved by the use of a sulfonating agent, such as sodium sulfite or sodium metabisulfite, which asymmetrically cleaves the cystine to cysteine and S-sulfocysteine, and an oxidant, which converts the cysteine produced in sulfonation to cystine. By further sulfonation of cystine complete conversion of all cystine to S-sulfocysteine is achieved. Oxidants which can be used include sodium tetrathionate, iodosobenzoate and cuprammonium hydroxide. In a preferred embodiment of this invention the sulfonating reagent used is sodium sulfite in the concentration range 0.02M to 0.2M and the oxidant used is cuprammonium hydroxide in the concentration range 0.02M to 0.08M, generated by the combination of copper sulfate and ammonia. The first stage of the procedure for solublising keratin is the soaking, for a residence time such as 24 hours, of the keratin source in a solution or sequence of solutions that convert the cystine to S-sulfocysteine, with a liquor to wool ratio (volume:weight) in the range 5:1 to 50:1. In another embodiment of the invention the sulfonating agent used is sodium metabisulfite in the concentration range 0.1 M to 0.5M, maintained at acidic pH. In this embodiment the wool is removed from the solution containing sodium metabisulfite before being added to a solution containing a cuprammonium complex in the concentration range 0.02M to 0.08M. Previous work relating to the use of the oxidative sulfitolysis procedure has required the use of large concentrations of chaotropic agents, such as urea or guanidinium hydrochloride, in order to swell the keratin source and facilitate the dissolution of keratin. This procedure is both expensive and impractical on an industrial scale. Previous work relating to the use of oxidative sulfitolysis using copper as the oxidant has been conducted under conditions of temperature and pH that are detrimental to the integrity of the protein causing high rates of conversion of cystine to lanthionine. Stage two of the process involves the conversion of highly sulfonated keratin from a solid state into solution without the use of chaotropic agents and under conditions of temperature and pH that maintain the structural integrity of the protein, by controlled, gradual washing of the sulfonated keratin with water in order to wash out the residual chemical reagents from the extraction procedure and alter the ionic strength of the extraction solution. This combination of effects results in the conversion of the highly sulfonated keratin from the solid state into aqueous solution. In the preferred procedure the reaction volume is replaced every 12 to 48 hours, either in a batch process or on a continuous basis. The rate and extent of dissolution can be controlled by the use of surfactants, the action of heat, agitation, and homogenisation of the sulfonated keratin. A feature of the invention is to use these factors to control the rate of extraction. The highly S-sulfonated keratin can, therefore, be kept in the solid state and separated from the extraction solution containing the bulk of the chemicals used for the sulfonation process. The preferred procedure uses a non-ionic surfactant, such as Triton X 100 in the range 0.1% to 5% by weight, and a temperature maintained in the range 15° C. to 50° C. An advantage of the invention when a copper based oxidant is used is the re-use of this copper-rich extraction solution for subsequent extraction processes, significantly reducing both the cost and environmental impact of the process. Re-use of the copper-rich solution is possible due, in part, to the regeneration of the active copper species through aerial oxidation. One method in which the copper-rich solution can be efficiently reused is by passing the solution over wool. Wool binds copper from the solution, and if this wool is then used for subsequent extraction processes, the demand for copper in those subsequent extractions is reduced. In this way, a ‘wool filter’ can be used as a key step in the processing of the copper-rich extraction solution, reducing the subsequent need for effluent treatment and also the need for copper to be added to the subsequent processes. In a typical procedure the liquid stream from stage 1 contained approximately 1800-1500 (parts per million) ppm copper, and after passing over the wool filter this was reduced to approximately 400-300ppm. The first stage of the process, and the recovery of reagents for use in the process are indicated in the attached FIG. 1. After S-sulfonation and homogenisation the keratin material becomes a gelatinous swollen fibrous mass. A further advantage of the invention is the separation of the highly S-sulfonated keratin derivatives in the solid state from solutions containing either chemicals used in the extraction process or the keratin protein in solution. This separation is effectively achieved by the use of a gentle, gravity based filtration through a fine mesh screen, followed by centrifugal separation of the filtrate from fine particulates. Solutions of highly S-sulfonated keratin derivatives can be purified with regard to metal ions, specifically the copper ions used as part of the extraction process, through the use of ion exchange media, in particular those containing iminodiacetic acid functionality known to possess a high affinity for divalent metal ions. This ion exchange medium may be present in the form of a packed resin column, over which the protein solution is passed, or it may alternatively form part of an electrochemical cell, in which copper is recovered from the ion exchange medium through the use of an applied voltage and a system containing permeable membranes. Once the highly S-sulfonated keratin derivates are in solution particular proteins eg. the S-sulfonated keratin intermediate filament protein can be readily isolated by isoelectric precipitation, around pH 4 or below, using acids such as sulfuric acid, hydrochloric acid, citric acid or acetic acid, with the preferred procedure using sulfuric acid. An advantage of the invention is the minimisation of the binding of copper and other metallic impurities to the protein prior to isoelectric precipitation through the use of ion exchange media as described, or by addition of a chelating agent, such as ethylenediaminetetraacetic acid (EDTA), to the protein solution. In the preferred example EDTA (0.2M) is added to the liquid stream from stage 2 at a rate of 25 ml per liter, or at a rate suitable to sequester all the copper ions present in solution as indicated by analysis of the solution. Metallic impurities can be further reduced by the washing of the protein, once isolated by precipitation, with a dilute acid solution, or solution of a chelating agent such as EDTA, or water. Following precipitation and washing the separated protein can be isolated in a stable, dry state using drying methods involving air flows at about ambient temperature, for example with the use of a fluid bed dryer. Alternatively, the product can be dried using a freeze dryer. The dry protein product contains cystine groups in the form of S-sulfonic acid and consequently the protein is only soluble in the presence of a base, such as sodium hydroxide or ammonium hydroxide. These processes are represented as drying in the attached FIG. 1. The highly soluble keratin derivatives that remain in solution following isoelectric precipitation, which in the case of wool are mainly the high sulfur matrix proteins from within the wool fibre, can be isolated in a stable form from solution through a process of ultrafiltration, to remove non-proteinacious species such as residual copper or EDTA, followed by spray drying. A feature of the invention is the use of a combination of isoelectric precipitation and ultrafiltration followed by spray drying to separate highly S-sulfonated keratins according to their properties in solution. In the case of wool keratin, this effectively separates the low sulfur intermediate filament protein class from the high sulfur matrix protein class and provides two product streams with different chemical properties. A feature of the invention is the preparation of a stable, water soluble form of the highly S-sulfonated keratin derivative, by dissolving the S-sulfonic acid form of keratin in the presence of base and spray drying the resulting solution. A feature of the invention is the combination of engineering components to allow solublisation of the keratin and isolation of the S-sulfonated keratin from solution in a continuous, semi-continuous, or batch process. This combination of engineering components and unit operations is detailed in FIG. 1. An advantage of the invention is the recovery and reuse of copper from the reaction mixtures and effluent streams of the process. Copper can be recovered using electrochemical methods, including the use of selective permeable membranes in order to separate copper ions from EDTA prior to electrochemical deposition. Alternatively, immobilized binding agents, in the form of copper-specific ion exchange resins, can be used to remove copper from the effluent stream. Copper removed using these methods can be reused, thereby minimizing the environmental impact of the process. The use of ion exchange media and/or chelating agents is represented as purification in the attached FIG. 1. Another advantage of the invention is the further processing of residual keratin which remains in the solid state following the extraction procedure. This functionalised keratin is highly S-sulfonated, therefore the disulfide bonds present in the native keratin that render it resistant to chemical and enzymatic attack have been cleaved and the keratin is readily digestible using other extraction methods. For example, a solution rich in keratin peptides can be prepared through the action on this residual keratin of alkaline solutions of a strong oxidant such as hydrogen peroxide, in the concentration range 10-100 ml of 50% hydrogen peroxide per kg of the keratin residue under alkaline conditions. The keratin residue contains approximately 5% solids. Alternatively, solutions of strong reductants such as sodium sulphide in the concentration range 0.5%-15% added to the keratin residue can be used to prepare a solution rich in keratin peptides. Alternatively, proteolytic enzymes, such as those of the subtilisin, papain or trypsin groups, can be employed at levels in the range 0.1 mg -20 mg of enzyme per gram of keratin residue at temperature and pH conditions appropriate for the specific enzyme to readily digest the residual keratin and prepare a solution rich in keratin peptides. All of these methods result in the formation of a solution rich in keratin peptides which can be processed in a similar manner to the liquid stream resulting from stage 2 described above, that is through the use of ion exchange media, pH adjustment and drying (shown as purification and drying in FIG. 1), to produce keratin peptide solids. Digestion of the keratin residue in this way minimises the keratin waste produced by the process as a whole, and ensures maximum utility of the keratin protein present in the keratin source. The two intact protein products from the process are S-sulfonated keratin intermediate filament protein and S-sulfonated keratin high sulfur protein. The S-sulfonated keratin intermediate filament protein typically produced by the process was analysed using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis using a reduction/alkylation procedure, which indicated a molecular weight distribution predominantly in the range 30-60 kD (intermediate filament proteins), with a small component of protein of mass 10 kD (high glycine high tyrosine proteins). The amino acid composition of this product is given in Table 1 and is typical for wool keratin intermediate filament proteins. The S-sulfonated keratin high sulfur protein was analysed using SDS-PAGE after a reduction/alkylation procedure, which indicated a molecular weight predominantly in the range 15-20 kD. The amino acid composition of this product is given in Table 1 and is typical for wool keratin high sulfur proteins. TABLE 1 amino acid composition of S-sulfonated keratin intermediate filament protein (STEP), S-suffonated keratin high sulfur protein (SHSP), intermediate filament protein (IFP) and high sulfur protein (HSP) (later two courtesy of Gillespie and Marshall, Variability in the proteins of wool and hair, Proc. Sixth Int. Wool Text. Res. Conf, Pretoria, 2, 67-77, 1980). All residues expressed as mol %. S-sulfocysteine, cystine and cysteine are measured as S-carboxymethyl cysteine following reduction and alkylation. Cya Asp Glu Ser Gly His Arg Thr Ala Pro Tyr Val Met Lan Ile Leu Phe Lys Cys SIFP 0.4 7.9 15.4 10.9 8.1 0.9 7.9 6.5 7.5 5.4 1.1 6.5 0.2 0.2 3.7 8.9 2.5 2.1 4.2 SHSP 1.7 2.6 8.6 14.3 9.1 0.8 6.8 10.4 3.6 12.6 1.8 6.3 0.0 0.2 2.9 3.9 1.5 0.4 12.4 IFP 0.0 9.6 16.9 8.1 5.2 0.6 7.9 4.8 7.7 3.3 2.7 6.4 0.6 0.0 3.8 10.2 2.0 4.1 6.0 HSP 0.0 2.3 7.9 13.2 6.2 0.7 6.2 10.2 2.9 12.6 2.1 5.3 0.0 0.0 2.6 3.4 1.6 0.6 22.1 An example of the process is shown diagrammatically in the attached FIG. 1. Ultrafiltration is considered as being a possible component in each purification stage. The key components are illustrated by the following examples of a protein extraction procedure. EXAMPLES Example 1 Stage 1, Digestion The digestion stage of the process involves the use of oxidative sulfitolysis to convert cystine to S-sulfocysteine within the keratin source. Example 1a Stage 1, Digestion In order to extract the keratin from 10 kg of wool, firstly 2 kg of copper sulfate pentahydrate was mixed using a high shear mixer with eight litres of concentrated ammonia. This mixture was diluted to 200 L with water and 10 kg of wool was added. Approximately 15 L of sulfuric acid (2M) was-added to the stirred mixture till a pH 9.4 was achieved. Anhydrous sodium sulfite (5.04 kg) was added and the solution mixed until complete dissolution of all of the reagents had occurred and the pH stabilised at 9.5. The final concentration of the cupric ammonia complex was 0.04M. The sodium sulfite had a final concentration of 0.2M. The temperature of the digestion solution was maintained at 20° C. After 24 hours of gentle agitation the fibrous gelatinous mass of softened wool was filtered. The filtrate was passed through a fresh wool filter, which decreased the copper level in the solution from 1725 ppm to 130 ppm, and further purified using Purolite S93O IDA ion exchange resin, which under acidic conditions further reduced the copper level to 12 ppm. Fresh water was added to the softened wool and the mixture was agitated. Example 1b Stage 1, Digestion with the Use of Surfactant In a variation of example 1a, the digestion solution was prepared with the addition of 1% of a non-ionic surfactant Triton X 100. The addition of this surfactant resulted in a delay in the release of soluble protein from the fibre, allowing a more effective separation of protein from residual reagents such as copper salts in the extraction solution. Example 1c Stage 1, Digestion In a variation of example 1a, the digestion stage occurs in two parts. In the first part wool is pretreated with sodium metabisulfite at a concentration of 0.2M, at pH 4.2. Following removal of the wool from this solution, and with no attempt to remove residual sulfite from the wool, the wool was immersed in a cuprammonium hydroxide solution, at the concentration and pH described in example 1a for a further 24 hours at 20° C. Example 2 Stage 2, Extraction Example 2a Stage 2, Batch Extraction Following completion of stage 1, described in examples 1, the mixture was agitated for a period of 16 hours, before being homogenized. Following a further 4 hours of agitation the solids and solution were separated using a two-stage filtration process involving a wedge wire screen followed by a settling tank and a spinning disc centrifuge. The solid phases were returned to the reaction vessel and water was added to give a final liquor to wool ratio of 20:1 based on original wool solids. Following 24 hours agitation or continuous homogenisation the mixture was separated by repeating the two-stage filtration process. The solid phases were returned to the extraction vessel and further diluted. This cycle was repeated 7 to 12 times. The liquid phases, containing soluble proteins, were further processed as detailed below in example 3. Example 2b Stage 2, Continuous Extraction Following completion of stage 1 the mixture was processed as described in example 2a, except that the two stage filtration process occurred on a continuous process, and solids and fresh water were added to the reaction tank at a rate equivalent to the volume of the tank being replaced in 24 hours. This process was continued for 120 hours. Example 3 Processing of Protein Solutions Ultrafiltration can be used at several points during the processing of protein solutions, in order to concentrate solutions and make the processes of drying and ion exchange more efficient. Ultrafiltration may be used prior to any processing step outlined in the following examples. Example 3a Processing of Protein Solutions Using EDTA The solution produced as a result of stage 2, as described in Example 2, was further processed to isolate purified soluble keratins. EDTA (0.2M ) was added to the liquid phase at a rate of 25 mL per liter, or at a rate suitable to sequester all the copper ions present in solution as indicated by analysis of the solution. Following 1 hour of mixing, the pH of the filtrate was reduced to 3.5 using sulfuric acid. The protein precipitate was isolated using a screen, and washed sequentially with dilute sulfuric acid and water. The protein, S-sulfonated keratin intermediate filament protein, was dried by one of three routes, freeze drying, fluid bed drying or spray drying following dissolution with dilute sodium hydroxide. The filtrate following the protein precipitation procedure was further processed using ultrafitration, to separate the protein components from the residual reagents. The retentate was spray dried to isolate further soluble protein, S-sulfonated keratin high sulfur protein. The permeate was further processed to recover copper and EDTA from the effluent stream using ion exchange media. Example 3b Processing of Protein Solution Using Ion Exchange Media The solution produced as a result of stage 2, as described in Example 2, was further processed to isolate purified soluble keratins. The liquid phase was passed over ion exchange resin, such as the chelating resin Purolite S930 IDA ion exchange resin containing the iminodiacetic acid functional group, in order to remove copper ions from the solution. Following ion exchange the pH of the filtrate was reduced to 3.5 using sulfuric acid and further processed in an identical manner to that described for Example 3a. 3c. Processing of Protein Solution Using pH Adjustment Prior to Ion Exchange. The solution produced as a result of stage 2, as described in example 2, was further processed to isolate purified soluble keratins. The pH of the liquid phase was reduced to 3.5 using sulfuric acid. The protein precipitate was isolated using a screen, redissolved using dilute sodium hydroxide and further purified with either the addition of EDTA or by passing over an ion exchange column. Following further purification, the pH of the solution was reduced to 3.5 using sulfuric acid and the protein was isolated as described in the earlier examples. The filtrate from the initial pH reduction step, which still contains significant amounts of soluble protein and other reagents, was purified by passing over ion exchange media and spray dried to isolate further soluble protein, S-sulfonated keratin high sulfur protein. Example 4 Dissolution of Residues from Stage 2 The solid stream isolated as a result of stage 2 can be further processed to produce keratin peptides by a range of methods. The high level of sulfonation of the residue makes it readily amenable to chemical and enzymatic digestion, as the disulfide bonds present in the original keratin source resistive to chemical and enzymatic attack have largely been cleaved. Example 4a Dissolution of Residues Using Sodium Sulfide Sodium sulfide solution (5% by weight) is added to an equal volume of the solid stream from stage 2 of the process, which comprises approximately 5% solids. The mixture is agitated for 12 hours after which time the solids are removed by filtering and centrifugation and sulfuric acid is added to the protein solution to decrease the pH to the range 2 to 3.5. The precipitate is collected on a screen and washed thoroughly with water. Example 4b Dissolution of Residues Using Hydrogen Peroxide Hydrogen peroxide (50%) is added to the solid stream from stage 2 at a level of 25-30 ml per kg of keratin residue (keratin residue contains approximately 5% solids). This is mixed and 1 M sodium hydroxide is added to obtain pH in the range of 10 to 13. The mixture is agitated gently for 24 hours and the protein and solids separated by the two stage filtration process described in Example 2 and protein isolated by acidification as described in Example 4a. Alternatively the protein solution is passed over an ion exchange resin, then acidified and the precipitated solid collected. The acidified solution may then be passed through an ion exchange column prior to freeze-drying or spray drying to collect a further protein-rich product. 4c Dissolution of Residues Using Proteolytic Enzymes An industrial subtilisin enzyme preparation (a solution containing 2.5% active enzyme) was added to the solid stream from stage 2 in the amount of 10 mg of active enzyme per gram of keratin residue. The pH was maintained at 9.5 with the addition of sodium hydroxide and the reaction heated to 60 ° C. for 2 hours. The resulting protein solution is isolated from solids and processed as described in 4a or passed through ion-exchange resin prior to and/or following acidification as described in 4b. Thus by the invention there is provided a method for the production of soluble keratin derivatives that is both economic and environmentally acceptable. Particular examples of the invention have been described and it is envisaged that improvements and modifications can take place without departing from the scope of the attached claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Keratins are a class of structural proteins widely represented in biological structures, especially in epithelial tissues of higher vertebrates. Keratins may be divided into two major classes, the soft keratins (occurring in skin and a few other tissues) and the hard keratins, forming the material of nails, claws, hair, horn, feathers and scales. The toughness and insolubility of hard keratins, which allow them to perform a fundamental structural role in many biological systems, are also desirable characteristics in many of the industrial and consumer materials currently derived from synthetic polymers. In addition to possessing excellent physical properties, keratin, as a protein, is a material with a high degree of chemical functionality and, consequently, exhibits many properties that synthetic materials cannot achieve. Keratin is, therefore, well suited to the development of products with high-value, niche-market applications. Keratin is also an environmentally acceptable polymer produced from a sustainable resource and therefore has environmental benefits over synthetic materials. Following the global trend of developing materials from renewable sources produced in a sustainable process, a range of materials has been produced from keratin, most commonly in the form of keratin films. At the core of a new industry producing biopolymer materials from keratin it is essential to have a process for extracting keratin from its source that is economically viable, sustainable from an environmental perspective, and produces a stable and versatile product. Methods used to date for the extraction of keratin that maintain the integrity of the individual proteins have been designed for the purpose of protein analysis and characterisation and consequently are not viable on an industrial scale, from an economic and environmental viewpoint. Methods used to date for the economic dissolution of keratin have significantly degrading effects on the protein, and consequently the dissolved protein retains few of the physicochemical properties that lead to the desirability of keratin as a biopolymer, such as the ability to reconstitute into tough materials. It is an object of the invention to go some way in overcoming the disadvantages with known processes or at least provide the public with a useful choice. In at least one embodiment the invention strives to provide an economic and environmentally acceptable process for the dissolution of keratin proteins that maintains the structural integrity and chemical functionality of the proteins during the dissolution process and leads to a stable and versatile keratin derivative product for the development of biopolymer materials.

<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect the invention provides a dissolution process for producing a range of stable, soluble keratin derivatives of high molecular weight, the molecular weight being similar to or greater than that of proteins originally expressed in the keratin source, with little or no damage to the structural integrity of the constituent proteins. The dissolution occurs in a two-stage process. According to a preferred aspect the invention provides a process for the preparation of keratin derivatives of high molecular weight, the process including a first stage digestion step of S-sulfonating a keratin source by oxidative sulfitolysis followed by a second stage extraction step using controlled washing with water to thereby obtain a highly S-sulfonated keratin derivative. The conversion of highly S-sulfonated keratin from a solid state into solution is without the use of chaotropic agents, by controlled, gradual washing of the sulfonated keratin with water in order to wash out the residual chemical reagents from the extraction procedure and alter the ionic strength of the extraction solution. The first stage involves oxidative sulfitolysis to convert cystine groups present in the protein to S-sulfocysteine, using industrially acceptable concentrations of inexpensive reagents for the purpose of sulfonation (eg. sodium sulfite) and oxidation (eg. cupraammonium hydroxide). According to another aspect, the invention provides a process for the separation of a gelatinous keratin product from a solution of S-sulfonated keratin produced by the above process, wherein the S-sulfonated keratin derivative solution is treated by the use of a gentle, gravity fed filtration system followed by separation. Preferably the separation is centrifugal. According to another aspect of the invention, a liquid stream remaining after the gelatinous keratin is removed is processed by passing over scoured wool, thereby removing residual chemicals from the solution and preparing the wool for subsequent protein extraction processes. Following conversion of the cystine groups, the second stage of the process is one in which the highly S-sulfonted keratin derivative is brought from a solid or gelatinous state into solution by extensive dilution with water. The rate and extent of dissolution can be controlled by the use of heat, surfactants, gentle agitation and vigorous chopping or homogenisation. By controlling the rate of dissolution, reaction solutions can be isolated, for example if a copper oxidant is used a reaction solution rich in copper is produced but it contains little or no dissolved protein, or are rich in protein but contain little or no copper. According to another aspect of the invention, a liquid stream resulting from the second stage of the process, which contains residual chemicals such as copper sulfate and sulfite, as well as S-sulfonated keratin derivatives, is processed using any one or more of a variety of methods that allow the recycling of reagents from the solution and the separate isolation of purified S-sulfonated Keratin Intermediate Filament Protein(s) (SIFP) and S-sulfonated Keratin High Sulfur Protein(s) (SHSP). This is achieved through the use of chelating agents, such as ethylenediamine tetraacetic acid, or chelating ion exchange resins, such as those containing the iminodiacetic functional group, and the use of isoelectric precipitation to separate protein types. Ultrafiltration can be used at several stages in the process to improve the efficiency of reagent removal or protein separation. Metallic impurities in the protein products can be further reduced by the washing of the protein derivative(s) following precipitation with dilute acids, water or chelating agents. Once separated, the protein products can be dried by a range of methods such as fluid bed, spray or freeze drying. Another aspect of the invention is the further processing of residual keratin not dissolved by the two stage sulfitolysis process, through the use of other reagents, such as hydrogen peroxide, sodium sulfide or proteolytic enzymes, to produce keratin peptides. Another aspect of the invention is the provision of a method for large scale recovery of proteins from a natural source, including subjecting said natural protein source to a treatment sufficient to render at least some of the protein(s) water soluble, and subsequently separating the water soluble protein(s). Another aspect of the invention is the provision of an installation for large scale recovery of proteins from a natural source, a treatment vessel to contain and subject a large quantity of natural protein source to a treatment sufficient to render at least some of the protein(s) contained in said feed, water soluble, and a separation apparatus to subsequently separate the water soluble protein(s). Another aspect of the invention is a method of selectively solubilising a protein having plurality of disulfide bonds from a mixture of proteins including subjecting said mixture of proteins to oxidative sulfitolysis to produce a soluble S-sulfonated protein fraction. The oxidative sulfitolysis is preferably effected in the absence of chaotropic agents with little or no damage to the structural integrity of the protein. Another aspect of the invention is method for obtaining a purified protein from an impure protein source with little or no damage to the structural integrity of the protein including subjecting said protein source to a treatment sufficient to render at least some of the protein(s) water soluble, and subsequently separating the water soluble protein(s) in the absence of chaotropic agents. detailed-description description="Detailed Description" end="lead"?

20040112

20061212

20050609

60891.0

NOAKES, SUZANNE MARIE

PRODUCTION OF SOLUBLE KERATIN DERIVATIES

SMALL

ACCEPTED

ACCEPTED

Treatment of textiles with fluorinated polyethers

A polymer adapted for the Shrink resist treatment of textile materials imparting water, stain and/or oil repellency. The polymer includes a fluorinated polyether.

1. A polymer adapted for the treatment of textile materials, comprising a fluorinated polyether. 2. A polymer according to claim 1, of the type —A—B—A—B—, where A is a polyether amine and B is a fluorine compound. 3. A polymer according to claim 2, where B is a polyether chain. 4. A polymer according to claim 3, where B is a perfluoro polyether. 5. A polymer according to claim 4, in which the perfluoro polyether is reacted with a hydropolyether. 6. A polymer according to claim 1, comprising an ester of a perfluoropolyether reacted with a polyether amine. 7. A polymer according to claim 6, in which the polyether amine comprises polytetrahydrofuran-diamine. 8. A polymer according to claim 6 or claim 7, with added epichlorohydrin. 9. A polymer according to claim 1, adapted for the shrink resist treatment of keratinous fibre and also imparting water, stain and/or oil repellency. 10. A polymer according to claim 1, adapted for the treatment of vegetable and synthetic fibre, imparting water, stain and/or oil repellency thereto with a soft handle as compared to fluorinated polyurethanes or fluorinated acrylates. 11. A polymer according to claim 1, in aqueous solution. 12. A polymer according to claim 11, in which the concentration of the polymer in the solution is up to 20%. 13. A polymer according to claim 12, in which the concentration is 10%. 14. A method for making a polymer according to claim 1, comprising reacting polytetrahydrofuran-diamine with a ester of a perfluoroether. 15. A method according to claim 14, in which the ester is Fomblin 5027X. 16. A method according to claim 14, in which the ester is Fomblin 5028X. 17. A method according to claim 14, in which the ratio of diamine to ester is between 7:6 and 2:1. 18. A method according to claim 17, in which the ratio is 7:6. 19. A method according to claim 17, in which the ratio is 5:4. 20. A method according to claim 17, in which the ratio is 3:2. 21. A method according to claim 17, in which the ratio is 2:1. 22. A method according to claim 14, in which the reaction is carried out by heating under vacuum in the presence of an acid. 23. A method according to claim 22, in which the acid is para-toluene sulphonic acid. 24. A method according to claim 23, in which the acid is present at 2% by weight on the total of reactants. 25. A method according to claim 22, in which the reaction is carried out at between 130° C. and 160° C. 26. A method according to claim 25, in which the reaction is carried out at 150° C. 27. A method according to claim 22, in which the heating is continued for between one and three hours. 28. A method according to claim 27, in which the heating is continued for two hours. 29. A method according to claim 27, in which after the heating the product is maintained under vacuum for a further period of one to four hours. 30. A method according to claim 29, in which the further period is two hours. 31. A method according to claim 29, in which the product is cooled to below 110° C. and, whilst still fluid, dissolved in iso-propanol and water with vigorous stirring. 32. A method according to claim 31, in which epichlorohydrin is added to the solution and reacted at 65° C. until the pH falls to a value below 7.2. 33. A method according to claim 25, in which formic acid is added, to halt the reaction, to give a pH of 3.5. 34. A method according to claim 33, in which the solution is diluted with water so as to contain up to 20% solids. 35. A method according to claim 34, in which the solution is diluted with water so as to contain 10% solids. 36. A method for the treatment of keratinous fibre comprising the step of applying a polymer comprising fluorinated polyether. 37. A method according to claim 36, in which the polymer is applied by padding. 38. A method according to claim 36, in which the polymer is applied by coating. 39. A method according to claim 36, in which the polymer is applied by exhausting it on to the fibre. 40. A method according to claim 39, in which a treatment bath is heated to 40° C. 41. A method according to claim 36, in which the polymer is applied at 4-8% by weight on weight of goods. 42. A method according to claim 36, in which, after the treatment, the fibres are dried at a temperature no higher than 80° C. 43. A method according to claim 36, in which the fibre is a keratinous fibre pre-treated with permonosulphate, chlorine or a chlorine donor, followed by sulphite neutralisation and rinsing. 44. A method for the treatment of vegetable and/or synthetic fibre to impart water, stain and/or oil repellency with soft handle comprising treating the fibre with a polymer according to claim 1. 45. A method according to claim 44, in which the polymer is applied from a solution containing 60 g/l of polymer in water. 46. A method according to claim 45, in which the rate of application of polymer to fibre is 6% polymer by weight of fabric. 47. A method for treating a textile fabric according to claim 36.

This invention relates to polymer treatments for textiles. Fluorinated polymers may be applied to textile articles so as to render them water, oil and/or stain repellent. There are many processes for imparting a chemical finish to wool garments to prevent them felting during domestic laundering. The Dylon GRB and SIMPLX process are two examples, which apply polymers to the garments. The polymers may additionally result in other desirable properties, for example, reduction in pilling. Woollen garments can be given a shrink resist (felting resist) treatment eg. by either of the processes named above, and then treated with a fluorinated polymer to impart water, stain and/or oil repellency. However, the latter treatment generally results in a harsh handle, and in order to be effective, the polymer must be cured by baking the treated articles, after drying, at temperatures up to 130° C., which has a deleterious effect on wool fibre. The present invention provides a novel polymer for the treatment of textile materials that does not suffer this disadvantage, and which, surprisingly, has wide application in imparting water, stain and oil repellency. The invention comprises a polymer adapted for the treatment of textile materials, comprising a fluorinated polyether. The polymer may be of the type —A—B—A—B—, where A is a polyether amine and B is a fluorine compound. B may be a polyether chain, and may be a perfluoro polyether. The perfluoro polyether may be reacted with a hydropolyether. The polymer may comprise an ester of a perfluoro polyether reacted with a polyether amine, such as polytetrahydrofuran-diamine. The polymer may have added epichlorohydrin. The polymer may be adapted for the shrink resist treatment of keratinous fibre and also imparting water, stain and/or oil repellency. The invention also comprises a polymer comprising a fluorinated polyether adapted for the treatment of vegetable and synthetic fibre imparting water, stain and/or oil repellency thereto with a soft handle as compared to fluorinated polyurethanes or fluorinated polyacrylates. The polymer may be adapted for the treatment of textiles by being in aqueous solution; the concentration of the polymer in the solution may be up to 20%, for example, 10%. The invention also comprises a method for making a polymer comprising a fluorinated polyether, comprising reacting a polyether amine, such as polytetrahydrofurandiamine with an ester of a perfluoroether. The ester may be Fomblin 5027X or Fomblin 5028X, of molecular weights approximately 1000 and 1500 respectively, supplied by Ausimont Spa. The ratio of diamine to ester may be between 7:6 and 2:1, and may be 7:6, 5:4, 3:2 or 2:1. The reaction may be carried out by heating under vacuum in the presence of an acid, which may be para-toluene sulphonic acid, which may be present at 2% by weight in the total reactants. The reaction may be carried out at between 130° C. and 160° C., say 150° C., the heating being continued for one to three hours, for example two hours. After the heating, the product may be maintained under vacuum for a further period of one to four hours, say three hours. The product may then be cooled to below 110° C. and, whilst still fluid, dissolved in iso-propanol and water with vigorous stirring. Epichlorohydrin may be added to this solution and reacted at 65° C. until the pH falls to a value below 7.2. Formic acid may then be added to halt the reaction, to give a pH of 3.5 The solution may then be diluted with water so as to contain up to 20%, eg. 10% solids. The invention also comprises a method for the treatment of keratinous fibre comprising applying to it a polymer comprising a fluorinated polyether, especially one made by a method as above described. The polymer may be applied by padding or by coating. The polymer may be applied by exhausting it on to the fibre. The polymer may be applied in a treatment bath with liquor to goods ratio of 30:1. The treatment bath may be heated to 40° C. The polymer may be applied at 4 to 8% by weight on weight of goods. After the treatment, the fibres may be dried at a temperature which need be no higher than 80° C., (ie. in a tumble drier) even at room temperature, thus avoiding deterioration of the fibre and hard handle. A keratinous fibre may be pre-treated with permonosulphate or chlorine or a chlorine donor, followed by sulphite neutralisation and rinsing. The invention also comprises a method for the treatment of vegetable and/or synthetic fibre to impart water, stain and/or oil repellency with soft handle, comprising treating the fibre with a fluorinated polyether as above described or made by a method as above described. The polymer may be applied from a solution containing 60 g/l of polymer in water. The rate of application of polymer to fibre may be 6% polymer by weight of fabric. For the treatment, the fibre will usually be in fabric, eg. woven or knitted form, but yam or tow may also be treated. The preparation of a fluorinated polyether according to the invention and its use in the treatment of textile materials will now be described with reference to the following Examples EXAMPLE 1 Polytetrahydrofuran-diamine (of approximate molecular weight 1700) and Fomblin 5027X or 5028X (the esters of a perfluoropolyether, molecular weights approximately 1000 and 1500 respectively, ex Ausimont, Spa) were reacted at various ratios (see Table 1) by heating at 150° C. under a vacuum in the present of para-toluene sulphonic acid (2% by weight on the total weight of reactants). The mixture was heated to 150° C. over a period of two hours under vacuum and maintain at this condition for a further three hours. The reaction mixture was cooled to below 100° C. and, whilst still hot, the resulting product was dissolved in iso-propanol and water with vigorous stirring. To this solution was added epichlorohydrin according to Table 1, and the whole mixture was further reacted at 65° C. until the pH of the solution fell to below a value of 7.2. To halt the reaction, sufficient formic acid was added to give a pH value of 3.5, and the whole was then diluted further with water to give a resulting solution containing approximately 10% solids. TABLE 1 Fomblin Ratio of A Ratio of F content Product reactant (PTHF) to B PTHF of polymer % Ref used (Fomblin) to ech (%) activity SP1252 5027X 2:1 0.83 11.5 10 SP1253 5028X 2:1 0.83 16.2 10 SP1254 5028X 3:2 1.25 19.2 10 SP1255 5027X 3:2 1.25 14.5 10 SP1256 5028X 1:1 1.25 25.5 Insoluble SP1260 5028X 5:4 2.00 22.6 10 SP1261 5028X 7:6 2.86 23.6 10 EXAMPLE 2 Knitted lambswool fabric swatches (2/17 Nm woollen spun yarn) were treated by the Dylan SIMPL-X method using permonosulphate. After sulphite neutralisation and rinsing, each of the swatches was further treated with some of the materials produced in Example 1 by exhausting the polymer on to the wool swatch in a treatment bath at 40° C. and a liquor to goods ratio of 30:1. The amount of product applied in each case was 4.5% by weight on weight of fabric. For comparison, further treatments were made with Polymer TM (a commercial shrink resist polymer) only at 4% by weight. Two swatches were made of each treatment; one was dried at room temperature, the second dried in a tumble dryer (70-75° C.). The prepared fabric swatches were tested (Table 2) for oil and water repellency immediately and after washing for and five machine wash cycles respectively in a domestic washing machine (using detergent) on a wool cycle. Good water repellency was achieved and maintained at these levels, although oil repellency was low, and was generally lost after washing. TABLE 2 Drying Initial 1 × HLCC7 5 × HLCC7 Product Temp* Oil Water Oil Water Oil Water SP1252 RT 2 5 1 3 0 5 TD 2 5 2 5 0 5 SP1253 RT 2 5 1 3 0 5 TD 2 5 2 5 0 5 SP1254 RT 2 6 0 5 1 5 TD 3 5 2 5 0 5 SP1255 RT 2 5 0 5 0 5 TD 2 5 0 5 0 5 Polymer RT 0 1 0 2 0 3 TM TD 0 3 0 3 0 3 *RT = Room temperature, TD = Tumble Dryer EXAMPLE 3 Further swatches were prepared in a similar manner to those in Example 2, using the material with the highest level of fluorine—SP1261. In this example, 8% by weight of fluorinated product was applied to SIMPL-X treated wool swatches. A comparison was made with a swatch treated with 4% Polymer TM followed (in a fresh bath) by 3% Foraperle 390 (ex Atofina) a commercial fluoroacrylate resin for textile treatments. Following the Polymer TM/Foraperle 390 treatment, the treated swatch was dried in a tumble dryer, then cured at 130° C. for 4 minutes. All other swatches were dried in a tumble dryer only. The swatches prepared in this Example were tested for the following: shrink resistance to the WoolMark Company's Total Easy care standard—ref TM254; oil repellency to AATCC Method 118; water repellency; spray rating to BS3702 and durability of these effects to machine washing on a wool cycle in a domestic washing machine (20 wash cycles). The results are shown in Table 3. TABLE 3 Initial Results After 20 wool cycle washes Product TM254 Oil Water Spray Oil Water Spray SP1261 +0.2% 2 5 4 0 5 3 TM/F390 +0.3% 3 6 4 0 3 0 EXAMPLE 4 Further applications of the material used in Example 3 were made at lower addition rates to determine the limit of effectiveness of the material as both a shrink resistant polymer and repellent finish. In these tests, SP1261 was applied at 8%, 6% and 4% by weight on SIMPL-X treated knitted wool swatches in the manner described in Example 2. The shrink-resist performance, oil and water repellency and spray rating were determined, and the durability of these effects to 20 wool cycle washes evaluated (Table 4). The performance of the product was found to be unaffected by decreasing application levels down to 4%. TABLE 4 Initial Results After 20 wool cycle washes % SP1261 TM254 Oil Water Spray Oil Water Spray 4% +2.6% 2 5 4 0 5 3 6% +0.15% 2 6 4 0 5 3 8% 0.9% 2 5 4 0 5 3 EXAMPLE 5 The product used in Example 3 (SP1261) was applied to cotton jersey fabric (single jersey) and woven polyester fabric by a padding process from a solution containing 60 g/l of product in water. The pick-up of liquor on the fabric after padding was adjusted to 100%, giving an equivalent application rate of 6% product by weight of fabric (equivalent to 0.6% solids). After drying in a tumble dryer (70-80° C.) the fabrics were tested for oil and water repellency and compared with untreated control fabrics. The following results were obtained (Table 5). TABLE 5 Cotton, Cotton + Polyester, Polyester + untreated SP1261 untreated SP1261 Oil repellency 0 0 0 1 Water repellency 0 4 0 4 It will be seen that the fluorinated polyether was effective as a water and stain repellent, even after multiple laundering cycles. It was initially effective as an oil repellent, but this property tended to be lost on laundering. Nevertheless, for goods which are not normally laundered, eg. awnings, tent canvasses and so forth, this can be useful protection. The polymer was very effective on keratinous fibre (lambs' wool) as well as a shrink-resist finish. On cotton and woven polyester fabrics, the polymer gives water repellency without the imposition of a harsh handle. Clearly, other fluorinated polyethers will have similar, if not identical effects. Armed with the present disclosure it will be straightforward to investigate other preparations and treatment specifications to achieve useful results. In addition, it has been found that when wool textiles and fibres are treated with a polymer in accordance with the invention, they can be washed at higher temperatures and/or using more agressive washes than would normally be the case. For example, a wool swatch treated with the polymer may be washed in temperatures up to 60° C.

20040601

20070306

20060518

68418.0

C08G602

KEYS, ROSALYND ANN

TREATMENT OF TEXTILES WITH FLUORINATED POLYETHERS

SMALL

ACCEPTED

C08G

ACCEPTED

Attachment to a hydroponic conduit

A hydroponic conduit can be converted to drainage conduit by providing an attachment on which a plant container can be supported. The attachment comprises a circular plate on which the plant containers sits, drainage means (ribs, grooves etc.) and a central aperture in the circular plate to allow water to drain from the circular plate, and a short collar or spout on the bottom of the circular plate which passes into an opening in the hydroponic conduit to allow water to drain into the conduit. A second support means can be provided which is attached to the hydroponic conduit and which provides additional support to the attachment.

1. An attachment for a hydroponic conduit of the type which has an at least partially rigid wall, the attachment comprising a support means to support a plant container and the like, drainage means adapted to collect water passing out of the container, and communication means to communicate the water from the drainage means into the hydroponic conduit. 2. The attachment as claimed in claim 1, wherein the support means comprises a drainage tray adapted to support the plant container. 3. The attachment as claimed in claim 2, wherein the drainage means comprises part of the drainage tray. 4. The attachment as claimed in claim 3, wherein the drainage means comprises at least one projection extending from the drainage tray and adapted to support the plant container thereby allowing water to pass between the bottom of the plant container and the drainage tray. 5. The attachment as claimed in claim 3, wherein the drainage means comprises at least one recess in the drainage tray to allow water to pass along the drainage tray. 6. The attachment as claimed in claim 2, wherein the drainage tray is provided with a drain opening. 7. The attachment as claimed in claim 6, wherein the communication means comprises the collar on a bottom wall of the drainage tray and extending about the drain opening, the collar adapted to pass into an opening in the hydroponic conduit to allow water to drain from the drainage tray into the hydroponic conduit. 8. The attachment as claimed in claim 1 comprising a second support means to assist in supporting the support means. 9. The attachment as claimed in claim 8, wherein the second support means comprises a platform, the platform being provided with an opening through which the communication means can pass, and at least one attachment means to attach the second support means to the hydroponic conduit. 10. The attachment as claimed in claim 1, wherein the support means comprises a circular plate having a top wall and a bottom wall and formed with a peripheral rim, the plate being dish shaped and having a central aperture, at least one radially extending rib extending from the top wall and on which the plant container is supported in use, the communication means comprising an integrally formed collar depending from the bottom wall and extending about the central aperture to drain water from the circular plate.

FIELD OF THE INVENTION This invention is directed to an attachment that can be fitted to hydroponic conduit to improve the versatility of the conduit. In one form, the attachment can allow a plant container such as a plant pot or a planter bag to be supported on the conduit such that any water/nutrient mixture passing through the pot or bag will pass into the conduit. BACKGROUND ART Hydroponics involves growing plants in the absence of soil. Typically, the required nutrient and water is delivered to the plant root system in the form of an aqueous nutrient solution that passes over the root ball of the plant. Hydroponic techniques have certain advantages over more conventional agriculture that includes the ability to carefully control optimum feeding, the elimination of weeds, and improved control of pests and diseases. Typically, a channel or conduit is provided through which the nutrient solution passes. The channel or conduit may comprise a closed pipe or tube, a closed channel or drain and the like. If a pipe or tube is provided, this may have various shapes including circular, oval, rectangular, square, irregular configurations and the like. The pipe or tube may be formed of a semirigid material such as PVC plastic, or may be formed from a very flexible plastic bag-like material. If the material is very flexible, it is generally required to fill the bag with a medium other than soil. These mediums can include sand, gravel, fibre mediums and the like. The medium will provide dimensional stability to the bag, but can interfere with flow-through of nutrient solution and the like. Therefore, it is generally preferable to have a semi rigid conduit typically formed of polyvinyl chloride, such that a growing medium is not required to provide shape and stability to the conduit. In our earlier U.S.A patent application Ser. No. 09/196,638, there is described an elliptical conduit for use with a hydroponic apparatus. The elliptical conduit provided an ideal cross-section for root growth that was similar to normal root growth in soil. It was found that the elliptical conduit provided a faster and better growth of plants. Some plants are best grown in pots or planter bags as opposed to in a hydroponic system. For instance, the plant might be too large to grow properly in a hydroponic system. Alternatively, the plant may not be suited for growing in a medium devoid of soil. A disadvantage of growing and maintaining plants in pots or planter bags is in dealing with the used water that drains from the pot or bag. In some countries, this water can contaminate aquifers, creeks, streams and rivers. In other countries, water is precious and should not be merely drained away. Many countries have introduced legislation to penalise growers who contaminate ground water with run-off. A hydroponic system efficiently reuses and recycles water. Therefore, there would be an advantage if part of a hydroponic system could be used for plants grown in pots or planter bags. OBJECT OF THE INVENTION The present invention is directed to an attachment or assembly that can be attached to a hydroponic conduit and which can support a plant container such as a plant pot or planter bag. The attachment or assembly can be designed to drain any water into the hydroponic conduit. In this manner, water is not lost from the system and does not contaminate aquifers, creeks, streams and the like. The water can also be reused. When not required, the attachment or assembly can be simply removed from the hydroponic conduit to allow plants to be grown in a hydroponic manner. It is an object of the invention to provide an attachment to a hydroponic conduit and which may overcome at least part of the abovementioned disadvantages and/or provide the public with a useful or commercial choice. In one form, the invention resides in an attachment for a hydroponic conduit of the type which has an at least partially rigid wall, the attachment comprising a support means to support a plant container and the like, drainage means adapted to collect water passing out of the container, and communication means to communicate the water from the drainage means into the hydroponic conduit. In this manner, the attachment can be used to “convert” the hydroponic conduit from a pure hydroponic system into a water recovery, recirculation and reuse system. Suitably, the hydroponic conduit is provided with at least one, and typically a plurality, of openings. These openings are typically substantially linearly aligned along a top of the hydroponic conduit and function to allow plants to grow through the openings using hydroponic techniques. Such hydroponic conduit is known. The conduit typically comprises a rigid or substantially rigid tube. The tube may have any suitable length and can have lengths of between 1-6 m or more. The tube may have various cross sections, and typical cross sections include circular, oval, and various channel shaped cross sections. A known type of tube is formed from PVC having a wall thickness of between 1-5 mm. The tube is provided with a number of cutouts or openings that are usually round and extend along an upper wall of the tube, with openings being in linear alignment. The spacing between the openings can vary (depending on the plant size etc.) but is typically between 10-30 cm. The opening has a diameter or cross-section that can vary (again depending on the plant size and plant type) but is typically between 2-10 cm. As mentioned above, the precise type of hydroponic conduit need not form part of the invention except that it is used as a support for the attachment that does form part of the invention. The attachment has a support means that is adapted to support a plant. As the plant is typically provided in a plant pot, planter bag, or some other type of plant container, this support means should be designed to provide support for this type of article. A simple type of support means comprises a substantially flat platform or tray on which the plant pot or other container can be placed. However, other types of support means are envisaged including support means which support the container against tipping, support means which can hold the container in a particular orientation, angle, height and the like. The support means may grip the side of the container, support the container via the rim of the container, or simply provide a platform on which the container can be placed. The attachment has a drainage means to collect water passing from the plant container. In a simple form of the invention, the support means and the drainage means may be at least partially combined, and may form a drainage tray which supports the plant container on top of the tray, and also drains water which passes from the plant container. The drainage tray may have various shapes and sizes. A preferred shape will be circular or substantially circular, as most plant pots or planter bags are substantially circular. However, the drainage tray may also have shapes other than circular including rectangular and the like. The drainage tray should be made of material which is strong enough to support a plant container, and should preferably be made of material which is resistant to corrosion, rusting, rotting, cracking and the like. A suitable material would include plastics, although the drainage tray is not to be limited to merely plastic material. The size of the drainage tray may vary depending on various factors. For instance, the drainage tray should be sufficiently large to support a common size/shape of plant container, or perhaps even a number of plant containers. However, as it is envisaged that a number of such attachments may be provided along the hydroponic conduit, the drainage tray should not be so large that it will interfere with adjacent attachments, or prevent the required number of attachments being placed on a single length of hydroponic conduit. Thus, a cross-section size of between 10-50 cm for the drainage tray is envisaged, with a preferred size being between 20-30 cm. The drainage means may be configured to promote water flow to a particular part of the drainage means. For instance, the drainage means may be slightly dish shaped to promote water flow to the central portion of the drainage means. Of course, the drainage means may also be otherwise configured to promote water flow over a particular edge region, or towards some other part of the drainage means. If desired, the drainage means can be provided with a peripheral lip or flange, or an upstanding ridge or barrier to promote water flow into a desired direction/area. The drainage means can also be provided with one or more ribs, projections and/or one or more grooves, gutters, channels and the like to facilitate water flow into a desired direction/area. In a preferred embodiment, the drainage means comprises a circular drainage tray provided with an upstanding peripheral lip, and where the drainage tray tapers slightly towards a central aperture such that water will flow towards and through the central aperture. The attachment includes a communication means to communicate water from the drainage means into the hydroponic conduit. Typically, the hydroponic conduit is provided with one or more openings (normally used to grow plants in a hydroponic manner) and through which water can pass. Thus the communication means can function to pass water from the drainage means, and through the opening into the hydroponic conduit. In a simple form, the communication means may comprise a pipe or tube that may be attached to, or form part of the drainage means and which passes through the opening in the hydroponic conduit. The pipe or tube may comprise a collar on the underside of the drainage tray. Suitably, the collar is designed to allow a plurality of trays to nest into each other to economize on packaging and transportation. To provide stability and rigidity to the attachment, a second support means may be provided. The second support means can function to assist in supporting the drainage means and/or the support means (which supports the plant container) onto the hydroponic conduit. The second support means may comprise a substantially flat platform having attachment means to enable the second support means to be attached to the hydroponic conduit. The attachment means may comprise hooks, claws, straps, fasteners or any other type of suitable attachment means. It is preferred that the attachment means allows the second support means to be releasably attached to the conduit. The substantially flat platform may be provided with an opening through which the pipe or tube can pass. The opening is typically defined by a collar that provide support to the pipe or tube, thereby providing support to the drainage tray/support means. BRIEF DESCRIPTION OF THE DRAWINGS An embodiment of the invention will be described with reference to the following drawings in which: FIG. 1. Illustrates the separate components of an attachment according to an embodiment of the invention. FIG. 2. Illustrates the attachment of FIG. 1 attached to a hydroponic conduit. FIG. 3. Illustrates an underneath view of a second support means which forms part of the attachment according to the embodiment. FIG. 4. Illustrates a plan view of the support means/drainage means. FIG. 5. Illustrates an underneath view of the support means/drainage means of FIG. 4. FIG. 6. Illustrates a part length of a typical known hydroponic conduit. FIG. 7. Illustrates a drainage tray according to a second embodiment and which allows several trays to nest into each other. FIG. 8. Illustrates the tray of FIG. 7 in plan view and illustrating raised ribs on which the pot/bag can sit. BEST MODE Referring to the figures, and initially to FIG. 1, there is illustrated an attachment according to an embodiment of the invention which comprises two parts being a combined support means/drainage means 10, and a second support means 11, with FIG. 1 additionally illustrating part of a hydroponic conduit 12. Referring initially to hydroponic conduit 12, this conduit is known and in the embodiment comprises an oval PVC pipe of any suitable length. The conduit 12 is provided with a number of spaced apart linearly aligned circular openings 13 which are used to grow plants in a hydroponic manner. Of course, although conduit 12 is described as a hydroponic conduit, a pipe or tube or similar conduit could also be used which need not be used only for hydroponic systems. The combined support means/drainage means 10 comprises a substantially flat circular drainage tray 14 having a diameter of between 25-40 cm, and being provided with an upright peripheral lip 15. The drainage tray 14 is slightly concave or tapered towards a central aperture 16. The shaping is to ensure that water will flow from any part of drainage tray 14 through central aperture 16. Drainage grooves or channels 17 (best illustrated in FIG. 4) extend radially from central aperture 16 to the peripheral lip 15. The drainage grooves function to allow water to drain from underneath a plant container. Drainage tray 14 is formed of strong stout plastic material that does not bend, crack, sag or otherwise deform under the weight of a plant container. Referring to FIG. 2, a plant container 18 can be placed on top of drainage tray 14. Any water that passes out of plant container 18 will be collected by the drainage tray and will flow across the tray and/or along the drainage grooves 17 and through central aperture 16. A short depending cylindrical spout 20 that is best illustrated in FIG. 5 defines central aperture 16. Spout 20 has a diameter of between 2-6 cm, and a length of between 2-10 cm. This can of course vary to suit. To provide stability to the drainage tray 14 when attached to hydroponic conduit 12, a second support means 11 is provided. Second support means 11 is illustrated in FIG. 1, and the underneath of second support means 11 is illustrated in FIG. 3. Second support means 11 comprises a substantially flat rectangular platform 21 that contains a central aperture 22 that is defined by a short depending collar 23 best illustrated in FIG. 3. Collar 23 is circular and has a diameter that is slightly larger than spout 20 on drainage tray 14. Thus, having spout 20 pass through collar 23 supports drainage tray 14. Having the bottom of drainage grooves 17, and/or the bottom wall of drainage tray 14 abutting against the top of platform 21 also support the drainage tray 14. Another advantage with this arrangement is that drainage tray 14 can be simply lifted out from collar 23, and can also rotate about a vertical axis. For instance, a plant container placed on drainage tray 14 can be rotated manually to allow the plant to be pruned, inspected, and the like. As well, if a number of smaller plant containers are placed on a single drainage tray, tray 14 can be rotated manually to allow each plant container to be inspected. Second support means 11 is attached to conduit 12 via a pair of spaced apart clips 24 which are best illustrated in FIG. 3 and FIG. 2. Clips 24 allow second support means 11 to be press-fitted to the outside wall of conduit 12. Also, the second support means can be simply removed by pulling the clips free from the outside wall of conduit 12. Collar 23 is designed to pass through an opening 13 in conduit 12. The length of collar 23 should be such that while it passes through opening 13, it does not abut against the opposite wall of conduit 12 thereby preventing proper flow of water through collar 23 and along conduit 12. Referring to FIG. 7, there is illustrated a section view of a drainage tray 30. Drainage tray 30 has a lower integrally formed collar portion 31 which has a stepped configuration. This allows a number of drainage trays to be stacked with the collar of one drainage tray passing partially into the collar of a below drainage tray. Referring to FIG. 8, there is illustrated a plan view of the drainage tray illustrated in FIG. 7 and particularly illustrating a plurality of radially extending ribs 32. A plant pot/bag sits on top of the ribs and the ribs provide a small spacing between the bottom of the pot/bag and the surface of the drainage tray to allow water to drain through the collar. In use, an existing hydroponic system can be modified to support plant containers by attaching one or more of the attachment means to the hydroponic conduit. The hydroponic conduit functions extremely well to retrieve waste water for recirculation, purification, or safe disposal. The attachment supports a plant container and ensures that any water drainage from the plant container drains into the hydroponic conduit and not somewhere else. It should be appreciated that various other changes and modifications can be made to the embodiment described without departing from the spirit and scope of the invention.

<SOH> BACKGROUND ART <EOH>Hydroponics involves growing plants in the absence of soil. Typically, the required nutrient and water is delivered to the plant root system in the form of an aqueous nutrient solution that passes over the root ball of the plant. Hydroponic techniques have certain advantages over more conventional agriculture that includes the ability to carefully control optimum feeding, the elimination of weeds, and improved control of pests and diseases. Typically, a channel or conduit is provided through which the nutrient solution passes. The channel or conduit may comprise a closed pipe or tube, a closed channel or drain and the like. If a pipe or tube is provided, this may have various shapes including circular, oval, rectangular, square, irregular configurations and the like. The pipe or tube may be formed of a semirigid material such as PVC plastic, or may be formed from a very flexible plastic bag-like material. If the material is very flexible, it is generally required to fill the bag with a medium other than soil. These mediums can include sand, gravel, fibre mediums and the like. The medium will provide dimensional stability to the bag, but can interfere with flow-through of nutrient solution and the like. Therefore, it is generally preferable to have a semi rigid conduit typically formed of polyvinyl chloride, such that a growing medium is not required to provide shape and stability to the conduit. In our earlier U.S.A patent application Ser. No. 09/196,638, there is described an elliptical conduit for use with a hydroponic apparatus. The elliptical conduit provided an ideal cross-section for root growth that was similar to normal root growth in soil. It was found that the elliptical conduit provided a faster and better growth of plants. Some plants are best grown in pots or planter bags as opposed to in a hydroponic system. For instance, the plant might be too large to grow properly in a hydroponic system. Alternatively, the plant may not be suited for growing in a medium devoid of soil. A disadvantage of growing and maintaining plants in pots or planter bags is in dealing with the used water that drains from the pot or bag. In some countries, this water can contaminate aquifers, creeks, streams and rivers. In other countries, water is precious and should not be merely drained away. Many countries have introduced legislation to penalise growers who contaminate ground water with run-off. A hydroponic system efficiently reuses and recycles water. Therefore, there would be an advantage if part of a hydroponic system could be used for plants grown in pots or planter bags.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>An embodiment of the invention will be described with reference to the following drawings in which: FIG. 1 . Illustrates the separate components of an attachment according to an embodiment of the invention. FIG. 2 . Illustrates the attachment of FIG. 1 attached to a hydroponic conduit. FIG. 3 . Illustrates an underneath view of a second support means which forms part of the attachment according to the embodiment. FIG. 4 . Illustrates a plan view of the support means/drainage means. FIG. 5 . Illustrates an underneath view of the support means/drainage means of FIG. 4 . FIG. 6 . Illustrates a part length of a typical known hydroponic conduit. FIG. 7 . Illustrates a drainage tray according to a second embodiment and which allows several trays to nest into each other. FIG. 8 . Illustrates the tray of FIG. 7 in plan view and illustrating raised ribs on which the pot/bag can sit. detailed-description description="Detailed Description" end="lead"?

20040914

20080819

20050113

94134.0

PALO, FRANCIS T

ATTACHMENT TO A HYDROPONIC CONDUIT

SMALL

ACCEPTED

ACCEPTED

Use of biologically active hiv-1 tat, fragments or derivatives thereof, to target and/or to activate antigen-presenting cells, and/or to deliver cargo molecules for preventive or therapeutic vaccination and/or to treat other diseases

The present invention concerns a method for prophylactic and/or therapeutic vaccination and/or treatment and/or diagnosis of HIV/AIDS, other infectious diseases, inflammatory and angiogenic diseases and tumours which utilizes a biologically active HIV-1 Tat protein, fragments or derivates thereof, as a module with one or more of the following features: antigen, adjuvant and targeting-delivery system to specific antigen-presenting cells including dendritic cells, endothelial cells and macrophages. In particular, it is claimed that Tat can be used only in its biologically active form as an antigen combined with one or more other antigens, to prime or to boost protective immune responses against itself as well as other antigens and/or to selectively deliver these antigen(s) as well as active compounds to dendritic cells, endothelial cells and macrophages, due to its capability of targeting these A PC and of activating their maturation and functions and of increasing Th-1 type immune responses as an adjuvant. Therefore, due to these characteristics and to the distribution of these cells in the body (during physiological and pathological disorders), biologically active Tat, fragments or derivates thereof containing the RGD region, can be used for preventive, therapeutic and/or diagnostic purposes for HIV/AIDS, other infectious diseases, inflammatory and angiogenic diseases and tumors.

1. Use of isolated native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target antigen presenting cells expressing α5β1 and/or αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, to deliver cargo molecules across their cellular and/or nuclear membrane and to induce their maturation and/or their antigen presenting functions. 2-55. (Canceled) 56. Method to selectively target antigen presenting cells expressing α5β1 and/or αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, to deliver cargo molecules across their cellular and/or nuclear membrane and to induce their maturation and/or their antigen presenting functions said method comprising the step of putting in contact the cells with an effective amount of isolated native, substantially monomeric, and biologically active HIV-1 Tat or tat DNA, fragments and derivatives thereof. 57. Method according to claim 56 wherein isolated native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, will selectively target antigen presenting cells expressing α5 β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, for the uptake of both Tat, fragments, derivatives thereof selectively bound to these cells, and cargo molecules bound to Tat, fragments, derivatives thereof. 58. Method according to claim 56 wherein isolated native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, will selectively target, bind and enter antigen presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, to induce their maturation and/or their antigen presenting functions. 59. Method according to claim 57 to selectively target antigen presenting cells expressing α5β1 and αvβ3 integrins, or other integrins, including, but not limited to, dendritic cells, endothelial cells and macrophages capable of taking up Tat via the integrin-mediated pathway and/or other uptake pathways conferring a selective uptake, in order to deliver antigens and/or therapeutic compounds. 60. Method according to claim 59 wherein Tat delivers antigens in the form of peptides, proteins or DNA encoding them. 61. Method according to claim 60 wherein Tat delivers one or more antigens to induce an immune response. 62. Method according to claim 61 wherein antigens are selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 63. Method according to claim 59 wherein Tat is fused to one or more compounds selected among proteins, peptides or DNA encoding them in order to deliver such compound (s), in vitro and in vivo, intracellularly or to the cell membrane. 64. Method according to claim 63 wherein compound is one or more antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 65. Method according to claim 63 wherein the compound to be fused with Tat is one or more therapeutic molecules selected among antiviral compounds, anti-inflammatory drugs, anti-angiogenic molecules, cytotoxic anti-tumor drugs, immunomodulating molecules such as chemokines or cytokines, antibodies and corresponding mixtures. 66. Method according to claim 57 wherein Tat is bound, alone or in combination with other compounds in the form of proteins, peptides or DNA encoding them, to particles such as microparticles, nanoparticles, liposomes and other particulated inert carriers and mixtures thereof. 67. Method according to claim 66 wherein compound is one or more antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 68. Method according to claim 66 wherein compound is one or more therapeutic molecules selected among antiviral compounds, anti-inflammatory drugs, anti-angiogenic molecules, cytotoxic anti-tumor drugs, immunomodulating molecules such as chemokines or cytokines, antibodies and corresponding mixtures. 69. Method according to claim 66 wherein compound is one or more expression vectors. 70. Method according to claim 69 wherein the expression vector is selected among plasmid DNA, bacterial or virus vectors expressing one or more antigens. 71. Method according to claim 58 to selectively target antigen presenting cells expressing α5β1 and αvβ3 integrins or other integrins, including, but not limited to, dendritic cells, endothelial cells and macrophages capable of taking up Tat via the integrin-mediated pathway and/or other uptake pathways conferring a selective uptake, in order to deliver one or more antigens to enhance an immune response and to induce Th-1 type immune responses against infectious diseases and tumors. 72. Method according to claim 71 wherein Tat delivers antigens in the form of peptides, proteins or DNA encoding them. 73. Method according to claim 72 wherein Tat delivers one or more antigens to induce an immune response. 74. Method according to claim 71 wherein Tat is fused to one or more compounds selected among proteins, peptides or DNA encoding them in order to deliver such compound (s), in vitro and in vivo, intracellularly or to the cell membrane. 75. Method according to claim 74 wherein compound is one or more immunomodulating molecules, such as chemokines or cytokines, antibodies and corresponding mixtures. 76. Method according to claim 74 wherein compound is one or more antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 77. Method according to claim 58 wherein Tat is bound, alone or in combination with other compounds in the form of proteins peptides or DNA encoding them, to particles such as microparticles, nanoparticles, liposomes and other particulated inert carriers and mixtures thereof. 78. Method according to claim 77 wherein compound is one or more antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 79. Method according to claim 77 wherein compound is one or more immunomodulating molecules, such as chemokines or cytokines, antibodies and corresponding mixtures. 80. Method according to claim 77 wherein compound is one or more expression vectors. 81. Method according to claim 80 wherein the expression vector is selected among plasmid DNA, bacterial or virus vectors expressing one or more antigens. 82. Method for preventive and therapeutic vaccination against tumors infectious diseases said method comprising the step of administering to a subject in need an effective amount of HIV-1 Tat or tat DNA according to claim 55. 83. Method for the treatment of tumors or infectious diseases or inflammatory and angiogenic diseases said method comprising the step of administering to a subject in need an effective amount of HIV-1 Tat or tat DNA according to claim 55. 84. Method according to claim 82 wherein tat DNA is in combination with antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 85. Method according to claim 83 wherein tat DNA is in combination with antigens selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 86. Method according to claim 82 wherein tat DNA is bound, alone or in combination with other antigens DNA or therapeutic compounds to particles such as microparticles, nanoparticles, liposomes and other particulated inert carriers and mixtures thereof. 87. Method according to claim 83 wherein tat DNA is bound, alone or in combination with other antigens DNA or therapeutic compounds to particles such as microparticles, nanoparticles, liposomes and other particulated inert carriers and mixtures thereof. 88. Method according to claim 56 wherein tat DNA comprises the nucleotide sequence according to SEQ ID NO. 1, 99, or 101. 89. Method according to claim 56 wherein Tat comprises the amino acid sequence according to SEQ ID NO. 2, 100, or 102. 90. Method according to claim 56 wherein the fragments of biologically active Tat or tat DNA are selected among Tat peptides or corresponding tat DNA comprising, alone or associated, the RGD domain, the cystein-rich domain, the basic domain. 91. Method according to claim 90 wherein the fragments are combined with other HIV-1 Tat peptides or corresponding tat DNA comprising the core domain: aa 38 to 47 in the HTLV-IIIB, clone BH-10, and/or the amminoterminal region aa 1 to 20 in the HTLV-IIIB, clone BH-10. 92. Method according to claim 90 wherein the RGD domain comprises: aa 73 to 86 in the HTLV-IIIB, clone BH-10, aa 74 to 84, aa 75 to 83, aa 76 to 82, aa 77 to 81, aa 77 to 82, aa 77 to 83, aa 76 to 83; the cystein-rich domain comprises: aa 22 to 37 in the HTLV-IIIB, clone BH-10; the basic domain comprises: aa 48 to 61 in the HTLV-IIIB, clone BH-10, and all their corresponding nucleotide sequences. 93. Method according to claim 56 wherein the fragments of biologically active Tat or tat DNA are selected among any HIV variant (HIV-1, HIV-2 and other HIV types and subtypes) that contain one or more T-cell epitopes in their amino acid sequences or corresponding nucleotide sequence HTLV-IIIB, clone BH-10 or 89.6. 94. Method according to claim 56 wherein the derivatives of Tat or tat DNA comprise Tat mutants of the HTLV-IIIB, clone BH-10, variant, selected among that ones comprising the amino acid sequence or corresponding nucleotide sequences, of cys22 and/or lys41. 95. Pharmaceutical composition comprising as active principle an effective amount of biologically active HIV Tat or tat DNA, fragments or derivative thereof, combined or fused with at least one of the following: antigens, therapeutic compounds, adjuvants, support particles, for preventive and therapeutic vaccination against infectious diseases and tumors or for the treatment of a disease selected among infectious diseases, inflammatory and angiogenic diseases, tumors. 96. Pharmaceutical composition according to claim 95 wherein the antigen is selected among antigens from intracellular pathogens such as viruses, mycobacterium tuberculosis, candida, malaria, or from tumor cells such as those from lung, colon, breast, prostatic cancer, but specifically excluding HIV antigens Gag, Nef, Rev. 97. Pharmaceutical composition according to claim 95 wherein the therapeutic compound is selected among antiviral compounds, anti-inflammatory drugs, anti-angiogenic molecules, cytotoxic anti-tumor drugs, immunomodulating molecules such as chemokines or cytokines, antibodies and corresponding mixtures. 98. Pharmaceutical composition according to claim 95 wherein the support particles are selected among: microparticles, nanoparticles, liposomes and other particulated delivery systems and mixtures thereof. 99. Pharmaceutical composition according to claim 95 wherein the adjuvant is selected among Alum, RIBI, ISCOMS, CpG sequence, Lipopeptides and corresponding mixtures. 100. Pharmaceutical composition according to claim 95 wherein the infectious disease is selected among those infections caused by human or animal viruses, bacteria or other intracellular and extracellular pathogens, including sexual infectious diseases, endocarditis, urinary tract infections, osteomyelitis, cutaneous infections, or streptococcus and staphylococcus infections, pneumococcus infections, tetanus, meningococcus infections, tuberculosis, malaria, candidosis, infections by Helicobacter, salmonella, syphilis, herpetic infections, including varicella, mononucleosis and Epstein-Barr-derived infections, human herpesvirus-8 infection, cytomegalovirus, herpes labialis and genitalis, hepatitis virus infection (A, B, C, D, G), papilloma virus-derived infections, influenza, lysteria, vibrio cholerae. 101. Pharmaceutical composition according to claim 95 wherein the inflammatory disease is an allergy or inflammation associated or not with a viral, bacterial or parasitic infection, including immune-mediated cutaneous diseases, Lupus erythematous systemic, rheumatoid arthritis, systemic sclerosis, dermatomiositis, Sjögren syndrome, Goodpasture syndrome, vasculitis, sarcoidosis, osteoarthrosis, infectious arthritis, psoriasis, Chron disease, rectocolitis ulcerosus, tyroiditis, scleroderma, allergic diseases. 102. Pharmaceutical composition according to claim 95 wherein the angiogenic disease is selected among non-neoplastic angioproliferative diseases including diabetic retinopathy, retrolental fibroplasia, trachoma, vascular glaucoma, immune inflammation, non-immune inflammation, atherosclerosis, excessive wound repair, angiodermatitis, colon angiodisplasia, angioedema and angiofybromas. 103. Pharmaceutical composition according to claim 95 wherein the tumor is selected among benign and malignant tumors including tumors of soft tissues, bones, cartilages and blood, such as, but not limited to, Kaposi's sarcoma and other neoplasia of the skin, lung, breast, gut, liver, pancreas, endocrine system, uterus, ovary, sarcomas, acute and chronic leukemia, and neoplasia of lymphatic cells. 104. Pharmaceutical composition according to claim 95 further comprising adjuvants, diluents, eccipients, carriers. 105. Pharmaceutical composition according to claim 95 in the form of tablets, pills, sprays, injectable solutions, suspensions, powders, creams, ointments. 106. Pharmaceutical composition according to claim 95 administered by the parenteral: subcute, intramuscular, intradermic; or mucosal: vaginal, rectal, oral, nasal; or topic route.

FIELD OF THE INVENTION The present invention relies on the novel and unexpected discovery that low amounts (picomolar-nanomolar) of native, substantially monomeric, biologically active HIV-1 Tat, fragments or derivatives thereof, (i) specifically bind, through the RGD domain, to the α5β1 and integrins that are selectively expressed on antigen-presenting cells such as dendritic cells, macrophages and cytokine-activated endothelial cells (henceforth APC), (ii) efficiently enter APC, (iii) promote dendritic cells and endothelial cells maturation and activation, and (iv) access to both the major histocompatibility complex class-I and class-II restricted antigen presentation pathway. Therefore, the present invention intends to exploit these novel findings of the aforementioned inherent and interrelated properties of biologically active HIV-1 Tat, fragments or derivatives thereof, as a delivery system for both antigenic and therapeutic (henceforth collectively referred to as “cargo”) molecules for the treatment of certain human diseases, such as, but not limited to, infectious diseases, inflammatory and angiogenic diseases, and tumors, and as an adjuvant and immunomodulator in single or multiple antigen vaccines for preventive and therapeutic vaccination applications, by: 1) selectively targeting, binding and delivering cargo molecules to APC, in the first embodiment of the present invention, 2) by selectively targeting and binding to dendritic cells and endothelial cells thus promoting their maturation and activation, and by inducing Th-1 type immune responses against itself and, most notably, other antigens, in a second embodiment of the present invention. In particular the present invention relates to, 1) a method for specifically targeting and delivering cargo molecules to APC to immunize or treat humans against infectious, inflammatory and angiogenic diseases or tumors, 2) a method for increasing the immunising activity of other antigens in preventive and therapeutic immunization of humans against infection by one or more pathogens. The present invention is specifically and univocally concerned with the use of native, substantially monomeric and biologically active HIV-1 Tat protein, fragments or derivatives thereof, to specifically target APC to deliver cargo molecules across the outer cell and nuclear membranes, in a drug or antigen delivery embodiment of the present invention; and to specifically target dendritic cells and endothelial cells to promote their maturation, activation and to induce Th-1 type immune responses against other antigens in a vaccine-adjuvant and immunomodulation embodiment of the present invention. BACKGROUND OF THE INVENTION Tat is a regulatory protein of human immunodeficiency virus type 1 (HIV-1) produced very early after infection and essential for virus gene expression, replication and infectivity (Arya 1985; Fisher 1986; Chang 1995). During acute infection of T cells by HIV, Tat is also released in the extracellular milieu and taken-up by neighbour cells (Frankel 1988; Ensoli 1990; Ensoli 1993; Chang 1997) where, according to the concentration, can increase virus infectivity. Specifically, upon uptake Tat can enhance, in infected cells, virus gene expression and replication (Frankel 1988; Ensoli 1993; Chang 1997), and, in uninfected cells, the expression of the β-chemokines receptors CCR5 and CXCR4 favouring transmission of both macrophage and T lymphocyte-tropic HIV-1 strains (Huang 1998; Secchiero 1999). Extracellular HIV-1 Tat protein is also responsible for the increased frequency and aggressiveness of Kaposi's sarcoma (KS) a vascular tumor particularly frequent in HIV-infected individuals (Friedman-Kien 1981; Safai 1985). In particular, previous work from our and other groups indicated that Tat cooperates with angiogenic and inflammatory cytokines that are highly expressed in KS patients (Samaniego 1998; Ensoli 1994) in inducing new blood vessels formation (angiogenesis) and the growth and locomotion of spindle shaped cells of endothelial cell origin (KS cells) and of activated endothelial cells (Barillari 1992; Albini 1995; Ensoli 1994). Moreover, the sequence comprised between residues 21 and 40 (core domain) in the HIV-1 BH-10 Tat protein has been shown to act as a transactivator, to induce HIV replication and to trigger angiogenesis (International Patent number WO 00/78969 A1). In particular, our data have shown that biologically active Tat binds through its RGD region the integrin receptors α5β1 and αvβ3 and that this interaction mediates the adhesion, growth and locomotion induced by Tat on KS cells and endothelial cells activated by inflammatory cytokines (Barillari 1993; Barillari 1999a and 1999b). In addition, Tat acts also as a chemotactic factor for these cell types as well as for monocytes and dendritic cells (DC) (Albini 1995; Benelli 1998; Lafrenie 1996; Mitola 1997). Finally, our data demonstrated that KS and HUVE cell migration and invasion are toward the Tat protein is mediated by the binding of the Tat RGD region to the α5β1 and αvβ3 integrins (Barillari, 1999b). Consistent with these findings, the immune response to Tat has been shown to play a key role in controlling the progression of AIDS and AIDS-associated diseases. In fact, a Tat-specific immune response is present in HIV-1 infected subjects and simian immunodeficiency virus (SIV)-infected monkeys, and correlates inversely with progression to the symptomatic stage of the infection (Reiss 1990; Venet 1992; Rodman 1993; Froebel 1994; Re 1995; Van Baalen 1997; Zagury 1998; Addo 2001). Moreover, vaccination with biologically active Tat protein or tat DNA induces protection against SHIV89.6P virus replication and disease onset which correlates with the presence of Th-1 responses including specific cytotoxic T lymphocytes (CTLs) (Cafaro 1999; Cafaro 2000; Cafaro 2001, and PCT WO99/27958). The same protection data have been more recently observed with a tat-rev vaccine delivered with viral vectors in macaques (Osterhaus 2001). In contrast, a limited containment of the infection has been observed in monkeys vaccinated with inactivated Tat or Tat peptides, in which antibodies and T helper specific responses but no CTLs nor Th-1 responses had been induced (Goldstein 2000; Pauza 2000). Again, the repeated intradermal (i.d.) inoculation of monkeys with native and active Tat protein alone (in the absence of any adjuvant) at low doses (5-6 μg) selectively induced a Th-1 response and specific CTLs in the absence of any significant antibody production (Cafaro 1999 and PCT WO99/27958). These immunological results were recently confirmed in a new vaccination protocol in which native Tat alone was repeatedly inoculated i.d. in 4 monkeys (unpublished data), and are comparable to those induced by i.m. vaccination with tat DNA in a published (Cafaro 2001 and PCT WO99/27958) and in an ongoing study. Similarly, recent work performed in SIV-infected macaques indicate that anti-Tat CTLs are key to control early virus replication after primary infection and exert a selective immune pressure on the virus leading to the appearance of slowly replicating, less pathogenic escape mutants (Allen 2000). Finally, Tat is presented with major histocompatibility complex (MHC) class I antigen (Moy 1996; Kim 1997), hence inducing anti-Tat CTL (Cafaro 1999). Micromolar concentrations of recombinant Tat protein (often of unknown biological activity) or peptides encompassing the basic region of Tat have been shown to enter many different cell types (Frankel 1988; Mann 1991; Ensoli 1993; Chang 1997; Fawell 1994; Moy 1996; Kim 1997). The highly basic charge of Tat residues 48-57, in fact, enables the protein to bind to heparan sulphate proteoglycans (HSPG) that are present on the membrane of all cell types (Chang 1997; Rusnati 1998). After release from acutely infected cells, a fraction of extracellular Tat binds, through its basic residues, to the HSPG (Chang 1997). This protects extracellular Tat from proteolytic degradation, as previously found for several growth factors (reviewed in Raines and Ross, 1992). Upon the binding of its basic region to cell surface HSPG, Tat is internalised through a receptor-independent pathway (Frankel 1988; Rusnati 1998; Tyagi 2001). In fact, Tat residues 49-57 (in the BH-10 Tat sequence) have been indicated to be able to translocate an OVA peptide into the cytosol of DC and to sensitize CD8+ T cells to this peptide (Kim, 1997). Furthermore, the 47-57 Tat sequence (from the BH-10 variant), fused with several effector proteins, has been suggested to be able to deliver them to cells (International patent number WO 01/19393 A1). However, this internalization mechanism requires high (micromolar) concentrations of Tat, occurs with any cell type and it is not sequence-specific. In fact, it has been shown that mutations of this region, which do not change its basic charge, do not affect the properties of the Tat basic region (Barillari 1999b). Similarly, the substitution of the Tat basic region with that of HIV rev or other genes does not change Tat properties. In this regard, the basic region of Tat has been shown to be very similar to the arginin-rich region carried by the members of the small family of proteins known as penetratins, that are all capable of entering many cell types (Derossi 1998). In fact, arginin homopolymers have been shown to enter cells even more efficiently than Tat basic region (Derossi 1998). The property of the Tat basic region of being internalized by cells has been exploited to deliver foreign proteins to a variety of cell types (Fawel 1994; Wender 2000; and WO 01/19393). To this purpose, foreign proteins have been conjugated or fused to the Tat basic region which has been used as a carrier for the protein to be transduced (Fawel 1994; Wender 2000; and WO 01/19393). However, the inventor believes that due to the ubiquitous expression of HSPG, Tat basic region cannot be used for selective targeting, delivery and/or uptake of Tat by specific primary cell types, including antigen presenting cells (APC). APC initiate and drive the type of immune response upon encountering foreign molecules (Bancherau 1998; Bell 1999). Typical APC include monocyte-derived DC (MDDC), T cell blasts (TCB), B-lymphoblastoid cell lines (BLCL) and monocytes-macrophages (Bancherau 1998; Bell 1999). In addition, when activated by inflammatory cytokines also endothelial cells acquire APC functions (Pober 1988). Among these inflammatory cytokines, interleukin (IL)-1, tumor necrosis factor (TNF) and interferon (IFN)γ are key for endothelial cell activation (Pober 1988). Exposure to these cytokines increases in endothelial cells the expression of α5β1 and αvβ3, that are among the several cell surface receptors binding Tat (Barillari 1993, Fiorelli 1999; Benelli 1998; Kolson 1993; Sabatier 1991; Vogel 1993; Boykins 1999; Ganju 1998; Milani 1996; Mitola 1997 and 2000; Weeks 1993; Albini 1996 and 1998; Chang 1997; Lafrenie 1996; Morini 2000; Rusnati 1998). Among all these APC, DC are the most efficient APC and are key to the induction of immune responses against infections and tumors (Banchereau 1998; Bell 1999). Their function is associated with a high expression of MHC and costimulatory molecules (CD40, CD80, CD86) and with the production of cytokines known to activate T lymphocytes, and β-chemokines. Upon encountering the antigens, DC undergo a maturation process characterized by an increase of costimulatory molecules expression and by a reduction of their phagocytic and pinocytic capability (Banchereau 1998; Bell 1999). Further, due to the upregulation of the homing receptor CCR7 and to the downregulation of CCR5, mature DC migrate to lymph nodes where they present antigens to T lymphocytes (Banchereau 1998; Bell 1999). Prior art indicates that the addition of Tat protein to DC blocks in these cells the extracellular calcium influx, the production of interleukin-12, and the uptake of apoptotic bodies (Zocchi 1997; Rubartelli 1997). As a result, it is predicted that profound impairment of important DC functions including antigen uptake, processing and presentation and induction of Th-1 responses should occur. Further, impairment of phagolysosomal fusion has been reported in peripheral blood monocytes upon exposure to Tat, suggesting impairment in this cell type of both microbicidal and antigen processing (and presentation) functions (Pittis 1996). Moreover, Tat has been reported to induce both monocytes/macrophages and lymphocytes to secrete IL-10 (Masood 1994; Badou 2000), while inhibiting IL-12 production in monocytes (Ito 1998). Finally, exposure of APC to Tat has been reported to impair their capability to organize cell clusters and to properly activate T cells (Mei 1997). Moreover, prior art indicates that Tat profoundly impairs also T cell functions including suppression of responses to mitogens anti-CD3 or specific antigens (Viscidi 1989; Benjouad 1993; Subramanyam 1993; Chirmule 1995; Wrenger 1996; Wrenger 1997; Zagury 1998), T cell hyperactivation (Ott 1997; Li 1997), and T cell apoptosis (Westendorp 1995; Li 1995; McCloskey 1997). Further, inoculation of biologically active Tat has been reported to be immunosuppressive in vivo (Cohen 1999). Part of the effects of Tat on the immune system have been related to upregulation by Tat of the chemokines receptors CCR5 and CXCR4 (Huang 1998; Secchiero 1999), or the direct interaction of Tat with the chemokine receptors CCR2 and CCR3 (Albini 1998a) or with other receptors including CD26 (Gutheil 1994), Flt-1 (Mitola 1997), KDR (Albini 1996; Morini 2000), that are expressed by immune cells, as well as by endothelial cells. Therefore, according to this previous art Tat is expected to drive a Th-2 type of immune response and/or to interfere with or abolish proper APC function and T cell activation. By contrast, our novel and unexpected finding, supported by experimental evidence exhibited in this patent application, indicate that: (i) APC are specifically targeted by Tat that selectively recognises and enters these cells at pico-nanomolar concentrations, but that this requires the interaction of native, substantially monomeric, biologically active Tat with α5β1, αvβ3 integrins, through the Tat RGD sequence; (ii) and that native, substantially monomeric, biologically active Tat activates, rather than inhibiting, APC function and induces, rather than suppressing, Th-1 type immune responses against itself and, most notably, other antigens. Specifically, our data show that Tat acts not only as an antigen but also as an adjuvant with potent immunomodulatory properties. These properties of Tat, namely of being selectively internalised as biologically active protein by APCs at picomolar-nanomolar concentrations and to act as an adjuvant, are strictly related each other. In particular, we have found, that Tat RGD sequence is key for the internalisation of active Tat by these cells through the α5β1 and αvβ3 integrin receptors. In fact, antibodies or competitor ligands blocking these integrins completely abolish or greatly reduce the uptake of picomolar-nanomolar concentrations of Tat, respectively. This uptake is very rapid, is dose-, cell maturation/differentiation- and time-dependent. Even more unexpectedly, we did not obtain similar results with other APC including monocytes, T cell blasts, or B cell blasts or non-activated endothelial cells. Therefore, these findings are completely novel since prior art indicates that Tat is taken up only at much higher concentrations (micromolar range), through its basic region, by a non-receptor-mediated pathway (Frankel 1988; Mann 1991; Rusnati 1998; Tyagi 2001). This internalization pathway occurs with any cell type, and it is not maturation/differentiation-dependent. Further, we have found that Tat in its native, substantially monomeric, and biologically active form is absolutely required to observe all the above novel effects which do not occur when Tat is oxidized and inactivated. In fact, Tat has 7 cysteines and it is extremely sensitive to oxidation which, when occurring, causes the loss of native protein conformation and consequent loss of biological activity (Frankel 1989). Therefore, Tat is likely to lose its native conformation and activity when purified with procedures that are not specifically designed at maintaining this protein in its native form. Although established concepts in the field claim that biologically active Tat is toxic (Gallo 1999; Sabatier 1991; Kolson 1993; Westendrop 1995; Purvis 1995), by contrast, the highly purified, biologically active preparations of recombinant Tat utilized by the inventor has no cytotoxic nor pro-apoptotic effects on endothelial cells, DC, macrophages, other cell type tested, nor in vivo in mice or monkeys (Ensoli 1994; Barillari 1999a; Zauli 1993, 1995a and 1995b; Cafaro 1999, 2000 and 2001). Thus, the inventor believes that full-length, wild type, native, substantially monomeric, and biologically active Tat from any HIV variant or its fragments or derivates containing the RGD region can be used as a highly efficient system for the selective targeting and delivery of molecules to specific cell types expressing the integrins recognized by the Tat RGD region (Barillari 1993, 1999a and 199b; Ensoli 1994). Given the very large amount and ubiquitous distribution of DC, macrophages and endothelial cells in the human body, the inventor believes that the capability of biologically active Tat or its fragments or derivatives containing the RGD sequence of targeting these APC and of driving Th-1 type cellular responses will offer a unique opportunity to, 1) to deliver cargo molecules to these cell types which represent a specific target for Tat and are recruited and activated in infections, pathologic angiogenesis, inflammatory diseases and tumors in the delivery system embodiment of the present invention; 2) induce a potent immune response against not only Tat but also against other antigens delivered by or with Tat, in the vaccine-adjuvant and immunomodulatory embodiment of the present invention. This belief is strongly supported by the successful previous work of the inventor with biologically active Tat as a vaccine to control HIV replication and to block disease onset (Cafaro 1999; Cafaro 2000; Cafaro 2001, and PCT WO99/27958) as opposed to inactivated Tat protein (Goldstein. 2000; Pauza 2000). The present patent application is substantially different and innovative as compared to our previous patent application WO 99/27958 in many aspects. In fact, the above mentioned application claimed biologically active Tat or Tat encoding DNA to be effective as a vaccine against HIV/AIDS. At the time when said patent application was filed it was not known to us that low (picomolar-nanomolar) amounts of biologically active Tat, or its fragments or derivatives containing the RGD region, (i) specifically target APC and thus we could have not claimed its use as a carrier to selectively deliver cargo molecules to them; (ii) cause EC and DC cell maturation and activation and induce Th-i type immune responses against different antigens, and thus we could have not claimed its use as a adjuvant and immunomodulator. Thus, in this invention, biologically active Tat is proposed, in the first embodiment, as a delivery system to deliver to APC (i) different antigens or combinations of antigens for vaccination against different infectious diseases (not only HIV/AIDS) and tumors, or for multivalent vaccination against one or more infectious diseases, and (ii) therapeutic molecules for the treatment of infectious, inflammatory and angiogenic diseases and tumor growth and metastasis; and in the second embodiment, biologically active Tat is proposed as an adjuvant to drive T-cell mediated immune responses against different antigens, and in particular to enhance the immunogenicity of poorly immunogenic antigens, such as those expressed by certain intracellular pathogens as well as tumor cells, by combining or fusing them with biologically active Tat or its fragments or derivatives containing the RGD region. In summary, the most important innovative aspect which makes the difference with the prior art is that here native, substantially monomeric, and biologically active Tat is claimed as a molecule which exerts different functions, i.e. it is a carrier to selectively deliver antigens to APCs or active compounds to specific tissues, and an adjuvant stimulating immune responses to other antigens. This unexpected properties make native, substantially monomeric, and biologically active Tat suitable for different applications in different infectious diseases (not only AIDS), inflammatory and angiogenic diseases and tumors. Thus, the inventor believes that native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, containing the RGD sequence, acts with at least one of the following actions: as delivery system to specific APC or as an adjuvant, and claims that it can be exploited for preventive and therapeutic vaccination and/or drug delivery for the prevention and treatment of HIV/AIDS, other infectious, inflammatory, and angiogenic diseases. SUMMARY OF THE INVENTION It is an object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target antigen-presenting cells expressing α5β1 and αvβ3 integrins. It is another object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target α5β1 and αvβ3 integrins expressed by antigen presenting cells, including dendritic cells, endothelial cells and macrophages, for the uptake of Tat, fragments or derivatives thereof, by these cells. It is another object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target antigen presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, to induce the maturation and/or the antigen presenting functions of these cells by Tat, fragments or derivatives thereof. Another object is the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, combined with one or more antigens, including, but not limited to, antigens from intracellular pathogens (such as viruses, mycobacterium tuberculosis, candida, malaria) and from tumor cells, (such as those from lung, colon, breast, prostatic cancer) in the form of peptides, proteins or DNA encoding them, to selectively target in vitro and in vivo antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, for preventive and therapeutic vaccination or treatment against infectious diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver in vitro and in vivo one or more antigens to antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages in order to induce immune responses for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver, intracellularly or to the cell membrane, in vitro and in vivo, to antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, one or more antigens or therapeutic compounds (such as, but not limited to, antiviral compounds, anti-inflammatory drugs, anti-angiogenic molecules, cytotoxic anti-tumor drugs or immunomodulating molecules such as, for example chemokines or cytokines, or antibodies) with or without the presence of support particles (such as, but not limited to, microparticles, nanoparticles, liposomes and other particulated delivery systems such as the ones described in Speiser 1991 and Takeuchi, 2001) for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, fused to other proteins or peptides or support particles (as defined in the above) to selectively deliver in vitro and in vivo antigens or therapeutic compounds (as defined in the above) to antigen presenting cells expressing β5β1 and αvβ3 integrins including dendritic cells, endothelial cells and macrophages for combined preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively target in vitro and in vivo cells expressing RGD-binding integrin receptors such as antigen-presenting cells and other cell types capable of taking up Tat via the integrin-mediated pathway, and/or other uptake pathways upon the binding to integrin receptors, in order to deliver antigens or therapeutic molecules (as defined in the above) for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, combined with antigens, adjuvants (such as, but not limited to, Alum, RIBI, ISCOMS, CpG sequences, Lipopeptides) or therapeutic molecules or support particles (as defined in the above) administered by the parenteral (subcute, intramuscular, intradermic) or mucosal (vaginal, rectal, oral, nasal) or topic route for preventive and therapeutic vaccination or treatment against infectious diseases inflammatory, and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof to selectively deliver in vitro and in vivo antigens or therapeutic molecules (as defined in the above) within or attached to support particles (as defined in the above), to antigen-presenting cells expressing RGD-binding integrin receptors including dendritic cells, endothelial cells and macrophages, for preventive and therapeutic vaccination or treatment against infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver in vitro and in vivo expression vectors including plasmid DNA and bacterial or virus vectors expressing one or more antigens, in the presence or absence of support particles (as defined in the above), to antigen presenting cells expressing RGD-binding integrin receptors, including dendritic cells, endothelial cells and macrophages for preventive and therapeutic vaccination or treatment against infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of tat DNA or native, substantially monomeric, and biologically active Tat protein, fragments or derivatives thereof, fused or combined with DNA coding for antigens, with or without support particles (as defined in the above), for combined preventive and therapeutic vaccination of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is native, substantially monomeric, and biologically active HIV Tat or tat DNA, fragments or derivative thereof, combined or fused with antigens, therapeutic molecules (as defined in the above), adjuvants (as defined in the above), or support particles (as defined in the above) such combination or fusion being defined as the association by means of chemical or physical interactions, or any other interactions, in any combination, such as, for example, but not limited to, the absorption of Tat and a DNA plasmid on nanoparticles; the inclusion of Tat and a synthetic drug in the same pharmaceutical preparation; the association of Tat or a fragment or a derivative thereof with a peptide by chemical crosslinking or by other means; the fusion of Tat, fragment or derivative thereof, with another protein or another peptide upon their expression in bacteria or eucariotic cells through chimeric DNA, where the DNA sequences encoding for the above polypeptides have been fused together using recombinant DNA technologies. Another object is the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, as adjuvant to activate or enhance in vitro and in vivo the antigen-presenting function of cells expressing RGD-binding integrin receptors including dendritic cells, endothelial cells and macrophages and to induce Th-1 type immune responses against HIV/AIDS, other infectious diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat protein, tat DNA, fragments or derivates thereof, as in the above for vaccination or therapeutic treatment by the parentheral (intradermic, intramuscular, subcute), mucosal (oral, nasal, vaginal, rectal) or topic route. Another object are fragments of native, substantially monomeric, and biologically active Tat, defined as Tat peptides from any HIV variant (HIV-1, HIV-2 and other types and subtypes) comprising, alone or associated, the RGD domain (aa 73 to 86 in the HTLV-IIIB, clone BH-10; aa 74 to 84; aa 75 to 83; aa 76 to 82; aa 77 to 81; aa 77 to 82; aa 77 to 83; aa 76 to 83); the cystein-rich domain (aa 22 to 37 in the HTLV-IIIB, clone BH-10); the basic domain (aa 48 to 61 in the HTLV-IIIB, clone BH-10), combined or not with other HIV-1 Tat peptides including the core domain (aa 38 to 47 in the HTLV-IIB, clone BH-10) and/or the amminoterminal region (aa 1 to 20 in the HTLV-IIIB, clone BH-10). Another object are fragments of native, substantially monomeric, and biologically active Tat are defined as nucleotide sequences from any HIV variant (HIV-1, HIV-2 and other types and subtypes) comprising, alone or associated, the RGD domain (sequence coding for aa 73 to 86 in the HTLV-IIIB, clone BH-10; sequence coding for aa 74 to 84 in the HTLV-IIIB, clone BH-10; sequence coding for aa 75 to 83 in the HTLV-IIIB, clone BH-10; sequence coding for aa 76 to 82 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 81 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 82 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 83 in the HTLV-IIIB, clone BH-10; sequence coding for aa 76 to 83 in the HTLV-IIIB, clone BH-10) the cystein-rich domain (sequence coding for aa 22 to 37 in the HTLV-IIIB, clone BH-10), the basic domain (sequence coding for aa 48 to 61 in the HTLV-IIIB, clone BH-10), combined or not with other HIV-1 Tat peptides including the core domain (sequence coding for aa 38 to 47 in the HTLV-IIB, clone BH-10) and/or the amminoterminal region (sequence coding for aa 1 to 20 in the HTLV-IIIB, clone BH-10). Another object are fragments of Tat from any HIV variant (HIV-1, HIV-2 and other HIV types and subtypes) that comprise one or more T-cell epitopes in their amino acid sequences (HTLV-IIIB, clone BH-10 or 89.6). Another object are fragments of Tat from any HIV variant (HIV-1, HIV-2 and other HIV types and subtypes) that comprise one or more T-cell epitopes in their nucleotide sequences (HTLV-IIIB, clone BH-10 or 89.6). Another object are derivatives of Tat which comprise Tat mutants of the HTLV-IIIB, clone BH-10, variant, selected among that ones having the following nucleotide sequences, or part of them: Nucleotide sequence of cys22 mutant and nucleotide sequence of lys41. Another object are derivatives of Tat which comprise Tat mutants of the HTLV-IIIB, clone BH-10, variant, selected among that ones having the following aminoacid sequences, or part of them: Amino acid sequence of cys22 mutant and amino acid sequence of lys41. Another object of the present invention is the use of native, substantially monomeric, and biologically active Tat protein acting and combined as above described to produce medicaments to cure affections in the group of infectious diseases, inflammatory and angiogenic diseases, tumors. Further objects will be evident from the detailed description of the invention. BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Native, substantially monomeric, and biologically active Tat is efficiently and selectively taken up in a dose- and time-dependent fashion by MDDC, but not by BLCL or TCB, as illustrated in FIG. 1A, FIG. 1B, FIG. 1C′ and FIG. 1C″. FIG. 2. Uptake of native, substantially monomeric, and biologically active Tat by MDDC increases with cell maturation and it is lost by oxidation/inactivation of the protein, as illustrated in FIG. 2A and FIG. 2B. FIG. 3. Anti-α5β1 and anti-αvβ3 antibodies block uptake of native, substantially monomeric, and biologically active Tat by MDDC, as illustrated in FIG. 3A and FIG. 3B. FIG. 4. Fibronectin and vitronectin block uptake of native, substantially monomeric, and biologically active Tat by MDDC, as illustrated in FIG. 4A and FIG. 4B. FIG. 5. Native, substantially monomeric, and biologically active Tat is efficiently taken up in a dose- and time-dependent fashion by macrophages but not by monocytes, as illustrated in FIG. 5A, FIG. 5B and FIG. 5C. FIG. 6. Schematic representation of the HIV-1 Tat protein, functional domains thereof and sequences of the Tat peptides utilized, as illustrated in FIG. 6A, FIG. 6B and FIG. 6C. FIG. 7. Uptake of native, substantially monomeric, and biologically active Tat is differently affected by Tat peptides bearing the RGD or basic region, as illustrated in FIG. 7A, FIG. 7B, FIG. 7C and FIG. 7D. FIG. 8. Rhodaminated Tat is taken up in a dose-dependent fashion by cytokine-activated endothelial cells but not by non-activated cells, as illustrated in FIG. 8A, FIG. 8B, FIG. 8C and FIG. 8D. FIG. 9. Time-course of uptake of 100 ng/ml rhodaminated Tat by cytokine-activated endothelial cells, as illustrated in FIG. 9A, FIG. 9B, FIG. 9C and FIG. 9D. FIG. 10. Time-course of uptake of 1 μg/ml rhodaminated Tat by cytokine-activated endothelial cells, as illustrated in FIG. 10A, FIG. 10B, FIG. 10C and FIG. 10D. FIG. 11. Dose-response analysis of uptake of native, substantially monomeric, and biologically active Tat protein by cytokine-activated endothelial cells versus non activated cells. FIG. 12. Dose- and time-course analysis of uptake of native, substantially monomeric, and biologically active Tat by cytokine-activated endothelial cells. FIG. 13. Inhibition of uptake of 10 ng/ml rhodaminated Tat by cytokine-activated endothelial cells with unlabelled Tat protein, as illustrated in FIG. 13A, FIG. 13B and FIG. 13C. FIG. 14. Inhibition of uptake of 10 ng/ml rhodaminated Tat by cytokine-activated endothelial cells with antibodies to α5β1 and αvβ3-integrin receptors, as illustrated in FIG. 14A, FIG. 14B, FIG. 14C, FIG. 14D and FIG. 14E. FIG. 15. Inhibition of uptake of 100 ng/ml rhodaminated Tat by cytokine-activated endothelial cells with antibodies to α5β1 and αvβ3 integrin receptors, as illustrated in FIG. 15A, FIG. 15B, FIG. 15C, FIG. 15D and FIG. 15E. FIG. 16. Uptake of 1 μg/ml rhodaminated Tat is partially inhibited by anti-α5β1 and anti-αvβ3 antibodies when cells are incubated with Tat for 15 minutes, as illustrated in FIG. 16A, FIG. 16B, FIG. 16C and FIG. 16D. FIG. 17. Uptake of 1 μg/ml rhodaminated Tat is not inhibited by anti-integrin antibodies when cells are incubated with Tat for 60 minutes, as illustrated in FIG. 17A, FIG. 17B and FIG. 17C. FIG. 18. Native, substantially monomeric, and biologically active Tat enhances the production of the cytokines IL-12, and TNF-a and of the β-chemokines MIP-1α, MIP-1β, and RANTES by MDDC, as illustrated in FIG. 18A, FIG. 18B, FIG. 18C and FIG. 18D. FIG. 19. Native, substantially monomeric, and biologically active Tat enhances allogeneic antigen presentation by MDDC. FIG. 20. Native, substantially monomeric, and biologically active Tat increases tetanus toxoid (TT)-specific presentation by MDDC to primed PBL enhancing specific T cell responses, as illustrated in FIG. 20A, FIG. 20B and FIG. 20C. FIG. 21. Scheme of the prime-boost vaccine protocol to assess the role as adjuvant of native, substantially monomeric, and biologically active Tat. FIG. 22. Vaccination of mice with Gag and Tat induces higher antibody response against Gag, as compared to mice vaccinated with gag alone. FIG. 23. Vaccination of mice with Gag and Tat induces higher anti-Gag cytolytic activity, as compared to mice vaccinated with gag alone. DETAILED DESCRIPTION OF THE INVENTION According to WO 99/27958 the biologically active HIV-1 Tat is defined as a protein capable of 1) entering and localizing in the nuclei of activated endothelial cells or DC, 2) activating the proliferation, migration and invasion of KS cells and cytokine-activated endothelial cells, 3) activating virus replication when added to infected cells as measured by a) the rescue of Tat-defective proviruses in HLM-1 cells after the addition of exogenous protein and/or b) the transactivation of HIV-1 gene expression in cells transfected with a HIV-1 promoter-reporter plasmid, and 4) inducing in mice the development of KS-like lesions in the presence of angiogenic factors or inflammatory cytokines). As used herein, the term native specifically identifies Tat in its native i.e. non-denaturated conformation and refers to an isolated Tat protein obtained by conventional techniques of recombinant DNA purified under non-denaturating conditions by techniques that take advantage of the capability of Tat to bind heparin (known in the prior art and widely discussed in the specification). As used herein, the term substantially monomeric refers to the fact that a Tat protein obtained as specified above is mostly (>95%) in a monomeric, as opposed to aggregated, form as determined by HPLC analysis. As used herein, the term biologically active refers to a Tat protein obtained as specified above and that is capable of 1) entering activated endothelial cells or dendritic cells at concentrations up to 10 nM and 2) performing at least one of the following actions: i) activating the proliferation, migration and invasion of Kaposi's sarcoma (KS) cells or cytokine-activated endothelial cells; ii) activating virus replication when added to infected cells as measured by a) the rescue of Tat-defective proviruses in HLM-1 cells after the addition of exogenous protein and/or b) the transactivation of HIV-1 gene expression in cells transfected with a HIV-1 promoter-reporter plasmid; iii) inducing in mice the development of KS-like lesions in the presence of angiogenic factors or inflammatory cytokines. As used herein the term DC maturation refers to a process leading to a progressive decrease of DC pino/phagocytic activity and antigen uptake, and to the concomitant enhancement of DC capability to process and present antigens, being such a process associated with the expression of DC maturation markers [(HLA)-ABC, HLA-DR, CD40, CD80, CD86 and CD83] and production of cytokines and chemokines (IL-12 and TNF-α, RANTES, MIP-1α, MIP-1). As used therein the term activation of antigen presenting cells, refers to induction or increase of the capability of taking up, processing and/or presenting antigens leading to enhancement of priming and boosting of immune responses, being such a process associated with the expression of co-stimulatory molecules [(HLA)-ABC, HLA-DR, CD40, CD80, CD86 and CD83, ICAM-1] and production of cytokines and chemokines (IL-12 and TNF-α, RANTES, MIP-1α, MIP-1). As used therein the term adjuvant refers to any substance that, when introduced into a host along with an antigen, enhances the immune responses against that antigen by several mechanisms including, for example, the induction of DC maturation and/or APC activation as defined above. Based on new data, briefly described below, which are considered novel and unexpected as compared to the previous art, we claim to use biologically active Tat, fragments or derivatives thereof, as a system that by virtue of its inherent and interrelated novel properties may display at least one or both the following features: delivery system and adjuvant. If Tat protein is oxidized and/or inactivated, it is not suitable for the purposes of the present invention. In fact, only biologically active, but not oxidized or inactivated, Tat protein is very efficiently, rapidly and selectively taken up by MDDC, macrophages and cytokine-activated endothelial cells, in a dose-, time-, and maturation/differentiation-dependent fashion. Uptake of Tat occurs by at least two pathways depending upon the concentration of the protein. At picomolar-nanomolar (0.01-1000 ng/ml) Tat concentrations, uptake of Tat is mostly mediated by the α5β1 and αvβ3 receptors through the interaction with the RGD sequence of the protein, while at higher concentrations of Tat an integrin-independent pathway, mediated by the binding of Tat basic region to HSPG, is predominant. Efficient uptake of Tat is observed only with these APC and not with TCB, BLCL, monocytes or non-activated endothelial cells. Upon uptake, Tat induces maturation and activation of MDDC including an increase of the expression of MHC and costimulatory molecules, and production of Th-1 cytokines (TNF-α, IL-12) and β chemokines [Rantes, macrophage inflammatory protein (MIP)-1α, MIP-1β]. All these effects are lost when Tat is oxidized and inactivated. Further, active Tat, but not its oxidized counterpart, enhances both allogeneic and antigen-specific presentation by MDDC, increasing T cell-specific immune responses against heterologous antigens. Thus, due to its capacity to target and efficiently enter specific antigen presenting cells, to enhance their functions and to drive Th-1 specific immune responses, active Tat favors its own presentation and that of other antigens and the induction of specific immune responses, and can also be used to selectively deliver active molecules to these cells. Based on these new data and on the capacity of Tat to be able to perform the activities (i) to (vi) hereinafter specified, we claim that active Tat functions as a delivery system capable of selectively deliver to antigen presenting cells including dendritic cells, endothelial cells and macrophages antigens or other active molecules and as an adjuvant capable of inducing Th-1 immune responses against antigens by a specific targeting of the most efficient antigen-presenting is cells and by driving specific immune responses. Therefore, biologically active Tat can be used not only as an antigen but also as a Th-1 type adjuvant for other antigens to induce immune responses against pathogens or tumors, and as a delivery system for DC, macrophages and activated endothelial cells for therapeutic intervention against infections, angiogenesis, inflammatory diseases and tumors. According to the present invention Tat is used as the delivery system to selectively deliver antigens and other active molecules to specific antigen presenting cells including DC, macrophages and cytokine-activated endothelial cells to induce immune responses to antigens, to adjuvate the immune responses to antigens for prophylactic or therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. For the ease of the presentation the several aspects of the invention will be described separately as follows. The inventor first found that MDDC have the specific capability of taking up very efficiently soluble active Tat at picomolar-nanomolar concentrations and found that this is a very rapid process with a peak after 5 to 10 min, depending on the concentration of Tat given to the cells. In contrast, the uptake of active Tat by TCB or BLCL is very poor, requiring micromolar concentrations of Tat (10 μg/ml) and much longer periods of time of incubation and, even under these conditions, most Tat remains bound to the cell surface and does not enter cells. Further, active Tat is also rapidly processed by MDDC, as indicated by the reduction of the intracellular staining after 30 min of incubation. Mature MDDC are able to take up Tat 10- to 100-fold more efficiently than immature cells, as indicated by the values of intracellular staining observed with low concentrations of Tat (100 ng/ml) as compared to those observed with 1 or 10 μg/ml of Tat with immature cells. In addition, Tat uptake requires a native conformation and full biological activity of the protein. In fact, oxidation and inactivation of Tat by exposure to light and air abolishes or markedly reduces (by approximately 100-fold) the uptake observed with active Tat by MDDC. Interestingly, the type of uptake by MDDC observed with oxidized Tat is similar or identical to that of native Tat with TCB and BLCL. Taken together these data indicate that active Tat targets MDDC and that the selective and efficient uptake of Tat by MDDC is not mediated by the high pino/phagocytic activity of these cells, but it requires specialized uptake pathways that are selectively expressed by immature MDDC and at higher levels by mature MDDC. Further, the different uptake observed at low versus high concentrations of Tat with MDDC indicates the presence of at least 2 different uptake pathways, the first one very efficient occurring at picomolar-nanomolar Tat concentrations and the other one at higher (micromolar) Tat concentrations. In fact, the inventor found that the uptake of low concentrations of Tat is mediated by specific integrins (α5β1, αvβ3) binding to the RGD region of Tat through a receptor-mediated internalization pathway, whereas at higher Tat concentration the uptake is mediated by the Tat basic region binding HSPG. Monocytes are not efficient in taking up Tat, whereas macrophages take up Tat more efficiently with a dose and time kinetic closer to that of DC indicating that differentiation of monocytes to either DC or macrophages induces selective and efficient mechanisms of Tat uptake. Similarly, the inventor found that endothelial cells activated by IFNγ, IL-1βand TNF-α, but not non-activated cells, bind and take up native Tat very efficiently and in fashion similar to MDDC. Tat uptake by activated endothelial cells also occurs via the RGD domain of Tat that binds the αvβ3 and α5 μl integrins [the classical receptors for vitronectin (VN) and fibronectin (FN)] and at high Tat concentration via the basic region of Tat that binds HSPG of the cell surface and extracellular matrix. Also for endothelial cells, integrin antagonists block uptake of pico-nanomolar but-not higher Tat concentrations. Similarly, uptake of picomolar-nanomolar concentrations of Tat is inhibited by the Tat peptide containing the RGD sequence, while uptake of higher concentrations of Tat is inhibited by the peptide encompassing the basic region of the protein. Thus, at least two pathways of Tat uptake exist: the first is via binding of the RGD region to integrins which is used by pico-nanomolar concentrations of active Tat and is blocked by integrin competitors, whereas the second pathway of Tat uptake is a relatively lower affinity pathway, is not blocked by the integrin antagonists, becomes predominant only when the concentrations of exogenous Tat are high and/or the time of incubation of the cells with Tat is prolonged, is blocked by the Tat basic peptide and occurs with all cell types. This second pathway may be identical to the receptor-independent pathway observed previously (Allen 2000; Barillari 1999b), via binding to a low affinity site, such as the interaction of the basic region of Tat with cell surface HSPG. Thus, Tat RGD region selectively targets cells expressing RGD-binding integrins receptors such as DC, endothelial cells and macrophages. Further, via this specialized pathway active Tat is very efficiently taken up. By this specialized pathway the inventor refers to a pathway that requires 1) at least one (RGD) or two Tat domains (basic and RGD), 2) the biological activity of the protein, 3) the native conformation of the protein, substantially in a monomeric form, and 4) integrin membrane receptors. In contrast, little or no uptake is observed with TCB, BLCL and monocytes or non-activated endothelial cells, indicating that. Tat can target and selectively deliver antigens or cargos to specific cell types that are key for the immune response against pathogens and tumors or to treat inflammatory and angiogenic diseases or tumors. The inventor stresses that according to her, biologically active Tat, but not oxidized Tat, upon binding to specific integrin receptors enters DC, endothelial cells and macrophages and even more importantly, promotes MDDC maturation and function. In fact, active Tat induces a dose-dependent enhancement of the surface expression of human leukocyte antigens (HLA)-ABC, HLA-DR, CD40, CD80, CD86 and CD83 on MDDC. This effect is observed with native but not with oxidized and inactivated Tat. In addition, active Tat induces a dose-dependent increase of the production of both IL-12 and TNF-α, cytokines essential for driving a Th-1 type response (Romagnani 1997), and of the β-chemokines RANTES, MIP-1α and MIP-1β which are key players in the effector phase of the lymphocyte response (Moser 2001). Importantly, in both cases the levels are comparable to those induced by the known activator LPS. Again, oxidized and inactivated Tat does not induce these effects. Active Tat also enhances the antigen presenting function of MDDC augmenting the proliferative response of T cells to allogeneic and recall antigens. Taken together these properties indicate that active Tat is not only an antigen but also a potent T cell adjuvant and delivery system to specific cells. The inventor believes that this feature is of a fundamental importance in inducing a specific type (Th-1) of immune response and in increasing this response against heterologous antigens. This also explains the reasons of why vaccination with the inactivated Tat induces different immune responses in vivo which are not protective. Since the induction of Th-1 responses and CTL controls infections by intracellular pathogens as well as tumor growth, the data presented indicate that native Tat protein or tat DNA can be exploited to drive or to increase Th-1 immune responses and CTL activity also against other HIV antigens or non-HIV antigens to support an effective and long-lasting immunity for preventive or therapeutic vaccination as well as to selectively deliver active molecules to DC, activated endothelial cells and macrophages for the treatment of infectious diseases, inflammatory and angiogenic diseases or tumors. In fact, activated endothelial cells, as well as macrophages and DC, are present in inflammatory and angioproliferative diseases, tumors and infectious diseases representing specific target for Tat which can selectively deliver to them antigens, inhibitory compounds or any molecule useful for preventive or therapeutic vaccination or treatment or for diagnostic purposes. Thus, according to the inventor, biologically active HIV-1 Tat, derivatives or fragments thereof, combined with other molecules including proteins, peptides, nucleic acids or support particles, can be used: to selectively deliver in vitro and in vivo antigens or active compounds to antigen-presenting cells expressing α5β1 and αvβ3 integrins, including DC, endothelial cells and macrophages in order to induce immune responses for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. as adjuvant, to activate or to enhance in vitro and in vivo the antigen-presenting function of cells expressing α5β1 and αvβ3 integrins including DC, activated endothelial cells and macrophages and to induce Th-1 type immune responses against HIV/AIDS, other infectious diseases and tumors. According to the present invention, HIV-1 Tat protein in its biologically active form, has the following amino acid sequence (SEQ ID NO. 2): NH2-MEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFHCQVCFITKALGIS YGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSRGDPTGPKE-COOH and HIV-2 Tat protein in its biologically active form, has the following amminoacid sequence, in which the RGD sequence has been inserted, for example, but not limited to, in position between amminoacid 92 and 93 of the original sequence (SEQ ID NO. 100): NH2-METPLKAPESSLKSCNEPFSRTSEQDVATQELARQGEEILSQLYRP LETCNNSCYCKRCCYHCQMCFLNKGLGICYERKGRRRRTPKKTKTHRGDP SPTPDKSISTRTGDSQPTKKQKKTVEATVETDTGPGR-COOH or the threonine at position 105 has been deleted (SEQ ID NO. 102): NH2-METPLKAPESSLKSCNEPFSRTSEQDVATQELARQGEEILSQLYRP LETCNNSCYCKRCCYHCQMCFLNKGLGICYERKGRRRRTPKKTKTHPSPT PDKSISTRGDSQPTKKQKKTVEATVETDTGPGR-COOH and any other Tat variant of any HIV-1 and HIV-2 subtype with a sequence homology greater than 50% to SEQ ID NO. 2, 100 or 102; preferably greater than 60%, more preferably greater than 70%, more preferably greater than 80%, more preferably greater than 90%, and in a substantially monomeric form, is able to fulfil at picomolar to nanomolar concentrations (from 0.01 ng/ml to 1 μg/ml, preferably 0.1 ng/ml to 100 ng/ml) at least one of the following criteria: (i) being selectively and efficiently taken up by antigen-presenting cells including-DC, endothelial cells and macrophages at picomolar nanomolar concentrations (0.01 to 1000 ng/ml) and within 5-10 minutes of exposure to cells. (ii) promoting the migration (recruitment), invasion and growth of cytokine-activated endothelial cells at picomolar-nanomolar concentrations. (iii) transactivating HIV gene expression or of rescuing Tat-defective HIV proviruses at nanomolar concentrations. (iv) activating the maturation and antigen presenting function of DC. (v) increasing T-cell mediated immune responses, including T-helper and/or cytotoxic activity against itself or heterologous antigens after addition to antigen-presenting cells. (vi) increasing T-cell mediated immune responses, including T-helper and/or cytotoxic activity against itself or heterologous antigens by addition to effector cells. Preferably criterium (i) or (ii), preferably both, should be fulfilled, more preferably criterium (i) or (ii) or both in combination with criterium (iii) a) and/or (iii) b) should be fulfilled. The best results will be obtained when all (i) to (vi) criteria are fulfilled. According to the present invention, HIV-1 tat DNA refers to the following nucleotide sequence (SEQ ID NO. 1): 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTGGAAGCATCCAGGAAG TCAGCCTAAAACTGCTTGTACCAATTGCTATTGTAAAAAGTGTTGCTTTC ATTGCCAAGTTTGTTTCATAACAAAAGCCTTAGGCATCTCCTATGGCAGG AAGAAGCGGAGACAGCGACGAAGACCTCCTCAAGGCAGTCAGACTCATCA AGTTTCTCTATCAAAGCAGCCCACCTCCCAATCCCGAGGGGACCCGACAG GCCCGAAGGAATGA 3′ and HIV-2 tat DNA refers to the following nucleotide sequence in which the sequence encoding the RGD has been inserted, for example, but not limited to, between nucleotides 276 and 277 of the original sequence (SEQ ID NO. 99): 5′ ATGGAGACACCCTTGAAGGCGCCAGAGAGCTCATTAAAGTCCTGCAA CGAGCCCTTTTCACGCACTTCAGAGCAGGATGTGGCCACTCAAGAATTGG CCAGACAAGGGGAGGAAATCCTCTCTCAGCTATACCGACCCCTAGAAACA TGCAATAACTCATGCTATTGTAAGCGATGCTGCTACCATTGTCAGATGTG TTTTCTAAACAAGGGGCTCGGGATATGTTATGAACGAAAGGGCAGACGAA GAAGGACTCCAAAGAAAACTAAGACTCATCGAGGGGACCCGTCTCCTACA CCAGACAAATCCATATCCACAAGGACCGGGGACAGCCAGCCAACGAAGAA ACAGAAGAAGACGGTGGAAGCAACGGTGGAGACAGATACTGGCCCTGGCC GATAG 3′ or the sequence ACC at position 322-324 encoding a threonine has been deleted (SEQ ID NO. 101): 5′ ATGGAGACACCCTTGAAGGCGCCAGAGAGCTCATTAAAGTCCTGCAA CGAGCCCTTTTCACGCACTTCAGAGCAGGATGTGGCCACTCAAGAATTGG CCAGACAAGGGGAGGAAATCCTCTCTCAGCTATACCGACCCCTAGAAACA TGCAATAACTCATGCTATTGTAAGCGATGCTGCTACCATTGTCAGATGTG TTTTCTAAACAAGGGGCTCGGGATATGTTATGAACGAAAGGGCAGACGAA GAAGGACTCCAAAGAAAACTAAGACTCATCCGTCTCCTACACCAGACAAA TCCATATCCACAAGGGGGGACAGCCAGCCAACGAAGAAACAGAAGAAGAC GGTGGAAGCAACGGTGGAGACAGATACTGGCCCTGGCCGATAG 3′ and any other variant of any HIV type and subtype with a sequence homology greater than 40% to SEQ ID NO. 1, 99, or 101 preferably greater than 50%, preferably greater than 60%, more preferably greater than 70%, more preferably greater than 80%, more preferably greater than 90%. According to the present invention, “fragments of biologically active Tat” are defined as Tat peptides, which correspond to the DNA sequence, from any HIV variant (HIV-1, HIV-2 and other types and subtypes) containing the RGD domain alone or associated with the the cystein-rich domain and/or the basic domain and/or other HIV-1 Tat peptides including the core domain and/or the amminoterminal region, where the RGD domain corresponds to the sequence coding for aa 73 to 86 in the HTLV-IIIB, clone BH-10, as a reference, SEQ ID NO. 3 and corresponding amminoacidic sequence, as a reference, SEQ ID NO.4; sequence coding for aa 74 to 84, SEQ ID NO. 5 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 6; sequence coding for aa 75 to 83, SEQ ID NO. 7 and corresponding amminoacidic sequence, as a reference, SEQ ID NO.8; sequence coding for aa 76 to 82, SEQ ID NO. 9 and corresponding amminoacidic sequence, as a reference, SEQ ID NO.10; sequence coding for aa 77 to 81, SEQ ID NO. 11 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 12; sequence coding for aa 77 to 82, SEQ ID NO. 13 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 14; sequence coding for aa 77 to 83, SEQ ID NO. 15 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 16; sequence coding for aa 76 to 83, SEQ ID NO. 17 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 18; the cystein-rich domain to the sequence coding for aa 22 to 37 in the HTLV-IIIB, clone BH-10, as a reference, SEQ ID NO. 19 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 20; the basic domain to the sequence coding for aa 48 to 61 in the HTLV-IIIB, clone BH-10, as a reference, SEQ ID NO. 21 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 22, the core domain to sequence coding for aa 38 to 47 in the HTLV-IIB, clone BH-10, as a reference, SEQ ID NO. 23 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 24 and the amminoterminal region to sequence coding for aa 1 to 20 in the HTLV-IIIB, clone BH-10, as a reference, SEQ ID NO. 25 and corresponding amminoacidic sequence, as a reference, SEQ ID NO. 26. 5′ CCCACCTCCCAATCCCGAGGGGACCCGACAGGCC SEQ ID NO. 3 CGAAGGAA 3′ PTSQSRGDPTGPKE SEQ ID NO. 4 5′ ACCTCCCAATCCCGAGGGGACCCGACAGGCCCG SEQ ID NO. 5 3′ TSQSRGDPTGP SEQ ID NO. 6 5′ TCCCAATCCCGAGGGGACCCGACAGGC 3′ SEQ ID NO. 7 SQSRGDPTG SEQ ID NO. 8 5′ CAATCCCGAGGGGACCCGACA 3′ SEQ ID NO. 9 QSRGDPT SEQ ID NO. 10 5′ TCCCGAGGGGACCCG 3′ SEQ ID NO. 11 SRGDP SEQ ID NO. 12 5′ TCCCGAGGGGACCCGACA 3′ SEQ ID NO. 13 SRGDPT SEQ ID NO. 14 5′ TCCCGAGGGGACCCGACAGGC 3′ SEQ ID NO. 15 SRGDPTG SEQ ID NO. 16 5′ CAATCCCGAGGGGACCCGACAGGC 3′ SEQ ID NO. 17 QSRGDPTG SEQ ID NO. 18 5′ TGTACCAATTGCTATTGTAAAAAGTGTTGCTTTC SEQ ID NO. 19 ATTGCCAAGTTTGT 3′ CTNCYCKKCCFHCQVC SEQ ID NO. 20 5′ GGCAGGAAGAAGCGGAGACAGCGACGAAGACCTC SEQ ID NO. 21 CTCAAGGC 3′ GRKKRRQRRRPPQG SEQ ID NO. 22 5′ TTCATAACAAAAGCCTTAGGCATCTCCTAT 3′ SEQ ID NO. 23 FITKALGISY SEQ ID NO. 24 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTGGA SEQ ID NO. 25 AGCATCCAGGAAGTCAGCCTAAAACT 3′ MEPVDPRLEPWKHPGSQPKT SEQ ID NO. 26 T-cell-epitopes according to the invention are preferably the following, in their nucleotide sequence and corresponding amino acid sequences (HTLV-IIIB, clone BH-10 or 89.6, as a reference): Epitope 1 (aa 1-20): 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTG SEQ ID NO. 27 GAAGCATCCAGGAAGTCAGCCTAAAACT 3′, MEPVDPRLEPWKHPGSQPKT, SEQ ID NO. 28 Epitope 2 (aa 11-24): 5′ TGGAAGCATCCAGGAAGTCAGCCTAAAACTGC SEQ ID NO. 29 TTGTACCAAT 3′, WKHPGSQPKTACTN, SEQ ID NO. 30 Epitope 3 (aa 21-40): 5′ GCTTGTACCAATTGCTATTGTAAAAAGTGTTG SEQ ID NO. 31 CTTTCATTGCCAAGTTTGTTTCATAACA 3′, ACTNCYCKKCCFHCQVCFIT, SEQ ID NO. 32 Epitope 4 (aa 36-50): 5′ GTTTGTTTCATAACAAAAGCCTTAGGCATCTC SEQ ID NO. 33 CTATGGCAGGAAG 3′, VCFITKALGISYGRK, SEQ ID NO. 34 Epitope 5 (aa 83-102): 5′ GGCCCGAAGGAACAGAAGAAGAAGGTGGAGAG SEQ ID NO. 35 AGAGACAGAGACAGATCCGGTCCATCAG 3′, 5 GPKEQKKKVERETETDPVHQ, SEQ ID NO. 36 Epitope 6 (aa 1-15): 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTG SEQ ID NO. 37 GAAGCATCCAGGA 3′, MEPVDPRLEPWKHPG, SEQ ID NO. 38 Epitope 7 (aa 6-20): 5′ CCTAGACTAGAGCCCTGGAAGCATCCAGGAAG SEQ ID NO. 39 TCAGCCTAAAACT 3′, PRLEPWKHPGSQPKT, SEQ ID NO. 40 Epitope 8 (aa 11-25): 5′ TGGAAGCATCCAGGAAGTCAGCCTAAAACTGC SEQ ID NO. 41 TTGTACCAATTGC 3′, WKHPGSQPKTACTNC, SEQ ID NO. 42 Epitope 9 (aa 16-30): 5′ AGTCAGCCTAAAACTGCTTGTACCAATTGCTA SEQ ID NO. 43 TTGTAAAAAGTGT 3′, SQPKTACTNCYCKKC, SEQ ID NO. 44 Epitope 10 (aa 21-35): 5′ GCTTGTACCAATTGCTATTGTAAAAAGTGTTG SEQ ID NO. 45 CTTTCATTGCCAA 3′, ACTNCYCKKCCFHCQ, SEQ ID NO. 46 Epitope 11 (aa 26-40): 5′ TATTGTAAAAAGTGTTGCTTTCATTGCCAAGT SEQ ID NO. 47 TTGTTTCATAACA 3′, YCKKCCFHCQVCFIT, SEQ ID NO. 48 Epitope 12 (aa 31-45): 5′ TGCTTTCATTGCCAAGTTTGTTTCATAACAAA SEQ ID NO. 49 AGCCTTAGGCATC 3′, CFHCQVCFITKALGI, SEQ ID NO. 50 Epitope 13 (aa 36-50): 5′ GTTTGTTTCATAACAAAAGCCTTAGGCATCTC SEQ ID NO. 51 CTATGGCAGGAAG 3′, VCFITKALGISYGRK, SEQ ID NO. 52 Epitope 14 (aa 41-55): 5′ AAAGCCTTAGGCATCTCCTATGGCAG GAAGA SEQ ID NO. 53 AGCGGAGACAGCGA 3′, KALGISYGRKKRRQR, SEQ ID NO. 54 Epitope 15 (aa 46-60): 5′ TCCTATGGCAGGAAGAAGCGGAGACAGCGAC SEQ ID NO. 55 GAAGACCTCCTCAA 3′, SYGRKKRRQRRRPPQ, SEQ ID NO. 56 Epitope 16 (aa 51-65): 5′ AAGCGGAGACAGCGACGAAGACCTCCTCAAG SEQ ID NO. 57 GCAGTCAGACTCAT 3′, KRRQRRRPPQGSQTH, SEQ ID NO. 58 Epitope 17 (aa 56-70): 5′ CGAAGACCTCCTCAAGGCAGTCAGACTCATCA SEQ ID NO. 59 AGTTTCTCTATCA 3′, RRPPQGSQTHQVSLS, SEQ ID NO. 60 Epitope 18 (aa 61-75): 5′ GGCAGTCAGACTCATCAAGTTTCTCTATCAAAG SEQ ID NO. 61 CAGCCCACCTCC 3′, GSQTHQVSLSKQPTS, SEQ ID NO. 62 Epitope 19 (aa 66-80): 5′ CAAGTTTCTCTATCAAAGCAGCCCACCTCCCAA SEQ ID NO. 63 TCCCGAGGGGAC 3′, QVSLSKQPTSQSRGD, SEQ ID NO. 64 Epitope 20 (aa 71-85): 5′ AAGCAGCCCACCTCCCAATCCCGAGGGGACCC SEQ ID NO. 65 GACAGGCCCGAAG 3′, KQPTSQSRGDPTGPK, SEQ ID NO. 66 Epitope 21 (aa 76-90): 5′ CAGTCCCGAGGGGACCCGACAGGCCCGAAGGA SEQ ID NO. 67 ACAGAAGAAGAAG 3′, QSRGDPTGPKEQKKK, SEQ ID NO. 68 Epitope 22 (aa 21-29): 5′ GCTTGTACCAATTGCTATTGTAAAAAG 3′, SEQ ID NO. 69 ACTNCYCKK, SEQ ID NO. 70 Epitope 23 (aa 26-34): 5′ TATTGTAAAAAGTGTTGCTTTCATTGC 3′, SEQ ID NO. 71 YCKKCCFHC, SEQ ID NO. 72 Epitope 24 (aa 31-39): 5′ TGCTTTCATTGCCTTGTTTGTTTCATA 3′, SEQ ID NO. 73 CFHCQVCFI, SEQ ID NO. 74 Epitope 25 (aa 36-44): 5′ GTTTGTTTCATAACAAAAGCCTTAGGC 3′, SEQ ID NO. 75 VCFITKALG, SEQ ID NO. 76 Epitope 26 (aa 41-49): 5′ AAAGCCTTAGGCATCTCCTATGGCAGG 3′, SEQ ID NO. 77 KALGISYGR, SEQ ID NO. 78 Epitope 27 (aa 46-54): 5′ TCCTATGGCAGGAAGAAGCGGAGACAG 3′, SEQ ID NO. 79 SYGRKKRRQ, SEQ ID NO. 80 Epitope 28 (aa 51-59): 5′ AAGCGGAGACAGCGACGAAGACCTCCT 3′, SEQ ID NO. 81 KRRQRRRPP, SEQ ID NO. 82 Epitope 29 (aa 56-64): 5′ CGAAGACCTCCTCAAGGCAGTCAGACT 3′, SEQ ID NO. 83 RRPPQGSQT, SEQ ID NO. 84 Epitope 30 (aa 61-69): 5′ GGCAGTCAGACTCATCAAGTTTCTCTA 3′, SEQ ID NO. 85 GSQTHQVSL, SEQ ID NO. 86 Epitope 31 (aa 66-74): 5′ CAAGTTTCTCTATCAAAGCAGCCCACC 3′, SEQ ID NO. 87 QVSLSKQPT, SEQ ID NO. 88 Epitope 32 (aa 71-79): 5′ AAGCAGCCCACCTCCCAATCCCGAGGG 3′, SEQ ID NO. 89 KQPTSQSRG, SEQ ID NO. 90 Epitope 33 (aa 76-84): QSRGDPTGP, SEQ ID NO. 91 5′ CAATCCCGAGGGGACCCGACAGGCCCG 3′, SEQ ID NO. 92 Epitope 34 (aa 81-89): 5′ CCGACAGGCCCGAAGGAACAGAAGAAG 3′. SEQ ID NO. 93 PTGPKEQKK. SEQ ID NO. 94 According to the present invention, “derivatives of Tat” include Tat mutants of the HTLV-IIIB, clone BH-10 variant, selected among the ones having the following: nucleotide sequences: Nucleotide sequence of cys22 mutant (SEQ ID NO. 95): 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTGGAAGCATCCAGGAAG TCAGCCTAAAACTGCTGGTACCAATTGCTATTGTAAAAAGTGTTGCTTTC ATTGCCAAGTTTGTTTCATAACAAAAGCCTTAGGCATCTCCTATGGCAGG AAGAAGCGGAGACAGCGACGAAGACCTCCTCAAGGCAGTCAGACTCATCA AGTTTCTCTATCAAAGCAGCCCACCTCCCAATCCCGAGGGGACCCGACAG GCCCGAAGGAATGA 3′ Amino acid sequence of cys22 mutant (SEQ ID NO. 96): NH2-MEPVDPRLEPWKHPGSQPKTAGTNCYCKKCCFHCQVCFITKALGIS YGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSRGDPTGPKE-COOH Nucleotide sequence of lys41 (SEQ ID NO. 97): 5′ ATGGAGCCAGTAGATCCTAGACTAGAGCCCTGGAAGCATCCAGGAAG TCAGCCTAAAACTGCTTGTACCAATTGCTATTGTAAAAAGTGTTGCTTTC ATTGCCAAGTTTGTTTCATAACAAACGCCTTAGGCATCTCCTATGGCAGG AAGAAGCGGAGACAGCGACGAAGACCTCCTCAAGGCAGTCAGACTCATCA AGTTTCTCTATCAAAGCAGCCCACCTCCCAATCCCGAGGGGACCCGACAG GCCCGAAGGAATGA 3′. Amino acid sequence of lys41 (SEQ ID NO. 98): NH2-MEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFHCQVCFITTA LGISYGRKKRRQRRRPPQGSQTHQVSLSKQPTSQSRGDPTGPKE-COOH Are considered within the scope of the present invention: DNA sequences having homology of at least 60% with the DNA sequences described in the above, preferably with homology of at least 70%, more preferably of at least 80%, more preferably of at least 90%. aminoacid sequences having homology of at least 40% with the aminoacid sequences described in the above, preferably with homology of at least 50%, preferably with homology of at least 60%, preferably with homology of at least 70%, more preferably of at least 80%, more preferably of at least 90%. According to the present invention, “Infectious diseases” include those caused by human or animal herpesviruses, hepatitis viruses, Mycobacterium Tuberculosis, Malaria plasmodia, Candida, Lysteria, Influenza virus and other infections caused in humans or animals by other intracellular or extracellular pathogens, including but not limited to, sexual infectious diseases, endocarditis, urinary tract infections, osteomyelitis, cutaneous infections, or streptococcus and staphylococcus infections, pneumococcus infections, tetanus, meningococcus infections, tuberculosis, malaria, candidosis, infections by Helicobacter, salmonella, syphilis, herpetic infections (including varicella, mononucleosis and Epstein-Barr-derived infections, human herpesvirus-8 infection, cytomegalovirus, herpes labialis and genitalis), hepatitis virus infection (A, B, C, D, G), papilloma virus-derived infections, influenza, lysteria, vibrio cholerae. According to the present invention, “inflammatory diseases” are defined as an allergy or inflammation associated or not with a viral, bacterial or parasitic infection, including but not limited to immune-mediated cutaneous diseases, Lupus erythematous systemic, rheumatoid arthritis, systemic sclerosis, dermatomiositis, Sjögren syndrome, Good pasture syndrome, vasculitis, sarcoidosis, osteoarthrosis, infectious arthritis, psoriasis, Chron disease, rectocolitis ulcerosus, tyroiditis, scleroderma, allergic diseases. According to the present invention, “angiogenic diseases” are defined as non-neoplastic angioproliferative diseases including diabetic retinopathy, retrolental fibroplasia, trachoma, vascular glaucoma, psoriasis, immune inflammation, non-immune inflammation, atherosclerosis, excessive wound healing, angiodermatitis, colon angiodisplasia, angioedema and angiofybromas. According to the present invention, “tumors” are defined as benign and malignant tumors including tumors of soft tissues, bones, cartilages and blood, such as, but not limited to, Kaposi's sarcoma and other neoplasia of the skin, lung, breast, gut, liver, pancreas, endocrine system, uterus, ovary, sarcomas, acute and chronic leukemia, and neoplasia of lymphatic cells. According to the present invention, “therapeutic compounds” are defined as other antigens (proteins, peptides or DNA) or active molecules According to the present invention, “support particles” are defined as, but not limited to, microparticles, nanoparticles, liposomes and other particulated delivery systems. According to the present invention, “non-HIV antigens or other antigens” includes any molecule or moiety recognized by immune cells with the exclusion of HIV antigens HIV-1 Tat, Rev, Nef, Gag. Tat according to the invention can be used to treat: infectious diseases, inflammatory diseases, angiogenic diseases, tumors. The Tat combinations as in the above can be mixed with adjuvants, diluents, eccipients, carriers and other substances known in the art to make medicaments for the scopes expressed. Such medicaments can be obtained in form of tablets, pills, sprays, injectable solutions, suspensions, powders, creams, ointments, for parenteral (subcute, intramuscular, intradermic), mucosal (vaginal, rectal, oral, nasal) administration or topical route with routes depending on the kind of disease and type of formulation. DETAILED DESCRIPTION OF THE FIGURES FIG. 1. Biologically active Tat is efficiently and selectively taken up in a dose- and time-dependent fashion by MDDC, but not by BLCL or TCB. A, MDDC were obtained from peripheral blood monocytes of 14 different healthy human donors according to established methods (Fanales Belasio 1997). Briefly, peripheral blood mononuclear cells (PBMC) were isolated by density gradient separation (Ficoll-Paque Research Grade, Pharmacia Biotech, Uppsala, Sweden). Monocytes were further purified by incubation with anti-CD14-coated microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany), followed by sorting with a magnetic device (MiniMacs Separation Unit, Miltenyi) according to the manufacturer's instructions. The purity of monocytes was always >95%, as assessed by flow cytometry (FACScan, Becton Dickinson, S. Jose, Calif.). Monocytes were induced to differentiate to DC (MDDC) by 6 days culture in complete medium in the presence of GM-CSF (200 ng/ml) (Leucomax, Novartis, Origgio, Italy) and IL-4 (100 ng/ml) (Peprotech, London, UK). Differentiation to DC was assessed by morphologic observation and by the detection of specific surface markers (HLA-DR, CD86, CD83, CD40, CD80) by flow cytometry. MDDC were then cultured at the density of 2×105 per ml in complete medium in the presence of serial concentrations (0.1 to 10,000 ng/ml) of active HIV-1 Tat or with reconstitution buffer or medium alone (negative controls) for 5, 10, 30 or 60 min at 37° C. in the dark. Tat protein was expressed from E. coli and purified as previously described (Ensoli 1993; Chang 1997; Ensoli 1994) and tested prior to use by cell growth assays and HIV-LTR transactivation, as described (Ensoli 1993; Chang 1997; Ensoli 1994). Tat protein was resuspended in degassed phosphate buffered saline, 0.1% bovine serum albumin (PBS-BSA). Precautions were taken to avoid oxidation and loss of activity of Tat as described elsewhere (Ensoli 1993; Chang 1997; Ensoli 1994). Cells were then washed with cold medium and treated for 10 min at 37° C. with trypsin-EDTA (Life-Technologies, Paisley, UK) to remove any externally bound protein. After fixation and permeabilization, MDDC were stained with affinity-purified rabbit polyclonal anti-Tat IgG antibodies (Ensoli 1993; Chang 1997; Ensoli 1994) or rabbit IgG control antibodies (ICN Biomedicals, Opera, Italy), followed by FITC-conjugated anti-rabbit Ig (Pierce, Rockford, Ill.). Fluorescence was analysed by flow cytometry and results expressed as the percentage of positive cells as compared to isotype-stained samples. To demonstrate the specific intracytoplasmatic localization of the protein, staining with anti-Tat antibodies was always performed also with non-permeabilized MDDC. The percentage of positive cells (as compared to isotype stained samples) is reported into the boxes. Data shown are from one representative donor out of 14 tested, whose levels of Tat uptake were the closest to the median of the values observed with all donors tested at both 10 min (49%, 52%, 49%, 70%, 94%, 98% positive cells for 0.1, 1, 10, 100, 1000 and 10,000 ng/ml) and 30 min (49%, 45%, 54%, 65%, 95%, 98% positive cells for 0.1, 1, 10, 100, 1000 and 10,000 ng/ml), respectively. B, MDDC were incubated with the active Tat protein (10 to 1000 ng/ml) for 10 or 30 min, as reported above and both permeabilized or non permeabilized cells were analyzed by FACS to demonstrate specific uptake of Tat. C, BLCL (circles) were generated by culturing human PBMC from 2 healthy donors for 2 h in the presence of supernatants from the Epstein-Barr virus producer B95-8 marmoset cell line, and further expansion for at least 4 weeks as described earlier (Micheletti 1999). TCB (triangles) were obtained by stimulation of human PBMC from 4 healthy donors with phytohemagglutinin (PHA) 1 μg/ml (Murex Diagnostics, Chatillon, France) for 3 days and further expansion for 2 weeks in complete medium supplemented with rIL-2 10 IU/ml (Becton Dickinson Labware, Bedford, Mass.) as described earlier (Micheletti 1999). BLCL and TCB were cultured at 5×105/ml in complete medium in the presence of active Tat at concentrations ranging from 100 to 10,000 ng/ml, reconstitution buffer or medium alone for 30 or 60 min at 37° C. in the dark and stained for intracellular Tat detection as reported above. Data are compared with those of MDDC (squares) cultured for the same times and with the same doses of the protein and chosen as a representative example since the levels of Tat uptake with this donor were very close to the median from 11 different donors tested (54%, range 17-91%, 65%, range 27-91%, and 95%, range 83-99%, of positive cells, at 10, 100 and 1,000 ng/ml of Tat, after 30 min of culture, respectively). FIG. 2. Uptake of biologically active Tat by MDDC increases with cell maturation and it is lost by oxidation and inactivation of the protein. A, MDDC were or were not induced to maturation with LPS for 18 h, and then incubated for 10 and 30 min in the presence of the active Tat protein (1 to 1000 ng/ml) as reported above. The data shown are from a donor who had lower uptake levels than the median values of all donors tested and that was chosen because well illustrates the increase of Tat uptake induced by cell maturation. B, MDDC were incubated for 10 min in the presence of active or oxidized (by exposure to light and air for 18 h) Tat protein (10 to 1000 ng/ml) and processed as reported above. The biological activity of native versus oxidized Tat used in the experiments is reported in Table I. FIG. 3. Anti-α5β1 and anti-αvβ3 antibodies block uptake of active Tat by MDDC. MDDC were incubated (5×105/ml) in complete medium [RPMI 15% fetal bovine serum (FBS)] in the presence of monoclonal antibodies directed against the α5β1 and αvβ3 integrins (10 □g/ml, Chemicon, Temecula, Calif.), alone or combined, for 2 h at 4° C. Subsequently, active Tat protein was added at doses ranging from 0.1 to 1000 ng/ml, for 10 min at 37° C. in the dark. After washing with cold complete medium, cells were processed and stained as described in FIG. 1. Data from a representative donor out of three are shown. A, Flow cytometric analysis of MDDC stained with anti-Tat antibodies. The percentage of positive cells (as compared to isotype stained samples) is reported into the boxes. The uptake of Tat is detected at all doses of the protein (up to 99% at 1000 ng/ml), whereas it is inhibited by preincubation of the cells with anti-α5β1 or anti-αvβ3 antibodies. The presence of both antibodies completely abolishes the uptake of picomolar concentrations of Tat and strongly reduces it up to the highest dose tested (21%). B, the same data are represented in a dot-plot to better appreciate the inhibitory effects of antibodies to β5β1 or αvβ3 integrins on Tat uptake by MDDC. FIG. 4. Fibronectin and vitronectin block the uptake of active Tat by MDDC. MDDC (5×105/ml) were incubated in complete medium (RPMI 15% FBS) in the presence of human plasma-derived FN or VN (25 μg/ml, Sigma-Aldrich, Stenheim, Germany), for 2 h at 4° C. Tat protein was then added at doses ranging from 10 to 1000 ng/ml, for 10 min at 37° C. in the dark. After washing with cold complete medium, cells were processed and stained as described in FIG. 1. Data from a representative donor out of three are shown. A, Flow cytometric analysis of MDDC stained with anti-Tat antibodies. The percentage of positive cells (as compared to isotype stained samples) is reported into the boxes. The uptake of Tat is detected at all doses of the protein (up to 99% at 1000 ng/ml). When cells are pre-incubated with FN or VN the uptake is greatly reduced and completely abolished at the lowest doses of Tat (1% and 2%, respectively, at 10 ng/ml). B, the same data are represented in a dot plot to better appreciate the inhibitory effects of FN and VN on Tat uptake by MDDC. FIG. 5. Active Tat is efficiently taken up in a dose- and time dependent fashion by macrophages but not by monocytes. A, Peripheral blood monocytes, enriched from PBMC upon 2 h of adherence on plastic plate wells, were incubated with Tat at doses ranging from 0.1 to 10,000 ng/ml for 60 min at 31° C. in the dark and processed and stained as described for MDDC in FIG. 1. A, Flow cytometric analysis of cells stained with anti-Tat antibodies are shown. The percentage of positive cells (as compared to isotype stained samples) is reported into the boxes. A significant uptake of Tat is detected only at the highest doses (45% and 67% at 1000 and 10,000 ng/ml, respectively) with some levels of protein attached to the cell surface (19% and 33% at 1000 and 10,000 ng/ml on non-permeabilized cells, respectively). B, Six days-old monocyte-derived macrophages (MDM) were incubated with Tat at doses ranging from 0.1 to 10,000 ng/ml for 60 min at 37° C. in the dark and processed and stained as described for MDDC in FIG. 1. The uptake of Tat is detected in the range from 10 to 10,000 ng/ml, with a proportion of positive cells ranging from 32% to 72%, respectively. However, at the highest dose (10,000 ng/ml) a substantial amount of the Tat protein is localized at the cell surface, as demonstrated by the 30% staining of non-permeabilized MDM. C, six days-old MDDC from the same donor were incubated with Tat at doses ranging from 0.1 to 1000 ng/ml for 10 and 30 min at 37° C. in the dark and processed and stained as described in FIG. 1. The uptake of Tat is detected at all the concentrations of the protein at levels higher than those from monocytes and macrophages from the same donor (80% and 73% at the dose of 1000 ng/ml after 10 and 30 min, respectively) without any detected binding to the cell membrane. FIG. 6. HIV-1 Tat protein, functional domains thereof and Tat peptides. Schematic representation of the HIV-1 Tat protein, both the 86 and 102 aminoacids long naturally occurring variants, with its functional domains (A) and of the sequences (based on the clade B consensus sequence) of the 15 and 38 aminoacids long peptides (indicated as 15mers and 38mers in panel B and C, respectively) utilized. FIG. 7. Uptake of Tat is differently affected by Tat peptides be ring the RGD or basic region. A, MDDC incubated for 2 h at 4° C. in the presence of couples of 15-mer Tat peptides (as defined in FIG. 6, panel B) spanning different regions of the protein: N-terminal (1-15 plus 6-20), cysteine rich (21-35 plus 26-40) basic (46-60 plus 51-65) or RGD sequence (66-80 plus 71-85) before the addition of Tat (0.1 to 1,000 ng/ml) for 30 min at 37° C. B and C, MDDC were pre-treated with the 15-mer Tat peptides 46-60 and 66-80, alone or combined at doses ranging from 400 to 50,000 ng/ml, before the addition of Tat at 10 (B) or 1000 ng/ml (C) for 10 min at 37° C. D, MDDC were incubated for 2 h at 4° C. in the presence of 38/46-mer Tat peptides (1-38, 21-58, 47-86, 57-102) covering different regions of the protein (as defined in FIG. 6, panel C), before the addition of Tat protein (0.1 to 1,000 ng/ml) for 10 min at 37° C. In all the cases the intracellular staining for Tat was then performed as reported above. Data are expressed as the means (and SEM) of the percentages of Tat-positive cells from three different donors. FIG. 8. Rhodaminated active Tat is taken up in a dose-dependent fashion by cytokine-activated endothelial cells. Human umbilical vein endothelial cells (HUVEC) were activated by culturing them for 5-6 days in the presence of conditioned media from CD4+ cells transformed by the human T-lymphotropic virus type-II (HTLV-II) or stimulated with PHA, as described previously (Ensoli 1990; Barillari 1992 and 1993; Fiorelli 1999). These conditioned media contain the same inflammatory cytokines (IC) including IL-1, TNF and interferon γ (IFNγ), which activate endothelial cells during inflammation or reparative processes. In particular, IL-1, TNF and/or IFNγ induce in endothelial cells the expression of the integrin receptors α5β1 and αvβ3 (Barillari 1993; Fiorelli 1999). After 5-6 days of culture, HUVEC were suspended by trypsinization, washed with trypsin inhibitors, plated on 8 well chamber slides (Nunc Inc. Naperville, Ill.) at 5×104 cells/well and cultured in RPMI medium (Life Technologies, Eragny, France) containing 15% FBS, in the absence of conditioned media, for 18 hrs. After that time, cells were washed with serum free RPMI and then cultured at 37° C. in a CO2 incubator for 15′ in serum-free RPMI containing serial dilutions of biologically active Tat protein which was rhodaminated at lysine residues essentially as described (Mann 1991). Briefly, 50 μg recombinant Tat (2 mg/ml), was brought to pH 9.0 by the addition of 2.5 μl of 1 M Na2CO3. Then, 2.5 μl of 1 mg/ml tetramethylrhodamine isothiocyanate (TRITC, Chemical Co., St. Louis, Mo.) in dimethylsulfoxide (DMSO) was added and the reaction allowed to proceed for 8 h at 4° C. Unreacted TRITC was quenched by the addition of 2.5 μl of 0.5 M NH4Cl, the pH was lowered to 7.0, using 1 M HCl, and the rhodaminated Tat was dialyzed against two changes of 50 nM Tris-HCl, pH 7.0, 1 mM dithiothreitol (DTT) to remove the quenched TRITC. BSA or PBS, rhodaminated in the same way, were used as negative controls. Rhodaminated Tat was tested for KS cells growth activity as described (Ensoli, 1990) to ensure that the biological activity was maintained. Tat resuspension buffer (PBS-0.1% BSA) was rhodaminated in the same way and employed as negative control. HUVEC were then fixed in ice-cold acetone-methanol (1:1). The uptake and the intracellular distribution of Tat were observed and photographed using a fluorescence microscopy. Results were evaluated by comparing the fluorescence of sample with the negative control and scored from—(negative) to ++++ (highly positive) on the amount of uptake without prior knowledge of sample code. Incubation were with: buffer (PBS-0.1% BSA), panel A; Tat 10 ng/ml, panel B; Tat 100 ng/m (, panel C; Tat 1 μg/ml, panel D. FIG. 9. Time-course analysis of uptake of 100 ng/ml rhodaminated active Tat by cytokine-activated endothelial cells. HUVEC were activated and plated on 8-well chamber slides as described in the legend to FIG. 8. Cells were then exposed to 100 ng/ml of rhodaminated Tat for the periods of time indicated below. BSA (fraction V, Sigma) was rhodaminated in the same way as for Tat and employed as negative control. Incubations were with: Tat 100 ng/ml, 15′ exposure, panel A; BSA, 15′ exposure, panel B; Tat 100 ng/ml, 60′ exposure, panel C; BSA, 60′ exposure, panel D. FIG. 10. Time-course analysis of uptake of 1 μg/ml rhodaminated active Tat by cytokine-activated endothelial cells. Cytokine-activated HUVEC were treated as described in FIG. 8, then incubated with 1 μg/ml rhodaminated Tat for 15 minutes, panel A; 30 minutes, panel B; 60 minutes, panel C; 120 minutes, panel D. FIG. 11. Dose-response analysis of uptake of active Tat protein by cytokine-activated endothelial cells versus non activated cells. HUVEC (7×104 cells/well in 6-well gelatinized plates) were grown in complete medium as described above (legend to FIG. 8) and incubated for 5 days in the presence (IC-EC) or in the absence (EC) of combined recombinant inflammatory cytokines (IFNγ 10 U/ml, IL-1β 5 ng/ml, TNF-a 2 ng/ml). Cells were then washed twice and incubated in 1 ml of RPMI 1640 containing 15% FCS in the presence or absence of serial dilutions of active Tat protein (0.01 to 1000 ng/ml) or Tat dilution buffer (PBS containing 0.1% BSA) for 10′ at 37° C. in the dark. Cells were then washed with cold RPMI 1640, trypsinized, fixed for 10′ at 4° C. with FACS lysing solution (Becton Dickinson), exposed for 30′ at 4° C. to permeabilizing solution (Becton Dickinson), stained with rabbit anti-Tat antibodies or rabbit IgG control antibodies and analyzed by FACS, as described for MDDC (legend to FIG. 1). Uptake of native Tat is increased in cytokine-activated cells as compared to non-activated cells. The percentage of positive cells after 10′ incubation with increasing concentration of native Tat protein in a representative experiment out of 3 performed is shown. FIG. 12. Dose- and time-course analysis of uptake of active Tat by cytokine-activated endothelial cells. Cells were activated and uptake experiments performed as described in FIG. 11. Incubation were for 5′, 10′, 30′ or 60′. In addition, to demonstrate the specific intracytoplasmatic localization of the protein, staining with anti-Tat antibodies was also performed with non-permeabilized HUVEC. Uptake of native Tat by activated endothelial cells is time- and dose-dependent, and is already detected at concentrations as low as 0.01 ng/ml. The percentage of positive cells (as compared to isotype antibodies stained samples) is reported into the boxes. Data are from one representative experiment out of 4 performed. FIG. 13. Inhibition of uptake of 10 ng/ml rhodaminated active Tat by cytokine-activated endothelial cells with unlabelled Tat protein. Cytokine-activated HUVEC were treated as described in FIG. 8, preincubated in serum free medium, containing buffer or 1 μg/ml unlabelled Tat, and then incubated for 15 minutes at 37° C. with 10 ng/ml rhodaminated Tat or rhodaminated BSA. Panel A, preincubated with buffer, incubated with BSA. Panel B, preincubated with buffer, incubated with Tat. Panel C, preincubated with 1 μg/ml unlabelled Tat, incubated with Tat. FIG. 14. Inhibition of uptake of 10 ng/ml rhodaminated active Tat by cytokine-activated endothelial cells with anti-α5β1 and anti-αvβ3 antibodies. HUVEC were activated with conditioned media from PHA-stimulated or HTLV II-transformed T cells (IC-HUVEC) and seeded onto 8 well chamber slides as described in the legend to FIG. 8. IC-HUVEC were then incubated in serum free medium on a rotating device for 2 h at 4° C. with monoclonal antibodies directed against the a chain of the α5β1 receptor (anti-CD49wE, Chemicon Inc. Temecula, Calif.) and P chain of the α5β1 receptor receptor (anti-CD29, Chemicon), or the a chain of the αvβ3 receptor (anti-CD51, Chemicon), and β chain of the αvβ3 receptor (anti-CD61, Chemicon). Monoclonal antibodies directed against the endothelial cell marker factor Vil related antigen (anti-FVIIIRA, Chemicon) were employed as control of specificity. All antibodies were employed at 5 μg/ml. Antibody dilution buffer (PBS containing 0.1% BSA) was employed as a negative control. After preincubation with antibodies, 10 ng/ml of rhodaminated Tat was added to the cells. Rhodaminated BSA was employed as negative control. IC-HUVEC were kept for 15′ at 37° C. in a CO2 incubator and then fixed in ice-cold acetone-methanol (1:1). The uptake and the intracellular distribution of Tat were-observed and photographed using fluorescence microscopy. Results were evaluated by comparing the fluorescence of sample with the negative control and scored from—(negative) to ++++ (highly positive) on the amount of uptake without prior knowledge of sample code. Panel A, preincubated with buffer, incubated with BSA. Panels B, preincubated with buffer, incubated with Tat. Panel C, preincubated with anti-α5 and anti-β1 monoclonal antibodies, incubated with Tat. Panel D, preincubated with anti-αv and anti-β3 monoclonal antibodies, incubated 1:5 with Tat. Panel E, preincubated with anti-human factor VIII antibodies (control antibodies), incubated with Tat. FIG. 15. Inhibition of uptake of 100 ng/ml rhodaminated active Tat by cytokine-activated endothelial cells with anti-α5β1 and anti-αvβ3 antibodies. IC-HUVEC were treated as described in FIG. 8, then preincubated in serum free medium, containing buffer or antibodies, then incubated for 15 minutes at 37° C. with 100 ng/ml rhodaminated Tat or rhodaminated BSA. Panel A, preincubated with buffer, incubated with BSA. Panel B, preincubated with buffer, incubated with Tat. Panel C, preincubated with monoclonal antibodies against the α and β chains of the α5β1 integrin and incubated with Tat. Panel D, preincubated with monoclonal antibodies against the a and 1 chains of the αvβ3 integrin and incubated with Tat. Panel E, preincubated with anti-human factor VIII antibodies (control antibodies), incubated with Tat. FIG. 16. Uptake of 1 μg/ml rhodaminated active Tat is partially inhibited by anti-α5β1 and anti-αvβ3 antibodies when cells are incubated with Tat for 15 minutes. HUVEC were activated as described in FIG. 8, preincubated with anti-α5 and anti-β1 or anti-αv and anti-β3 monoclonal antibodies, or buffer, and then incubated with 1 μg/ml rhodaminated Tat or rhodaminated BSA for 15 minutes at 37° C. Panel A, preincubated with buffer, incubated with BSA. Panel B, preincubated with buffer, incubated with Tat. Panel C, preincubated with anti-α5 and anti-β1 monoclonal antibodies, incubated with Tat. Panel D, preincubated with anti-αv and anti-β3 monoclonal antibodies, incubated with Tat. FIG. 16. Uptake of 1 μg/ml rhodaminated active Tat is not inhibited by anti-integrin antibodies when cells are incubated with Tat for 60 minutes. HUVEC were activated as described in FIG. 8, preincubated with anti-α5 and anti-β1 or anti-αv and anti-β3 monoclonal antibodies, or buffer, and then incubated with 1 μg/1 ml rhodaminated Tat for 60 minutes at 37° C. Panel A, preincubated with buffer, incubated with Tat. Panel B, preincubated with anti-α5 and anti-β1 monoclonal antibodies, incubated with Tat. Panel C, preincubated with anti-αv and anti-β3 monoclonal antibodies, incubated with Tat. FIG. 18. Active Tat enhances the production of the cytokines IL-12 and TNF-α, and of the β-chemokines MIP-1α, MIP-1β and RANTES by MDDC. MDDC from 8 donors were cultured at the density of 2×105 per ml for 18 h in complete medium in the absence or presence of serial concentrations (20 to 20,000 ng/ml) of native or oxidized Tat. Tat reconstitution buffer was employed as negative control. LPS from E. coli, serotype 055: B5 (10 μg/ml, Sigma-Aldrich, Milano, Italy) was used as the positive control. After 18 h the cell supernatants were collected and assayed for the presence of TNF-α, IL-12, RANTES, MIP-1α and MIP-1β with commercially available kits according to the manufacturer's instructions (Cytoscreen TNF-alpha and IL-12 ELISA kits, Biosource Europe, Nivelle, Belgium; Quantikine RANTES, MIP-1α and MIP-1β R&D Systems Europe, Abingdon, UK). Grey, empty and black symbols represent values from cells treated with Tat, buffer or LPS, respectively. Data are reported as the mean values (±SEM) from the eight different donors and are expressed in pg/ml. A very poor cytokine or β-chemokine production was induced by oxidized-inactivated Tat protein. FIG. 19. Active Tat enhances allogeneic antigen presentation by MDDC. MDDC (2×105 cells/ml) were incubated for 18 h with LPS (positive control) (filled circles), active Tat protein (10 μg/ml) (filled triangles), reconstitution buffer (empty triangles) or culture medium (empty circles). Then, they were washed and cultured in medium (containing 5% FBS) in 96 wells plates together with monocyte-depleted allogeneic PBL (2×105/well) at ratios ranging from 1:10 to 1:640. To evaluate lymphocyte proliferation, after 6 days 3[H]-thymidine was added to the wells for an additional 16 h and samples harvested onto glass fibre filters (Printed Filtermat A, Wallac, Turku, Finland), counted with a Betaplate (Wallac) and the values expressed in cpm. Data are from a representative experiment and have been reproduced with 3 other donors. Means and SEM are reported. FIG. 20. Active Tat increases TT-specific presentation by MDDC to primed PBL enhancing specific T cell responses. MDDC (2×105 cells/ml) from 3 healthy donors, two responsive (B16 and B42) and one unresponsive (B45) to TT in proliferation assays, were incubated for 18 h with active Tat protein (10 μg/ml), reconstitution buffer or culture medium, and then cultured in complete medium (containing 5% FBS), together with autologous PBL (2×105/well) at a ratio of 1:20 in the absence (empty columns) or in the presence (grey columns) of 5 μg/ml TT (Connaught, Willowdale, Canada). To evaluate lymphocyte proliferation, after 6 days 3[H]-thymidine was added for an additional 16 h, samples harvested and cpm counted as reported above. Data are represented as stimulation indexes (S.I.) that indicates the ratios between counts from DC-PBL co-cultures versus those from PBL alone. FIG. 21. Prime-boost vaccine protocol to evaluate the adjuvant activity of biologically active Tat protein. Two groups of Balb/c mice were utilized. The first group (arm 1) was immunized twice intradermally with Gag alone (priming) and subsequently twice intranasally with Gag associated to the mucosal adjuvant Malp-2 (boosting). The second group (arm 2) was immunized twice intradermally with Gag and Tat mixed together (priming) and subsequently twice intranasally with Gag mixed with Tat and associated to the mucosal adjuvant Malp-2 (boosting). The vaccinations were performed at the time indicated. FIG. 22. Antibody response against Gag. Anti-Gag antibodies were measured in the serum from mice of both arms by a commercial Elisa (ELAVIA AB HIV2, BIO-RAD Laboratories Sri, MI, Italy) according to the manufacturer's instructions. The sera were diluted 1:100 before testing. The cut-off value was an optical density of 0.3. FIG. 23. Anti-Gag cytolytic activity. Splenocytes from mice from both arms were stimulated in vitro with Gag peptides for 6 days in the presence of IL-2 (Effectors) and thereafter incubated with p815 cells pulsed with Gag peptides and labeled with 51Cr (Targets), at the indicated ratios. The specific lysis was determined according to standard methodology. The spontaneous 51Cr release did not exceed 10% of the maximum release. A specific 51Cr release above 10% was considered positive. The following examples are given to better illustrate the invention and are not to be considered as limiting the scope thereof. EXAMPLE 1 Active Tat is Efficiently Taken Up by MDDC But Not by TCB and BLCL The uptake of active Tat by MDDC, TCB and BLCL was evaluated by intracellular immunofluorescence in flow cytometry, using a specific affinity-purified polyclonal antibody on permeabilized cells. FIG. 1 shows the results of a representative donor whose levels of Tat uptake represented the median of the values obtained from 14 donors tested. Tat uptake by MDDC was very efficient and occurred in a dose- and time-dependent fashion (FIG. 1A). Uptake was already evident with the lowest dose of Tat utilized (0.1 ng/ml). Regardless of the Tat concentration tested, the level of staining always peaked after 5 min of incubation and was reduced after 60 min, likely due to the processing of the protein. However, uptake of Tat remained high (98%) up to 60 min of incubation at the highest dose of Tat (10 μg/ml) utilized. No staining was observed with cells incubated in medium alone or reconstitution buffer (FIG. 1A). In addition, the Tat detected was almost entirely intracellular since no staining was observed after 10 min or 30 min of incubation of Tat with non-permeabilized cells (FIG. 1B). Similar dose- and time-kinetic of Tat uptake by MDDC was reproducibly observed with different protein lots. In contrast to MDDC, uptake of active Tat by TCB and BLCL was much less efficient. In fact, little or no specific intracellular staining was observed with both cell types at concentrations of Tat up to 10 μg/ml after 30 or 60 min of incubation with values, at the highest dose of Tat, much lower than those obtained with MDDC (0-15% and 3-10% for BLCL and TCB, respectively, versus 98%) (FIG. 1C). Thus, efficient uptake of active Tat is a selective feature of MDDC. EXAMPLE 2 Uptake of Active Tat by MDDC Increases With Cell Maturation and is Lost By Oxidation and Inactivation of the Protein Immature MDDC take up antigens by phagocytosis and pinocytosis (Bankereau 1998; Bell 1999). Mature DC lose these activities while acquiring strong antigen presentation capability. To verify whether cell maturation affects the uptake of native Tat, MDDC were induced to maturate with LPS. As compared to immature MDDC, mature MDDC expressed higher levels of HLA-DR, CD83 and CD86 surface markers. Both immature or mature cells were then used for the uptake experiments. Tat uptake was highly increased by MDDC maturation at all protein concentrations tested (FIG. 2A). In fact, incubation of mature MDDC with low Tat concentrations gave levels of intracellular staining similar to those observed in immature cells with the highest doses of Tat (FIGS. 1A and 2A). Tat contains 7 cysteins, and is extremely sensitive to oxidation which causes conformational changes and loss of biological activity. To verify the role of conformation and biological activity of Tat in the uptake process by MDCC, the protein was exposed to air and light, the loss of biological activity tested (Table I), and active or inactive Tat protein were then compared in the uptake experiments. As shown in FIG. 2B, no staining was observed with oxidized Tat up to 1 μg/ml of the protein, and, at this concentration, only a very low Tat specific staining was detected as compared to native Tat. Thus, Tat must have native conformation and biological activity for efficient uptake by MDDC. Since MDDC maturation, that is associated with a reduced pino/phagocytic activity, increases Tat uptake, whereas oxidation and inactivation of the protein greatly reduces it to levels comparable to those observed with BLCL and TCB, it is conceivable that uptake of native Tat by MDDC is mediated by specific receptors and entry mechanisms that are not related to the pino/phagocytic activity of the cells, but are increased upon MDDC maturation. TABLE I Oxidation of Tat abolishes its biological activity Tat (ng/ml) Cell line Buffer 500 1,000 2,500 5,000 10,000 HLM-1 14 434 491 971 1507 5028 native 19 21 22 40 34 117 oxidized HL3T1 0 29 34 79 81 187 native 0 3 2 2 4 6 oxidized Tat was oxidized by exposure to air and light for 18 h. Biological activity of the native and oxidized protein was then tested (at doses from 500 to 10,000 ng/ml) by measuring the capacity of rescuing the replication of Tat-defective HIV provirus in the HLM-1 cell line # (Ensoli 1993; Chang 1997) or of inducing CAT activity in the HL3T1 cell line containing the LTR-CAT construct (Felber 1988). Values of the p24 (pg/ml) from culture supernatants of HLM-1 cells and CAT activity from HL3T1 cell extracts (% acetylation/100 μg of protein) are reported. EXAMPLE 3 Block of Active Tat Uptake by MDDC With Anti-α5β1 and Anti-αvβ3 Monoclonal Antibodies or With Their Natural Ligands FN or VN. To verify whether uptake of native Tat by MDDC follows a specific receptor-mediated endocytic pathway, experiments were carried out with specific monoclonal antibodies or competitor ligands directed against the integrin receptors α5β1 and αvβ3. These receptors were chosen among the several receptors binding Tat on different cell types, since they are highly expressed by activated endothelial cells and KS cells that proliferate, migrate and adhere in the presence of Tat and this is mediated by the binding of the RGD region of Tat to the α5β1 and αvβ3 integrins. As shown in FIG. 3A, B, Tat uptake by MDDC is inhibited by both anti-α5β1 and anti-αvβ3 monoclonal antibodies and the block is complete in the presence of both antibodies (FIG. 3A, B). The natural ligands for these receptors, namely FN and VN, block Tat uptake in a similar fashion (FIG. 4A, B). Thus, α5β1 and αvβ3 integrins mediate Tat entry in MDDC. This pathway of uptake is predominant at picomolar-nanomolar concentrations of the protein, whereas at higher Tat concentrations block of Tat entry is still evident but is not complete (FIGS. 3A and B). This indicates that MDDC use at least two pathways for Tat uptake, the first one occurring at low Tat concentrations (picomolar-nanomolar) is an integrin-mediated endocytosis, whereas at higher Tat concentration a low affinity cell surface interaction is also present. EXAMPLE 4 Active Tat is Efficiently Taken Up in a Dose- and Time-Dependent Fashion By Both MDM and MDDC But Not By Monocytes. Since MDDC derive from monocytes and since monocytes and MDM are known to efficiently present antigens to lymphocytes, uptake of active Tat from these cells was analysed and compared to that of MDDC from the same donors. Monocytes were purified from peripheral blood and induced to differentiate to MDDC or MDM (as described in FIG. 1 and FIG. 5). As shown in FIG. 5, monocytes took up active Tat only at the highest doses (45% and 67% at 1,000 and 10,000 ng/ml, respectively) with evidence of binding of the protein to cell surface (19% and 33%, respectively, on non-permeabilized cells). MDM took up Tat more efficiently than monocytes, with staining detectable at relatively low doses (32% and 43% at 10 ng/ml and 100 ng/ml, respectively) up to the highest dose of Tat tested (72% at 10,000 ng/ml) when surface binding of the protein (30% on non-permeabilized cells) was observed. MDDC from the same donor took up Tat more efficiently with specific staining detected already at the lowest dose tested (0.1 ng/ml) than monocytes and MDM both at 10 min and 30 min (22% and 13%, respectively). At the highest dose (1000 ng/ml) 80% and 73% of MDDC were positive after 10 and 30 min of exposure to Tat, respectively. At all the doses of the protein MDDC and MDM took up Tat markedly more efficiently than monocytes. Since both MDDC and MDM differentiate from monocytes, these data indicate that cell differentiation provides the cells with specific Tat protein targeting and uptake mechanisms. EXAMPLE 5 Inhibition of the Uptake of Active Tat by Peptides Encompassing the Basic Region and the RGD Domain of the HIV-1 Tat Protein. To verify which domain of Tat is responsible for the uptake of of the biologically active protein, blocking experiments were performed by preincubating MDDC with the Tat peptides (15mers) spanning the N-terminal region (1-15 plus 6-20), cysteine-rich region (21-35 plus 2640), the basic region (46-60 plus 51-65), RGD region (66-80 plus 71-85)(FIG. 6, panel A and B). Peptides spanning the N-terminal and cysteine-rich region did not affect the uptake of Tat at any of the doses tested (0.1-1,000-ng/ml) (FIG. 7, panel A). Peptides spanning the basic region markedly reduced the uptake of Tat at high doses (100 and 1000 ng/ml), but did not affect the uptake of lower concentrations (0.1-10 ng/ml) of the biologically active Tat protein. Conversely, peptides spanning the RGD region abolished the uptake of Tat at doses up to 10 ng/ml, and markedly reduced it at 100 and 1000 ng/ml. Of note, the combination of the Tat peptides 46-60 and 66-80 abolished the uptake of biologically active Tat both at 10 and 1000 ng/ml dose ((FIG. 7, panel B and C). Under the same experimental conditions, a longer Tat peptide spanning both the N terminal and cysteine regions (1-38) (FIG. 6, panel C) did not affect the uptake of biologically active Tat, while Tat peptide 21-58, spanning both cysteine and basic regions, markedly reduced the uptake of Tat at 100 and 1000 ng/ml, and the Tat peptide 57-102 spanning the RGD region abolished the uptake of Tat at doses below 100 ng/ml ((FIG. 7, panel D). The Tat peptide 47-86, spanning both the basic and RGD regions, abolished the uptake of Tat at doses under 100 ng/ml and strongly reduced it at 1000 ng/ml ((FIG. 7, panel D). Thus, the blocking of α5β1 and αvβ3 integrins by peptides encompassing the RGD motif abolishes the uptake of picomolar-nanomolar (0.1-0.10 ng/ml) concentrations of biologically active Tat, while the uptake of higher (nano- to micromolar, 10-1,000 ng/ml) concentrations of Tat is mediated by the basic region of Tat via interaction with heparin-bound proteoglycans. Of relevance, a combination of peptides encompassing both the basic and the RGD region determines the complete abolishment of Tat uptake at any of the doses tested by interfering with both the pathways of binding and internalization of biologically active Tat protein. Thus, while these data demonstrate that both domains are needed for optimal Tat uptake, they also indicate that the RGD region is key for efficient (i.e., at low concentrations) and selective {(i.e., cell types expressing α5β1 and αvβ3 integrins, such as MDDC and activated EC (see below)} Tat uptake, whereas the basic region participates in the uptake only at high Tat concentrations, and lacks specificity of targeting since it occurs with any cell type. EXAMPLE 6 Uptake of Active Tat by Primary Endothelial Cells Before and After Cell Activation With Inflammatory-Cytokines To analyze the uptake of active Tat by endothelial cells, HUVEC were or not activated with inflammatory cytokines and used in uptake studies with rhodaminated Tat protein. After rhodamination Tat was active since it was still capable of promoting KS cell proliferation at the same concentration range as unlabelled Tat. This indicates that the attachment of the fluorescent label did not compromise its biological function. Cells were exposed to a wide range of Tat concentrations. In addition, to be consistent with uptake inhibition experiments (see below), cells were preincubated at 40 C for 2 h with medium without fetal calf serum. This preincubation does not affect the subsequent uptake of rhodaminated Tat. With rhodaminated Tat, the uptake and translocation of the protein to the nucleus or nucleoli of activated HUVEC (IC-HUVEC) became detectable within 15 minutes of incubation with 10 ng/ml rhodaminated Tat (FIG. 8). The intracellular Tat activity increased in a dose-dependent (FIG. 8) and time-dependent manner (FIGS. 9 and 10). Rhodaminated BSA or buffer (negative controls) showed little or no uptake (FIG. 8, 9, 10). To verify these data with cold active Tat, experiments were repeated by intracellular staining and FACS analysis (FIG. 11, 12). Uptake of native Tat was much more efficient by IC-HUVEC as compared to non activated cells (FIG. 11) and doses as low as 0.01 ng/ml of Tat were taken up very rapidly by the cells in a dose- and time-dependent fashion with kinetics similar or identical to those of MDDC (FIG. 12). No staining was observed with non-permeabilized cells indicating that all or most of the Tat was taken up by the cells. Thus, MDDC, IC-HUVEC and MDM possess specific mechanisms to take up Tat very efficiently. EXAMPLE 7 Inhibition of Uptake of Active Tat by Unlabelled Protein To verify whether the uptake of rhodaminated Tat protein by IC-HUVEC was occurring via a specific and saturable pathway(s), IC-HUVEC were incubated with 1 μg/ml unlabelled Tat prior to incubation with rhodaminated Tat at concentrations ranging from 10 ng/ml to 1 μg/ml. This procedure almost totally inhibited the uptake of rhodaminated Tat (FIG. 13 and Table II) with fluorescence levels comparable to those of the negative control (BSA). This indicates that uptake of Tat protein by IC-HUVEC is specific and saturable, suggesting that a receptor(s) is involved in this process. TABLE II Inhibition of uptake of 100 ng/ml and 1 μg/ml rhodaminated active Tat by IC-HUVEC after preincubation of the cells with 1 μg/ml of unlabelled Tat Incubation with Uptake of Preincubation Rhodaminated Tat Rhodaminated Tat Serum free medium 100 ng/ml +++ 1 μg/ml unlabelled Tat 100 ng/ml +/− Serum free medium 1 μg/ml ++++ 1 μg/ml unlabelled Tat 1 μg/ml +/− IC-HUVEC were preincubated for 2 h with serum free medium in the absence or presence of 1 μg/ml unlabelled active Tat and then incubated with 100 ng/ml or 1 μg/ml rhodaminated Tat for 60 minutes. Tat uptake was visualized by fluorescence microscopy as described in the legend to FIG. 6. Negative controls (+/− uptake) were preincubation with serum free medium, followed by incubation with rhodaminated BSA. EXAMPLE 8 Inhibition of the Uptake of Picomolar Concentrations (10 to 100 ng/ml) of Active Tat By Monoclonal Antibodies Directed Against the α5β1 and αvβ3 Integrins or By Their Ligands FN and VN. To determine whether Tat uptake by IC-HUVEC was mediated by the same integrins identified with MDDC, inhibition experiments were performed by preincubating IC-HUVEC with the physiological ligands for these receptors, FN or VN, or by preincubating the cells with monoclonal antibodies directed against the RGD binding regions of the α5β1 and αvβ3 receptors. The cells were then incubated with rhodaminated Tat at concentrations ranging from 10 ng/ml to 1 μg/ml. The uptake and nuclear localization of 10 ng/ml of rhodaminated Tat was inhibited by prior treatment of the cells with FN or VN both employed at 100 ng/ml (Table III). Similarly, uptake of 10 to 100 ng/ml of Tat was inhibited by prior treatment of the cells with monoclonal antibodies directed against the RGD binding regions of both the FN receptor, α5β1, and the VN receptor, αvβ3 (FIG. 14,15). The intensity of cellular fluorescence was reduced to the levels seen with negative controls (FIG. 12, 13). These results indicate that uptake of picomolar concentrations of Tat is mediated by the same integrins recognized with MDDC. In contrast, no inhibition was observed by prior incubation of IC-HUVEC with monoclonal antibodies directed against the factor VIII, used as negative control (FIG. 14,15), thus indicating that inhibition of Tat uptake by anti-integrin antibodies was specific. TABLE III Inhibition of uptake of 10 ng/ml rhodaminated active Tat by IC-HUVEC by preincubation of the cells with an excess of FN or VN Preincubation Uptake of Rhodaminated Tat Serum free medium ++++ 100 ng/ml FN +/− 100 ng/ml VN +/− IC-HUVEC were preincubated for 2 h with serum free medium in the absence or in the presence of human FN or VN (Roche, Monza, Italy), and then incubated with 10 ng/ml rhodaminated Tat for 60 minutes. Tat uptake was visualized by fluorescence microscopy as described in the legend to FIG. 8. Negative controls (+/− uptake) were preincubation with serum free medium, followed by incubation with rhodaminated BSA. EXAMPLE 9 Uptake of 1 μg/ml of Active Tat is Only Partially Mediated By Integrin Receptors To determine the involvement of integrins in the uptake of higher (nanomolar-micromolar) concentrations of active Tat, IC-HUVEC were incubated with 1 g/ml rhodaminated Tat. A very intense fluorescence signal was seen in the cells within 15 minutes (FIG. 8 panel D, FIG. 10 panel A and FIG. 16 panel B). At this time of incubation, prior treatment of the cells with monoclonal antibodies against α5β1 (FIG. 16 panel C) or αvβ3 (FIG. 16 panel D) showed some inhibition of Tat uptake, but lower than that observed with 10 or 100 ng/ml of Tat. When IC-HUVEC were incubated with 1 μg/ml of rhodaminated Tat for longer periods of time (60 minutes), prior treatment of the cells with the anti-α5β1 or anti αvβ3 monoclonal antibodies did not inhibit Tat uptake (FIG. 17). These results indicated that, at this concentration and periods of incubation of Tat, the integrin-dependent uptake is saturated and another pathway of Tat uptake is predominant. EXAMPLE 10 Tat Domains Mediating Uptake of Active Tat To verify which domain of Tat is responsible for the uptake of picomolar-nanomolar versus micromolar concentrations of the protein, blocking experiments were performed by preincubating IC-HUVEC with the Tat peptides spanning the RGD region (Tat 65-80) and the basic region (Tat 46-60) (Table-IV). The Tat peptide 11-24 was used as a negative control. When rhodaminated Tat was added to the cells uptake of picomolar concentrations of Tat was inhibited by the Tat peptide 65-80 but not by Tat 46-60 or 11-24 (Table IV). In contrast, at high concentrations of extracellular Tat (1 μg/ml) uptake was not inhibited by Tat 65-80 while the Tat 46-60 had some inhibitory effects. This confirms that uptake of picomolar-nanomolar concentrations of Tat is mediated by Tat RGD region interacting with the α5β1 and αvβ3 integrins. In contrast, uptake of high (nano- to micromolar) concentrations of Tat is mediated by Tat basic region via interaction with heparin-bound proteoglycans. Thus, the RGD region is key for efficient Tat uptake, whereas the basic region participates in uptake of high Tat concentrations, however it lacks specificity of targeting since it occurs with any cell type. TABLE IV Tat domains mediating uptake of active Tat Competitor Rhodaminated Tat (ng/ml) Fluorescence intensity Buffer 0 − Buffer 10 ++ (11-24) Tat 10 ++ (46-60) Tat 10 ++ (65-80) Tat 10 − Buffer 100 +++ (11-24) Tat 100 +++ (46-60) Tat 100 +++ (65-80) Tat 100 −/+ Buffer 1000 ++++ (11-24) Tat 1000 ++++ (46-60) Tat 1000 ++ (65-80) Tat 1000 +++ IC-HUVEC were incubated on a rotating device for 2 h at 4° C. with an excess (10 μg/ml) of # (11-24)Tat, (46-60)Tat or (65-80)Tat in serum free medium. Peptide resuspension buffer (PBS-0.1% BSA) # was employed as a negative control. After preincubation with competitor peptides, rhodaminated Tat was added to # the cells at 10, 100 and 1000 ng/ml and cells were kept for 15′ at 37° C. in a CO2 incubator. # Cells were then fixed in ice-cold acetone-methanol (1:1). The uptake and the cellular distribution of Tat # were observed and photographed using fluorescence microscopy, as described in the legend to FIG. 8. EXAMPLE 11 Active But Not Oxidized and Inactivated Tat Induces MDDC Activation and Maturation To evaluate the effect of the active Tat protein on MDDC activation and maturation, the surface expression of MHC, HLA-ABC and HLA-DR and of the costimulatory molecules CD40, CD80, CD86 and CD83 was analyzed by flow cytometry on cells cultured for 18 h in the presence of the protein, complete medium, reconstitution buffer, or LPS (positive control). Experimental data obtained with 10 different donors indicated that Tat induces a dose-dependent enhancement of the expression of MHC and co-stimulatory molecules in the absence of any cellular toxicity (Table V, panel A). A marked increase of the mean fluorescence intensity (MFI) was observed for HLA-ABC (3/6 donors, average 0.37%), for HLA-DR (10/10, average 49%), for CD40 (6/10, average 35%), for CD80 (8/8, average 50%), for CD83 (9/10, average 164%) and for CD86 (10/10, average 140%). Reconstitution buffer or medium alone did not change the expression levels of the molecules analyzed. Of note, oxidation and inactivation of Tat (Table I) markedly reduced the capacity of the protein to upregulate MHC and costimulatory molecules on MDDC (Table V, panel B). Thus, only active Tat promotes the activation and maturation of MDDC. TABLE V Active (A) but not oxidized and inactivated (B) Tat enhances the expression of HLA and costimulatory molecules on MDDC A. % increase vs control Donor Medium Buffer Tat μg/ml Code (MFI) (MFI) 1 5 20 LPS HLA-ABC B 19 392 332 55.4 55.7 78.3 74.0 B 24 291 309 6.1 49.2 49.2 140.9 B 26 304 297 −4.0 −4.7 15.8 32.6 B 38 130 127 31.5 54.3 63.8 168.5 B 53 276 272 −8.5 −6.3 2.2 48.9 B 55 251 259 2.7 11.2 13.9 9.2 HLA-DR B 19 145 192 1.0 −1.0 27.1 84.8 B 24 164 143 11.9 60.8 10.5 48.8 B 26 175 177 15.8 23.2 60.5 60.6 B 38 464 366 62.3 98.1 94.5 85.6 B 40 1040 1127 27.9 38.9 34.6 58.9 B 43 415 408 18.6 27.7 ND ND B 44 687 692 5.1 11.3 31.4 ND B 45 847 797 14.3 23.7 40.4 ND B 53 471 493 11.0 30.8 94.7 94.5 B 55 313 303 38.6 47.2 46.9 30.7 CD40 B 19 53 51 23.5 21.6 19.6 77.4 B 24 60 58 19.0 36.2 41.4 103.3 B 26 42 43 4.7 11.6 16.3 45.2 B 38 70 62 45.2 62.9 95.2 64.3 B 40 85 76 38.2 59.2 60.5 76.5 B 43 48 48 −2.1 −4.2 −6.3 ND B 44 69 68 2.9 16.2 14.7 ND B 45 87 76 1.3 15.8 18.4 ND B 53 82 80 20.0 38.8 52.5 75.6 B 55 34 36 5.6 22.2 38.9 14.7 CD80 B 19 8 8 62.5 50.0 37.5 350.0 B 24 16 16 12.5 37.5 43.8 143.8 B 26 10 9 44.4 22.2 44.4 90.0 B 38 21 19 68.4 84.2 100.0 109.5 B 40 27 23 43.5 73.9 69.6 63.0 B 43 9 8 12.5 25.0 25.0 ND B 44 18 18 0.0 11.1 27.8 ND B 45 21 21 0.0 23.8 52.4 ND CD83 B 19 7 6 66.7 100.0 166.7 442.9 B 24 9 7 57.1 257.1 128.6 200.0 B 26 8 9 0.0 −11.1 55.6 62.5 B 38 5 6 33.3 150.0 233.3 520.0 B 40 12 10 100.0 190.0 310.0 233.3 B 43 8 9 0.0 11.1 22.2 ND B 44 9 13 −23.1 −38.5 7.7 ND B 45 7 10 −30.0 0.0 90.0 ND B 53 3 6 0.0 33.3 150.0 433.3 B 55 6 5 40.0 180.0 480.0 ND CD86 B 19 81 76 82.9 76.3 69.7 133.3 B 24 35 41 17.1 48.8 7.3 77.1 B 26 128 129 4.7 25.6 48.1 55.5 B 38 95 103 129.2 220.8 266.7 288.0 B 40 25 24 68.0 95.1 88.3 144.0 B 43 75 74 16.2 35.1 41.9 ND B 44 70 75 −4.0 26.7 80.0 ND B 45 51 50 44.0 70.0 166.0 ND B 53 15 14 35.7 85.7 535.7 693.3 B 55 37 40 72.5 80.0 97.5 32.4 B. Medium Buffer Tat (MFI) (MFI) (% increase vs control) HLA-DR 313 303 46.9 Native 10.6 Oxidized CD40 34 36 38.9 Native 8.3 Oxidized CD83 6 5 480.0 Native 40.0 Oxidized CD86 37 40 97.5 Native 15.0 Oxidized % increase of HLA-DR or CD antigens expression induced by Tat or LPS as compared to buffer or medium, respectively. Cells were exposed for 18 h to native or oxidized and inactivated Tat, reconstitution buffer, complete medium, or LPS (10 μg/ml), # stained with the following fluorochrome-conjugated monoclonal antibodies: FITC- or PE-conjugated IgG isotypes, FITC-conjugated anti-CD14 # and -HLA-DR (Becton-Dickinson), FITC-conjugated anti-CD40, -CD80, -CD83, PE-conjugated anti-CD86 (Pharmingen, San Diego, CA) and then analyzed by flow cytometry. # In panel A the expression of the surface molecules on MDDC from 10 different donors is reported as the percentage increase of the mean fluorescence intensity (MFI) # as compared to the MFI of cells incubated with Tat buffer (for Tat) or medium (for LPS). Data with oxidized versus native Tat (20 μg/ml) from a representative donor are shown in panel B. # MDDC cultured with LPS were used as the positive control for the induction of HLA and costimulatory molecules. MDDC cultured in presence of native or oxidized Tat were always viable, not differing from those treated with medium or reconstitution buffer (data not shown). EXAMPLE 12 Native But Not Oxidized and Inactivated Tat Activates MDDC and Enhances the Production of Th-1 Type Cytokines and β-chemokines by MDDC To evaluate the effects of active Tat on DC activation, the production of the cytokines IL-12 and TNF-α, known to activate immune cells and to induce Th-1 type responses (Romagnani 1997), and of the β-chemokines RANTES, MIP-1α and MIP-1β, that are known mediators of immune responses (Moser 2001), was assessed by ELISA in the supernatants of cells cultured for 18 h with the protein, reconstitution buffer (negative control) or LPS (positive control) (FIG. 18). Incubation with active Tat induced a dose-dependent increase of the levels of IL-12 and TNFα, reaching, at the highest dose of Tat, an increase of 23-fold (p<0.02) for IL-12 and 20-fold (p<0.03) for TNF-α as compared to cells treated with buffer alone. Similarly, Tat markedly enhanced, in a dose-dependent fashion, the production of RANTES (10-fold, p<0.02), MIP-1α (97-fold, p<0.005) 0.005) and MIP-1β (15-fold, p<0.01). The reconstitution buffer had no effects, whereas LPS (positive control) markedly enhanced the production of both cytokines and β-chemokines. In contrast to the effects of native Tat protein, oxidized and inactivated Tat did not increase the production of IL-12 or TNF-α. Thus, only native and active Tat increases the production and secretion of Th-1 cytokines and β chemokines by MDDC. EXAMPLE 13 Active Tat Increases Allogeneic Presentation by MDDC To evaluate the effect of Tat on the antigen presenting capacity of MDDC, cells were exposed to the Tat protein, reconstitution buffer, complete medium or LPS (positive control), and cultured with allogeneic PBL at serial cell to cell ratios (FIG. 19). This assay was chosen because, although not specific for a given antigen, it provides adequate information on the overall antigen presenting function of MDDC. Untreated MDDC induced some levels of proliferation of allogeneic lymphocytes, depending on the number of APC used. However, the proliferative response of allogeneic PBL was significantly enhanced by MDDC pulsed with Tat (3.3-fold, p<0.01, at the highest DC/PBL ratio), reaching levels similar to those induced by LPS (3.8-fold, p<0.005 at the same cell to cell ratio). In contrast, no enhancement of allogeneic lymphocyte proliferation was observed by treatment of MDDC with reconstitution buffer (FIG. 19). Thus, native Tat increases DC presentation function. EXAMPLE 14 Active Tat Enhances the Presentation of Heterologous Antigens by MDDC and Specific T Cell Responses The effect of active Tat on the antigen-specific presenting capacity of MDDC was evaluated by transiently treating the cells with the protein, reconstitution buffer or complete medium, and culturing them together with autologous lymphocytes in the presence of the recall antigen TT. As shown in FIG. 20, untreated MDDC induced TT-specific proliferation of autologous lymphocytes in 2 out of the 3 donors analyzed (S.I. 15.4 and 7.3, respectively) and this effect was enhanced by their treatment with active Tat (S.I. 27.9 and 12.5, respectively), but not with reconstitution buffer (S.I. 13 and 5.9, respectively). Tat-treated MDDC did not induce lymphocyte proliferation to TT in the subject who did not respond to it. Thus, Tat can boost specific T cell responses to other antigens. EXAMPLE 15 Immunization of Mice With Biologically Active Tat Combined With SIV Gag+MALP-2 Mucosal Adjuvant Induces Stronger Anti-Gag Humoral and Cellular Immune Responses as Compared to Vaccination with Gag+MALP-2. Because of its potent adjuvant activity, as indicated by the effects on MDDC activities, biologically active Tat is expected to increase both mucosal and systemic immune response to a nominal antigen when co-administered mucosally. To this aim, Balb/c mice (arm 2 in FIG. 21) received 2 intradermal priming with 10 μg of SIV Gag protein mixed together with biologically active Tat (10 μg) followed by 2 intranasal boosting with Tat+Gag+Malp-2. In these animals the levels, determined by Elisa, of the anti-Gag antibodies induced were higher (arm 2 in FIG. 22) than those detected in the animals immunized with Gag alone (arm 1 in FIGS. 21 and 22). More importantly, Th-1 type T cell immune responses were induced, including CTL responses as determined in a classical 5 h 51chromium release assay measuring the killing of p815 murine mastocytoma cells pulsed with a pools of Gag peptides (Targets) for 34 h prior to the addition to effector cells (splenocytes cultured for 6 days with pools of Gag peptides in the presence of exogenous IL-2). Both humoral and cellular immune responses were stronger than those induced in the control group immunized as above but without Tat (FIG. 23). Thus, immunization with a nominal antigen together with biologically active Tat generated a better immune response as compared to that of mice immunized with the nominal antigen alone. In particular, substantially higher titers of serum IgG and CTL responses to the nominal antigen were found. Similarly, enhancement of mucosal immune response (i.e., secretory IgA from lung and vaginal lavage) by biologically active Tat is foreseen. Prophetic Example 16 Systemic immunization of monkeys with biologically active Tat expressed by a vector DNA alone or combined with DNA expressing other HIV antigens increases Th-1 responses against other antigens and confers a better control of infection upon virus challenge. Systemic immunization of monkeys with the Tat-DNA expressing vector alone or associated with DNA expressing other antigens is expected to induce a T cell immune response and IFNγ Elispot (Th-1 type) against itself and to increase Th-1 responses against other antigens as compared to vaccination with other antigens in the absence of Tat. Furthermore, the association of Tat with other HIV antigens such as Env, Gag and Pol is expected to provide better protection than vaccination with Tat alone upon challenge with the pathogenic SHIV89.6P. In particular, intramuscular immunization (3 inoculations in 6 weeks time period) of juvenile rhesus monkeys (Macaca mulatta) with DNA of HIV-1 tat (0.5 mg) alone or associated with HIV-1 env and SIVmac239 gag DNA (0.5 mg each) followed by 2 intramuscular boosts with either biologically active Tat protein (25 μg) and ISCOMs alone or associated with 25 μg of HIV-1 Env and 25 μg of SIVmac239 Gag proteins, is expected to generate a specific Th-i immune response, including induction of specific antibodies, lymphoproliferative responses and CTL assessed by Elispot for IFNγ, IL-2 and IL-4 to biologically active Tat protein and/or peptides thereof alone, or to biologically active Tat protein and/or peptides thereof and to HIV-1 Env and SIVmac239 Gag proteins and/or peptides thereof. Further, given the immunodominance of Env and Gag/Pol antigens as compared to Tat and the inherent adjuvanticity of Tat itself, it is predicted that immunization with the latter will need to be performed at least twice prior to initiation of vaccination with the former antigens to obtain a comparable immune response to all immunogens. Thus, it is foreseen that vaccination (9 inoculations in 36 weeks time period) of juvenile rhesus monkeys (Macaca mulatta) with DNA of HIV-1 tat (0.5 mg) alone or associated (starting from the 3rd inoculation) with 0.5 mg each of HIV-1 env and SIVmac239 gag/pol DNA (7 inoculations in 30 weeks time period) followed by 2 intramuscular boosts with either biologically active Tat protein (25 μg) and ISCOMs alone or associated with 25 μg each of HIV-1 Env and of SIVmac239 Gag/Pol proteins and ISCOMs will generate a stronger and broader (as compared to the former and shorter immunization schedule) specific immune response to all the vaccine antigens, especially in terms of CTL responses, as assessed by Elispot for IFNγ, IL-2 and IL4 to biologically active Tat protein and/or peptides thereof alone, or to biologically active Tat protein and/or peptides thereof and to HIV-1 Env and SIVmac239 Gag proteins and/or peptides thereof. Finally it is foreseen that vaccination against Tat, Env and Gag/Pol will confer better control of infection, as compared to animals vaccinated with Tat or Gag/Pol alone, upon intravenous challenge with SHIV 89.6P. REFERENCES Addo, M. M., et al. Proc. Natl. Acad. Sci. USA 98:1781, 2001. Albini, A., et al. Proc. Natl. Acad. Sci. USA 92:4838, 1995. Albini, A., et al. Nat. Med. 2:1371, 1996. Albini, A., et al. Proc. Natl. Acad. Sci. USA. 95:13153, 1998a. Albini, A., et al. J. Biol. Chem. 273:15895, 1998b. Allen, T. M., et al. Nature 407:386, 2000. Arya, S. K., et al. Science 229:69, 1985. Badou, A., et al. J. Virol. 74:10551, 2000. Banchereau, J., and R. M. Steinman. Nature 392:245, 1998. Barillari, G., et al. J. Immunol. 149:3727, 1992. Barillari, G., et al. Proc. Natl. Acad. Sci. USA 90:7941, 1993. Barillari, G., et al. J. Immunol. 163:1929, 1999a. Barillari, G., et al. Blood 94:663, 1999b. Bell, D., et al. Adv. Immunol. 72:255, 1999. Benelli, R., et al. AIDS 12:261, 1998. 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<SOH> BACKGROUND OF THE INVENTION <EOH>Tat is a regulatory protein of human immunodeficiency virus type 1 (HIV-1) produced very early after infection and essential for virus gene expression, replication and infectivity (Arya 1985; Fisher 1986; Chang 1995). During acute infection of T cells by HIV, Tat is also released in the extracellular milieu and taken-up by neighbour cells (Frankel 1988; Ensoli 1990; Ensoli 1993; Chang 1997) where, according to the concentration, can increase virus infectivity. Specifically, upon uptake Tat can enhance, in infected cells, virus gene expression and replication (Frankel 1988; Ensoli 1993; Chang 1997), and, in uninfected cells, the expression of the β-chemokines receptors CCR5 and CXCR4 favouring transmission of both macrophage and T lymphocyte-tropic HIV-1 strains (Huang 1998; Secchiero 1999). Extracellular HIV-1 Tat protein is also responsible for the increased frequency and aggressiveness of Kaposi's sarcoma (KS) a vascular tumor particularly frequent in HIV-infected individuals (Friedman-Kien 1981; Safai 1985). In particular, previous work from our and other groups indicated that Tat cooperates with angiogenic and inflammatory cytokines that are highly expressed in KS patients (Samaniego 1998; Ensoli 1994) in inducing new blood vessels formation (angiogenesis) and the growth and locomotion of spindle shaped cells of endothelial cell origin (KS cells) and of activated endothelial cells (Barillari 1992; Albini 1995; Ensoli 1994). Moreover, the sequence comprised between residues 21 and 40 (core domain) in the HIV-1 BH-10 Tat protein has been shown to act as a transactivator, to induce HIV replication and to trigger angiogenesis (International Patent number WO 00/78969 A1). In particular, our data have shown that biologically active Tat binds through its RGD region the integrin receptors α5β1 and αvβ3 and that this interaction mediates the adhesion, growth and locomotion induced by Tat on KS cells and endothelial cells activated by inflammatory cytokines (Barillari 1993; Barillari 1999a and 1999b). In addition, Tat acts also as a chemotactic factor for these cell types as well as for monocytes and dendritic cells (DC) (Albini 1995; Benelli 1998; Lafrenie 1996; Mitola 1997). Finally, our data demonstrated that KS and HUVE cell migration and invasion are toward the Tat protein is mediated by the binding of the Tat RGD region to the α 5 β 1 and αvβ 3 integrins (Barillari, 1999b). Consistent with these findings, the immune response to Tat has been shown to play a key role in controlling the progression of AIDS and AIDS-associated diseases. In fact, a Tat-specific immune response is present in HIV-1 infected subjects and simian immunodeficiency virus (SIV)-infected monkeys, and correlates inversely with progression to the symptomatic stage of the infection (Reiss 1990; Venet 1992; Rodman 1993; Froebel 1994; Re 1995; Van Baalen 1997; Zagury 1998; Addo 2001). Moreover, vaccination with biologically active Tat protein or tat DNA induces protection against SHIV89.6P virus replication and disease onset which correlates with the presence of Th-1 responses including specific cytotoxic T lymphocytes (CTLs) (Cafaro 1999; Cafaro 2000; Cafaro 2001, and PCT WO99/27958). The same protection data have been more recently observed with a tat-rev vaccine delivered with viral vectors in macaques (Osterhaus 2001). In contrast, a limited containment of the infection has been observed in monkeys vaccinated with inactivated Tat or Tat peptides, in which antibodies and T helper specific responses but no CTLs nor Th-1 responses had been induced (Goldstein 2000; Pauza 2000). Again, the repeated intradermal (i.d.) inoculation of monkeys with native and active Tat protein alone (in the absence of any adjuvant) at low doses (5-6 μg) selectively induced a Th-1 response and specific CTLs in the absence of any significant antibody production (Cafaro 1999 and PCT WO99/27958). These immunological results were recently confirmed in a new vaccination protocol in which native Tat alone was repeatedly inoculated i.d. in 4 monkeys (unpublished data), and are comparable to those induced by i.m. vaccination with tat DNA in a published (Cafaro 2001 and PCT WO99/27958) and in an ongoing study. Similarly, recent work performed in SIV-infected macaques indicate that anti-Tat CTLs are key to control early virus replication after primary infection and exert a selective immune pressure on the virus leading to the appearance of slowly replicating, less pathogenic escape mutants (Allen 2000). Finally, Tat is presented with major histocompatibility complex (MHC) class I antigen (Moy 1996; Kim 1997), hence inducing anti-Tat CTL (Cafaro 1999). Micromolar concentrations of recombinant Tat protein (often of unknown biological activity) or peptides encompassing the basic region of Tat have been shown to enter many different cell types (Frankel 1988; Mann 1991; Ensoli 1993; Chang 1997; Fawell 1994; Moy 1996; Kim 1997). The highly basic charge of Tat residues 48-57, in fact, enables the protein to bind to heparan sulphate proteoglycans (HSPG) that are present on the membrane of all cell types (Chang 1997; Rusnati 1998). After release from acutely infected cells, a fraction of extracellular Tat binds, through its basic residues, to the HSPG (Chang 1997). This protects extracellular Tat from proteolytic degradation, as previously found for several growth factors (reviewed in Raines and Ross, 1992). Upon the binding of its basic region to cell surface HSPG, Tat is internalised through a receptor-independent pathway (Frankel 1988; Rusnati 1998; Tyagi 2001). In fact, Tat residues 49-57 (in the BH-10 Tat sequence) have been indicated to be able to translocate an OVA peptide into the cytosol of DC and to sensitize CD8+ T cells to this peptide (Kim, 1997). Furthermore, the 47-57 Tat sequence (from the BH-10 variant), fused with several effector proteins, has been suggested to be able to deliver them to cells (International patent number WO 01/19393 A1). However, this internalization mechanism requires high (micromolar) concentrations of Tat, occurs with any cell type and it is not sequence-specific. In fact, it has been shown that mutations of this region, which do not change its basic charge, do not affect the properties of the Tat basic region (Barillari 1999b). Similarly, the substitution of the Tat basic region with that of HIV rev or other genes does not change Tat properties. In this regard, the basic region of Tat has been shown to be very similar to the arginin-rich region carried by the members of the small family of proteins known as penetratins , that are all capable of entering many cell types (Derossi 1998). In fact, arginin homopolymers have been shown to enter cells even more efficiently than Tat basic region (Derossi 1998). The property of the Tat basic region of being internalized by cells has been exploited to deliver foreign proteins to a variety of cell types (Fawel 1994; Wender 2000; and WO 01/19393). To this purpose, foreign proteins have been conjugated or fused to the Tat basic region which has been used as a carrier for the protein to be transduced (Fawel 1994; Wender 2000; and WO 01/19393). However, the inventor believes that due to the ubiquitous expression of HSPG, Tat basic region cannot be used for selective targeting, delivery and/or uptake of Tat by specific primary cell types, including antigen presenting cells (APC). APC initiate and drive the type of immune response upon encountering foreign molecules (Bancherau 1998; Bell 1999). Typical APC include monocyte-derived DC (MDDC), T cell blasts (TCB), B-lymphoblastoid cell lines (BLCL) and monocytes-macrophages (Bancherau 1998; Bell 1999). In addition, when activated by inflammatory cytokines also endothelial cells acquire APC functions (Pober 1988). Among these inflammatory cytokines, interleukin (IL)-1, tumor necrosis factor (TNF) and interferon (IFN)γ are key for endothelial cell activation (Pober 1988). Exposure to these cytokines increases in endothelial cells the expression of α5β1 and αvβ3, that are among the several cell surface receptors binding Tat (Barillari 1993, Fiorelli 1999; Benelli 1998; Kolson 1993; Sabatier 1991; Vogel 1993; Boykins 1999; Ganju 1998; Milani 1996; Mitola 1997 and 2000; Weeks 1993; Albini 1996 and 1998; Chang 1997; Lafrenie 1996; Morini 2000; Rusnati 1998). Among all these APC, DC are the most efficient APC and are key to the induction of immune responses against infections and tumors (Banchereau 1998; Bell 1999). Their function is associated with a high expression of MHC and costimulatory molecules (CD40, CD80, CD86) and with the production of cytokines known to activate T lymphocytes, and β-chemokines. Upon encountering the antigens, DC undergo a maturation process characterized by an increase of costimulatory molecules expression and by a reduction of their phagocytic and pinocytic capability (Banchereau 1998; Bell 1999). Further, due to the upregulation of the homing receptor CCR7 and to the downregulation of CCR5, mature DC migrate to lymph nodes where they present antigens to T lymphocytes (Banchereau 1998; Bell 1999). Prior art indicates that the addition of Tat protein to DC blocks in these cells the extracellular calcium influx, the production of interleukin-12, and the uptake of apoptotic bodies (Zocchi 1997; Rubartelli 1997). As a result, it is predicted that profound impairment of important DC functions including antigen uptake, processing and presentation and induction of Th-1 responses should occur. Further, impairment of phagolysosomal fusion has been reported in peripheral blood monocytes upon exposure to Tat, suggesting impairment in this cell type of both microbicidal and antigen processing (and presentation) functions (Pittis 1996). Moreover, Tat has been reported to induce both monocytes/macrophages and lymphocytes to secrete IL-10 (Masood 1994; Badou 2000), while inhibiting IL-12 production in monocytes (Ito 1998). Finally, exposure of APC to Tat has been reported to impair their capability to organize cell clusters and to properly activate T cells (Mei 1997). Moreover, prior art indicates that Tat profoundly impairs also T cell functions including suppression of responses to mitogens anti-CD3 or specific antigens (Viscidi 1989; Benjouad 1993; Subramanyam 1993; Chirmule 1995; Wrenger 1996; Wrenger 1997; Zagury 1998), T cell hyperactivation (Ott 1997; Li 1997), and T cell apoptosis (Westendorp 1995; Li 1995; McCloskey 1997). Further, inoculation of biologically active Tat has been reported to be immunosuppressive in vivo (Cohen 1999). Part of the effects of Tat on the immune system have been related to upregulation by Tat of the chemokines receptors CCR5 and CXCR4 (Huang 1998; Secchiero 1999), or the direct interaction of Tat with the chemokine receptors CCR2 and CCR3 (Albini 1998a) or with other receptors including CD26 (Gutheil 1994), Flt-1 (Mitola 1997), KDR (Albini 1996; Morini 2000), that are expressed by immune cells, as well as by endothelial cells. Therefore, according to this previous art Tat is expected to drive a Th-2 type of immune response and/or to interfere with or abolish proper APC function and T cell activation. By contrast, our novel and unexpected finding, supported by experimental evidence exhibited in this patent application, indicate that: (i) APC are specifically targeted by Tat that selectively recognises and enters these cells at pico-nanomolar concentrations, but that this requires the interaction of native, substantially monomeric, biologically active Tat with α5β1, αvβ3 integrins, through the Tat RGD sequence; (ii) and that native, substantially monomeric, biologically active Tat activates, rather than inhibiting, APC function and induces, rather than suppressing, Th-1 type immune responses against itself and, most notably, other antigens. Specifically, our data show that Tat acts not only as an antigen but also as an adjuvant with potent immunomodulatory properties. These properties of Tat, namely of being selectively internalised as biologically active protein by APCs at picomolar-nanomolar concentrations and to act as an adjuvant, are strictly related each other. In particular, we have found, that Tat RGD sequence is key for the internalisation of active Tat by these cells through the α5β1 and αvβ3 integrin receptors. In fact, antibodies or competitor ligands blocking these integrins completely abolish or greatly reduce the uptake of picomolar-nanomolar concentrations of Tat, respectively. This uptake is very rapid, is dose-, cell maturation/differentiation- and time-dependent. Even more unexpectedly, we did not obtain similar results with other APC including monocytes, T cell blasts, or B cell blasts or non-activated endothelial cells. Therefore, these findings are completely novel since prior art indicates that Tat is taken up only at much higher concentrations (micromolar range), through its basic region, by a non-receptor-mediated pathway (Frankel 1988; Mann 1991; Rusnati 1998; Tyagi 2001). This internalization pathway occurs with any cell type, and it is not maturation/differentiation-dependent. Further, we have found that Tat in its native, substantially monomeric, and biologically active form is absolutely required to observe all the above novel effects which do not occur when Tat is oxidized and inactivated. In fact, Tat has 7 cysteines and it is extremely sensitive to oxidation which, when occurring, causes the loss of native protein conformation and consequent loss of biological activity (Frankel 1989). Therefore, Tat is likely to lose its native conformation and activity when purified with procedures that are not specifically designed at maintaining this protein in its native form. Although established concepts in the field claim that biologically active Tat is toxic (Gallo 1999; Sabatier 1991; Kolson 1993; Westendrop 1995; Purvis 1995), by contrast, the highly purified, biologically active preparations of recombinant Tat utilized by the inventor has no cytotoxic nor pro-apoptotic effects on endothelial cells, DC, macrophages, other cell type tested, nor in vivo in mice or monkeys (Ensoli 1994; Barillari 1999a; Zauli 1993, 1995a and 1995b; Cafaro 1999, 2000 and 2001). Thus, the inventor believes that full-length, wild type, native, substantially monomeric, and biologically active Tat from any HIV variant or its fragments or derivates containing the RGD region can be used as a highly efficient system for the selective targeting and delivery of molecules to specific cell types expressing the integrins recognized by the Tat RGD region (Barillari 1993, 1999a and 199b; Ensoli 1994). Given the very large amount and ubiquitous distribution of DC, macrophages and endothelial cells in the human body, the inventor believes that the capability of biologically active Tat or its fragments or derivatives containing the RGD sequence of targeting these APC and of driving Th-1 type cellular responses will offer a unique opportunity to, 1) to deliver cargo molecules to these cell types which represent a specific target for Tat and are recruited and activated in infections, pathologic angiogenesis, inflammatory diseases and tumors in the delivery system embodiment of the present invention; 2) induce a potent immune response against not only Tat but also against other antigens delivered by or with Tat, in the vaccine-adjuvant and immunomodulatory embodiment of the present invention. This belief is strongly supported by the successful previous work of the inventor with biologically active Tat as a vaccine to control HIV replication and to block disease onset (Cafaro 1999; Cafaro 2000; Cafaro 2001, and PCT WO99/27958) as opposed to inactivated Tat protein (Goldstein. 2000; Pauza 2000). The present patent application is substantially different and innovative as compared to our previous patent application WO 99/27958 in many aspects. In fact, the above mentioned application claimed biologically active Tat or Tat encoding DNA to be effective as a vaccine against HIV/AIDS. At the time when said patent application was filed it was not known to us that low (picomolar-nanomolar) amounts of biologically active Tat, or its fragments or derivatives containing the RGD region, (i) specifically target APC and thus we could have not claimed its use as a carrier to selectively deliver cargo molecules to them; (ii) cause EC and DC cell maturation and activation and induce Th-i type immune responses against different antigens, and thus we could have not claimed its use as a adjuvant and immunomodulator. Thus, in this invention, biologically active Tat is proposed, in the first embodiment, as a delivery system to deliver to APC (i) different antigens or combinations of antigens for vaccination against different infectious diseases (not only HIV/AIDS) and tumors, or for multivalent vaccination against one or more infectious diseases, and (ii) therapeutic molecules for the treatment of infectious, inflammatory and angiogenic diseases and tumor growth and metastasis; and in the second embodiment, biologically active Tat is proposed as an adjuvant to drive T-cell mediated immune responses against different antigens, and in particular to enhance the immunogenicity of poorly immunogenic antigens, such as those expressed by certain intracellular pathogens as well as tumor cells, by combining or fusing them with biologically active Tat or its fragments or derivatives containing the RGD region. In summary, the most important innovative aspect which makes the difference with the prior art is that here native, substantially monomeric, and biologically active Tat is claimed as a molecule which exerts different functions, i.e. it is a carrier to selectively deliver antigens to APCs or active compounds to specific tissues, and an adjuvant stimulating immune responses to other antigens. This unexpected properties make native, substantially monomeric, and biologically active Tat suitable for different applications in different infectious diseases (not only AIDS), inflammatory and angiogenic diseases and tumors. Thus, the inventor believes that native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, containing the RGD sequence, acts with at least one of the following actions: as delivery system to specific APC or as an adjuvant, and claims that it can be exploited for preventive and therapeutic vaccination and/or drug delivery for the prevention and treatment of HIV/AIDS, other infectious, inflammatory, and angiogenic diseases.

<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target antigen-presenting cells expressing α5β1 and αvβ3 integrins. It is another object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target α5β1 and αvβ3 integrins expressed by antigen presenting cells, including dendritic cells, endothelial cells and macrophages, for the uptake of Tat, fragments or derivatives thereof, by these cells. It is another object of the present invention the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, to selectively target antigen presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, to induce the maturation and/or the antigen presenting functions of these cells by Tat, fragments or derivatives thereof. Another object is the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, combined with one or more antigens, including, but not limited to, antigens from intracellular pathogens (such as viruses, mycobacterium tuberculosis, candida, malaria) and from tumor cells, (such as those from lung, colon, breast, prostatic cancer) in the form of peptides, proteins or DNA encoding them, to selectively target in vitro and in vivo antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, for preventive and therapeutic vaccination or treatment against infectious diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver in vitro and in vivo one or more antigens to antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages in order to induce immune responses for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver, intracellularly or to the cell membrane, in vitro and in vivo, to antigen-presenting cells expressing the α5β1 and αvβ3 integrins, including dendritic cells, endothelial cells and macrophages, one or more antigens or therapeutic compounds (such as, but not limited to, antiviral compounds, anti-inflammatory drugs, anti-angiogenic molecules, cytotoxic anti-tumor drugs or immunomodulating molecules such as, for example chemokines or cytokines, or antibodies) with or without the presence of support particles (such as, but not limited to, microparticles, nanoparticles, liposomes and other particulated delivery systems such as the ones described in Speiser 1991 and Takeuchi, 2001) for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, fused to other proteins or peptides or support particles (as defined in the above) to selectively deliver in vitro and in vivo antigens or therapeutic compounds (as defined in the above) to antigen presenting cells expressing β5β1 and αvβ3 integrins including dendritic cells, endothelial cells and macrophages for combined preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively target in vitro and in vivo cells expressing RGD-binding integrin receptors such as antigen-presenting cells and other cell types capable of taking up Tat via the integrin-mediated pathway, and/or other uptake pathways upon the binding to integrin receptors, in order to deliver antigens or therapeutic molecules (as defined in the above) for preventive and therapeutic vaccination or treatment of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, combined with antigens, adjuvants (such as, but not limited to, Alum, RIBI, ISCOMS, CpG sequences, Lipopeptides) or therapeutic molecules or support particles (as defined in the above) administered by the parenteral (subcute, intramuscular, intradermic) or mucosal (vaginal, rectal, oral, nasal) or topic route for preventive and therapeutic vaccination or treatment against infectious diseases inflammatory, and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof to selectively deliver in vitro and in vivo antigens or therapeutic molecules (as defined in the above) within or attached to support particles (as defined in the above), to antigen-presenting cells expressing RGD-binding integrin receptors including dendritic cells, endothelial cells and macrophages, for preventive and therapeutic vaccination or treatment against infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat, fragments or derivatives thereof, to selectively deliver in vitro and in vivo expression vectors including plasmid DNA and bacterial or virus vectors expressing one or more antigens, in the presence or absence of support particles (as defined in the above), to antigen presenting cells expressing RGD-binding integrin receptors, including dendritic cells, endothelial cells and macrophages for preventive and therapeutic vaccination or treatment against infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is the use of tat DNA or native, substantially monomeric, and biologically active Tat protein, fragments or derivatives thereof, fused or combined with DNA coding for antigens, with or without support particles (as defined in the above), for combined preventive and therapeutic vaccination of infectious diseases, inflammatory and angiogenic diseases and tumors. Another object is native, substantially monomeric, and biologically active HIV Tat or tat DNA, fragments or derivative thereof, combined or fused with antigens, therapeutic molecules (as defined in the above), adjuvants (as defined in the above), or support particles (as defined in the above) such combination or fusion being defined as the association by means of chemical or physical interactions, or any other interactions, in any combination, such as, for example, but not limited to, the absorption of Tat and a DNA plasmid on nanoparticles; the inclusion of Tat and a synthetic drug in the same pharmaceutical preparation; the association of Tat or a fragment or a derivative thereof with a peptide by chemical crosslinking or by other means; the fusion of Tat, fragment or derivative thereof, with another protein or another peptide upon their expression in bacteria or eucariotic cells through chimeric DNA, where the DNA sequences encoding for the above polypeptides have been fused together using recombinant DNA technologies. Another object is the use of native, substantially monomeric, and biologically active HIV-1 Tat, fragments or derivatives thereof, as adjuvant to activate or enhance in vitro and in vivo the antigen-presenting function of cells expressing RGD-binding integrin receptors including dendritic cells, endothelial cells and macrophages and to induce Th-1 type immune responses against HIV/AIDS, other infectious diseases and tumors. Another object is the use of native, substantially monomeric, and biologically active Tat protein, tat DNA, fragments or derivates thereof, as in the above for vaccination or therapeutic treatment by the parentheral (intradermic, intramuscular, subcute), mucosal (oral, nasal, vaginal, rectal) or topic route. Another object are fragments of native, substantially monomeric, and biologically active Tat, defined as Tat peptides from any HIV variant (HIV-1, HIV-2 and other types and subtypes) comprising, alone or associated, the RGD domain (aa 73 to 86 in the HTLV-IIIB, clone BH-10; aa 74 to 84; aa 75 to 83; aa 76 to 82; aa 77 to 81; aa 77 to 82; aa 77 to 83; aa 76 to 83); the cystein-rich domain (aa 22 to 37 in the HTLV-IIIB, clone BH-10); the basic domain (aa 48 to 61 in the HTLV-IIIB, clone BH-10), combined or not with other HIV-1 Tat peptides including the core domain (aa 38 to 47 in the HTLV-IIB, clone BH-10) and/or the amminoterminal region (aa 1 to 20 in the HTLV-IIIB, clone BH-10). Another object are fragments of native, substantially monomeric, and biologically active Tat are defined as nucleotide sequences from any HIV variant (HIV-1, HIV-2 and other types and subtypes) comprising, alone or associated, the RGD domain (sequence coding for aa 73 to 86 in the HTLV-IIIB, clone BH-10; sequence coding for aa 74 to 84 in the HTLV-IIIB, clone BH-10; sequence coding for aa 75 to 83 in the HTLV-IIIB, clone BH-10; sequence coding for aa 76 to 82 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 81 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 82 in the HTLV-IIIB, clone BH-10; sequence coding for aa 77 to 83 in the HTLV-IIIB, clone BH-10; sequence coding for aa 76 to 83 in the HTLV-IIIB, clone BH-10) the cystein-rich domain (sequence coding for aa 22 to 37 in the HTLV-IIIB, clone BH-10), the basic domain (sequence coding for aa 48 to 61 in the HTLV-IIIB, clone BH-10), combined or not with other HIV-1 Tat peptides including the core domain (sequence coding for aa 38 to 47 in the HTLV-IIB, clone BH-10) and/or the amminoterminal region (sequence coding for aa 1 to 20 in the HTLV-IIIB, clone BH-10). Another object are fragments of Tat from any HIV variant (HIV-1, HIV-2 and other HIV types and subtypes) that comprise one or more T-cell epitopes in their amino acid sequences (HTLV-IIIB, clone BH-10 or 89.6). Another object are fragments of Tat from any HIV variant (HIV-1, HIV-2 and other HIV types and subtypes) that comprise one or more T-cell epitopes in their nucleotide sequences (HTLV-IIIB, clone BH-10 or 89.6). Another object are derivatives of Tat which comprise Tat mutants of the HTLV-IIIB, clone BH-10, variant, selected among that ones having the following nucleotide sequences, or part of them: Nucleotide sequence of cys22 mutant and nucleotide sequence of lys41. Another object are derivatives of Tat which comprise Tat mutants of the HTLV-IIIB, clone BH-10, variant, selected among that ones having the following aminoacid sequences, or part of them: Amino acid sequence of cys22 mutant and amino acid sequence of lys41. Another object of the present invention is the use of native, substantially monomeric, and biologically active Tat protein acting and combined as above described to produce medicaments to cure affections in the group of infectious diseases, inflammatory and angiogenic diseases, tumors. Further objects will be evident from the detailed description of the invention.

20040823

20101012

20050217

61582.0

HUMPHREY, LOUISE WANG ZHIYING

COMPOSITIONS OF ANTIGENS BOUND TO HIV-1 TAT, FRAGMENTS OR DERIVATIVES THEREOF

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for transmitting audio-visual programmes proposed by users, terminal and server therefor

The present invention concerns a method of receiving audiovisual programmes transmitted to terminals. The users of the terminals choose a programme from a catalogue and make a proposition to a server to download it to their terminals. The proposition is accompanied by a price and/or deadline. The server analyses the propositions it receives and, taking account of its profitability constraints, decides whether or not it will transmit the programme. Depending on the case, it sends the acceptance to each user who has made a proposition with profitable parameters for the transmission of the programme and gives the users the means of receiving the programme for viewing. The decision to transmit the programme is determined according to various strategies the common criterion of which is profitability. The invention also concerns a terminal and a server for the implementation of the method.

1. A method of transmitting audiovisual programmes from a server to at least one terminal comprising a first step of viewing a catalogue of downloadable audiovisual programmes on the terminal, comprising the following chronological steps: at the terminal: a step of selecting at least one audiovisual program; a step of generating a proposition conditioning the reception of the selected program; a step of transmitting the proposition to the server, the proposition comprising at least one of the following parameters: deadline, price; and at the server: a step of analysing the propositions sent by the terminals and of determining a decision to transmit the transmission taking account of the parameters; if the decision to transmit the programme is taken: a step of transmitting the selected programme over a broadcast network, a step of transmitting a code enabling each terminal that has sent a proposition to view the received program, viewing occurring after payment of a minimum price and/or not later than expiry of the determined deadline. 2. The method of transmitting programs as claimed in claim 1, wherein at the server, the analysis step is activated after a determined time from the moment when the programme is placed in the catalogue. 3. The method of transmitting programs as claimed in claim 1, wherein at the server, the analysis step is activated after a determined number of propositions is received. 4. The method of transmitting programs as claimed in claim 1, additionally comprising a step of transmission by the server to at least one terminal of a notification indicating that the server has decided not to transmit the program. 5. The method of transmitting programs as claimed in claim 4, wherein the said notification comprises an indication of the reason for the server's refusal to transmit the program. 6. Method of transmitting programs as claimed in claim 4, wherein the said notification comprises a parameter value such as the price or deadline which, incorporated in a proposition, would enable the user to view the program. 7. The method of transmitting programs as claimed in claim 1, wherein the proposition sent by the terminal comprises an indication determining a subset of programmes in the catalogue and in that, in the course of the analysis and determination step, the server selects from the subset a programme from the catalogue the transmission of which to the terminals satisfies the server's own criteria. 8. The method of transmitting programs as claimed in claim 1, wherein the decision to transmit a programme is taken preferably when many users have proposed that programme. 9. The method of transmitting programs as claimed in claim 1, additionally comprising a step of recording the program within the terminal. 10. An audiovisual terminal comprising a central processor unit, a means of receiving audiovisual programmes from a broadcast network, a means of two-way communication with a second network, a means of displaying a catalogue of available programs and a means of selecting an audiovisual program, comprising a means of generating at least one parameter such as the price and/or deadline, associated with the downloading of at least one selected programme, a first means for transmitting to the second network a proposition comprising at least one program identifier and the parameter entered, and a means of receiving a decision concerning the proposition, to download the programme from the broadcast network according to the previously generated parameter. 11. The audiovisual terminal as claimed in claim 10, additionally comprising a means of receiving a notification of refusal to download, the refusal being displayed on the display means. 12. The audiovisual terminal as claimed in claim 11, additionally comprising a means of receiving a second parameter such as the price or deadline incorporated in the notification of refusal to download, the second parameter being displayed on the display means. 13. The audiovisual terminal as claimed in claim 10, wherein only one of the parameters such as price or deadline is incorporated in the proposition, the agreement to download received from the network is accompanied by a value of the other parameter (deadline or price), and in that it comprises a second means of transmission over the network of a second proposition comprising the two parameters. 14. The audiovisual terminal as claimed in claim 10, wherein the proposition comprises an identifier (TOPIC) of a subset of programs presented in the catalogue, and in that it comprises a means of receiving an identifier of a program likely to be received according to the parameters defined in the proposition. 15. The audiovisual terminal as claimed in claim 10, additionally comprising a means of receiving (5) a channel and network reference (6) to receive the selected programme. 16. The audiovisual terminal as claimed in claim 10, additionally comprising a means of storing the programs received. 17. A server comprising a database containing audiovisual programs, the server having a communication interface for establishing a link (6) with a plurality of terminals, said server additionally comprising: a means of receiving propositions to transmit at least one program contained in the database, the said propositions coming from at least one terminal comprising at least one parameter such as a price or a deadline relating to the transmission of the program from the server to the terminals, a means of analysis of the propositions received, a means of determining a decision to transmit the program taking account of the parameters transmitted over a broadcast network; and a means of transmitting to the terminal a code for viewing at least one selected program. 18. The server as claimed in claim 17, wherein the means of analysis and determination is activated after a determined time from the moment when the programme is accessible to the users of the terminals. 19. The server as claimed in claim 17, wherein the means of analysis and determination is activated after receipt of a determined number of propositions from the terminals. 20. The server as claimed in claim 17, wherein a proposition received from a terminal comprises only one of the parameters from the set: price, deadline; and in that the acceptance sent to that terminal comprises a value of the other parameter in the set. 21. The server as claimed in claim 17, wherein a proposition received from a terminal comprises only one indication determining a subset of programs, the means of analysis and determination also comprises a means of determining a program belonging to that subset, for which the parameters sent in the proposition enable a transmission to that terminal. 22. The server as claimed in claim 17, additionally comprising a means of determining the means of transmission of the program, the notification of acceptance of the transmission to the terminals comprising an identifier of the means of transmission.

The invention concerns a method of transmitting audiovisual programmes in at least one terminal linked to a network as well as a terminal implementing the method and a server for transmitting the programmes to the terminals. The invention applies more particularly when the reception of the audiovisual programmes is conditional upon a payment. The context of the present invention is that of audiovisual servers capable of supplying audiovisual programmes on demand, and of any domestic device capable of displaying audiovisual programmes received from a terrestrial, microwave or satellite network and communicating with a server with the aid of a broadcast network. The audiovisual programme is typically transmitted over a one-way broadcast network. Access to the audiovisual programmes is usually conditional upon a payment by the user of the device. Electronic Program Guides (EPG for short) offer users a catalogue of audiovisual programmes, and particularly films. The user chooses a programme from this catalogue and after paying for the access rights, he receives the means of viewing it in clear. The programme is transmitted in encrypted form over the broadcast network and the receiver decrypts the programme by means of a previously received code. Another way of operating consists in setting up a call with the server supplying the programmes, interrogating its catalogue, and downloading the programme after a payment. The price, which is fixed by the programme supplier, is usually displayed by the EPG, so that the user knows the cost of the operation before committing himself. Certain devices have a hard disk or some other means of storing programmes (cassette, cartridge, DVD-RAM, etc.). A programme can then be downloaded over the network directly to the hard disk, in compressed form, irrespective of the display constraints. The programme can then be downloaded at any moment, without the user's intervention, and at a time that does not disturb him, at night for example. The programme is stored as it is received. During viewing, the device reads the programme from the storage means, decompresses it and sends the audiovisual signals to a screen. In fact the profitability of a download fluctuates considerably depending on the circumstances. One of the aims of the present invention is to be able to optimise the profitability of such downloads. For this purpose, the invention concerns a method of transmitting audiovisual programmes from a server to at least one terminal comprising a first step of viewing a catalogue of downloadable audiovisual programmes on the terminal, characterized in that it comprises the following chronological steps: at the terminal: a step of selecting at least one audiovisual programme; a step of generating a proposition conditioning the reception of the selected programme; a step of transmitting the proposition to the server, the proposition comprising at least one of the following parameters: deadline, price; and at the server: a step of analysing the propositions sent by the terminals and of determining a decision to transmit the programme taking account of the parameters; if the decision to transmit the programme is taken: a step of transmitting the selected programme, a step of transmitting a code enabling each terminal that has sent a proposition to view the received programme, viewing occurring after payment of a minimum price and/or not later than expiry of the determined deadline. In this way, the present solution means that the server does not have to propose at a low price a programme which, downloaded to a restricted population of users, will not be profitable for the server. Contrary to prior art which discloses a fixed programme price, the price in the invention can be fixed by the users according to their interests and validated by the server according to the profitability. As an improvement, the analysis step is activated after a determined time from the moment when the programme is placed in the catalogue. As a variant, the analysis step is activated after a determined number of propositions have been received. As an improvement, the server sends to the terminals a notification indicating after the analysis step that it has decided not to transmit the programme. This notification may include an indication of the reason for the server's refusal to transmit the programme. This notification may also include a parameter value which, incorporated in a proposition, would enable the user to view the programme. As another improvement, the proposition transmitted by a terminal includes an indication determining a subset of programmes from the catalogue, for example a precise topic. The server then selects from the subset a programme the transmission of which complies with the server's own criteria. As another improvement, the decision to transmit a programme is preferably taken when many users have proposed that programme. In this way, the present invention enables the server to download programmes only to a number of users known in advance and to defer the download or remove that programme from the catalogue if this number is too low. As a final improvement, the method comprises a step of recording the programme that one wishes to receive under certain conditions on the terminals. The present invention also concerns an audiovisual terminal comprising a central processor unit, a means of receiving audiovisual programmes, a means of two-way communication with a network, a means of displaying a catalogue of available programmes and a means of selecting an audiovisual programme, characterized in that it also comprises a means of generating at least one parameter such as the price and/or deadline, associated with the downloading of at least one selected programme, a first means of transmitting to the network a proposition comprising at least one programme identifier and the parameter entered, and a means of receiving an agreement to download the programme according to the previously generated parameter. The present invention also concerns a server comprising a database containing audiovisual programmes, the server having a communication interface for establishing a link with a plurality of terminals, characterized in that it comprises a means of receiving propositions for transmitting at least one programme contained in the database, the said propositions coming from at least one terminal comprising at least one parameter such as a price or a deadline relating to the transmission of the programme from the server to the terminals, a means of analysing the propositions received, a means of determining a decision to transmit the programme taking account of the parameters transmitted; and a means of transmitting to the terminal a code for viewing at least one selected programme. The present invention will now appear in greater detail in the context of the description that follows of exemplary embodiments given for illustrative purposes with reference to the appended figures amongst which: FIG. 1 is a block diagram of an audiovisual receiver for the implementation of the invention, FIG. 2 is a diagram showing the different elements of a server according to the invention, FIG. 3 illustrates the different communications between a user and the server, FIGS. 4a, 4b, 4c and 4d represent what appears on the screen for the implementation of the invention. We will first describe with the aid of FIG. 1 the operation of an audiovisual receiver 1 provided with a display device 2. The receiver comprises a central processor unit 3 linked to a program (ROM) and work (RAM) memory 12, and an interface 5 for a two-way communication with a network 6. This interface is also called a return channel. This network is for example an IEEE 1394 network. The receiver may also receive audio/video data from a broadcast network via a receive antenna associated with a demodulator 4. The antenna may also be replaced by a physical connection to any type of high bit rate local digital bus for transmitting audio/video data in real time, such as a cable access point or a DSL connection. The receiver also comprises an infrared signal receiver 7 to receive the signals from a remote control 8, a means of storage 9 for the storage of audiovisual programmes and an audio/video decoding logic system 10 to generate the audiovisual signals sent to the television screen 2. The nature of the audiovisual programmes being digital, the means of storage 9 is preferably a hard disk (HDD), it may also be a recordable optical disk drive (DVD-RAM). The remote control 8 has direction buttons ↑, ↓, → and ← and “OK”, “Buy” and “Send” buttons the use of which will be revealed later in the description. The receiver also has a clock (not shown) to wake up the receiver when a programme to be recorded is on the point of being downloaded. The receiver also comprises a circuit 11 for displaying data on the screen, often called an OSD circuit, “On Screen Display”. The OSD circuit 11 is a text and graphics generator which is used to display on-screen menus, pictograms (for example a number corresponding to the channel displayed) or which is used to mix two audiovisual contents. The OSD circuit is controlled by the central processor unit 3 and a program called a “Loader” which is resident in the memory 12. The Loader typically consists of a program module written in read only memory and of parameters saved in work memory. The Loader may also be implemented in the form of a specific circuit of the ASIC type for example. This circuit may have security functions for making a payment following a user's decision to view a pay-per-view programme. The receiver receives audiovisual programme identification data from the return channel 6 or the broadcast network. This data comprises viewable elements, the title for example or an image of the preview trailer. With the aid of an EPG and the buttons on his remote control, the user selects one or more programmes with a view to receiving them and recording them on the hard disk 9. The server described in FIG. 2 comprises a central processor unit 2.1, a program memory 2.2, a memory containing a database 2.3 preferably implemented by a hard disk and a communication interface providing a two-way link 2.4 over the two-way network 6 with the previously described receivers. The database 2.3 mainly contains the catalogue of available programmes. The server is also in contact with the broadcast network manager via an interface (not shown). It sends to this manager mainly instructions to broadcast programmes at determined dates and times. After having described the different elements of the invention we will now explain how they cooperate. The different communications between the user and the server are illustrated in FIG. 3. First the user starts the Loader program which initially downloads from the broadcast network the catalogue of available programmes. A variant consists in logging on to the server over the network 6 and in downloading the catalogue. The catalogue managed by the server contains a list of programmes proposed to the users, these programmes being identified by a title or an image of its preview trailer. The catalogue is then displayed on the screen 2 so that the user can select at least one programme. Taking account of his availability and budget, the user determines parameters with the ultimate aim of viewing that programme on his receiver: a price and a latest date for making the programme available to him. Then, during a first communication (communication 3.1), the user sends the server the triplet formed of the following elements: identifier of the programme tagged in the EPG, the latest date for receiving the programme, the proposed price. The server records all the propositions and, following an analysis step, determines the server parameters beyond which the broadcast becomes profitable for the server. These parameters are calculated according to the duration of broadcast of the programme, which, because of this, occupies the network for a determined time, and according to the time of broadcast. For example, transmission at night costs less than during the day. After the proposition analysis step for a given programme, the server compares the parameters of each proposition with those previously calculated. If the price proposed by the user is equal to or greater than that determined by the server AND if the latest date proposed by the user is equal to or later than that predicted by the server, THEN the server accepts the proposition from that user and notifies him of its agreement in a communication (communication 3.2). The server also sends the user a payment request (communication 3.3). It is important to note that the server does not transmit its parameters, so the users cannot know them and are obliged to propose a considerable sum to be sure that the server has an interest in instructing the broadcast of that programme so that the user can receive it. The user receives the notification that his proposition has been accepted and that the server requires him to pay for the programme. He then makes the payment according to known techniques, using for example prepaid tokens or a bank type smart card inserted into his receiver. The payment parameters are sent to the server (communication 3.4). The server checks that the payment parameters are authentic and, if they are, sends a particular code to the receiver (communication 3.5) which will enable it to decrypt the programme when it is received. In a possible variant, the user does not make the payment directly but commits to pay for the received programme against an invoice which will be presented to him later. This invoice may include the user's different uses of the service during a given period, and even of other services, such as a subscription to a cable access supplier or to a satellite television operator. The programme may be made available to the user in different ways. A first way consists in recording the programme in encrypted form in each receiver that has sent a proposition. Then, if the proposition is accepted and if the payment is made, a code used for decryption is transmitted to the receiver. In this way, payment can be made independent of reception. A variant consists in first transmitting to the receiver the acceptance of the proposition and, if the payment is made, the decryption code. Then, the programme is transmitted in encrypted form, decrypted on receipt and recorded in clear in the receiver's memory. This other method has the advantage of avoiding decryption every time the recorded programme is viewed. The Loader displays menus by which the user can enter his parameters and start the communications between the server and the receiver. The first menu illustrated in FIG. 4.a is for presenting the catalogue of programmes proposed by the server. In the example, three programmes are available: “Life of Brian”, “Super Bowl” and “Jaws”. Icons marked “BUY” are placed beside the titles. The user selects the icon corresponding to the programme he wishes to receive. A variant consists in using a special “Buy” button on the remote control 8. The menu illustrated in FIG. 4.b appears. This menu lets the user enter the parameters of his proposition. In a window, the user enters the price he wants to pay on the buttons of the digital keypad of his remote control 8, in the example: 25F. In another window, the user enters the latest date and time for receiving that programme, “12h00”, at the price he has set. Then, the user confirms his proposition by pressing the “Send” button. The proposition consisting of an identifier of the selected programme and the parameters the user has entered is then sent to the server. The server receives the proposition over the network 6 and records it in its database 2.3 with the other propositions relating to the same programme. At the end of a certain time after the programme is placed in the catalogue (six hours for example), the server initiates the step of analysing the propositions received. It first determines the set of propositions that have not lapsed, that is which concern programmes that may still be transmitted within the deadline proposed by the users. The server then calculates the total price of the propositions of that set and the transmission deadlines imposed by the users. According to a strategy that is described later, the server decides whether or not to program the programme broadcast. If the server cancels the broadcast because it is not profitable, it notifies its refusal in a communication, indicating the programme's identifier. This notification can be made either over the broadcast network or over the return channel. If the notification is made over the broadcast network, each receiver verifies whether it has previously sent a proposition for that programme and, if it has, informs the user via a message on the screen 2 that he will not receive the programme corresponding to his proposition. If the server programs the broadcast of the programme considering it to be profitable, it then repeats the communication with each user. For this, it sends a message to all the receivers that have sent a proposition, indicating agreement, the programme's identifier, the parameters proposed by each user, and the date of availability of that programme. The receiver then displays the menu illustrated in FIG. 4.c indicating the time of download of the programme. The server then requests payment. The user confirms by pressing the “OK” button which has the effect of initiating the transaction for the sum of 25F according to the previous example. The server receives the payment certificate and returns to the user the acknowledgement of receipt which is displayed in the form of the menu illustrated in FIG. 4.d. The sentence “The “Life of Brian” programme will be delivered” is displayed. Acceptance of the proposition sent to the user is transmitted no later than immediately before the download of the programme. The step for analysing the propositions is initiated in a simple manner a determined time from the moment when the programme is proposed in the catalogue. A variant consists in counting the propositions for a given programme and in initiating the analysis step when a certain number of propositions have been received. If, after a maximum deadline set at the beginning by the server, the minimum number of propositions has not been reached, the server does not instruct its broadcast. Naturally, if other propositions arrive after the analysis step and before the broadcast, and if they are compatible with the price and deadline parameters calculated by the server, they are accepted and the programme is downloaded to the users who have requested it. An improvement of the invention consists in the server indicating at least one reason for refusal of the propositions. For example, a proposition for a programme of very long duration while requesting a short deadline cannot be accepted for material reasons of bandwidth occupancy of the broadcast network. Whatever price is proposed, the proposition cannot be satisfied. The server does not wait for the end of the proposition analysis step and responds immediately to the user in the negative indicating the reason for the refusal. This improvement enables the user to reformulate his proposition taking account of the reason for the refusal, in this case by indicating another deadline and sending it to the server. This new proposition has more chance of being accepted. An improvement consists in the user not defining precisely the programme he wants to receive but one or more of the criteria transmitted in signalling tables (for example a table described in the DVB-SI standard). These tables contain attributes characteristic of audiovisual programmes. The criteria define subsets of programmes that have a criterion in common. For example, the user may define one or more topics and/or sub-topics of programmes, such as: Nature: film and topic: science fiction, or “documentary” and “wildlife”. The user may also use the name of an actor or that of a producer. For example, he may ask the server for a “western” with “John Wayne”. In return the server chooses a programme, which corresponds to the criteria or for which the analysis step has culminated in an acceptance of broadcast, and then it proposes it to the user. We will now explain how the server determines which programmes to download and in what order. Suppose that the server proposes m programmes Ei (i=1 to m) in its catalogue. We have previously said that the server records all the propositions from the users in its database 2.3. At a certain moment, it analyses all the propositions and calculates parameters beyond which the programme broadcast is profitable. For a given programme “Ei”, the amount of money the propositions would generate for it if they were satisfied varies according to the deadline for transmitting that programme. This is for two reasons: on the one hand the longer the server waits, the fewer users it satisfies. On the other hand, the users who want to receive the programme quickly are likely to make a better offer, whereas those who are not in a hurry to receive it propose a lower price. The present invention enables the server to program the broadcast of the programme according to the price that that broadcast will generate for it. The server constantly updates an array indicating, for each programme and for the subsequent eight time bands, the number of users and the amount of money that the users are proposing to receive the programme. When a programme is transmitted, it disappears from the array. But it may reappear if it is not removed from the catalogue because users may continue to request it. Certain programmes are very popular and may be transmitted a set number of times, so they must not be removed from the catalogue after the first broadcast. To simplify, the array below contains only four programmes. Trans- Broad- mission 1 st 2nd 3rd 4th 5th 6th 7th 8th cast: duration hour hour hour hour hour hour hour hour E1 58 min 23/ 65/ 89/ 85/ 45/ 23/ 9/ 5/ 412F 925F 1230F 1050F 602F 245F 98F 65F E2 131 min 51/ 95/ 88/ 81/ 61/ 52/ 40/ 26/ 982F 1756F 1622F 1460F 801F 560F 456F 287F E5 28 min 23/ 24/ 26/ 29/ 25/ 12/ 12/ 5/ 321F 322F 331F 348F 305F 185F 160F 64F E9 90 min 45/ 32/ 25/ 19/ 18/ 15/ 12/ 16/ 765F 612F 498F 358F 321F 301F 205F 198F (the figures are given as an example, the prices are the totals of the propositions). A first strategy consists in the server taking account of the immediate propositions, that is within the hour. The proposition analysis step is in this case reduced to an hour. This strategy is justified because it makes it possible to satisfy all the users who have requested a programme irrespective of the proposed deadline. After a time band, the server erases from the array the data concerning the programmes transmitted (unless it has been agreed to transmit it several times), and analyses the next time band. The server then determines which programmes are to be downloaded during that time band. The array is continually updated in line with the propositions, if a proposition arrives but does not concern a programme listed in the catalogue, the server sends a refusal notification to the user. Indeed, as soon as a programme is in the catalogue, it is automatically listed in the array. For each programme, the server adds together the amounts of money corresponding to each time band and chooses the programmes that generate the most. From the numerical values given in the above array, we can see that downloading the programmes would generate: For programme E1: 4627 F For programme E2: 7924 F For programme E5: 2036 F For programme E9: 3258F According to the first strategy, the server gives priority to transmitting the programmes which generate the most for it: first E2, then E1, then E9 and E5. This first strategy is appropriate when the server receives few propositions and if the catalogue contains a restricted number of programmes. But, if many choices are offered to the users, the server will probably receive propositions for each programme. It must therefore make a selection. At the end of each time band, it determines the programmes which are the most profitable to download. To determine the profitability of downloading a programme, the server can take account of the duration of its broadcast. For that, it calculates for each broadcast the revenue per unit of time (a minute for example) of its transmission: For programme E1: 4627 F/58=80 F/min For programme E2: 7924 F/131=60 F/min For programme E5: 2036 F/28=73 F/min For programme E9: 3258F/90=36 F/min Suppose for example that the bandwidth of the broadcast network allows the downloading of only approximately three hours of audiovisual programmes per time band. It is therefore important to optimise this time band and to download the most profitable programmes first. In the present case, programmes E1 and E5 are the most profitable and will be run before programme E2. There then remain 180−(58+28)=94 minutes of transmission, which is insufficient to broadcast programme E2. Because of its duration, the broadcast of E2 will occur over two time bands. So the propositions to receive E2 within at least two hours will be satisfied, but not those to receive in the hour. The broadcast of E2 will therefore not satisfy all the propositions. The 131−94=37 remaining minutes to transmit E1 will be taken in the next time window. To the users for whom the proposed deadline is not satisfied, the server sends a message indicating the predicted time of downloading and a price lower than the one initially proposed. These users are then free to accept or reject the new offer made to them by the server. Another strategy (which may also be used to choose between two equivalent options in terms of profitability) consists in choosing the programmes that satisfy the maximum of users. The server will then choose programme E9 which can be broadcasted within the remaining time span of 94 minutes, rather than programme E1. So the server can satisfy all the users that have requested E1, E5 and E9. It should be noted that the user is not sure, when he makes a download proposition, of obtaining what he wants. After the analysis step, the server determines the groups of propositions that are the most valuable and chooses the most advantageous ones. Certain propositions will then be refused. An improvement consists in that the downloads are carried out on several channels. Certain channels with higher bit rates will be used for short deadline downloads. Other channels are used for programmes with a low financial return. The means of communication may be different, the server may use microwave or satellite channels. Another improvement consists in the server taking account of the evolution of the deadlines proposed by the users. When analysing the evolution of the propositions versus proposed deadline: 1 hour, 2 hours, 3 hours, etc., we see that as a general rule the number of propositions increases and then decreases after a certain deadline known as the “extremum”. If the server delays the transmission of a programme by one or more time bands, the number of unsatisfied propositions remains low compared with the total number of propositions. If the extremum is in the first time band, the transmission delay for that programme means that a large number of propositions are not satisfied. Determining the position of the extremum in the time bands is therefore an important factor in defining the next downloads. For example, by analysing the numerical values in the above array, we see that the maxima of the propositions occur in the following time bands: For programme E1: 3 hours For programme E2: 2 hours For programme E5: 4 hours For programme E9: 1 hour In the present case, if the server must make a selection while favouring this strategy, it will download as a priority E9 for which the extremum occurs during the first time band, then E2 (second time band), then E1 (third time band) and finally E5 (fourth time band). This strategy minimizes the loss of revenue due to unsatisfied propositions. A improvement of the present invention consists in the user sending an incomplete proposition, in which a parameter is missing. For example he sends a price without any deadline or vice versa. The server receives his proposition and, because of the schedule of downloads, proposes in return a value of the missing parameter to satisfy the user. For example, the user sends a proposition indicating a programme and a price but without indicating the deadline. After the analysis step, the server replies, indicating the predicted deadline taking account of the parameters calculated at the end of the analysis step. If many propositions have been received and confirmed, the deadline will be short because the rapid download of such a programme is profitable. However, if few propositions have arrived, the deadline is long, or the server responds that it currently cannot program a download for that programme. If several servers propose different catalogues, certain elements of the catalogues may be identical. Another improvement of the present invention consists in the loader launching the same proposition to several servers and after the various interchanges, transmits to the user the best offer, indicating which server could download the programme.

20040902

20100309

20050106

58620.0

HICKS, CHARLES N

METHOD FOR TRANSMITTING AUDI-VISUAL PROGRAMS PROPOSED BY USERS, TERMINAL AND SERVER

UNDISCOUNTED

ACCEPTED

ACCEPTED

Selective metal removal process for metallized retro-reflective and holographic films and radio frequency devices made therewith

A method for selectively removing metal from a metallized substrate (e.g., a metallized polymer film) and the formation of devices thereby are provided. Th method involves selectively exposing the metallized surface to a demetallizing (i.e., an oxidizing) chemical solution. The metallized layer can be selectively exposed to the demetallizing solution using a flexographic printing process wherein printing rollers are used to transfer the demetallizing solution to the metallized surface. An identification device including, for example, a holographic, retro-reflective, or other metallized material and a radio-frequency transponder are also provided. The radio-frequency transponder includes an RF chip and an antenna in electrical communication with the chip. The identification device including the holographic image allows both electronic identification through the reading or identification data stored in the chip and optical identification via the holographic image.

1. An identification device, comprising: a base layer; a radio-frequency (RF) transponder comprising an RF chip and an antenna disposed on the base layer, wherein the antenna is in electrical communication with the chip; and a discontinuous metallized region; wherein the discontinuous metallized region enables the RF transponder is to transmit and receive information at radio frequencies. 2. The device of claim 1, wherein the discontinuous metallized region comprises an image. 3. The device of claim 2, wherein the image is a holographic image. 4. The device of claim 1, wherein the discontinuous metallized region comprises a retro-reflective layer. 5. The device of claim 1, wherein the discontinuous metallized region comprises a holographic image and wherein the holographic image and the antenna form a single metal layer. 6. The device of claim 1, wherein the base layer has at least one side, and wherein the antenna and the discontinuous metallized region are located on the same side of the base layer. 7. The device of claim 1, wherein the base layer has at least a first side and a second side, the first side being opposite the second side, and wherein the antenna and the discontinuous metallized region are located on opposite sides of the base layer. 8. The device of claim 1, wherein the base layer has at least a first side and a second side, the first side being opposite the second side, and wherein a first part of the antenna and the discontinuous metallized region are located on the first side, and a second part of the antenna is located on the second side of the base layer, and wherein the first part of the antenna is electrically connected to the second part of the antenna. 9. The device of claim 1, wherein the device comprises an upper metal layer positioned above the base layer and a lower metal layer positioned below the base layer, wherein a first part of the antenna is formed on the upper metal layer and a second part of the antenna is formed on the lower metal layer, the device further comprising a through contact connecting the first part of the antenna to the second part of the antenna. 10. The device of claim 1, wherein the discontinuous metallized region is in electrical communication with the antenna. 11. The device of claim 10, wherein the discontinuous metallized region comprises an electronic commutation element. 12. The device of claim 10, wherein the discontinuous metallized region comprises a capacitor. 13. The device of claim 1, wherein the discontinuous metallized region comprises a plurality of electrically isolated holographic regions. 14. The device of claim 1, wherein the base layer is an electrically conductive layer. 15. The device of claim 14, wherein an isolation layer is formed on the base layer. 16. The device of claim 15, wherein the radio frequency (RF) chip is mounted on the isolation layer. 17. The device of claim 15, wherein the base layer includes a depressed region, and wherein the isolation layer is formed in the depressed region. 18. The device of claim 1, wherein the base layer has at least one side, and wherein the antenna and the discontinuous metallized region are formed on the same side of the base layer in discrete, non-overlapping areas. 19. The device of claim 1, wherein the antenna comprises a conductive wire inlaid in a polymer layer. 20. The device of claim 1, wherein the device is selected from the group consisting of a decal, a license plate, and an identification card. 21. The device of claim 1, wherein the discontinuous metallized region comprises a square grid pattern. 22. The device of claim 21, wherein the squares in the square grid pattern have a length of about 5 mm or less. 23. The device of claim 21, wherein the squares in the square grid pattern have a length of about 3 mm or less. 24. A method of forming a pattern in a metallized region, the method comprising: transferring a metal etching solution to portions of an exposed surface of the metallized region using a printing process; allowing the etching solution to react with the metallized region to selectively demetallize the surface; and washing the selectively demetallized surface. 25. The method of claim 24, wherein the printing process is selected from the group consisting of a flexographic printing process, an offset printing process and a screen printing process. 26. The method of claim 24, wherein the metal etching solution is an aqueous solution of sodium hydroxide. 27. The method of claim 26, wherein the metal etching solution further comprises ethylene glycol. 28. A method of making an identification device comprising a base layer and a plurality of metallized regions disposed thereon, the method comprising: forming an antenna in a first metallized region; and forming a holographic image in a second metallized region; wherein the antenna is formed by a method comprising: transferring a metal etching solution to portions of an exposed surface of the metallized layer using a printing process; allowing the etching solution to react with the metal to selectively demetallize the surface; and washing the selectively demetallized surface. 29. The method of claim 28, wherein the first and second metallized regions form a single metal layer. 30. A method of making a radio-frequency (RF) identification device comprising: forming an antenna on a base layer; and mounting an radio frequency (RF) chip on the base layer in electrical communication with the antenna to form an RF transponder; wherein the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. 31. The method of claim 30, wherein the antenna is formed by partial deposition of a discontinuous metallized layer by a method selected from the group consisting of chemical deposition, electrical deposition, sputtering and vapor coating. 32. The method of claim 30, further comprising: forming a discontinuous metallized region on the base layer, wherein the discontinuous metallized region comprises a retro-reflective material or a holographic material. 33. The method of claim 32, wherein the discontinuous metallized region and the antenna are formed simultaneously. 34. The method of claim 30, wherein the antenna is formed by selective de-metallization of a continuous metallized layer, and wherein selective demetallization comprises: transferring a metal etching solution to portions of an exposed surface of the continuous metallized layer using a printing process; allowing the etching solution to react with the metal; and washing the exposed surface of the metallized layer. 35. A method of making an identification device comprising a base layer and a metallized retro-reflective layer, the method comprising: forming a discontinuous retro-reflective layer on the base layer, forming an antenna on the base layer, and mounting a radio frequency (RF) chip on the base layer; wherein the chip the and the antenna are in electrical communication to form an RF transponder, and wherein the discontinuous retro-reflective layer retains retro-reflective properties while allowing the RF transponder to transmit and receive information at radio frequencies. 36. The method of claim 35, wherein the base layer has at least one side, and wherein the antenna and the retro-reflective layer are formed on the same side of the base layer in discrete, non-overlapping regions. 37. The method of claim 35, wherein forming an antenna comprises: forming an inlaid antenna by embedding a conductive wire in a polymer layer; and affixing the inlaid antenna to the base layer. 38. The method of claim 37, wherein the inlaid antenna is affixed to a demetallized region of the retro-reflective layer 39. The method of claim 37, wherein the inlaid antenna is provided with an adhesive layer and wherein affixing an antenna further comprises: adhesively bonding the antenna to the device through the adhesive layer. 40. The method of claim 38, wherein the adhesive is selected from a group consisting of an auto-adhesive and a pressure sensitive adhesive. 41. The method of claim 37, wherein the polymer layer comprises polyvinyl chloride (PVC) or polyethylene terephthalate (PET). 42. The method of claim 36, wherein the radio frequency (RF) chip is mounted on the same side of the base layer as the antenna and retro-reflective layer. 43. The method of claim 35, further comprising: forming a depressed region in the base layer, and forming an isolation layer in the depressed region; wherein the radio frequency (RF) chip is mounted on the isolation layer. 44. The method of claim 43, wherein the antenna is formed on top of the depressed region. 45. The method of claim 43, wherein the isolation layer comprises a ferrite composite. 46. The method of claim 35, further comprising: over-printing a design on the surface of the retro-reflective material. 47. The method of claim 35, wherein forming a discontinuous retro-reflective layer comprises: transferring a metal etching solution to portions of an exposed surface of a continuous metallized retro-reflective layer using a printing process; allowing the etching solution to react with the metal of the retro-reflective layer; and washing the exposed surface of the metallized retro-reflective layer. 48. The method of claim 47, wherein the metal etching solution is transferred to the exposed surface of the metallized retro-reflective layer as a plurality of lines arranged in a square pattern. 49. The method of claim 48, wherein the lines are spaced apart about 5 mm or less. 50. The method of claim 48, wherein the lines are spaced apart about 3 mm or less. 51. The method of claim 35, wherein the base layer comprises a polymeric material and wherein forming an antenna comprises: forming an inlaid antenna by embedding a conductive wire in the base layer. 52. The method of claim 51, wherein a demetallized portion of the retro-reflective layer is applied over the antenna layer. 53. The device of claim 1, wherein the discontinuous metallized layer is directly disposed on at least one surface of the base layer. 54. The device of claim 1, wherein the discontinuous metallized layer comprises at least one metal selected from the group consisting of aluminum, aluminum alloys, nickel, silver and copper. 55. The device of claim 1, wherein the discontinuous metallized layer is formed by a process selected from a group consisting of a chemical deposition, electrical deposition, sputtering and vapor coating. 56. The device of claim 1, wherein the antenna is formed by selective demetallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. 57. The device of claim 56, wherein the antenna is formed by partial deposition of a discontinuous metallized layer by a method selected from a group consisting of chemical deposition, electrical deposition, sputtering and vapor coating. 58. The device of claim 1, wherein the antenna comprises at least one metal selected from a group consisting of aluminum, aluminum alloy, nickel, silver and copper. 59. The device of claim 58, wherein the antenna comprises an amorphous metal. 60. The device of claim 1, wherein the thickness of the antenna is between about 0.5 and 3 microns. 61. The device of claim 1, wherein the thickness of the base layer is between about 5 and 3,000 microns. 62. An identification device, comprising: a base layer; and a radio-frequency (RF) transponder comprising an RF chip and an antenna disposed on the base layer, wherein the antenna is in electrical communication with the chip; wherein the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. 63. The device of claim 62, wherein the antenna comprises at least one metal selected from a group consisting of aluminum, aluminum alloy, nickel, silver and copper. 64. The device of claim 62, wherein the antenna comprises an amorphous metal. 65. The device of claim 62, wherein the thickness of the antenna is between about 0.5 and 3 microns. 66. The device of claim 62, wherein the thickness of the base layer is between about 5 and 3,000 microns.

This application claims priority from German Patent Application No. 10121126.0 filed 30 Apr. 2001 and from Mexican Patent Applications No. 010967 filed 26 Oct. 2001, No. 010968 filed 26 Oct. 2001, No. 010969 filed 26 Oct. 2001, No. 010971 filed 26 Oct. 2001, No. 003141 filed 25 Mar. 2002, and No. 003202 filed 26 Mar. 2002, the disclosures of all of which are hereby incorporated by reference. This application is a continuation-in-part of U.S. patent application Ser. No. 10/118,092 filed 09 Apr. 2002, the disclosure of which is also hereby incorporated by reference. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to a process for selectively removing metallic material from a metallized film and, in particular, to the removal of metallic material from a metallized polymeric film using a printing method such as flexographic printing. The film can be a reflective film (e.g., a retro-reflective film) or a holographic film that can be used, for example, in an identification device comprising a radio frequency (RF) transponder. 2. Background of the Technology Retro-reflective materials can reflect and re-emit incident light in a direction that is parallel to that of the source of the incident light. In other words, retro-reflective materials reflect light directly back toward the source of the light Such materials and devices are widely used in the areas of nighttime transportation and safety. For example, retro-reflective materials are used to identify highway lanes and road signs using the light emitted from vehicle headlights. Retro-reflective materials are also used for the production of car plates, decals and distinctives for all kinds of vehicles and for truck containers, tractors and other applications. Retro-reflective materials have a bright effect under direct light without disturbing human sight Holographic materials have also been used for identification purposes. Since holograms are all but impossible to counterfeit, they are being increasingly used on all types of identification, including driver's licenses, credit cards, bus passes, etc., to increase security. Both retro-reflective and holographic materials typically contain a very high level of metal such as aluminum. Holograms, for example, are typically stamped from metal foils. It is known that metal blocks the transmission and reception of radio frequency (RF) signals because the RF signal is absorbed or distorted by the metal content in the material. As a result, the signal cannot be received by an antenna blocked by metal. Such a blocked signal cannot be used, for example, to activate a connected device. This same blocking effect can occur whether the device is positioned on top of or underneath the metallic material because the distortion and absorption of the RF signal will be affected in either case. Thus, there is a problem in the prior art with regard to using retro-reflective and holographic materials, as well as other materials containing metals, on the surface of devices for receiving RF signals. It would be desirable to incorporate an RF transponder into an identification device comprising a retro-reflective material, a holographic image, or other material containing a metal. The RF transponder could be used for electronic identification. SUMMARY OF THE INVENTION According to a first aspect of the invention, an identification device is provided that includes retro-reflective or holographic materials, or other materials containing metal, and a usable antenna for receiving radio frequency (RF) signals. The identification device comprises: a base layer, an RF transponder comprising a mounted RF chip and an antenna disposed on the base layer, and a metallized region. The metallized region can comprise a holographic image or a ret reflective layer. The antenna is in electrical communication with the chip. According to this aspect of the invention, the metallized region is discontinuous, such that the RF transponder can transmit and receive information at radio frequencies. According to a second aspect of the invention, a method of forming a pattern in a metallized layer is provided. The method comprises: transferring a metal etching solution to portions of an exposed surface of the metallized layer using a printing process; allowing the etching solution to react with the metallized layer to selectively demetallize the surface; and washing the selectively demetallized surface. According to a third aspect of the invention, a method of making an identification device comprising a base layer and at least one metal region disposed thereon is provided. The method comprises: selectively demetallizing a first metal region of the device; forming a holographic image in the first metal region; forming an antenna on the base layer; and mounting an RF chip on the base layer in electrical communication with the antenna to form an RF transponder. According to this aspect of the invention, the selective demetallization of the first metal region allows the RF transponder to transmit and receive information. According to a fourth aspect of the invention, a method of making an identification device comprising a base layer and a metallized retro-reflective layer is provided. The method comprises: forming an antenna on a base layer; and mounting a radio frequency (RF) chip on the base layer in electrical communication with the antenna to form an RF transponder. According to this aspect of the invention, the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. According to a fifth aspect of the invention, an identification device is provided. The device includes a base layer and a radio-frequency (RF) transponder comprising an RF chip and an antenna disposed on the base layer wherein the antenna is in electrical communication with the chip. According to this aspect of the invention, the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. Additional advantages and novel features of the invention will be set forth in part in the description that follows, and in part will become more apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention. BRIEF DESCRIPTION OF THE FIGURES The invention will be described with reference to the accompanying figures, wherein: FIG. 1 is a lateral cross-sectional view of a metallized substrate suitable for making an identification device according to the invention; FIG. 2 is a top view of an identification device according to the invention comprising a holographic image and an antenna; FIG. 3 is a bottom view of the identification unit shown in FIG. 2, showing a chip module mounted on the bottom surface of the identification device; FIG. 4 is a lateral cross-sectional view of a further embodiment of a device according to the invention, comprising two metallized layers arranged one above the other; FIG. 5 is a top view of a device according to the invention, wherein the antenna is in electrical communication with the holographic image; FIG. 6 is a top view of a further embodiment of an identification device according to the invention, wherein the device has a selectively demetallized holographic image; FIG. 7 illustrates a method of making identification devices from a continuous strip of metallized material having multiple segments that may be separated from the strip to make individual identification devices, in accordance with embodiments of the invention; FIG. 8 illustrates a method of selectively removing metal from a metallized substrate according to the invention; FIG. 9 shows an apparatus that can be used for the continuous selective demetallization of a metallized film according to the invention; FIG. 10 shows a method of making a license plate having a retro-reflctive layer and an RF transponder according to the invention; FIG. 11 shows a license plate according to the invention, comprising a retro-reflective layer and an RF transponder made by the method illustrated in FIG. 10; FIG. 12 shows a method of forming an inlaid antenna according to the invention; and FIG. 13 shows a method of forming an identification device according to the invention comprising inlaying an antenna in the base layer and overlying a selectively demetallized retro-reflective layer. DETAILED DESCRIPTION OF THE INVENTION The present inventors have discovered a method by which a radio frequency (RF) device can be integrated into an identification device comprising a metallized reflective (e.g., a retro-reflective) or holographic material. In particular, the present inventors have discovered that, by selectively removing or depositing metal to form a discontinuous metal layer, the conductivity of the metallized layer can be broken and the effect of absorption and distortion of the radio waves that an RF device uses as a power source can be reduced. In this manner, a radio frequency device can be incorporated into a retro-reflective or holographic material, such as a license plate, a decal (e.g., for a car license plate) or an identification card. According to the invention, a demetallizing solution, such as a solution of sodium hydroxide (NaOH), can be used in place of ink in a printing process to selectively demetallize a metal layer. In particular, the demetallizing solution can be poured into the stainless steel trays of a printing apparatus. The demetallizing solution can then be applied to the metallized surface using a printing process. For example, the solution can be applied to a printing plate having a raised pattern. The plate can then be contacted with the metallized surface such that the solution on the raised areas is transferred to the metallized surface. The application of the demetallizing solution to the metallized surface can be controlled by the inking rollers of a printing apparatus (e.g., by the pressure applied to the inking rollers). According to a preferred embodiment of the invention, the demetallizing solution is applied to the metallized layer using a flexographic printing process. The flexographic printing process is a rotary in-line printing method that uses flexible resilient plates with raised images to apply inks to a substrate. According to a preferred embodiment of the invention, the flexographic printing process can be performed using laser-engraved anilox rolls to allow for high resolutions. By using a printing process, such as a flexographic printing process, the sodium hydroxide solution can be transferred to selective portions of the metallized film. In this manner, metal can be selectively removed from those areas. According to the invention, the exposure time of the metallized layer to the sodium hydroxide solution can be controlled to ensure that the resulting chemical reaction sufficiently removes metal from the desired areas. According to the invention, after the demetallization process is complete, the selectively demetallized film can be transferred to a washing unit where any excess or remaining chemical solution can be removed. According to a preferred embodiment of the invention, washing of the demetallized surface can be accomplished using fine sprinklers. The metallized film, which has been moistened by the previous wash, can then be subjected to a residue evaporation process. Residue evaporation can be accomplished using a set of two rolls (e.g., one made of rubber, one made of steel), as well as by such processes as use of air-cleaning filters, sponges and/or blown air. The residue evaporation process can be used as a preparation step preliminary to a heat-driven drying stage. During the heat-driven drying stage, the heat can be generated, for example, by electrical resistance. The metal removal process according to the invention can be used to produce a metallized material that is non-blocking to radio frequency transmissions. Therefore, a radio frequency device can be incorporated into an identification device (e.g. a card or plate) having a metallized (i.e., a retro-reflective or holographic) layer. As a result of the demetallization process, the radio-frequency device can transmit or receive information while in close proximity to the metallized layer. Additionally, by using a selective demetallization process according to the invention, the metallized film can be made translucent. Therefore, a visible seal can be incorporated beneath the metallized layer according to the invention. Features of the present invention directed to a metal-removal process for a metallized material (e.g., a metallized polymer film) will now be described in greater detail. According to a preferred embodiment of the invention, the method comprises subjecting the metallized material to a flexographic printing process, wherein the inks are replaced by a metal etching solution. According to a preferred embodiment of the invention, the metal etching solution is an oxidizing solution. For example, an oxidizing solution can be poured into the stainless steel ink trays of a standard flexographic printing station. The oxidizing solution according to the invention preferably comprises sodium hydroxide (NaOH), water (H2O), and, optionally, ethylene-glycol. The ethylene glycol can be used as a density-reduction agent. According to a preferred embodiment of the invention, the oxidizing solution can be transferred to the inking rollers through a second roller (i.e., an “anilox” roller). The oxidizing solution can then be transferred to a third roller, which conveys the solution to the metallized surface. The exposure time of the metallized surface to the demetallizing solution can be controlled to ensure that the resulting chemical reaction removes the metal properly from the desired areas. As set forth above, the demetallizing solution according to the invention can be an aqueous solution of sodium hydroxide (NaOH). When NaOH contacts the metallic surface, the metal is converted into a metallic oxide via an oxidative chemical reaction. To stop this oxidative process, the metallized surface can be washed with water. For example, the metallized surface can be washed using fine sprinklers to cover the entire metallized surface to ensure the removal of any residue and/or excess of the demetallizing solution. The present invention also relates to the manufacture of an identification device created with a metallized material (e.g., a retro-reflective or holographic material), which device includes a chip and an antenna (i.e., a radio frequency device). According to a preferred embodiment of the invention, the antenna can be formed from the same metallized layer used to manufacture the reflective or holographic material. When the device is made with a holographic image, an identification device can be provided having a capability of both electronic identification (i.e., via the reading of data stored in the chip) and optical identification (i.e., using the holographic image). For example, the device can be configured as an identification card that allows an electronic identification through the reading of data stored in the chip and the optical identification via a check of the hologram on the device. For the holographic image on the identification device, metallic films such as aluminum films can be used. The metallic films can be grouped on the device to form the hologram using known techniques. For example, the hologram can be made using conventional techniques, such as forming the hologram by stamping a metal foil with a hologram plate made using an engraving process. In the case of identification cards or identification stickers, which can allow the transmission of identification data stored in a chip to a reading device, a grouping technique can be used involving coupling a transporting unit with a chip and an antenna The antenna can be made by placing a wire conductor on the device or by etching the antenna in the metallic film. One purpose of the invention is therefore to provide an identification device that allows both optical identification via a holographic image on the device and electronic identification via an RF chip mounted on the device. The metallized layer can be used to prepare both the antenna for the RF device as well as to prepare the optical image on the device. The fact that the antenna and the image can be made from the same metallized layer represents an advantage since only a single metallized layer is required. As a result, the manufacturing process can be simplified and the cost of manufacturing the device can be reduced. Although the aforementioned method of selective de-metallization is preferred, other methods of selective de-metallization can be employed according to the invention. For example, a photo-mask layer can be formed on the metallized layer and a pattern formed on the mask layer using a photo-lithographic technique. Afterward, exposed portions of the metallized layer can be removed using either a wet (e.g., chemical) or dry (e.g., plasma) etching technique. Additionally, the antenna and/or the discontinuous metallized region forming the hologram or retro-reflective layer according to the invention can be made by selectively de-metallizing a continuous metallized layer or, alternatively, by partial or selective deposition of a metallized layer. Partial deposition of the metallized layer can be performed, for example, using a masking technique. The antenna and/or the discontinuous metallized region can be formed, for example, by partial or selective deposition of a metallized layer using a deposition method selected from the group consisting of chemical deposition, electrical deposition, sputtering and vapor coating. The metallized layer of the antenna and/or the discontinuous metallized region preferably comprises at least one metal selected from the group consisting of aluminum, aluminum alloys, nickel, silver and copper. The metal layer from which the antenna and/or the discontinuous metallized region is formed preferably comprises an amorphous metal. An amorphous metal layer can be formed using conventional deposition techniques. By using an amorphous metal, higher conductivities can be achieved. As a result, a thinner layer can be used for the antenna, thus providing an identification device having increased flexibility. The thickness of the metallized layer used to form the antenna is preferably from 0.5 to 3 microns. The use of an amorphous metal layer can also facilitate demetallization using a chemical etching solution, according to the invention. The thickness of the base layer according to the invention is preferably between about 5 and 3,000 microns. Thinner base layers can be used to provide more flexible identification devices. By forming the antenna from a metallized layer, tamper proof characteristics can be imparted to the device. For example, according to the invention, an antenna formed from a metallized layer (e.g., either a selectively demetallized or a partially deposited metallized layer) can be manufactured such that attempts to tamper with the device (e.g., by delaminating one or more layers of the device) are likely to result in damage to the antenna In this manner, an attempt to tamper with an identification device according to the invention can render the RF transponder inoperative. Additionally, the antenna and the image device can be formed on opposite sides of a substrate material. It may also be advantageous to build the antenna on the device in several parts (i.e., by making one part of the antenna on the same side as the image device and the other part of the antenna on the side opposite the optical image). In this case, a high power antenna can be made on a relatively small identification device. Depending specifically of the desired frequency of the oscillating circuit made by the chip and the antenna, the antenna may be produced as a coil or as a dipole. To influence the oscillating chip frequency behavior, it may be advantageous to use the image material at least partially to make an electronic commutation element For example, the image material may be used for making a part of the antenna. This is particularly advantageous when the antenna is made as an antenna coil. It is also possible to use the image material to make a capacitor element To prevent the creation of metallic layers that may negatively affect the antenna's electromagnetic field, it may be useful to superimpose the image structure with a superficial structure to separate the metallic surface from the hologram support, thereby creating electrically isolated partial metallic layers. Turning to the figures, FIG. 1 shows the side view of an identification unit 10 according to the invention having a substrate or base layer 11 which has a metallized film or foil 12 mounted on its upper surface 33. The lower surface 30 of the substrate 11 is also shown. As shown, the metallized film or foil 12 comprises a film 13 coated with a metallic layer 14. The film 13 is preferably a dielectric film, such as a polymer film. Polyethylene terephthalate (PET) is a preferred material for the film. Other materials, however, can also be used for the film 13. The substrate is also preferably a dielectric material. However, the substrate 11 can be made of material with either electrically conductive or dielectric properties depending on the type of film 13 used. For example, if the film 13 is a dielectric material, such as a polymer film, the substrate 11 does not have to be a dielectric material. The identification device 10 shown in FIG. 1 can be in the form of a card or an identification label. A label is typically more flexible than an identification card. The rigidity of the identification device can be varied by the choice of the material used for substrate 11 and by the thickness of substrate 11. In addition, it should be noted that the identification device 10 shown in FIG. 1 does not necessarily represent the actual end product but can, in addition to the layers shown in FIG. 1, be provided with further layers, particularly layers covering the top and the bottom. Further, if the identification unit is to be constructed as an identification label, the device can be provided with an adhesive surface such as a pressure sensitive adhesive surface. FIG. 2 is a top view of an identification device 10 according to the invention. As shown in FIG. 2, metallized layer 12 has been divided into two fields placed in adjacent position: a holographic image field 16 and an antenna field 17. In the holographic field 16, the metallic film 12 forms a holographic image 18 that can be transferred to the identification device in a known manner (e.g., by using a stamping process) to form a hologram 20. As shown in FIG. 2, the antenna field 17 comprises an antenna coil 22 created, for example, by using a chemical etching technique according to the invention. The coil as shown is provided on each end with contact fields 23 and 24. Contact fields 23 and 24 are provided as through contacts that provide an electric connection with the bottom surface 30 of the base layer 11, as shown in FIG. 3. For the construction of the antenna coil 22 shown in FIG. 2, a corrosive material (i.e., an aqueous NaOH solution) can be printed onto the metallic layer 14 to selectively remove portions of the metallic layer 18 from the metal foil 12, thereby leaving behind only the area defined as the antenna coil 22. FIG. 3 shows the bottom view of the device of FIG. 2. As shown in FIG. 3, the contact points 23, 24 of the antenna coil 22 are connected as through-contacts to a chip 31 on the bottom side 30 of the substrate 11 which, as shown, is mounted in a chip module 32 to make electrical contact between the antenna 22 and chip 31 easier. The antenna coil 22 and the chip 31 of the identification device 10 shown in FIGS. 1 to 3 forms a transponder unit 34 which enables, by means of a reader unit, contact-free access to the data on the chip 31 for purposes of electronic identification. At the same time, the hologram 20 mounted on the upper side of the identification unit 10 enables optical identification to be made. FIG. 4 illustrates an identification device 40 having two substrates 41, 42 lying on top of each other, each of which has a metallized foil 45, 46 mounted on its upper surface 43, 44. The components are arranged in such a way that metallized foil 45 is positioned between substrates 41 and 42 and metallized foil 46 is situated on the upper surface 43 of the metallized layer 41 and forms at the same time the top layer of the identification device 40. As shown in FIG. 4, each of the metal foils 45, 46 comprises a film or foil layer 47 having a metallized surface 39. According to a preferred embodiment of the invention, the metal foils 45, 46 comprise a polymer film having a metallized surface comprising aluminum. In the identification unit 40 shown in FIG. 4, the upper metal foil 46 is structured or divided up in the same way as metal foil 12 of FIG. 2. That is to say, the identification device 40 is provided with both a hologram 20, for example, in a hologram area 16 as well as an antenna coil 22 in an antenna area 17. As shown, the metal foil 45 mounted on the upper side 44 of substrate 42 and arranged between substrate 42 and substrate 41 is provided with a second antenna coil 49 which is in electrical contact with a first antenna coil located on antenna area 17 via through-contacts with contact points 23, 24. The second antenna coil 49 is itself connected by through-contacts with contact points 50, 51 which themselves are connected to a chip module 53, which is mounted in a recess 52 in the bottom of substrate 42. In this way, the antenna coils 22 and 49 each form a component of the complete antenna unit 54 of identification device 40. FIG. 5 illustrates a top view of an identification device 55 comprising a metal foil 56 on the upper side of a substrate, not shown. In a similar manner to metal foils 12 and 46 of FIGS. 2 and 4, respectively, identification device 55 comprises, for example, a hologram or retro-reflective area 57, or other metallized substance, and an antenna area 58. The antenna area 58 as shown in FIG. 5 comprises a single antenna coil 59, which can be created in the manner previously described by selectively etching a metal foil made up of a metallic layer 61 deposited on a film or foil layer (not shown). As shown, the antenna coil 59 is provided with contact points 62, 63. Contact points 62, 63 can be designed as through-contacts connected to contact areas of a chip module 64 mounted on the bottom side of the substrate. In the hologram or other metallized area 57 of metal foil 56, a hologram or other image 65 is formed in the metallic layer in the manner previously described. As shown in FIG. 5, however, the hologram or other metal material 65 comprises two image sections 66, 67 which are electrically isolated from each other and which form, when viewed, a complex connected optical structure. The smaller image section 67, is electrically isolated from the larger image section 66. As shown, the smaller image section 67 comprises two metal surfaces which appear generally as two U-shaped islands. As shown in FIG. 5, each of these metal surfaces are connected with a contact area 62 or 63 and form the panels 68, 69 of a capacitor unit 70. FIG. 6 shows an identification device 71 comprising a metal film 72, similar to the metal films 12, 46, 56 shown in FIGS. 2, 4, and 5, respectively. As shown, the identification device 71 also comprises a holographic field 73, which could also or alternatively include other types of images, or for example, retro-reflective material, and an antenna field 74. In contrast to the metal film 12 shown in FIG. 2, however, the metal film 72 is a reticulated metallic coating having lines or stripes of metallic material 75. As a result, the image is formed from non-metallic fields 76 alternating with metallic fields 77. Such a structure can be created using the same process as the antenna coil 22 using the previously described printing/chemical etching procedure. In particular, the continuous metal coating in the holographic field 73 can be reticulated by printing lines of a chemical etchant on the continuous metal coating. As a result, a reticulated holographic material (i.e., with alternating lines or stripes of metallic material removed) can be formed. When FIGS. 2 and 6 are compared, it can be seen that the image contents of the holographic material 78 of FIG. 6 and the holographic material 20 of FIG. 2 are similar. However, the images have different resolutions. In particular, the image in FIG. 6 has a lower resolution due to the reticulated structure of holographic material 78. However, the reticulated structure of holographic material 78 reduces interference with RF energy such that an RF transponder can be mounted on the identification device 71. FIG. 7 illustrates a method of manufacturing a metal foil having a holographic or other metallized field and an antenna field, such as the metal foil 12 shown in FIG. 2. In particular, a metal foil strip 25 with a large number of foil segments 26 connected to each other in continuous order is shown in FIG. 7. When the metal foil strip 25 is separated lengthwise along the dotted severance lines 27, individual metal foil sections, such as metal foil 12 in FIG. 2, can be provided. As shown in FIG. 7, the metal foil strip 25 comprises, in the running direction 28, a sequence of hologram or other metallized areas 16 and antenna areas 17, continuously following on from each other, which, as shown, are situated on the left and right sides of a central running line 29. The arrangement of the hologram or other metallized areas 16 and the antenna areas 17 in one long line following each other in the running direction 28 enables the continuous production of holograms or other metallized materials 20 in the hologram or other metallized area 16 and of antenna coils 22 in the antenna area 17 when the metal foil strip 25 moves forward in the running direction 28. In addition, the forward movement of the metal foil strip 25 can be phased in such a way that, at various stages (indicated in FIG. 7 as stages I, II and III), various operations can be performed on the foil. In particular, the antenna area 17 on the metal foil strip 25 can undergo printing with a metal etchant in stage 1. The remains of the corrosive material can be washed away, while, at the same time, the oxidized areas of the metallic layer 14 can be removed in stage II. Finally, the antenna area 17 of the metal foil strip 25 can be dried (stage III). In conjunction with the production of the antenna coil 22 in the antenna area 17 of the metal foil strip 25, the metallized layer in the holographic or other metallized field 16 can be selectively demetalized as shown in FIG. 7. Further, the holographic or other metallized material 20 can be formed in the hologram or other area 16 of the metal foil strip 25 (e.g., by means of a revolving press) after the demetalzation process. In order to construct the identification device 10 shown in FIG. 2, the metal foil strip 25 having holograms or other metallized materials 20 formed in the hologram or other metallized areas 16 and antenna coils 22 formed in the antenna areas 17 can be positioned on a substrate, not shown, laminated (e.g., with an adhesive) and separated along the severance lines 27 to provide individual identification devices, such as the identification device 10 shown in FIG. 2. A demetallizing process according to the invention will now be described in more detail. Once the areas to be demetallized have been determined (e.g., using graphical design) a rubber engraving (e.g., flexographic plate) can be made to cover the printing roller that is going to be used to deposit the demetallizing solution (e.g., an aqueous solution of sodium hydroxide) on the metallized surface of the film. The sodium hydroxide solution can, for example, be placed in one of the printing stations of a conventional flexographic printing apparatus. For example, the demetallizing solution can be placed in a stainless steel tray typically used for holding ink. The demetallizing solution can then be applied to the metallized surface by means of the printing roller such that the demetallizing solution is selectively transferred to areas of the metallized surface which are going to be demetallized. The volume of sodium hydroxide that is “printed” on the metallized film can be controlled, as with printing using ink, by, for example, the structure (i.e., the resolution) of the printing roller (i.e., the anilox roller) and the inking rollers and by the pressure that is exerted on the printing roller. Although the demetallizing effect is practically immediate once the demetallizing solution is applied to the metallized surface, it may be desirable to allow the demetallizing solution to remain a certain amount of time in contact with the metallized surface so that the chemical reaction is completed in those areas in contact with the solution. To stop the oxidizing effect of the solution, the metallized surface can be washed with water (preferably non-recycled). For example, the metallized surface (previously printed) can be passed through a washing area where the residual sodium hydroxide and the oxidized metal (i.e., aluminum oxide) can be removed. In a preferred embodiment, the water will wet the entire printed area of the metallized surface. For example, fine sprinklers can be used to cover the entire printed area. In order to make the washing process more efficient and to completely remove the residuals of the chemical process, washing may be repeated one or more times using fresh water each time. Before the film enters the drying station, it may be desirable to remove excess water from the metallized surface in order to facilitate the evaporation of and remaining residual water. In order to remove the water, it is recommendable to use a pair of rollers (e.g., one of rubber and another metallic), air cleaners, sponges and/or air sprinklers. Finally the film is passed through the drying unit through for a heat dry (e.g., using electrical resistance heating) to completely remove the water from the material. As a complement to the method of selective demetallizing, it is possible to include in the same line of production an overprinting process with ink. In this manner, the effects of demetallizing and printing can be obtained on the same material. Compared with solvent based inks, water based inks are very manageable, clean and highly resistant to ultraviolet (UV) light. For these reasons, water based inks are desirable. Nevertheless, because one of the sub-processes of the demetallizing process is washing, it is preferable to print with water based inks after the demetallizing and washing steps have been completed. In addition, if certain metallized areas are desired not to be printed, it is possible to use a transparent solvent based varnish for print protecting the metallized film. After print protection, the metallized layer can be demetallized. In this manner, higher resolutions can be achieved. This technique can be used in high security applications to produce microtext and/or very fine lines. A demetallizing process for use with a metallized, such as a retro-reflective material, according to the invention is described below in reference to FIG. 8. First, any liner or protective layer 81 present on the metal layer 83 is removed to expose the metal. In FIG. 8, the metal layer 132 is shown disposed on a carrier or base layer 78. The carrier or base layer 78 can be polyvinyl chloride or polyethylene terephthalate. The metal layer 132 is then selectively exposed 79 to the corrosive action of a corrosive material, such as a sodium hydroxide solution, using a flexographic, screen, offset or any other printing process to remove metal from the desired areas. This process is described in detail in Mexican Patent Application Nos. 2001/010968 and 2001/010969 as well as in German Patent Application No. 101 21 126. These applications are herein incorporated in their entirety by reference. Selective metal removal can be used to form an antenna for the RF transponder. As a second step, a fine line demetallizing process can be performed over the remaining metal surface using the same demetallizing process to break the conductivity of the metal layer and the absorption or distortion of radio waves. This allows the RF energy to be captured by the antenna of the radio frequency device. This process is preferably done at a high resolution to maintain the retro-reflective (or, for example, holographic) properties of the remaining metal layer while, at the same time, interrupting the conductivity of the metal to allow RF reception and transmission. According to a preferred embodiment of the invention, the metallized layer is demetallized in a square grid pattern comprising a first set of parallel lines of demetallized material oriented at right angels to a second set of parallel lines or demetallized material. According to a further embodiment of the invention, the squares of metallized material in the square grid pattern will have dimensions of 5 mm×5 mm or less, more preferably 3 mm×3 mm or less. It has been found that, when the squares of metallized material have dimensions of about 5 mm or less, shielding (i.e., distorion and/or absorption) is reduced to about 5% or less and when the squares of metallized material have dimensions of about 3 mm or less, shielding (i.e., distorion and/or absorption) is reduced to about 1% or less. Although a square grid demetallized pattern is preferred, other patterns can be employed according to the invention. When other patterns are employed, it is preferred that the longest straight line that can be drawn on any metallized area is about 5 mm or less, more preferably about 3 mm or less. A schematic of an apparatus for selective demetallization of a roll of metallized material is shown in FIG. 9. As shown in FIG. 9, metallized material (e.g., retro-reflective material) from a roll 121 is unrolled and passed over a printing roller 123 where a chemical etchant (e.g., NaOH) from reservoir 35 is applied in a desired pattern. The printed metallized layer is then passed over a temperature application roller 128 to a washing station 36. After washing, hot air from dryer 37 is directed over the surface of the washed material. Afterward, the selectively demetallized material is optionally transferred to various printing stations 38, 120 so that designs can be overprinted thereon. After over-printing, the metallized material can be transferred to an adhesive application roller 122 and adhesively bonded to a carrier material or base layer material 124. The base layer material 124 can have perforations (not shown) to allow for separation of individual identification devices from the continuous length. After bonding to the base layer, the material is shown wound onto a take-off roller 126. After exposing the material to the demetallizing agent, the demetallizing process can be terminated by washing the surface with water and immediately drying. Afterward, a design can be over-printed on the identification device using a fixed or variable printing process. Once the metal is removed from an area of the device, it is possible to mount a radio frequency device in the demetallized area. The radio-frequency device can be used as a label or as an identification tag, such as a car license plate. In one example application, labels according to the invention can, for example, be used for all types of vehicle control. The labels can be provided in auto-adhesive form for use with a car license plate, a tractor platform or for container information, vehicle control applications, etc. The labels can be provided with read and write capabilities and can include biometric data, such as fingerprints, iris recognition data, facial recognition data, voice recognition data, picture data and traffic violation data for drivers. Car license plates are typically made from metal, acrylic or polycarbonate. Regardless of the material, the process of applying an RF device will usually be similar. This process is described below with reference to FIG. 10 for a metal license plate. First, an upper surface 82 of a metal plate 80 is embossed to form a depressed region 84. An isolation layer 86 (e.g., a ferrite composite layer) is then deposited in depressed region 84. A radio frequency device 88 is then mounted on the isolation layer. In this manner, RF device 88 is able to transmit and receive information without interference from the metal plate 80. Afterward, the license plate can be laminated with, for example, a selectively demetallized retro-reflective material 90. According to a preferred embodiment of the invention, the region of the reflective material 90 above the area 92 where the radio frequency device 88 is mounted will be free of metallized material. Further, the rest of the retro-reflective material 90 is preferably selectively demetallized with a fine line demetallizing pattern 93 using a demetallizing process as described above to reduce interference. The resulting license plate is shown in FIG. 11. As can be seen from FIG. 11, the license plate 94 comprises an antenna region 96 and a retro-reflective region 98. The retro-reflective region is shown over-printed with a license plate number. As can be seen from FIG. 11, the retro-reflective material has been removed from the antenna region 96. The antenna can be formed by selectively demetallizing a continuous metal layer using a printing procedure as described above. An alternative process of forming the antenna comprises producing a thin polymer layer (e.g., polyvinyl chloride (PVC) or polyethylene terephthalate) having an antenna (preferably a copper antenna) embedded therein. Structures of this type are commonly referred to as inlays. A method of manufacturing an inlaid antenna according to the invention is shown in FIG. 12. As shown in FIG. 12, a conductive wire 100 (preferably a copper wire) is unrolled from a spool 102 and embedded in the surface of a polymer sheet 104. As shown in FIG. 12, the conductive wire 100 passes over a thermal ultrasound head 106 and under a bridge 108 before being embedded in the polymer sheet 104 to form the antenna 110. The inlaid antenna can be applied with an auto-adhesive or pressure sensitive adhesive to the base layer or substrate of the identification device. The antenna should be applied in an area of the device that has been demetallized to avoid contact with any metal in the identification device. An alternative way of obtaining a retro-reflective or other metalized material on a metal plate or sticker can be employed wherein the carrier or base layer is a polymer such as PVC or PET. In this embodiment, the antenna can be embedded directly in the carrier using ultrasonic energy as set forth above. The retro-reflective or other metallized layer can then be applied onto the carrier. Portions of the retro-reflective or other metallized layer overlying the antenna should be demetallized to avoid any contact of the antenna with the metal content of the retro-reflective or other metallized material. A fine line demetallization process can be used as describe above over the remainder of the retro-reflective or other metallized material to minimize RF distortion or absorption that can interfere with the radio frequency device. Afterward, an acrylic or epoxy resin can be applied to transform the identification device into a label FIG. 13 shows an identification device according to this embodiment of the invention wherein an inlaid antenna 110 is positioned on a carrier layer (not shown) beneath a demetallized portion 112 of a retro-reflective or other metallized layer 114. Also as shown in FIG. 13, a fine line demetallizing process has been used on the continuous metal portion 116 of the retro-reflective layer 114 to reduce interference and thereby ensure adequate performance of the radio frequency transmitting 118 and receiving 119 functions. In this manner, the retro-reflective or other metallized material properties can be retained while allowing for the adequate transmission and reception of RF energy. These and other modifications and variations to the present invention may be practiced by those of ordinary skill in the art, without departing from the spirit and scope of the present invention. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the invention.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates generally to a process for selectively removing metallic material from a metallized film and, in particular, to the removal of metallic material from a metallized polymeric film using a printing method such as flexographic printing. The film can be a reflective film (e.g., a retro-reflective film) or a holographic film that can be used, for example, in an identification device comprising a radio frequency (RF) transponder. 2. Background of the Technology Retro-reflective materials can reflect and re-emit incident light in a direction that is parallel to that of the source of the incident light. In other words, retro-reflective materials reflect light directly back toward the source of the light Such materials and devices are widely used in the areas of nighttime transportation and safety. For example, retro-reflective materials are used to identify highway lanes and road signs using the light emitted from vehicle headlights. Retro-reflective materials are also used for the production of car plates, decals and distinctives for all kinds of vehicles and for truck containers, tractors and other applications. Retro-reflective materials have a bright effect under direct light without disturbing human sight Holographic materials have also been used for identification purposes. Since holograms are all but impossible to counterfeit, they are being increasingly used on all types of identification, including driver's licenses, credit cards, bus passes, etc., to increase security. Both retro-reflective and holographic materials typically contain a very high level of metal such as aluminum. Holograms, for example, are typically stamped from metal foils. It is known that metal blocks the transmission and reception of radio frequency (RF) signals because the RF signal is absorbed or distorted by the metal content in the material. As a result, the signal cannot be received by an antenna blocked by metal. Such a blocked signal cannot be used, for example, to activate a connected device. This same blocking effect can occur whether the device is positioned on top of or underneath the metallic material because the distortion and absorption of the RF signal will be affected in either case. Thus, there is a problem in the prior art with regard to using retro-reflective and holographic materials, as well as other materials containing metals, on the surface of devices for receiving RF signals. It would be desirable to incorporate an RF transponder into an identification device comprising a retro-reflective material, a holographic image, or other material containing a metal. The RF transponder could be used for electronic identification.

<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the invention, an identification device is provided that includes retro-reflective or holographic materials, or other materials containing metal, and a usable antenna for receiving radio frequency (RF) signals. The identification device comprises: a base layer, an RF transponder comprising a mounted RF chip and an antenna disposed on the base layer, and a metallized region. The metallized region can comprise a holographic image or a ret reflective layer. The antenna is in electrical communication with the chip. According to this aspect of the invention, the metallized region is discontinuous, such that the RF transponder can transmit and receive information at radio frequencies. According to a second aspect of the invention, a method of forming a pattern in a metallized layer is provided. The method comprises: transferring a metal etching solution to portions of an exposed surface of the metallized layer using a printing process; allowing the etching solution to react with the metallized layer to selectively demetallize the surface; and washing the selectively demetallized surface. According to a third aspect of the invention, a method of making an identification device comprising a base layer and at least one metal region disposed thereon is provided. The method comprises: selectively demetallizing a first metal region of the device; forming a holographic image in the first metal region; forming an antenna on the base layer; and mounting an RF chip on the base layer in electrical communication with the antenna to form an RF transponder. According to this aspect of the invention, the selective demetallization of the first metal region allows the RF transponder to transmit and receive information. According to a fourth aspect of the invention, a method of making an identification device comprising a base layer and a metallized retro-reflective layer is provided. The method comprises: forming an antenna on a base layer; and mounting a radio frequency (RF) chip on the base layer in electrical communication with the antenna to form an RF transponder. According to this aspect of the invention, the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. According to a fifth aspect of the invention, an identification device is provided. The device includes a base layer and a radio-frequency (RF) transponder comprising an RF chip and an antenna disposed on the base layer wherein the antenna is in electrical communication with the chip. According to this aspect of the invention, the antenna is formed by selective de-metallization of a continuous metallized layer or by partial deposition of a discontinuous metallized layer. Additional advantages and novel features of the invention will be set forth in part in the description that follows, and in part will become more apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention.

20041007

20081209

20050303

65968.0

LEE, BENJAMIN C

SELECTIVE METAL REMOVAL PROCESS FOR METALLIZED RETRO-REFLECTIVE AND HOLOGRAPHIC FILMS AND RADIO FREQUENCY DEVICES MADE THEREWITH

UNDISCOUNTED

CONT-ACCEPTED

ACCEPTED

Method for performing power diffraction analysis

A method for successively performing a powder diffraction analysis of at least two powder samples being contained in sample holding means. Use is made of an apparatus comprising:—a source of radiation being adapted to direct a radiation beam to a power sample,—a detector for detecting diffraction radiation of a powder sample,—a drive means associated with said sample holding means for effecting a movement of an irradiated powder sample during irradiation and detection. The method comprises the steps of irradiating a powder sample and detecting the diffraction radiation of the powder sample, arranging a further powder sample such that said radiation beam is directed to said further powder sample, and irradiating said further powder sample and detecting the diffraction radiation of said further sample. During irradiation and detecting of each sample the drive means effect a movement of the irradiated sample with respect to the radiation beam for the purpose of improving particle statistics. The sample holding means comprise a common multiple samples holder holding said at least two powder samples. Said drive means effect, during irradiation and detection of a sample contained in said common multiple samples holder, a movement of said common multiple samples holder with respect to the radiation beam.

1. A method for successively performing a powder diffraction analysis of at least two powder samples being contained in sample holding means, wherein use is made of an apparatus comprising: a source of radiation being adapted to direct a radiation beam to a powder sample, a detector for detecting diffraction radiation of a powder sample, a drive means for effecting a movement of an irradiated powder sample during irradiation and detection with respect to the radiation beam, wherein the method comprises the steps of: irradiating a powder sample and detecting the diffraction radiation of the powder sample, arranging a further powder sample such that said radiation beam is directed to said further powder sample, and irradiating said further powder sample and detecting the diffraction radiation of said further sample, wherein during irradiation and detection of each sample the drive means effect a movement of the irradiated sample with respect to the radiation beam for the purpose of improving particle statistics, and wherein the sample holding means comprise a common multiple samples holder holding said at least two powder samples. 2. The method according to claim 1, wherein the drive means are connected to said common multiple samples holder and wherein said drive means effect, during irradiation and detection of a sample contained in said common multiple samples holder, a movement of said common multiple samples holder with respect to the radiation beam. 3. The method according to claim 1, wherein said drive means are connected to radiation source and detector for the purpose of effecting the movement of the common multiple samples holder with respect to the radiation beam. 4. The method according to claim 1, wherein said irradiated sample has a centre and wherein said movement of said common multiple samples holder with respect to the radiation beam includes a predetermined variation of the orientation of an axis perpendicular to a sample plane and intersecting the centre of the irradiated sample with respect to the radiation beam. 5. The method according to claim 1, wherein the movement of said common multiple samples holder with respect to the radiation beam includes at least of the following movements: a precession movement, a translation, or a tilting of said common multiple samples holder with respect to the radiation beam. 6. The method according to claim 1, wherein the drive means cause the common multiple samples holder to perform a precession movement with respect to the radiation beam during the step of irradiation and detection of a powder sample. 7. The method according to claim 1, wherein the drive means cause the common multiple samples holder to perform a combination of a precession movement and a translation with respect to the radiation beam during the step of irradiation and detection of a powder sample. 8. The method according to claim 1, wherein the source of radiation is an X-ray source. 9. The method according to claim 1, wherein the diffraction analysis is a transmission diffraction analysis. 10. The method according to claim 1, wherein the detector is a 2D-detector. 11. The method according to claim 1, wherein said common multiple samples holder is a plate having an array of wells, each being well adapted to contain a powder sample. 12. The method according to claim 11, wherein said wells are arranged at a centre to centre distance of between 2 and 10 millimetres. 13. In combination an apparatus for performing a powder diffraction analysis of a powder sample and a sample holding means, wherein said apparatus comprises: a source of radiation being adapted to direct a radiation beam to a powder sample in said sample holding means, a detector for detecting diffraction radiation of a powder sample, a drive means for effecting a movement of an irradiated powder sample held in said sample holding means during irradiation and detection with respect to the radiation beam, wherein the sample holding means comprise a common multiple samples holder holding said at least two powder samples. 14. The combination of claim 13, wherein the drive means are connected to said common multiple samples holder and wherein said drive means are adapted to effect, during irradiation and detection of a sample contained in said common multiple samples holder, a movement of said common multiple samples holder with respect to the radiation beam.

The present invention relates a method for successively performing a powder diffraction analysis of at least two powder samples being contained in sample holding means. Scattering of incident radiation such as X-rays, gamma rays, cathode rays, etc. from a sample of material can yield information about the atomic structure of the material. When such a beam of radiation strikes a sample, a pattern of diffracted radiation is created, which has a spatial intensity distribution that depends on the wavelength of the incident radiation and the atomic structure of the material and that can be recorded on a suitable detector such as a point detector, a 1D array detector or a 2D detector. Diffraction analysis is the method of choice for studying crystalline materials, crystallisation behaviour and liquid, gel or solid phase, or phase transitions of materials. DE 15 98 413 discloses an apparatus wherein a single sample is held in a sample holder. During the irradiation and detection of diffracted radiation, the drive means associated with the single sample holder cause the sample to perform a translation in combination with a rotation of the sample about an axis at right angles to the irradiated plane of the sample. The purpose of the sample movement during the irradiation and detection is to improve the so called “particle statistics” and to obtain more reliable reflection intensities, or intensities with reduced standard deviation. A problem that is encountered when using the apparatus of DE 15 98 413 is that it is time consuming when a plurality of powder samples have to be analysed. This problem is particularly pertinent in case of high throughput experimentation. According to the known method each powder sample is prepared one by one in an associated single sample holder and placed in the apparatus for performing the powder diffraction analysis. Then the apparatus is set and aligned, whereupon irradiation and detection take places. Subsequently, the powder is removed and a further powder sample is prepared and so on. This results in an ineffective way of working and thus in a considerable loss of time. In U.S. Pat. No. 6,111,930 a powder diffraction analysis apparatus is disclosed having a sample changer. Said changer has a plurality of ring-shaped containers each for receiving a sample. The containers are mounted on a linear magazine, such that the samples can be successively brought into the irradiation beam. This known apparatus allows for the spinning of ring-shaped container holding the irradiated sample about an axis perpendicular of the sample surface, which is a common approach to improve the particle statistics. A problem that is encountered with other known powder diffraction analysis equipment using a 2D detector is that during detection of the diffraction radiation, single diffraction spots and arcs are often observed instead of rings, especially when organic crystalline material (such as pharmaceuticals) is irradiated. This may be the result of the fact that not all lattice planes of the crystalline powder material have been in reflection or not for the same time or same amount, because the crystals were not random oriented or only a few crystals were present. As a result, the peak intensities of the powder diffraction patterns are not correct, and no representative 1D-powder diffraction pattern (intensity vs. diffraction angle 2θ) is created after integration of the detected 2D diffraction patterns causing problems during comparison of diffraction patterns for identification. It is an object of the present invention to provide a method for performing powder diffraction analysis of a plurality of powder samples in a time effective way. It is a further object of the present invention to allow a diffraction pattern to be obtained with correct reflection intensities. The above and other objects can be achieved by a method according to the present invention for successively performing a powder diffraction analysis of at least two powder samples being contained in sample holding means, wherein use is made of an apparatus comprising: a source of radiation being adapted to direct a radiation beam to a powder sample, a detector for detecting diffraction radiation of a powder sample, a drive means associated with said sample holding means for effecting a movement of an irradiated powder sample during irradiation and detection, wherein the method comprises the steps of: irradiating a powder sample and detecting the diffraction radiation of the powder sample, arranging a further powder sample such that said radiation beam is directed to said further powder sample, and irradiating said further powder sample and detecting the diffraction radiation of said further sample, wherein during irradiation and detection of each sample the drive means effect a movement of the sample with respect to the radiation beam for the purpose of improving particle statistics. The method is characterised in that the sample holding means comprise a common multiple samples holder holding said at least two powder samples. Using the method according to the invention a plurality of powder samples may be analysed in a time effective way. The powder samples may be all prepared at the same time in said common multiple samples holder, and are be placed at the same time in the apparatus for performing a powder sample diffraction analysis. Then, the powder samples are all analysed one by one, without the need to remove an earlier powder sample and resetting and fine tuning the apparatus as in DE 15 91 413. A “powder sample” is defined herein as a powder sample of a compound of which the diffraction or crystallisation behaviour is to be determined. Such a compound may be a chemical substance, or a mixture of different substances. Also, at least one crystal form of the compound may be known or expected to exist. A compound of the invention may comprise an organic or organo-metallic molecular compound, such as a pharmaceutically active molecule or catalyst-ligand complex or a dimer, salt, ester, solvate or functional part thereof. A powder sample of the present invention may also comprise a biomolecule, for instance a nucleic acid (such as DNA, RNA and PNA), a polypeptide, peptides, glycoprotein and other proteinaceous substances, a lipoprotein, protein-nucleic acid complex, carbohydrate, biomimetic or a functional part, derivative and/or analogue thereof. It is to be noted that the powder sample may indeed be in the form of a powder. The person skilled in the art of diffraction analysis understands, however, that a “powder sample” also includes a number of crystals which are contained in a solid material, such as is the case for metals, polymers, etc. Thus, in the latter case, the powder sample appears as a solid material in one piece. According to the present invention “powder diffraction analysis” comprises both transmission and reflection diffraction analysis. Transmission and reflection diffraction analysis are well known in the art an do not require further explanation. According to the present invention, with “common multiple samples holder” is meant any sample holder capable of holding at least two powder samples, either in form of a powder or in form of a solid material in one piece, such that the irradiated sample as well as the other sample(s) in said holder are subjected by the drive means to the prescribed movement. The common multiple samples holder may be a plate, e.g. similar to a microtiter plate, having a plurality of wells, each for receiving a powder sample. Preferably said wells are arranged in an array, more preferably a 2D-array. Examples of such sample holders are 8 by 12 mm up to 32 by 48 mm, with orthogonal centre to centre distance varying from 2 to 10 mm between the wells. Preferably the common multiple samples holder is fabricated from material that is translucent to the irradiation beam, e.g. X-rays in the case of X-ray diffraction. The common multiple samples holder is preferably chemically inert to the substances and solvents employed. The common multiple samples holder is preferably also transparent to visual light (ca 200 nm to 1000 nm) to allow visual or optical inspection. The common multiple samples holder is preferably also capable of transferring heat, thereby allowing for temperature variations. Of course, the apparatus may be provided with means for controlling and/or adjusting the atmosphere conditions in or directly above the wells. For this purpose the sample holder is for instance fitted with sealing devices or sealing substances which seal off individual wells or groups of wells. Balls, plates, caps, inert liquids like paraffin oil, silicon oil, etc. can be provided for said sealing purposes. In this respect it is noted that the sealing devices and/or sealing substances do not necessarily (and preferably do not) attach the powder sample to the sample holder, but are provided for controlling the atmosphere in or directly above an individual well or a group of wells. According to the present invention, with “suitable radiation” any radiation is meant which can be used for performing a transmission or reflection diffraction analysis (preferably transmission diffraction analysis) of the powder samples, such as X-rays, gamma rays, and cathode rays. Preferably as the radiation X-rays are used. In a possible embodiment the drive means are associated with said samples holder, and the drive means effect, during irradiation and detection of a sample contained in common multiple samples holder, a movement of said common multiple samples holder with respect to the irradiation beam. In a further embodiment the drive means are (also) connected to radiation source and detector for the purpose of effecting the movement of the samples holder with respect to the radiation beam. Preferably the the irradiated sample has a centre and the movement includes a predetermined variation of the orientation of an axis perpendicular to a sample plane and intersecting the centre of the irradiated sample with respect to the radiation beam. Preferably the movement includes a precession movement, a translation, a tilting or a combination thereof of said common multiple samples holder with respect to the radiation beam. According to a first preferred embodiment of the method, the common multiple sample holder is subjected by the drive means to a precession movement with respect to the radiation beam. Herewith, the irradiated sample also performs said precession movement and thus account can be taken of different orientations of the crystals in said sample. “Precession movement” is a technique that is well known in the art for single crystal measurement techniques. Detailed explanation of an exemplary precession movement technique may for example be found in ‘Fundamentals of Crystallography’, edited by C. Giacovazzo, pp. 254-259 (1991) or in various internet-sites of Astrophysics sciences, the latter explaining the precession movement of the equinox. In this respect it is noted that, although it is known since the early 1940's to use precession movements for single crystal measurements, this technique has not been used for powder sample measurements. Further, in single crystal measurements, precession movement is used to obtain single crystal unit cell parameters and not for performing a powder diffraction analysis which is completely different. It is noted that the precession movement can be conducted in part. According to a second preferred embodiment of method, the common multiple samples holder is subjected to a translation with respect to the radiation beam during the irradiation and detection of a sample, i.e. the normal to the irradiated sample surface is translated with respect to the radiation beam, in parallel orientation to the radiation beam, allowing other crystals in the powder sample to be analysed. Preferably the holder is such that all sample surfaces to be irradiated lie in a common plane. Herewith powder diffraction rings may be obtained instead of single diffraction spots, as the particle statistics is significantly improved. Particle statistics is a term known in the art. With achieving ‘improved particle statistics’ is meant obtaining a powder diffraction pattern with more reliable reflection intensities, or intensities with reduced standard deviation. According to a particularly preferred embodiment, the common multiple sample holder is subjected to a combination of a precession movement and a translation during the irradiation and detection of a sample. Herewith at the same time improved particle statistics can be obtained and account can be taken of different orientations of the crystals in a surprisingly simple manner. In a further embodiment the common multiple samples holder is subjected to a so-called omega-rotation, wherein the normal to the irradiated sample plane performs a tilting movement with respect to the radiation beam. If one would conduct a series of such tilting movements in combination with a suitable (stepwise) rotation of the holder the man skilled in the art will understand that the effect similar to performing a precession movement can be obtained. The invention relates to an apparatus for performing powder diffraction analysis of multiple powder sample according to the above disclosed method. Hereinafter the present invention will be illustrated in more detail by the drawings, wherein: FIG. 1 shows schematically a first embodiment of a transmission mode X-ray diffraction analysing apparatus to be used in accordance with the method of the invention; FIG. 2 shows an example of a common multiple sample holder to be used in the method according to the invention; FIG. 3 shows a schematic diagram of an exemplary path that the radiation beam may follow over one powder sample during irradiation and detection, using a translation movement; FIG. 4 shows a result of a known powder diffraction measurement, wherein single diffraction spots are obtained; FIG. 5 shows a result of a powder diffraction measurement obtained using the method according to the present invention, using a translation, wherein powder diffraction rings are obtained; and FIG. 6 shows a second embodiment of a transmission mode X-ray diffraction analysing apparatus to be used in accordance with the method of the invention. FIG. 1 shows a diagram of an exemplary transmission mode X-ray diffraction analysing apparatus 1. The apparatus 1 comprises a source 2 adapted to generate an intense X-ray radiation beam 3, such as a conventional X-ray tube. The beam 3 is passed through a focussing device 2b. The apparatus 1 further includes a drive means 5, which is adapted to receive a common multiple samples holder 6. In said sample holder 6, of which an example is shown in FIG. 2, a plurality of powder samples 7 are contained, e.g. in a two-dimensional array of wells. The radiation beam 3 strikes a single powder sample 7a. The apparatus 1 further includes a diffracted radiation detector 8 for the detection of diffracted radiation 9 passed through the powder sample 7a. In the shown embodiment the source 2 of X-ray radiation is located above the powder samples 7, but the inverted and other arrangements are also possible. The detector 8 may be any suitable detector, such as a stimulable phosphor image plate detector. Preferably the detector 8 is a position sensitive 2D radiation detector. The drive means 5 are designed in FIG. 1 to cause a displacement of the common multiple samples holder 6 such that the radiation beam 3 successively strikes each of the samples 7 in said holder 6 and are usually motorised as well as automated. The drive means 5 are further designed such that during the irradiation of a sample 7 and the detection and recording of the diffracted radiation, the common multiple samples holder 6 is caused to effect a translation such that the radiation beam 3 strikes different points of said sample 7 while maintaining a parallel orientation between the beam 3 and the normal to the irradiated surface of the sample 7. As the analysis of a sample is completed, the drive means caused the sample holder 6 to move such that the beam 3 can irradiate a further sample 7. This sequence is continued preferably in an automated manner until all samples 7 have been analysed. FIG. 3 shows a schematic diagram of an exemplary path that the radiation beam 6 of FIG. 1 may follow during irradiation of one of the powder samples 7 in the sample holder 6 in FIG. 2 using translation, preferably in a stepwise manner. The path of the diffraction radiation obtained by the translation is denoted with 10. Herewith several areas 11 of the powder sample 7 are irradiated, whereby diffraction rings (see FIG. 5) instead of diffraction arcs or spots (see FIG. 4) may be obtained. FIG. 4 shows a two-dimensional X-ray diffraction image of manually crunched sugar using a 0.4 mm X-ray beam fixed at the centre of the sample according to the state of the art. FIG. 5 shows a two-dimensional X-ray diffraction image of the same crunched sugar as in FIG. 4 using a 0.4 mm X-ray beam while the radiation beam is subjected to a translation according to the invention. FIG. 6 shows a second embodiment of an apparatus 20 for performing radiation diffraction analysis of multiple samples according to the invention. In FIG. 6 parts corresponding to parts of the apparatus of FIG. 1 have been given the same reference numerals. The drive means associated with the sample holder 6 includes translation drive means 5, which allow for a translation as explained with reference to FIG. 1. The drive means in FIG. 6 also include a precession drive means 21 which allows for a precession movement of the sample holder 6, such that the normal to the sample plane of a powder sample 7 precesses about the radiation beam 6. In the shown embodiment of transmission diffraction, this means that the normal to the sample plane of the irradiated powder sample 7 revolves about the radiation beam 3, while keeping e.g. a constant angle, the “precession angle”. The normal to the sample plane thus follows a cone-shaped path relative to the radiation beam 3. The movement can consist of only a part of said cone-shaped path. Also the movement is not restricted to a constant precession angle. Also, the precession movement may be effected as a series of tilting movements in combination with suitable (stepwise) rotation of the sample holder 6 as will be apparent to the man skilled in the art. The drive means 5 and 21 thus allow for a combination of a translation and precession movement during the analysis of a sample 7. In an alternative embodiment the drive means 5 only allow the displacement of the sample holder 6 so that sequentially all samples are irradiated but do not allow for a translation during the irradiation. A combination of the above precession movement and translation allows the normal to the sample plane to rotate about all possible axes in the plane of the sample, or all possible rotations about the centre of the sample surface except for in-plane rotation. As will be apparent to the man skilled in the art the movement of the sample holder with respect to the radiation beam can be obtained using a source and detector which are held stationary while moving the sample holder or using a stationary samples holder and moving the source and detector, or by using a combined movement of the source and detector on the one hand and the samples holder on the other hand.

20040203

20100420

20050106

58120.0

ARTMAN, THOMAS R

METHOD FOR PERFORMING POWDER DIFFRACTION ANALYSIS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Power reduction in microprocessor systems

method of preventing an electronic file containing a computer virus from infecting a computer system using the Symbian™ operating system, the method comprising the steps of scanning files using an anti-virus application, and if an infected file is identified, maintaining the file in an open non-sharing state, whereby other applications running on the computer system may not operate on an infected file.

1-13. (canceled) 14. A method of reducing the power consumption of a microprocessor system which comprises a microprocessor and a memory connected by at least one bus, the microprocessor being arranged to execute a program stored in said memory, wherein: a) said processor is pipelined in the sense that at least one subsequent instruction is fetched before the current instruction has been completely executed, and b) said program comprises at least one branch instruction, the execution of which can result in a non-consecutive instruction being fetched, the method comprising duplicating at least one branch instruction so as to reduce the number of transitions on said bus when the program is executed. 15. A method as claimed in claim 14, wherein conditional branch instructions are only replicated if the number of times which the branch is taken, or is likely to be taken, during operation of the program exceeds a predetermined threshold. 16. A method as claimed in claim 15, wherein the number of times which a conditional branch instruction is taken, or is likely to be taken, during operation of the program is determined by code profiling. 17. A method as claimed in claim 14, wherein conditional branch instructions are replicated only if they satisfy one or more heuristic rules. 18. A method as claimed in claim 17, wherein one of said heuristic rules is that backwards conditional branch instructions are replicated. 19. A method as claimed in claim 17, wherein one of said heuristic rules is that forwards conditional branch instructions are not replicated. 20. A method as claimed in claim 14, wherein all conditional branch instructions are replicated. 21. A method as claimed in claim 14, wherein unconditional branch instructions are replicated if they satisfy one or more unconditional branch rules. 22. A method as claimed in claim 21, wherein one of said unconditional branch rules is that an unconditional branch instruction is replicated if it forms an early exit instruction of a loop. 23. A method as claimed in claim 21, wherein one of said unconditional branch rules is that an unconditional branch instruction is replicated if it forms the jump back to a saved return address from a function call. 24. A method as claimed in claim 14, which further includes: determining which branch instructions, whether conditional or unconditional, are executed, or likely to be executed, more than a predetermined number of times during operation of the program, and can therefore be considered to lie on a “critical path” through the program, and when carrying out the steps of the method, not allowing duplication of any branch instructions which do not lie on said “critical path”, so as to minimize the overall size of the program while at the same time achieving a reduction in power consumption by allowing duplication of branch instructions on said “critical path”. 25. A program for reducing the power consumption of a microprocessor system, wherein at least one branch instruction has been replicated in accordance with claim 14. 26. A reduced power microprocessor system comprising a microprocessor and a memory connected by at least one bus, wherein said memory contains a program as claimed in claim 25 for execution by said microprocessor.

The invention relates to power reduction in microprocessor systems comprising a microprocessor and a memory connected by at least one bus. The methods described in this specification aim to improve the processor's average inter-instruction Hamming distance. The next few paragraphs describe this metric and explain its relation to power efficiency. The Hamming distance between two binary numbers is the count of the number of bits that differ between them. For example: Numbers in Numbers in binary Hamming decimal (inc. leading zeros) distance 4 and 5 0100 and 0101 1 7 and 10 0111 and 1010 3 0 and 15 0000 and 1111 4 Hamming distance is related to power efficiency because of the way that binary numbers are represented by electrical signals. Typically a steady low voltage on a wire represents a binary 0 bit and a steady high voltage represents a binary 1 bit. A number will be represented using these voltage levels on a group of wires, with one wire per bit. Such a group of wires is called a bus. Energy is used when the voltage on a wire is changed. The amount of energy depends on the magnitude of the voltage change and the capacitance of the wire. The capacitance depends to a large extent on the physical dimensions of the wire. So when the number represented by a bus changes, the energy consumed depends on the number of bits that have changed—the Hamming distance—between the old and new values, and on the capacitance of the wires. If one can reduce the average Hamming distance between successive values on a high-capacitance bus, keeping all other aspects of the system the same, the system's power efficiency will have been increased. The capacitance of wires internal to an integrated circuit is small compared to the capacitance of wires fabricated on a printed circuit board due to the larger physical dimensions of the latter. Many systems have memory and microprocessor in distinct integrated circuits, interconnected by a printed circuit board. Therefore we aim to reduce the average Hamming distance between successive values on the microprocessor-memory interface bus, as this will have a particularly significant influence on power efficiency. Even in systems where microprocessor and memory are incorporated into the same integrated circuit the capacitance of the wires connecting them will be larger than average, so even in this case reduction of average Hamming distance on the microprocessor-memory interface is worthwhile. Processor-memory communications perform two tasks. Firstly, the processor fetches its program from the memory, one instruction at a time. Secondly, the data that the program is operating on is transferred back and forth. Instruction fetch makes up the majority of the processor-memory communications. The instruction fetch bus is the bus on which instructions are communicated from the memory to the processor. We aim to reduce the average Hamming distance on this bus, i.e. to reduce the average Hamming distance from one instruction to the next. In a non-pipelined processor, each instruction is executed completely before the processor begins to execute the next one. When a processor is pipelined, it will have a number of instructions in various states of simultaneous execution. Depending on the depth of the pipeline, one or more instructions will have been fetched from program memory before the current instruction is executed. For example, in a typical four-stage pipeline: → Time Instr #1 Fetch Decode Execute Write Instr #2 Fetch Decode Execute Write Instr #3 Fetch Decode Execute Write Instr #4 Fetch Decode Execute Write By the time instruction #1 reaches the execute stage, instruction #2 has already been fetched. For sequential program execution, this parallelism helps increase the instruction throughput of the processor, as one instruction completes execution on every clock cycle. However, when the executed instruction causes a change in the flow of execution (such as a branch or a jump), there is an unwanted instruction from the location after the branch that will have been fetched prior to the time the branch instruction is executed. Some processors may simply execute this instruction; this is called a delayed branch. This invention applies to those processors that choose to discard this instruction instead. When the branch is taken, the fetched instruction is cancelled, for example by internally converting it into a no-operation instruction. → Time Branch: Fetch Decode Execute Write Cancelled: Fetch Branch Fetch Decode Execute Write Target: Fetch Decode Execute Write In a deeper pipeline, more than one instruction may be in the process of being decoded for execution, so more than one instruction may need to be cancelled. According to the invention there is provided a method of reducing the power of a microprocessor system, a program, and a reduced power microprocessor system as set out in the accompanying claims. Embodiments of the invention will now be described, by way of example only, with reference to the accompanying figure. The accompanying figure shows a microprocessor system 2 suitable for implementation of the invention. The microprocessor system 2 comprises a microprocessor 4 connected to a memory 6 by a bus 8. The microprocessor 4 and memory 6 may of course be incorporated into the same integrated circuit. Consider the activity on the instruction bus for the branch example given above. When the second instruction is fetched, there will be a number of bit transitions, T1. Similarly, when the target of the branch is fetched, there will be a second set of transitions T2. When the branch is taken, the second instruction is thrown away, so no useful work is obtained for the bit transitions. We would like to eliminate the number of transitions ‘wasted’ when fetching the second instruction. We conclude that, in the cases when a branch is taken, it is better to fill the subsequent instruction in the program with a replicate copy of the branch instruction. The second instruction will never be executed, as it will be cancelled internally. By duplicating the previous branch, the bit pattern will be identical to the previous one, so there will be no transitions on the instruction bus. As well as these unconditional branches, there are also branches that are conditional on the result of a previous operation. In this case duplication is still possible, but the decision whether or not to replicate the branch depends on the relative frequency of when the branch is taken. Both of these cases will now be considered in more detail. The unconditional branches that can be replicated include the early exit portion of a loop, or the jump back to a saved return address from a function call. It does not include jumps to subroutines, as subroutines return to the point from which they were called and any duplication would cause them to be called multiple times. Unconditional branches are always taken, so they should always be replicated to minimise power. When generating the code, each instruction can be output ‘n’ times, where ‘n’ is the depth of the pre-fetch, or branch shadow, in the instruction pipeline. Care must be taken that the address or offset contained in the immediate field of the jump is the same in all cases. Consider the following code fragment, complete with assembled bit patterns: movi %0, #0 00001000000000000000000000000000 movi %1, #1 00001000000000010000000000000001 L1: st.b (%2), %1 01000100010000010000000000000000 st.b (%2), %0 01000100010000000000000000000000 jmp L1 01111011111111111111111111110100 L2: addi %0, %0, #−10 00010000000000001111111111110110 For every iteration of the loop, the instruction at L2 will be fetched following the unconditional ‘JMP’ jump instruction. However, it will never be executed. Fetching the shadow instruction causes 15 transitions. This will then be followed by a further 19 transitions when the instruction at L1 is fetched. Duplicating the JMP into the branch shadow produces the following code: movi %0, #0 00001000000000000000000000000000 movi %1, #1 00001000000000010000000000000001 L1: st.b (%2), %1 01000100010000010000000000000000 st.b (%2), %0 01000100010000000000000000000000 jmp L1 01111011111111111111111111110100 jmp (L1 + 4) 01111011111111111111111111110100 L2: addi %0, %0, #−10 00010000000000001111111111110110 Because branch targets are specified as offsets relative to the current instruction address, the destination of the replicated branch is no longer L1 but is rather the instruction following L1 to ensure the branch offset is the same. This reduces the number of transitions by 9. A conditional branch is not always taken, so deciding when to replicate it is harder. Conditional branches can always be replicated without affecting the overall program behaviour. If the conditional branch is taken, then the replicate instructions in the branch shadow will not be executed; if the branch is not taken, then the condition will be the same for all of the replicates and none of them will be taken. However, in this second case, every branch that is not taken will still pass through the pipeline, thereby reducing total instruction throughput. Duplicating conditional branches will always reduce the number of transitions, albeit at the possible expense of instruction throughput. Consider the following code: L1: ld.bu %0, (%1) 01000000001000000000000000000000 st.b (%1), %0 01000100001000000000000000000000 bnz %0, L1 01101100000000001111111111110100 L2: addi %0, %0, #−10 00010000000000001111111111110110 The ‘BNZ’ instruction is a conditional branch that jumps to the destination label if the value in the source register (in this assembler notation, %0 represents register zero) contains a non-zero value. Hence the mnemonic BNZ—Branch if Non-Zero. When we take the branch, the number of ‘wasted’ transitions is 6, followed by a further 17 transitions to reach the target instruction. If we replicate the branch, then we would end up with the following code: L1: ld.bu %0, (%1) 01000000001000000000000000000000 st.b (%1), %0 01000100001000000000000000000000 bnz %0, L1 01101100000000001111111111110100 bnz %0, (L1 + 4) 01101100000000001111111111110100 L2: addi %0, %0, #−10 00010000000000001111111111110110 In the cases where the branch is taken, the number of transitions is reduced by 6 transitions. When the branch is not taken, the number of transitions is identical to the original non-replicated program. However, the replicate branch is effectively a no-operation, so the ‘exit’ case of the loop will take an additional cycle to execute. Depending on the relative frequency of the branch being taken compared to the branch not being taken, this additional execution overhead may be insignificant. Given that duplicating infrequently taken branches will reduce instruction throughput for little power-saving benefit, some additional analysis to identify which branches should be replicated is beneficial. One way of achieving this is through the use of code profiling. Another is through the use of simple branch characteristic heuristics. Code profiling will be discussed first. Initially, the application is run without any branch duplication. For each conditional branch, a count is kept of the number of times the branch is taken verses when it is not taken. The code is then recompiled, but this time using the statistics from the profiler. Only the conditional branches that are taken more frequently than a threshold selected by the user can be replicated. This threshold value represents a trade-off between power saving and instruction throughput. Branch heuristics will now be discussed. Consider the following C code fragment: int example(int size, int *flags, int *value) { int loop, result; 1 size= (size<0) ? −size : size; 2 for (loop= 0; loop<size; loop++) { 3 if(*(flags++)) { 4 result += *(values++); } } 5 return result; } Compiling this code for our example instruction set produces the following assembly code: example: 1 bnn %0, L3 01110100000000000000000000000100 rsubi %0, %0, 01100100000000000000000000000000 #0 L3: cmplti %7, %0, 00011000000001110000000000000001 #1 2 bnz %7, L5 01101000111000000000000000100000 L7: ld.w %7, (%1) 01010100001001110000000000000000 addi %1, %1, 00010000001000010000000000000100 #4 3 bz %7, L6 01101000111000000000000000001100 ld.w %7, (%2) 01010100010001110000000000000000 add %6, %6, 00000000110001110000000010000110 %7 addi %2, %2, 00010000010000100000000000000100 #4 L6: addi %0, %0, 00010000000000001111111111111111 #−1 4 bnz %0, L7 01101100000000001111111111100000 L5: mov %0, %6 00010000110000000000000000000000 6 jmpr (% lr) 00000011111000000000001111000000 All of the conditional and unconditional branch instructions have been numbered. The first branch, labelled #1, is a conditional branch that is taken when there is a non-negative value in its source register. Branches #2 and #4 are also conditional branches, but this time are taken when the value in the source register is non-zero. Branch #3 is another type of conditional branch, and is taken when the value in the source register is equal to zero. Finally, branch #6 is an unconditonal branch that always jumps to the destination address as specified in the source register. The first heuristic is that branch #6 is unconditional, so it should always be replicated to save power. A common compiler heuristic is that backward branches tend to be taken. Backward branches are branches that branch to an earlier instruction. Backward branch instructions occur in places such as the end of a loop, which is why they are often taken. This would imply branch #4 should be replicated. For an array of size ‘n’, branch #4 will be taken ‘n−1’ times. Therefore, the overhead of this optimisation is 1 wasted instruction in ‘n’. However, each time the branch is taken, there will be around 18 transitions saved by not pre-fetching the instruction that will not be executed. Branch #3 is used to check a flag. Without knowledge of the data, it is not possible to predict when this branch will be taken. Again, a common compiler heuristic is that forward branches are taken less frequently. Therefore, it would be better not to replicate this branch. This heuristic also applies to branch #1 and #2. With code profile information, the choice of which branches to replicate would be tailored for the particular execution pattern of the test data cases. Therefore, test data must be carefully chosen to reflect the typical behaviour expected when deployed. Adding additional instructions that will never be executed will clearly result in an increase in code size. This can be a problem when compiling code for an embedded system that typically has more limited storage resources. The impact on code size can be minimised by identifying the critical path of the program (that is, the routines that are executed the most frequently) and then only applying the branch duplications to the routines on this path. Once again, code profiling is a powerful tool. If the basic blocks making up a function are annotated with execution counts then only those branches that are executed more than a fixed threshold would be replicated. As these routines represent the bulk of the instruction fetches, the power saved will approach the maximal amount. Any code that is not executed as frequently will not be expanded, thereby keeping the total code size down.

20050216

20071120

20051013

73718.0

TREAT, WILLIAM M

POWER REDUCTION IN MICROPROCESSOR SYSTEMS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method of extended culture for antigen-specific cytotoxic lumphocytes

The present invention is a method for inducing cytotoxic T cell having an antigen-specific cytotoxic activity, a method for maintaining the cell, a method for continuously culturing the cell or a method for expanding the cell, comprising the step of culturing a cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof.

1. A method for inducing cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating a precursor cell capable of differentiating to cytotoxic T cell with an antigen presenting cell in the presence of at least one substance selected from the group consisting of: (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof. 2. The method according to claim 1, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 3. The method according to claim 2, wherein the CD44 ligand is hyaluronic acid. 4. The method according to claim 1, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 5. The method according to claim 4, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 6. The method according to any one of claims 1, 4 and 5, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 7. The method according to claim 1, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 8. A method for maintaining cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of continuously culturing the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of claim 1. 9. The method according to claim 8, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 10. The method according to claim 9, wherein the CD44 ligand is hyaluronic acid. 11. The method according to claim 8, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 12. The method according to claim 11, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 13. The method according to any one of claims 8, 11 and 12, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 14. The method according to claim 8, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 15. A method for expanding cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of claim 1. 16. The method according to claim 15, wherein the cytotoxic T cell is incubated further in the presence of anti-CD3 antibody in said step. 17. The method according to claim 15 or 16, wherein the cytotoxic T cell is incubated together with a feeder cell in said step. 18. The method according to claim 17, wherein the feeder cell is a non-virus-infected cell. 19. The method according to claim 15, wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody. 20. The method according to claim 19, wherein the CD44 ligand is hyaluronic acid. 21. The method according to claim 15, wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor. 22. The method according to claim 21, wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody. 23. The method according to claim 15, wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2. 24. The method according to claim 15, wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain. 25. A method for collecting cytotoxic T cell, comprising the step of selecting a cell population rich in cytotoxic T cell having an antigen-specific cytotoxic activity from a culture containing the cytotoxic T cell obtained by the method of any one of claims 1, 8 and 15. 26. A cytotoxic T cell having an antigen-specific cytotoxic activity prepared by the method of any one of claims 1, 8 and 15. 27. A therapeutic agent, characterized in that the therapeutic agent comprises the cytotoxic T cell of claim 26 as an effective ingredient.

TECHNICAL FIELD The present invention relates to methods for inducing, maintaining and expanding cytotoxic T cell having an antigen-specific cytotoxic activity, which is useful in the medical field. BACKGROUND ART A living body is protected from foreign substances mainly by an immune response, and an immune system has been established by various cells and the soluble factors produced thereby. Among them, leukocytes, especially lymphocytes, play a key role. The lymphocytes are classified in two major types, B lymphocyte (which may be hereinafter referred to as B cell) and T lymphocyte (which may be hereinafter referred to as T cell), both of which specifically recognize an antigen and act on the antigen to protect the living body. T cell is subclassified to helper T cell having CD(Cluster Designation)4 marker (hereinafter referred to as TH), mainly involved in assisting in antibody production and induction of various immune responses, and cytotoxic T cell having CD8 marker (Tc: cytotoxic T lymphocyte, also referred to as killer T cell, which may be hereinafter referred to as CTL), mainly exhibiting a cytotoxic activity. CTL, which plays the most important role in recognizing, destroying and eliminating tumor cell, virus-infected cell or the like, does not produce an antibody specifically reacting with an antigen like in B cell, but directly recognizes and acts on antigens (antigenic peptide) from a target cell which is associated with major histocompatibility complex (MHC, which may be also referred to as human leukocyte antigen (HLA) in human) Class I molecules existing on the surface of the target cell membrane. At this time, T cell receptor (hereinafter referred to as TCR) existing on the surface of the CTL membrane specifically recognizes the above-mentioned antigenic peptides and MHC Class I molecules, and determines whether the antigenic peptide is derived from itself or nonself. Target cell which has been determined to be from nonself is then specifically destroyed and eliminated by CTL. Recent years, a therapy which would cause a heavier physical burden on a patient, such as pharmacotherapy and radiotherapy, has been reconsidered, and an interest has increased in an immunotherapy with a lighter physical burden on a patient. Especially, there has been remarked an effectiveness of adoptive immunotherapy in which CTL capable of specifically reacting with an antigen of interest is induced in vitro from CTL or T cell derived from a human having normal immune function, and then transferred to a patient. For instance, it has been suggested that adoptive immunotherapy using an animal model is an effective therapy for virus infection and tumor (authored by Greenberg, P. D., Advances in Immunology, published in 1992). Further, use of CTL to a patient with congenital, acquired or iatrogenic T cell immunodeficiency has been remarked, from the fact that administration of CTL to a patient with immunodeficiency results in reconstruction of specific CTL response, by which cytomegalovirus is rapidly and persistently eliminated without showing toxicity [Reusser P., et al., Blood, 78(5), 1373-1380 (1991)] and the like. In this therapy, it is important to maintain or increase the cell number with maintaining or enhancing the antigen-specific cytotoxic activity of the CTL. Also, as to maintenance and increase of the cell number of CTL, if an effective cell number in adoptive immunotherapy for human is deduced on the basis of the studies on an animal model, it is thought that 109 to 1010 antigen-specific T cells are necessary (authored by Greenberg, P. D., Advances in Immunology, published in 1992). In other words, in adoptive immunotherapy, it can be said that it is a major problem to obtain the above cell number in vitro in a short period of time. As to maintenance and enhancement of an antigen-specific cytotoxic activity of CTL, there has been generally employed a method of repeating stimulation with an antigen of interest when a specific response to an antigen for CTL is induced. However, in this method, the cell number may temporarily be increased, but the cell number is eventually decreased, and necessary cell number cannot be obtained. As its countermeasure, there are no other means in the current situation but to lyophilize the cells in an earlier stage during repeat of stimulation with an antigen, or to obtain antigen-specific CTL clones, lyophilize a part of the clones, and repeat antigen stimulation to the lyophilized cells after thawing if the cell number or antigen-specific cytotoxic activity of the CTL clones is lowered due to a long-term culture. A method for establishing T cell by a long-term culture using mouse T cell has been reported [Paul W. E. et al., Nature, 294(5843), 697-699 (1981)], which is a method for isolating T cell and establishing a cell strain therewith. However, it is impossible to proliferate T cell to 109 to 1010 cells by this method. Next, U.S. Pat. No. 5,057,423 discloses a method comprising inducing lymphokine-activated killer (LAK) cell using a large amount of interleukin 2 (IL-2) in a high concentration, thereby increasing the cell number in 100 folds in 3 to 4 days. This cell number is enormous, considering that it usually takes about 24 hours for a single cell to be divided and proliferated into two cells. In addition, adoptive immunotherapy has been tried by inducing tumor-infiltrating lymphocyte (TIL) using IL-2 in a high concentration as above [Rosenberg S. A. et al, New Engl. J. Med., 313(23), 1485-1492 (1985); Rosenberg S. A. et al, New Engl. J. Med., 319(25), 1676-1680 (1988); Ho M. et al., Blood, 81(8), 2093-2101 (1993)]. However, the former is a method for obtaining T cell which is non-specific for an antigen, and in the latter, antigen specificity is very low, if any, because activated polyclonal lymphocyte population is used. Further, in both of the above-mentioned methods, IL-2 is used in a high concentration in order to promote cell proliferation. It is reported that apoptosis (cell death) may occur when T cell treated with IL-2 in a high concentration is stimulated with a specific antigen in the absence of IL-2 [Lenardo M. J. et al., Nature, 353(6347), 858-861 (1991); Boehme S. A. et al., Eur. J. Immunol., 23(7), 1552-1560 (1993)]. Therefore, the effectiveness of LAK cell or TIL obtained by the above-mentioned methods is problematic. In addition, when T cell is cultured at a low density (5×103 to 1×104 cells/ml) in the presence of T-cell growth factor and IL-2, T cell rapidly proliferates over a period of 7 days, and eventually proliferates to a saturation density of 3 to 5×105 cells/ml. However, it is also reported that the cell always dies once the cell reaches the saturation density [Gillis S. et al., Immunol. Rev., 54, 81-109 (1981)]. Therefore, LAK cell, TIL and the method for culturing T cell at a low density are problematic in both aspects of actual use and usefulness. Next, regarding the antigen-specific CTL, there are reported adoptive immunotherapy in which allogenic cytomegalovirus(CMV)-specific CTL is cultured in vitro for 5 to 12 weeks to proliferate CTL, and then administered intravenously to a patient with immunodeficiency [Riddell S. A. et al., Science, 257(5067), 238-240 (1992)]; and a method for isolating and expanding a CMV-specific CTL clone using self-CMV infected fibroblast and IL-2 [Riddell S. A. et al., J. Immunol., 146(8), 2795-2804 (1991)] or using anti-CD3 monoclonal antibody (anti-CD3 mAb) and IL-2 [Riddell S. A. et al., J. Immunol. Methods, 128(2), 189-201 (1990)]. However, there is a serious problem in these methods. Specifically, it takes about 3 months to obtain 1×109 cells/ml of antigen-specific CTLs, during which time the symptoms of the patient advance, so that it is difficult to appropriately treat the disease depending on the situation. As a method of solving the above-mentioned problem, WO 96/06929 discloses an REM method (rapid expansion method). This REM method is a method for expanding a primary T cell population containing antigen-specific CTL and TH in a short period of time. In other words, this method is characterized in that a large amount of T cell can be provided by expanding individual T cell clones. However, there is a problem as described below. In the REM method, antigen-specific CTL is expanded using anti-CD3 antibody, IL-2, and PBMC (peripheral blood mononuclear cell) made deficient in an ability for proliferation by irradiation, and Epstein-Barr virus (hereinafter simply referred to as EBV)-infected cells. However, there are problems that risk of admixing EBV-transformed B cell (EBV-B cell) into T cell is not deniable (problem in safety); that a large amount of PBMC (PBMC in an amount of about 40 times the number of antigen-specific CTL required) is required as feeder cell; that the antigen-specific cytotoxic activity of the expanded CTL cannot be sufficiently satisfactory; that the antigen-specific cytotoxic activity possessed by T cell is decreased with the cell proliferation when CTL is allowed to proliferate using a T cell population other than the T cell clone; and the like. In other words, in a conventional method for preparing antigen-specific CTL, there have not been solved the problems essential to adoptive immunotherapy in which CTL having an antigen-specific cytotoxic activity effectively used in the treatment, is prepared in a sufficient amount for a short period of time. DISCLOSURE OF INVENTION An object of the present invention is to provide methods for inducing, maintaining and expanding CTL having an antigen-specific cytotoxic activity at a high level, which is suitably used in adoptive immunotherapy. Concretely, the present invention relates to: (1) a method for inducing cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating a precursor cell capable of differentiating to cytotoxic T cell with an antigen presenting cell in the presence of at least one substance selected from the group consisting of: (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof; (2) the method according to the above (1), wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody; (3) the method according to the above (2), wherein the CD44 ligand is hyaluronic acid; (4) the method according to the above (1), wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor; (5) the method according to the above (4), wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody; (6) the method according to any one of the above (1), (4) and (5), wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2; (7) the method according to the above (1), wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain; (8) a method for maintaining cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of continuously culturing the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of the above (1); (9) the method according to the above (8), wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody; (10) the method according to the above (9), wherein the CD44 ligand is hyaluronic acid; (11) the method according to the above (8), wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor; (12) the method according to the above (11), wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody; (13) the method according to any one of the above (8), (11) and (12), wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2; (14) the method according to the above (8), wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain; (15) a method for expanding cytotoxic T cell having an antigen-specific cytotoxic activity, characterized in that the method comprises the step of incubating the cytotoxic T cell in the presence of at least one substance selected from the group consisting of (A) to (E) of the above (1); (16) the method according to the above (15), wherein the cytotoxic T cell is incubated further in the presence of anti-CD3 antibody in the above step; (17) the method according to the above (15) or (16), wherein the cytotoxic T cell is incubated together with a feeder cell in the above step; (18) the method according to the above (17), wherein the feeder cell is a non-virus-infected cell; (19) the method according to any one of the above (15) to (18), wherein the substance having a binding activity to CD44 is the CD44 ligand and/or an anti-CD44 antibody; (20) the method according to the above (19), wherein the CD44 ligand is hyaluronic acid; (21) the method according to any one of the above (15) to (18), wherein the substance capable of inhibiting binding of a growth factor to a growth factor receptor is a substance having a binding activity to the growth factor; (22) the method according to the above (21), wherein the substance having a binding activity to the growth factor is an anti-growth factor antibody; (23) the method according to any one of the above (15) to (18), (21) and (22), wherein the growth factor is at least one growth factor selected from the group consisting of hepatocyte growth factor, insulin-like growth factor-1 and insulin-like growth factor-2; (24) the method according to the above (15), wherein the fragment of the fibronectin is a fragment having at least one domain selected from the group consisting of: (a) a VLA-4 binding domain, (b) a VLA-5 binding domain, and (c) a heparin binding domain; (25) a method for collecting cytotoxic T cell, comprising the step of selecting a cell population rich in cytotoxic T cell having an antigen-specific cytotoxic activity from a culture containing the cytotoxic T cell obtained by the method of any one of the above (1) to (24); (26) a cytotoxic T cell having an antigen-specific cytotoxic activity prepared by the method of any one of the above (1) to (25); (27) a therapeutic agent, characterized in that the therapeutic agent comprises the cytotoxic T cell of the above (26) as an effective ingredient. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing an activity of hyaluronic acid to inhibit binding of a soluble CD44 and a soluble CD44-recognizing antibody. FIG. 2 is a graph showing a binding activity of FL-labeled hyaluronic acid and CD44 on CTL cell surface. FIG. 3 is a graph showing a binding activity of a soluble CD44-recognizing antibody and a soluble CD44 in a medium. FIG. 4 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and a soluble CD44 in a medium. FIG. 5 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and CD44 on CTL cell surface. FIG. 6 is a graph showing a binding of an HA Non-Blocking anti-CD44 antibody on cell surface of CTL after expansion of CTL in which the antibody is added to a medium. BEST MODE FOR CARRYING OUT THE INVENTION It has been found that unexpectedly an ability (also referred to hereinafter as action) of maintaining or enhancing an antigen-specific cytotoxic activity of CTL is exhibited by at least one substance (the substance being used as an effective ingredient in the present invention) selected from the group consisting of the following (A) to (E): (A) a substance having a binding activity to CD44; (B) a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44; (C) a substance capable of inhibiting binding of a growth factor to a growth factor receptor; (D) a substance capable of regulating a signal emitted by binding of a growth factor to a growth factor receptor; and (E) fibronectin, a fragment thereof or a mixture thereof, and the present invention has been accomplished thereby. Therefore, according to the present invention, there are provided methods for inducing, maintaining and expanding CTL having an antigen-specific cytotoxic activity at a high level, which is suitably used in adoptive immunotherapy. The present invention will be explained concretely hereinbelow. (1) Method for Inducing Cytotoxic T Cell of Present Invention It has been known that CTL induced by antigen-presenting cell usually lowers its antigen-specific cytotoxic activity during the period of maintaining or proliferating CTL. According to the present invention, there is provided a method for inducing antigen-specific CTL which does not cause a marked lowering of the antigen-specific cytotoxic activity as conventionally observed, even when the cell after induction is maintained over a long period of time or proliferated. One of the great features of the method for inducing CTL of the present invention resides in that CTL is induced in the presence of the above-mentioned effective ingredient. CTL is induced by incubating a precursor cell capable of differentiating to CTL with an appropriate antigen-presenting cell in the presence of the effective ingredient in order to give the CTL obtained an ability of recognizing the desired antigen. The precursor cell is not particularly limited, so long as the precursor cell is a cell which is in a stage before the cell becomes CTL and fated to differentiate to CTL, and includes, for instance, peripheral blood mononuclear cell (PBMC), naive cell, memory cell and the like. The antigen-presenting cell is not particularly limited, so long as the cell has an ability to present an antigen to be recognized to T cell. For instance, mononuclear cell, B cell, T cell, macrophage, dendritic cell, fibroblast or the like which is allowed to present a desired antigen can be used in the present invention. The antigen-presenting cell can be prepared by adding an antigenic peptide to a cell having an antigen-presenting ability, thereby allowing the cell to present the antigenic peptide on its surface [see, for instance, Bednarek M. A. et al., J. Immunol. 147(12), 4047-4053 (1991)]. In addition, in the case where a cell having an antigen-presenting ability has an ability to process an antigen, an antigen is added to the cell, whereby the antigen is incorporated into the cell and processed therein, and fragmented antigenic peptides are presented on the cell surface. Incidentally, when an antigenic peptide is added to a cell having an antigen-presenting ability, an antigenic peptide matching the HLA restriction of the antigen-presenting cell used and the CTL to be induced are used. Incidentally, the antigen used in the present invention is not particularly limited, and includes, for instance, exogenous antigens such as bacteria and viruses, endogenous antigens such as tumor-associated antigens (cancer antigens) and the like. In the present invention, it is preferable that the antigen-presenting cell is made non-proliferative. In order to make the cell non-proliferative, for instance, the cell may be subjected to irradiation with X ray or the like, or a treatment with an agent such as mitomycin. The medium used in the method for inducing CTL of the present invention is not particularly limited. There can be used known media prepared by blending components necessary for maintenance or growth of CTL, a precursor cell thereof and an antigen-presenting cell. The media may be, for instance, commercially available ones. These media may contain appropriate proteins, cytokines, and other components in addition to the originally contained constituents. Preferably, a medium containing interleukin-2 (IL-2) is used in the present invention. In addition, these proteins, cytokines and other components may be used by immobilizing them to a substrate such as a culture equipment or microbeads usable in the method of the present invention. Those components may be immobilized to the culture equipment or the like in an amount so as to give a desired effect by a known immobilization method which will be described later. CD44 is a cell surface receptor widely existing in hematopoietic cells, fibroblasts, macrophages, and the like. Hyaluronic acid, heparan sulfate, chondroitin sulfate, osteopontin, type 1 collagen, type 4 collagen, fibronectin serglycin or the like has been reported as its ligands. As its function, there has been known to transduce a signal into cells through cell-cell adhesion or cell-extracellular matrix adhesion, thereby exhibiting functions such as activation of other adhesion molecules, and cytokine production. It has been known that CD44 also exists in CTL, and if hyaluronic acid or an anti-CD44 antibody binds to CD44, a tyrosine kinase domain existing in an intracellular region of CD44 is activated, thereby causing phosphorylation of tyrosine in an intracellular substrate protein, whereby intracellular signal transduction is carried out. In other words, it has been known that a signal is emitted by binding to CD44 its ligand or an anti-CD44 antibody, thereby leading to various functions. In the present invention, the substance having a binding activity to CD44 is not particularly limited, so long as the substance exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL. The substance is exemplified by, for instance, a CD44 ligand and/or an anti-CD44 antibody. The CD44 ligand is not particularly limited, so long as the ligand exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL. The ligand includes, for instance, hyaluronic acid, heparan sulfate, chondroitin sulfate, osteopontin, type 1 collagen, type 4 collagen, fibronectin, serglycin and the like, and hyaluronic acid is especially preferable. In addition, the anti-CD44 antibody is not particularly limited, so long as the antibody exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL. For instance, a commercially available anti-CD44 antibody can be used, and a derivative such as a fluorescence-labeled derivative can be used without particular limitation, so long as the derivative exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL. In the present invention, regardless of the presence or absence of the binding of CD44 to the substance having a binding activity to CD44, the desired effect can be obtained by regulating a signal emitted by binding of the CD44 ligand to CD44. In other words, the present invention can be carried out by using, as an effective ingredient, a substance capable of regulating a signal emitted by binding a CD44 ligand to CD44, in place of the substance having a binding activity to CD44. Here, the signal emitted by binding a CD44 ligand to CD44 also encompasses a signal emitted from a molecule of a living body receiving the signal. In other words, the signal includes, for instance, activation of a tyrosine kinase domain existing in an intracellular region of CD44, phosphorylation of tyrosine in an intracellular substrate protein by the above activated tyrosine kinase, and the like. A substance regulating these signals includes, for instance, various phosphokinases. In addition, the term “regulate or regulation” as used herein refers to transduce an activated signal to a downstream region in a signal transduction pathway, or to inhibit the transduction of the activated signal to a downstream region. The term “growth factor” is a generic term of polypeptides promoting division or development of various cells. It has been known that the growth factor acts on a target cell via a specific receptor on cell membrane, and that most of the receptors of the growth factor activate tyrosine kinase domains existing in an intracellular region, thereby transducing a signal to a target cell. In the present invention, the growth factor is not particularly limited, so long as the growth factor exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL by inhibiting the binding of the growth factor to a growth factor receptor, or regulating a signal emitted by binding the growth factor to a growth factor receptor. The growth factor is exemplified by, for instance, hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), nerve growth factor (NGF), neurotrophic factor, epidermal growth factor, milk-derived growth factor, basic fibroblast growth factor (bFGF), brain-derived fibroblast growth factor, acidic fibroblast growth factor, keratinocyte growth factor, platelet-derived growth factor (PDGF), platelet basic protein, platelet fourth factor, connective tissue-activating peptide, colony-stimulating factor, erythropoietin, thrombopoietin, T cell growth factor, B cell growth factor, cartilage-derived factor, cartilage-derived growth factor, bone-derived growth factor, skeletal growth factor, epithelial cell growth factor, epithelial cell-derived growth factor, oculus-derived growth factor, testis-derived growth factor, Sertoli's cell-derived growth factor, mammotropic factor, spinal cord-derived growth factor, macrophage-derived growth factor, mesodermal growth factor, transforming growth factor-α, transforming growth factor-β, heparin-binding EGF-like growth factor, amphyllegrin, smooth muscle cell-derived growth factor (SDGF), betacellulin, epiregulin, neuregulin-1, -2 and -3, vascular endotherial growth factor, neurotrophin, brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, -4, -5, -6 and -7, glial cell line-derived neurotrophic factor, stem cell factor, midkine, pleiotrophin, ephrin, angiopoietin, activin, tumor necrosis factor, and the like. According to the present invention, preferred growth factors are exemplified by hepatocyte growth factor, insulin-like growth factor-1, and insulin-like growth factor-2. HGF is a growth factor exhibiting proliferating action for hepatocytes, accelerating action for protein synthesis, ameliorating action for cholestasia, and further prophylactic action for renal disorders caused by drugs, and the like. As the HGF receptor, c-Met has been known, and all of various physiological actions of HGF are exhibited via c-Met. c-Met possesses a tyrosine kinase domain in its intracellular domain. The insulin-like growth factor (IGF) is an insulin-like active substance which cannot be neutralized with an insulin antibody. There have been known the existence of two kinds of IGF, IGF-1 and IGF-2. The receptor to which IGF binds includes an insulin receptor, IGF-1 receptor and IGF-2 receptor, and especially the insulin receptor and IGF-1 receptor have a tyrosine kinase domain in their intracellular domain. In the present invention, the substance capable of inhibiting the binding of the growth factor to its growth factor receptor is not particularly limited, so long as the substance exhibits an ability of maintaining or enhancing a specific cytotoxic activity of CTL. The substance includes a substance having a binding activity to the growth factor, and forming a complex with the growth factor, thereby inhibiting the binding of the growth factor to its growth factor receptor, or a substance having a binding activity to a growth factor receptor, thereby inhibiting the binding of the growth factor to the growth factor receptor. The former includes, for instance, an anti-growth factor antibody, preferably an anti-HGF antibody, an anti-IGF-1 antibody and an anti-IGF-2 antibody. The latter includes, for instance, an anti-growth factor receptor antibody, preferably an anti-c-Met antibody, an anti-insulin receptor antibody, an anti-IGF-1 receptor antibody and an anti-IGF-2 receptor antibody. In addition, in the present invention, regardless of the presence or absence of the binding of the growth factor to a growth factor receptor, the desired effect can be obtained by regulating a signal emitted by binding the growth factor to a growth factor receptor. In other words, the present invention can also be carried out by using as an effective ingredient a substance capable of regulating a signal emitted by binding the growth factor to a growth factor receptor, in place of the substance capable of inhibiting the binding of the growth factor to a growth factor receptor. Here, the signal emitted by binding the growth factor to a growth factor encompasses a signal emitted from a molecule of a living body receiving the signal. The signal includes, for instance, activation of a tyrosine kinase domain existing in an intracellular region of the growth factor, phosphorylation of tyrosine in an intracellular substrate protein by tyrosine kinase, and the like. The substance for regulating these signals includes, for instance, a kinase inhibitor and the like. The fibronectin and a fragment thereof as mentioned herein may be those obtained from nature, or those artificially synthesized by using a conventional genetic recombination technique or the like. The fibronectin and a fragment thereof can be prepared in a substantially pure form from a substance of natural origin, on the basis of the disclosure of Ruoslahti E. et al. [J. Biol. Chem., 256(14), 7277-7281 (1981)]. The term “substantially pure fibronectin or fibronectin fragment” as referred to herein means that these fibronectin and fibronectin fragment do not substantially contain other proteins and the like originated from its source and co-existing with fibronectin in nature. Each of the above-mentioned fibronectin and a fragment thereof can be used in the present invention alone or in admixture of plural kinds. The useful information relating to the fibronectin fragments which can be used in the present invention and the preparation of the fragments can be obtained from Kimizuka F., et al. [J. Biochem., 110(2), 284-291 (1991)], Kornblihtt A. R. et al. [EMBO J., 4(7), 1755-1759 (1985)], Sekiguchi K., et al [Biochemistry, 25(17), 4936-4941 (1986), and the like. Fibronectin is a gigantic glycoprotein having a molecular weight of from 220 to 250 kD and binding to many of macromolecules of a living body, such as collagen, heparin, fibrin, integrin families VLA-4 and VLA-5, cells and microorganisms. Also, the fibronectin molecule is divided into some domain structures as its functional regions (Taisha (Metabolism), 23(11) (1986)). A domain 1 has a molecular weight of about 30000 and binds to heparin, fibrin, Staphylococcus aureus or the like. A domain 2 has a molecular weight of about 40000 and binds to collagen. A domain 3 has a molecular weight of about 20000, and is considered to bind weakly to fibrin. A domain 4 has a molecular weight of about 75000 and is a cell-binding domain. A domain 5 (heparin-binding domain) has a molecular weight of about 35000 and binds strongly to heparin. A domain 6 has a molecular weight of about 30000 and binds to fibrin. A domain 7 is a carboxyl-terminal domain having a molecular weight of about 3,000. The domain 4 contains a VLA-5-binding domain and contains a VLA-4-binding domain between the domains 5 and 6. Also, there has been known that fibronectin has 3 modules of ED-A, ED-B and IIICS, and selective splicing is performed therefor. Further, IIICS has CS-1 and CS-5, each having a cell adhesion activity (FIBRONECTIN, Edited by Deane F. Mosher, ACADEMIC PRESS, INC. (1989)). In the present invention, the fibronectin fragment is preferably, but not particularly limited to, for instance, a fragment having a region selected from the domains 1 to 7, VLA-4-binding domain, VLA-5-binding domain, ED-A, ED-B, IIICS, CS-1 and CS-5. In addition, the fibronectin fragment used in the present invention is preferably, but not particularly limited to, a fragment of from 1 to 200 kD, more preferably from 5 to 190 kD, even more preferably from 10 to 180 kD. In the present invention, as the especially preferred fibronectin fragment, a fragment having at least one domain selected from the group consisting of (a) an integrin α5β1 (VLA-5)-binding domain as a cell-binding domain derived from fibronectin; (b) an integrin α4β1 (VLA-4)-binding domain; and (c) a heparin-binding domain is preferably used. For instance, the fragment comprising the VLA-5-binding domain includes a fragment having the amino acid sequence shown in SEQ ID NO: 1; the fragment comprising the VLA-4-binding domain includes a fragment having the amino acid sequence shown in SEQ ID NO: 2; and the fragment comprising the heparin-binding domain includes a fragment having the amino acid sequence shown in SEQ ID NO: 3, respectively. The fragment preferably used in the present invention may have substitution, deletion, insertion or addition of one or more amino acids in an amino acid sequence derived from fibronectin within the range in which the fragment has the above-mentioned binding activity. For instance, a fragment having one or more amino acids inserted as a linker between two different domains can also be used in the present invention. The substantially pure fibronectin fragment as referred to herein can also be prepared from a genetic recombinant on the basis of the description of e.g. U.S. Pat. No. 5,198,423. In particular, recombinant fragments referred to as H-271 (SEQ ID NO: 3), H-296 (SEQ ID NO: 4), CH-271 (SEQ ID NO: 5) and CH-296 (SEQ ID NO: 6) in Examples set forth below and a method of preparing these recombinant fragments are described in detail in this patent. In addition, a C-274 fragment (SEQ ID NO: 1) used in Examples set forth below can be obtained in accordance with the method described in U.S. Pat. No. 5,102,988. Further, a C-CS1 fragment (SEQ ID NO: 7) can be obtained in accordance with the method described in Japanese Patent Gazette No. 3104178. Each of the above-mentioned fragments CH-271, CH-296, C-274 and C-CS1 is a polypeptide having a cell-binding domain having a binding activity to VLA-5. Also, C-CS1, H-296 or CH-296 is a polypeptide having a cell-binding domain having a binding activity to VLA-4. Further, H-271, H-296, CH-271 or CH-296 is a polypeptide having a heparin-binding domain. A fragment in which each of the above domains is modified can also be used in the present invention. The heparin-binding site of fibronectin is constituted by three type III analogous sequences (III-12, III-13 and III-14). A fragment containing a heparin-binding site having deletion of one or two of the type III analogous sequences can also be used in the present invention. For instance, the fragments may be exemplified by CHV-89 (SEQ ID NO: 8), CHV-90 (SEQ ID NO: 9) or CHV-92 (SEQ ID NO: 10), which is a fragment in which a cell-binding site of fibronectin (VLA-5-binding domain: Pro1239 to Ser1515) and one of the III type analogous sequences are bound, or CHV-179 (SEQ ID NO: 11) or CHV-181 (SEQ ID NO: 12), which is a fragment in which the cell-binding site of fibronectin and two of the type III analogous sequences are bound. CHV-89, CHV-90 and CHV-92 contain III-13, III-14 and III-12, respectively; CHV-179 contains III-13 and III-14, and CHV-181 contains III-12 and III-13, respectively. CHV-89, CHV-90 and CHV-179 can be obtained in accordance with the method described in Japanese Patent Gazette No. 2729712. CHV-181 can be obtained in accordance with the method described in WO 97/18318. Further, CHV-92 can be obtained by genetic engineering technique using a plasmid constructed in a usual manner on the basis of the plasmid described in the above literature. In addition, an H-275-Cys (SEQ ID NO: 13) used in Examples set forth below is a fragment having a heparin-binding domain of fibronectin and a C-terminal cysteine residue. This fragment can also be used in the present invention. These fragments or their derived fragments obtained in a usual manner can be prepared by using microorganisms deposited to the International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology (formerly the Ministry of International Trade and Industry, National Institute of Bioscience and Human-Technology, Agency of Industrial Science and Technology), Tsukuba Central 6, 1-1, Higashi 1-chome Tsukuba-shi, Ibaraki-ken, Japan (Zip code 305-8566) under the following accession numbers, or by modifying a plasmid carried in each microorganism in accordance with a known method (for instance, site-directed mutagenesis). FERM-BP-2799 (Escherichia coli carrying a plasmid encoding H-271) International Date of Deposit: May 12, 1989; FERM-BP-2800 (Escherichia coli carrying a plasmid encoding CH-296) International Date of Deposit: May 12, 1989; FERM-BP-5723 (Escherichia coli carrying a plasmid encoding C-CS1) Original Date of Deposit: Mar. 5, 1990, Date of Transfer to International Deposit: Oct. 23, 1996; FERM P-10721 (Escherichia coli carrying a plasmid encoding H-296) Japanese National Date of Deposit: May 12, 1989; FERM P-12182 (Escherichia coli carrying a plasmid encoding CHV-89) Japanese National Date of Deposit: Apr. 8, 1991; and FERM P-12183 (Escherichia coli carrying a plasmid encoding CHV-179) Japanese National Date of Deposit: Apr. 8, 1991. The binding of the cell-binding domain of the fragment used in the present invention to a cell can be assayed by using a conventional method. For instance, such methods include a method of Williams D. A. et al. [Nature, 352(6334), 438-441 (1991)]. This method is a method of determining the binding of a cell to a fragment immobilized to a culture plate. Also, the heparin-binding domain of the fragment can be evaluated in the same manner as above by using a heparin, for instance, a labeled heparin, in place of the cell in the above method. As described above, since the fibronectin is a gigantic molecule, in the present invention, a fibronectin fragment is preferably used, from the viewpoint of convenience in use. When the fibronectin or a fragment thereof usable in the present invention is a product obtained from plasma or organs derived from an animal, since careful attention should be paid to contamination with animal-derived viruses (HCV, HIV and the like), purity and homogeneity, it is especially preferable that the fibronectin or a fragment thereof obtained by a genetic engineering technique as described above is preferably used. The effective ingredient usable in the present invention can be used alone or in admixture of two or more kinds. In the present invention, common conditions for incubating a precursor cell capable of differentiating to CTL together with an antigen-presenting cell (co-culturing) to induce CTL may be known conditions [see, for instance, Bednarek M. A. et al., J. Immunol., 147(12), 4047-4053 (1991)]. The conditions for co-culturing are not particularly limited, and the conditions usually used for cell culturing can be used. For instance, the cells can be cultured under the conditions of 37° C. in the presence of 5% CO2, and the like. The co-culture is usually carried out for about 2 to about 15 days, during which time the antigen-presenting cell may be exchanged with freshly prepared one for restimulation. In addition, the medium can be exchanged with a fresh one at appropriate time intervals. The content of the effective ingredient of the present invention in the medium used for the co-culture is not particularly limited, so long as the desired effect can be obtained. The content of the effective ingredient is preferably from 0.001 to 1000 μg/ml, more preferably from 0.01 to 100 μg/ml. The expression “contain(ing) components such as effective ingredients in a medium” as used herein is intended to encompass an embodiment of immobilizing the components to a substrate such as a culture equipment into which a medium is introduced during cell culture, or microbeads which are used by introducing them into a medium, and contacting the substrate with the medium in order to contain the above components in the medium (regardless of whether or not the components remain immobilized to the substrate after contacting with the medium). It is desired that the effective ingredient is present by dissolving the effective component in the medium or immobilizing the effective component to the substrate such as a culture equipment or microbeads. In addition, the above effective ingredient preferably includes at least one member selected from the group consisting of hyaluronic acid, an anti-CD44 antibody, an anti-HGF antibody, an anti-IGF-1 antibody, an anti-IGF-2 antibody, and a fibronectin fragment. The CTL thus induced has an ability of specifically recognizing the desired antigen, for instance, specifically destroying a cell having the antigen by its cytotoxic activity. This cytotoxic activity of CTL can be evaluated by a known method. For instance, the cytotoxic activity can be evaluated by determining cytotoxicity to a target cell labeled with the peptide presented by an antigen-presenting cell and a radioactive substance, a fluorescent substance or the like; an antigen-specific increase in CTL proliferation which can be determined by uptake of radioactivity; or the amount of cytokine such as GM-CSF or IFN-γ released antigen-specifically from CTL or target cell (see item (3) of Example 1-1 set forth below). Besides them, the cytotoxic activity can also be directly confirmed by using an antigenic peptide or complex labeled with a fluorescent pigment or the like. In this case, for instance, CTL is contacted with a first fluorescent marker coupled with a CTL specific antibody, and then with an antigenic peptide-MHC complex coupled with a second fluorescent marker, and the presence of a double-labeled cell is detected by FACS (fluorescence-activated cell sorting) analysis. The CTL induced by the method of the present invention has an excellent property that the antigen-specific cytotoxic activity is not markedly lowered, as conventionally observed, even when the cell after induction is maintained or allowed to rapidly proliferate over a long period of time. Therefore, the induced CTL can be cloned, so that the CTL can also be maintained as a lymphocyte having a stable cytotoxic activity. For instance, the induced CTL can be allowed to proliferate and expanded by stimulating the CTL with an antigen, various cytokines or anti-CD3 antibodies. For the maintenance and the expansion of the CTL, a known method can be used without limitation. For instance, it is preferable to use the method for maintaining or the method for expanding cytotoxic T cell of the present invention described below. (2) Method for Maintaining Cytotoxic T Cell of Present Invention The method for maintaining cytotoxic T Cell of the present invention is a method for maintaining CTL with keeping its antigen-specific cytotoxic activity. One of the great features of the method resides in that CTL is continuously cultured in a medium containing the effective ingredient of the present invention, whereby the antigen-specific cytotoxic activity of the cell can be continuously maintained. The CTL which can be applied to the above-mentioned method is not limited, and CTL obtained by a known method can be maintained by the method of the present invention, with keeping its antigen-specific cytotoxic activity. In addition, the method is also preferably used for maintaining CTL obtained by the method for inducing cytotoxic T cell of the present invention described in the above item (1). In the present invention, common conditions for continuously culturing CTL may be in accordance with known conditions [see, for instance, Carter J. et al., Immunology 57(1), 123-129 (1986)]. The media used for the method for maintaining cytotoxic T cell of the present invention are not particularly limited, and for instance, the medium used for the above-mentioned method for inducing CTL can be used. The method of the present invention is carried out by using a medium containing the above-mentioned effective ingredient. The content of the effective ingredient of the present invention in the medium for culturing is not particularly limited, so long as the desired effect can be obtained. The content of the effective ingredient is preferably from 0.001 to 1000 μg/ml, more preferably from 0.01 to 100 μg/ml. Incidentally, it is preferable that the effective ingredient is present in the medium by dissolving them in the medium, or immobilizing them to the substrate such as a culture equipment or microbeads. In addition, the above-mentioned effective ingredient is preferably at least one member selected from the group consisting of hyaluronic acid, an anti-CD44 antibody, an anti-HGF antibody, an anti-IGF-1 antibody, an anti-IGF-2 antibody, and a fibronectin fragment. Further, a cytokine or other known component can be added to the medium. In the present invention, a medium containing IL-2 is preferably used. In addition, these cytokine and other known components may be used by immobilizing them to the substrate such as a culture equipment or to microbeads in the same manner as above. The culture conditions are not particularly limited, and the conditions used for ordinary cell culture can be used. For instance, the cells can be cultured under the conditions at 37° C. in the presence of 5% CO2, and the like. In addition, the medium can be exchanged with a fresh one at appropriate time intervals. As described above, CTL can be maintained with suppressing lowering of its specific cytotoxic activity by continuously culturing CTL in a medium containing the effective ingredient of the present invention. The effects of the present invention described above can be confirmed by determining the cytotoxic activity possessed by CTL maintained by the method of the present invention according to the method described in item (3) of Example 1-1. In addition, the CTL maintained by the method can be allowed to proliferate by a known expanding method, and the CTL thus proliferated also maintains a specific cytotoxic activity. Incidentally, as a method for expanding CTL, the method for expanding CTL of the present invention described below can be preferably used. (3) Method for Expanding Cytotoxic T Cell of Present Invention Cytotoxic T cell is cultured under appropriate conditions, whereby the cell number can be increased (expansion). Conventionally, several methods for expanding CTL have been developed. As a method capable of efficiently proliferating CTL in a short period of time, the above-mentioned REM method developed by Riddell et al. has been known. This method uses PBMC made non-proliferative by X ray irradiation (used as feeder cell) and EBV-transformed B cell (EBV-B cell) and comprises culturing CTL in the presence of IL-2 and an anti-CD3 monoclonal antibody. However, this method has been problematic in that risk of admixing EBV-B cell into T cell is not deniable. The method for expanding cytotoxic T cell of the present invention is a method capable of increasing the cell number with keeping its antigen-specific cytotoxic activity. The method is characterized by incubating (culturing) the cell in the presence of the above-mentioned effective ingredient of the present invention. In the method of the present invention, CTL which can be applied to the method is not limited. The method can be suitably used for expansion of CTL having a cytotoxic activity obtained from a living body, CTL induced by a known method, CTL obtained by the method for inducing CTL of the present invention described in the above item (1), and CTL obtained by the method for maintaining CTL of the present invention described in the above item (2). Incidentally, in the present invention, common conditions for expanding CTL may be in accordance with known conditions [see, for instance, Uberti J. P. et al., Clin. Immunol. Immunopathol. 70(3), 234-240 (1994)]. In the method for expanding cytotoxic T cell of the present invention, it is desired that CTL is co-cultured in a medium further containing an anti-CD3 antibody, preferably an anti-CD3 monoclonal antibody, in addition to the above-mentioned effective ingredient. In addition, more preferably, CTL is co-cultured with appropriate feeder cell. The medium used for the above-mentioned method is not particularly limited. A known medium prepared by blending components necessary for culture or growth of CTL can be used, and may be, for instance, commercially available ones. Incidentally, in the case where CTL is co-cultured with feeder cell, it is desired that the medium is suitable for maintenance and growth of both the CTL and the feeder cell. These media may contain appropriate proteins, cytokines and other components in addition to the originally contained constituents. For instance, a medium containing IL-2 is preferably used in the present invention. An anti-CD3 antibody, especially an anti-CD3 monoclonal antibody, can be added for the purpose of activating T cell receptor on CTL. Incidentally, the content of the anti-CD3 antibody in the medium may be determined according to the known conditions. For instance, the content is preferably from 0.01 to 400 μg/ml. Incidentally, these proteins, cytokines and other known components may be contained in the medium by dissolving them in the medium, or by immobilizing them to a substrate such as a culture equipment or microbeads. The method for expanding CTL of the present invention is carried out by using a medium containing the above-mentioned effective ingredient. Incidentally, the above-mentioned effective ingredient is preferably at least one member selected from the group consisting of hyaluronic acid, an anti-CD44 antibody, an anti-HGF antibody, an anti-IGF-1 antibody, an anti-IGF-2 antibody, and a fibronectin fragment. In addition, the content of the effective ingredient of the present invention in the medium for culture is not particularly limited, so long as the desired effects can be obtained. The content of the effective ingredient is preferably from 0.001 to 1000 μg/ml, more preferably from 0.01 to 100 μg/ml. Incidentally, it is preferable that the effective ingredient is present in the medium by dissolving the effective ingredient in the medium, or by immobilizing the effective ingredient to the substrate such as a culture equipment or microbeads. The feeder cell used for the method of the present invention is not particularly limited, so long as the feeder cell stimulates CTL cooperatively with an anti-CD3 antibody, especially an anti-CD3 monoclonal antibody, to activate T cell receptor or costimulatory signal receptor. In the present invention, for instance, PBMC or EBV-B cell is used. Usually, a feeder cell is used after its proliferating ability is taken away by means of irradiation or the like. Incidentally, the content of the feeder cell in the medium may be determined according to the known conditions. For instance, the content is preferably from 1×105 to 1×107 cells/ml. In a particularly preferred embodiment of the present invention, non-virus-infected cell, for instance, a cell other than EBV-B cell, concretely self-derived or nonself-derived PBMC, is used as a feeder cell. By using the non-virus-infected cell, the possibility that EBV-B cell is admixed in an expanded CTL can be eliminated, thereby making it possible to increase the safety in medical treatments utilizing CTL, such as adoptive immunotherapy. In the method for expanding CTL of the present invention, the conditions for culture are not particularly limited, and the conditions used for usual cell culture can be used. For instance, the cell can be cultured under the conditions of 37° C. in the presence of 5% CO2, and the like. In addition, the medium can be exchanged with a fresh one at appropriate time intervals. The method for expanding CTL of the present invention is not particularly limited to a certain method, so long as the effective ingredient of the present invention is added to the medium used in the method. The present invention encompasses an embodiment of adding the effective ingredient of the present invention to a medium in conventional methods for expanding CTL other than the above-mentioned method. According to the method for expansion of the present invention, for instance, CTL of which cell number is increased 102- to 103-folds can be obtained by an expansion for 14 days. Further, CTL thus obtained has a higher antigen-specific cytotoxic activity, as compared to those obtained by a conventional method for expansion, for instance, the REM method. The effects of the present invention as described above can be confirmed by determining the cytotoxic activity possessed by CTL expanded by the method of the present invention according to the method described in item (3) of Example 1-1. In addition, the effective ingredient used in the present invention can be used as an agent for inducing CTL, an agent for maintaining CTL or an agent for expanding CTL (these agents are hereinafter referred to as an agent for culturing CTL), which acts for maintaining or enhancing an antigen-specific cytotoxic activity of CTL. The agent for culturing CTL may be the effective ingredient itself, or the agent for culturing CTL further comprises any other optional components, for instance, components necessary for culture or growth of CTL, feeder cell and the like, which are contained in the medium used in a method for inducing CTL, the medium used in a method for maintaining CTL or the medium used in a method for expanding CTL; appropriate proteins and cytokines (preferably IL-2); and other desired components. Also, a medium containing these agents for culturing CTL can be used as a medium for inducing, maintaining, or expanding CTL (a medium for CTL). In addition, these agents for culturing CTL may be mixed with the medium (including dissolving the agent), or may be immobilized to a substrate such as a culture equipment or microbeads. These media optionally contain the basic constituents for cell culture. Incidentally, the agents for culturing CTL and the media for CTL mentioned above can be prepared by appropriately mixing the desired components by known methods. Further, according to the present invention, there can be provided substrates for inducing, maintaining or expanding CTL, in which the above-mentioned effective ingredient is immobilized to a substrate such as a given culture equipment (vessel) such as a culture plate, a petri dish, a flask or a bag, or a supporting carrier such as beads or membrane (more concretely the portion of the substrate contacting with the medium during the cell culture). The amount of the effective ingredient immobilized to the substrate is not particularly limited, so long as the desired effects of the present invention are obtained. When the CTL is induced or the like by using the substrate, it is preferable that the effective ingredient is in an amount that the effective ingredient can be contained in the given medium used for the substrate within the preferred range of the content of the effective ingredient in the medium as given in the explanation for the method for inducing CTL, method for maintaining CTL or method for expanding CTL of the present invention. In addition, in addition to the above-mentioned effective ingredient, the above-mentioned proteins, cytokines and other components may be optionally immobilized. The immobilization method is not particularly limited. For instance, there can be employed a known immobilization method such as protein adsorption, binding of biotin and avidin or streptoavidin, or chemical immobilization. The substrate is suitably used in the method for inducing CTL, method for maintaining CTL or method for expanding CTL of the present invention. Usually, in the CTL-containing culture obtained by using the method for inducing CTL, the method for maintaining CTL and the method for expanding CTL as described above, cells other than CTL such as helper T cell are admixed therein. In the present invention, the cells in the culture are collected from the culture by centrifugation or the like, and the cells can be directly used as the CTL obtained by the method of the present invention. In addition, a cell population (or a culture) rich in CTL having an antigen-specific cytotoxic activity can be further separated from the culture by a known method, and used as CTL obtained by the method of the present invention. Concretely, in the present invention, a cell population with a concentrated antigen-specific cytotoxic activity can be prepared by subjecting the culture to a separation procedure of CTL from cell other than the CTL (for instance, helper T cell) in the above-mentioned CTL-containing culture to use the cell population. The concentration of the antigen-specific cytotoxic activity by separating the above-mentioned cell population as described above could not have been accomplished by the conventional REM method. Therefore, as one embodiment of the present invention, there is provided a method for collecting cytotoxic T cell comprising the step of selecting a cell population rich in cytotoxic T cell having an antigen-specific cytotoxic activity from a CTL-containing culture obtained by any one of the method for inducing CTL, the method for maintaining CTL and the method for expanding CTL of the present invention. The method for collecting CTL of the present invention in a sense refers to a method of selectively obtaining a cell population of CTL having a high antigen-specific cytotoxic activity, and in a broad sense refers to a method for producing or acquiring a cell population of the CTL. The method of selecting the cell population is not particularly limited. For instance, the cell population rich in CTL can be obtained by selectively collecting only CTL from a CTL-containing culture obtained by using the method for inducing CTL, the method for maintaining CTL and the method for expanding CTL as described above, using magnetic beads or a column to which an antibody against a cell surface antigen expressed on the CTL cell surface, for instance, an anti-CD8 antibody, is bound. CTL can also be selectively separated using a flow cytometer. The cell population rich in CTL can be obtained by removing cells other than CTL from a CTL-containing culture obtained by the method for inducing CTL, the method for maintaining CTL and the method for expanding CTL of the present invention. For instance, the cell population rich in CTL can be obtained by selectively removing helper T cell using magnetic beads or a column to which an antibody against a cell surface antigen expressed on helper T cell surface, for instance, an anti-CD4 antibody, is bound, in order to remove helper T cell from the culture. Also, a flow cytometer can be used for removing helper T cell. The cell population rich in CTL thus obtained has a more potent cytotoxic activity, as compared to a cell population collected non-selectively from a CTL-containing culture, so that it is more preferably used as the CTL obtained by the method of the present invention. In addition, in the present invention, the cell population rich in CTL also encompasses a cell population of CTL alone. In addition, CTL can be further maintained or expanded according to the method for maintaining CTL or the method for expanding CTL of the present invention using the CTL obtained by the method for maintaining CTL or the method for expanding CTL of the present invention. For instance, CTL having an even higher cytotoxic activity can also be obtained by obtaining a fraction rich in CTL according to the method described above from CTL obtained by the method for expansion of the present invention, and subjecting the fraction obtained to the method for expansion of the present invention. In addition, the cytotoxic activity of CTL obtained by the method for expansion of the present invention can be maintained by using the method for maintaining CTL of the present invention. Further, the present invention provides CTL obtained by the method for inducing CTL, the method for maintaining CTL and the method for expanding CTL of the present invention mentioned above (including CTL collected by the above-mentioned collecting method from the CTL-containing culture obtained by these methods). All of the above-mentioned CTLs have an antigen-specific cytotoxic activity, in which there is little lowering of cytotoxic activity, even when the CTL is subjected to the continuous culture or expansion over a long period of time. In addition, the present invention provides a therapeutic agent comprising the CTL as an effective ingredient. The therapeutic agent is especially suitably used in adoptive immunotherapy. In the adoptive immunotherapy, CTL having an antigen-specific cytotoxic activity suitable for treating a patient is administered to the patient by, for instance, intravenous administration. The therapeutic agent can be prepared by, for instance, blending the CTL prepared by the method of the present invention as an effective ingredient with, for instance, a known organic or inorganic carrier suitable for parenteral administration, an excipient, a stabilizing agent and the like, according to a method known in the pharmaceutical field. As the CTL, CTL prepared by the method for expanding CTL of the present invention without using EBV-infected cell is especially preferable for this purpose. Incidentally, various conditions for the therapeutic agent, such as the content of CTL in the therapeutic agent and the dosage of the therapeutic agent, can be appropriately determined according to the known adoptive immunotherapy. The present invention will be more concretely described by means of the examples, without by no means limiting the scope of the present invention thereto. EXAMPLE 1 Method of Expanding CTLs Having Specific Cytotoxic Activity Using Hyaluronic Acid Example 1-1 (1) Isolation and Storage of PBMCs Blood component was collected from a human normal individual donor having HLA-A2.1. The collected blood component was diluted 2-folds with PBS(−), overlaid on Ficoll-paque (manufactured by Pharmacia), and centrifuged at 500×g for 20 minutes. After the centrifugation, the peripheral blood mononuclear cells (PBMCs) in the intermediate layer were collected with a pipette, and washed. The collected PBMCs were suspended in a storage solution of 90% FBS (manufactured by Bio Whittaker)/10% DMSO (manufactured by SIGMA), and stored in liquid nitrogen. During CTL induction, these stored PBMCs were rapidly melted in water bath at 37° C., and washed with RPMI 1640 medium (manufactured by Bio Whittaker) containing 10 μg/ml Dnase (manufactured by Calbiochem). Thereafter, the number of living cells was calculated by trypan blue staining method, and the cells were subjected to each experiment. (2) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed by partially modifying the method of Bednarek et al. [Bednarek, M. A. et al, J. Immunology, 147, 4047-4053 (1991)]. Concretely, PBMCs prepared in item (1) of Example 1-1 were suspended in RPMI 1640 medium (manufactured by Bio Whittaker) containing 5% human AB-type serum, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine (hereinabove being all manufactured by Bio Whittaker), 10 mM HEPES (manufactured by nakalai tesque), 1% streptomycin-penicillin (manufactured by Gibco BRL) (hereinafter simply referred to as “5HRPMI”) so as to have a concentration of 1 to 4×106 cells/ml. Thereafter, the suspension was spread on a 24-well cell culture plate (manufactured by Falcon) in a volume of 1 ml/well, and the cells were incubated in a 5% CO2 wet-type incubator at 37° C. for 1.5 hours, to give plastic-adherent mononuclear cells. Thereafter, nonadherent cells were collected using RPMI 1640 medium, and stored on ice as responder cells. To separated mononuclear cells was added 0.5 ml each of 5HRPMI containing as an antigen peptide 5 μg/ml epitope peptide derived from influenza virus protein [HLA A2.1-binding peptide derived from the matrix protein of SEQ ID NO: 18 of Sequence Listing] and 1 μg/ml β2 microglobulin (manufactured by Scrips). The mixture was incubated at room temperature for 2 hours, and thereafter the cells were subjected to X-ray irradiation (5500R) to give antigen-presenting cells. The peptide solution was removed by aspiration from each of the wells, and the wells were washed with RPMI 1640 medium. Thereafter, the responder cells previously stored on ice were suspended in 5HRPMI so as to have a concentration of 0.5 to 2×106 cells/ml, and the suspension was added to antigen-presenting cells in an amount of 1 ml per well. At this time, hyaluronic acid (manufactured by Calbiochem) was added so as to have a final concentration of 10 μg/ml. A group without addition of the sample was set as the control. The plate was cultured at 37° C. in the presence of 5% CO2. On the second day from the initiation of the culture, 1 ml of 5HRPMI containing 60 U/ml IL-2 (manufactured by Shionogi & Co., Ltd.) and 10 μg/ml hyaluronic acid was added to each well (the control containing only IL-2). Also, on the fifth day, a half of the culture supernatant was removed, and 1 ml each of IL-2 and hyaluronic acid-containing medium (the control containing only IL-2), the same as those mentioned above, was added thereto. On the seventh day, the antigen-presenting cells were prepared in the same manner as above, and thereafter the responder cells which had been cultured for one week were suspended in 5HRPMI so as to have a concentration of 0.5 to 2×106 cells/ml. The suspension was added to the antigen-presenting cells prepared in an amount of 1 ml/well each to re-stimulate the cells. At this time, hyaluronic acid was added so as to have a final concentration of 10 μg/ml (the control being without addition). On the second day from re-stimulation, 1 ml of 5HRPMI containing 60 U/ml IL-2 and 10 μg/ml hyaluronic acid was added to each well (the control containing only IL-2). Also, on the fifth day, a half of the culture supernatant was removed, and 1 ml each of the medium having the same content as that before removal was added thereto. The culture was continued for additional two days, thereby inducing CTLs. (3) Determination for Cytotoxic Activity of CTLs The cytotoxic activity of CTLs prepared in item (2) of Example 1-1 on the fourteenth day after the initiation of induction was evaluated by a determination method for cytotoxic activity using Calcein-AM [R. Lichtenfels et al., J. Immunological Methods, 172(2), 227-239 (1994)]. HLA-A2.1-having EBV transformed B-cells (name of cells: 221A2.1), which were cultured overnight together with an epitope peptide or in the absence of the epitope peptide, were suspended in RPMI 1640 medium containing 5% FBS (fetal bovine serum, manufactured by Bio Whittaker) so as to have a concentration of 1×106 cells/ml. Thereafter, Calcein-AM (manufactured by Dotite) was added to the suspension so as to have a final concentration of 25 μM, and the cells were cultured at 37° C. for 1 hour. The cells were washed with a medium not containing Calcein-AM, and thereafter mixed with K562 cells in an amount 20 times that of the cells, to give Calcein-labeled target cells. The K562 cells were used for excluding nonspecific cytotoxic activity by NK cells admixed in the responder cells. The memory CTLs prepared in item (2) of Example 1-1 were stepwise diluted with 5HRPMI so as to have a concentration of from 1×105 to 9×106 cells/ml as effector cells. Thereafter, each of the dilutions was poured into each well of 96-well cell culture plate in an amount of 100 μl/well each. Thereto were added the Calcein-labeled target cells prepared to have a concentration of 1×105 cells/ml in an amount of 100 μl/well each. The plate containing the above-cell suspension was centrifuged at 400×g for 1 minute, and thereafter incubated in a wet-type CO2 incubator at 37° C. for 4 hours. After 4 hours, 100 μl of the culture supernatant was collected from each well, and the amount of calcein released into the culture supernatant was determined by using fluorescence plate reader (485 nm/538 nm). The “specific cytotoxic activity (%)” was calculated by the following equation 1: Specific Cytotoxic Activity (%)={(Found Value in Each Well−Minimum Released Amount)/(Maximum Released Amount−Minimum Released Amount)}×100 Equation 1 In the above equation, the minimum released amount is the amount of calcein released in the well containing only target cells and K562 cells, showing the amount of calcein naturally released from the target cells. In addition, the maximum released amount refers to the amount of calcein released when the cells are completely disrupted by adding 0.1% of the surfactant Triton X-100 (manufactured by nakalai tesque) to the target cells. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of hyaluronic acid during the induction. (4) Expansion of CTLs CTLs prepared in item (1) of Example 1-1 were washed with 5HRPMI, and then made into a suspension having a concentration of 3×104 cells/ml. On the other hand, allogenic PBMCs not having HLA-A2.1 which were collected in the same manner as in item (1) of Example 1-1 were subjected to X-ray irradiation (3300R), and the cells were washed with the medium and then made into a suspension having a concentration of 2 to 5×106 cells/ml. These 3×104 cells of CTLs and 4 to 10×106 cells of allogenic PBMCs were suspended in 10 ml of 5HRPMI, and anti-CD3 antibody (manufactured by Janssen-Kyowa) was further added thereto so as to give a final concentration of 50 ng/ml. The mixture was placed into a flask of 12.5 cm2 (manufactured by Falcon), and the cells were cultured in a wet-type CO2 incubator at 37° C. for 14 days. During the culture, a group with addition of hyaluronic acid, which had been added during the CTL induction of item (2) of Example 1-1 (final concentration: 10 μg/ml), and a group without addition of hyaluronic acid were set. Stimulation by a peptide was not added at all during this expansion. On the first day after the initiation of the expansion, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. During the culture, the sample in the same concentration was added to the medium for the group with addition of hyaluronic acid. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 1. In the table, an E/T ratio means a ratio of the number of the effector cells (E) to the number of the target cells (T), and the peptide pulse means the presence or absence of peptide pulse to the target cells. In addition, the expansion fold was obtained as a proliferation percentage of a ratio of the cell number at the time of the termination of the expansion to the cell number at the beginning of the expansion. TABLE 1 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 547 − 7.3 8.4 9.1 12.7 − − 547 + 8.1 11.2 21.5 45.9 Hyaluronic + + 493 − 7.3 8.6 13.1 17.0 Acid + + 493 + 31.1 49.8 90.8 105.6 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the groups with addition of hyaluronic acid in both of the stage during the CTL induction and the stage during the expansion, CTLs had specific, high cytotoxic activities even after the expansion for 14 days. On the other hand, in the group without addition of the sample in both of the stage during the CTL induction and the stage during the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out with maintaining a specific, high cytotoxic activity for a long period of time by adding hyaluronic acid in the stage during the CTL induction and the stage during the expansion. Example 1-2 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was carried out in the same manner as in item (2) of Example 1-1 using the PBMCs which were isolated and stored in the same manner as in item (1) of Example 1-1. During the induction, hyaluronic acid was added to a medium so as to have a final concentration of 10 μg/ml. Further, the group without addition of the sample was set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 1-2 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, hyaluronic acid which had been added during the CTL induction in item (1) of Example 1-2 was not added at all. During the expansion, stimulation by a peptide was not added at all. On the first day of the initiation of the expansion, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 2. TABLE 2 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 480 − 0 0 0.4 6.8 − − 480 + 4 11.2 29.3 59.7 Hyaluronic + + 423 − 0 0 1.9 14.3 Acid + + 423 + 7.2 23.3 59.6 85.1 + − 393 − 3.0 1.4 4.7 9.3 + − 393 + 9.9 22.1 47.7 78.0 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of hyaluronic acid only during the CTL induction, CTLs maintained specific, high cytotoxic activity even after the expansion for 14 days even when these samples were not added during the expansion. On the other hand, in the group without addition of these samples in either of the stage during the CTL induction or the stage during the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out with maintaining the specific, high cytotoxic activity for a long period of time even if hyaluronic acid is added only during the CTL induction. Example 1-3 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, there were set a group with addition of hyaluronic acid (simply referred to as “HA” in Table 3) (final concentration: 10 μg/ml), and a group without addition of the sample at all. As to the groups added with hyaluronic acid, there were set a group added simultaneously together with an anti-CD44 antibody (hyaluronic acid-bound Blocking antibody; in the table referred to as “HA Blocking Anti-CD44 Antibody”) or with an anti-CD44 antibody (hyaluronic acid-bound Non-blocking antibody; in the table referred to as “HA Non-blocking Anti-CD44 Antibody”) each at a final concentration of 0.2 μg/ml (each being manufactured by Ancell, monoclonal antibody), and the inhibitory effects by these antibodies were studied. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 1-3 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of hyaluronic acid, which had been added during the CTL induction in item (1) of Example 1-3, so as to have a final concentration of 10 μg/ml and a group without addition of hyaluronic acid at all from the stage of induction. In addition, as to the group with addition of hyaluronic acid together with the anti-CD44 antibody, the same sample and antibody were also added during the expansion. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the expansion, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 3. TABLE 3 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 330 − 2.4 6.2 7.4 9.6 − − 330 + 3.9 5.8 7.2 10.9 HA + + 350 − 0 0 1.9 5.3 + + 350 + 4.8 15.3 35.3 70.2 HA + HA Blocking + + 357 − 5.9 4.7 15.0 14.9 Anti-CD44 Antibody + + 357 + 10.9 11.8 19.5 17.5 HA + HA Non Blocking + + 413 − 6 4.7 5 7.6 Anti-CD44 Antibody + + 413 + 12.2 17.5 34.9 69.9 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of hyaluronic acid during the CTL induction and during the expansion, CTLs maintained specific, high cytotoxic activity even after the expansion for 14 days. On the other hand, in the group without addition of the sample in either of the stage during the CTL induction or the stage during the expansion, its activity was clearly lowered. In addition, in the group with addition of hyaluronic acid together with the anti-CD44 antibody (hyaluronic acid-bound Blocking antibody), the effect of maintaining CTL activity by hyaluronic acid was completely inhibited. On the other hand, in the group with addition of hyaluronic acid together with the anti-CD44 antibody (hyaluronic acid-bound Non-Blocking antibody), the effect of maintaining CTL activity by hyaluronic acid was not inhibited. In other words, it was clarified that the effect of maintaining cytotoxic activity by hyaluronic acid is exhibited by binding of hyaluronic acid to a CD44 antigen on the cell surface. EXAMPLE 2 Method of Expanding CTLs Having Specific Cytotoxic Activity Using Anti-Human CD44 Antibody (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, there were added a purified mouse IgG1 (manufactured by Genzyme/Techne) or the two kinds of anti-human CD44 antibodies used in item (1) of Example 1-3, each so as to have a final concentration of 0.2 μg/ml. Further, a group without addition of any antibodies was set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 2 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of mouse IgG1, which had been added during the CTL induction in item (1) of Example 2, or the above-mentioned two kinds of anti-human CD44 antibodies, each so as to have a final concentration of 0.2 μg/ml, and a group without addition of the antibody at all from the stage of induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the expansion, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 0.2 μg/ml mouse IgG1 or the above-mentioned two kinds of anti-human CD44 antibodies to each flask were carried out every 2 to 3 days. Here, in the group without addition of the antibody, the antibody was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 4. TABLE 4 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 3 10 30 Control − − 413 − 5.9 10.5 12.8 − − 413 + 4.0 14.8 48.9 Mouse IgG1 + + 357 − 5.6 0 2 + + 357 + 6.2 6.8 13.3 HA Non Blocking + + 357 − 10.3 14.2 21.2 Anti-CD44 Antibody + + 357 + 32.4 60.1 104.8 HA Blocking + + 420 − 1.6 1.3 3.5 Anti-CD44 Antibody + + 420 + 9.5 9.8 17.7 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human CD44 antibody (hyaluronic acid-bound Non-Blocking antibody) during the CTL induction and during the expansion, CTLs maintained specific, high cytotoxic activity even after the expansion for 14 days. On the other hand, in the group without addition of these antibodies and the group with the anti-human CD44 antibody (hyaluronic acid-bound Blocking antibody) in both of the stage during the CTL induction and the stage during the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which the specific, high cytotoxic activity is maintained for a long period of time by adding an antibody not inhibiting the binding of hyaluronic acid among the anti-human CD44 antibody in the stage of CTL induction and expansion. EXAMPLE 3 Binding Property of Hyaluronic Acid and Anti-Human CD44 Antibody with CD44 Antigen Being Soluble or Existing on Cell Surface There are two kinds of existing modes for CD44: one existing in the culture supernatant in a soluble state (hereinafter referred to as “soluble CD44”) and the other existing on the surface of cell membrane (hereinafter referred to as “CD44 existing on cell surface”). CD44 is a receptor of hyaluronic acid, and hyaluronic acid has an effect of maintaining cytotoxic activity by its addition during the expansion. Therefore, which of the CD44 antigens the effect of maintaining the activity is dependent upon was studied. Example 3-1 (1) Evaluation of Binding Property of Soluble CD44 and Hyaluronic Acid The binding property of the soluble CD44 and hyaluronic acid was evaluated by the following method. Concretely, Nunc-Immuno plate (manufactured by Nunc), to which PBS (manufactured by Nissui) containing 5 μg/ml anti-human CD44 antibody (soluble CD44-recognizing antibody, manufactured by Ancell) had been poured into each well at 100 μl/well and the plate which was preincubated at room temperature overnight, was washed with 0.025% Tween 20 (manufactured by SIGMA)/PBS three times. Thereafter, Blockace (manufactured by Dainippon Pharmaceutical Co., Ltd.) was added thereto at 300 μl/well, and the incubation was carried out at room temperature for 1 hour or more. On the other hand, hyaluronic acid was added to a soluble CD44 (15 ng/ml)-containing RPMI medium so as to have a final concentration of 0, 0.25, 0.5 or 1 μg/ml, and the media were preincubated at 37° C. for 1 hour. Each well of the plate after blocking was washed again three times with 0.025% Tween 20/PBS, and each of preincubated soluble CD44 (15 ng/ml)-containing RPMI medium with or without hyaluronic acid was added at 100 μl/well. Further, an HRP-labeled conjugate (reagent attached to ELISA system for determining soluble CD44, manufactured by BenderMed) was added to each well at 50 μl/well, and the incubation was carried out at room temperature for 3 hours. After the incubation, each well was washed three times with 0.025% Tween 20/PBS, a TMB (3,3′,5,5′-tetramethylbenzidine) solution (manufactured by SIGMA) was added at 100 μl/well, the incubation was carried out at room temperature for 15 minutes, and 2 N sulfuric acid was added thereto at 50 μl/well to stop the reaction. Each absorbance was determined using a plate reader (450 nm). The determination results are shown in FIG. 1. As a result, even when hyaluronic acid was added to the soluble CD44-containing medium, the recognition by the soluble CD44-recognizing antibody was not inhibited at all. In other words, hyaluronic acid did not bind to the soluble CD44 existing in the medium at all. It was clarified from this finding that the soluble CD44 in the medium is not involved at all in the effect of maintaining the specific cytotoxic activity of CTLs by hyaluronic acid. (2) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction. (3) Expansion of CTLs CTLs prepared in item (2) of Example 3-1 were expanded in the same manner as in item (4) of Example 1-1. Stimulation by a peptide was not added at all during this expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. It was confirmed that these CTLs have specific cytotoxic activity. (4) Evaluation of Binding Property of Hyaluronic Acid and CD44 on Cell Surface The CTLs prepared in item (3) of Example 3-1 in an amount of 2×105 cells were immobilized with PBS (manufactured by Nissui) containing 1% paraformaldehyde (manufactured by nakalai tesque), and washed with PBS. The immobilized cells were suspended in PBS containing 10 μg/ml FL-labeled hyaluronic acid (manufactured by Molecular Probes), and the cells were incubated at 37° C. for 30 minutes. As a negative control, a group to be incubated in PBS without containing FL-labeled hyaluronic acid (FL-HA) was also set. After the incubation, the cells were washed with PBS, and suspended again in PBS containing 1% paraformaldehyde. The prepared CTLs were applied to FACS Vantage (manufactured by Becton, Dickinson) to determine fluorescent intensity on the cell surface of CTLs. The results are shown in FIG. 2. As a result, the FL-labeled hyaluronic acid was bound to the cell surface of CTLs. In other words, it was clarified that the effect of maintaining the specific cytotoxic activity of CTLs by hyaluronic acid is exhibited by the binding of hyaluronic acid to CD44 existing on the cell surface of CTLs. Example 3-2 (1) Evaluation of Binding Property of Anti-Human CD44 Antibody (HA Non-Blocking Anti-CD44 Antibody) and Soluble CD44 The binding property of the HA Non-Blocking anti-CD44 antibody and the soluble CD44 was evaluated by the following method. Concretely, the Nunc-Immuno plate (manufactured by Nunc) to which PBS (manufactured by Nissui) containing 5 μg/ml of HA Non-Blocking anti-CD44 antibody or anti-human CD44 antibody (soluble CD44-recognizing antibody) (manufactured by Ancell) as a primary antibody had been poured at 100 μl/well, and the plate which was incubated at room temperature overnight, was washed three times with 0.025% Tween 20 (manufactured by SIGMA)/PBS. Thereafter, Blockace (manufactured by Dainippon Pharmaceutical) was added thereto at 300 μl/well, and the incubation was carried out at room temperature for 1 hour or more. Each well of the plate after blocking was washed again three times with 0.025% Tween 20/PBS, and the soluble CD44 (15 ng/ml)-containing RPMI medium was added thereto at 100 μl/well. Further, an HRP-labeled conjugate (reagent attached to ELISA system for measuring soluble CD44, manufactured by BenderMed) was added to each well at 50 μl/well, and the incubation was carried out at room temperature for 3 hours. After incubation, each well was washed three times with 0.025% Tween 20/PBS, TMB solution (manufactured by SIGMA) was added thereto at 100 μl/well, the incubation was carried out at room temperature for 15 minutes, and thereafter 2 N sulfuric acid was added thereto at 50 μl/well to stop the reaction. Each absorbance was determined with a plate reader (450 nm). Experiments were carried out twice, and an average value was taken. The results are shown in FIGS. 3 and 4. As a result, the soluble CD44-recognizing antibody used as a primary antibody recognized the soluble CD44 in the medium in an antibody concentration-dependent manner. On the other hand, the HA Non-Blocking anti-CD44 antibody did not recognize the soluble CD44 in the medium at all. In other words, the HA Non-Blocking anti-CD44 antibody did not bind to the soluble CD44 existing in the medium. It was clarified from this finding that the soluble CD44 in the medium is not involved at all in the effect of maintaining the specific cytotoxic activity of CTLs by the HA Non-Blocking anti-CD44 antibody. (2) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction. (3) Expansion of CTLs CTLs prepared in item (2) of Example 3-2 were expanded in the same manner as in item (4) of Example 1-1. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1, and it was confirmed that these CTLs have specific cytotoxic activity. (4) Evaluation of Binding Property of Anti-Human CD44 Antibody (HA Non-Blocking Anti-CD44 Antibody) and CD44 on Cell Surface The CTLs prepared in item (3) of Example 3-2 in an amount of 2×105 cells were immobilized with PBS (manufactured by Nissui) containing 1% paraformaldehyde (manufactured by nakalai tesque), and thereafter washed with PBS. The immobilized cells were suspended in PBS containing 1% BSA (manufactured by SIGMA) and 1 μg/ml anti-CD44/FITC (FITC-labeled HA Non-Blocking anti-CD44 antibody (CD44-FITC), manufactured by Ancell), and the cells were incubated on ice for 30 minutes. As a control, a group to be incubated in PBS containing 1 μg/ml mouse IgG1/FITC (FITC-labeled mouse IgG antibody (IgG1-FITC), manufactured by DAKO) was also set. After the incubation, the cells were washed with PBS, and suspended again in PBS containing 1% paraformaldehyde. The prepared CTLs were applied to FACS Vantage to determine the fluorescent intensity on the cell surface of CTLs. The results are shown in FIG. 5. As a result, the FITC-labeled HA -Non-Blocking anti-CD44 antibody was bound to the cell surface of CTLs. In other words, there was suggested a possibility that the effect of maintaining the specific cytotoxic activity of CTLs by the anti-human HA Non-Blocking anti-CD44 antibody is exhibited by binding of hyaluronic acid to CD44 existing on the cell surface of CTLs. Example 3-3 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, the HA Non-Blocking Anti-CD44 antibody was added so as to have a final concentration of 0.2 μg/ml. Further, a group without addition of the antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 3-3 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, the HA Non-Blocking Anti-CD44 antibody, which had been added during the induction of CTLs in item (1) of Example 3-3, was each added so as to have a final concentration of 0.2 μg/ml. In addition, as to the group without addition of the antibody during the induction, the antibody was not added at this stage. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 0.2 μg/ml HA Non-Blocking Anti-CD44 antibody to each flask were carried out every 2 to 3 days. Here, in the group without addition of the antibody, the antibody was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. As a result, it was confirmed that in the group with addition of HA Non-Blocking Anti-CD44 antibody during the induction of CTLs and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for fourteen days. On the other hand, it was confirmed that in the group without addition of these antibodies during neither the induction of CTLs nor the expansion, its activity was clearly lowered. (3) Evaluation of Binding Property of Antibody on Cell Surface of CTLs After Expansion with Addition of HA Non-Blocking Anti-CD44 Antibody The CTLs prepared in item (1) of Example 3-3 in an amount of 2×105 cells (CTLs cultured under the conditions of addition of HA Non-Blocking Anti-CD44 Antibody) were immobilized with PBS (manufactured by Nissui) containing 1% paraformaldehyde (manufactured by nakalai tesque), and washed with PBS. The immobilized cells were suspended in PBS containing 1% BSA (manufactured by SIGMA) and 1 μg/ml FITC-labeled mouse IgG or FITC-labeled anti-mouse IgG antibody, and the cells were incubated on ice for 30 minutes. After the incubation, the cells were washed with PBS, and suspended again in PBS containing 1% paraformaldehyde. The prepared CTLs were analyzed by FACS Vantage to determine the fluorescent intensity on the cell surface of CTLs. The results are shown in FIG. 6. As a result, binding of the HA Non-Blocking anti-CD44 antibody was confirmed on the cell surface of CTLs obtained by expanding under the conditions of addition of this antibody. In other words, it was clarified that the effect of maintaining the specific cytotoxic activity of CTLs by the HA Non-Blocking anti-CD44 antibody is exhibited by binding of this antibody to CD44 existing on the cell surface of CTLs. EXAMPLE 4 Expansion of CTLs Maintaining Specific Cytotoxic Activity Using Anti-Human HGF Antibody Example 4-1 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, a purified mouse IgG1 (manufactured by Genzyme/Techne) or an anti-human HGF antibody (mouse monoclonal antibody; manufactured by Genzyme/Techne) was added so as to have a final concentration of 2 μg/ml. Further, a group without addition of antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 4-1 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of the mouse IgG1 or the anti-human HGF antibody, which had been added during the induction of CTLs in item (1) of Example 4-1, each so as to have a final concentration of 2 μg/ml, and a group without addition of the antibody at all from the stage of the induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 2 μg/ml mouse IgG1 or anti-human HGF antibody to each flask were carried out every 2 to 3 days. Here, in the group without addition of the antibody, the antibody was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 5. TABLE 5 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 340 − 0.6 0.6 1.5 19.4 − − 340 + 0 3.2 6.8 21.3 Mouse IgG1 + + 207 − 0 0 0.1 3.9 + + 207 + 0 4.1 9.3 30.3 Anti-HGF + + 435 − 1.2 3.1 0 4.0 Antibody + + 435 + 7.2 19.5 39.6 74.5 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human HGF antibody during the induction of CTLs and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for fourteen days. On the other hand, in the group without addition of these antibodies during neither the induction of CTLs nor the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which a specific, high cytotoxic activity is maintained for a long period of time by adding the anti-human HGF antibody during the induction of CTLs and during the expansion. Example 4-2 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, an anti-human HGF antibody (mouse monoclonal antibody; manufactured by Genzyme/Techne) was added so as to have a final concentration of 2 μg/ml. Further, a group without addition of antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 4-2 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, the anti-human HGF antibody, which had been added during the induction of CTLs in item (1) of Example 4-2, was not added at all. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 6. TABLE 6 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 547 − 7.3 8.4 9.1 12.7 − − 547 + 8.1 11.2 21.5 45.9 Anti-HGF + + 540 − 6.8 7.3 8.5 10.2 Antibody + + 540 + 23.3 40.8 72.4 103.4 + − 463 − 7.4 7.9 10.5 14.4 + − 463 + 22.2 38.1 70.4 94.5 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human HGF antibody only during the induction of CTLs, a specific, high cytotoxic activity was maintained after the expansion for fourteen days even when the antibody was not added during the expansion. On the other hand, in the group without addition of the antibody during neither the induction of CTLs nor the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which a specific, high cytotoxic activity is maintained for a long period of time even when the anti-human HGF antibody was added only during the induction of CTLs. EXAMPLE 5 Expansion of CTLs Maintaining Specific Cytotoxic Activity Using Anti-Human IGF-1 Antibody Example 5-1 (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, a purified goat IgG (manufactured by CHEMICON International) or an anti-human IGF-1 antibody (goat polyclonal antibody; manufactured by Genzyme/Techne) was added so as to have a final concentration of 2 μg/ml. Further, a group without addition of antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 5-1 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of the goat IgG or anti-human IGF-1 antibody, which had been added during the induction of CTLs in item (1) of Example 5-1 each so as to have a final concentration of 2 μg/ml, and a group without addition of the antibody at all from the stage of the induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 2 μg/ml goat IgG or anti-human IGF-1 antibody to each flask were carried out every 2 to 3 days. Here, in the group without addition of the antibody, the antibody was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 7. TABLE 7 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 340 − 0.8 0.6 1.5 19.4 − − 340 + 0 3.2 6.8 21.3 Goat IgG + + 463 − 0 0 1.6 5.6 + + 463 + 0.7 2.1 6.6 18.9 Anti-IGF-1 + + 368 − 0 0 0.4 3.4 Antibody + + 368 + 13.0 40.2 80.4 90.9 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human IGF-1 antibody during the induction of CTLs and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for fourteen days. On the other hand, in the group without addition of these antibodies during neither the induction of CTLs nor the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which a specific, high cytotoxic activity is maintained for a long period of time by adding the anti-human IGF-1 antibody during the induction of CTLs and during the expansion. Example 5-2 (1) Induction of Anti-Influenza Virus Memory CTLs he induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, an anti-human IGF-1 antibody (goat polyclonal antibody; manufactured by Genzyme/Techne) was added so as to have a final concentration of 2 μg/ml. Further, a group without addition of antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 5-2 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, the anti-human IGF-1 antibody, which had been added during the induction of CTLs in item (1) of Example 5-2, was not added at all. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 8. TABLE 8 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 Control − − 547 − 7.3 8.4 9.1 − − 547 + 8.1 11.2 21.5 Anti-IGF-1 + + 637 − 3.8 3.2 7.5 Antibody + + 637 + 20.8 47.4 69.0 + − 553 − 9.4 11.6 15.0 + − 553 + 49.6 82.6 111.0 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human IGF-1 antibody during the induction of CTLs, a specific, high cytotoxic activity was maintained after the expansion for fourteen days even when the antibody was not added during the expansion. On the other hand, in the group without addition of the antibody during neither the induction of CTLs nor the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which a specific, high cytotoxic activity is maintained for a long period of time even when the anti-human IGF-1 antibody was added only during the induction of CTLs. EXAMPLE 6 Expansion of CTLs Maintaining Specific Cytotoxic Activity Using Anti-Human IGF-2 Antibody (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, a purified mouse IgG1 (manufactured by Genzyme/Techne) or an anti-human IGF-2 antibody (mouse monoclonal antibody; manufactured by Genzyme/Techne) was added so as to have a final concentration of 2 μg/ml. Further, a group without addition of antibody was also set. The cytotoxic activity of CTLs prepared as described above on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the antibody during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 6 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of the mouse IgG1 or anti-human IGF-2 antibody, which had been added during the induction of CTLs in item (1) of Example 6 each so as to have a final concentration of 2 μg/ml, and a group without addition of the antibody at all from the stage of the induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the expansion, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 2 μg/ml mouse IgG1 or anti-human IGF-2 antibody to each flask were carried out every 2 to 3 days. Here, in the group without addition of the antibody, the antibody was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 9. TABLE 9 Addition of Sample* During Expansion Cytotoxic Activity (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 1 3 10 30 Control − − 237 − 2.1 3.9 5.6 9.7 − − 237 + 0 4.1 6.9 12.4 Mouse IgG1 + + 370 − 0 0 0 0 + + 370 + 0 0 0 3.1 Anti-IGF-2 + + 225 − 3.9 5.0 5.8 10.2 Antibody + + 225 + 7.1 16.5 37.7 71.5 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-human IGF-2 antibody during the induction of CTLs and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for fourteen days. On the other hand, in the group without addition of the antibody during neither the induction of CTLs nor the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs can be carried out in a state in which a specific, high cytotoxic activity is maintained for a long period of time even when the anti-human IGF-2 antibody was added only during the induction of CTLs. EXAMPLE 7 Expansion of CTLs Maintaining Tumor-Associated Antigen-Specific Cytotoxic Activity Example 7-1 (1) Induction of Anti-Tumor-Associated Antigen (MAGE3)-Specific CTLs The induction of anti-tumor-associated antigen (melanoma-associated antigen 3, MAGE3)-specific CTLs was performed using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. The induction of the anti-tumor-associated antigen (MAGE3)-specific CTLs was carried out by partly modifying the method of Plebanski M. et al. [Eur. J. Immunol., 25(6), 1783-1787 (1995)]. Concretely, PBMCs prepared in item (1) of Example 1-1 were suspended in 5HRPMI so as to have a concentration of 2 to 4×107 cells/ml, and thereafter the suspension was divided into halves. A half was stored as responder cells on ice, the other half was used as antigen presenting cells, and an equivolume of 5HRPMI containing 80 μg/ml melanoma antigen MAGE3-derived epitope peptide (melanoma antigen MAGE3-derived HLA-A2.1 binding peptide described in SEQ ID NO: 19 of Sequence Listing) as an antigen peptide and 6 μg/ml β2 microglobulin (manufactured by Scrips) was added thereto, and the cells were incubated at 37° C. for 2 hours in a 5% CO2 wet incubator. Thereafter, the cells were washed with 5HRPMI, and the washed cells were mixed with the responder cells stored on ice, and thereafter a concentration was made to 2×106 cells/ml. IL-7 and KLH were added thereto so as to have final concentrations of 25 ng/ml and 5 μg/ml, respectively, and each mixture was placed into a 24-well cell culture plate (manufactured by Falcon) at 2 ml/well. At this stage, hyaluronic acid (manufactured by Calbiochem) was added so as to have a final concentration of 10 μg/ml. In addition, as a control, a group without addition of the sample was also set. The plate was subjected to culture at 37° C. in 5% CO2. On the fourth day after the initiation of the culture, a half of the culture supernatant was removed, and 1 ml of 5HRPMI containing 60 U/ml IL-2 and 10 μg/ml hyaluronic acid (the control containing only IL-2) was added to each well. On the seventh day, antigen presenting cells were prepared in the same manner as described above, and the cells were irradiated with X-ray (5500R) and prepared so as to have a concentration of 4×106 cells/ml. The responder cells which had been cultured for 1 week were suspended in 5HRPMI so as to have a concentration of 2×106 cells/ml, and mixed with an equivolume of the prepared antigen presenting cells, and each mixture was added to a 24-well cell culture plate at 1 ml/well, and IL-7 was further added so as to have a final concentration of 25 ng/ml to re-stimulate the cells. At this stage, hyaluronic acid was added thereto so as to have a final concentration of 10 μg/ml (in the case of the control, not being added). On the first day after re-stimulation, 1 ml of 5HRPMI containing 60 U/ml IL-2 and 10 μg/ml hyaluronic acid (the control containing only IL-2) was added to each well. On the third day, a half of the culture supernatant was removed, and the medium having the same content as that before removing the supernatant was added in an amount of 1 ml each. The same re-stimulation was carried out once a week for a total of four times, to induce CTLs. (2) Determination for Cytotoxic Activity of CTLs The cytotoxic activity of CTLs prepared in item (1) of Example 7-1 on the thirty-fifth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. Here, as target cells, there were used HLA-A2.1-having EBV transformed B-cells (name of cells: 221A2.1), which were cultured overnight together with the epitope peptide or in the absence of the epitope peptide. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of hyaluronic acid during the induction. (3) Expansion of CTLs CTLs prepared in item (1) of Example 7-1 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of hyaluronic acid, which had been added during the induction of CTLs in item (1) of Example 7-1, so as to have a concentration of 10 μg/ml, and a group without addition of the sample at all from the stage of the induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 10 μg/ml hyaluronic acid to each flask were carried out every 2 to 3 days. Here, in the group without addition of the sample, the sample was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 10. TABLE 10 Addition of Sample* Cytotoxic Activity During Expansion (%) CTL During Fold Peptide E/T Ratio Sample Induction Expansion (Times) Pulse¶ 2 6 Control − − 237 − 0 0 − − 237 + 29.8 56.0 Hyaluronic + + 217 − 3.6 0 Acid + + 217 + 50.3 67.7 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of hyaluronic acid during the CTL induction and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for 14 days. On the other hand, in the group without addition of the sample during the CTL induction and during the expansion, its activity was clearly lowered. In other words, it was clarified that the expansion of CTLs for the anti-tumor associated antigen (MAGE3) can be carried out in a state in which a specific, high cytotoxic activity was maintained for a long period of time by adding hyaluronic acid during the CTL induction and during the expansion. Example 7-2 (1) Induction of Anti-Tumor-Associated Antigen(MART1)-Specific CTLs The induction of anti-tumor-associated antigen(melanoma antigen recognized by T cell, MART1)-specific CTLs was carried out in the same manner as in item (1) of Example 7-1 using the PBMCs which were isolated and stored in the same manner as in item (1) of Example 1-1. As an antigen peptide, an epitope peptide derived from melanoma antigen MART1 (HLA A2. 1-binding peptide derived from melanoma antigen MART1 of SEQ ID NO: 20 of Sequence Listing). At this stage, hyaluronic acid (manufactured by Calbiochem) was added to the medium so as to have a final concentration of 10 μg/ml. Also, as the control, a group without addition of the sample was also set. The cytotoxic activity of CTLs which were thus prepared on the thirty-fifth day after the initiation of the induction was evaluated in the same manner as in item (3) of Example 1-1. Here, in the evaluation, as target cells, there were used HLA-A2.1-having EBV transformed B-cells (name of cells: 221A2.1) which were cultured overnight together with the epitope peptide or in the absence of the epitope peptide; a cancer cell line having HLA-A2.1 (name of cells: 624mel; HLA-A2.1-having MART1-expressing cells) which was cultured for two nights in the presence of 100 U/ml IFN-γ; or a cancer cell line not having HLA-A2.1 (name of cells: 888mel; HLA-A2.1-not having MART1-expressing cells). As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the sample during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 7-2 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of hyaluronic acid, which had been added during the CTL induction in item (1) of Example 7-2, so as to have a concentration of 10 μg/ml and a group without addition of the sample at all from the stage of the induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 10 μg/ml hyaluronic acid to each flask were carried out every 2 to 3 days. Here, in the group without addition of the sample, the sample was not added even during medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 11. TABLE 11 Addition of Sample* Cytotoxic During Expansion Activity (%) CTL During Fold Peptide Target E/T Ratio Sample Induction Expansion (Times) Pulse¶ Cells 2 7 20 Control − − 287 − 221A2.1 0 3.8 4.1 − − 287 + 221A2.1 8.1 27.5 43.5 − − 287 − 888mel 32.5 44.8 43.7 − − 287 − 624mel 27.4 55.8 81.6 E/T Ratio 2 6 17 Hyaluronic + + 217 − 221A2.1 0 0 0 Acid + + 217 + 221A2.1 9.1 52.8 74.4 + + 217 − 888mel 0 0 0 + + 217 − 624mel 29.6 73.8 90.6 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of hyaluronic acid during the CTL induction and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for 14 days. On the other hand, in the group without addition of the sample during the CTL induction and during the expansion, its activity was clearly lowered. In addition, with regard to the specific cytotoxic activity for the tumor cell line, in the group with addition of hyaluronic acid during the CTL induction and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for 14 days. In other words, it was clarified that the expansion of CTLs can be also carried out in a state in which a specific, high cytotoxic activity was maintained for a long period of time during the expansion of anti-tumor-associated antigen(MART1)-CTLs by adding hyaluronic acid during the CTL induction and during the expansion. EXAMPLE 8 Comparison with REM Method and Combination with REM Method (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was carried out in the same manner as in item (2) of Example 1-1 using the PBMCs which were isolated and stored in the same manner as in item (1) of Example 1-1. During the induction, hyaluronic acid was added to a medium so as to have a final concentration of 10 μg/ml. Further, the group without addition of the sample was also set. The cytotoxic activity of CTLs which were thus prepared on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As the antigen peptide, a 5 μg/ml epitope peptide derived from influenza virus protein described in item (2) of Example 1 was used. (2) Expansion of CTLs Maintaining Specific Activity by Anti-CD3 Antibody CTLs prepared in item (1) of Example 8 were washed with 5HRPMI, and then made into a suspension having a concentration of 5×104 cells/ml. On the other hand, allogenic PBMCs not having HLA-A24 and HLA-A2.1 which were collected in the same manner as in item (1) of Example 1-1 were subjected to X-ray irradiation (3300R), and the cells were washed with the medium and then made into a suspension having a concentration of 5×106 cells/ml. These CTLs in an amount of 3.0×104 cells and allogenic PBMCs in an amount of 4 to 10×106 cells were suspended in 10 ml of 5HRPMI, and anti-CD3 antibody (manufactured by Janssen-Kyowa) was further added thereto so as to have a final concentration of 50 ng/ml. The mixture was placed into a flask of 12.5 cm2 (manufactured by Falcon), and the cells were cultured in a wet-type CO2 incubator at 37° C. for 14 days. During the culture, there were set a group with addition of hyaluronic acid as a sample (a final concentration: 10 μg/ml) and a group without addition of the sample. Stimulation by a peptide was not added at all during this culture. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. During this culture, hyaluronic acid was added to the medium for the group with addition of the sample so as to have a final concentration of 10 μg/ml. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 12. On the other hand, the expansion according to the REM method was carried out as follows. Allogenic PBMCs not having HLA-A24 and HLA-A2.1 were subjected to X-ray irradiation (3300R), and the cells were washed with the medium and then made into a suspension having a concentration of 5×106 cells/ml. In addition, EBV-B cells were subjected to X-ray irradiation (8000R), and the cells were washed with the medium and then made into a suspension having a concentration of 1×106 cells/ml. The CTLs prepared in item (1) of Example 8-1 in an amount of 3.0×104 cells and the allogenic PBMCs in an amount of 4 to 10×106 cells, and the EBV-B cells in an amount of 2.5×106 cells were suspended in 10 ml of 5HRMPI, and anti-CD3 antibody (manufactured by Janssen-Kyowa) was further added so as to have a final concentration of 50 ng/ml. The mixture was placed into a flask of 12.5 cm2 (manufactured by Falcon), and the cells were cultured in a wet-type CO2 incubator at 37° C. for 14 days. During the culture, there were set a group with addition of hyaluronic acid as a sample so as to have a final concentration of 10 μg/ml and a group without addition of the sample. Stimulation by a peptide was not added at all during this culture. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 to each flask were carried out every 2 to 3 days. During this culture, hyaluronic acid was added to the medium for the group with addition of the sample so as to have a final concentration of 10 μg/ml. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 12. TABLE 12 Addition of Sample* Cytotoxic During Addition Expansion Activity (%) CTL During of EBV-B Fold Peptide E/T Ratio Sample Induction Expansion Cells† (Times) Pulse¶ 10 Control − − − 392 − 6.2 − − − 392 + 10.6 Hyaluronic Acid + + − 335 − 2.3 + + − 335 + 60.0 REM Method − − + 427 − 11.5 − − + 427 + 52.8 REM Method + + + + 587 − 8.1 Hyaluronic Acid + + + 587 + 95.5 *+: sample being pulsed; −: sample not being pulsed. †+: EMV-B cells being pulsed; −: EMV-B cells not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, the CTLs which were induced without addition of hyaluronic acid (without addition of CTL activity maintaining substance) maintained a high cytotoxic activity when the expansion was carried out according to the REM method. However, the cytotoxic activity was drastically lowered when the expansion was carried out by a method without using the EBV-B cells. On the other hand, when hyaluronic acid was added during the CTL induction and during the expansion, the cytotoxic activity of CTLs could be maintained at a sufficiently high level after the expansion for 14 days even in a case where the EBV-B cells were not added. Furthermore, the antigen-specific cytotoxic activity of CTLs after the expansion according to the present invention was higher as compared to that of the cells obtained according to the REM method. In addition, when the expansion was carried out according to the REM method, the cytotoxic activity could be maintained at a higher level as compared to that of the CTLs obtained by expanding the CTL cells which had been induced by a conventional technique simply by the REM method, if hyaluronic acid, one of the substances having effects for maintaining CTL activity in the method of the present invention, was added at the stage of CTL induction prior to the expansion. In other words, in the method for expansion of CTLs according to the present invention, the EBV-B cells which are essential in the REM method are not required, so that the risks involved in the use of the EBV-B cells can be avoided. Furthermore, there can be maintained the activity of CTLs higher than that obtained by the REM method. From these findings, the method for expanding CTL cells of the present invention is a method which is safer and more excellent than the REM method. Furthermore, when hyaluronic acid is introduced into the REM method, an even higher activity can be maintained. Therefore, hyaluronic acid can be applied to all sorts of methods for expanding CTLs. In other words, the CTLs can be expanded in a state in which a specific, high cytotoxic activity is maintained for a long period of time by utilizing the substance usable in the present invention in various methods for expanding CTLs. EXAMPLE 9 Preparation of Fibronectin Fragment (1) Preparation of Fibronectin Fragment H-271, a fragment derived from human fibronectin, was prepared from Escherichia coli HB101/pHD101 (FERM BP-2264) in accordance with the method described in U.S. Pat. No. 5,198,423. In addition, H-296, CH-271 and CH-296, fragments derived from human fibronectin, were each prepared from a culture obtained by culturing Escherichia coli HB101/pHD102 (FERM P-10721), Escherichia coli HB101/pCH101 (FERM BP-2799) or Escherichia coli HB101/pCH102 (FERM BP-2800), in accordance with the method described in the above-mentioned gazette. C-274, a fragment derived from human fibronectin, was prepared from a culture obtained by culturing Escherichia coli JM109/pTF7221 (FERM BP-1915) in accordance with the method described in U.S. Pat. No. 5,102,988. C-CS1, a fragment derived from human fibronectin, was prepared from a culture obtained by culturing Escherichia coli HB101/pCS25 (FERM BP-5723) in accordance with the method described in Japanese Patent Gazette No.3104178. CHV-89 and CHV-179, fragments derived from human fibronectin, were each prepared from a culture obtained by culturing Escherichia coli HB101/pCHV89 (FERM P-12182) or Escherichia coli HB101/pCHV179 (FERM P-12183), in accordance with the method described in Japanese Patent Gazette No. 2729712. In addition, CHV-90, a fragment derived from human fibronectin, was prepared in accordance with the method described in the above-mentioned gazette. Concretely, a plasmid pCHV90 was constructed in accordance with the procedures described in the gazette, and thereafter a transformant carrying the plasmid was cultured, and CHV-90 was prepared from the culture. CHV-181, a fragment derived from human fibronectin, was prepared by constructing the plasmid (pCHV181) comprising a DNA encoding CHV-181 in accordance with the method described in WO 97/18318, thereafter culturing Escherichia coli HB101/pCHV181 into which the plasmid had been introduced, and preparing the fragment from the culture in the same manner as that for the above CHV-179. (2) Preparation of CHV-92 As to pCHV181, a plasmid for expressing the above-mentioned polypeptide CHV-181, there was constructed a plasmid CHV92 having deletion of a region encoding a III-13 region in the region encoding CHV-181. The deletion procedures were performed in accordance with procedures for deleting a III-14 coding region from a plasmid pCHV179, which are described in Japanese Patent Gazette No. 2729712. Escherichia coli HB101 (Escherichia coli HB101/pCHV92) transformed with the above-mentioned plasmid pCHV92 was cultured, and the purification procedures were carried out in accordance with the method of purifying the CHV-89 polypeptide described in Japanese Patent Gazette No. 2729712, to obtain a purified CHV-92 preparation from the resulting culture. (3) Preparation of H-275-Cys A plasmid for expressing a polypeptide H-275-Cys was constructed in accordance with the following procedures. Concretely, a plasmid pCH102 was prepared from Escherichia coli HB101/pCH102 (FERM BP-2800). PCR was carried out using a primer 12S having the nucleotide sequence shown in SEQ ID NO: 14 of Sequence Listing and a primer 14A having the nucleotide sequence shown in SEQ ID NO: 15 of Sequence Listing with this plasmid as a template, to give a DNA fragment of about 0.8 kb, encoding a heparin binding polypeptide of fibronectin. The resulting DNA fragment was digested with NcoI and BamHI (both manufactured by Takara Shuzo Co., Ltd.), and thereafter ligated with pTV118N (manufactured by Takara Shuzo Co., Ltd.) digested with NcoI and BamHI, to construct a plasmid pRH1. A plasmid vector pINIII-ompA1 [Ghrayeb J. et al., EMBO J., 3(10), 2437-2442 (1984)] was digested with BamHI and HincII (manufactured by Takara Shuzo Co., Ltd.) to collect a DNA fragment of about 0.9 kb, containing a lipoprotein terminator region. This fragment was mixed and ligated with the above-mentioned plasmid pRH1 which had been digested with BamHI and HincII, to give a plasmid pRH1-T containing a lac promoter, a DNA fragment encoding a heparin binding polypeptide and a lipoprotein terminator in this order. The reaction for PCR was carried out by using a primer Cys-A having the nucleotide sequence shown in SEQ ID NO: 16 of Sequence Listing and a primer Cys-S having the nucleotide sequence shown in SEQ ID NO: 17 of Sequence Listing with this plasmid pRH1-T as a template. Thereafter, the collected amplified DNA fragment was digested with NotI (manufactured by Takara Shuzo Co., Ltd.), and the DNA fragment was further self-ligated. A cyclic DNA thus obtained was digested with SpeI and ScaI (manufactured by Takara Shuzo Co., Ltd.) to give a DNA fragment of 2.3 kb, and the resulting fragment was mixed and ligated with a DNA fragment of 2.5 kb, obtained by digesting the plasmid pRH1-T with SpeI and ScaI (manufactured by Takara Shuzo Co., Ltd.), to give a plasmid pRH-Cys. The plasmid encodes a polypeptide (H-275-Cys) in which four amino acids Met-Ala-Ala-Ser were added to an N-terminal side of the above-mentioned H-271, and further Cys was added to a C-terminal of the H-271. The polypeptide H-275-Cys was prepared by the following method. Escherichia coli HB101 transformed with the above-mentioned plasmid pRH-Cys (Escherichia coli HB101/pRH-Cys) was cultured overnight at 37° C. in 120 ml of an LB medium. The cells collected from the culture medium were suspended in 40 ml of a buffer for disruption (50 mM Tris-HCl, 1 mM EDTA, 150 mM NaCl, 1 mM DTT, 1 mM PMSF, pH 7.5), and the suspension was subjected to ultrasonic treatment to disrupt the cells. The supernatant obtained by centrifugation was subjected to HiTrap-heparin column (manufactured by Pharmacia) which had been equilibrated with a purifying buffer (50 mM Tris-HCl, pH 7.5). The non-adsorbed fraction in the column was washed with the same buffer, and thereafter the elution was carried out with a purifying buffer having a 0 to 1 M NaCl concentration gradient. The eluate was analyzed by SDS-PAGE, and fractions corresponding to a molecular weight of H-275-Cys were collected to give a purified H-275-Cys preparation. EXAMPLE 10 Expansion of CTLs Maintaining Specific Cytotoxic Activity Using Fibronectin Fragment (FNfr) (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, each of the fibronectin fragments (hereinafter referred to as FNfr) described in Example 9 was added so as to have a final concentration of 10 μg/ml. As a control, a group without addition of FNfr was also set. The cytotoxic activity of CTLs which were thus prepared on the fourteenth day after the initiation of induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of addition of FNfr during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 10 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, FNfr, which had been added during the CTL induction, was added so as to have a final concentration of 10 μg/ml. FNfr was not added to the control group in which the induction was carried out without addition of FNfr. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant an, thereafter adding to each flask 5 ml of 5HRPMI containing 60 U/ml of IL-2 or RPMI 1640 medium (manufactured by Bio Whittaker) containing 10% Hyclone FBS, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine (all manufactured by Bio Whittaker), 10 mM HEPES (manufactured by nakalai tesque) and 1% streptomycin-penicillin (manufactured by Gibco BRL) (hereinafter simply referred to as 10HycloneRPMI) were carried out every 2 to 3 days. During the expansion, FNfr was added so as to have the same concentration as that mentioned above to a medium for the group with addition of FNfr. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTL was determined in the same manner as in item (3) of Example 1-1. The degree in which the specific cytotoxic activity before the expansion is maintained was calculated as “specific cytotoxic activity maintenance (%).” The “specific cytotoxic activity maintenance (%)” was calculated according to the following equation 2: Specific Cytotoxic Activity Maintenance (%)={Specific Cytotoxic Activity (%) After Expansion/Specific Cytotoxic Activity (%) Before Expansion }×100 Equation 2 The determination results are shown in Table 13. TABLE 13 Expansion Fibronectin Fold Cytotoxic Activity Medium Fragment (Times) Maintenance (%) E/T Ratio = 3 5HRPMI Control (Without 417 17.3 Addition of FNfr) CH-271 397 53.5 H-296 413 49.3 C-CS1 393 49.3 CHV-92 370 66.2 10HycloneRPMI Control (Without 130 48.1 Addition of FNfr) CH-271 132 250.8 H-296 75 162.3 H-271 52 72.2 C-CS1 130 100.2 CHV-92 35 157.8 E/T Ratio = 10 10HycloneRPMI Control (Without 42 46.3 Addition of FNfr) CHV-89 35 69.0 CHV-90 36 75.6 As shown in Table 13, the CTLs of the group with addition of various fibronectin fragments during the induction and during the expansion maintained a specific, high cytotoxic activity even after the expansion for 14 days as compared to that of the control without addition of fibronectin fragment. In other words, it was clarified that the CTLs could be expanded in a state in which a high cytotoxic activity was maintained for a long period of time by carrying out the induction and the expansion in the co-presence of the fibronectin fragment. Example 11 Induction and Expansion of CTLs in the Presence of Fibronectin (1) Induction of Anti-Influenza Virus Memory CTLs The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, fibronectin (manufactured by Calbiochem) was added in place of FNfr so as to have a final concentration of 10 μg/ml (a control being without addition). The cytotoxic activity of CTLs on the fourteenth day after the initiation of the induction was determined in the same manner as in item (3) of Example 1-1. As a result, there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of FNfr during the induction. (2) Expansion of CTLs CTLs prepared in item (1) of Example 11 were expanded in the same manner as in item (2) of Example 10. During the expansion, to the group with addition of fibronectin during the induction, fibronectin (manufactured by Calbiochem) was added, so as to have a final concentration of 10 μg/ml (a control without addition). The cytotoxic activity of the CTLs was determined in the same manner as that of item (3) of Example 1-1, and to which degree the specific cytotoxic activity before the expansion is maintained was calculated as “specific cytotoxic activity maintenance (%).” The “specific cytotoxic activity maintenance (%)” was calculated according to the above equation 2. The determination results are shown in Table 14. TABLE 14 Expansion Cytotoxic Activity Fold Maintenance (%) (Times) E/T Ratio = 3 Control (Without 130 48.1 Addition of FNfr) Fibronectin 157 148.9 As shown in Table 14, the group in which the induction of CTLs and the expansion were carried out in the presence of fibronectin maintained a high cytotoxic activity. On the other hand, the cytotoxic activity of the control 10 without addition of fibronectin during the induction of CTLs and during the expansion was clearly lowered. In other words, it was clarified that CTL could be expanded in a state in which a specific cytotoxic activity was maintained for a long period of time by adding fibronectin during the induction of CTLs and during the expansion. EXAMPLE 12 Expansion of CTLs in the Presence of Immobilized Fibronectin (FN) Fragment (1) Immobilization of FN Fragment A fibronectin fragment was immobilized to a culture equipment (vessel) used in the following experiment. Concretely, PBS containing various fibronectin fragments (final concentration: 10 μg/ml) was added in an amount of 1 to 2 ml each to a 24-well cell culture plate and a 12.5 cm2 flask. The plate and flask were subjected to incubation at room temperature for 2 hours, and then stored at 4° C. until use. In addition, the plate and the flask were washed twice with PBS before use. (2) Induction of Anti-Influenza Virus Memory CTL The induction of anti-influenza virus memory CTLs was performed in accordance with the method described in item (2) of Example 1-1 using the PBMCs isolated and stored in accordance the method described in item (1) of Example 1-1. During the induction, a plate immobilized with FNfr was used as a culture equipment (for a control, a plate without immobilized treatment was used). The cytotoxic activity of CTLs after the induction was evaluated in the same manner as in item (3) of Example 1-1. As a result, there were hardly any differences in the cytotoxic activity by the presence or absence of immobilization of FNfr to the plate used during the induction. (3) Expansion of CTLs The CTLs prepared in item (2) of Example 12 were expanded in the same manner as in item (2) of Example 10. During the expansion, flasks with various FNfr's immobilized thereto were used as culture equipments (for a control, a flask without immobilized treatment was used). In addition, 10Hyclone/RPMI was used as a medium. To which degree the cytotoxic activity of CTLs thus expanded was maintained as compared to that before the expansion was evaluated as “specific cytotoxic activity maintenance (%).” The “specific cytotoxic activity maintenance (%)” was calculated according to the above-mentioned equation 2. The determination results are shown in Table 15. TABLE 15 Expansion Cytotoxic Activity Fold Maintenance (%) Fibronectin Fragment (Times) E/T Ratio = 3 Control (Without 130 48.1 Immobilization of FNfr) CH-271 128 95.4 H-296 27 95.0 H-271 40 133.9 C-CS1 130 73.8 H-275-Cys 87 137.7 CHV-92 122 92.7 As shown in Table 15, in the group in which the culture equipment (plate, flask) immobilized with the fibronectin fragment was used during the induction of CTLs and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion. On the other hand, in the control in which the equipment without immobilization with the fibronectin fragment was used during the induction of CTLs and during the expansion, the cytotoxic activity was clearly lowered. In other words, it was clarified that the CTLs could be expanded in a state in which a high cytotoxic activity was maintained for a long period of time, comparable to that of the fragment dissolved in the medium, by using the immobilized fibronectin fragment. EXAMPLE 13 Expansion of CTLs Maintaining Tumor-Associated Antigen-Specific Cytotoxic Activity (1) Induction of Anti-Tumor-Associated Antigen (MART1)-Specific CTLs The induction of anti-tumor-associated antigen (melanoma antigen recognized by T cell, MART1)-specific CTLs was performed in accordance with the method described in item (1) of Example 7-2 using the PBMCs isolated and stored in accordance with the method described in item (1) of Example 1-1. During the induction, an anti-HGF antibody was added so as to have a final concentration of 2 μg/ml. As a control, a group without addition of the sample was also set. The cytotoxic activity of CTLs which were thus prepared on the thirty-fifth day after the initiation of the induction was evaluated in the same manner as in item (3) of Example 1-1. In the evaluation, as target cells, there were used HLA-A2.1-having EBV-transformed B cells (name of cells: 221A2.1), which were cultured overnight together with an epitope peptide, or in the absence of the epitope peptide, HLA-A2.1-having cancer cell strain (name of cells: 624mel; HLA-A 2.1-having MART1-expressing cell) or HLA-A2.1-not having cancer cell strain (name of cells: 938mel; HLA-A 2.1-not having MART1-expressing cell) which was cultured for two nights in the presence of 100 U/ml of IFN-γ. As a result, the specific cytotoxic activity was induced immediately after the induction, but there were hardly any differences in the cytotoxic activity by the presence or absence of the addition of the sample during the induction. (2) Expansion of CTLs The CTLs prepared in item (1) of Example 13 were expanded in the same manner as in item (4) of Example 1-1. During the expansion, there were set a group with addition of anti-HGF antibody, which had been added during the CTL induction in item (1) of Example 13, so as to have a concentration of 2 μg/ml, and a group without addition of the sample at all from the stage of induction. Stimulation by a peptide was not added at all during the expansion. On the first day of the initiation of the culture, IL-2 was added so as to have a final concentration of 120 U/ml. Further, on the fourth day and on after the initiation of the culture, procedures of removing a half of the culture supernatant, and thereafter adding 5 ml of 5HRPMI containing 60 U/ml IL-2 and 2 μg/ml anti-HGF antibody to each flask were carried out every 2 to 3 days. Here, in the group without addition of the sample, the sample was not added even during the medium exchange. On the fourteenth day after the initiation of the expansion, the specific cytotoxic activity of CTLs was determined in the same manner as in item (3) of Example 1-1. The determination results are shown in Table 16. TABLE 16 Addition of Sample* Cytotoxic During Expansion Activity (%) CTL During Fold Peptide Target E/T Ratio Sample Induction Expansion (Times) Pulse¶ Cells 3 Control − − 83 − 221A2.1 0 − − 83 + 221A2.1 31.7 − − 83 − 938mel 2.3 − − 83 − 624mel 60.0 Anti-HGF + + 107 − 221A2.1 0 Antibody + + 107 + 221A2.1 59.1 + + 107 − 938mel 0 + + 107 − 624mel 81.2 *+: sample being pulsed; −: sample not being pulsed. ¶+: peptide being pulsed; −: peptide not being pulsed. As a result, in the group with addition of the anti-HGF antibody during the CTL induction and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion for 14 days. On the other hand, in the group without addition of these samples during the CTL induction and during the expansion, its activity was clearly lowered. In addition, with regard to the specific cytotoxic activity for a tumor cell line, in the group with addition of the anti-HGF antibody during the CTL induction and during the expansion, the CTLs maintained a specific, high cytotoxic activity even after the expansion was carried out for 14 days. In other words, it was clarified that even during the expansion of anti-tumor-associated antigen(MART1)-CTLs, the expansion of CTLs could be carried out in a state in which a specific, high cytotoxic activity was maintained by adding the anti-HGF antibody during the CTL induction and during the expansion. Sequence Listing Free Text SEQ ID NO: 1 is an amino acid sequence of a peptide fragment derived from human fibronectin named C-274. SEQ ID NO: 3 is an amino acid sequence of a peptide fragment derived from human fibronectin named H-271. SEQ ID NO: 4 is an amino acid sequence of a peptide fragment derived from human fibronectin named H-296. SEQ ID NO: 5 is an amino acid sequence of a peptide fragment derived from human fibronectin named CH-271. SEQ ID NO: 6 is an amino acid sequence of a peptide fragment derived from human fibronectin named CH-296. SEQ ID NO: 7 is an amino acid sequence of a peptide fragment derived from human fibronectin named C-CS1. SEQ ID NO: 8 is an amino acid sequence of a peptide fragment derived from human fibronectin named CHV-89. SEQ ID NO: 9 is an amino acid sequence of a peptide fragment derived from human fibronectin named CHV-90. SEQ ID NO: 10 is an amino acid sequence of a peptide fragment derived from human fibronectin named CHV-92. SEQ ID NO: 11 is an amino acid sequence of a peptide fragment derived from human fibronectin named CHV-179. SEQ ID NO: 12 is an amino acid sequence of a peptide fragment derived from human fibronectin named CHV-181. SEQ ID NO: 13 is an amino acid sequence of a peptide fragment derived from human fibronectin named H-275-Cys. SEQ ID NO: 14 is a nucleotide sequence of a primer 12S. SEQ ID NO: 15 is a nucleotide sequence of a primer 14A. SEQ ID NO: 16 is a nucleotide sequence of a primer Cys-A. SEQ ID NO: 17 is a nucleotide sequence of primer Cys-S. SEQ ID NO: 18 is an amino acid sequence of a peptide designed on the basis of an HLA-A2. 1-binding peptide derived from a matrix protein of influenza virus. SEQ ID NO: 19 is an amino acid sequence of a peptide designed on the basis of an HLA-A2.1-binding peptide derived from a melanoma antigen MAGE3. SEQ ID NO: 20 is an amino acid sequence of a peptide designed on the basis of an HLA-A2.1-binding peptide derived from a melanoma antigen MART1. INDUSTRIAL APPLICABILITY According to the present invention, there are provided a method for inducing, a method for maintaining and a method for expanding CTL capable of maintaining and/or expanding CTL with maintaining the antigen-specific cytotoxic activity at a high level. This method is extremely useful in the field of cell remedy such as adoptive immunotherapy requiring a large amount of CTLs. In addition, since the CTL prepared by this method is prepared by a safe method, the CTL can be a cell medicament having very high safety.

<SOH> BACKGROUND ART <EOH>A living body is protected from foreign substances mainly by an immune response, and an immune system has been established by various cells and the soluble factors produced thereby. Among them, leukocytes, especially lymphocytes, play a key role. The lymphocytes are classified in two major types, B lymphocyte (which may be hereinafter referred to as B cell) and T lymphocyte (which may be hereinafter referred to as T cell), both of which specifically recognize an antigen and act on the antigen to protect the living body. T cell is subclassified to helper T cell having CD(Cluster Designation)4 marker (hereinafter referred to as T H ), mainly involved in assisting in antibody production and induction of various immune responses, and cytotoxic T cell having CD8 marker (T c : cytotoxic T lymphocyte, also referred to as killer T cell, which may be hereinafter referred to as CTL), mainly exhibiting a cytotoxic activity. CTL, which plays the most important role in recognizing, destroying and eliminating tumor cell, virus-infected cell or the like, does not produce an antibody specifically reacting with an antigen like in B cell, but directly recognizes and acts on antigens (antigenic peptide) from a target cell which is associated with major histocompatibility complex (MHC, which may be also referred to as human leukocyte antigen (HLA) in human) Class I molecules existing on the surface of the target cell membrane. At this time, T cell receptor (hereinafter referred to as TCR) existing on the surface of the CTL membrane specifically recognizes the above-mentioned antigenic peptides and MHC Class I molecules, and determines whether the antigenic peptide is derived from itself or nonself. Target cell which has been determined to be from nonself is then specifically destroyed and eliminated by CTL. Recent years, a therapy which would cause a heavier physical burden on a patient, such as pharmacotherapy and radiotherapy, has been reconsidered, and an interest has increased in an immunotherapy with a lighter physical burden on a patient. Especially, there has been remarked an effectiveness of adoptive immunotherapy in which CTL capable of specifically reacting with an antigen of interest is induced in vitro from CTL or T cell derived from a human having normal immune function, and then transferred to a patient. For instance, it has been suggested that adoptive immunotherapy using an animal model is an effective therapy for virus infection and tumor (authored by Greenberg, P. D., Advances in Immunology , published in 1992). Further, use of CTL to a patient with congenital, acquired or iatrogenic T cell immunodeficiency has been remarked, from the fact that administration of CTL to a patient with immunodeficiency results in reconstruction of specific CTL response, by which cytomegalovirus is rapidly and persistently eliminated without showing toxicity [Reusser P., et al., Blood, 78(5), 1373-1380 (1991)] and the like. In this therapy, it is important to maintain or increase the cell number with maintaining or enhancing the antigen-specific cytotoxic activity of the CTL. Also, as to maintenance and increase of the cell number of CTL, if an effective cell number in adoptive immunotherapy for human is deduced on the basis of the studies on an animal model, it is thought that 10 9 to 10 10 antigen-specific T cells are necessary (authored by Greenberg, P. D., Advances in Immunology, published in 1992). In other words, in adoptive immunotherapy, it can be said that it is a major problem to obtain the above cell number in vitro in a short period of time. As to maintenance and enhancement of an antigen-specific cytotoxic activity of CTL, there has been generally employed a method of repeating stimulation with an antigen of interest when a specific response to an antigen for CTL is induced. However, in this method, the cell number may temporarily be increased, but the cell number is eventually decreased, and necessary cell number cannot be obtained. As its countermeasure, there are no other means in the current situation but to lyophilize the cells in an earlier stage during repeat of stimulation with an antigen, or to obtain antigen-specific CTL clones, lyophilize a part of the clones, and repeat antigen stimulation to the lyophilized cells after thawing if the cell number or antigen-specific cytotoxic activity of the CTL clones is lowered due to a long-term culture. A method for establishing T cell by a long-term culture using mouse T cell has been reported [Paul W. E. et al., Nature, 294(5843), 697-699 (1981)], which is a method for isolating T cell and establishing a cell strain therewith. However, it is impossible to proliferate T cell to 10 9 to 10 10 cells by this method. Next, U.S. Pat. No. 5,057,423 discloses a method comprising inducing lymphokine-activated killer (LAK) cell using a large amount of interleukin 2 (IL-2) in a high concentration, thereby increasing the cell number in 100 folds in 3 to 4 days. This cell number is enormous, considering that it usually takes about 24 hours for a single cell to be divided and proliferated into two cells. In addition, adoptive immunotherapy has been tried by inducing tumor-infiltrating lymphocyte (TIL) using IL-2 in a high concentration as above [Rosenberg S. A. et al, New Engl. J. Med., 313(23), 1485-1492 (1985); Rosenberg S. A. et al, New Engl. J. Med., 319(25), 1676-1680 (1988); Ho M. et al., Blood, 81(8), 2093-2101 (1993)]. However, the former is a method for obtaining T cell which is non-specific for an antigen, and in the latter, antigen specificity is very low, if any, because activated polyclonal lymphocyte population is used. Further, in both of the above-mentioned methods, IL-2 is used in a high concentration in order to promote cell proliferation. It is reported that apoptosis (cell death) may occur when T cell treated with IL-2 in a high concentration is stimulated with a specific antigen in the absence of IL-2 [Lenardo M. J. et al., Nature, 353(6347), 858-861 (1991); Boehme S. A. et al., Eur. J. Immunol., 23(7), 1552-1560 (1993)]. Therefore, the effectiveness of LAK cell or TIL obtained by the above-mentioned methods is problematic. In addition, when T cell is cultured at a low density (5×10 3 to 1×10 4 cells/ml) in the presence of T-cell growth factor and IL-2, T cell rapidly proliferates over a period of 7 days, and eventually proliferates to a saturation density of 3 to 5×10 5 cells/ml. However, it is also reported that the cell always dies once the cell reaches the saturation density [Gillis S. et al., Immunol. Rev., 54, 81-109 (1981)]. Therefore, LAK cell, TIL and the method for culturing T cell at a low density are problematic in both aspects of actual use and usefulness. Next, regarding the antigen-specific CTL, there are reported adoptive immunotherapy in which allogenic cytomegalovirus(CMV)-specific CTL is cultured in vitro for 5 to 12 weeks to proliferate CTL, and then administered intravenously to a patient with immunodeficiency [Riddell S. A. et al., Science, 257(5067), 238-240 (1992)]; and a method for isolating and expanding a CMV-specific CTL clone using self-CMV infected fibroblast and IL-2 [Riddell S. A. et al., J. Immunol., 146(8), 2795-2804 (1991)] or using anti-CD3 monoclonal antibody (anti-CD3 mAb) and IL-2 [Riddell S. A. et al., J. Immunol. Methods, 128(2), 189-201 (1990)]. However, there is a serious problem in these methods. Specifically, it takes about 3 months to obtain 1×10 9 cells/ml of antigen-specific CTLs, during which time the symptoms of the patient advance, so that it is difficult to appropriately treat the disease depending on the situation. As a method of solving the above-mentioned problem, WO 96/06929 discloses an REM method (rapid expansion method). This REM method is a method for expanding a primary T cell population containing antigen-specific CTL and T H in a short period of time. In other words, this method is characterized in that a large amount of T cell can be provided by expanding individual T cell clones. However, there is a problem as described below. In the REM method, antigen-specific CTL is expanded using anti-CD3 antibody, IL-2, and PBMC (peripheral blood mononuclear cell) made deficient in an ability for proliferation by irradiation, and Epstein-Barr virus (hereinafter simply referred to as EBV)-infected cells. However, there are problems that risk of admixing EBV-transformed B cell (EBV-B cell) into T cell is not deniable (problem in safety); that a large amount of PBMC (PBMC in an amount of about 40 times the number of antigen-specific CTL required) is required as feeder cell; that the antigen-specific cytotoxic activity of the expanded CTL cannot be sufficiently satisfactory; that the antigen-specific cytotoxic activity possessed by T cell is decreased with the cell proliferation when CTL is allowed to proliferate using a T cell population other than the T cell clone; and the like. In other words, in a conventional method for preparing antigen-specific CTL, there have not been solved the problems essential to adoptive immunotherapy in which CTL having an antigen-specific cytotoxic activity effectively used in the treatment, is prepared in a sufficient amount for a short period of time.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph showing an activity of hyaluronic acid to inhibit binding of a soluble CD44 and a soluble CD44-recognizing antibody. FIG. 2 is a graph showing a binding activity of FL-labeled hyaluronic acid and CD44 on CTL cell surface. FIG. 3 is a graph showing a binding activity of a soluble CD44-recognizing antibody and a soluble CD44 in a medium. FIG. 4 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and a soluble CD44 in a medium. FIG. 5 is a graph showing a binding activity of an HA Non-Blocking anti-CD44 antibody and CD44 on CTL cell surface. FIG. 6 is a graph showing a binding of an HA Non-Blocking anti-CD44 antibody on cell surface of CTL after expansion of CTL in which the antibody is added to a medium. detailed-description description="Detailed Description" end="lead"?

20040212

20110322

20050224

76433.0

BELYAVSKYI, MICHAIL A

METHOD OF EXTENDED CULTURE FOR ANTIGEN-SPECIFIC CYTOTOXIC LYMPHOCYTES

UNDISCOUNTED

ACCEPTED

ACCEPTED

Retroreflection device

The first reflective lateral face of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral face of the tetrahedral retroreflective unit, the second reflective lateral face of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral face of the tetrahedral retroreflective unit, the third reflective lateral face of the first triangular-pyramidal retroreflective unit is parallel to one of the two lateral faces forming a V-shaped groove, the third reflective lateral face of the second triangular-pyramidal retroreflective unit is identical with, or parallel to, the other of the two faces forming said V-shaped groove, and the third reflective lateral face of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove.

1. A retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, characterized in that the three reflective lateral faces (a1, b1, c1 and a2, b2, c2) of each of the first and second triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral face (f11), the second reflective lateral face (e11) and the third reflective lateral face (g11) of said at least one tetrahedral retroreflective unit form a mutually perpendicular cube-corner reflective surfaces, said first reflective lateral face (a1) of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral face (f11) of said tetrahedral retroreflective unit, said second reflective lateral face (b1) of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral face (e11) of said tetrahedral retroreflective unit, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c1) of said first triangular-pyramidal retroreflective unit is parallel to one of the two lateral faces (g11) forming said V-shaped groove, the third reflective lateral face (c2) of said second triangular-pyramidal retroreflective unit is identical with, or parallel to, the other (g21) of the two faces forming said V-shaped groove, and the third reflective lateral face (g11) of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove. 2. A retroreflective device according to claim 1, in which all of the tetrahedral retroreflective units form pairs of rotation symmetrical configuration mutually rotated by 180° and said complex cube-corner retroreflective elements have a rotation symmetrical configuration. 3. A retroreflective device according to claim 1, in which at least one tetrahedral retroreflective unit is not in a rotation symmetrical configuration rotated by 180°. 4. A retroreflective device according to any one of claims 1-3, which is characterized in that the optical axis is tilted in such a manner, where the point of intersection of a perpendicular line drawn from apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with Sx plane determined by x-x′ line group is represented by P and the point of intersection of the optical axis of same tetrahedral retroreflective unit with said Sx plane is represented by Q, that the distance (q) from x-x′ line to point Q and the distance (p) from x-x′ line to point P are not the same. 5. A retroreflective device according to claim 4, which is characterized in that the optical axis is tilted in such a manner, where the point of intersection of a perpendicular line drawn from the apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with the Sx plane determined by x-x′ line group is represented by P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is represented by Q, that the difference (q-p) between the distance (q) from x-x′ line to point Q, and the distance (p) from x-x′ line to the point P, takes a positive value. 6. A retroreflective device according to claim 5, which is characterized in that the optical axis is tilted by 0.5°-30° in the direction, where the point of intersection of a perpendicular line drawn from an apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with the Sx plane determined by x-x′ line group is represented by P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is represented by Q, that the difference between the distance (q) from the x-x′ line to the point Q and the distance (p) from the x-x′ line to the point P, i.e., (q-p), takes a positive (+) value. 7. A retroreflective device according to claim 6, which is characterized in that the optical axis is tilted by 5°-20° in the direction, where the point of intersection of a perpendicular line drawn from an apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with the Sx plane determined by x-x′ line group is represented by P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is represented by Q, that the difference between the distance (q) from the x-x′ line to the point Q and the distance (p) from the x-x′ line to the point P, i.e., (q-p), takes a positive (+) value. 8. A retroreflective device according to claim 7, which is characterized in, where the distance from an apex (H) of the tetrahedral retroreflective unit to Sx plane determined by the x-line group is expressed as hx; the distance from the same apex to Sy plane defined by the y-line group, as hy; the distance to Sz plane defined by the z-line group, as hz, and that to Sw plane defined by w-line group determined by base line of the fourth reflective lateral face (d1 or d2) of said tetrahedral retroreflective unit, as hw, that hx is not equal to at least either one of hy and hz, and hw is not equal to at least either one of hy and hz. 9. A retroreflective device according to claim 8, which is characterized in that hx of the tetrahedral retroreflective unit is greater than at least either one of hy and hz, and hw is greater than at least either one of hy and hz. 10. A retroreflective device according to claim 8 or 9, which is characterized in that the ratio of hx of the tetrahedral retroreflective unit having one of its base lines on x-x′ line to at least either one of hy and hz is 1.05-1.5, and the ratio of hw to at least either one of hy and hz is 1.05-1.5. 11. A retroreflective device according to claim 10, which is characterized in that hx of the tetrahedral retroreflective unit having one of its base lines on x-x′ line equals hw, hy equals hz, and the ratio of hx to hy is 1.05-1.5. 12. A retroreflective device according to claim 11, which is characterized in that the bottoms of at least one group of those substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are defined by said x-, y-, z- and w-line groups forming the triangular-pyramidal retroreflective units or tetrahedral retroreflective units, are formed of a flat surface or a curved quadratic surface. 13. A retroreflective device according claim 12, which is characterized in that deviation is given to at least one of the two lateral faces of at least one group of the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are determined by the x-, y-, z- and w-line groups of triangular-pyramidal retroreflective units or tetrahedral retroreflective unit(s), so that the prismatic vertical angles of the triangular-pyramidal retroreflective units or of the tetrahedral retroreflective unit(s) which are formed by said V-shaped parallel grooves are given a deviation of ±(0.00-0.1)° from 90°. 14. A retroreflective device according to claim 12, which is characterized in that deviation is given to at least one V-shaped parallel groove group among the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are determined by the x-, y-, z- and w-line groups of the triangular-pyramidal retroreflective units or tetrahedral retroreflective unit(s), such that the vertical angles of the cube-corner reflective elements formed by said group of V-shaped parallel grooves show deviations of ±(0.001-0.1)° from 90°, in a pattern of repeating at least two different sets of deviations. 15. A retroreflective device according to claim 14, in which the angle formed by the x-line of the retroreflective device with an outer edge of a product formed of said retroreflective device is 5-85°. 16. A retroreflective device according to claim 15, in which the angle formed by the x-line of the retroreflective device with an outer edge of a product formed of said retroreflective device is 30-60°. 17. A retroreflective device according to claim 16, in which the retroreflective device has a first zone and a second zone, the angle formed by x1-line of said first zone with x2-line of said second zone being 5-175°. 18. A retroreflective device according to claim 17, in which the retroreflective device has a first zone and a second zone, the angle formed by x1-line of said first zone with x2-line of said second zone being 80-100°. 19. A retroreflective device according to claim 18, which is characterized in that many complex cube-corner retroreflective elements, each comprising first and second triangular-pyramidal retroreflective units and at least a pair of tetrahedral retroreflective units, are disposed in the closest-packed state, said device being characterized in that all the tetrahedral retroreflective units have an identical shape and mutually form rotation symmetrical pair as rotated by 180° to one another, said complex cube-corner retroreflective elements have rotation-symmetrical configurations, where the point of intersection of a perpendicular line drawn from the apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with Sx plane determined by x-x′ line group is represented by P and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is represented by Q, the optical axis is tilted by 5-20° in such direction that the difference between the distance (q) from x-x′ line to the point Q and the distance (p) from x-x′ line to the point P, i.e., (q-p), takes a positive (+) value, in the tetrahedral retroreflective unit having one of its base lines on said x-x′ line, hx equals hw, hy equals hz, and the ratio of hx to hy is 1.05-1.5, and among the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) determined by x-, y-, z- and w-line groups forming the triangular retroreflective units or the tetrahedral retroreflective units, at least one group of said grooves have bottoms formed of flat or quadratic plane.

TECHNICAL FIELD TO WHICH THE INVENTION BELONGS This invention relates to a triangular-pyramidal cube-corner retroreflective sheeting and retroreflective articles of novel structures. More particularly, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit. Specifically, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, which device is useful for signs such as traffic signs (commonly used traffic signs and delineators), road surface signs (pavement markers) and construction signs; number plates for vehicles such as automobiles and motorcycles; safety goods such as reflective tapes to be adhered to bodies of tracks or trailers, clothing and life preservers; marking on signboards; and reflective plates of visible light, laser-beams or infrared light-reflective sensors. That is, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, characterized in that the three reflective lateral faces (a1, b1, c1 and a2, b2, c2) of each of the first and second triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral face (f1) of said at least one tetrahedral retroreflective unit, the second reflective lateral face (e1) and the third reflective lateral face (g1) thereof form a mutually perpendicular cube-corner reflective surfaces, said first reflective lateral face (a1) of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral face (f1) of said tetrahedral retroreflective unit, said second reflective lateral face (b1) of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral face (e1) of said tetrahedral retroreflective unit, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c1) of said first triangular-pyramidal retroreflective unit is parallel to one of the two lateral faces (g1) forming said V-shaped groove, the third reflective lateral face (c2) of said second triangular-pyramidal retroreflective unit is parallel to the other (g2 or c2) of the two faces forming said V-shaped groove, and the third reflective lateral face (g1) of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove. PRIOR ART Retroreflective sheetings and retoreflective articles which reflect incoming light rays toward the light sources are well known, and such sheetings whose retroreflectivity is utilized are widely used in the fields as above-described. Of those, particularly cube-corner retroreflective sheetings and retroreflective articles which utilize the retroreflection principle of cube-corner retroreflective elements such as triangular-pyramidal reflective elements exhibit drastically higher retroreflectivity of light compared with those of conventional micro glass bead retroreflective sheetings or retroreflective articles, and due to the excellent retroreflective performance their utility is yearly increasing. Whereas, heretofore known triangular-pyramidal retroreflective element exhibits favorable retroreflectivity where an angle formed by its optical axis (an axis passing through the apex of the triangular-pyramid and the point equidistant from the three faces which intersect with each other at an angle of 90° and constitute the triangular-pyramidal cube-corner retroreflective element) with an entering light (which angle is hereafter referred to as an entrance angle) is small. However, because of its principle of reflection, retroreflectivity of the element rapidly decreases as the entrance angle broadens (i.e., entrance angularity is inferior). Furthermore, a light ray from a light source which enters into such a triangular-pyramidal reflective element surface at an angle less than the critical angle (αc) satisfying the total internal reflection condition, which is determined by the ratio of the refractive index of individual transparent medium constituting said triangular-pyramidal reflective element and the refractive index of ambient air, is not totally reflected at the interfaces of the element but is transmitted to the back of the element. Hence retroreflective sheetings and articles using triangular pyramidal reflective elements have a defect that they are generally inferior in entrance angularity. On the other hand, because a triangular pyramidal retroreflective element can reflect a light ray toward the incoming direction of the same ray from over nearly the whole area of the element, the reflected light is not excessively diverged for such causes as spherical aberration, unlike micro glass bead reflective elements. From practical standpoint, however, the narrow divergence angle of retroreflective light is apt to produce such an inconvenience, e.g., when light rays emitted from head lamps of a car are retroreflected by a traffic sign, the reflected light rays are difficult to be caught by the driver of the car at a position deviating from the incidental axis of the light. This kind of inconvenience is enhanced particularly as the car approaches near the traffic sign, because the angle (observation angle) formed by the incidental axis of the light and the axis (observation axis) connecting the driver and the point of reflection increases (i.e., observation angurality becomes inferior). For improving entrance angurality or observation angurality of cube-corner retroreflective sheetings and retroreflective articles, in particular, triangular-pyramidal cube-corner retroreflective sheetings and retroreflective articles, many proposals have been made of old and various improving means have been investigated. For example, U.S. Pat. No. 2,481,757 to Jungersen describes installation of various forms of retroreflective elements on a thin sheet. Triangular-pyramidal reflective units exemplified in said US Patent include those in which their optical axes are not tilted, the position of their apices corresponding to the center points of their respective triangular bases, and tilted triangular-pyramidal reflective units whose apices do not correspond to the center points of their respective triangular bases, and the patent states that the sheeting effectively reflects light rays toward an approaching car (improvement in entrance angularity). As the size of the triangular-pyramidal reflective units, the same patent states, as the depth of the units, up to one tenth of an inch (2,540 μm). Furthermore, FIG. 15 of this US patent shows a triangular-pyramidal reflective unit pair whose optical axes are tilted in positive (+) directions as explained later, the angle of tilt (θ) of each optical axis being presumed to be approximately 6.5°, as calculated from the length ratio between the longer side and the shorter side of the triangular base of the shown triangular-pyramidal reflective unit. Said US patent to Jungersen, however, contains no specific disclosure about extremely small size triangular-pyramidal reflective units as described later, or no disclosure or suggestion about the desirable size or tilt in optical axis of triangular-pyramidal reflective units for exhibiting excellent observation angularity or entrance angularity. U.S. Pat. No. 3,712,706 to Stamm discloses a retroreflective sheeting and a retroreflector in which so called regular triangular-pyramidal cube corner retroreflective elements whose triangular bases are in the shape of regular triangles are arranged in the closest-packed state with said bases lying on a common plane of a thin sheet. This US patent to Stamm specularly reflects incident light by vapor depositing a metal such as aluminum on reflective surfaces of the reflective elements, to increase the incident angle, whereby improving the problem such as the drop in retroreflective efficiency and such a drawback that an incident light entered at an angle less than the total internal reflection condition transmits through interfaces of the elements and does not retroreflect. However, because the above proposal by Stamm provides a specular layer on reflective lateral faces as a means to improve wide angularity, such drawbacks as that appearance of the formed retroreflective sheeting and retroreflector is apt to become dark, or the metal used for the specular layer such as aluminum or silver is oxidized during use by infiltrated water or air, which leads to occasional decrease in reflectivity. Furthermore, this patent is entirely silent on the means for improving wide angularity by tilting optical axes. EP 137,736 B1 to Hoopman describes a retroreflective sheeting and retroreflector in which multitude of pairs of tilted triangular-pyramidal cube-corner retroreflective elements having their bases on a common plane are arranged at the highest density on a thin sheet, each pair of said elements having isosceles triangular bases and being rotated 180° from one another. The optical axis of the triangular-pyramidal retroreflective element as described in this patent is tilted in negative (−) direction in the sense described in the present specification, the angle of tilt being about 7°-13°. U.S. Pat. No 5,138,488 to Szczech also discloses a retroreflective sheet and retroreflective article, in which tilted triangular-pyramidal cube-corner retroreflective elements each having an isosceles triangular base are arranged on a thin sheet in such a manner that their bases are on a common plane at the highest density. In this US patent, optical axes of each two triangular-pyramidal reflective elements, which face each other and form a pair, are tilted toward the common edge therebetween, i.e., in the positive (+) direction as later explained, the angle of tilt being about 2°-5° and the element height being 25 μm -100 μm. Also in EP 548,280 B1 corresponding to the above patent states that the direction of tilt in the optical axes is such that the distance between the apex of the element and a plane, which contains the common edge of said pair of elements and is perpendicular to the common base plane, is not equal to the distance between said plane and the point of intersection of the optical axis with the common plane, the angle of tilt being about 2°-5° and the element height being 25 μm -100 μm. As above, EP 548,280 B1 to Szczech proposes an angle of tilt of the optical axis within a range of about 2°-5°, inclusive of both positive (+) and negative (−) regions. Examples given in said US patent and EP patent to Szczech, however, disclose only those triangular-pyramidal reflective elements with their optical axes canted with an angle of tilt of (−)8.2°, (−)9.2° or (−)4.3°, having an element height (h) of 87.5 μm. Those triangular-pyramidal cube-corner retroreflective elements known from so far described U.S. Pat. No 2,481,757 to Jungersen, U.S. Pat. No. 3,712,706 to Stamm, EP 137,736 B1 to Hoopman, U.S. Pat. No. 5,138,488 and corresponding EP 548,280 B1 to Szczech have the features in common, as illustrated in FIG. 3, that the multitude of triangular-pyramidal reflective elements, which play the kernel role in receiving entering light and reflecting the same, have their bases positioned in a common plane and that each of matched pairs facing with each other have similar configuration and equal height. Such retroreflective sheets and articles constructed of triangular-pyramidal reflective elements with their bases positioned in a common plane are invariably inferior in entrance angularity, i.e., they are subject to a defect that retroreflectivity rapidly drops with increased entrance angle of light rays entering into the triangular-pyramidal reflective elements. Furthermore, retroreflective element arrays including asymmetrical retroreflective element pairs, V-shaped grooves extending in three directions not intersecting at any one point are also known. U.S. Pat. Nos. 5,831,767 and 5,557,836 to Benson, et al. disclose retroreflective articles and methods of preparation thereof, which are proposed for the purpose of improving retroreflective efficiency and wide angurality, said articles being constructed of retroreflective element arrays bounded by asymmetric V-shaped grooves in which one of the side walls has an angle approximately perpendicular or close thereto with the base plane. In these Benson, et al.'s retroreflectors, as shown in said international publications, a substrate is so machined that two sets of tilted V-shaped grooves of different directions form rhombic bases and another set of tilted V-shaped grooves of still different direction are cut not to pass any point of intersection of said rhombic base pattern. By varying the crossing angle, depth, angle of V-shape and degree of tilt in the V-shape each of the first and second sets of grooves extending in two different directions; and the off-set position, number of grooves, depth, angle of V-shape and extent of tilt in the V-shape of the third set of grooves of a still different direction, large varieties of reflecting elements including those not exhibiting retroreflectivity can be formed, which constitute the retroreflector. Furthermore, it is clearly indicated: because one side wall surface of each V-shaped groove in the retroreflective article of Benson, et al. is approximately perpendicular to the base plane to form an asymmetrical V-shaped groove, the intermediate configuration of the elements having the rhombic bases as defined by said V-shaped grooves extending in two different directions is bilaterally asymmetrical as shown in FIG. 2 attached to this specification, and at that intermediate stage the reflective lateral surfaces are a2 and b2 in said FIG. 2. Whereas, the intermediate shape in conventional art is formed by symmetrical V-shaped grooves as shown in FIG. 1, and the reflective lateral surfaces formed are symmetrical, paired surfaces (a1, b1, and a2, b2). Hence those reflective elements of conventional art formed via the FIG. 1 stage become a pair of symmetrical triangular-pyramidal cube-corner element pair facing with each other as illustrated in FIG. 3 when a pair of surfaces (a1, b1 and a2, b2) are cut off with the third V-shaped groove. By contrast, cube-corner elements in Benson, et al.'s retroreflective article, which are formed as plural V-shaped grooves are cut, do not form any pair, as illustrated in FIG. 4. FIG. 6 shows an example of the retroreflective element array as shown in FIG. 30 of Benson, et al.'s U.S. Pat. No 5,831,767. In such a reflective element array, optical axes of any two reflective elements facing with each other across a V-shaped groove are alined in identical direction, as understood from their configuration. For example, where the optical axes are tilted, they are tilted in a same direction. Consequently, although a certain extent of improvement in observation angularity can be expected due to divergence of reflective light attributable to versatility of the reflective elements, in respect of entrance angularity the reflective element array has very high directivity. That is, in the direction to which their optical axes are tilted, excellent entrance angularity can be expected, but the array must have inferior entrance angularity in other directions. U.S. Pat. No. 5,889,615 to Dreyer, et al. shows retroreflective element pair having plural optical axes constituted of a pair of a triangular-pyramidal cube-corner element and a tent-type cube-corner element, which is formed of a pair of triangular-pyramidal cube-corner reflective elements having one base edge in common and confronting with each other, with their apices cut off with another V-shaped groove extending in parallel with said common base edge. FIG. 5 attached to the present specification shows four sets of said retroreflective element pairs arranged in the closest-packed state. This retroreflective element of Dreyer, et al. has plural optical axes which turn to mutually different directions. Hence, light rays coming from the directions corresponding to those of optical axes of particular retroreflective elements are effectively reflected by the particular elements, but other elements show markedly decreased reflection efficiency, and as a whole the retroreflective article has to show inferior retroreflective characteristics. U.S. Pat. No. 4,775,219 to Appeldorn, et al. discloses a retroreflective article which carries on one surface an array of cube-corner retroreflective elements, the three lateral reflecting faces of the elements being formed by three intersecting sets of V-shaped grooves, at least one of the sets including, in a repeating pattern, at least two groove side angles that differ from one another, whereby the array of cube-corner retroreflective elements is divided into repeating sub-arrays that each comprise a plurality of cube-corner retroreflective elements in a plurality of distinctive shapes that retroreflect incident light in distinctively shaped light patterns. The retroreflective sheeting obtained according to the above proposal by Appeldorn, et al. shows improved observation angularity to a certain extent, but is insufficient as to improvement in entrance angularity. U.S. Pat. No. 5,764,413 to Smith, et al. discloses a tiled cube-corner retroreflective sheeting comprising a substrate having a base surface and a structured surface displaced from the base surface, the structured surface including at least two distinct arrays of cube corner elements, wherein: each cube corner array is formed by three intersecting sets of substantially parallel grooves including a primary groove set and two secondary groove sets, for at least one cube corner array, the secondary groove sets intersect each other to define an included angle less than 60°; and a major portion of substantially every groove in the primary groove set of the at least one cube corner array is disposed in a plane that intersects the edge of the sheeting at an acute angle selected from the group of angles consisting of 5 to 25°, 35 to 55°, and 65 to 85°. U.S. Pat. No. 5,812,315 discloses a retroreflective cube corner article formed from a substantially optically transparent material, comprising: a substrate having a base surface disposed in a base plane; a structured surface displaced from the base surface and including an array of canted cube corner element matched pairs formed by three mutually intersecting sets of substantially parallel grooves, each matched pair including a first cube corner element and an optically opposing second cube corner element, wherein: a plurality of cube corner elements in the array have their symmetry axes canted in a first plane through a cant angle measuring between 4° and 15°; the article exhibits its broadest range of entrance angularity in a second plane, angularly displaced from the first plane; and the cube corner elements are oriented such that the second plane intersects an edge of the article at an angle less than 15°. Furthermore, U.S. Pat. Nos. 5,822,121 and 5,926,314 disclose cube-corner articles wherein a plurality of cube corner elements in the array as above-described comprise a base triangle bounded by one groove from each of the three intersecting, groove sets, the base triangle being scalene. While these proposals by Smith, et al. can achieve improvement in entrance angularity by specifying the angle of the products with the outer edge of the sheeting or by providing at least two arrays, the products have a defect that reduction in frontal reflectivity is notable with the retroreflective elements with heavily canted optical axes. PROBLEM TO BE SOLVED BY THE INVENTION Generally as the basic optical characteristics desirable for triangular-pyramidal retroreflective sheeting and retroreflective article, high reflectivity, i.e., high level (magnitude) of reflectivity represented by the reflectivity of light entering from the front of the sheeting, and wide angularity are required. Moreover, concerning the wide angularity, three properties, i.e., observation angularity, entrance angularity and rotation angularity, are required. Of these three properties, improvement in entrance angularity is known to be accomplished by tilting optical axes of retroreflective elements, i.e., entrance angularity in the direction of tilt of the optical axes is improved. Whereas, excessive tilt in optical axes increases the areal ratio among the reflective lateral faces constituting each element, which leads to reduction in retroreflective efficiency toward light source via trihedral reflection, presenting a technical problem. MEANS TO SOLVE THE PROBLEM I now have discovered that entrance angularity could be markedly improved by a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second trianglar-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, characterized in that the three reflective lateral faces (a1, b1, c1 and a2, b2, c2) of each of the first and second triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral face (f1), the second reflective lateral face (e1) and the third reflective lateral face (g1) of said at least one tetrahedral retroreflective unit form a mutually perpendicular cube-corner reflective surfaces, said first reflective lateral face (a1) of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral face (f1) of said tetrahedral retroreflective unit, said second reflective lateral face (b1) of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral face (e1) of said tetrahedral retroreflective unit, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c1) of said first triangular-pyramidal retroreflective unit is parallel to one of the two lateral faces (g1) forming said V-shaped groove, the third reflective lateral face (c2) of said second triangular-pyramidal retroreflective unit is parallel to the other (g2 or c2) of the two faces forming said V-shaped groove, and the third reflective lateral face (g1) of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove. BRIEF EXPLANATION OF DRAWINGS FIG. 1 shows a plan view and cross-sectional view illustrating cutting procedure of a retroreflective element pair by a conventional technology. FIG. 2 shows a plan view and cross-sectional view illustrating cutting procedure of a retroreflective element pair by a conventional technology. FIG. 3 shows a plan view and cross-sectional view of a retroreflective element pair according to a conventional technology. FIG. 4 shows a plan view and cross-sectional view of a retroreflective element pair according to a conventional technology. FIG. 5 is a plan view of a retroreflective device according to a conventional technology. FIG. 6 is a plan view of a retroreflective device according to a conventional technology. FIG. 7 shows a plan view and cross-sectional view of a retroreflective element pair according to a conventional technology. FIG. 8 is a graph showing the relationship of angle of tilt in optical axis versus retroreflection efficiency. FIG. 9 shows a plan view and cross-sectional view of a retroreflective device according to the present invention. FIG. 10 shows a plan view and cross-sectional view of a complex cube-corner retroreflective element according to the present invention. FIG. 11 shows a plan view and cross-sectional view of a complex cube-corner retroreflective element according to the present invention. FIG. 12 shows a plan view and cross-sectional view of a complex cube-corner retroreflective element according to the present invention. FIG. 13 shows a plan view and cross-sectional view of a complex cube-corner retroreflective element according to the present invention. FIG. 14 is a plan view of a retroreflective device according to the present invention. FIG. 15 is a plan view of a retroreflective device according to the present invention. FIG. 16 is a plan view of a retroreflective device according to the present invention. FIG. 17 is a plan view of a retroreflective device according to the present invention. FIG. 18 shows cross-sectional construction of a retroreflective device of the present invention. FIG. 19 shows cross-sectional construction of a retroreflective device of the present invention. WORKING EMBODIMENTS OF THE INVENTION Before explaining the present invention, known prior art technologies are explained. FIGS. 7(A) and 7(B) are a plan view and cross-sectional view for explaining a triangular-pyramidal cube-corner retroreflective element according to conventional technology, for comparison with a complex cube-corner retroreflective element of the present invention (which may be hereafter referred to simply as a complex reflective element). FIG. 7(A) shows a triangular-pyramidal cube-corner retroreflective element device projecting on a common plane with their bases arranged in the closest-packed state on said common plane (S-S′) as multiple element pairs each having one base line (x,x . . ) in common and facing with each other approximately symmetrically at equal height with respect to a plane (Lx-Lx′) perpendi cular to a common plane (S-S′) including said common base lines (x,x . . . ) of said many elements. FIG. 7(B) shows the cross-section of said pair of reflective elements among the triangular-pyramidal reflective element group shown in FIG. 7(A). The element pair consists of canted triangular-pyramidal cube-corner retroreflective elements whose optical axes are tilted in the directions exactly opposite to each other, the optical axes tilting toward said perpendicular plane (Lx-Lx′), i.e., in such directions that the respective differences between the respective distances (p1, p2) from the points of intersection (P1, P2) of perpendicular lines drawn from apices (H1, H2) of the pair of elements toward the base plane (S-S′) with said base plane (S-S′) to the base line (x,x . . . ) shared in common by said pair of elements, and the respective distances (q1, q2) from the points of intersection (Q1, Q2) of the optical axes with said base plane (S-S′) to said base line (x,x . . . ) shared in common by the element pair, i.e., (q1-p1, q2-p2), take positive (+) values. Each of these element pairs share a base line (x) in common and face each other in the optically similar shapes as rotated 180° from one another. The two triangular-pyramidal reflective elements have equal height (h1, h2). With increased tilt in the optical axis of above triangular-pyramidal cube-corner reflective element, the areal ratios between one lateral face (c1) of said element to the other lateral faces (a1, b1) also increase. Hence, a retroreflective element whose optical axis is excessively tilted must have a reduced probability for entering light to be retroreflected via trihedral reflection and its retroreflective efficiency inavoidably drops. The concept is explained referring to FIG. 7(A). Within the oval portions (F1, F2) shown in the figure, an incoming light can be effectively retroreflected, while the rest of the portions markedly less contribute to retroreflection. The relevancy of angle of tilt in optical axis with specific coefficient of retroreflection where the coefficient of reflection of light entering at an incident angle of 5° into a retroreflective element with untilted optical axis is made 1, as determined by the inventor's ray-tracing computer simulation is shown in FIG. 8. The more the optical axis is tilted, the less becomes the specific coefficient of retroreflection, and it is demonstrated that the specific coefficient of retroreflection of a retroreflective element with its optical axis tilted by 150 drops to about 50% that of the retroreflective element with untilted optical axis. The invention is explained in further details hereinafter, referring to the drawings time to time where appropriate. FIGS. 9(A) and 9(B) show a plan view and cross-sectional view to explain one embodiment of retroreflective element device according to the present invention. FIGS. 10(A) and 10(B) show one pair of the complex cube-corner retroreflective elements taken out from the device illustrated in FIGS. 9(A) and 9(B). These figures show a retroreflective device in which many complex cube-corner retroreflective elements, each comprising first and second triangular-pyramidal retroreflective units and at least two pairs of tetrahedral retroreflective units, are disposed in the closest-packed state, said device being characterized in that the three reflective lateral faces (a1, b1, c1 and a2, b2, c2) of each of the first and second triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral faces (f11, f12 and f21, f22), the second reflective lateral faces (e11, e12 and e21, e22) and the third reflective lateral faces (g11, g12 and g21, g22) of said two tetrahedral retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, said first reflective lateral face (a1) of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral faces (f11 and f12), respectively, of said tetrahedral retroreflective units, said second reflective lateral face (b1) of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral faces (e11, e12) of said tetrahedral retroreflective units, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c1) of said first triangular-pyramidal retroreflective unit is parallel to one (g11) of the two lateral faces forming said V-shaped groove, the third reflective lateral face (c2) of said second triangular-pyramidal retroreflective unit is parallel to the other (g21) of the two faces forming said V-shaped groove, and the third reflective lateral face (g11) of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove. Whereby formed three pairs of cube-corner retroreflective units, optical axes of each pair having substantially same tilt (θ) in respect of the common base line (x) although differing in direction by 180° to each other, constitute the complex cube-corner retroreflective element. FIGS. 9(B) and 10(B) show cross-sections of each pair of the complex cube-corner retroreflective elements constituting the retroreflective element device as shown in FIGS. 9(A) and 10(A). The pair of elements are tilted complex cube-corner retroreflective elements and optical axes of each element forming the pair (t11, t12, t13 and t21, t22, t23, respectively) are tilted in the exactly opposite directions, by an angle θ to a plane (Lx-Lx′) perpendicular to the base plane (S-S′) including the common base lines (x,x,x . . . ) in such a direction that the difference (q11-p11) between the distance (p11) from a point of intersection (P11) of a perpendicular line drawn from one apex (H11) of an element of said pair toward the base plane (S-S′) with said base plane, to the base lines (x,x . . . ) shared in common by the element pair, and the distance (q11) from the point of intersection (Q11) of the optical axis passing said apex (H11) with said base plane to the base lines (x,x . . . ) shared in common by the element pair, takes a positive (+) value. In these element pairs, heights of the first and second triangular-pyramidal reflective units in the forms rotated by 180° to one another in respect of the common base line (x) is the same, as so are the heights of respectively matched tetrahedral retroreflective units. Because the complex cube-corner retroreflective elements used in the invention can contain plural optical axes (t11, t12, t13 and t21, t22, t23 in FIG. 10) in one pair, improvement can be achieved in the drawback arising particularly when tilt in optical axis is increased that the areal ratio of one of reflective lateral face (c1) of an element to the other reflective lateral faces (a1, b1) as shown in FIG. 7(A) becomes great and the element's reflective efficiency drops. The fourth V-shaped groove set (w-lines) can traverse, for example referring to FIG. 7(A), other portions of the lateral faces a1 and b1 not contributing to retroreflection, without treversing the effective retroreflective regions (F1, F2). This enables to increase the effective areas of the element's reflective lateral faces, and hence to improve the drawback of drop in retroreflective efficiency with increased degree of tilt of the optical axis as demonstrated in FIG. 8. FIGS. 11(A) and (B) illustrate another embodiment of complex cube-corner retroreflective element. FIGS. 11(A) and 11(B) concern a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a pair of triangular-pyramidal retroreflective units and a pair of tetrahedral retroreflective units, characterized in that the three reflective lateral faces (a1, b1, c1 and a2, b2, c2) of each of the pair of triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral faces (f11, f21), the second reflective lateral faces (e11, e21) and the third reflective lateral faces (g11, g21) of said pair of tetrahedral retroreflective units form a mutually perpendicular cube-corner reflective surfaces, respectively, said first reflective lateral faces (a1, a2) of the pair of triangular-pyramidal retroreflective units are on the same plane with the first lateral faces (f11, f21) of said tetrahedral retroreflective units, said second reflective lateral faces (b1, b2) of the first triangular-pyramidal retroreflective units are on the same plane with the second lateral faces (e11, e21) of said tetrahedral retroreflective units, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c1) of said first triangular-pyramidal retroreflective unit is parallel to one (g11) of the two lateral faces forming said V-shaped groove, the third reflective lateral face (c2) of said second triangular-pyramidal retroreflective unit is parallel to the other (g21) of the two faces forming said V-shaped groove, and the third reflective lateral faces (g11, g21) of said pair of tetrahedral retroreflective units are same as one of the two faces forming said V-shaped groove, respectively. Optical axes (t11, t12 and t21, t22) of this complex reflective element have a substantially same degree of tilt (θ) in respect of the common base line (x), although differing in direction by 180° to each other. FIG. 11(B) shows a complex reflective element in which, where the distance from an apex (H) to Sx plane determined by the x-line group is expressed as hx; the distance to Sy plane defined by the y-line group, as hy; the distance to Sz plane defined by the z-line group, as hz, and that to Sw plane defined by w-ine group determined by base line of the fourth reflective lateral face of said tetrahedral retroreflective unit (d1 or d2), as hw, hx equals hw, hy equals hz, and the ratio of hx to hy is 1.05-1.5. In the complex cube-corner retroreflective element according to the present invention, as illustrated in FIGS.11(A) and 11(B), the V-shaped grooves providing the base line (x) and base line (w) are formed deeper than the other grooves providing the base lines (y,z) so that hx equals hw, hy equals hz and the ratio of hx to hy is 1.05-1.5. Hence, compared with such elements in which grooves having an identical depth are formed, areas of reflective lateral faces (g11, g21) and of reflective lateral faces (c1, c2) can be increased to achieve improvement in reflective efficiency. Such embodiments with deeper grooves are particularly effective, when the optical axes are tilted in such directions, where the point of intersection of a perpendicular line drawn from apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line with Sx plane as defined by x-x′ line group is represented by P and the point of intersection of the optical axis of same tetrahedral retroreflective unit with said Sx plane is represented by Q, the difference (q-p) between the distance (q) from x-x′ line to point Q and the distance (p) from x-x′ line to point P takes a positive (+) value (positive tilting). It is preferred to deepen the V-shaped grooves formed by x-lines or w-lines to render hx greater than hy, so that the depth ratio, hx/hy, should fall within a range of 1.05-1.5, preferably 1.07-1.4. In such elements wherein the difference (q-p) between the distance (q) from x-x′ line to point Q and the distance (p) from x-x′ line to point P takes a negative value, there appears an opposite tendency from those having positively tilted optical axes, that areas of the reflective lateral faces (g11, g21) and those (c1, c2) become excessively large as compared with those elements having grooves of an equal depth. Hence the areas of said reflective lateral faces (g11, g21) and reflective lateral faces (c1, c2) can be decreased by shallowing the V-shaped grooves which form the base line (x) and/or base line (w). In such occasions, it is preferred to shallow the V-shaped grooves which are formed by x-lines and/or w-lines to make hx greater than hy so that the depth ratio, hx/hy, in the elements with negatively tilted optical axes should fall within a range of 0.67-0.95, preferably 0.71-0.93. Generally when a light beam passes through a fine aperture, the beam is diverged with an intensity inversely proportional to the area of said aperture, due to diffractive effect. The divergence improves visibility of reflected light to an observer (vehicle driver) present at a distant place from the light source (head lamp) (improvement in observation angularity). Explaining the above referring to, for example, a known triangular-pyramidal retroreflective element as shown in FIG. 7(A), the aperture through which a light beam passes signifies the faces surrounded by three reflective lateral faces (a1, b1, c1 or a2, b2, c2) of the shown triangular-pyramids, respectively, (bases of the elements, ABC1 and ABC2) whose area varies in proportion to height of the element. Where the element height is small, the aperture area decreases, and divergence of the reflected light enlarges due to increased diffraction effect. According to the calculation based on simulation on computer by ray-tracing method, with the element height of 50 μm or less, divergence of the reflected light rapidly increases. On the other hand, excessively small element dimensions results in excessive divergence of light and leads to decrease in retroreflection intensity in the front direction from which the light entered. The complex cube-corner retroreflective element according to the present invention includes plural optical axes differing in height, and the cube-corner units each having one optical axis have aperture area differing from one another. This enables to enlarge divergence of reflected light by increased diffractive effect, without excessively reducing the element height, which leads to improvement in observation angularity compared with known element pairs containing a pair of optical axes. Where the reflective element height (h) is less than 30 μm, the reflective element size becomes too small, and due to the diffraction effect which is decided by the aperture area of the reflective element, divergence of retroreflected light becomes excessive to reduce retroreflectivity. Whereas, any of the heights (h) of the element exceeding 400 μm is undesirable because it renders thickness of the sheeting too large to make a flexible sheeting. Therefore, where a windable, flexible sheet-formed product is to be obtained according to the present invention, a cube-corner. retroreflective sheeting having triangular-pyramidal reflective units, in which the distance (hx) from the Sx plane determined by the x-line group of the many complex cube-corner retroreflective elements to the apex (H1, H2) of one of the complex cube-corner retroreflective element pair is 30-400 μm, in particular, 50-200 μm, inter alia, 60-120 μm, is preferred. FIGS. 12(A) and 12(B) show a retroreflective device as described in any one of claims 1-11, which is characterized in that the bottoms of at least one of those substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are defined by said x-, y-, z- and w-line groups forming the triangular-pyramidal retroreflective units or tetrahedral retroreflective units are formed of a flat surface or a curved quadratic surface. In FIG. 12(B), the base of at least one of the substantially symmetrical V-shaped parallel groove groups (Vx and Vw) which are defined by the x and w line groups is formed of a flat surface, and the width of the flat portion at the bottom of the V-shape is δ. The shape of the bottom of said V shape grooves may be flat or a curved quadratic surface. In such a complex cube-corner retroreflective element, the cross-sectional shape of the V-shaped groove (Vx) forming the reflective lateral faces which face each other (g1, g2) and/or the cross sectional shape of the fourth V-shaped groove group (Vw) which cut off the lateral faces (a1, b1) is substantially symmetrical trapezoid, the width (δ) of the bottom of the grooves being preferably 3-20 μm. Where such complex cube-corner retroreflective element pairs constructed of the V-shaped grooves having said cross-sectional shapes are used, such an inconvenience occurring when tilt angle of optical axes is large, i.e., the bottom angles of the V-shaped grooves (Vx and Vw) become too small and invite insufficient strength of cutting tool or difficulty in parting the shaped resin product from inverted die having said shape, can be improved. Where the point of intersection of a perpendicular line drawn from the apex (H) of the tetrahedral retroreflective unit having one of its base lines on x-x′ line of a complex cube-corner retroreflective element of the present invention, with the Sx plane determined by x-x′ line group is made P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is made Q, the optical axis is tilted to such an extent that the distance (q) between x-x′ line and said point Q and the distance (p) between x-x′ line and the point P are not equal. As the reflective lateral faces (a1, a2) of the triangular-pyramidal retroreflective units are disposed on the same plane with the lateral faces (f1, f2) and the reflective lateral faces (c1, c2) are parallel to the faces (g1, g2) forming the V-shaped groove, respectively, tilt angles of the optical axes of the pair of triangular-pyramidal retroreflective elements are the same. Preferably, where the point of intersection of a perpendicular line drawn from an apex (H) of one of the tetrahedral retroreflective units having one of its base lines on x-x′ line with the Sx plane determined by x-x′ line group is made P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is made Q, the optical axes are tilted in the direction where the difference between the distance (q) from the x-x′ line to the point Q and the distance (p) from the x-x′ line to the point P, i.e., (q-p), takes a positive (+) value. In particular, the optical axes are tilted by 0.5-30°, preferably 5-20°, in the direction, where the point of intersection of a perpendicular line drawn from an apex (H) of one of the tetrahedral retroreflective units having one base line on x-x′ line with the Sx plane determined by x-x′ line group is made P, and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is made Q, that the difference between the distance (q) from the x-x′ line to the point Q and the distance (p) from the x-x′ line to the point P, i.e., (q-p), takes a positive (+) value. With the view to improve observation angularity a deviation is given, to at least one of the two lateral faces of at least one group of the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are determined by the x-, y-, z- and w-line groups of triangular-pyramidal retroreflective units or tetrahedral retroreflective unit(s), so that the prism angles of the triangular-pyramidal retroreflective units or of the tetrahedral retroreflective unit(s) which are formed by said V-shaped parallel grooves are given a deviation of ±(0.001-0.1)° from 90°. Furthermore, with the view to impart a uniform observation angularity, it is most advantageous that at least one V-shaped parallel groove group among the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) which are determined by the x-, y-, z- and w-line groups of the triangular-pyramidal retroreflective units or tetrahedral retroreflective unit(s), are given deviations such that the vertical angles of the cube-corner reflective elements formed by said group of V-shaped parallel grooves show deviations of ±(0.001-0.1)° from 90°, in a pattern of repeating at least two different sets of deviations. As a means to deviate the vertical angles, in the occasion of cutting the groove groups in four directions (x, y, z and w) for forming the complex cube-corner retroreflective elements, angle of the V-shaped grooves in at least one direction is minutely and symmetrically deviated from the angle to give 90° to the prism angles. This means to impart the deviation can be accomplished by using a bilaterally symmetrical cutting tool. As another means to impart a deviation to the vertical angles, in the occasion of cutting the V-shaped grooves in three directions (x, y, z and w) which form the complex cube-corner retroreflective elements, the V-shaped grooves in at least one direction can be cut at an angle minutely and bilaterally asymmetrically deviated from the angle to give 90° to the prismatic vertical angles. This means to impart the deviation can be accomplished by using a bilaterally asymmetrical cutting tool or by slightly canting a bilaterally symmetrical cutting tool at the time of cutting. In the V-shaped parallel groove group (Vw) formed symmetrically in respect of w-lines, the face which forms a right angle with the prismatic vertical angle is only one of the lateral faces or side walls of the V-shaped groove (referring to FIG. 10, g12, c1 and g22, c2). Therefore, the cross-sectional configuration of the V-shaped groove is not necessarily symmetrical, but the other side wall not contributing to retroreflection (d12, d11 and d21, d22) can have an optional angle. Whereas, each adjacent complex reflective elements take bilaterally reversed configurations and cannot form cube-corner reflective faces. Therefore, the V-shaped grooves are preferably substantially symmetrical. Where such retroreflective elements having deviated vertical angles are used, whereby retroreflected light does not return to the light source but retroreflect to a position slightly distant threfrom. Hence the light can be effectively directed, for example, to a vehicle driver (observer) present at a distant position from the vehicle's head lamps, and the observation angularity is improved. In particular, where V-shaped grooves are formed with a pattern of repeating at least two sets of deviations to deviate vertical angles of retroreflective elements, the retroreflective elements are given various deviations in their vertical angles to advantageously provide a uniform observation angularity. FIGS. 13(A) and 13(B) show a complex cube-corner retroreflective element comprising a pair of triangular-pyramidal retroreflective units and three tetrahedral retroreflective units whose bases are difined by base lines in four directions, in which said pair of triangular-pyramidal retroreflective units have different sizes and are disposed at spaced positions and the three reflective lateral faces (e, f, g) of each of the tetrahedral retroreflective units are mutually perpendicular to form cube corners where they meet, said tetrahedral units being disposed between the pair of triangular-pyramidal retroreflective units, two being at the right side and one, at the left side. FIG. 14 shows a plan view of a retroreflective device in which a large number of the complex cube-corner retroreflective elements as shown in FIG. 13 are disposed in the closest-packed state. FIG. 14 shows a repeated pattern of forming x line group and w line group, in which one w line is formed between two parallel x lines and between the next two parallel x lines, two w-symmetrical lines are formed. FIG. 15 shows a plan view of a retroreflective device in which the angle formed between the x lines of the device as illustrated above and an outer edge of a product formed of the retroreflective device is 5-85°, preferably 30-60°. Outer edge of the product as referred to herein signifies, where the product is a thin sheet-formed retroreflective sheeting, the longitudinal edge of a wound-up roll; or, where the product is an article like a thick-walled reflector, the edge in the horizontal direction may be the outer edge; or where the product has a circular shape, the standard edge may be the tangential line in the horizontal direction. In such a retroreflective device in which the angle formed between x lines of the retroreflective device and the outer edge of the product formed from the retroreflective device is 5-85°, preferably 30-60°, entrance angularity can be further improved. FIG. 16 shows a plan view of an example of retroreflective device which has first zone(s) and second zone(s), the angle formed between any x1 line of the first zone and x2 line in the second zone ranging 5-175°, preferably 80-100°. The two zones are combined in such a manner that the angle [η1] of the first zone formed with the outer edge is 0° and the angle [η2] of the second zone formed with the outer edge is 90°, which are disposed in repetitive pattern. FIG. 17 shows a plan view of an example of a retroreflective device in which a first zone and second zone are combined in repeated pattern, in such a manner that the angle [η1] of the first zone formed with the outer edge is 135°, and the angle [η2] of the second zone with the outer edge is 45°. Such a retroreflective device having first zone(s) and second zone(s), x1 line of the first zone and x2 line of the second zone form an angle of 5-175°, preferably 80-100°, can uniformize entrance angularity in horizontal and vertical directions and directions therebetween, by combining said zones. Furthermore, the retroreflective device may have three or more zones, in which x-lines of each zone are selected to form divided angles with the outer edge so that the angles become uniform in all directions. By combining the zones in such a manner, entrance angularity in horizontal direction and perpendicular direction and directions therebetween can be still more uniformized. The most favorable retroreflective device according to the present invention is a retroreflective device in which many complex cube-corner retroreflective elements, each comprising first and second triangular-pyramidal retroreflective units and at least a pair of tetrahedral retroreflective units, are disposed in the closest-packed state, said device being characterized in that all the tetrahedral retroreflective units have an identical shape and mutually form rotation symmetrical pair as rotated by 180° to one another, said complex cube-corner retroreflective elements have rotation-symmetrical shapes, where the point of intersection of a perpendicular line drawn from the apex (H) of the tetrahedral retroreflective unit having one base line on x-x′ line with Sx plane determined by x-x′ line group is made P and the point of intersection of the optical axis of said tetrahedral retroreflective unit with said Sx plane is made Q, the optical axis is tilted by 5-20° in the direction such that the difference between the distance (q) from x-x′ line to the point Q and the distance (p) from x-x′ line to the point P, i.e., (q-p), takes a positive (+) value, in the tetrahedral retroreflective unit having one of its base lines on said x-x′ line, hx equals hw, hy equals hz, and the ratio of hx to hy is 1.05-1.5, and among the substantially symmetrical V-shaped parallel groove groups (Vx, Vy, Vz and Vw) determined by x-, y-, z- and w-line groups forming the triangular retroreflective units or the tetrahedral retroreflective units, at least one bottom is formed of a flat or quadratic bottom plane. In general, triangular-pyramidal cube-corner retroreflective sheetings and retroreflective articles of the present invention can be manufactured with cube-corner-molding dies, e.g., a metallic belt on which reversed female pattern of complex cube-corner retroreflective elements are arranged in closest-packed state as described in the foregoing is inscribed. By hot-pressing a pliable, adequate resin sheet excelling in optical transparency and uniformity as described later against such a molding die, the pattern inscribed on the die is transferred to the resin in reversed form, to provide a desired product. A representative method for manufacturing above cube-corner molding die is described in detail, for example, in earlier cited U.S. Pat. No 3,712,706 to Stamm. A method analogous to said method can be adopted also in this invention. Specific exlanation is given referring to the triangular-pyramidal cube-corner elements as illustrated in FIGS. 9 (A) to 13. On a substrate with a flatly ground surface, V-shaped parallel groove groups in two directions (e.g., in the directions of y lines and z lines in FIG. 9(A)), the groove groups having an identical depth (hy or hz) and substantially symmetrical cross-sectional shape, are cut, the repetition pitch in each direction, groove depth (e.g., h in FIG. 9(B), and mutual crossing angle of said grooves being determined according to the configuration of desired triangular-pyramidal reflective elements, with a super-hard cutting tool (e.g., diamond-tipped tool or tool made of tungsten carbide) having a point angle of around 47-86°. Then another group of parallel, V-shaped grooves having a same depth (hx) and substantially symmetrical cross-section are so cut in the third direction (x-direction) as to pass the intersections (A, B, C1, C2) of the previously formed V-shaped grooves in y-direction and z-direction, using a similar super-hard cutting tool having a point angle of about 30-110°. Moreover, the fourth group of V-shaped grooves (w-direction) having a depth (hw) are cut in parallel with the V-shaped grooves in x-direction at such a repetition pitch as to divide each pitch between any two x grooves into an integral number of plural parts, with a super-hard cutting tool having a point angle similar to that of the tool used for cutting the V-shaped grooves in x-direction. In the present invention, depths of the grooves in x- and w-directions (hx, hw) may be the same with that of the grooves in y- and z-directions (hy or hz) or can be made deeper or shallower. In a preferred embodiment of the present invention, where a windable, flexible sheet-formed product is intended, the V-shaped grooves in x-direction are so cut as to make the distance (h) between the plane (Sx-Sx′ ) inclusive of the many base lines (x,x, . . . ) of the many complex cube-corner retroreflective elements projecting on the common base (Sx-Sx′ ) and apices (H1, H2) of said complex cube-corner retroreflective element pair, 30-400 μm, in particular, 50-200 μm, inter alia, 60-120 μm. The depth of the V-shaped grooves in y- and z-directions may be same with that of the V-shaped grooves in x-direction, or may be made deeper to give the depth ratio hx/hyz to fall within a range of 1.05-1.5, preferably 1.07-1.4. The depth of the V-shaped grooves in w-direction may be the same to, or different from, that of the grooves in x-direction. As the substrate suitable for making said microprismatic master mold, metallic materials having a Vickers hardness as defined by JIS Z 2244 of at least 350, in particular, at least 380, are preferred, specific examples including amorphous copper, electrodeposited nickel and aluminum; and as alloy materials, copper-zinc alloy (brass), copper-tin-zinc alloy, nickel-cobalt alloy, nickel-zinc alloy and aluminum alloy. As the substrate, synthetic resins can also be used, which preferably are those having a glass transition point of at least 150° C, in particular, at least 200° C, and a Rockwell hardness (JIS Z 2245) of at least 70, in particular, at least 75, to avoid such inconvenience that a resin softens during the cutting process to make high precision cutting difficult. Specific examples of useful resins include polyethylene tetraphthalate resins, polybutylene phthalate resins, polycarbonate resins, polymethyl methacrylate resins, polyimide resins, polyarylate resins, polyether sulfon resins, polyether imide resins and cellulose triacetate resins. Thus obtained microprismatic master mold is given an electroforming processing to form a metallic coating on its surface. Upon removing the metallic coating from the master mold surface, a metallic die to be used for molding a triangular-pyramidal cube-corner retroreflective sheeting or an article of the present invention is provided. In general, said electroforming is conducted, for example, in 60 wt% aqueous solution of nickel sulfamate, under such conditions as around 40° C. and 10A/dm2 electric current. As the formation rate of electroformed layer, for example, one not faster than about 0.02 mm/hr is suitable for providing a uniform electroformed layer. At a formation rate greater than that, troubles such as lack in surface smoothness or formation of defective part in the electroformed layer are apt to be caused. The first generation electroformed die made from the prismatic master mold can be repetitively used as an electroformed master die for making second generation electroformed dies. Therefore, plural electroformed dies can be made from one prismatic master mold. Thus manufactured plural electroformed dies are precisely cut, and can be assembled and bonded to a final die size for molding microprismatic sheeting of synthetic resin. As a means for the bonding, cut end surfaces may be simply pressed against each other, or the joining parts of an assembly may be welded by such means as electron beam welding, YAG laser welding, carbon dioxide gas laser welding, and the like. The assembled electroformed die is used for molding synthetic resin, as a synthetic resin-molding die. As the means for molding synthetic resin, compression molding or injection molding can be adopted. Compression molding comprises, for example, inserting a thin-walled nickel electroformed die prepared as above, a synthetic resin sheet of a prescribed thickness and a silicone rubber sheet of approximately 5 mm in thickness as a cushioning material into a compression molding press which has been heated to a prescribed temperature; preheating the inserted materials under a pressure of 10-20% that of the prescribed molding pressure for 30 seconds; and heating and pressurizing said materials under such conditions as around 180-250° C. ad 10-30 kg/cm2, for about 2 minutes. Thereafter the press is cooled to room temperature while maintaining the pressurized condition, and then the pressure is released to provide a prismatic molded product. The injection molding can be conducted using a thick-walled electroformed nickel die which was formed by the above-described method as an injection molding die according to accepted practice, and a customarily used injection molding machine. In that occasion, an injection molding method wherein a mobile die and fixed die are kept under pressure during pouring molten resin into the dies, or an injection compression method can be adopted wherein the mobile die and fixed die are not given a pressure and the molten resin is poured through a minor aperture opened and thereafter the system is pressurized. These methods are suitable particularly for making thick-walled products, e.g., a pavement marker. Moreover, about 0.5 mm-thick thin-walled electroformed dies made by the above method can be bonded by aforementioned welding method to form an endless belt die, which is mounted on a pair of a heating roll and a cooling roll and rotated. Onto the belt die on the heating roll, molten synthetic resin is supplied in sheet form, pressure molded with at least one silicone roll, cooled on the cooling roll to a temperature not higher than the glass transition point, and stripped off from the belt die. Thus a continuous sheet-formed product can be obtained. Now an embodiment of a structure of preferred cube-corner retroreflective sheeting and retroreflective article of the present invention shall be explained, referring to their cross-sectional view shown in FIG. 18. In FIG. 18, the numeral 4 is a reflective element layer in which the complex cube-corner retroreflective elements (R1, R2) of the present invention are disposed in closest packed state; 3 is a holder layer which holds the reflective elements; and the arrow 11 shows the direction of incident light. Normally the reflective element layer (4) and the holder layer (3) form an integral body (5), but they may be a laminate of two different layers. Depending on the intended use of a retroreflective sheeting or a retroreflective article of the present invention and the circumstances under which they are used, a surface protective layer (1), print layer (2) to convey information to a viewer or to impart color to the sheeting, binder layer (7) to provide an airtightly sealed structure to prevent infiltration of water to the back of the reflective element layer, support layer (8) to support the binder layer (7); and an adhesive layer (9) with a peeling layer (10) for adhering the retroreflective sheeting or the retroreflective article to another structure, can be provided. The print layer (2) can be installed normally between the surface protective layer (1) and the holder layer (3) or on the surface protective layer (1) or the reflection surface of the reflective elements (4) by such ordinary means as gravure, screen printing, or ink-jet printing. While the material for making said reflective element layer (4) and holder layer (3) is not critical so long as it satisfies pliability which is one of the objects to be achieved by the present invention, one having optical transparency and homogeneity is preferred. Examples of the material useful for the invention include polycarbonate resin, vinyl chloride resin, (meth)acrylic resin, epoxy resin, polystyrene resin, polyester resin, fluorine-contained resin, polyolefin resin such as polyethylene resin or polypropylene resin, cellulose resin, and polyurethane resin. Furthermore, with the view to improve weatherability, ultraviolet absorber, photostabilizer, antioxidant and the like can be used either singly or in combination. Any of various organic pigments, inorganic pigments, fluorescent pigments, dyes, fluorescent dyes as colorlant may also be contained. For the surface protective layer (1), the same resin as used for the retroreflective element layer (4) can be used, which may be incorporated with ultraviolet absorber, photostabilizer, antioxidant and the like which can be used either singly or in combination. Still in addition, various organic pigments, inorganic pigments, fluorescent pigments, dyes, fluorescent dyes and the like as colorlant may be incorporated. It is a general practice with the reflective element layer (4) of the present invention, to provide an air layer (6) behind the complex cube-corner retroreflective elements, for enlarging the critical angle satisfying the total internal reflection conditions. To prevent such troubles under conditions of use as decrease in critical angle,. corrosion of metallic layer or the like due to infiltrated moisture, the reflective element layer (4) and the support layer (8) are airtightly sealed by a binder layer (7). As means for this airtight sealing, those described in U.S. Pat. Nos. 3,190,178 and 4,025,159 and JP-Utility Model Show a 50 (1975)-28669A can be used. As the resin to be used for the binder layer (7), (meth)acrylic resin, polyester resin, alkyd resin, epoxy resin and the like can be named, and as the bonding means, known thermofusing resin binding method, thermosetting resin binding method, ultraviolet curable resin binding method, electron beam curable resin binding method and the like can be suitably adopted. The binder layer (7) used in the present invention may be applied over the entire surface of the support layer (8), or can be selectively provided at the bonding portion(s) with the retroreflective element layer, by such means as printing method. Examples of the material for constituting the support layer (8) include resins for making the retroreflective element layer, film-forming resins in general, fibers, fabric, metallic foil or plate such as of stainless steel or aluminum, which can be used either singly or in combination. The adhesive layer (9) used for adhering the retroreflective sheeting or retroreflective article of the present invention onto metallic plate, wood board, glass sheet, plastic sheet and the like, and the peeling layer (10) for the adhesive can be suitably selected from known materials. The adhesive can be suitably selected among pressure-sensitive adhesives, heat-sensitive adhesives, crosslinkable adhesives and the like. Examples of pressure-sensitive adhesive include polyacrylate agglutinants obtained by copolymerizing acrylic acid esters such as butyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, nonyl acrylate and the like, with acrylic acid, vinyl acetate and the like; silicone resin agglutinants; and rubber agglutinants. As heat-sensitive adhesives, acrylic, polyester or epoxy resins can be used. Now another embodiment of a preferred structure of the cube-corner retroreflective sheeting or retroreflective article of the present invention is explained referring to FIG. 19 which is a cross-sectional view of the embodiment. In FIG. 19, a metallic specular reflective layer (12) is provided on the surfaces of the elements in the reflective element layer (4), and an adhesive layer and a peeling layer are laminated on, and in direct contact with, the specular reflection layer (12). The cube-corner retroreflective sheeting or retroreflective article of this embodiment do not require an air layer because they retroreflect on principle of specular reflection, and hence do not require any binder layer or support layer. The metallic specular reflection layer (12) installed on the element surfaces in the reflective element layer (4) of the present invention may cover the entire region of the element surfaces or cover it only partially. The specular reflection layer (12) formed of a metal such as aluminum, copper, silver, nickel or the like can be provided on the elements in the reflective element layer (4) of the triangular-pyramidal cube-corner retroreflective sheeting or retroreflective article of the present invention by such means as vacuum vapor deposition, chemical plating or sputtering. Of these means for providing said specular reflective layer (12), vapor deposition means using aluminum is preferred, because the vapor deposition temperature can be lowered to minimize thermal deformation of the retroreflective elements during the vapor deposition step, and also the resulting specular reflective layer (12) shows the fairest color tone. An apparatus suitable for continuous vapor deposition of aluminum specular reflection layer (12) comprises a vacuum vessel which is capable of maintaining a degree of vacuum at around 7 to 9×10−4 mm Hg, said vacuum vessel accommodating therein a feeder for feeding an original prism sheeting formed of a base sheet and a surface protective layer which is laminated on the light entrance side surface of said base sheet; a take-up winder for winding up the original prism sheeting which has been vacuum-deposition treated; and a heating system installed therebetween which is capable of fusing the aluminum in a graphite crucible with an electric heater. Pure aluminum pellets having a purity of at least 99.99 wt% are put in the graphite crucible, melted and vaporized under the conditions, e.g., an AC voltage of 350-360 V, an electric current of 115-120 A and a treating rate of 30-70 m/min. With the vaporized aluminum atoms, a specular reflection layer (12) can be deposited on the surfaces of retroreflective elements at a thickness of, for example, 800-2000 Å. EXAMPLES Hereinafter the particulars of the present invention are explained more specifically, referring to working Examples, it being understood that the invention is not limited to the Examples only. <Coefficient of Retroreflection> Coefficient of retroreflection referred to in the specification, in particular, in Examples, was measured by the following method. Using a reflectometer “Model 920” of Gamma-Scientific Co., coefficients of retroreflection of each 100 mm×100 mm retroreflective sheeting were measured following ASTM E810-91 at optional five spots, under the angular conditions of observation angle, 0.2°; and incident angles, 5°, 10°, 20°, 30°, 40° and 500. The mean values of the measured values are indicated as the coefficients of retroreflection of the measured retroreflective sheeting. Also for comparison of observation angularity, coefficients of retroreflection at an incident angle of 5° and observation angle of 1.0° were measured. Example 1 A large number of parallel V-formed groove groups of symmetrical cross-sections were cut in y-direction and z-direction in a repetitive pattern by fly cutting method, on a 100 mm square brass plate with a flatly ground surface, with a diamond-tipped cutting tool having a point angle of 83.11°. The repetition pitch of V-shaped grooves in y-direction and z-direction was 201.45 μm, the groove depth was 100.00 μm, and crossing angle of the V-shaped grooves in y-direction with those in z-direction was 38.207°. An intermediate configuration as shown in FIG. 1 was formed. Furthermore, another group of parallel V-shaped grooves were cut in the x-direction in repetitive pattern with a diamond-tipped cutting tool having a symmetrical cross-section and point angle of 40.53°, at a repetition pitch of said V-shaped grooves of 307.77 μm and to the V-shaped groove depth of 100.00 μm, each of said grooves passing through two points of intersection of the y-directioned grooves and z-directioned grooves, to form on said brass plate many male triangular-pyramidal cube-corner elements arranged in closest-packed state, each element taking an intermediate configuration as illustrated in FIG. 3. Thereafter still another group of parallel V-shaped grooves were cut in a repetitive pattern in the w-direction with a diamond-tipped cutting tool having a symmetrical cross-section and a point angle of 40.53°, at a repetition pitch of said V-shaped grooves of 307.77 μm and to the V-shaped groove depth of 100.00 μm, each of said grooves passing through the center point of two adjacent V-formed grooves in x-direction. Thus on the brass plate a master mold according to the present invention, formed of a large number of male complex cube-corner retroreflective elements which were disposed in the closest-packed state on said plate, was prepared. This master mold was formed of an array of the element as illustrated in FIG. 10 (A), and the number of V-shaped groove in w-direction between two V-shaped grooves in x-direction was one. In so formed complex cube-corner retroreflective element pair, the height (h) from the apex (H11 or H21) to the base plane (S-S′) was 100 μm. The tilt angle (θ) of each optical axis of this complex cube-corner retroreflective element was ±15°, and the vertical angles of the three lateral faces constituting the reflective element were invariably 90°. The cutting parameters used to make the master mold of Example 1 are listed in the following: depth of V-shaped grooves in x-, y-, z- and w-directions: 100.00 μm angle of V-shaped grooves in y- and z-directions: 83.11° angle of V-shaped grooves in x- and w-directions: 40.53° pitch of V-shaped grooves in y- and z-directions: 201.46 μm pitch of V-shaped grooves in x- and w-directions: 307.77 μm crossing angle of y-directioned V grooves with z-directioned V grooves: 38.21° crossing angle of y- and z-directioned V grooves with x-directioned V grooves: 70.90° tilt angle of optical axes: 15° Using this brass master mold, a female cube-corner forming die with reversed configuration made of nickel was prepared by electroforming method using a nickel sulfamate solution of 55% in concentration. Compression molding a 200 μm-thick polycarbonate resin sheet (Iupilon TMH3000, Mitsubishi Engineering Plastics K.K.) using this molding die, under the conditions of molding temperature of 200° C. and molding pressure of 50 kg/cm2, the resin sheet was cooled to 30° C. under the elevated pressure and removed. Thus a retroreflective device with about 150° μm-thick holder layer on whose surface a large number of polycarbonate resin complex cube-corner retroreflective elements were disposed in closest packed state was prepared. Example 2 A polycarbonate resin retroreflective device in which a large number of the complex cube-corner retroreflective elements as illustrated in FIGS. 11(A) and 11(B) were disposed in closest-packed state was prepared by the same method as described in Example 1, except that the depth of V-shaped grooves in x- and w-directions was made 115.00 μm. The cutting parameters used to make the master mold of Example 2 are listed in the following: depth of V-shaped grooves in y and z-directions: 100.00 μm depth of V-shaped grooves in x- and w-directions: 115.00 μm angle of V-shaped grooves in y- and z-directions: 83.11° angle of V-shaped grooves in x- and w-directions: 40.53° pitch of V-shaped grooves in y- and z-directions: 201.46 μm pitch of V-shaped grooves in x- and w-directions: 307.77 μm crossing angle of y-directioned V grooves with z-directioned V grooves: 38.21° crossing angle of y- and z-directioned V grooves with x-directioned V grooves: 70.90° tilt angle of optical axes: 15° Example 3 A polycarbonate resin retroreflective device in which a large number of the complex cube-corner retroreflective elements as illustrated in FIG. 12(A) and 12(B) were disposed in closest-packed state was prepared by the same method as described in Example 1, except that the point of the diamond-tipped tool used for cutting V-shaped grooves of x- and w-directions was advancedly lapped to have a width (dw) of 8 μm. The cutting parameters used to make the master mold of Example 3 are listed in the following: depth of V-shaped grooves in x-, y-, z- and w-directions: 100.00 μm angle of V-shaped grooves in y- and z-directions: 83.11° angle of V-shaped grooves in x- and w-directions: 40.53° pitch of V-shaped grooves in y- and z-directions: 201.46 μm pitch of V-shaped grooves in x- and w-directions: 307.77 μm crossing angle of y-directioned V grooves with z-directioned V grooves: 38.21° crossing angle of y- and z-directioned V grooves with x-directioned V grooves: 70.90° width of bottom portion of each of V-shaped grooves in x- and w-directions: 8 μm tilt angle of optical axes: 15° Example 4 In the production of the elements according to Example 2, the angles of diamond-tipped tools for cutting V-shaped grooves in x- and w-directions were varied as follows: the angle of tool A was same with that used in said Example, that of tool B was made asymmetrical by a deviation of ±0.01° given to one of the lateral faces forming the V shape, and that of tool C was made asymmetrical by a deviation of −0.01° given to one of the lateral faces forming the V-shape. Using these three kinds of cutting tools, V-shaped grooves in x- and w-directions were cut in a repetitive pattern of A-B-C, to form a master mold in which a large number of complex cube-corner retroreflective elements with varied deviations given to their vertical angles were disposed in closest-packed state. Using this master mold a polycarbonate resin retroreflective device in which a large number of complex cube-corner retroreflective elements were disposed in closest-packed state was prepared by the method as described in Example 1. Example 5 A polycarbonate resin retroreflective device in which a large number of complex cube-corner retroreflective elements were disposed in closest-packed state was prepared from polycarbonate resin triangular-pyramidal cube-corner retroreflective sheet product as prepared in Example 2, in which a large number of complex cube-corner retroreflective elements were disposed in closest-packed state, said sheet product being given an azimuth so that the x-lines of said retroreflective device each formed an angle of 45° with the outer edge thereof. Example 6 A polycarbonate resin retroreflective device in which a large number of complex cube-corner retroreflective elements were disposed in closest-packed state was prepared from polycarbonate resin triangular-pyramidal cube-corner retroreflective sheet product as prepared in Example 2, in which a large number of complex cube-corner retroreflective elements were disposed in closest-packed state, by combining the sheetings such that two zones, in one of which the x-lines thereof each formed an angle of 45° with the outer edge and in the other the x-lines thereof each formed an angle of 135° with the outer edge, should appear repeatedly to form a pattern of 10 mm-wide stripes. Comparative Example A polycarbonate resin retroreflective device in which a large number of complex cube-corner retroreflective elements as illustrated in FIG. 3 were disposed in closest-packed state was prepared by the same method as in Example 1, except that V-shaped grooves in x-, y- and z-directions were cut but V-shaped grooves in w-direction were not cut. The cutting parameters used to make the master mold of the Comparative Example are listed in the following: depth of V-shaped grooves in x-, y- and z-directions: 100.00 μm angle of V-shaped grooves in y- and z-directions: 83.11° angle of V-shaped grooves in x-direction: 40.53° pitch of V-shaped grooves in y- and z-directions: 201.46 μm pitch of V-shaped grooves in x-direction: 307.77 μm crossing angle of y-directioned V grooves with z-directioned V grooves: 38.21° crossing angle of y- and z-directioned V grooves with x-directioned V grooves: 70.90° tilt angle of optical axes: 15° Coefficients of retroreflection of those retroreflective devices as prepared in above Examples 1-6, in which the complex cube-corner retroreflective elements were disposed in closest-packed state, and the coefficients of retroreflection of the triangular-pyramidal cube-corner retroreflective sheeting as prepared in Comparative Example are shown in Table 1. The coefficients of retroreflection of those retroreflective devices of Examples 1-6 according to the present invention excelled over those of the triangular-pyramidal cube-corner retroreflective sheeting of the Comparative Example based on conventional technology, in both retroreflectivity in the front direction and retroreflective characteristics in directions of large entrance angles. Furthermore, the observation angularity (observation angle=1.0° ) of the retroreflective device (retroreflective sheeting) in which a large number of the complex cube-corner retroreflective elements were arranged in the closest-packed state, which was prepared from the master mold in which a large number of complex cube-corner retroreflective devices with vertical angles deviated in various manner as described in Example 4 were arranged in closest-packed state, excelled over observation angularity of other retroreflective devices which were not given such vertical angle deviations. TABLE 1 Observation Entrance Comparative angle angle Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 0.2° 5° 780 797 631 562 720 704 493 10° 700 747 574 497 704 689 470 20° 400 550 374 306 545 544 280 30° 300 362 287 211 420 430 207 40° 250 270 216 199 345 350 192 50° 150 169 135 118 321 329 104 1.0° 5° 45 43 43 89 39 44 37

<SOH> TECHNICAL FIELD TO WHICH THE INVENTION BELONGS <EOH>This invention relates to a triangular-pyramidal cube-corner retroreflective sheeting and retroreflective articles of novel structures. More particularly, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit. Specifically, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, which device is useful for signs such as traffic signs (commonly used traffic signs and delineators), road surface signs (pavement markers) and construction signs; number plates for vehicles such as automobiles and motorcycles; safety goods such as reflective tapes to be adhered to bodies of tracks or trailers, clothing and life preservers; marking on signboards; and reflective plates of visible light, laser-beams or infrared light-reflective sensors. That is, the invention relates to a retroreflective device in which a large number of complex cube-corner retroreflective elements are arranged in closest-packed state, each of said complex cube-corner retroreflective elements having a first and second triangular-pyramidal retroreflective units and at least one tetrahedral retroreflective unit, characterized in that the three reflective lateral faces (a 1 , b 1 , c 1 and a 2 , b 2 , c 2 ) of each of the first and second triangular-pyramidal retroreflective units form mutually perpendicular cube-corner reflective surfaces, respectively, the first reflective lateral face (f 1 ) of said at least one tetrahedral retroreflective unit, the second reflective lateral face (e 1 ) and the third reflective lateral face (g 1 ) thereof form a mutually perpendicular cube-corner reflective surfaces, said first reflective lateral face (a 1 ) of the first triangular-pyramidal retroreflective unit is on the same plane with the first lateral face (f 1 ) of said tetrahedral retroreflective unit, said second reflective lateral face (b 1 ) of the first triangular-pyramidal retroreflective unit is on the same plane with the second lateral face (e 1 ) of said tetrahedral retroreflective unit, said complex cube-corner retroreflective element has a quadrangular circumference defined by mutually parallel y-lines and mutually parallel z-lines, said complex cube-corner retroreflective element has a substantially symmetrical V-shaped groove with its center line x-x′ passing through the points of intersection of said parallel y-lines and parallel z-lines, the third reflective lateral face (c 1 ) of said first triangular-pyramidal retroreflective unit is parallel to one of the two lateral faces (g 1 ) forming said V-shaped groove, the third reflective lateral face (c 2 ) of said second triangular-pyramidal retroreflective unit is parallel to the other (g 2 or c 2 ) of the two faces forming said V-shaped groove, and the third reflective lateral face (g 1 ) of said tetrahedral retroreflective unit is same as one of the two faces forming said V-shaped groove.

20040210

20050426

20050127

61310.0

CHERRY, EUNCHA P

RETROREFLECTION DEVICE

UNDISCOUNTED

ACCEPTED

ACCEPTED

3-phenoxy-4-pyridazinol derivatives and herbicide composition containing the same

A compound represented by the formula: [wherein R1 represents a hydrogen atom, a halogen, atom, alkyl group, etc., R2 represents a hydrogen atom, a halogen atom, alkyl group, etc., R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a halogen atom, a substitutable alkyl group, a substitutable alkenyl group, alkynyl group, a substituteable cycloalkyl group, etc., or R3, R4, R5, R6 and R7 may form a ring which may be substituted, which is formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, m and n each independently represent 0 or 1.] a salt thereof, an ester derivative thereof and an agricultural chemical containing the same as an effective ingredient, and a herbicidal composition containing the compound and a second herbicidally active compound as effective ingredients.

1. A compound represented by the formula: wherein R1 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a C3 to C6 cycloalkyl group, a C2 to C6 alkenyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a di(C1 to C6 alkyl)carbamoyl group, a phenyl group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a 5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may further contain 1 or 2 nitrogen atom(s)), a C1 to C6 alkoxy group, a phenoxy group which may be substituted (the substituent is a substituent selected from the following substituent Group A) or a 5- or 6-membered heterocycloxy group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further contain 1 or 2 nitrogen atom(s), the substituent is a substituent(s) selected from the group consisting of a benzoyl group which may be substituted (the substituent is a substituent selected from the following substituent Group A) and a C1 to C6 alkyl group}, R2 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a (C1 to C6 alkoxy)C1 to C6 alkyl group, a benzoyl group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a C2 to C7 alkoxycarbonyl group, a phenoxy group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a phenylthio group which may be substituted (the substituent is a substituent selected from the following substituent Group A) or a tri(C1 to C6 alkyl)silyl group, R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a halogen atom, a C1 to C6 alkyl group which may be substituted (the substituent is a substituent selected from the following substituent Group B), a C2 to C6 alkenyl group which may be substituted (the substituent is a cyano group or a nitro group), a C2 to C6 alkynyl group, a C3 to C6 cycloalkyl group which may be substituted (the substituent is a substituent selected from the following substituent Group C), a C4 to C10 bicycloalkyl group, a cyano group, a formyl group, a C2 to C7 alkylcarbonyl group, a benzoyl group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a carboxyl group, a C2 to C7 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C6 alkyl)carbamoyl group, a phenyl group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a 3- to 6-membered heterocyclic group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may further contain 1 or 2 nitrogen atom(s), which may be fused with a benzene ring, the substituent is a substituent selected from the following substituent Group E), an amino group which may be substituted (the substituent is a substituent selected from the following substituent Group D), a nitro group, a hydroxyl group, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a (C1 to C6 alkoxy) C1 to C6 alkoxy group, a phenoxy group which may be substituted (the substituent is a hydroxyl group or a pyridazinyloxy group substituted by a substituent(s) selected from the group consisting of a halogen atom and a C1 to C6 alkoxy group), a 5- to 6-membered heterocycloxy group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further contain 1 or 2 nitrogen atom(s), the substituent is a substituent selected from the following substituent Group E), a phenylsulfonyloxy group which may be substituted (the substituent is a substituent selected from the following substituent Group A), a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group or a tri(C1 to C6 alkyl)silyl group, or R3, R4, R5, R6 and R7 may form a 3- to 6-membered cyclic hydrocarbon group which may be substituted, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded (the cyclic hydrocarbon may be interrupted by the same or different 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, the substituent is a halogen atom, a C1 to C6 alkyl group, a hydroxy-C1 to C6 alkyl group, a C1 to C6 alkoxy group, an oxo group, a hydroxyimino group or a C1 to C6 alkoxyimino group, and when the C1 to C6 alkyl group is substituted, it may form another 3-membered ring by combining with the other C1 to C6 alkyl group or a carbon atom(s)in the cyclic hydrocarbon), m and n each independently represent 0 or 1, the substituent Group A is selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a C3 to C6 cycloalkyl group, a cyano group and a tri(C1 to C6 alkyl)silyl group, the substituent Group B is selected from the group consisting of a halogen atom, a C3 to C6 cycloalkyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a phenyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group, a C1 to C4 alkylenedioxy group, a hydroxyimino group and a C1 to C6 alkoxyimino group, the substituent Group C is selected from the group consisting of a halogen atom, a C1 to C6 alkyl group which may be substituted (the substituent is a substituent selected from the substituent Group B), a C3 to C6 cycloalkyl group, a C2 to C6 alkenyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a benzoyl group, a carboxyl group, a C2 to C7 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C6 alkyl)carbamoyl group, a phenyl group which may be substituted (the substituent is a substituent selected from the above-mentioned substituent Group A), a 5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further contain 1 or 2 nitrogen atom(s)), an amino group which may be substituted (the substituent is a substituent selected from the following substituent Group D), a nitro group, a hydroxyl group, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a phenoxy group, a C1 to C6 alkylthio group, a phenylthio group, a C1 to C6 alkylsulfinyl group and a C1 to C6 alkylsulfonyl group, the substituent Group D is selected from the group consisting of a C1 to C6 alkyl group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a di(C1 to C6 alkyl)carbamoyl group and a C1 to C6 alkylsulfonyl group, the substituent Group E is selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a hydroxyl group, a phenylsulfonyl group which may be substituted (the substituent is a substituent selected from the above-mentioned substituent Group A) and a di(C1 to C6 alkyl)sulfamoyl group], a salt thereof and an ester derivative thereof. 2. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (the halogen atom is 1 to 3 fluorine atom(s)), a cyclopropyl group, a C2 to C3 alkenyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a di(C1 to C3 alkyl)carbamoyl group, a phenyl group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a furyl group, a thienyl group, a C1 to C3 alkoxy group, a phenoxy group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 fluorine atom(s), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group} or a substituted pyrazolyloxy group (the substituent is a benzoyl group which is substituted by two chlorine atoms and two C1 to C3 alkyl groups). 3. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom, a bromine atom, a trifluoromethyl group or a cyano group. 4. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom or a bromine atom. 5. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom. 6. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a (C1 to C3 alkoxy)C1 to C3 alkyl group, a benzoyl group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a C2 to C4 alkoxycarbonyl group, a phenoxy group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a phenylthio group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group} or a tri(C1 to C3 alkyl)silyl group. 7. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethoxycarbonyl group or a trimethylsilyl group. 8. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R2 is a hydrogen atom. 9. The compound, a salt thereof and an ester derivative thereof according to any of claims 1 to 8, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C3 to C4 cycloalkyl group, a C1 to C3 alkylthio group or a C1 to C3 alkoxyimino group), a C2 to C3 alkenyl group, a C2 to C3 alkynyl group, a C3 to C5 cycloalkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group, a cyano group, a C1 to C3 alkoxy group and a C1 to C3 alkylthio group), a C6 to C7 bicycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group which may be substituted {the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group or a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a 5- to 6-membered heterocyclic group which may be substituted with 1 to 2 substituents which are the same or different {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may further contain 1 or 2 nitrogen atom(s), the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a nitro group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a phenoxy group which may be substituted (the substituent is a pyridazinyloxy group which is substituted by a fluorine atom, a chlorine atom, a bromine atom or a C1 to C3 alkoxy group) or a C1 to C3 alkylthio group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2—, —CH2CH2CH2—, —CH(CH3)CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded. 10. The compound, a salt thereof and an ester derivative thereof according to any of claims 1 to 8, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (the substituent is 1 to 3 fluorine atom(s), or a cyclopropyl group), a C3 to C4 cycloalkyl, group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C2 alkyl group, a cyclopropyl group and a C1 to C2 alkoxy group), a cyano group, a C2 to C3 alkoxycarbonyl group, a nitro group, a C1 to C3 alkoxy group or a trifluoromethoxy group, or R3, R4, R6 and R7 are a group represented by —CH2CH2CH2—, —CH(CH3)CH2CH2—, —OCH2CH2—, —OCH═CH— or which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom. 11. The compound, a salt thereof and an ester derivative thereof according to any of claims 1 to 8, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a chlorine atom and C1 to C2 alkyl group), a cyano group or a C1 to C2 alkoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2— or —OCH═CH—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom. 12. The compound, a salt thereof and an ester derivative thereof according to any of claims 1 to 8 or 13, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group which may be substituted (the substituent is two chlorine atoms) or a methoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom. 13. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein m and n are both 0. 14. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 fluorine atom(s), a cyclopropyl group, a C2 to C3 alkenyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a di(C1 to C3 alkyl)carbamoyl group, a phenyl group which may be substituted {the substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a furyl group, a thienyl group, a C1 to C3 alkoxy group, a phenoxy group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 fluorine atom(s), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group} or a substituted pyrazolyloxy group (the substituent is a benzoyl group which is substituted by two chlorine atoms and two C1 to C3 alkyl groups), R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a (C1 to C3 alkoxy)C1 to C3 alkyl group, a benzoyl group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a C2 to C4 alkoxycarbonyl group, a phenoxy group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group}, a phenylthio group which may be substituted with 1 to 2 substituents which are the same or different {the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group} or a tri(C1 to C3 alkyl)silyl group, R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C3 to C4 cycloalkyl group, a C1 to C3 alkylthio group or a C1 to C3 alkoxyimino group), a C2 to C3 alkenyl group, a C2 to C3 alkynyl group, a C3 to C5 cycloalkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group, a cyano group, a C1 to C3 alkoxy group and a C1 to C3 alkylthio group), a C6 to C7 bicycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group which may be substituted {the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group or a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a 5- to 6-membered heterocyclic group which may be substituted with 1 to 2 substituents which are the same or different {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may further contain 1 or 2 nitrogen atom(s), the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a nitro group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a phenoxy group which may be substituted (the substituent is a pyridazinyloxy group substituted by a fluorine atom, a chlorine atom, a bromine atom and C1 to C3 alkoxy group) or a C1 to C3 alkylthio group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2—, —CH2CH2CH2—, —CH(CH3)CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, or which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, and m and n are both 0. 15. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom, a bromine atom, a trifluoromethyl group or a cyano group, R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethoxycarbonyl group or a trimethylsilyl group, R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (the substituent is 1 to 3 fluorine atom(s), or a cyclopropyl group), a C3 to C4 cycloalkyl group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C2 alkyl group, a cyclopropyl group and a C1 to C2 alkoxy group), a cyano group, a C2 to C3 alkoxycarbonyl group, a nitro group, a C1 to C3 alkoxy group or a trifluoromethoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2—, —CH(CH3)CH2CH2—, —OCH2CH2—, —OCH═CH— or which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom, and m and n are both 0. 16. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom or a bromine atom, R2 is a hydrogen atom, R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a chlorine atom and C1 to C2 alkyl group), a cyano group or a C1 to C2 alkoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2— or —OCH═CH—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom, and m and n are both 0. 17. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein R1 is a chlorine atom, R2 is a hydrogen atom, R3, R4, R5 R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group which may be substituted (the substituents are two chlorine or a methoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2—, which is formed by two adjacent members of them R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom, and m and n are both 0. 18. The compound, a salt thereof and an ester derivative thereof according to claim 1, wherein the compound is selected from the group consisting of 6-chloro-3-(2-iodophenoxy)-4-pyridazinol, 6-chloro-3-(2-methylphenoxy)-4-pyridazinol, 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol, 6-chloro-3-(2,3-dihydro-1H-inden-4-yloxy)-4-pyridazinol, 3-(1-benzofuran-7-yloxy)-6-chloro-4-pyridazinol, 6-chloro-3-(2-methoxy-5-methylphenoxy)-4-pyridazinol, 6-chloro-3-(2-chloro-6-cyclopropylphenoxy)-4-pyridazinol, 3-(2-bromo-6-methylphenoxy)-6-chloro-4-pyridazinol, 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol and 6-chloro-3-(2-cyclopropyl-3,5-dimethylphenoxy)-4-pyridazinol. 19. An agricultural chemical composition which comprises the compound, a salt thereof and an ester derivative thereof according to claim 1 as an effective ingredient in combination with a carrier. 20. A herbicidal composition which comprises (i) at least one 3-phenoxy-4-pyridazinol compound selected from the group consisting of the compound, a salt thereof and an ester derivative thereof according to claim 1, and (ii) at least one herbicidally active compound selected from the group consisting of 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-pyrazolyl-p-toluenesulfonate, 2-[4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazol-5-yloxy]acetophenone, 2-[4-(2,4-dichloro-m-toluoyl)-1,3-dimethylpyrazol-5-yloxy]-4′-methylacetophenone, 5-cyclopropyl-1,2-oxazol-4-yl α-α-α-trifluoro-2-mesyl-p-tolyl ketone, 2-(2-chloro-4-mesylbenzoyl)cyclohexan-1,3-dione, 2-(4-mesyl-2-nitrobenzoyl)cyclohexan-1,3-dione and 4-chloro-2-(methylsulfonyl)phenyl 5-cyclopropyl-4-isoxazolyl ketone, as effective ingredients. 21. The herbicidal composition according to claim 20, wherein the herbicidally active compound is 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-pyrazolyl-p-toluenesulfonate. 22. 2-Cyclopropyl-6 methylphenol. 23. The compound, a salt thereof and an ester derivative thereof according to claim 13, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C3 to C4 cycloalkyl group, a C1 to C3 alkylthio group or a C1 to C3 alkoxyimino group), a C2 to C3 alkenyl group, a C2 to C3 alkynyl group, a C3 to C5 cycloalkyl group which may be substituted with 1 to 3 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group, a cyano group, a C1 to C3 alkoxy group and a C1 to C3 alkylthio group), a C6 to C7 bicycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group which may be substituted {the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group or a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a 5- to 6-membered heterocyclic group which may be substituted with 1 to 2 substituents which are the same or different {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may further contain 1 or 2 nitrogen atom(s), the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and a C1 to C3 haloalkyl group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom)}, a nitro group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group having 1 to 3 halogen atoms which are the same or different (the halogen atom is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a phenoxy group which may be substituted (the substituent is a pyridazinyloxy group which is substituted by a fluorine atom, a chlorine atom, a bromine atom and a C1 to C3 alkoxy group) or a C1 to C3 alkylthio group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2—, —CH2CH2CH2—, —CH(CH3)CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded. 24. The compound, a salt thereof and an ester derivative thereof according to claim 13, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (the substituent is 1 to 3 fluorine atom(s), or a cyclopropyl group), a C3 to C4 cycloalkyl group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C2 alkyl group, a cyclopropyl group and a C1 to C2 alkoxy group), a cyano group, a C2 to C3 alkoxycarbonyl group, a nitro group, a C1 to C3 alkoxy group or a trifluoromethoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2—, —CH (CH3) CH2CH2—, —OCH2CH2—, —OCH═CH— or which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom. 25. The compound, a salt thereof and an ester derivative thereof according to claim 13, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group which may be substituted with 1 to 2 substituents which are the same or different (the substituent is selected from the group consisting of a chlorine atom and C1 to C2 alkyl group), a cyano group or a C1 to C2 alkoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2— or —OCH═CH—, which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom. 26. The compound, a salt thereof and an ester derivative thereof according to claim 13, wherein R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group which may be substituted (the substituent is two chlorine atoms) or a methoxy group, or R3, R4, R5, R6 and R7 are a group represented by —CH2CH2CH2— which is formed by two adjacent members of R3, R4, R5, R6 and R7 with carbon atoms to which respective substituents are bonded, provided that R3 is not a hydrogen atom.

TECHNICAL FIELD The present invention relates to a 3-phenoxy-4-pyridazinol compound, its salt, its ester derivative and agricultural chemical containing the same as an effective ingredient, and a herbicidal composition containing 3-phenoxy-4-pyridazinol compound and a second herbicidally active compound as effective ingredients. BACKGROUND ART In Chemical Pharmaceutical Bulletin, 1972, vol. 20, No. 10, pp. 2191-2203, 3-(2-allylphenoxy)-6-chloro-4-methoxypyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed, and there is no description about a herbicide. In Journal of the Chemical Society: Perkin Transaction I, 1975, No. 6, pp. 534-538, 3-(2-hydroxyphenoxy)-4-methoxypyridazine and 6-chloro-3-(2-hydroxyphenoxy)-4-methoxypyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed, and there is no description about a herbicide. In U.S. Pat. No. 5,559,080, a 3-(phenoxy which may be substituted)pyridazine compound having a haloalkylphenoxy group at the 4-position of the pyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed. Also, in the 3-(phenoxy which may be substituted)pyridazine compound having a haloalkylphenoxy group at the 4-position of the pyridazine, an oxygen atom bonded to the 4-position of the pyridazine is bonded by a benzene ring, and its herbicidal activity was insufficient. Also, at present, a number of herbicides have been practically used as a herbicide for a paddy field, and widely been used for general purpose as a single agent and a mixed agent. However, there are many kinds of paddy field weeds, and germination and growth period of the respective weeds are not uniform, in particular, occurrence of perennial weeds ranges for a long period of time. Thus, it is extremely difficult to prevent from and kill all weeds with one time spread of a herbicide. Accordingly, as a herbicide, an appearance of a chemical which can kill many kinds of weeds including annual weeds and perennial weeds, that is, which has a wide weed-killing spectrum, is effective for already grown weeds, preventing and killing effects of weeds of which can be maintained for a certain period of time, and has high safety to paddy rice has earnestly been desired. Also, as upland herbicides, a number of herbicides have now been commercially available and practically used, but there are many kinds of weeds to be prevented, and occurrence thereof ranges for a long period of time, so that a herbicide which has higher herbicidal effects, has broad weed-killing spectrum, and causes no chemical damage to crops has been desired. One of the effective ingredient of the herbicidal composition of the present invention (hereinafter referred to as a second herbicidally active compound), 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-pyrazolyl-p-toluenesulfonate [hereinafter referred to as Compound A. General name: Pyrazolate], 2-[4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazol-5-yloxy]acetophenone [hereinafter referred to as Compound B. General name: Pyrazoxyfen], 2-[4-(2,4-dichloro-m-toluoyl)-1,3-dimethylpyrazol-5-yloxy]-4′-methylacetophenone (hereinafter referred to as Compound C. General name: Benzofenap], 5-cyclopropyl-1,2-oxazol-4-yl α,α,α-trifluoro-2-mesyl-p-tolyl ketone [hereinafter referred to as Compound D. General name: Isoxaflutole], 2-(2-chloro-4-mesylbenzoyl)cyclohexan-1,3-dione [hereinafter referred to as Compound E. General name: sulcotrione], 2-(4-mesyl-2-nitrobenzoyl)cyclohexan-1,3-dione [hereinafter referred to as Compound F. General name: mesotrion] and 4-chloro-2-(methylsulfonyl)phenyl 5-cyclopropyl-4-isoxazolyl ketone [hereinafter referred to as Compound G. General name: Isoxachlortole] are each conventionally known herbicidal compound, and each described in The Pesticide Manual 11th Edition, pp. 1049 to 1050, Ibid. pp. 1054 to 1055, Ibid. pp. 111 to 112, The Pesticide Manual, 12th Edition p. 563, Ibid. p. 848, Ibid. p. 602 and EP 470 856(1990). These compounds have high effects against annual broad-leaved weeds and a part of perennial weeds, but their effects against rice plant weeds or a part of perennial weeds are not necessarily sufficient. DISCLOSURE OF THE INVENTION The present inventors have earnestly studied about pyridazine derivatives having a phenoxy group at the 3-position thereof, and as a result, they have found that a compound having a hydroxyl group at the 4-position of the pyridazine ring shows substantially no chemical damage against paddy rice, and shows excellent herbicidal activity against a wide range of weeds in a paddy fied with a low dosage to accomplish the present invention. Moreover, they have found that similar herbicidal activities are possessed by an ester derivative thereof in which a bonding between an oxygen atom at the 4-position of the pyridazine ring and an acyl group is cleaved in a soil or in a plant body to be converted into a compound in which a hydrogen atom binds to the oxygen atom, whereby accomplished the present invention. Also, the present inventors have continued to search on a herbicide which can completely prevent and remove various kinds of weeds with one time spread, has extremely high safety to paddy rice or upland crops, and has extremely low toxicity against humans and animals for the purpose of overcoming the above-mentioned problems involved in the conventional herbicides such as second herbicidally active compounds A, B, C, D, E, F and G, and as a result, they have found that by formulating the above-mentioned 3-phenoxy-4-pyridazinol derivatives and the second herbicidally active compound as effective ingredients, a weed-killing spectrum can be enlarged, and serious weeds can be prevented and killed with a smaller amount of effective ingredients by their synergistic action, whereby accomplished the present invention. The present invention relates to a compound represented by the formula: [wherein R1 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a C3 to C6 cycloalkyl group, a C2 to C6 alkenyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a di(C1 to C6 alkyl)carbamoyl group, a phenyl group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a 5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s).), a C1 to C6 alkoxy group, a phenoxy group which may be substituted (The substituent is a substituent selected from the following substituent Group A.) or a 5- or 6-membered heterocycloxy group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is a substituent(s) selected from the group consisting of a benzoyl group which may be substituted (The substituent is a substituent selected from the following substituent Group A.) and a C1 to C6 alkyl group.}, R2 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a (C1 to C6 alkoxy)C1 to C6 alkyl group, a benzoyl group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a C2 to C7 alkoxycarbonyl group, a phenoxy group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a phenylthio group which may be substituted (The substituent is a substituent selected from the following substituent Group A.) or a tri(C1 to C6 alkyl)silyl group, R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a halogen atom, a C1 to C6 alkyl group which may be substituted (The substituent is a substituent selected from the following substituent Group B.), a C2 to C6 alkenyl group which may be substituted (The substituent is a cyano group or a nitro group.), a C2 to C6 alkynyl group, a C3 to C6 cycloalkyl group which may be substituted (The substituent is a substituent selected from the following substituent Group C.), a C4 to C10 bicycloalkyl group, a cyano group, a formyl group, a C2 to C7 alkylcarbonyl group, a benzoyl group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a carboxyl group, a C2 to C7 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C6 alkyl)-carbamoyl group, a phenyl group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a 3- to 6-membered heterocyclic group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s), or may be fused with a benzene ring. The substituent is a substituent selected from the following substituent Group E.), an amino group which may be substituted (The substituent is a substituent selected from the following substituent Group D.), a nitro group, a hydroxyl group, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a (C1 to C6 alkoxy)C1 to C6 alkoxy group, a phenoxy group which may be substituted (The substituent is a hydroxyl group or a pyridazinyloxy group substituted by a substituent(s) selected from the group consisting of a halogen atom and a C1 to C6 alkoxy group.), a 5- to 6-membered heterocycloxy group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is a substituent selected from the following substituent Group E.), a phenylsulfonyloxy group which may be substituted (The substituent is a substituent selected from the following substituent Group A.), a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group or a tri(C1 to C6 alkyl)silyl group, or R3, R4, R5, R6 and R7 may form a 3- to 6-membered cyclic hydrocarbon group which may be substituted, which is formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded (the cyclic hydrocarbon may be interrupted by the same or different 1 to 2 hetero atom(s) selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The substituent is a halogen atom, a C1 to C6 alkyl group, a hydroxy-C1 to C6 alkyl group, a C1 to C6 alkoxy group, an oxo group, a hydroxyimino group or a C1 to C6 alkoxyimino group, and when the C1 to C6 alkyl group is substituted, it may form another 3-membered ring by combining, with the other C1 to C6 alkyl group or a carbon atom(s) in the cyclic hydrocarbon.), m and n each independently represent 0 or 1, the substituent Group A is a group selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a C3 to C6 cycloalkyl group, a cyano group and a tri(C1 to C6 alkyl)silyl group, the substituent Group B is a group selected from the group consisting of a halogen atom, a C3 to C6 cycloalkyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a phenyl group, a C1 to C6 alkoxy group, a C1 to C6 alkylthio group, a C1 to C6 alkylsulfinyl group, a C1 to C6 alkylsulfonyl group, a C1 to C4 alkylenedioxy group, a hydroxyimino group and a C1 to C6 alkoxyimino group, the substituent Group C is a group selected from the group consisting of a halogen atom, a C1 to C6 alkyl group which may be substituted (The substituent is a substituent selected from the above-mentioned substituent Group B.), a C3 to C6 cycloalkyl group, a C2 to C6 alkenyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a benzoyl group, a carboxyl group, a C2 to C7 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C6 alkyl)carbamoyl group, a phenyl group which may be substituted (The substituent is a substituent selected from the above-mentioned substituent Group A.), a 5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s).), an amino group which may be substituted (The substituent is a substituent selected from the following substituent Group D.), a nitro group, a hydroxyl group, a C1 to C6 alkoxy group, a C1 to C6 haloalkoxy group, a phenoxy group, a C1 to C6 alkylthio group, a phenylthio group, a C1 to C6 alkylsulfinyl group and a C1 to C6 alkylsulfonyl group, the substituent Group D is a group selected from the group consisting of a C1 to C6 alkyl group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a di(C1 to C6 alkyl)carbamoyl group and a C1 to C6 alkylsulfonyl group, the substituent Group E is a group selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C6 haloalkyl group, a hydroxyl group, a phenylsulfonyl group which may be substituted (The substituent is a substituent selected from the above-mentioned substituent Group A.) and a di(C1 to C6 alkyl)sulfamoyl group.], its salt or its ester derivative, an agricultural chemical containing the same as an effective ingredient, and, a herbicidal composition containing one or more 3-phenoxy-4-pyridazinol derivatives selected from the group consisting of the above-mentioned compounds, their salt and their ester derivatives, and one or more second herbicidally active compound selected from the group consisting of 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-pyrazolyl-p-toluenesulfonate, 2-[4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazol-5-yloxy]acetophenone, 2-[4-(2,4-dichloro-m-toluoyl)-1,3-dimethylpyrazol-5-yloxy]-4′-methylacetophenone, 5-cyclopropyl-1,2-oxazol-4-yl α,α,α-trifluoro-2-mesyl-p-tolyl ketone, 2-(2-chloro-4-mesylbenzoyl)cyclohexan-1,3-dione, 2-(4-mesyl-2-nitrobenzoyl)cyclohexan-1,3-dione and 4-chloro-2-(methylsulfonyl)phenyl 5-cyclopropyl-4-isoxazolyl ketone as effective ingredients. In the present invention, “a halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a chlorine atom or a bromine atom, still further preferablya chlorine atom. In the present invention, the “C1 to C6 alkyl group” is a straight or branched alkyl group having 1 to 6 carbon atoms, for example, it may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably a straight or branched alkyl group having 1 to 4 carbon atoms (a C1 to C4 alkyl group), more preferably a straight or branched alkyl group having 1 to 3 carbon atoms (a C1 to C3 alkyl group), still further preferablyan alkyl group having 1 to 2 carbon atoms (a C1 to C2 alkyl group), particularly preferably a methyl group. In the present invention, the “C1 to C6 haloalkyl group” is the “C1 to C6 alkyl group” to which the same or different above-mentioned 1 to 5 “a halogen atom(s)” is/are substituted, and for example, it may be chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 4-chlorobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, fluorochloromethyl, bromomethyl, 1-bromoethyl, 2-bromoethyl or iodomethyl group, preferably a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, more preferably a C1 to C2 alkyl group substituted by the same 1 to 3 fluorine atom(s) or chlorine atom(s), still further preferably a fluoromethyl, difluoromethyl, trifluoromethyl or 2,2,2-trichloroethyl group, particularly preferably a trifluoromethyl group. In the present invention, the “C3 to C6 cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, preferably cyclopropyl or cyclobutyl group, more preferably cyclopropyl group. In the present invention, the “C2 to C6 alkenyl group” is a straight or branched alkenyl group having 2 to 6 carbon atoms, for example, it may be vinyl, 1-methylvinyl, 1-propenyl, 1-methyl-1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl group, preferably a straight or branched alkenyl group having 2 to 4 carbon atoms (a C2 to C4 alkenyl group), more preferably a vinyl, 1-methylvinyl, 2-propenyl or 1-methyl-2-propenyl group. In the present invention, the “C2 to C7 alkylcarbonyl group” is a carbonyl group to which the above-mentioned “C1 to C6 alkyl group” is bonded, and for example, it may be an acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl or heptanoyl group, preferably a carbonyl group to which a straight or branched alkyl group having 1 to 4 carbon atoms is bonded (a C2 to C5 alkylcarbonyl group), still further preferably a carbonyl group to which a straight or branched alkyl group having 1 to 3 carbon atoms is bonded (a C2 to C4 alkylcarbonyl group), particularly preferably an acetyl, propionyl, valeryl or pivaloyl group, most preferably an acetyl group. In the present invention, the “di(C1 to C6 alkyl)-carbamoyl group” is a carbamoyl group in which the same or different two above-mentioned “C1 to C6 alkyl groups” are bonded to a nitrogen atom, and for example, it may be a dimethylcarbamoyl, methylethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl or dihexylcarbamoyl group, preferably a carbamoyl group in which the same two straight or branched alkyl groups having 1 to 3 carbon atoms are bonded {a di(C1 to C3 alkyl)carbamoyl group}, more preferably a dimethylcarbamoyl group or a diethylcarbamoyl group, still further preferably a dimethylcarbamoyl group. In the present invention, the “tri(C1 to C6 alkyl)-silyl group” is a silicon atom to which the same or different three above-mentioned “C1 to C6 alkyl groups” are bonded, and for example, it may be a trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl or trihexylsilyl group, preferably a silicon atom to which the same or different three straight or branched alkyl groups having 1 to 3 carbon atoms are bonded {a tri(C1 to C3 alkyl)silyl group}, more preferably a trimethylsilyl or dimethylisopropylsilyl group, still further preferably a trimethylsilyl group. In the present invention, “a phenyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a phenyl group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)-silyl group”, and for example, it may be a phenyl, fluorophenyl, difluorophenyl, trifluorophenyl, chlorophenyl, dichlorophenyl, trichlorophenyl, fluorochlorophenyl, methylphenyl, dimethylphenyl, trimethylphenyl, tetramethylphenyl, pentamethylphenyl, ethylphenyl, fluoro(methyl)phenyl, chloro(methyl)phenyl, bromo(methyl)phenyl, cyclopropylphenyl, cyclopropyl(fluoro)phenyl, chloro(cyclopropyl)phenyl, cyclopropyl(methyl)phenyl, (trifluoromethyl)phenyl or fluoro(trifluoromethyl)phenyl group, preferably a phenyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a phenyl, chlorophenyl, methylphenyl, trifluorophenyl or cyanophenyl group. In the present invention, the “5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s).)” is a 5- to 6-membered heterocyclic group which contains one nitrogen atom, oxygen atom or sulfur atom as a hetero atom and may further contain 1 to 2 nitrogen atom(s), and for example, it may be a furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyranyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl group, preferably a 5-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring.), more preferably a furyl or thienyl group. In the present invention, the “C1 to C6 alkoxy group” is a straight or branched alkoxy group having 1 to 6 carbon atoms, and for example, it may be a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, 1-ethylpropoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy or 2-ethylbutoxy group, preferably a straight or branched alkoxy group having 1 to 3 carbon atoms (a C1 to C3 alkoxy group), more preferably a methoxy or ethoxy group, still further preferably a methoxy group. In the present invention, the “phenoxy group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a phenoxy group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)-silyl group”, and for example, it may be a phenoxy, fluorophenoxy, difluorophenoxy, trifluorophenoxy, chlorophenoxy, dichlorophenoxy, trichlorophenoxy, fluorochlorophenoxy, methylphenoxy, dimethylphenoxy, trimethylphenoxy, tetramethylphenoxy, pentamethylphenoxy, ethylphenoxy, fluoro(methyl)phenoxy, chloro(methyl)phenoxy, bromo(methyl)phenoxy, cyclopropylphenoxy, cyclopropyl(fluoro)phenoxy, chloro(cyclopropyl)phenoxy, cyclopropyl(methyl)phenoxy, (trifluoromethyl)phenoxy or fluoro(trifluoromethyl)phenoxy group, preferably a phenoxy group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a phenoxy, chlorophenoxy, methylphenoxy, trifluorophenoxy or cyanophenoxy group. In the present invention, “a benzoyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a benzoyl group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)silyl group”, and for example, it may be a benzoyl, fluorobenzoyl, difluorobenzoyl, trifluorobenzoyl, chlorobenzoyl, dichlorobenzoyl, trichlorobenzoyl, fluorochlorobenzoyl, methylbenzoyl, dimethylbenzoyl, trimethylbenzoyl, tetramethylbenzoyl, pentamethylbenzoyl, ethylbenzoyl, fluoro(methyl)benzoyl, chloro(methyl)benzoyl, bromo(methyl)benzoyl, cyclopropylbenzoyl, cyclopropyl(fluoro)benzoyl, chloro(cyclopropyl)benzoyl, cyclopropyl(methyl)benzoyl, (trifluoromethyl)benzoyl or fluoro(trifluoromethyl)benzoyl group, preferably a benzoyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a benzoyl, chlorobenzoyl, dichlorobenzoyl, methylbenzoyl, trifluorobenzoyl or cyanobenzoyl group. In the present invention, “the 5- or 6-membered heterocycloxy group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent may be substituted by a substituent(s) selected from the group consisting of a benzoyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.) and a C1 to C6 alkyl group.}” is “a 5- to 6-membered heterocycloxy group which contains one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and may contain further 1 or 2 nitrogen atom(s)” which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of the above-mentioned “a benzoyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” and the above-mentioned “C1 to C6 alkyl group”, preferably a benzoyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, and “a 5-membered heterocycloxy group which contains one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and which may contain further one nitrogen atom” substituted by the same two C1 to C3 alkyl groups, more preferably a benzoyl group substituted by two chlorine atoms and a pyrazolyloxy group substituted by two C1 to C2 alkyl groups. In the present invention, “the (C1 to C6 alkoxy)-C1 to C6 alkyl group” is the above-mentioned “C1 to C6 alkyl group” substituted by one of the above-mentioned “C1 to C6 alkoxy groups”, and for example, it may be a methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl or methoxyhexyl group, preferably a C1 to C6 alkyl group substituted by one C1 to C3 alkoxy group, more preferably a methoxyethyl, ethoxyethyl or ethoxymethyl group. In the present invention, “C2 to C7 alkoxycarbonyl group” is a carbonyl group to which the above-mentioned “C1 to C6 alkoxy group” is bonded, and for example, it may be a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, 1-ethylpropoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 1-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl or 2-ethylbutoxycarbonyl group, preferably a carbonyl group to which a C1 to C3 alkoxy group is bonded (a C2 to C4 alkoxycarbonyl group), more preferably a methoxycarbonyl or ethoxycarbonyl group, still further preferably a methoxycarbonyl group. In the present invention, “the phenylthio group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a phenylthio group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)silyl group”, and for example, it may beta phenylthio, fluorophenylthio, difluorophenylthio, trifluorophenylthio, chlorophenylthio, dichlorophenylthio, trichlorophenylthio, fluorochlorophenylthio, methylphenylthio, dimethylphenylthio, trimethylphenylthio, tetramethylphenylthio, pentamethylphenylthio, ethylphenylthio, fluoro(methyl)phenylthio, chloro(methyl)phenylthio, bromo(methyl)phenylthio, cyclopropylphenylthio, cyclopropyl(fluoro)phenylthio, chloro(cyclopropyl)phenylthio, cyclopropyl(methyl)phenylthio, (trifluoromethyl)phenylthio or fluoro(trifluoromethyl)phenylthio group, preferably a phenylthio group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group which is substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a phenylthio, chlorophenylthio, methylphenylthio, trifluorophenylthio or cyanophenylthio group. In the present invention, “the C1 to C6 alkylthio group” is a straight or branched alkylthio group having 1 to 6 carbon atoms, and for example, it may be a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, t-butylthio, pentylthio, isopentylthio, 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio or 2-ethylbutylthio group, preferably a straight or branched alkylthio group having 1 to 3 carbon atoms (a C1 to C3 alkylthio group), more preferably a methylthio or ethylthio group, still further preferably a methylthio group. In the present invention, “the C1 to C6 alkylsulfinyl group” is a straight or branched alkylsulfinyl group having 1 to 6 carbon atoms, and for example, it may be a methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, 2-methylbutylsulfinyl, neopentylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl or 2-ethylbutylsulfinyl group, preferably a straight or branched alkylsulfinyl group having 1 to 3 carbon atoms (a C1 to C3 alkylsulfinyl group), more preferably a methylsulfinyl or ethylsulfinyl group, still further preferably a methylsulfinyl group. In the present invention, “the C1 to C6 alkylsulfonyl group” is a straight or branched alkylsulfonyl group having 1 to 6 carbon atoms, and for example, it may be a methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl or 2-ethylbutylsulfonyl group, preferably a straight or branched alkylsulfonyl group having 1 to 3 carbon atoms (a C1 to C3 alkylsulfonyl group), more preferably a methylsulfonyl or ethylsulfonyl group, still further preferably a methylsulfonyl group. In the present invention, “the C1 to C4 alkylenedioxy group” is a straight or branched alkylenedioxy group having 1 to 4 carbon atoms, and for example, it may be a methylenedioxy, ethylenedioxy, propylenedioxy, trimethylenedioxy or tetramethylenedioxy group, preferably an alkylenedioxy group having 1 to 2 carbon atoms, more preferably a 1,2-ethylenedioxy group. In the present invention, “the C1 to C6 alkoxyimino group” is a straight or branched alkoxyimino group having 1 to 6 carbon atoms, and for example, it may be a methoxyimino, ethoxyimino, propoxyimino, isopropoxyimino, butoxyimino, isobutoxyimino, s-butoxyimino, t-butoxyimino, pentoxyimino, isopentoxyimino, 2-methylbutoxyimino, neopentoxyimino, 1-ethylpropoxyimino, hexyloxyimino, 4-methylpentoxyimino, 3-methylpentoxyimino, 2-methylpentoxyimino, 1-methylpentoxyimino, 3,3-dimethylbutoxyimino, 2,2-dimethylbutoxyimino, 1,1-dimethylbutoxyimino, 1,2-dimethylbutoxyimino, 1,3-dimethylbutoxyimino, 2,3-dimethylbutoxyimino or 2-ethylbutoxyimino group, preferably a straight or branched alkoxyimino group having 1 to 3 carbon atoms (a C1 to C3 alkoxyimino group), more preferably a methoxyimino or ethoxyimino group, still further preferably a methoxyimino group. In the present invention, “the C1 to C6 alkyl group which may be substituted (The substituent is a substituent selected from the substituent Group B.)” is the above-mentioned “C1 to C6 alkyl group” which may be substituted by the above-mentioned “a halogen atom”, or by the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group, the above-mentioned “C2 to C7 alkylcarbonyl group”, the above-mentioned “C2 to C7 alkoxycarbonyl group”, a phenyl group, the above-mentioned “C1 to C6 alkoxy group”, the above-mentioned “C1 to C6 alkylthio group”, the above-mentioned “C1 to C6 alkylsulfinyl group”, the above-mentioned “C1 to C6 alkylsulfonyl group”, the above-mentioned “C1 to C4 alkylenedioxy group”, a hydroxyimino group or the above-mentioned “C1 to C6 alkoxyimino group”, and for example, it may be a fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, cyclopropylmethyl, cyanomethyl, acetylmethyl, acetylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, benzyl, methoxmethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methylthiomethyl, methylthioethyl, ethylthiomethyl, ethylthioethyl, methylsulfinylmethyl, methylsulfonylmethyl, 2-(1,3-dioxolanyl), hydroxyiminomethyl or methoxyiminomethyl group, preferably a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C1 to C3 alkyl group which may be substituted by a C3 to C4 cycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group, a C1 to C3 alkoxy group, a C1 to C3 alkylthio group, a C1 to C3 alkylsulfinyl group, a C1 to C3 alkylsulfonyl group, a C1 to C2 alkylenedioxy group, a hydroxyimino group or a C1 to C3 alkoxyimino group, more preferably a C1 to C2 alkyl group substituted by the same 1 to 3 fluorine atom(s) or chlorine atom(s), or a C1 to C2 alkyl group which may be substituted by a cyclopropyl group, a cyano group, a C2 to C3 alkylcarbonyl group, a C2 to C3 alkoxycarbonyl group, a phenyl group, a C1 to C2 alkoxy group, a C1 to C2 alkylthio group, a C1 to C2 alkylsulfinyl group, a C1 to C2 alkylsulfonyl group, an ethylenedioxy group, a hydroxyimino group or a C1 to C2 alkoxyimino group. In the present invention, “the substituted C2 to C6 alkenyl group (The substituent is a cyano group or a nitro group.) ” is the above-mentioned “C2 to C6 alkenyl group” substituted by a cyano group or a nitro group, preferably a C2 to C3 alkenyl group substituted by a cyano group or a nitro group, more preferably a cyanovinyl or nitrovinyl group. In the present invention, “the C2 to C6 alkynyl group” is a straight or branched alkynyl group having 2 to 6 carbon atoms, and for example, it may be ethynyl, 2-propynyl, 1-methyl-2-propynyl, 1-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 1-ethyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, preferably a straight or branched alkynyl group having 3 to 4 carbon atoms (a C3 to C4 alkynyl group), more preferably an ethynyl, 1-propynyl or 2-propynyl group. In the present invention, “the amino group which may be substituted (The substituent is a substituent selected from the substituent Group D.)” is an amino group which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C2 to C7 alkylcarbonyl group”, the above-mentioned “C2 to C7 alkoxycarbonyl group”, the above-mentioned “di(C1 to C6 alkyl)carbamoyl group” and the above-mentioned “C1 to C6 alkylsulfonyl group”, and for example, it may be an amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, isopentylamino, (2-methylbutyl)amino, neopentylamino, (1-ethylpropyl)amino, hexylamino, (4-methylpentyl)amino, (3-methylpentyl)amino, (2-methylpentyl)amino, (1-methylpentyl)amino, (3,3-dimethylbutyl)amino, (2,2-dimethylbutyl)amino, (1,1-dimethylbutyl)amino, (1,2-dimethylbutyl)amino, (1,3-dimethylbutyl)amino, (2,3-dimethylbutyl)amino, (2-ethylbutyl)amino, dimethylamino, (methyl)(ethyl)amino, diethylamino, dipropylamino, (methyl)(isopropyl)amino, di(isopropyl)amino, dibutylamino, di(isobutyl)amino, di(s-butyl)amino, di(t-butyl)amino, dipentylamino, diisopentylamino, di(2-methylbutyl)amino, dineopentylamino, di(1-ethylpropyl)amino, dihexylamino, di(4-methylpentyl)amino, di(3-methylpentyl)amino, di(2-methylpentyl)amino, di(1-methylpentyl)amino, di(3,3-dimethylbutyl)amino, di(2,2-dimethylbutyl)amino, di(1,1-dimethylbutyl)amino, di(1,2-dimethylbutyl)amino, di(1,3-dimethylbutyl)amino, di(2,3-dimethylbutyl)amino, di(2-ethylbutyl)amino, acetylamino, propionylamino, butanoylamino, (2-methylpropanoyl)amino, pentanoylamino, (2,2-dimethylpropanoyl)amino, (2,2-dimethylpentanoyl)amino, (2-methylbutanoyl)amino, (3-methylbutanoyl)amino, hexanoylamino, heptanoyl amino, (3,3-dimethylbutanoyl)amino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, s-butoxycarbonylamino, t-butoxycarbonylamino, pentoxycarbonylamino, isopentoxycarbonylamino, (2-methylbutoxycarbonyl)amino, neopentoxycarbonylamino, (1-ethylpropoxycarbonyl)amino, hexyloxycarbonylamino, (4-methylpentoxycarbonyl)amino, (3-methylpentoxycarbonyl)amino, (2-methylpentoxycarbonyl)amino, (1-methylpentoxycarbonyl)amino, (3,3-dimethylbutoxycarbonyl)amino, (2,2-dimethylbutoxycarbonyl)amino, (1,1-dimethylbutoxycarbonyl)amino, (1,2-dimethylbutoxycarbonyl)amino, (1,3-dimethylbutoxycarbonyl)amino, (2,3-dimethylbutoxycarbonyl)amino, (2-ethylbutoxycarbonyl)amino, dimethylcarbamoylamino, (methylethylcarbamoyl)amino, diethylcarbamoylamino, dipropylcarbamoylamino, dibutylcarbamoylamino, dihexylcarbamoylamino, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, t-butylsulfonylamino or hexylsulfonylamino, preferably an amino group which may be substituted by the same or different 1 to 2 C1 to C3 alkyl groups, or a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a di(C1 to C3 alkyl)carbamoyl group or a C1 to C3 alkylsulfonyl group, more preferably an methylamino, ethylamino, dimethylamino, diethylamino, acetylamino, propionylamino, (2-methylpropanoyl)amino, (2,2-dimethylpropanoyl)amino, methoxycarbonylamino, ethoxycarbonylamino, dimethylcarbamoylamino, diethylcarbamoylamino, methylsulfonylamino or ethylsulfonylamino group. In the present invention, “the C1 to C6 haloalkoxy group” is the above-mentioned “C1 to C6 alkoxy group” substituted by the same or different 1 to 5 above-mentioned “halogen atoms”, and for example, it may be a chloromethoxy, dichloromethoxy, trichloromethoxy, 1-chloroethoxy, 2-chloroethoxy, 2,2,2-trichloroethoxy, 1-chloropropoxy, 3-chloropropoxy, 1-chlorobutoxy, 4-chlorobutoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, fluorochloromethoxy, bromomethoxy, 1-bromoethoxy, 2-bromoethoxy or iodomethoxy group, preferably a C1 to C3 alkoxy group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, more preferably a C1 to C2 alkoxy group substituted by the same 1 to 3 fluorine atom(s) or chlorine atom(s), still further preferably a fluoromethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trichloroethoxy group, particularly preferably a trifluoromethoxy group. In the present invention, “the substituted C3 to C6 cycloalkyl group (The substituent is a substituent selected from the substituent Group C.)” is the above-mentioned “C3 to C6 cycloalkyl group” substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group which may be substituted (The substituent is a substituent selected from the substituent Group B.)”, the above-mentioned “C3 to C6 cycloalkyl group”, the above-mentioned “C2 to C6 alkenyl group”, a cyano group, the above-mentioned “C2 to C7 alkylcarbonyl group”, a benzoyl group, a carboxyl group, the above-mentioned “C2 to C7 alkoxycarbonyl group”, a carbamoyl group, the above-mentioned “di(C1 to C6 alkyl)carbamoyl group”, the above-mentioned “phenyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)”, the above-mentioned “5 or 6-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s).)”, the above-mentioned “amino group which may be substituted (The substituent is a substituent selected from the substituent Group D.)”, a nitro group, a hydroxyl group, the above-mentioned “C1 to C6 alkoxy group”, the above-mentioned “C1 to C6 haloalkoxy group”, a phenoxy group, the above-mentioned “C1 to C6 alkylthio group”, a phenylthio group, the above-mentioned “C1 to C6 alkylsulfinyl group” and the above-mentioned “C1 to C6 alkylsulfonyl group”, and for example, it may be a fluorocyclopropyl, difluorocyclopropyl, chlorocyclopropyl, dichlorocyclopropyl, bromocyclopropyl, dibromocyclopropyl, iodocyclopropyl, methylcyclopropyl, ethylcyclopropyl, propylcyclopropyl, isopropylcyclopropyl, butylcyclopropyl, t-butylcyclopropyl, hexylcyclopropyl, cyclopropylcyclopropyl, cyclobutylcyclopropyl, cyclopentylcyclopropyl, (fluoromethyl)cyclopropyl, (chloromethyl)cyclopropyl, (bromomethyl)cyclopropyl, (difluoromethyl)cyclopropyl, (trifluoromethyl)cyclopropyl, (trichloromethyl)cyclopropyl, (2,2,2-trifluoroethyl)cyclopropyl, (2,2,2-trichloroethyl)cyclopropyl, vinylcyclopropyl, (methoxymethyl)cyclopropyl, (ethoxymethyl)cyclopropyl, (isopropoxymethyl)cyclopropyl, (methylthiomethyl)cyclopropyl, (ethylthiomethyl)cyclopropyl, (isopropylthiomethyl)cyclopropyl, (methylsulfinylmethyl)cyclopropyl, (ethylsulfinylmethyl)cyclopropyl, (methylsulfonylmethyl)cyclopropyl, (ethylsulfonylmethyl)cyclopropyl, cyanocyclopropyl, (1-methoxyiminoethyl)cyclopropyl, acetylcyclopropyl, propionylcyclopropyl, benzoylcyclopropyl, carboxylcyclopropyl, methoxycarbonylcyclopropyl, ethoxycarbonylcyclopropyl, carbamoylcyclopropyl, (dimethylcarbamoyl)cyclopropyl, (diethylcarbamoyl)cyclopropyl, phenylcyclopropyl, (fluorophenyl)cyclopropyl, (chlorophenyl)cyclopropyl, tolylcyclopropyl, furylcyclo-7 propyl, thienylcyclopropyl, pyridylcyclopropyl, aminocyclopropyl, (methylamino)cyclopropyl, (dimethylamino)cyclopropyl, (acetylamino)cyclopropyl, (methoxycarbonylamino)cyclopropyl, (3,3-dimethylureido)cyclopropyl, (methylsulfonylamino)cyclopropyl, nitrocyclopropyl, hydroxycyclopropyl, methoxycyclopropyl, ethoxycyclopropyl, (trifluoromethoxy)cyclopropyl, phenoxycyclopropyl, methylthiocyclopropyl, ethylthiocyclopropyl, phenylthiocyclopropyl, methylsulfinylcyclopropyl, ethylsulfinylcyclopropyl, methylsulfonylcyclopropyl, ethylsulfonylcyclopropyl, dimethylcyclopropyl, methyl(ethyl)cyclopropyl, diethylcyclopropyl, biscyanocyclopropyl, trimethylcyclopropyl, tetramethylcyclopropyl, pentamethylcyclopropyl, methylcyclobutyl, vinylcyclobutyl, cyanocyclobutyl, carboxylcyclobutyl, acetylcyclobutyl, methoxycarbonylcyclobutyl or aminocyclobutyl group, preferably a C3 to C4 cycloalkyl group substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group and a cyano group, or substituted by “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C1 to C3 alkyl group substituted by a C3 to C4 cycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group, a C1 to C3 alkoxy group, a C1 to C3 alkylthio group, a C1 to C3 alkylsulfinyl group, a C1 to C3 alkylsulfonyl group, a C1 to C2 alkylenedioxy group, an imino group or a C1 to C3 alkoxyimino group”, a C2 to C4 alkenyl group, a C2 to C4 alkylcarbonyl group, a benzoyl group, a carboxyl group, a C2 to C4 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C3 alkyl)carbamoyl group, “a phenyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group”, a 5-membered heterocyclic group (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring.), “an amino group which may be substituted by the same or different 1 to 2 C1 to C3 alkyl group, or by a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a di(C1 to C3 alkyl)carbamoyl group or a C1 to C3 alkylsulfonyl group”, a nitro group, a hydroxyl group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group, a phenoxy group, a C1 to C3 alkylthio group, a phenylthio group, a C1 to C3 alkylsulfinyl group or a C1 to C3 alkylsulfonyl group, more preferably a cyclopropyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a chlorine atom, a bromine atom, a C1 to C2 alkyl group, cyclopropyl group and a cyano group, or by “a C1 to C2 alkyl group substituted by a C1 to C2 alkyl group which is substituted by the same 1 to 3 substituent(s) selected from the group consisting of a chlorine atom and a bromine atom, or substituted by a cyclopropyl group, a cyano group, a C2 to C3 alkylcarbonyl group, a C2 to C3 alkoxycarbonyl group, a phenyl group, a C1 to C2 alkoxy group, a C1 to C2 alkylthio group, a C1 to C2 alkylsulfinyl group, a C1 to C2 alkylsulfonyl group, a 1,2-ethylenedioxy group, an imino group or a C1 to C2 alkoxyimino group”, a C2 to C3 alkenyl group, a C2 to C3 alkylcarbonyl group, a benzoyl group, a carboxyl group, a C2 to C3 alkoxycarbonyl group, a carbamoyl group, a di(C1 to C2 alkyl)carbamoyl group, “a phenyl group which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of a chlorine atom, a bromine atom, a C1 to C2 alkyl group, “a C1 to C2 alkyl group substituted by the same 1 to 3 fluorine atom(s) or chlorine atom(s)”, a cyclopropyl group, a cyano group and a tri(C1 to C2 alkyl)-silyl group”, a furyl group, a thienyl group, “an amino group which may be substituted by the same 1 to 2 C1 to C2 alkyl group(s), or by a C2 to C3 alkylcarbonyl group, a C2 to C3 alkoxycarbonyl group, a di(C1 to C2 alkyl)carbamoyl group or a C1 to C2 alkylsulfonyl group”, a nitro group, a hydroxyl group, a C1 to C2 alkoxy group, a C1 to C2 haloalkoxy group, a phenoxy group, a C1 to C2 alkylthio group, a phenylthio group, a C1 to C2 alkylsulfinyl group or a C1 to C2 alkylsulfonyl group. In the present invention, “the C4 to C10 bicycloalkyl group” is a bicyclic hydrocarbon having 4 to 10 carbon atoms, and for example, it may be a bicyclobutyl, bicyclepentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl or bicyclodecyl group, preferably a bicyclehexyl or bicycleheptyl group, more preferably a bicycle[3.1.0]hexyl or bicyclo[4.1.0]heptyl group, still further preferably a bicyclo[3.1.0]hexan-6-yl group. In the present invention, “the phenylsulfonyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a phenylsulfonyl group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)silyl group”, and for example, it may be a phenylsulfonyl, fluorophenylsulfonyl, difluorophenylsulfonyl, trifluorophenylsulfonyl, chlorophenylsulfonyl, dichlorophenylsulfonyl, trichlorophenylsulfonyl, fluorochlorophenylsulfonyl, methylphenylsulfonyl, dimethylphenylsulfonyl, trimethylphenylsulfonyl, tetramethylphenylsulfonyl, pentamethylphenylsulfonyl, ethylphenylsulfonyl, fluoro(methyl)phenylsulfonyl, chloro(methyl)phenylsulfonyl, bromo(methyl)phenylsulfonyl, cyclopropylphenylsulfonyl, cyclopropyl(fluoro)phenylsulfonyl, chloro(cyclopropyl)phenylsulfonyl, cyclopropyl(methyl)phenylsulfonyl, (trifluoromethyl)phenylsulfonyl or fluoro(trifluoromethyl)phenylsulfonyl group, preferably a phenylsulfonyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a phenylsulfonyl, chlorophenylsulfonyl, methylphenylsulfonyl, trifluorophenylsulfonyl or cyanophenylsulfonyl group. In the present invention, “the di(C1 to C6 alkyl)sulfamoyl group” is a sulfamoyl group in which the same or different 2 above-mentioned “C1 to C6 alkyl groups” are bonded to the nitrogen atom, and for example, it may be a dimethylsulfamoyl, methylethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, dibutylsulfamoyl or dihexylsulfamoyl, preferably a sulfamoyl group to which the same or different 2 C1 to C3 alkyl groups are bonded, more preferably a dimethylsulfamoyl or diethylsulfamoyl group, still further preferably a dimethylsulfamoyl group. In the present invention, “the 3- to 6-membered heterocyclic group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s), or may be fused with a benzene ring. The substituent is a substituent selected from the substituent Group E.)” is “a 3- to 6-membered heterocyclic group which contains one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and may contain further 1 to 2 nitrogen atom(s)” which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group” and the above-mentioned “C1 to C6 haloalkyl group”, or by a hydroxyl group, the above-mentioned “phenylsulfonyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” or the above-mentioned “di(C1 to C6 alkyl)sulfamoyl group”, or may be fused with a benzene ring, preferably “a 3- to 6-membered heterocyclic group which contains one nitrogen atom, oxygen atom or sulfur atom as a hetero atom, and may contain further one nitrogen atom” which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, or may be substituted by a hydroxyl group, “a phenylsulfonyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group” or “a sulfamoyl group to which the same or different 2 C1 to C3 alkyl groups are bonded”, or may be fused with a benzene ring, more preferably an aziridine, oxiranyl, oxetanyl, pyrrolyl, furyl, thienyl, pyrazolyl, thiazolyl, pyridyl, benzimidazolyl or benzothiazolyl, each of which may be substituted by the same 1 to 2 substituent(s) selected from the group consisting of a chlorine atom, a bromine atom, methyl group, ethyl group and trifluoromethyl group, or may be substituted by a hydroxyl group, phenylsulfonyl group, tolylsulfonyl group or dimethylsulfamoyl group, still further preferably a thienyl, pyrazolyl, thiazolyl group which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of a chlorine atom, methyl group and trifluoromethyl group. In the present invention, “the (C1 to C6 alkoxy)C1 to C6 alkoxy group” is an alkoxy group having 1 to 6 carbon atoms to which an alkoxy group having 1 to 6 carbon atoms is bonded, and for example, it may be a methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, s-butoxymethoxy, t-butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, methoxybutoxy, methoxypentyloxy or methoxyhexyloxy group, preferably an alkoxy group having 1 to 3 carbon atoms to which an alkoxy group having 1 to 3 carbon atoms is substituted, more preferably a methoxyethoxy, ethoxyethoxy or ethoxymethoxy group. In the present invention, “a phenoxy group which may be substituted (The substituent is a hydroxyl group or a pyridazinyloxy group substituted by a substituent(s) selected from the group consisting of a halogen atom and a C1 to C6 alkoxy group.)” is a phenoxy group which may be substituted by one hydroxyl group, or a phenoxy group substituted by a pyridazinyloxy group which is substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of the above-mentioned “halogen atom” and the above-mentioned “C1 to C6 alkoxy group”, preferably a hydroxyphenoxy group, or a phenoxy group substituted by a pyridazinyloxy group which is substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and C1 to C3 alkoxy group, more preferably a phenoxy group substituted by a pyridazinyloxy group which is substituted by each one of a chlorine atom, and a methoxy or ethoxy group. In the present invention, “the 5- to 6-membered heterocycloxy group which may be substituted (the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is a substituent selected from the substituent Group E.)” is “a 5- to 6-membered heterocycloxy group which contains one nitrogen atom, oxygen atom or sulfur atom as a heteroatom, and may contain further 1 to 2 nitrogen atom(s)” which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, a hydroxyl group, the above-mentioned “phenylsulfonyl group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” and the above-mentioned “di(C1 to C6 alkyl)sulfamoyl group”, preferably “a 5- to 6-membered heterocycloxy group which contains one nitrogen atom, oxygen atom or sulfur atom as a heteroatom, and may contain further one nitrogen atom” which may be substituted by the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a hydroxyl group, “a phenylsulfonyl group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group” and “a sulfamoyl group to which the same or different two C1 to C3 alkyl groups are bonded”, more preferably a pyridyloxy, pyrrolyloxy, furyloxy, thienyloxy, pyrazolyloxy, thiazolyloxy, pyrimidyloxy, pyrazinyloxy or a pyridazinyloxy group, each of which may be substituted by 1 to 2 different substituents selected from the group consisting of a chlorine atom, a bromine atom, a methyl group, an ethyl group, a trifluoromethyl group, a hydroxyl group, a phenylsulfonyl group, a tolylsulfonyl group and a dimethylsulfamoyl group, still further preferably a pyridazinyloxy group which may be substituted by a chlorine atom and a hydroxyl group. In the present invention, “the phenylsulfonyloxy group which may be substituted (The substituent is a substituent selected from the substituent Group A.)” is a phenylsulfonyloxy group which may be substituted by the same or different 1 to 5 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 haloalkyl group”, the above-mentioned “C3 to C6 cycloalkyl group”, a cyano group and the above-mentioned “tri(C1 to C6 alkyl)silyl group”, and for example, it may be a phenylsulfonyloxy, fluorophenylsulfonyloxy, difluorophenylsulfonyloxy, trifluorophenylsulfonyloxy, chlorophenylsulfonyloxy, dichlorophenylsulfonyloxy, trichlorophenylsulfonyloxy, fluorochlorophenylsulfonyloxy, methylphenylsulfonyloxy, dimethylphenylsulfonyloxy, trimethylphenylsulfonyloxy, tetramethylphenylsulfonyloxy, pentamethylphenylsulfonyloxy, ethylphenylsulfonyloxy, fluoro(methyl)phenylsulfonyloxy, chloro(methyl)phenylsulfonyloxy, bromo(methyl)phenylsulfonyloxy, cyclopropylphenylsulfonyloxy, cyclopropyl(fluoro)phenylsulfonyloxy, chloro(cyclopropyl)phenylsulfonyloxy, cyclopropyl(methyl)phenylsulfonyloxy, (trifluoromethyl)phenylsulfonyloxy or fluoro(trifluoromethyl)phenylsulfonyloxy group, preferably a phenylsulfonyloxy group which may be substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, “a C1 to C3 alkyl group substituted by the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom”, a C3 to C4 cycloalkyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group, more preferably a phenylsulfonyloxy, chlorophenylsulfonyloxy, methylphenylsulfonyloxy, trifluorophenylsulfonyloxy or cyanophenylsulfonyloxy group. In R3, R4, R5, R6 and R7 according to the present invention, “the 3- to 6-membered cyclic hydrocarbon group which may be substituted, which is formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded (the cyclic hydrocarbon may be interrupted by 1 to 2 hetero atom(s) selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The substituent is a halogen atom, a C1 to C6 alkyl group, a hydroxy-C1 to C6 alkyl group, a C1 to C6 alkoxy group, an oxo group, a hydroxyimino group or a C1 to C6 alkoxyimino group, and when the C1 to C6 alkyl group is substituted, it may form another 3-membered ring by binding with the other C1 to C6 alkyl group or a carbon atom(s)in the cyclic hydrocarbon.)” is a saturated or unsaturated 3- to 6-membered cyclic hydrocarbon group which may be substituted by the same or different 1 to 4 substituent(s) selected from the group consisting of the above-mentioned “halogen atom”, the above-mentioned “C1 to C6 alkyl group”, the above-mentioned “C1 to C6 alkyl group” substituted by 1 to 2 hydroxyl group(s), the above-mentioned “C1 to C6 alkoxy group”, an oxo group, a hydroxyimino group and the above-mentioned “C1 to C6 alkoxyimino group”, and may be interrupted by the same or different 1 to 2 hetero atom(s) selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and further may form a cyclopropane ring on the cyclic hydrocarbon group, preferably a group represented by —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH (CH3) CH2CH2—, —CH2CH (CH3) CH2—, —C(CH3)2CH2CH2—, —CH2C(CH3) 2CH2—, —CH (OCH3) CH2CH2—, —C(OCH3)2CH2CH2—, —CH2C (OCH3)2CH2—, —C(═O) CH2CH2—, —CH2C(═O) CH2—, —C(═NOCH3) CH2CH2—, —CH2CH2CH2CH2—, —CH (CH3) CH2CH2CH2—, —C(CH3)2CH2CH2CH2—, —CH (OCH3) CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH (CH3) CH2—, —OCH2CH(CH3)—, —OC(CH3)2CH2—, —OCH═CH—, —OC(CH3)═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH (CH3)O—, —OC(CH3)2O—, —OCF2O—, —OCH2CH2O—, —OCH═N—, —OC(CH3) ═N—, more preferably a group represented by —CH2CH2—, —CH2CH2CH2——CH (CH3) CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, still further preferably a group represented by —CR2CR2CR2—, —CH (CH3) CH2CH2—, —OCH2CH2—, —OCH═CH— or The compound (I) of the present invention can be made a salt to be generally used in agricultural chemicals, and for example, it can be made an alkali metal salt, an alkaline earth metal salt or an ammonium salt, and when a basic portion exists in the molecule, it can be made a salt, for example, a sulfate, hydrochloride, nitrate, phosphate, or the like. These salts are included in the present invention so long as they can be used as a herbicide for agricultural and horticultural chemicals. In the present invention, “the alkali metal salt” may be, for example, a sodium salt, potassium salt or lithium salt, preferably a sodium salt or potassium salt. In the present invention, “the alkaline earth metal salt” may be, for example, a calcium salt or magnesium salt, preferably a calcium salt. A solvate of the compounds of the present invention is also included in the present invention. In the compounds of the present invention, there are compounds having an asymmetric carbon(s), and in that case, the present invention also includes a kind of optical isomers and a mixture of several kinds of optical isomers with an optional ratio. In the present invention, “ester derivative” is a compound in which an acyl group bonds to an oxygen atom of a hydroxyl group bonded at the 4-position of the pyridazine ring, and for example, a compound to which is/are bonded a C2 to. C15 alkylcarbonyl group which may be substituted [The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkoxy group, a C2 to C7 alkoxycarbonyl group, a C2 to C6 alkenyloxycarbonyl group which may be substituted {The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a C3 to C6 cycloalkyl group, a cyano group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a C3 to C6 cycloalkenyloxycarbonyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of an oxo group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a 5 or 6-membered heterocycloxycarbonyl group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or deferent 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a phenyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group and a C2 to C7 alkoxycarbonyl group.), a phenoxy group and a C1 to C6 alkylthio group.], a C4 to C7 cycloalkylcarbonyl group, an adamantylcarbonyl group, a C3 to C7 alkenylcarbonyl group which may be substituted (The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a halogen atom and a phenyl group.), a C3 to C7 alkynylcarbonyl group, a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom and a phenyl group.), a cyano group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a C3 to C7 alkenyloxycarbonyl group which may be substituted {The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a C3 to C6 cycloalkyl group, a cyano group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a C4 to C7 cycloalkenyloxycarbonyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of an oxo group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a phenyl group, a nitro group, a C1 to C6 alkoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom and a phenyl group.), a phenoxy group, a 5 or 6-membered heterocyclic oxycarbonyl group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).} and a 5 or 6-membered heterocycloxysulfonyl group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}.], a naphthoyl group, a 3- to 6-membered heterocyclic carbonyl group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s), or may form a 5- to 6-membered spiro ring containing 1 to 2 oxygen atom(s) on an optional carbon atom in the heterocycle. The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom and a phenyl group.), a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a phenyl group which may be substituted (The substituent is the same or different 1 to 3 halogen atom(s).), a nitro group, a hydroxyl group, a C1 to C6 alkoxy group, a phenoxy group, a C1 to C6 alkylthio group, a C2 to C6 alkenylthio group and a phenylthio group.}, a 7 to 14-membered fused bi- or tri-cyclic heterocyclic carbonyl group which may be substituted (The heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 to 2 nitrogen atom(s) or oxygen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom and a C1 to C6 alkyl group.), a 5 or 6-membered heterocycle carbonylcarbonyl group (The heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s).), a C2 to C7 alkoxycarbonyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkoxy group and a phenyl group.), a C3 to C7 alkenyloxycarbonyl group, a phenoxycarbonyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C6 alkoxy group.), a fused polycyclic hydrocarbyloxycarbonyl group, a 5 or 6-membered heterocycloxycarbonyl group which may be substituted {The heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a carbamoyl group which may be substituted {The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a C1 to C6 alkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C2 to C7 alkoxycarbonyl group, a cyano group, a phenyl group and a C1 to C6 alkoxy group.), a C3 to C6 alkenyl group, a phenyl group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group and a C1 to C6 alkoxy group.}, a (C1 to C6 alkylthio)carbonyl group, a (phenylthio)carbonyl group, a C1 to C8 alkylsulfonyl group which may be substituted (The substituent is the same or different 1 to 3 halogen atom(s).), a phenylsulfonyl group which may be substituted [The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a cyano group, a C2 to C7 alkylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a nitro group, a C1 to C6 alkoxy group, a C2 to C6 alkenyloxysulfonyl group which may be substituted {The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a C3 to C6 cycloalkyl group, a cyano group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a C3 to C6 cycloalkenyloxysulfonyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of an oxo group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).} and a 5 or 6-membered heterocycloxysulfonyl group which may be substituted {The heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}.], a 5 or 6-membered heterocycloxysulfonyl group which may be substituted {The heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a phenoxy group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C3 to C6 cycloalkyl group and a C2 to C7 alkoxycarbonyl group.), a 2,3-dihydro-1H-indenyloxy group and a benzoyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, a C1 to C3 haloalkyl group, a C2 to C7 alkoxycarbonyl group, a nitro group and a C1 to C3 alkylsulfonyl group.).}, a di(C1 to C6 alkyl)sulfamoyl group, a C1 to C6 alkoxysulfonyl group, a di(C1 to C6 alkyl)phosphoryl group, a tri(C1 to C6 alkyl)silyl group or a triphenylsilyl group, preferably a compound to which bonded is/arena C2 to C10 alkylcarbonyl group, a benzoyl group which may be substituted (The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 alkoxy group or a 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yloxycarbonyl group.), a pyrrolidinylcarbonyl group, azetidinylcarbonyl group, morpholinyl carbonyl group, a C2 to C5 alkoxycarbonyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a di(C1 to C3 alkyl)carbamoyl group, a (C1 to C3 alkyl) (C1 to C3 alkoxy)carbamoyl group, a C1 to C3 alkylsulfonyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.) or a phenylsulfonyl group which may be substituted (The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yloxysulfonyl group and a nitro group.), more preferably a compound to which bonded is/are a C2 to C4 alkylcarbonyl group, a benzoyl group which may be substituted (The substituent is a methyl group or a 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yloxycarbonyl group.), a 1-acetidinylcarbonyl group, a 4-morpholinylcarbonyl group, a C2 to C3 alkoxycarbonyl group which may be substituted (The substituent is 1 to 3 chlorine atom(s).), a dimethylcarbamoyl group, a methoxy(methyl)carbamoyl group, a C1 to C3 alkylsulfonyl group which may be substituted (The substituent is 1 to 3 fluorine atom(s).) or a phenylsulfonyl group which may be substituted (The substituent is a chlorine atom, a methyl group, a 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yloxysulfonyl group or a nitro group.). (a) In the present invention, R1 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, C1 to C3 alkyl group, C1 to C3 haloalkyl group (The halogen atom is 1 to 3 fluorine atom(s).), cyclopropyl group, C2 to C3 alkenyl group, a cyano group, C2 to C4 alkylcarbonyl group, di(C1 to C3 alkyl)carbamoyl group, a phenyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a furyl group, a thienyl group, a C1 to C3 alkoxy group, a phenoxy group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is 1 to 3 fluorine atom(s).), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.} or the substituted pyrazolyloxy group (The substituent is a benzoyl group substituted by two chlorine atoms, and two C1 to C3 alkyl groups.), more preferably a chlorine atom, a bromine atom, trifluoromethyl group or a cyano group, still further preferably a chlorine atom or a bromine atom, particularly preferably a chlorine atom. (b) In the present invention, R2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a (C1 to C3 alkoxy)C1 to C3 alkyl group, a benzoyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a C2 to C4 alkoxycarbonyl group, a phenoxy group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a phenylthio group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.} or a tri(C1 to C3 alkyl)silyl group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethoxycarbonyl group or a trimethylsilyl group, still further preferably a hydrogen atom. (c) In the present invention, R3, R4, R5, R6 and R7 each independently represent preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C3 to C4 cycloalkyl group, a C1 to C3 alkylthio group or a C1 to C3 alkoxyimino group.), a C2 to C3 alkenyl group, a C2 to C3 alkynyl group, a C3 to C5 cycloalkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group, a cyano group, a C1 to C3 alkoxy group and a C1 to C3 alkylthio group.), a C6 to C7 bicycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group which may be substituted {The substituent is a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group or a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.).}, a 5- to 6-membered heterocyclic group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.).}, a nitro group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a phenoxy group which may be substituted (The substituent is a pyridazinyloxy group substituted by a substituent(s) selected frome the group consisting of a fluorine atom, a chlorine atom, a bromine atom a C1 to C3 alkoxy group.) or a C1 to C3 alkylthio group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by CH2CH2—, —CH2CH2CH2—, —CH(CH3)CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, more preferably each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (The substituent is 1 to 3 fluorine atom(s), or a cyclopropyl group.), a C3 to C4 cycloalkyl group which may be substituted (The substituent is the same 1 to 2 substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C2 alkyl group, a cyclopropyl group and a C1 to C2 alkoxy group.), a cyano group, C2 to C3 alkoxycarbonyl group, a nitro group, C1 to C3 alkoxy group or trifluoromethoxy group, or , R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2—, —CH(CH3)CH2CH2—, —OCH2CH2—, —OCH═CH— or provided that R3 is not a hydrogen atom, still further preferably each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, C1 to C3 alkyl group, a C3 to C4 cycloalkyl group which may be substituted (The substituent is the same 1 to 2 substituent(s) selected from the group consisting of a chlorine atom and a C1 to C2 alkyl group.), a cyano group or a C1 to C2 alkoxy group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2— or —OCH═CH—, provided that R3 is not a hydrogen atom, particularly preferably each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group which may be substituted (The substituents are two chlorine atoms.) or a methoxy group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2—, provided that R3 is not a hydrogen atom, most preferably R3 is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a methoxy group , and R7 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or methoxy group, and R4, R5 and R6 each independently represent a hydrogen atom or a methyl group. (d) In the present invention, m and n are preferably both 0. The compound (I) of the present invention is preferably a compound wherein (1a) R1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is 1 to 3 fluorine atom(s).), a cyclopropyl group, a C2 to C3 alkenyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a di(C1 to C3 alkyl)carbamoyl group, a phenyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a furyl group, a thienyl group, a C1 to C3 alkoxy group, a phenoxy group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is 1 to 3 fluorine atom(s).), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.} or the substituted pyrazolyloxy group (The substituent is a benzoyl group substituted by two chlorine atoms and two C1 to C3 alkyl groups.), (1b) R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C3 alkyl group, a (C1 to C3 alkoxy)C1 to C3 alkyl group, a benzoyl group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a C2 to C4 alkoxycarbonyl group, a phenoxy group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.}, a phenylthio group which may be substituted {The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a cyclopropyl group, a cyano group and a tri(C1 to C3 alkyl)silyl group.} or a tri(C1 to C3 alkyl)silyl group, (1c) R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or a C3 to C4 cycloalkyl group, a C1 to C3 alkylthio group or a C1 to C3 alkoxyimino group.), a C2 to C3 alkenyl group, a C2 to C3 alkynyl group, a C3 to C5 cycloalkyl group which may be substituted (The substituent is the same or different 1 to 3 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group, a C3 to C4 cycloalkyl group, a cyano group, a C1 to C3 alkoxy group and a C1 to C3 alkylthio group.), a C6 to C7 bicycloalkyl group, a cyano group, a C2 to C4 alkylcarbonyl group, a C2 to C4 alkoxycarbonyl group, a phenyl group which may be substituted {The substituent is a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group or a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.).}, a 5- to 6-membered heterocyclic group which may be substituted {the heterocycle contains one nitrogen atom, oxygen atom or sulfur atom in the ring, and may contain further 1 or 2 nitrogen atom(s). The substituent is the same or different 1 to 2 substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C3 alkyl group and a C1 to C3 haloalkyl group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.).}, a nitro group, a C1 to C3 alkoxy group, a C1 to C3 haloalkoxy group (The halogen atom is the same or different 1 to 3 halogen atom(s) selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), a phenoxy group which may be substituted (The substituent is a pyridazinyloxy group substituted by a substituent(s) selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom or a C1 to C3 alkoxy group.) or C1 to C3 alkylthio group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2—, —CH2CH2CH2—, —CH(CH3) CH2CH2—, —CH2CH2CH2CH2—, —CH═CH—CH═CH—, —OCH2CH2—, —OCH═CH—, —OCH═C(CH3)—, —SCH═CH—, —N═CH—CH═CH—, —OCH2O—, —OCH2CH2O—, (1d) m and n are both 0, more preferably a compound wherein (2a) R1 is a chlorine atom, a bromine atom, a trifluoromethyl group or a cyano group, (2b) R2 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethoxycarbonyl group or a trimethylsilyl group, (2c) R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a C1 to C4 alkyl group which may be substituted (The substituent is 1 to 3 fluorine atom(s), or a cyclopropyl group.), a C3 to C4 cycloalkyl group which may be substituted (The substituent is the same 1 to 2 substituent selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, a C1 to C2 alkyl group, a cyclopropyl group and a C1 to C2 alkoxy group.), a cyano group, a C2 to C3 alkoxycarbonyl group, a nitro group, a C1 to C3 alkoxy group or a trifluoromethoxy group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2—, —CH(CH3)CH2CR2—, —OCH2CH2—, —OCH═CH— or provided that R3 is not a hydrogen atom, (2d) m and n are both 0, still further preferably a compound wherein (3a) R1 is a chlorine atom or a bromine atom, (3b) R2 is a hydrogen atom, (3c) R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, C1 to C3 alkyl group, a C3 to C4 cycloalkyl group which may be substituted (The substituent is the same 1 to 2 substituent(s) selected from the group consisting of a chlorine atom and a C1 to C2 alkyl group.), a cyano group or a C1 to C2 alkoxy group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2— or —OCH═CH—, provided that R3 is not a hydrogen atom, (3d) m and n are both 0, particularly preferably a compound wherein (4a) R1 is a chlorine atom, (4b) R2is a hydrogen atom, (4c) R3, R4, R5, R6 and R7 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group which may be substituted (The substituents are two chlorine atoms.) or a methoxy group, or R3, R4, R5, R6 and R7 are a group(s) which is/are formed by the adjacent two of them with carbon atoms to which the respective substituents are bonded, and include a group represented by —CH2CH2CH2—, provided that R3 is not a hydrogen atom, (4d) m and n are both 0. Representative compounds of the present invention are exemplified in the following Table 1, but the present invention is not limited by these compounds. In the following, in R3 to R7, “H” means that all the R3, R4, R5, R6 and R7 are hydrogen atoms, in R3 to R7, “2-Cl” means that R3 is a chlorine atom, “Me” represents a methyl group, “Et” represents an ethyl group, “Pr” represents a propyl group, “iPr” represents an isopropyl group, “cPr” represents a cyclopropyl group, “Bu” represents a butyl group, “iBu” represents an isobutyl group, “nsBu” represents a s-butyl group, “tBu” represents a tert-butyl group, “cBu” represents a cyclobutyl group, “Pen” represents a pentyl group, “cPen” represents a cyclopentyl group, “neoPen” represents a neopentyl group, “Hx” represents a hexyl group, “cHx” represents a cyclohexyl group, in R3 to R7, “2-CH2CH2CH2-3” means that R3 and R4 are a trimethylene group and form a 5-membered ring together with carbon atoms to which they are bonded, “═N—OMe” represents a methoxyimino group, “═O” represents a carbonyl group together with carbon atom(s) to which they are bonded, “SO2 (Ph-4-Me)” represents a p-tolylsulfonyl group, “cPr-1-F” represents a 1-fluorocyclopropyl group, “cPr-cis-2-(CH2)3-cis-3” represents a group represented by “C(—CH2CH2—)—CH2CH2” represents a group represented by “CH(CH2)CH—CH2” represents a group represented by “CH(OCH2)2” represents a group represented by “Fur” represents a furyl group, “Thi” represents a thienyl group, “Pyr” represents a pyridyl group, “Azr” represents a aziridinyl group, “Pyrd” represents a pyrrolidinyl group, “Pyrr” represents a pyrrolyl group, “Pyza” represents a pyrazolyl group, “Thiz” represents a thiazolyl group, “Pyzn” represents a pyridazinyl group, “Np” represents a naphthyl group, “1-Ad” represents a 1-adamantyl group, “Ioxa” represents an isoxazolyl group, “Tdia” represents a 1,2,3-thiadiazolyl group, “Bfur” represents a 1-benzofuranyl group, “Bthi” represents a 1-benzothienyl group, “Bthia” represents a 1,3-benzothiazolyl group, “Boxaz” represents a 1,3-benzodioxolyl group, “Iqu” represents an isquinolyl group, “Azet” represents an azetidinyl group, “Ppri” represents a piperidyl group, “1-Ppri-4-OCH2CH2O-4” represents a group represented by the formula: “Ppra” represents a piperadinyl group, “Morp” represents a morpholinyl group, “Tmor” represents a thiomorpholinyl group, “Carb” represents a carbazolyl group, “Pthia” represents a phenothiazinyl group, “Thpy” represents a tetrahydro-2H-pyranyl group, “Q1” represents an oxiranyl group, “Q2” represents a benzoxazolyl group, “Q3” represents a benzothiazolyl group, “Q4” represents a fluorenyl group, “Q5” represents a 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl group, “Q6” represents a 6-chloro-3-(2-methylphenoxy)-4-pyridazinyl group, “Q7” represents a 6-chloro-3-(2-isopropylphenoxy)-4-pyridazinyl group, “Q8” represents a 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl group, “Q9” represents a 6-chloro-3-(2,3-dihydro-1H-inden-4-yloxy)-4-pyridazinyl group, “Q10” represents a 6-chloro-3-(2,6-dimethylphenoxy)-4-pyridazinyl group, “Q11” represents a 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl group, “Ql2” represents a 4-[2-chloro-3-(methoxycarbonyl)-4-(methylsulfonyl)benzoyl]-1-ethyl-1H-pyrazol-5-yl group, “Q13” represents a 4-(2,4-dichloro-3-methylbenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl group, “Q14” represents a 2-[2-chloro-4-(methylsulfonyl)benzoyl]-3-oxo-1-cyclohexen-1-yl group, “Q15” represents a 2-[4-(methylsulfonyl)-2-nitrobenzoyl]-3-oxo-1-cyclohexen-1-yl group, “Q16” represents a 2-cyano-1-cyclopropyl-3-[2-(methylsulfonyl)-4-(trifluoromethyl)phenyl]-3-oxo-1-propenyl group, “Q17” represents a 3-[4-chloro-2-(methylsulfonyl)phenyl]-2-cyano-1-cyclopropyl-3-oxo-1-propenyl group, and “Q18” represents a 3,4-dihydro-2 (1H)-isoquinolinyl group, respectively. TABLE 1 Compound No. R1 R2 X R3 to R7 m n 1 H H H H 0 0 2 H H H 2-Cl 0 0 3 H H H 2-Br 0 0 4 H H H 2-I 0 0 5 H H H 2-Me 0 0 6 H H H 2-iPr 0 0 7 H H H 2-cPr 0 0 8 H H H 2-cBu 0 0 9 H H H 2-CH2CH2CH2-3 0 0 10 H H H 2-cPr,5-Me 0 0 11 H H H 2-OMe,5-Me 0 0 12 H H H 2-F, 6-iPr 0 0 13 H H H 2-Cl, 6-cPr 0 0 14 H H H 2-Br, 6-Me 0 0 15 H H H 2-I, 6-Me 0 0 16 H H H 2, 6-Me2 0 0 17 H H H 2-Me, 6-Et 0 0 18 H H H 2-Me, 6-cPr 0 0 19 H H H 2, 6-cPr2 0 0 20 H H H 2-cPr, 3,5-Me2 0 0 21 H H H 2-cPr, 5,6-Me2 0 0 22 H H SO2 (Ph-4-Me) 2-Cl 0 0 23 H H SO2 (Ph-4-Me) 2-Br 0 0 24 H H SO2 (Ph-4-Me) 2-I 0 0 25 H H SO2 (Ph-4-Me) 2-Me 0 0 26 H H SO2 (Ph-4-Me) 2-iPr 0 0 27 H H SO2 (Ph-4-Me) 2-cPr 0 0 28 H H SO2 (Ph-4-Me) 2-cBu 0 0 29 H H SO2 (Ph-4-Me) 2-CH2CH2CH2-3 0 0 30 H H SO2 (Ph-4-Me) 2-cPr, 5-Me 0 0 31 H H SO2 (Ph-4-Me) 2-OMe, 5-Me 0 0 32 H H SO2 (Ph-4-Me) 2-F, 6-iPr 0 0 33 H H SO2 (Ph-4-Me) 2-Cl, 6-cPr 0 0 34 H H SO2 (Ph-4-Me) 2-Br, 6-Me 0 0 35 H H SO2 (Ph-4-Me) 2-I, 6-Me 0 0 36 H H SO2 (Ph-4-Me) 2, 6-Me2 0 0 37 H H SO2 (Ph-4-Me) 2-Me, 6-Et 0 0 38 H H SO2 (Ph-4-Me) 2-Me, 6-cPr 0 0 39 H H SO2 (Ph-4-Me) 2, 6-cPr2 0 0 40 H H SO2 (Ph-4-Me) 2-cPr, 3,5-Me2 0 0 41 H H SO2 (Ph-4-Me) 2-cPr, 5, 6-Me2 0 0 42 H Cl H 2-Cl 0 0 43 H Cl H 2-Br 0 0 44 H Cl H 2-I 0 0 45 H Cl H 2-Me 0 0 46 H Cl H 2-Et 0 0 47 H Cl H 2-iPr 0 0 48 H Cl H 2-cPr 0 0 49 H Cl H 2-cBu 0 0 50 H Cl H 2-CH2CH2CH2-3 0 0 51 H Cl H 2-cPr, 5-Me 0 0 52 H Cl H 2-OMe, 5-Me 0 0 53 H Cl H 2-F, 6-iPr 0 0 54 H Cl H 2-Cl, 6-cPr 0 0 55 H Cl H 2-Br, 6-Me 0 0 56 H Cl H 2-I, 6-Me 0 0 57 H Cl H 2, 6-Me2 0 0 58 H Cl H 2-Me, 6-Et 0 0 59 H Cl H 2-Me, 6-cPr 0 0 60 H Cl H 2,6-cPr2 0 0 61 H Cl H 2-cPr, 3,5-Me2 0 0 62 H Cl H 2-cPr, 5, 6-Me2 0 0 63 H Cl SO2 (Ph-4-Me) 2-Cl 0 0 64 H Cl SO2 (Ph-4-Me) 2-Br 0 0 65 H Cl SO2 (Ph-4-Me) 2-I 0 0 66 H Cl SO2 (Ph-4-Me) 2-Me 0 0 67 H Cl SO2 (Ph-4-Me) 2-iPr 0 0 68 H Cl SO2 (Ph-4-Me) 2-cPr 0 0 69 H Cl SO2 (Ph-4-Me) 2-cBu 0 0 70 H Cl SO2 (Ph-4-Me) 2-CH2CH2CH2-3 0 0 71 H Cl SO2 (Ph-4-Me) 2-cPr, 5-Me 0 0 72 H Cl SO2 (Ph-4-Me) 2-OMe, 5-Me 0 0 73 H Cl SO2 (Ph-4-Me) 2-F, 6-iPr 0 0 74 H Cl SO2 (Ph-4-Me) 2-Cl, 6-cPr 0 0 75 H Cl SO2 (Ph-4-Me) 2-Br, 6-Me 0 0 76 H Cl SO2 (Ph-4-Me) 2-I, 6-Me 0 0 77 H Cl SO2 (Ph-4-Me) 2,6-Me2 0 0 78 H Cl SO2 (Ph-4-Me) 2-Me, 6-Et 0 0 79 H Cl SO2 (Ph-4-Me) 2-Me, 6-cPr 0 0 80 H Cl SO2 (Ph-4-Me) 2,6-cPr2 0 0 81 H Cl SO2 (Ph-4-Me) 2-cPr, 3,5-Me2 0 0 82 H Cl SO2 (Ph-4-Me) 2-cPr, 5, 6-Me2 0 0 83 H SiMe3 H 2-Cl 0 0 84 H SiMe3 H 2-Br 0 0 85 H SiMe3 H 2-I 0 0 86 H SiMe3 H 2-Me 0 0 87 H SiMe3 H 2-iPr 0 0 88 H SiMe3 H 2-cPr 0 0 89 H SiMe3 H 2-cBu 0 0 90 H SiMe3 H 2-CH2CH2CH2-3 0 0 91 H SiMe3 H 2-cPr, 5-Me 0 0 92 H SiMe3 H 2-OMe, 5-Me 0 0 93 H SiMe3 H 2-F, 6-iPr 0 0 94 H SiMe3 H 2-Cl, 6-cPr 0 0 95 H SiMe3 H 2-Br, 6-Me 0 0 96 H SiMe3 H 2-I, 6-Me 0 0 97 H SiMe3 H 2,6-Me2 0 0 98 H SiMe3 H 2-Me, 6-Et 0 0 99 H SiMe3 H 2-Me, 6-cPr 0 0 100 H SiMe3 H 2,6-cPr2 0 0 101 H SiMe3 H 2-cPr, 3,5-Me2 0 0 102 H SiMe3 H 2-cPr, 5,6-Me2 0 0 103 H SiMe3 SO2 (Ph-4-Me) 2-Cl 0 0 104 H SiMe3 SO2 (Ph-4-Me) 2-Br 0 0 105 H SiMe3 SO2 (Ph-4-Me) 2-I 0 0 106 H SiMe3 SO2 (Ph-4-Me) 2-Me 0 0 107 H SiMe3 SO2 (Ph-4-Me) 2-iPr 0 0 108 H SiMe3 SO2 (Ph-4-Me) 2-cPr 0 0 109 H SiMe3 SO2 (Ph-4-Me) 2-cBu 0 0 110 H SiMe3 SO2 (Ph-4-Me) 2-CH2CH2CH2-3 0 0 111 H SiMe3 SO2 (Ph-4-Me) 2-cPr, 5-Me 0 0 112 H SiMe3 SO2 (Ph-4-Me) 2-OMe, 5-Me 0 0 113 H SiMe3 SO2 (Ph-4-Me) 2-F, 6-iPr 0 0 114 H SiMe3 SO2 (Ph-4-Me) 2-Cl, 6-cPr 0 0 115 H SiMe3 SO2 (Ph-4-Me) 2-Br, 6-Me 0 0 116 H SiMe3 SO2 (Ph-4-Me) 2-I, 6-Me 0 0 117 H SiMe3 SO2 (Ph-4-Me) 2,6-Me2 0 0 118 H SiMe3 SO2 (Ph-4-Me) 2-Me, 6-Et 0 0 119 H SiMe3 SO2 (Ph-4-Me) 2-Me, 6-cPr 0 0 120 H SiMe3 SO2 (Ph-4-Me) 2,6-cPr2 0 0 121 H SiMe3 SO2 (Ph-4-Me) 2-cPr, 3,5-Me2 0 0 122 H SiMe3 SO2 (Ph-4-Me) 2-cPr, 5,6-Me2 0 0 123 Cl H H H 0 0 124 Cl H H 2-F 0 0 125 Cl H H 2-Cl 0 0 126 Cl H H 2-Br 0 0 127 Cl H H 2-I 0 0 128 Cl H H 2-Me 0 0 129 Cl H H 2-Me 1 0 130 Cl H H 2-Et 0 0 131 Cl H H 2-Pr 0 0 132 Cl H H 2-iPr 0 0 133 Cl H H 2-Bu 0 0 134 Cl H H 2-iBu 0 0 135 Cl H H 2-sBu 0 0 136 Cl H H 2-tBu 0 0 137 Cl H H 2-Pen 0 0 138 Cl H H 2-Hx 0 0 139 Cl H H 2-cPr 0 0 140 Cl H H 2-(cPr-1-F) 0 0 141 Cl H H 2-(cPr-1-Cl) 0 0 142 Cl H H 2-(cPr-1-Br) 0 0 143 Cl H H 2-(cPr-1-I) 0 0 144 Cl H H 2-(cPr-1-Me) 0 0 145 Cl H H 2-(cPr-1-Et) 0 0 146 Cl H H 2-(cPr-1-Pr) 0 0 147 Cl H H 2-(cPr-1-iPr) 0 0 148 Cl H H 2-(cPr-1-Bu) 0 0 149 Cl H H 2-(cPr-1-tBu) 0 0 150 Cl H H 2-(cPr-1-Hx) 0 0 151 Cl H H 2-(cPr-1-cPr) 0 0 152 Cl H H 2-(cPr-1-cBu) 0 0 153 Cl H H 2-(cPr-1-cPen) 0 0 154 Cl H H 2-(cPr-1-CH2F) 0 0 155 Cl H H 2-(cPr-1-CH2Cl) 0 0 156 Cl H H 2-(cPr-1-CH2Br) 0 0 157 Cl H H 2-(cPr-1-CHF2) 0 0 158 Cl H H 2-(cPr-1-CF3) 0 0 159 Cl H H 2-(cPr-1-CCl3) 0 0 160 Cl H H 2-(cPr-1-CH2CF3) 0 0 161 Cl H H 2-(cPr-1-CH2CCl3) 0 0 162 Cl H H 2-(oPr-1-CH═CH22) 0 0 163 Cl H H 2-(cPr-1-CH2OMe) 0 0 164 Cl H H 2-(cPr-1-CH2OEt) 0 0 165 Cl H H 2-(cPr-1-CH2OiPr) 0 0 166 Cl H H 2-(cPr-1-CH2SMe) 0 0 167 Cl H H 2-(cPr-1-CH2SEt) 0 0 168 Cl H H 2-(cPr-1-CH2S-iPr) 0 0 169 Cl H H 2-(cPr-1-CH2SOMe) 0 0 170 Cl H H 2-(cPr-1-CH2SOEt) 0 0 171 Cl H H 2-(cPr-1-CH2SO2Me) 0 0 172 Cl H H 2-(cPr-1-CH2SO2Et) 0 0 173 Cl H H 2-(cPr-1-CN) 0 0 174 Cl H H 2-{cPr-1-C(λNOMe)Me} 0 0 175 Cl H H 2-(cPr-1-COMe) 0 0 176 Cl H H 2-(cPr-1-COEt) 0 0 177 Cl H H 2-(cPr-1-COPh) 0 0 178 Cl H H 2-(cPr-1-CO2H) 0 0 179 Cl H H 2-(cPr-1-CO2Me) 0 0 180 Cl H H 2-(cPr-1-CO2Et) 0 0 181 Cl H H 2-(cPr-1-CONH2) 0 0 182 Cl H H 2-(cPr-1-CONMe2) 0 0 183 Cl H H 2-(cPr-1-CONEt2) 0 0 184 Cl H H 2-(cPr-1-Ph) 0 0 185 Cl H H 2-{cPr-1-(Ph-2-F)} 0 0 186 Cl H H 2-{cPr-1-(Ph-2-Cl)} 0 0 187 Cl H H 2-{cPr-1-(Ph-2-Me)} 0 0 188 Cl H H 2-{cPr-1-(Ph-4-Cl)} 0 0 189 Cl H H 2-{cPr-1-(Ph-4-Me)} 0 0 190 Cl H H 2-{cPr-1-(2-Fur)} 0 0 191 Cl H H 2-{cPr-1-(2-Thi)} 0 0 192 Cl H H 2-{cPr-1-(2-Pyr)} 0 0 193 Cl H H 2-(cPr-1-NH2) 0 0 194 Cl H H 2-(cPr-1-NHMe) 0 0 195 Cl H H 2-(cPr-1-NMe2) 0 0 196 Cl H H 2-(cPr-1-NHCOMe) 0 0 197 Cl H H 2-(cPr-1-NHCO2Me) 0 0 198 Cl H H 2-(cPr-1-NHCONMe2) 0 0 199 Cl H H 2-(cPr-1-NHSO2Me) 0 0 200 Cl H H 2-(cPr-1-NO2) 0 0 201 Cl H H 2-(cPr-1-OH) 0 0 202 Cl H H 2-(cPr-1-OMe) 0 0 203 Cl H H 2-(cPr-1-OEt) 0 0 204 Cl H H 2-(cPr-1-OCF3) 0 0 205 Cl H H 2-(cPr-1-OPh) 0 0 206 Cl H H 2-(cPr-1-SMe) 0 0 207 Cl H H 2-(cPr-1-SEt) 0 0 208 Cl H H 2-(cPr-1-SPh) 0 0 209 Cl H H 2-(cPr-1-SOMe) 0 0 210 Cl H H 2-(cPr-1-SOEt) 0 0 211 Cl H H 2-(cPr-1-SO2Me) 0 0 212 Cl H H 2-(cPr-1-SO2Et) 0 0 213 Cl H H 2-(cPr-2-F) 0 0 214 Cl H H 2-(cPr-2-Cl) 0 0 215 Cl H H 2-(cPr-2-Br) 0 0 216 Cl H H 2-(cPr-2-I) 0 0 217 Cl H H 2-(cPr-2-Me) 0 0 218 Cl H H 2-(cPr-2-Et) 0 0 219 Cl H H 2-(cPr-2-Pr) 0 0 220 Cl H H 2-(cPr-2-iPr) 0 0 221 Cl H H 2-(cPr-2-Bu) 0 0 222 Cl H H 2-(cPr-2-tBu) 0 0 223 Cl H H 2-(cPr-2-Hx) 0 0 224 Cl H H 2-(cPr-2-cPr) 0 0 225 Cl H H 2-(cPr-2-CF3) 0 0 226 Cl H H 2-(cPr-2-CN) 0 0 227 Cl H H 2-(cPr-2-CH2OMe) 0 0 228 Cl H H 2-(cPr-2-CH2OEt) 0 0 229 Cl H H 2-{cPr-2-C(═NOMe)Me} 0 0 230 Cl H H 2-(cPr-2-COMe) 0 0 231 Cl H H 2-(cPr-2-COEt) 0 0 232 Cl H H 2-(cPr-2-COPh) 0 0 233 Cl H H 2-(cPr-2-CO2H) 0 0 234 Cl H H 2-(cPr-2-CO2Me) 0 0 235 Cl H H 2-(cPr-2-CO2Et) 0 0 236 Cl H H 2-(cPr-2-CONH2) 0 0 237 Cl H H 2-(cPr-2-CONMe2) 0 0 238 Cl H H 2-(cPr-2-CONEt2) 0 0 239 Cl H H 2-(cPr-2-NH2) 0 0 240 Cl H H 2-(cPr-2-NHMe) 0 0 241 Cl H H 2-(cPr-2-NMe2) 0 0 242 Cl H H 2-(cPr-2-NHCOMe) 0 0 243 Cl H H 2-(cPr-2-NHCO2Me) 0 0 244 Cl H H 2-(cPr-2-NHCONMe2) 0 0 245 Cl H H 2-(cPr-2-NHSO2Me) 0 0 246 Cl H H 2-(cPr-2-NO2) 0 0 247 Cl H H 2-(cPr-2-OH) 0 0 248 Cl H H 2-(cPr-2-OMe) 0 0 249 Cl H H 2-(cPr-2-OEt) 0 0 250 Cl H H 2-(cPr-2-OCF3) 0 0 251 Cl H H 2-(cPr-2-OPh) 0 0 252 Cl H H 2-(cPr-2-SMe) 0 0 253 Cl H H 2-(cPr-2-SEt) 0 0 254 Cl H H 2-(cPr-2-SPh) 0 0 255 Cl H H 2-(cPr-2-SOMe) 0 0 256 Cl H H 2-(cPr-2-SOEt) 0 0 257 Cl H H 2-(cPr-2-SO2Me) 0 0 258 Cl H H 2-(cPr-2-SO2Et) 0 0 259 Cl H H 2-(cPr-1,2-Me2) 0 0 260 Cl H H 2-(cPr-1-Me-2-Et) 0 0 261 Cl H H 2-(cPr-1-Et-2-Me) 0 0 262 Cl H H 2-(cPr-1,2-Et2) 0 0 263 Cl H H 2-{cPr-1,2-(CN)2} 0 0 264 Cl H H 2-(cPr-2,2-F2) 0 0 265 Cl H H 2-(cPr-2,2-Cl2) 0 0 266 Cl H H 2-(cPr-2,2-Br2) 0 0 267 Cl H H 2-(cPr-2,2-Me2) 0 0 268 Cl H H 2-{cPr-2,2-(CN)2} 0 0 269 Cl H H 2-(cPr-2-cis-3-cis-Me2) 0 0 270 Cl H H 2-(cPr-2-cis-3-trans-Me2) 0 0 271 Cl H H 2-(cPr-2-trans-3-trans-Me2) 0 0 272 Cl H H 2-{cPr-cis-2-(CH2)3-cis-3} 0 0 273 Cl H H 2-{cPr-trans-2-(CH2)3-trans-3} 0 0 274 Cl H H 2-{cPr-cis-2-(CH2)4-cis-3} 0 0 275 Cl H H 2-(cPr-trans-2-(CH2)4-trans-3) 0 0 276 Cl H H 2-{cPr-2,3-(CN)2} 0 0 277 Cl H H 2-(cPr-1,2,2-Me3) 0 0 278 Cl H H 2-(cPr-1,2,3-Me3) 0 0 279 Cl H H 2-(cPr-2,2,3-cis-Me3) 0 0 280 Cl H H 2-(cPr-2,2,3-trans-Me3) 0 0 281 Cl H H 2-(cPr-1,2,2,3-Me4) 0 0 282 Cl H H 2-(cPr-2,2,3,3-Me4) 0 0 283 Cl H H 2-(cPr-1,2,2,3,3-Me5) 0 0 284 Cl H H 2-cBu 0 0 285 Cl H H 2-(cBu-1-Me) 0 0 286 Cl H H 2-(cBu-1-CH═CH2) 0 0 287 Cl H H 2-(cBu-1-CN) 0 0 288 Cl H H 2-(cBu-1-CO2H) 0 0 289 Cl H H 2-(cBu-1-COMe) 0 0 290 Cl H H 2-(cBu-1-CO2Me) 0 0 291 Cl H H 2-(cBu-1-NH2) 0 0 292 Cl H H 2-cPen 0 0 293 Cl H H 2-cHx 0 0 294 Cl H H 2-CH2F 0 0 295 Cl H H 2-CH2Cl 0 0 296 Cl H H 2-CH2Br 0 0 297 Cl H H 2-CHF2 0 0 298 Cl H H 2-CHCl2 0 0 299 Cl H H 2-CHBr2 0 0 300 Cl H H 2-CF3 0 0 301 Cl H H 2-CCl3 0 0 302 Cl H H 2-CBr3 0 0 303 Cl H H 2-CH═CH2 0 0 304 Cl H H 2-CMe═CH2 0 0 305 Cl H H 2-CH═CHMe 0 0 306 Cl H H 2-CH═CHCN 0 0 307 Cl H H 2-CH2CH═CH2 0 0 308 Cl H H 2-C CH 0 0 309 Cl H H 2-C CMe 0 0 310 Cl H H 2-C CSiMe3 0 0 311 Cl H H 2-CH2cPr 0 0 312 Cl H H 2-CH2cBu 0 0 313 Cl H H 2-CH2cPen 0 0 314 Cl H H 2-CH2cHx 0 0 315 Cl H H 2-CH2Ph 0 0 316 Cl H H 2-CH2CN 0 0 317 Cl H H 2-CHMeCN 0 0 318 Cl H H 2-CMe2CN 0 0 319 Cl H H 2-CH2COMe 0 0 320 Cl H H 2-CH2CO2Me 0 0 321 Cl H H 2-CHMeCO2Me 0 0 322 Cl H H 2-CH2CO2Et 0 0 323 Cl H H 2-CHMeCO2Et 0 0 324 Cl H H 2-CH2OMe 0 0 325 Cl H H 2-CH2OEt 0 0 326 Cl H H 2-CH2SMe 0 0 327 Cl H H 2-CH2SO2Et 0 0 328 Cl H H 2-CH(OMe)2 0 0 329 Cl H H 2-CH(OCH2)2 0 0 330 Cl H H 2-CN 0 0 331 Cl H H 2-CH═NOH 0 0 332 Cl H H 2-CH═NOMe 0 0 333 Cl H H 2-CMe═NOH 0 0 334 Cl H H 2-CMe═NOMe 0 0 335 Cl H H 2-CHO 0 0 336 Cl H H 2-COMe 0 0 337 Cl H H 2-COtBu 0 0 338 Cl H H 2-COPh 0 0 339 Cl H H 2-CO2Me 0 0 340 Cl H H 2-CO2tBu 0 0 341 Cl H H 2-CO2H 0 0 342 Cl H H 2-CONH2 0 0 343 Cl H H 2-CONMe2 0 0 344 Cl H H 2-Ph 0 0 345 Cl H H 2-(Ph-2-Cl) 0 0 346 Cl H H 2-(Ph-2-Me) 0 0 347 Cl H H 2-(Ph-2-CF3) 0 0 348 Cl H H 2-(Ph-3-CF3) 0 0 (Isomer A) 349 Cl H H 2-(Ph-3-CF3) 0 0 (Isomer B) 350 Cl H H 2-(1-Azr) 0 0 351 Cl H H 2-(2-Azr) 0 0 352 Cl H H 2-{2-Azr-1-SO2_(Ph-4-Me)} 0 0 353 Cl H H 2-(2-Q1-2-Me) 0 0 354 Cl H H 2-(2-Q1-3-Me) 0 0 355 Cl H H 2-(1-Pyrd) 0 0 356 Cl H H 2-(1-Pyrr) 0 0 357 Cl H H 2-(2-Fur) 0 0 358 Cl H H 2-(3-Fur) 0 0 359 Cl H H 2-(2-Thi) 0 0 360 Cl H H 2-(2-Thi-3-Cl) 0 0 361 Cl H H 2-(3-Thi) 0 0 362 Cl H H 2-(1-Pyza) 0 0 363 Cl H H 2-(1-Pyza-3-Me) 0 0 364 Cl H H 2-(1-Pyza-3,5-Me2) 0 0 365 Cl H H 2-(1-Pyza-3-CF3) 0 0 366 Cl H H 2-(1-Pyza-4-CF3) 0 0 367 Cl H H 2-(1-Pyza-5-CF3) 0 0 368 Cl H H 2-(3-Pyza-1-SO2NMe2) 0 0 369 Cl H H 2-(5-Pyza-1-SO2NMe2) 0 0 370 Cl H H 2-(2-Thiz-4-Me) 0 0 371 Cl H H 2-(2-Pyr) 0 0 372 Cl H H 2-(3-Pyr) 0 0 373 Cl H H 2-(4-Pyr) 0 0 374 Cl H H 2-(1-Pyr-2-OH) 0 0 375 Cl H H 2-(2-Q2) 0 0 376 Cl H H 2-(2-Q3) 0 0 377 Cl H H 2-NH2 0 0 378 Cl H H 2-NHMe 0 0 379 Cl H H 2-NMe2 0 0 380 Cl H H 2-NHCOMe 0 0 381 Cl H H 2-NHCO2Me 0 0 382 Cl H H 2-NHCONMe2 0 0 383 Cl H H 2-NO2 0 0 384 Cl H H 2-OH 0 0 385 Cl H H 2-OMe 0 0 386 Cl H H 2-OEt 0 0 387 Cl H H 2-OiPr 0 0 388 Cl H H 2-OtBu 0 0 389 Cl H H 2-OCH2F 0 0 390 Cl H H 2-OCHF2 0 0 391 Cl H H 2-OCF3 0 0 392 Cl H H 2-OCH2CF3 0 0 393 Cl H H 2-OCH2CCl3 0 0 394 Cl H H 2-OCH2OMe 0 0 395 Cl H H 2-OCH2OEt 0 0 396 Cl H H 2-OCH2CH2OMe 0 0 397 Cl H H 2-OCH2CH2OEt 0 0 398 Cl H H 2-OPh 0 0 399 Cl H H 2-O(Ph-2-OH) 0 0 400 Cl H H 2-O{Ph-2-O(3-Pyzn-6-Cl-4-OEt)} 0 0 401 Cl H H 2-SMe 0 0 402 Cl H H 2-SEt 0 0 403 Cl H H 2-S-iPr 0 0 404 Cl H H 2-SOMe 0 0 405 Cl H H 2-SOEt 0 0 406 Cl H H 2-SO2Me 0 0 407 Cl H H 2-SO2Et 0 0 408 Cl H H 2-SiMe3 0 0 409 Cl H H 3-F 0 0 410 Cl H H 3-Cl 0 0 411 Cl H H 3-Br 0 0 412 Cl H H 3-I 0 0 413 Cl H H 3-Me 0 0 414 Cl H H 3-Et 0 0 415 Cl H H 3-iPr 0 0 416 Cl H H 3-tBu 0 0 417 Cl H H 3-cPr 0 0 418 Cl H H 3-CF3 0 0 419 Cl H H 3-(2-Fur) 0 0 420 Cl H H 3-CN 0 0 421 Cl H H 3-CHO 0 0 422 Cl H H 3-COMe 0 0 423 Cl H H 3-CO2Me 0 0 424 Cl H H 3-NO2 0 0 425 Cl H H 3-OMe 0 0 426 Cl H H 4-F 0 0 427 Cl H H 4-Cl 0 0 428 Cl H H 4-Br 0 0 429 Cl H H 4-I 0 0 430 Cl H H 4-Me 0 0 431 Cl H H 4-Et 0 0 432 Cl H H 4-iPr 0 0 433 Cl H H 4-tBu 0 0 434 Cl H H 4-cPr 0 0 435 Cl H H 4-OMe 0 0 436 Cl H H 4-SiMe3 0 0 437 Cl H H 2,3-F2 0 0 438 Cl H H 2-F, 3-Cl 0 0 439 Cl H H 2-F, 3-Br 0 0 440 Cl H H 2-F, 3-Me 0 0 441 Cl H H 2-F, 3-CF3 0 0 442 Cl H H 2-Cl, 3-F 0 0 443 Cl H H 2,3-Cl2 0 0 444 Cl H H 2-Cl, 3-Br 0 0 445 Cl H H 2-Cl, 3-Me 0 0 446 Cl H H 2-Cl, 3-CF3 0 0 447 Cl H H 2-Cl, 3-OMe 0 0 448 Cl H H 2-Br, 3-F 0 0 449 Cl H H 2-Br, 3-Cl 0 0 450 Cl H H 2-Br, 3-Me 0 0 451 Cl H H 2-Br, 3-CF3 0 0 452 Cl H H 2-Br, 3-OMe 0 0 453 Cl H H 2-Me, 3-F 0 0 454 Cl H H 2-Me, 3-Cl 0 0 455 Cl H H 2-Me, 3-Br 0 0 456 Cl H H 2,3-Me2 0 0 457 Cl H H 2-Me, 3-CF3 0 0 458 Cl H H 2-Me, 3-NO2 0 0 459 Cl H H 2-Me, 3-OMe 0 0 460 Cl H H 2-Me, 3-O(3-Pyzn-6-Cl-4-OH) 0 0 461 Cl H H 2-Et, 3-F 0 0 462 Cl H H 2-Et, 3-Cl 0 0 463 Cl H H 2-Et, 3-Br 0 0 464 Cl H H 2-Et, 3-Me 0 0 465 Cl H H 2-iPr, 3-F 0 0 466 Cl H H 2-iPr, 3-Cl 0 0 467 Cl H H 2-iPr, 3-Me 0 0 468 Cl H H 2-iPr, 3-Et 0 0 469 Cl H H 2-cPr, 3-F 0 0 470 Cl H H 2-cPr, 3-Cl 0 0 471 Cl H H 2-cPr, 3-Br 0 0 472 Cl H H 2-cPr, 3-Me 0 0 473 Cl H H 2-cPr, 3-Et 0 0 474 Cl H H 2-cPr, 3-CF3 0 0 475 Cl H H 2-cPr, 3-CN 0 0 476 Cl H H 2-cPr, 3-CO2Me 0 0 477 Cl H H 2-cPr, 3-NO2 0 0 478 Cl H H 2-cPr, 3-OMe 0 0 479 Cl H H 2-cBu, 3-F 0 0 480 Cl H H 2-cBu, 3-Cl 0 0 481 Cl H H 2-cBu, 3-Br 0 0 482 Cl H H 2-cBu, 3-Me 0 0 483 Cl H H 2-CF3, 3-F 0 0 484 Cl H H 2-CF3, 3-Cl 0 0 485 Cl H H 2-CF3, 3-Br 0 0 486 Cl H H 2-CF3, 3-Me 0 0 487 Cl H H 2-CN, 3-F 0 0 488 Cl H H 2-CN, 3-Cl 0 0 489 Cl H H 2-CN, 3-Br 0 0 490 Cl H H 2-CN, 3-Me 0 0 491 Cl H H 2-CO2Me, 3-F 0 0 492 Cl H H 2-CO2Me, 3-Cl 0 0 493 Cl H H 2-CO2Me, 3-Br 0 0 494 Cl H H 2-CO2Me, 3-Me 0 0 495 Cl H H 2-NO2, 3-F 0 0 496 Cl H H 2-NO2, 3-Cl 0 0 497 Cl H H 2-NO2, 3-Br 0 0 498 Cl H H 2-NO2, 3-Me 0 0 499 Cl H H 2-OMe, 3-F 0 0 500 Cl H H 2-OMe, 3-Cl 0 0 501 Cl H H 2-OMe, 3-Br 0 0 502 Cl H H 2-OMe, 3-Me 0 0 503 Cl H H 2-OMe, 3-OMe 0 0 504 Cl H H 2-CH2-3 0 0 505 Cl H H 2-CH2CH2-3 0 0 506 Cl H H 2-CH2CH2CH2-3 0 0 507 Cl H H 2-CHMeCH2CH2-3 0 0 508 Cl H H 2-CH(OMe)CH2CH2-3 0 0 509 Cl H H 2-CH2CHMeCH2-3 0 0 510 Cl H H 2-CH2CH2CHMe-3 0 0 511 Cl H H 2-CMe2CH2CH2-3 0 0 512 Cl H H 2-C(OMe)2CH2CH2-3 0 0 513 Cl H H 2-CH2CMe2CH2-3 0 0 514 Cl H H 2-C(—CH2CH2—)—CH2CH2-3 0 0 515 Cl H H 2-CH(CH2)CH—CH2-3 0 0 516 Cl H H 2-CH2—CH(CH2)CH-3 0 0 517 Cl H H 2-C(═O)CH2CH2-3 0 0 518 Cl H H 2-CH2C(═O)CH2-3 0 0 519 Cl H H 2-CH2CH2C(═O)-3 0 0 520 Cl H H 2-C(═NOMe)CH2CH2-3 0 0 521 Cl H H 2-CH2CH2CH2CH2-3 0 0 522 Cl H H 2-CHMeCH2CH2CH2-3 0 0 523 Cl H H 2-CMe2CH2CH2CH2-3 0 0 524 Cl H H 2-C(—CH2CH2—)—CH2CH2CH2-3 0 0 525 Cl H H 2-CH(CH2)CH—CH2CH2-3 0 0 526 Cl H H 2-CH(OMe)CH2CH2CH2-3 0 0 527 Cl H H 2-CH═CHCH═CH-3 0 0 528 Cl H H 2-CH2CH2O-3 0 0 529 Cl H H 2-CHMeCH2O-3 0 0 530 Cl H H 2-CH2CHMeO-3 0 0 531 Cl H H 2-CH═CH—O-3 0 0 532 Cl H H 2-CMeCH—O-3 0 0 533 Cl H H 2-CH═CMe-O-3 0 0 534 Cl H H 2-CH═CH—S-3 0 0 535 Cl H H 2-N═CHCH═CH-3 0 0 (Isomer A) 536 Cl H H 2-N═CHCH═CH-3 0 0 (Isomer B) 537 Cl H H 2-N═CH—O-3 0 0 538 Cl H H 2-NCMe—O-3 0 0 539 Cl H H 2-OCH2CH2-3 0 0 540 Cl H H 2-OCMe2CH2-3 0 0 541 Cl H H 2-OCH═CH-3 0 0 542 Cl H H 2-OCMeCH-3 0 0 543 Cl H H 2-OCF2O-3 0 0 544 Cl H H 2-OCH2O-3 0 0 545 Cl H H 2-OCHMeO-3 0 0 546 Cl H H 2-OCMe2O-3 0 0 547 Cl H H 2-OCH2CH2O-3 0 0 548 Cl H H 2-OCH═N-3 0 0 549 Cl H H 2-OCMeN-3 0 0 550 Cl H H 2,4-F2 0 0 551 Cl H H 2-Cl, 4-F 0 0 552 Cl H H 2,4-Cl2 0 0 553 Cl H H 2-Br, 4-F 0 0 554 Cl H H 2,4-Br2 0 0 555 Cl H H 2-Br, 4-Me 0 0 556 Cl H H 2-Br, 4-tBu 0 0 557 Cl H H 2-Me, 4-F 0 0 558 Cl H H 2-Me, 4-Cl 0 0 559 Cl H H 2,4-Me2 0 0 560 Cl H H 2-Et, 4-F 0 0 561 Cl H H 2-Et, 4-Cl 0 0 562 Cl H H 2-Et, 4-I 0 0 563 Cl H H 2-Et, 4-Me 0 0 564 Cl H H 2-iPr, 4-F 0 0 565 Cl H H 2-iPr, 4-Cl 0 0 566 Cl H H 2-iPr, 4-Br 0 0 567 Cl H H 2-tBu, 4-Me 0 0 568 Cl H H 2-cPr, 4-F 0 0 569 Cl H H 2-cPr, 4-Cl 0 0 570 Cl H H 2-cPr, 4-Br 0 0 571 Cl H H 2-cPr, 4-Me 0 0 572 Cl H H 2-cPr, 4-Et 0 0 573 Cl H H 2-cPr, 4-CF3 0 0 574 Cl H H 2-cPr, 4-CN 0 0 575 Cl H H 2-cPr, 4-CO2Me 0 0 576 Cl H H 2-cPr, 4-NO2 0 0 577 Cl H H 2-cPr, 4-OMe 0 0 578 Cl H H 2-cBu, 4-F 0 0 579 Cl H H 2-cBu, 4-Cl 0 0 580 Cl H H 2-cBu, 4-Br 0 0 581 Cl H H 2-cBu, 4-Me 0 0 582 Cl H H 2-CF3, 4-F 0 0 583 Cl H H 2-CF3, 4-Cl 0 0 584 Cl H H 2-CF3, 4-Br 0 0 585 Cl H H 2-CF3, 4-Me 0 0 586 Cl H H 2-CN, 4-F 0 0 587 Cl H H 2-CN, 4-Cl 0 0 588 Cl H H 2-CN, 4-Br 0 0 589 Cl H H 2-CN, 4-Me 0 0 590 Cl H H 2-CO2Me, 4-F 0 0 591 Cl H H 2-CO2Me, 4-Cl 0 0 592 Cl H H 2-CO2Me, 4-Br 0 0 593 Cl H H 2-CO2Me, 4-Me 0 0 594 Cl H H 2-NO2, 4-F 0 0 595 Cl H H 2-NO2, 4-Cl 0 0 596 Cl H H 2-NO2, 4-Br 0 0 597 Cl H H 2-NO2, 4-Me 0 0 598 Cl H H 2-OMe, 4-F 0 0 599 Cl H H 2-OMe, 4-Cl 0 0 600 Cl H H 2-OMe, 4-Br 0 0 601 Cl H H 2-OMe, 4-Me 0 0 602 Cl H H 2,4-(OMe)2 0 0 603 Cl H H 2,5-F2 0 0 604 Cl H H 2-F, 5-Cl 0 0 605 Cl H H 2-F, 5-Br 0 0 606 Cl H H 2-F, 5-I 0 0 607 Cl H H 2-F, 5-Me 0 0 608 Cl H H 2-F, 5-CF3 0 0 609 Cl H H 2-F, 5-OMe 0 0 610 Cl H H 2-Cl, 5-F 0 0 611 Cl H H 2,5-Cl2 0 0 612 Cl H H 2-Cl, 5-Br 0 0 613 Cl H H 2-Cl, 5-I 0 0 614 Cl H H 2-Cl, 5-Me 0 0 615 Cl H H 2-Cl, 5-CF3 0 0 616 Cl H H 2-Cl, 5-OMe 0 0 617 Cl H H 2-Me, 5-F 0 0 618 Cl H H 2-Me, 5-Cl 0 0 619 Cl H H 2-Me, 5-Br 0 0 620 Cl H H 2-Me, 5-I 0 0 621 Cl H H 2,5-Me2 0 0 622 Cl H H 2-Me, 5-Et 0 0 623 Cl H H 2-Me, 5-iPr 0 0 624 Cl H H 2-Me, 5-CF3 0 0 625 Cl H H 2-Me, 5-CN 0 0 626 Cl H H 2-Me, 5-CO2H 0 0 627 Cl H H 2-Me, 5-NH2 0 0 628 Cl H H 2-Me, 5-NMe2 0 0 629 Cl H H 2-Me, 5-OMe 0 0 630 Cl H H 2-Et, 5-F 0 0 631 Cl H H 2-Et, 5-Cl 0 0 632 Cl H H 2-Et, 5-Br 0 0 633 Cl H H 2-Et, 5-Me 0 0 634 Cl H H 2-Et, 5-CN 0 0 635 Cl H H 2-Et, 5-OMe 0 0 636 Cl H H 2-iPr, 5-F 0 0 637 Cl H H 2-iPr, 5-Cl 0 0 638 Cl H H 2-iPr, 5-Br 0 0 639 Cl H H 2-iPr, 5-I 0 0 640 Cl H H 2-iPr, 5-Me 0 0 641 Cl H H 2-iPr, 5-Et 0 0 642 Cl H H 2-iPr, 5-iPr 0 0 643 Cl H H 2-iPr, 5-CF3 0 0 644 Cl H H 2-iPr, 5-CN 0 0 645 Cl H H 2-iPr, 5-OMe 0 0 646 Cl H H 2-tBu, 5-F 0 0 647 Cl H H 2-tBu, 5-Cl 0 0 648 Cl H H 2-tBu, 5-Br 0 0 649 Cl H H 2-tBu, 5-I 0 0 650 Cl H H 2-tBu, 5-Me 0 0 651 Cl H H 2-tBu, 5-Et 0 0 652 Cl H H 2-tBu, 5-iPr 0 0 653 Cl H H 2-tBu, 5-tBu 0 0 654 Cl H H 2-tBu, 5-cPr 0 0 655 Cl H H 2-tBu, 5-CF3 0 0 656 Cl H H 2-tBu, 5-CN 0 0 657 Cl H H 2-tBu, 5-OMe 0 0 658 Cl H H 2-cPr, 5-F 0 0 659 Cl H H 2-cPr, 5-Cl 0 0 660 Cl H H 2-cPr, 5-Br 0 0 661 Cl H H 2-cPr, 5-I 0 0 662 Cl H H 2-cPr, 5-Me 0 0 663 Cl H H 2-cPr, 5-Et 0 0 664 Cl H H 2-cPr, 5-iPr 0 0 665 Cl H H 2-cPr, 5-tBu 0 0 666 Cl H H 2-cPr, 5-CF3 0 0 667 Cl H H 2-cPr, 5-CN 0 0 668 Cl H H 2-cPr, 5-OMe 0 0 669 Cl H H 2-CF3, 5-F 0 0 670 Cl H H 2-CF3, 5-Cl 0 0 671 Cl H H 2-CF3, 5-Br 0 0 672 Cl H H 2-CF3, 5-I 0 0 673 Cl H H 2-CF3, 5-Me 0 0 674 Cl H H 2-CF3, 5-CN 0 0 675 Cl H H 2-CF3, 5-OMe 0 0 676 Cl H H 2-CH═CH2, 5-F 0 0 677 Cl H H 2-CH═CH2, 5-Cl 0 0 678 Cl H H 2-CHCH2, 5-Me 0 0 679 Cl H H 2-C═CHMe, 5-F 0 0 680 Cl H H 2-CH═CHMe, 5-Cl 0 0 681 Cl H H 2-CH═CHMe, 5-Me 0 0 682 Cl H H 2-CMe═CH2, 5-F 0 0 683 Cl H H 2-CMe═CH2, 5-Cl 0 0 684 Cl H H 2-CMe═CH2, 5-Me 0 0 685 Cl H H 2-CN, 5-F 0 0 686 Cl H H 2-CN, 5-Cl 0 0 687 Cl H H 2-CN, 5-Br 0 0 688 Cl H H 2-CN, 5-I 0 0 689 Cl H H 2-CN, 5-Me 0 0 690 Cl H H 2-CN, 5-CN 0 0 691 Cl H H 2-CN, 5-OMe 0 0 692 Cl H H 2-CHO, 5-NMe2 0 0 693 Cl H H 2-CO2Me, 5-F 0 0 694 Cl H H 2-CO2Me, 5-Cl 0 0 695 Cl H H 2-CO2Me, 5-Br 0 0 696 Cl H H 2-CO2Me, 5-I 0 0 697 Cl H H 2-CO2Me, 5-Me 0 0 698 Cl H H 2-CO2Me, 5-CN 0 0 699 Cl H H 2-CO2Me, 5-OMe 0 0 700 Cl H H 2-OMe, 5-F 0 0 701 Cl H H 2-OMe, 5-Cl 0 0 702 Cl H H 2-OMe, 5-Br 0 0 703 Cl H H 2-OMe, 5-I 0 0 704 Cl H H 2-OMe, 5-Me 0 0 705 Cl H H 2-OMe, 5-Et 0 0 706 Cl H H 2-OMe, 5-CF3 0 0 707 Cl H H 2-OMe, 5-CN 0 0 708 Cl H H 2-OMe, 5-NO2 0 0 709 Cl H H 2-OMe, 5-OMe 0 0 710 Cl H H 2,6-F2 0 0 711 Cl H H 2-F, 6-Cl 0 0 712 Cl H H 2-F, 6-Br 0 0 713 Cl H H 2-F, 6-I 0 0 714 Cl H H 2-F, 6-Me 0 0 715 Cl H H 2-F, 6-Et 0 0 716 Cl H H 2-F, 6-Pr 0 0 717 Cl H H 2-F, 6-iPr 0 0 718 Cl H H 2-F, 6-tBu 0 0 719 Cl H H 2-F, 6-cPr 0 0 720 Cl H H 2-F, 6-cBu 0 0 721 Cl H H 2-F, 6-cPen 0 0 722 Cl H H 2-F, 6-CF3 0 0 723 Cl H H 2-F, 6-CH2OMe 0 0 724 Cl H H 2-F, 6-CH2OEt 0 0 725 Cl H H 2-F, 6-CH2CH2OMe 0 0 726 Cl H H 2-F, 6-CH2SMe 0 0 727 Cl H H 2-F, 6-CH2SEt 0 0 728 Cl H H 2-F, 6-CHMeSEt 0 0 729 Cl H H 2-F, 6-CN 0 0 730 Cl H H 2-F, 6-CO2Me 0 0 731 Cl H H 2-F, 6-NO2 0 0 732 Cl H H 2-F, 6-OMe 0 0 733 Cl H H 2,6-Cl2 0 0 734 Cl H H 2-Cl, 6-Br 0 0 735 Cl H H 2-Cl, 6-I 0 0 736 Cl H H 2-Cl, 6-Me 0 0 737 Cl H H 2-Cl, 6-Et 0 0 738 Cl H H 2-Cl, 6-iPr 0 0 739 Cl H H 2-Cl, 6-tBu 0 0 740 Cl H H 2-Cl, 6-cPr 0 0 741 Cl H H 2-Cl, 6-cBu 0 0 742 Cl H H 2-Cl, 6-cPen 0 0 743 Cl H H 2-Cl, 6-CF3 0 0 744 Cl H H 2-Cl, 6-CH═CH2 0 0 745 Cl H H 2-Cl, 6-CH2CH═CH2 0 0 746 Cl H H 2-Cl, 6-CH2CMeCH2 0 0 747 Cl H H 2-Cl, 6-CH2OMe 0 0 748 Cl H H 2-Cl, 6-CH2OEt 0 0 749 Cl H H 2-Cl, 6-CH2CH2OMe 0 0 750 Cl H H 2-Cl, 6-CH2SMe 0 0 751 Cl H H 2-Cl, 6-CH2SEt 0 0 752 Cl H H 2-Cl, 6-CN 0 0 753 Cl H H 2-Cl, 6-CO2Me 0 0 754 Cl H H 2-Cl, 6-NO2 0 0 755 Cl H H 2-Cl, 6-OMe 0 0 756 Cl H H 2,6-Br2 0 0 757 Cl H H 2-Br, 6-I 0 0 758 Cl H H 2-Br, 6-Me 0 0 759 Cl H H 2-Br, 6-Et 0 0 760 Cl H H 2-Br, 6-iPr 0 0 761 Cl H H 2-Br, 6-tBu 0 0 762 Cl H H 2-Br, 6-cPr 0 0 763 Cl H H 2-Br, 6-cBu 0 0 764 Cl H H 2-Br, 6-cPen 0 0 765 Cl H H 2-Br, 6-cHx 0 0 766 Cl H H 2-Br, 6-CF3 0 0 767 Cl H H 2-Br, 6-CHCH2 0 0 768 Cl H H 2-Br, 6-CH2CHCH2 0 0 769 Cl H H 2-Br, 6-CH2CMe═CH2 0 0 770 Cl H H 2-Br, 6-CH2OMe 0 0 771 Cl H H 2-Br, 6-CH2OEt 0 0 772 Cl H H 2-Br, 6-CH2CH2OMe 0 0 773 Cl H H 2-Br, 6-CH2SMe 0 0 774 Cl H H 2-Br, 6-CH2SEt 0 0 775 Cl H H 2-Br, 6-CN 0 0 776 Cl H H 2-Br, 6-CO2Me 0 0 777 Cl H H 2-Br, 6-NO2 0 0 778 Cl H H 2-Br, 6-OMe 0 0 779 Cl H H 2,6-I2 0 0 780 Cl H H 2-I, 6-Me 0 0 781 Cl H H 2-I, 6-Et 0 0 782 Cl H H 2-I, 6-iPr 0 0 783 Cl H H 2-I, 6-tBu 0 0 784 Cl H H 2-I, 6-cPr 0 0 785 Cl H H 2-I, 6-cBu 0 0 786 Cl H H 2-I, 6-cPen 0 0 787 Cl H H 2-I, 6-cHx 0 0 788 Cl H H 2-I, 6-CF3 0 0 789 Cl H H 2-I, 6-CH═CH2 0 0 790 Cl H H 2-I, 6-CH2CH═CH2 0 0 791 Cl H H 2-I, 6-CH2CMeCH2 0 0 792 Cl H H 2-I, 6-CH2OMe 0 0 793 Cl H H 2-I, 6-CH2OEt 0 0 794 Cl H H 2-I, 6-CH2CH2OMe 0 0 795 Cl H H 2-I, 6-CH2SMe 0 0 796 Cl H H 2-I, 6-CH2SEt 0 0 797 Cl H H 2-I, 6-CN 0 0 798 Cl H H 2-I, 6-CO2Me 0 0 799 Cl H H 2-I, 6-NO2 0 0 800 Cl H H 2-I, 6-OMe 0 0 801 Cl H H 2,6-Me2 0 0 802 Cl H H 2-Me, 6-Et 0 0 803 Cl H H 2-Me, 6-iPr 0 0 804 Cl H H 2-Me, 6-sBu 0 0 805 Cl H H 2-Me, 6-tBu 0 0 806 Cl H H 2-Me, 6-cPr 0 0 807 Cl H H 2-Me, 6-(cPr-1-F) 0 0 808 Cl H H 2-Me, 6-(cPr-1-Cl) 0 0 809 Cl H H 2-Me, 6-(cPr-1-Br) 0 0 810 Cl H H 2-Me, 6-(cPr-1-I) 0 0 811 Cl H H 2-Me, 6-(cPr-1-Me) 0 0 812 Cl H H 2-Me, 6-(cPr-1-Et) 0 0 813 Cl H H 2-Me, 6-(cPr-1-cPr) 0 0 814 Cl H H 2-Me, 6-(cPr-1-CN) 0 0 815 Cl H H 2-Me, 6-(cPr-1-OMe) 0 0 816 Cl H H 2-Me, 6-(cPr-1-OEt) 0 0 817 Cl H H 2-Me, 6-(cPr-2-Me) 0 0 818 Cl H H 2-Me, 6-(cPr-2-Et) 0 0 819 Cl H H 2-Me, 6-(cPr-2-CN) 0 0 820 Cl H H 2-Me, 6-(cPr-2-OMe) 0 0 821 Cl H H 2-Me, 6-(cPr-2-OEt) 0 0 822 Cl H H 2-Me, 6-(cPr-2-OCF3) 0 0 823 Cl H H 2-Me, 6-(cPr-1,2-Me2) 0 0 824 Cl H H 2-Me, 6-{cPr-1,2-(CN)2} 0 0 825 Cl H H -Me, 6-(cPr-2,2-Me2) 0 0 826 Cl H H 2-Me, 6-(cPr-2,2-F2) 0 0 827 Cl H H 2-Me, 6-(cPr-2,2-Cl2) 0 0 828 Cl H H 2-Me, 6-(cPr-2,2-Br2) 0 0 829 Cl H H 2-Me, 6-{cPr-2,2-(CN)2} 0 0 830 Cl H H 2-Me, 6-cBu 0 0 831 Cl H H 2-Me, 6-cPen 0 0 832 Cl H H 2-Me, 6-cHx 0 0 833 Cl H H 2-Me, 6-CF3 0 0 834 Cl H H 2-Me, 6-CHCH2 0 0 835 Cl H H 2-Me, 6-CH2CH═CH2 0 0 836 Cl H H 2-Me, 6-CH═CH—NO2 0 0 837 Cl H H 2-Me, 6-CH2OMe 0 0 838 Cl H H 2-Me, 6-CH2OEt 0 0 839 Cl H H 2-Me, 6-CH2CH2OMe 0 0 840 Cl H H 2-Me, 6-CH2SMe 0 0 841 Cl H H 2-Me, 6-CH2SEt 0 0 842 Cl H H 2-Me, 6-CN 0 0 843 Cl H H 2-Me, 6-CO2Me 0 0 844 Cl H H 2-Me, 6-NO2 0 0 845 Cl H H 2-Me, 6-OMe 0 0 846 Cl H H 2,6-Et2 0 0 847 Cl H H 2-Et, 6-iPr 0 0 848 Cl H H 2-Et, 6-sBu 0 0 849 Cl H H 2-Et, 6-tBu 0 0 850 Cl H H 2-Et, 6-cPr 0 0 851 Cl H H 2-Et, 6-(cPr-1-F) 0 0 852 Cl H H 2-Et, 6-(cPr-1-Cl) 0 0 853 Cl H H 2-Et, 6-(cPr-1-Br) 0 0 854 Cl H H 2-Et, 6-(cPr-1-I) 0 0 855 Cl H H 2-Et, 6-(cPr-1-Me) 0 0 856 Cl H H 2-Et, 6-(cPr-1-Et) 0 0 857 Cl H H 2-Et, 6-(cPr-1-cPr) 0 0 858 Cl H H 2-Et, 6-(cPr-1-CN) 0 0 859 Cl H H 2-Et, 6-(cPr-1-OMe) 0 0 860 Cl H H 2-Et, 6-(cPr-1-OEt) 0 0 861 Cl H H 2-Et, 6-(cPr-2-Me) 0 0 862 Cl H H 2-Et, 6-(cPr-2-Et) 0 0 863 Cl H H 2-Et, 6-(cPr-2-CN) 0 0 864 Cl H H 2-Et, 6-(cPr-2-OMe) 0 0 865 Cl H H 2-Et, 6-(cPr-2-OEt) 0 0 866 Cl H H 2-Et, 6-(cPr-2-OCF3) 0 0 867 Cl H H 2-Et, 6-(cPr-1,2-Me2) 0 0 868 Cl H H 2-Et, 6-{cPr-1,2-(CN)2} 0 0 869 Cl H H 2-Et, 6-(cPr-2,2-Me2) 0 0 870 Cl H H 2-Et, 6-(cPr-2,2-F2) 0 0 871 Cl H H 2-Et, 6-(cPr-2,2-Cl2) 0 0 872 Cl H H 2-Et, 6-(cPr-2,2-Br2) 0 0 873 Cl H H 2-Et, 6-{cPr-2,2-(CN)2} 0 0 874 Cl H H 2-Et, 6-cBu 0 0 875 Cl H H 2-Et, 6-cPen 0 0 876 Cl H H 2-Et, 6-cHx 0 0 877 Cl H H 2-Et, 6-CF3 0 0 878 Cl H H 2-Et, 6-CH═CH2 0 0 879 Cl H H 2-Et, 6-CH2CH═CH2 0 0 880 Cl H H 2-Et, 6-CH2CMe═CH2 0 0 881 Cl H H 2-Et, 6-CH2OMe 0 0 882 Cl H H 2-Et, 6-CH2OEt 0 0 883 Cl H H 2-Et, 6-CH2CH2OMe 0 0 884 Cl H H 2-Et, 6-CH2SMe 0 0 885 Cl H H 2-Et, 6-CH2SEt 0 0 886 Cl H H 2-Et, 6-CN 0 0 887 Cl H H 2-Et, 6-CO2Me 0 0 888 Cl H H 2-Et, 6-NO2 0 0 889 Cl H H 2-Et, 6-OMe 0 0 890 Cl H H 2,6-Pr2 0 0 891 Cl H H 2-Pr, 6-iPr 0 0 892 Cl H H 2-Pr, 6-tBu 0 0 893 Cl H H 2-Pr, 6-cPr 0 0 894 Cl H H 2,6-iPr2 0 0 895 Cl H H 2-iPr, 6-tBu 0 0 896 Cl H H 2-iPr, 6-cPr 0 0 897 Cl H H 2-iPr, 6-cBu 0 0 898 Cl H H 2-iPr, 6-cPen 0 0 899 Cl H H 2-iPr, 6-cHx 0 0 900 Cl H H 2-iPr, 6-CF3 0 0 901 Cl H H 2-iPr, 6-CH═CH2 0 0 902 Cl H H 2-iPr, 6-CH2CH═CH2 0 0 903 Cl H H 2-iPr, 6-CH2CMe═CH2 0 0 904 Cl H H 2-iPr, 6-CH2OMe 0 0 905 Cl H H 2-iPr, 6-CH2OEt 0 0 906 Cl H H 2-iPr, 6-CH2CH2OMe 0 0 907 Cl H H 2-iPr, 6-CH2SMe 0 0 908 Cl H H 2-iPr, 6-CH2SEt 0 0 909 Cl H H 2-iPr, 6-CN 0 0 910 Cl H H 2-iPr, 6-CO2Me 0 0 911 Cl H H 2-iPr, 6-NO2 0 0 912 Cl H H 2-iPr, 6-OMe 0 0 913 Cl H H 2,6-tBu2 0 0 914 Cl H H 2-tBu, 6-cPr 0 0 915 Cl H H 2-tBu, 6-cBu 0 0 916 Cl H H 2-tBu, 6-cPen 0 0 917 Cl H H 2-tBu, 6-cHx 0 0 918 Cl H H 2-tBu, 6-CF3 0 0 919 Cl H H 2-tBu, 6-CHCH2 0 0 920 Cl H H 2-tBu, 6-CH2CH═CH2 0 0 921 Cl H H 2-tBu, 6-CH2CMe═CH2 0 0 922 Cl H H 2-tBu, 6-CH2OMe 0 0 923 Cl H H 2-tBu, 6-CH2OEt 0 0 924 Cl H H 2-tBu, 6-CH2CH2OMe 0 0 925 Cl H H 2-tBu, 6-CH2SMe 0 0 926 Cl H H 2-tBu, 6-CH2SEt 0 0 927 Cl H H 2-tBu, 6-CN 0 0 928 Cl H H 2-tBu, 6-CO2Me 0 0 929 Cl H H 2-tBu, 6-NO2 0 0 930 Cl H H 2-tBu, 6-OMe 0 0 931 Cl H H 2,6-cPr2 0 0 932 Cl H H 2-cPr, 6-(cPr-1-cPr) 0 0 933 Cl H H 2-cPr, 6-(cPr-1-CN) 0 0 934 Cl H H 2-cPr, 6-(cPr-1-OMe) 0 0 935 Cl H H 2-cPr, 6-(cPr-1-OEt) 0 0 936 Cl H H 2-cPr, 6-(cPr-2-Me) 0 0 937 Cl H H 2-cPr, 6-(cPr-2-Et) 0 0 938 Cl H H 2-cPr, 6-(cPr-2-CN) 0 0 939 Cl H H 2-cPr, 6-(cPr-2-OMe) 0 0 940 Cl H H 2-cPr, 6-(cPr-2-OEt) 0 0 941 Cl H H 2-cPr, 6-(cPr-2-OCF3) 0 0 942 Cl H H 2-cPr, 6-(cPr-1,2-Me2) 0 0 943 Cl H H 2-cPr, 6-{cPr-1,2-(CN)2} 0 0 944 Cl H H 2-cPr, 6-(cPr-2,2-Me2) 0 0 945 Cl H H 2-cPr, 6-(cPr-2,2-F2) 0 0 946 Cl H H 2-cPr, 6-(cPr-2,2-Cl2) 0 0 947 Cl H H 2-cPr, 6-(cPr-2,2-Br2) 0 0 948 Cl H H 2-cPr, 6-{cPr-2,2-(CN)2} 0 0 949 Cl H H 2-cPr, 6-cBu 0 0 950 Cl H H 2-cPr, 6-cPen 0 0 951 Cl H H 2-cPr, 6-cHx 0 0 952 Cl H H 2-cPr, 6-CF3 0 0 953 Cl H H 2-cPr, 6-CHCH2 0 0 954 Cl H H 2-cPr, 6-CH2CH═CH2 0 0 955 Cl H H 2-cPr, 6-CH2CMe═CH2 0 0 956 Cl H H 2-cPr, 6-CH2OMe 0 0 957 Cl H H 2-cPr, 6-CH2OEt 0 0 958 Cl H H 2-cPr, 6-CH2CH2OMe 0 0 959 Cl H H 2-cPr, 6-CH2SMe 0 0 960 Cl H H 2-cPr, 6-CH2SEt 0 0 961 Cl H H 2-cPr, 6-CN 0 0 962 Cl H H 2-cPr, 6-CO2Me 0 0 963 Cl H H 2-cPr, 6-NO2 0 0 964 Cl H H 2-cPr, 6-OMe 0 0 965 Cl H H 2-cPr, 6-OEt 0 0 966 Cl H H 2-cPr, 6-SMe 0 0 967 Cl H H 2-CF3, 6-CH═CH2 0 0 968 Cl H H 2-CF3, 6-CH2CH═CH2 0 0 969 Cl H H 2-CF3, 6-CH2CMeCH2 0 0 970 Cl H H 2-CF3, 6-CH2OMe 0 0 971 Cl H H 2-CF3, 6-CH2OEt 0 0 972 Cl H H 2-CF3, 6-CH2CH2OMe 0 0 973 Cl H H 2-CF3, 6-CH2SMe 0 0 974 Cl H H 2-CF3, 6-CH2SEt 0 0 975 Cl H H 2-CF3, 6-CN 0 0 976 Cl H H 2-CF3, 6-CO2Me 0 0 977 Cl H H 2-CF3, 6-NO2 0 0 978 Cl H H 2-CF3, 6-OMe 0 0 979 Cl H H 2,6-(CH═CHMe)2 0 0 980 Cl H H 2-CH═CHMe, 6-CN 0 0 981 Cl H H 2-CH═CHMe, 6-OMe 0 0 982 Cl H H 2,6-(CH2CH═CH2)2 0 0 983 Cl H H 2-CH2CH═CH2, 6-CN 0 0 984 Cl H H 2-CH2CH═CH2, 6-OMe 0 0 985 Cl H H 2,6-(CN)2 0 0 986 Cl H H 2-CN, 6-OMe 0 0 987 Cl H H 2,6-(OMe)2 0 0 988 Cl H H 3,5-F2 0 0 989 Cl H H 3-F, 5-Cl 0 0 990 Cl H H 3-F, 5-Br 0 0 991 Cl H H 3-F, 5-I 0 0 992 Cl H H 3,5-Cl2 0 0 993 Cl H H 3-Cl, 5-Br 0 0 994 Cl H H 3-Cl, 5-I 0 0 995 Cl H H 3,5-Br2 0 0 996 Cl H H 3-Br, 5-I 0 0 997 Cl H H 3,5-I2 0 0 998 Cl H H 3,5-Me2 0 0 999 Cl H H 3-Me, 5-Et 0 0 1000 Cl H H 3-Me, 5-iPr 0 0 1001 Cl H H 3-Me, 5-cPr 0 0 1002 Cl H H 3-Me, 5-cBu 0 0 1003 Cl H H 3-Me, 5-CF3 0 0 1004 Cl H H 3-Me, 5-CN 0 0 1005 Cl H H 3-Me, 5-NO2 0 0 1006 Cl H H 3-Me, 5-OMe 0 0 1007 Cl H H 3,5-iPr2 0 0 1008 Cl H H 3-iPr, 5-CF3 0 0 1009 Cl H H 3,5-(CF3)2 0 0 1010 Cl H H 2-F, 3,5-Me2 0 0 1011 Cl H H 2-Cl, 3,5-Me2 0 0 1012 Cl H H 2,3,5-Cl3 0 0 1013 Cl H H 2-Br, 3,5-Me2 0 0 1014 Cl H H 2-Br, 3,5-Cl2 0 0 1015 Cl H H 2-I, 3,5-Me2 0 0 1016 Cl H H 2,3,5-Me3 0 0 1017 Cl H H 2-Me, 3,5-Cl2 0 0 1018 Cl H H 2-Et, 3,5-Me2 0 0 1019 Cl H H 2-Et, 3,5-Cl2 0 0 1020 Cl H H 2-Pr, 3,5-Me2 0 0 1021 Cl H H 2-iPr, 3,5-Me2 0 0 1022 Cl H H 2-iPr, 3,5-Cl2 0 0 1023 Cl H H 2-cPr, 3,5-Me2 0 0 1024 Cl H H 2-cBu, 3,5-Me2 0 0 1025 Cl H H 2-CN, 3,5-Me2 0 0 1026 Cl H H 2-OMe, 3,5-Me2 0 0 1027 Cl H H 2-SMe, 3,5-Me2 0 0 1028 Cl H H 2-F, 3,6-Me2 0 0 1029 Cl H H 2-F, 3-Me, 6-cPr 0 0 1030 Cl H H 2-F, 3-Me, 6-OMe 0 0 1031 Cl H H 2-Cl, 3,6-Me2 0 0 1032 Cl H H 2-Cl, 3-Me, 6-cPr 0 0 1033 Cl H H 2-Cl, 3-Me, 6-OMe 0 0 1034 Cl H H 2,3,6-Cl3 0 0 1035 Cl H H 2,3-Cl2, 6-cPr 0 0 1036 Cl H H 2-Br, 3,6-Cl2 0 0 1037 Cl H H 2,6-Br2, 3-Cl 0 0 1038 Cl H H 2-Br, 3-Cl, 6-cPr 0 0 1039 Cl H H 2,6-Br2, 3-Me 0 0 1040 Cl H H 2-Br, 3,6-Me2 0 0 1041 Cl H H 2-Br, 3-Me, 6-cPr 0 0 1042 Cl H H 2-Br, 3-Me, 6-OMe 0 0 1043 Cl H H 2,2,3-CN 0 0 1044 Cl H H 2-Br, 3-CN, 6-cPr 0 0 1045 Cl H H 2,6-Br2, 3-OMe 0 0 1046 Cl H H 2-Br, 3-OMe, 6-cPr 0 0 1047 Cl H H 2-I, 3,6-Me2 0 0 1048 Cl H H 2-Me, 3,6-F2 0 0 1049 Cl H H 2-Me, 3-F, 6-Cl 0 0 1050 Cl H H 2-Me, 3-F, 6-Br 0 0 1051 Cl H H 2-Me, 3-F, 6-I 0 0 1052 Cl H H 2-Me, 3-F, 6-cPr 0 0 1053 Cl H H 2-Me, 3-Cl, 6-Br 0 0 1054 Cl H H 2-Me, 3-Cl, 6-I 0 0 1055 Cl H H 2-Me, 3-Cl, 6-cPr 0 0 1056 Cl H H 2,3-Me2, 6-F 0 0 1057 Cl H H 2,3-Me2, 6-Cl 0 0 1058 Cl H H 2,3-Me2, 6-Br 0 0 1059 Cl H H 2,3-Me2, 6-I 0 0 1060 Cl H H 2,3,6-Me3 0 0 1061 Cl H H 2,3-Me2, 6-cPr 0 0 1062 Cl H H 2,3-Me2, 6-CN 0 0 1063 Cl H H 2,3-Me2, 6-CH═NOMe 0 0 1064 Cl H H 2,3-Me2, 6-OMe 0 0 1065 Cl H H 2-Me, 3-OMe, 6-Cl 0 0 1066 Cl H H 2-Me, 3-OMe, 6-Br 0 0 1067 Cl H H 2-Me, 3-OMe, 6-I 0 0 1068 Cl H H 2,6-Me2, 3-OMe 0 0 1069 Cl H H 2-Me, 3-OMe, 6-cPr 0 0 1070 Cl H H 2-cPr, 3-Me, 6-F 0 0 1071 Cl H H 2-cPr, 3-Me, 6-Cl 0 0 1072 Cl H H 2-cPr, 3-Me, 6-Br 0 0 1073 Cl H H 2-cPr, 3,6-Me2 0 0 1074 Cl H H 2-cPr, 3-Me, 6-Et 0 0 1075 Cl H H 2,6-cPr2, 3-Me 0 0 1076 Cl H H 2-cPr, 3-Me, 6-CN 0 0 1077 Cl H H 2-cPr, 3-Me, 6-OMe 0 0 1078 Cl H H 2-cBu, 3,6-Me2 0 0 1079 Cl H H 2-CH2CHCH2, 3,6-Me2 0 0 1080 Cl H H 2-CH2CHCH2, 3-OMe, 6-Et 0 0 1081 Cl H H 2-CN, 3,6-Me2 0 0 1082 Cl H H 2-OMe, 3,6-Me2 0 0 1083 Cl H H 2-CH2SMe, 3,6-Me2 0 0 1084 Cl H H 6-F, 2-CH2CH2CH2-3 0 0 1085 Cl H H 6-Cl, 2-CH2CH2CH2-3 0 0 1086 Cl H H 6-Br, 2-CH2CH2CH2-3 0 0 1087 Cl H H 6-I, 2-CH2CH2CH2-3 0 0 1088 Cl H H 6-Me, 2-CH2CH2CH2-3 0 0 1089 Cl H H 6-Et, 2-CH2CH2CH2-3 0 0 1090 Cl H H 6-iPr, 2-CH2CH2CH2-3 0 0 1091 Cl H H 6-cPr, 2-CH2CH2CH2-3 0 0 1092 Cl H H 6-CN, 2-CH2CH2CH2-3 0 0 1093 Cl H H 6-OMe, 2-CH2CH2CH2-3 0 0 1094 Cl H H 6-Cl, 2-OCH2CH2-3 0 0 1095 Cl H H 6-Br, 2-OCH2CH2-3 0 0 1096 Cl H H 6-Me, 2-OCH2CH2-3 0 0 1097 Cl H H 6-Et, 2-OCH2CH2-3 0 0 1098 Cl H H 6-cPr, 2-OCH2CH2-3 0 0 1099 Cl H H 6-Br, 2-OCH═CH-3 0 0 1100 Cl H H 6-Me, 2-OCH═CH-3 0 0 1101 Cl H H 6-Et, 2-OCH═CH-3 0 0 1102 Cl H H 6-cPr, 2-OCH═CH-3 0 0 1103 Cl H H 6-Cl, 2-CH2CH2O-3 0 0 1104 Cl H H 6-Br, 2-CH2CH2O-3 0 0 1105 Cl H H 6-Me, 2-CH2CH2O-3 0 0 1106 Cl H H 6-Et, 2-CH2CH2O-3 0 0 1107 Cl H H 6-cPr, 2-CH2CH2O-3 0 0 1108 Cl H H 6-Br, 2-CH═CHO-3 0 0 1109 Cl H H 6-Me, 2-CHCHO-3 0 0 1110 Cl H H 6-Et, 2-CH═CHO-3 0 0 1111 Cl H H 6-cPr, 2-CH═CHO-3 0 0 1112 Cl H H 2,4,6-F3 0 0 1113 Cl H H 2,4-F2, 6-Me 0 0 1114 Cl H H 2,2,6-cPr 0 0 1115 Cl H H 2-F, 4,6-cPr2 0 0 1116 Cl H H 2,4,6-Cl3 0 0 1117 Cl H H 2,4,6-Br3 0 0 1118 Cl H H 2,4-Br2, 3,6-Me2 0 0 1119 Cl H H 2-Br, 4,6-Me2 0 0 1120 Cl H H 2,4-I2, 6-Et 0 0 1121 Cl H H 2-Me, 4-F, 6-cPr 0 0 1122 Cl H H 2,4,6-Me3 0 0 1123 Cl H H 2,2,6-cPr 0 0 1124 Cl H H 2-Br, 3,5,6-Me3 0 0 1125 Cl H H 2,3,5,6-Me4 0 0 1126 Cl H H 2,3,3,6-cPr 0 0 1127 Cl H H 2,3,5-Me3, 6-CN 0 0 1128 Cl H H 2,3,3,6-OMe 0 0 1129 Cl H H 5,6-Me2, 2-CH2CH2CH2-3 0 0 1130 Cl H H 5-Me, 6-cPr, 2-CH2CH2CH2-3 0 0 1131 Cl H H 5-Me, 6-CN, 2-CH2CH2CH2-3 0 0 1132 Cl H H 5-Me, 6-OMe, 2-CH2CH2CH2-3 0 0 1133 Cl H H 2-CH2CH2CH2-3,5-CH2CH2CH2-6 0 0 1134 Cl H COMe 2-F 0 0 1135 Cl H COMe 2-Cl 0 0 1136 Cl H COMe 2-Br 0 0 1137 Cl H COMe 2-I 0 0 1138 Cl H COMe 2-Me 0 0 1139 Cl H COMe 2-iPr 0 0 1140 Cl H COMe 2-cPr 0 0 1141 Cl H COMe 2-cBu 0 0 1142 Cl H COMe 2-CH2CH2CH2-3 0 0 1143 Cl H COMe 2-cPr, 5-Me 0 0 1144 Cl H COMe 2-OMe, 5-Me 0 0 1145 Cl H COMe 2-F, 6-iPr 0 0 1146 Cl H COMe 2-Cl, 6-cPr 0 0 1147 Cl H COMe 2-Br, 6-Me 0 0 1148 Cl H COMe 2-I, 6-Me 0 0 1149 Cl H COMe 2,6-Me2 0 0 1150 Cl H COMe 2-Me, 6-Et 0 0 1151 Cl H COMe 2-Me, 6-cPr 0 0 1152 Cl H COMe 2,6-cPr2 0 0 1153 Cl H COMe 2-cPr, 3,5-Me2 0 0 1154 Cl H COMe 2-cPr, 5,6-Me2 0 0 1155 Cl H COEt 2-Me 0 0 1156 Cl H COEt 2-iPr 0 0 1157 Cl H COEt 2-cPr 0 0 1158 Cl H COEt 2-CH2CH2CH2-3 0 0 1159 Cl H COEt 2,6-Me2 0 0 1160 Cl H COEt 2-Me, 6-cPr 0 0 1161 Cl H COPr 2-Me 0 0 1162 Cl H COPr 2-iPr 0 0 1163 Cl H COPr 2-cPr 0 0 1164 Cl H COPr 2-CH2CH2CH2-3 0 0 1165 Cl H COPr 2,6-Me2 0 0 1166 Cl H COPr 2-Me, 6-cPr 0 0 1167 Cl H COiPr 2-Me 0 0 1168 Cl H COiPr 2-iPr 0 0 1169 Cl H COiPr 2-cPr 0 0 1170 Cl H COiPr 2-CH2CH2CH2-3 0 0 1171 Cl H COiPr 2,6-Me2 0 0 1172 Cl H COiPr 2-Me, 6-cPr 0 0 1173 Cl H COBu 2-Me 0 0 1174 Cl H COBu 2-iPr 0 0 1175 Cl H COBu 2-cPr 0 0 1176 Cl H COBu 2-CH2CH2CH2-3 0 0 1177 Cl H COBu 2,6-Me2 0 0 1178 Cl H COBu 2-Me, 6-cPr 0 0 1179 Cl H COiBu 2-Me 0 0 1180 Cl H COiBu 2-iPr 0 0 1181 Cl H COiBu 2-cPr 0 0 1182 Cl H COiBu 2-CH2CH2CH2-3 0 0 1183 Cl H COiBu 2,6-Me2 0 0 1184 Cl H COiBu 2-Me, 6-cPr 0 0 1185 Cl H COsBu 2-Me 0 0 1186 Cl H COsBu 2-iPr 0 0 1187 Cl H COsBu 2-cPr 0 0 1188 Cl H COsBu 2-CH2CH2CH2-3 0 0 1189 Cl H COsBu 2,6-Me2 0 0 1190 Cl H COsBu 2-Me, 6-cPr 0 0 1191 Cl H COtBu 2-Cl 0 0 1192 Cl H COtBu 2-Br 0 0 1193 Cl H COtBu 2-I 0 0 1194 Cl H COtBu 2-Me 0 0 1195 Cl H COtBu 2-iPr 0 0 1196 Cl H COtBu 2-cPr 0 0 1197 Cl H COtBu 2-cBu 0 0 1198 Cl H COtBu 2-CH2CH2CH2-3 0 0 1199 Cl H COtBu 2-cPr, 5-Me 0 0 1200 Cl H COtBu 2-OMe, 5-Me 0 0 1201 Cl H COtBu 2-F, 6-iPr 0 0 1202 Cl H COtBu 2-Cl, 6-cPr 0 0 1203 Cl H COtBu 2-Br, 6-Me 0 0 1204 Cl H COtBu 2-I, 6-Me 0 0 1205 Cl H COtBu 2,6-Me2 0 0 1206 Cl H COtBu 2-Me, 6-Et 0 0 1207 Cl H COtBu 2-Me, 6-cPr 0 0 1208 Cl H COtBu 2,6-cPr2 0 0 1209 Cl H COtBu 2-cPr, 3,5-Me2 0 0 1210 Cl H COtBu 2-cPr, 5,6-Me2 0 0 1211 Cl H COtPen 2-Me 0 0 1212 Cl H COtPen 2-iPr 0 0 1213 Cl H COtPen 2-cPr 0 0 1214 Cl H COtPen 2-CH2CH2CH2-3 0 0 1215 Cl H COtPen 2,6-Me2 0 0 1216 Cl H COtPen 2-Me, 6-cPr 0 0 1217 Cl H COHx 2-Me 0 0 1218 Cl H COHx 2-iPr 0 0 1219 Cl H COHx 2-cPr 0 0 1220 Cl H COHx 2-CH2CH2CH2-3 0 0 1221 Cl H COHx 2,6-Me2 0 0 1222 Cl H COHx 2-Me, 6-cPr 0 0 1223 Cl H COC7H15 2-Me 0 0 1224 Cl H COC7H15 2-iPr 0 0 1225 Cl H COC7H15 2-cPr 0 0 1226 Cl H COC7H15 2-CH2CH2CH2-3 0 0 1227 Cl H COC7H15 2,6-Me2 0 0 1228 Cl H COC7H15 2-Me, 6-cPr 0 0 1229 Cl H COC8H17 2-Me 0 0 1230 Cl H COC8H17 2-iPr 0 0 1231 Cl H COC8H17 2-cPr 0 0 1232 Cl H COC8H17 2-CH2CH2CH2-3 0 0 1233 Cl H COC8H17 2,6-Me2 0 0 1234 Cl H COC8H17 2-Me, 6-cPr 0 0 1235 Cl H COC9H19 2-Cl 0 0 1236 Cl H COC9H19 2-Br 0 0 1237 Cl H COC9H19 2-I 0 0 1238 Cl H COC9H19 2-Me 0 0 1239 Cl H COC9H19 2-iPr 0 0 1240 Cl H COC9H19 2-cPr 0 0 1241 Cl H COC9H19 2-cBu 0 0 1242 Cl H COC9H19 2-CH2CH2CH2-3 0 0 1243 Cl H COC9H19 2-cPr, 5-Me 0 0 1244 Cl H COC9H19 2-OMe, 5-Me 0 0 1245 Cl H COC9H19 2-F, 6-iPr 0 0 1246 Cl H COC9H19 2-Cl, 6-cPr 0 0 1247 Cl H COC9H19 2-Br, 6-Me 0 0 1248 Cl H COC9H19 2-I, 6-Me 0 0 1249 Cl H COC9H19 2,6-Me2 0 0 1250 Cl H COC9H19 2-Me, 6-Et 0 0 1251 Cl H COC9H19 2-Me, 6-cPr 0 0 1252 Cl H COC9H19 2,6-cPr2 0 0 1253 Cl H COC9H19 2-cPr, 3,5-Me2 0 0 1254 Cl H COC9H19 2-cPr, 5,6-Me2 0 0 1255 Cl H COC14H29 2-Me 0 0 1256 Cl H COC14H29 2-iPr 0 0 1257 Cl H COC14H29 2-cPr 0 0 1258 Cl H COC14H29 2-CH2CH2CH2-3 0 0 1259 Cl H COC14H29 2,6-Me2 0 0 1260 Cl H COC14H29 2-Me, 6-cPr 0 0 1261 Cl H COcPr 2-Cl 0 0 1262 Cl H COcPr 2-Br 0 0 1263 Cl H COcPr 2-I 0 0 1264 Cl H COcPr 2-Me 0 0 1265 Cl H COcPr 2-iPr 0 0 1266 Cl H COcPr 2-cPr 0 0 1267 Cl H COcPr 2-cBu 0 0 1268 Cl H COcPr 2-CH2CH2CH2-3 0 0 1269 Cl H COcPr 2-cPr, 5-Me 0 0 1270 Cl H COcPr 2-OMe, 5-Me 0 0 1271 Cl H COcPr 2-F, 6-iPr 0 0 1272 Cl H COcPr 2-Cl, 6-cPr 0 0 1273 Cl H COcPr 2-Br, 6-Me 0 0 1274 Cl H COcPr 2-I, 6-Me 0 0 1275 Cl H COcPr 2,6-Me2 0 0 1276 Cl H COcPr 2-Me, 6-Et 0 0 1277 Cl H COcPr 2-Me, 6-cPr 0 0 1278 Cl H COcPr 2,6-cPr2 0 0 1279 Cl H COcPr 2-cPr, 3, 2 0 0 1280 Cl H COcPr 2-cPr, 5,6-Me2 0 0 1281 Cl H COcBu 2-Me 0 0 1282 Cl H COcBu 2-iPr 0 0 1283 Cl H COcBu 2-cPr 0 0 1284 Cl H COcBu 2-CH2CH2CH2-3 0 0 1285 Cl H COcBu 2,6-Me2 0 0 1286 Cl H COcBu 2-Me, 6-cPr 0 0 1287 Cl H COcPen 2-Me 0 0 1288 Cl H COcPen 2-iPr 0 0 1289 Cl H COcPen 2-cPr 0 0 1290 Cl H COcPen 2-CH2CH2CH2-3 0 0 1291 Cl H COePen 2,6-Me2 0 0 1292 Cl H COcPen 2-Me, 6-cPr 0 0 1293 Cl H COcHx 2-Me 0 0 1294 Cl H COcHx 2-iPr 0 0 1295 Cl H COcHx 2-cPr 0 0 1296 Cl H COcHx 2-CH2CH2CH2-3 0 0 1297 Cl H COcHx 2,6-Me2 0 0 1298 Cl H COcHx 2-Me, 6-cPr 0 0 1299 Cl H COCF3 2-Me 0 0 1300 Cl H COCF3 2-iPr 0 0 1301 Cl H COCF3 2-cPr 0 0 1302 Cl H COCF3 2-CH2CH2CH2-3 0 0 1303 Cl H COCF3 2,6-Me2 0 0 1304 Cl H COCF3 2-Me, 6-cPr 0 0 1305 Cl H COCH2Cl 2-Me 0 0 1306 Cl H COCH2Cl 2-iPr 0 0 1307 Cl H COCH2Cl 2-cPr 0 0 1308 Cl H COCH2Cl 2-CH2CH2CH2-3 0 0 1309 Cl H COCH2Cl 2,6-Me2 0 0 1310 Cl H COCH2Cl 2-Me, 6-cPr 0 0 1311 Cl H COCCl3 2-Me 0 0 1312 Cl H COCCl3 2-iPr 0 0 1313 Cl H COCCl3 2-cPr 0 0 1314 Cl H COCCl3 2-CH2CH2CH2-3 0 0 1315 Cl H COCCl3 2,6-Me2 0 0 1316 Cl H COCCl3 2-Me, 6-cPr 0 0 1317 Cl H COCH2Br 2-Me 0 0 1318 Cl H COCH2Br 2-iPr 0 0 1319 Cl H COCH2Br 2-cPr 0 0 1320 Cl H COCH2Br 2-CH2CH2CH2-3 0 0 1321 Cl H COCH2Br 2,6-Me2 0 0 1322 Cl H COCH2Br 2-Me, 6-cPr 0 0 1323 Cl H COCH2CF3 2-Me 0 0 1324 Cl H COCH2CF3 2-iPr 0 0 1325 Cl H COCH2CF3 2-cPr 0 0 1326 Cl H COCH2CF3 2-CH2CH2CH2-3 0 0 1327 Cl H COCH2CF3 2,6-Me2 0 0 1328 Cl H COCH2CF3 2-Me, 6-cPr 0 0 1329 Cl H COCHBrEt 2-Me 0 0 1330 Cl H COCHBrEt 2-iPr 0 0 1331 Cl H COCHBrEt 2-cPr 0 0 1332 Cl H COCHBrEt 2-CH2CH2CH2-3 0 0 1333 Cl H COCHBrEt 2,6-Me2 0 0 1334 Cl H COCHBrEt 2-Me, 6-cPr 0 0 1335 Cl H COCH2CH2CH2Cl 2-Me 0 0 1336 Cl H COCH2CH2CH2Cl 2-iPr 0 0 1337 Cl H COCH2CH2CH2Cl 2-cPr 0 0 1338 Cl H COCH2CH2CH2Cl 2-CH2CH2CH2-3 0 0 1339 Cl H COCH2CH2CH2Cl 2,6-Me2 0 0 1340 Cl H COCH2CH2CH2Cl 2-Me, 6-cPr 0 0 1341 Cl H COCH═CH2 2-Me 0 0 1342 Cl H COCH═CH2 2-iPr 0 0 1343 Cl H COCH═CH2 2-cPr 0 0 1344 Cl H COCH═CH2 2-CH2CH2CH2-3 0 0 1345 Cl H COCH═CH2 2,6-Me2 0 0 1346 Cl H COCH═CH2 2-Me, 6-cPr 0 0 1347 Cl H COCH═CHMe 2-Me 0 0 1348 Cl H COCH═CHMe 2-iPr 0 0 1349 Cl H COCH═CHMe 2-cPr 0 0 1350 Cl H COCH═CHMe 2-CH2CH2CH2-3 0 0 1351 Cl H COCH═CHMe 2,6-Me2 0 0 1352 Cl H COCH═CHMe 2-Me, 6-cPr 0 0 1353 Cl H COCH═CMe2 2-Me 0 0 1354 Cl H COCH═CMe2 2-iPr 0 0 1355 Cl H COCH═CMe2 2-cPr 0 0 1356 Cl H COCH═CMe2 2-CH2CH2CH2-3 0 0 1357 Cl H COCH═CMe2 2,6-Me2 0 0 1358 Cl H COCH═CMe2 2-Me, 6-cPr 0 0 1359 Cl H COCH═CHPh 2-Me 0 0 1360 Cl H COCH═CHPh 2-iPr 0 0 1361 Cl H COCH═CHPh 2-cPr 0 0 1362 Cl H COCH═CHPh 2-CH2CH2CH2-3 0 0 1363 Cl H COCH═CHPh 2,6-Me2 0 0 1364 Cl H COCH═CHPh 2-Me, 6-cPr 0 0 1365 Cl H COC CH 2-Me 0 0 1366 Cl H COC CH 2-iPr 0 0 1367 Cl H COC CH 2-cPr 0 0 1368 Cl H COC CH 2-CH2CH2CH2-3 0 0 1369 Cl H COC CH 2,6-Me2 0 0 1370 Cl H COC CH 2-Me, 6-cPr 0 0 1371 Cl H COCH2Ph 2-Me 0 0 1372 Cl H COCH2Ph 2-iPr 0 0 1373 Cl H COCH2Ph 2-cPr 0 0 1374 Cl H COCH2Ph 2-CH2CH2CH2-3 0 0 1375 Cl H COCH2Ph 2,6-Me2 0 0 1376 Cl H COCH2Ph 2-Me, 6-cPr 0 0 1377 Cl H COCH2CH2CO2Me 2-Me 0 0 1378 Cl H COCH2CH2CO2Me 2-iPr 0 0 1379 Cl H COCH2CH2CO2Me 2-cPr 0 0 1380 Cl H COCH2CH2CO2Me 2-CH2CH2CH2-3 0 0 1381 Cl H COCH2CH2CO2Me 2,6-Me2 0 0 1382 Cl H COCH2CH2CO2Me 2-Me, 6-cPr 0 0 1383 Cl H COPh 2-F 0 0 1384 Cl H COPh 2-Cl 0 0 1385 Cl H COPh 2-Br 0 0 1386 Cl H COPh 2-I 0 0 1387 Cl H COPh 2-Me 0 0 1388 Cl H COPh 2-Et 0 0 1389 Cl H COPh 2-iPr 0 0 1390 Cl H COPh 2-tBu 0 0 1391 Cl H COPh 2-cPr 0 0 1392 Cl H COPh 2-(cPr-1-Me) 0 0 1393 Cl H COPh 2-(cPr-2-Me) 0 0 1394 Cl H COPh 2-(cPr-2,2-Cl2) 0 0 1395 Cl H COPh 2-cBu 0 0 1396 Cl H COPh 4-SiMe3 0 0 1397 Cl H COPh 2-CH2CH2CH2-3 0 0 1398 Cl H COPh 2-CH═CHO-3 0 0 1399 Cl H COPh 2-CH2CH2O-3 0 0 1400 Cl H COPh 2-OCH═CH-3 0 0 1401 Cl H COPh 2-OCH2CH2-3 0 0 1402 Cl H COPh 2-cPr, 5-F 0 0 1403 Cl H COPh 2-cPr, 5-Cl 0 0 1404 Cl H COPh 2-cPr, 5-Me 0 0 1405 Cl H COPh 2-OMe, 5-Me 0 0 1406 Cl H COPh 2-F, 6-iPr 0 0 1407 Cl H COPh 2-F, 6-cPr 0 0 1408 Cl H COPh 2-Cl, 6-Me 0 0 1409 Cl H COPh 2-Cl, 6-cPr 0 0 1410 Cl H COPh 2-Br, 6-Me 0 0 1411 Cl H COPh 2-Br, 6-Et 0 0 1412 Cl H COPh 2-Br, 6-cPr 0 0 1413 Cl H COPh 2-I, 6-Me 0 0 1414 Cl H COPh 2-I, 6-Et 0 0 1415 Cl H COPh 2,6-Me2 0 0 1416 Cl H COPh 2-Me, 6-Et 0 0 1417 Cl H COPh 2-Me, 6-cPr 0 0 1418 Cl H COPh 2-Et, 6-cPr 0 0 1419 Cl H COPh 2-iPr, 6-cPr 0 0 1420 Cl H COPh 2-tBu, 6-cPr 0 0 1421 Cl H COPh 2,6-cPr2 0 0 1422 Cl H COPh 2-cPr, 6-OMe 0 0 1423 Cl H COPh 2-Br, 3,6-Me2 0 0 1424 Cl H COPh 2-cPr, 3,5-Me2 0 0 1425 Cl H COPh 2-cPr,4, 6-Me2 0 0 1426 Cl H COPh 2-Br, 5,6-Me2 0 0 1427 Cl H COPh 2-cPr, 5,6-Me2 0 0 1428 Cl H COPh 2-Br, 5-CH═CH—O-6 0 0 1429 Cl H COPh 2-Me, 5-CH2CH2CH2-6 0 0 1430 Cl H COPh 2-Me, 5-CH2CH2O-6 0 0 1431 Cl H COPh 2-Me, 5-CH═CH—O-6 0 0 1432 Cl H COPh 2-Et, 5-CH2CH2CH2-6 0 0 1433 Cl H COPh 2-cPr, 5-CH2CH2CH2-6 0 0 1434 Cl H COPh 2-cPr, 5-CH═CH—O-6 0 0 1435 Cl H COPh 2-Br, 3,5,6-Me3 0 0 1436 Cl H CO(Ph-2-Cl) 2-Me 0 0 1437 Cl H CO(Ph-2-Cl) 2-iPr 0 0 1438 Cl H CO(Ph-2-Cl) 2-cPr 0 0 1439 Cl H CO(Ph-2-Cl) 2-CH2CH2CH2-3 0 0 1440 Cl H CO(Ph-2-Cl) 2,6-Me2 0 0 1441 Cl H CO(Ph-2-Cl) 2-Me, 6-cPr 0 0 1442 Cl H CO(Ph-2-Me) 2-F 0 0 1443 Cl H CO(Ph-2-Me) 2-Cl 0 0 1444 Cl H CO(Ph-2-Me) 2-Br 0 0 1445 Cl H CO(Ph-2-Me) 2-I 0 0 1446 Cl H CO(Ph-2-Me) 2-Me 0 0 1447 Cl H CO(Ph-2-Me) 2-Et 0 0 1448 Cl H CO(Ph-2-Me) 2-iPr 0 0 1449 Cl H CO(Ph-2-Me) 2-tBu 0 0 1450 Cl H CO(Ph-2-Me) 2-sBu 0 0 1451 Cl H CO(Ph-2-Me) 2-(cPr-1-Me) 0 0 1452 Cl H CO(Ph-2-Me) 2-cPr 0 0 1453 Cl H CO(Ph-2-Me) 2-(cPr-2,2-Cl2) 0 0 1454 Cl H CO(Ph2-Me) 2-cBu 0 0 1455 Cl H CO(Ph-2-Me) 2-cHx 0 0 1456 Cl H CO(Ph-2-Me) 2-Ph 0 0 1457 Cl H CO(Ph-2-Me) 3-tBu 0 0 1458 Cl H CO(Ph-2-Me) 3-OMe 0 0 1459 Cl H CO(Ph-2-Me) 2-iPr, 5-Me 0 0 1460 Cl H CO(Ph-2-Me) 2-CH2CH2CH2-3 0 0 1461 Cl H CO(Ph-2-Me) 2-CH═CHCH═CH-3 0 0 1462 Cl H CO(Ph-2-Me) 2-CH═CHO-3 0 0 1463 Cl H CO(Ph-2-Me) 2-CH2CH2O-3 0 0 1464 Cl H CO(Ph-2-Me) 2-OCH═CH-3 0 0 1465 Cl H CO(Ph-2-Me) 2-OCH2CH2-3 0 0 1466 Cl H CO(Ph-2-Me) 2-cPr, 5-F 0 0 1467 Cl H CO(Ph-2-Me) 2-cPr, 5-Cl 0 0 1468 Cl H CO(Ph-2-Me) 2-cPr, 5-Me 0 0 1469 Cl H CO(Ph-2-Me) 2-OMe, 5-Me 0 0 1470 Cl H CO(Ph-2-Me) 2-F, 6-iPr 0 0 1471 Cl H CO(Ph-2-Me) 2-F, 6-cPr 0 0 1472 Cl H CO(Ph-2-Me) 2-Cl, 6-Me 0 0 1473 Cl H CO(Ph-2-Me) 2-Cl, 6-cPr 0 0 1474 Cl H CO(Ph-2-Me) 2-Br, 6-Me 0 0 1475 Cl H CO(Ph-2-Me) 2-Br, 6-Et 0 0 1476 Cl H CO(Ph-2-Me) 2-Br, 6-cPr 0 0 1477 Cl H CO(Ph-2-Me) 2-I, 6-Me 0 0 1478 Cl H CO(Ph-2-Me) 2-I, 6-Et 0 0 1479 Cl H CO(Ph-2-Me) 2,6-Me2 0 0 1480 Cl H CO(Ph-2-Me) 2-Me, 6-Et 0 0 1481 Cl H CO(Ph-2-Me) 2-Me, 6-cPr 0 0 1482 Cl H CO(Ph-2-Me) 2-Et, 6-cPr 0 0 1483 Cl H CO(Ph-2-Me) 2-iPr, 6-cPr 0 0 1484 Cl H CO(Ph-2-Me) 2-tBu, 6-cPr 0 0 1485 Cl H CO(Ph-2-Me) 2,6-cPr2 0 0 1486 Cl H CO(Ph-2-Me) 2-cPr, 6-OMe 0 0 1487 Cl H CO(Ph-2-Me) 2-Br, 3,6-Me2 0 0 1488 Cl H CO(Ph-2-Me) 2-cPr, 3,5-Me2 0 0 1489 Cl H CO(Ph-2-Me) 2-cPr, 4, 6-Me2 0 0 1490 Cl H CO(Ph-2-Me) 2-Br, 5,6-Me2 0 0 1491 Cl H CO(Ph-2-Me) 2-cPr, 5,6-Me2 0 0 1492 Cl H CO(Ph-2-Me) 2-Br, 5-CH═CH-O-6 0 0 1493 Cl H CO(Ph-2-Me) 2-Me, 5-CH2CH2CH2-6 0 0 1494 Cl H CO(Ph-2-Me) 2-Me, 5-CH2CH2O-6 0 0 1495 Cl H CO(Ph-2-Me) 2-Me, 5-CH═CH—O-6 0 0 1496 Cl H CO(Ph-2-Me) 2-Et, 5-CH2CH2CH2-6 0 0 1497 Cl H CO(Ph-2-Me) 2-cPr, 5-CH2CH2CH2-6 0 0 1498 Cl H CO(Ph-2-Me) 2-cPr, 5-CHCH—O-6 0 0 1499 Cl H CO(Ph-2-Me) 2-Br, 3,5,6-Me3 0 0 1500 Cl H CO(Ph-2-CN) 2-Me 0 0 1501 Cl H CO(Ph-2-CN) 2-iPr 0 0 1502 Cl H CO(Ph-2-CN) 2-cPr 0 0 1503 Cl H CO(Ph-2-CN) 2-CH2CH2CH2-3 0 0 1504 Cl H CO(Ph-2-CN) 2,6-Me2 0 0 1505 Cl H CO(Ph-2-CN) 2-Me, 6-cPr 0 0 1506 Cl H CO(Ph-2-OMe) 2-Cl 0 0 1507 Cl H CO(Ph-2-OMe) 2-Br 0 0 1508 Cl H CO(Ph-2-OMe) 2-I 0 0 1509 Cl H CO(Ph-2-OMe) 2-Me 0 0 1510 Cl H CO(Ph-2-OMe) 2-iPr 0 0 1511 Cl H CO(Ph-2-OMe) 2-cPr 0 0 1512 Cl H CO(Ph-2-OMe) 2-cBu 0 0 1513 Cl H CO(Ph-2-OMe) 2-CH2CH2CH2-3 0 0 1514 Cl H CO(Ph-2-OMe) 2-cPr, 5-Me 0 0 1515 Cl H CO(Ph-2-OMe) 2-OMe, 5-Me 0 0 1516 Cl H CO(Ph-2-OMe) 2-F, 6-iPr 0 0 1517 Cl H CO(Ph-2-OMe) 2-Cl, 6-cPr 0 0 1518 Cl H CO(Ph-2-OMe) 2-Br, 6-Me 0 0 1519 Cl H CO(Ph-2-OMe) 2-I, 6-Me 0 0 1520 Cl H CO(Ph-2-OMe) 2,6-Me2 0 0 1521 Cl H CO(Ph-2-OMe) 2-Me, 6-Et 0 0 1522 Cl H CO(Ph-2-OMe) 2-Me, 6-cPr 0 0 1523 Cl H CO(Ph-2-OMe) 2,6-cPr2 0 0 1524 Cl H CO(Ph-2-OMe) 2-cPr, 3,5-Me2 0 0 1525 Cl H CO(Ph-2-OMe) 2-cPr, 5,6-Me2 0 0 1526 Cl H CO(Ph-3-Me) 2-Me 0 0 1527 Cl H CO(Ph-3-Me) 2-iPr 0 0 1528 Cl H CO(Ph-3-Me) 2-cPr 0 0 1529 Cl H CO(Ph-3-Me) 2-CH2CH2CH2-3 0 0 1530 Cl H CO(Ph-3-Me) 2,6-Me2 0 0 1531 Cl H CO(Ph-3-Me) 2-Me, 6-cPr 0 0 1532 Cl H CO(Ph-4-Cl) 2-Me 0 0 1533 Cl H CO(Ph-4-Cl) 2-iPr 0 0 1534 Cl H CO(Ph-4-Cl) 2-cPr 0 0 1535 Cl H CO(Ph-4-Cl) 2-CH2CH2CH2-3 0 0 1536 Cl H CO(Ph-4-Cl) 2,6-Me2 0 0 1537 Cl H CO(Ph-4-Cl) 2-Me, 6-cPr 0 0 1538 Cl H CO(Ph-4-Br) 2-Me 0 0 1539 Cl H CO(Ph-4-Br) 2-iPr 0 0 1540 Cl H CO(Ph-4-Br) 2-cPr 0 0 1541 Cl H CO(Ph-4-Br) 2-CH2CH2CH2-3 0 0 1542 Cl H CO(Ph-4-Br) 2,6-Me2 0 0 1543 Cl H CO(Ph-4-Br) 2-Me, 6-cPr 0 0 1544 Cl H CO(Ph-4-I) 2-Me 0 0 1545 Cl H CO(Ph-4-I) 2-iPr 0 0 1546 Cl H CO(Ph-4-I) 2-cPr 0 0 1547 Cl H CO(Ph-4-I) 2-CH2CH2CH2-3 0 0 1548 Cl H CO(Ph-4-I) 2,6-Me2 0 0 1549 Cl H CO(Ph-4-I) 2-Me, 6-cPr 0 0 1550 Cl H CO(Ph-4-Me) 2-Cl 0 0 1551 Cl H CO(Ph-4-Me) 2-Br 0 0 1552 Cl H CO(Ph-4-Me) 2-I 0 0 1553 Cl H CO(Ph-4-Me) 2-Me 0 0 1554 Cl H CO(Ph-4-Me) 2-iPr 0 0 1555 Cl H CO(Ph-4-Me) 2-cPr 0 0 1556 Cl H CO(Ph-4-Me) 2-cBu 0 0 1557 Cl H CO(Ph-4-Me) 2-CH2CH2CH2-3 0 0 1558 Cl H CO(Ph-4-Me) 2-cPr, 5-Me 0 0 1559 Cl H CO(Ph-4-Me) 2-OMe, 5-Me 0 0 1560 Cl H CO(Ph-4-Me) 2-F, 6-iPr 0 0 1561 Cl H CO(Ph-4-Me) 2-Cl, 6-cPr 0 0 1562 Cl H CO(Ph-4-Me) 2-Br, 6-Me 0 0 1563 Cl H CO(Ph-4-Me) 2-I, 6-Me 0 0 1564 Cl H CO(Ph-4-Me) 2,6-Me2 0 0 1565 Cl H CO(Ph-4-Me) 2-Me, 6-Et 0 0 1566 Cl H CO(Ph-4-Me) 2-Me, 6-cPr 0 0 1567 Cl H CO(Ph-4-Me) 2-cPr2 0 0 1568 Cl H CO(Ph-4-Me) 2-cPr, 3,5-Me2 0 0 1569 Cl H CO(Ph-4-Me) 2-cPr, 5,6-Me2 0 0 1570 Cl H CO(Ph-4-tBu) 2-Me 0 0 1571 Cl H CO(Ph-4-tBu) 2-iPr 0 0 1572 Cl H CO(Ph-4-tBu) 2-cPr 0 0 1573 Cl H CO(Ph-4-tBu) 2-CH2CH2CH2-3 0 0 1574 Cl H CO(Ph-4-tBu) 2,6-Me2 0 0 1575 Cl H CO(Ph-4-tBu) 2-Me, 6-cPr 0 0 1576 Cl H CO(Ph-4-CO2Me) 2-Me 0 0 1577 Cl H CO(Ph-4-CO2Me) 2-iPr 0 0 1578 Cl H CO(Ph-4-CO2Me) 2-cPr 0 0 1579 Cl H CO(Ph-4-CO2Me) 2-CH2CH2CH2-3 0 0 1580 Cl H CO(Ph-4-CO2Me) 2,6-Me2 0 0 1581 Cl H CO(Ph-4-CO2Me) 2-Me, 6-cPr 0 0 1582 Cl H CO(Ph-4-COtBu) 2-Me 0 0 1583 Cl H CO(Ph-4-COtBu) 2-iPr 0 0 1584 Cl H CO(Ph-4-COtBu) 2-cPr 0 0 1585 Cl H CO(Ph-4-COtBu) 2-CH2CH2CH2-3 0 0 1586 Cl H CO(Ph-4-COtBu) 2,6-Me2 0 0 1587 Cl H CO(Ph-4-COtBu) 2-Me, 6-cPr 0 0 1588 Cl H CO(Ph-4-NO2) 2-Me 0 0 1589 Cl H CO(Ph-4-NO2) 2-iPr 0 0 1590 Cl H CO(Ph-4-NO2) 2-cPr 0 0 1591 Cl H CO(Ph-4-NO2) 2-CH2CH2CH2-3 0 0 1592 Cl H CO(Ph-4-NO2) 2,6-Me2 0 0 1593 Cl H CO(Ph-4-NO2) 2-Me, 6-cPr 0 0 1594 Cl H CO(Ph-4-OMe) 2-Me 0 0 1595 Cl H CO(Ph-4-OMe) 2-iPr 0 0 1596 Cl H CO(Ph-4-OMe) 2-cPr 0 0 1597 Cl H CO(Ph-4-OMe) 2-CH2CH2CH2-3 0 0 1598 Cl H CO(Ph-4-OMe) 2,6-Me2 0 0 1599 Cl H CO(Ph-4-OMe) 2-Me, 6-cPr 0 0 1600 Cl H CO(Ph-2,4-Cl2) 2-Cl 0 0 1601 Cl H CO(Ph-2,4-Cl2) 2-Br 0 0 1602 Cl H CO(Ph-2,4-Cl2) 2-I 0 0 1603 Cl H CO(Ph-2, 4-Cl2) 2-Me 0 0 1604 Cl H CO(Ph-2,4-Cl2) 2-iPr 0 0 1605 Cl H CO(Ph-2,4-Cl2) 2-cPr 0 0 1606 Cl H CO(Ph-2,4-Cl2) 2-cBu 0 0 1607 Cl H CO(Ph-2,4-Cl2) 2-CH2CH2CH2-3 0 0 1608 Cl H CO(Ph-2,4-Cl2) 2-cPr, 5-Me 0 0 1609 Cl H CO(Ph-2,4-Cl2) 2-OMe, 5-Me 0 0 1610 Cl H CO(Ph-2,4-Cl2) 2-F, 6-iPr 0 0 1611 Cl H CO(Ph-2,4-Cl2) 2-Cl, 6-cPr 0 0 1612 Cl H CO(Ph-2,4-Cl2) 2-Br, 6-Me 0 0 1613 Cl H CO(Ph-2,4-Cl2) 2-I, 6-Me 0 0 1614 Cl H CO(Ph-2,4-Cl2) 2,6-Me2 0 0 1615 Cl H CO(Ph-2,4-Cl2) 2-Me, 6-Et 0 0 1616 Cl H CO(Ph-2,4-Cl2) 2-Me, 6-cPr 0 0 1617 Cl H CO(Ph-2,4-Cl2) 2,6-cPr2 0 0 1618 Cl H CO(Ph-2,4-Cl2) 2-cPr, 3,5-Me2 0 0 1619 Cl H CO(Ph-2,4-Cl2) 2-cPr, 5,6-Me2 0 0 1620 Cl H CO(Ph-2-CO2Q5) 2-Me 0 0 1621 Cl H CO(Ph-2-CO2Q5) 2-iPr 0 0 1622 Cl H CO(Ph-2-CO2Q5) 2-cPr 0 0 1623 Cl H CO(Ph-2-CO2Q5) 2-CH2CH2CH2-3 0 0 1624 Cl H CO(Ph-2-CO2Q5) 2,6-Me2 0 0 1625 Cl H CO(Ph-2-CO2Q5) 2-Me, 6-cPr 0 0 1626 Cl H CO(Ph-3-CO2Q5) 2-Me 0 0 1627 Cl H CO(Ph-3-CO2Q5) 2-iPr 0 0 1628 Cl H CO(Ph-3-CO2Q5) 2-cPr 0 0 1629 Cl H CO(Ph-3-CO2Q5) 2-CH2CH2CH2-3 0 0 1630 Cl H CO(Ph-3-CO2Q5) 2,6-Me2 0 0 1631 Cl H CO(Ph-3-CO2Q5) 2-Me, 6-cPr 0 0 1632 Cl H CO(Ph-4-CO2Q5) 2-Me 0 0 1633 Cl H CO(Ph-4-CO2Q5) 2-iPr 0 0 1634 Cl H CO(Ph-4-CO2Q5) 2-cPr 0 0 1635 Cl H CO(Ph-4-CO2Q5) 2-CH2CH2CH2-3 0 0 1636 Cl H CO(Ph-4-CO2Q5) 2,6-Me2 0 0 1637 Cl H CO(Ph-4-CO2Q5) 2-Me, 6-cPr 0 0 1638 Cl H CO(2-Fur) 2-Me 0 0 1639 Cl H CO(2-Fur) 2-iPr 0 0 1640 Cl H CO(2-Fur) 2-cPr 0 0 1641 Cl H CO(2-Fur) 2-CH2CH2CH2-3 0 0 1642 Cl H CO(2-Fur) 2,6-Me2 0 0 1643 Cl H CO(2-Fur) 2-Me, 6-cPr 0 0 1644 Cl H CO(2-Thi) 2-Me 0 0 1645 Cl H CO(2-Thi) 2-iPr 0 0 1646 Cl H CO(2-Thi) 2-cPr 0 0 1647 Cl H CO(2-Thi) 2-CH2CH2CH2-3 0 0 1648 Cl H CO(2-Thi) 2,6-Me2 0 0 1649 Cl H CO(2-Thi) 2-Me, 6-cPr 0 0 1650 Cl H CO2Me 2-F 0 0 1651 Cl H CO2Me 2-Cl 0 0 1652 Cl H CO2Me 2-Br 0 0 1653 Cl H CO2Me 2-I 0 0 1654 Cl H CO2Me 2-Me 0 0 1655 Cl H CO2Me 2-Et 0 0 1656 Cl H CO2Me 2-iPr 0 0 1657 Cl H CO2Me 2-tBu 0 0 1658 Cl H CO2Me 2-cPr 0 0 1659 Cl H CO2Me 2-(cPr-1-Me) 0 0 1660 Cl H CO2Me 2-(cPr-2-Me) 0 0 1661 Cl H CO2Me 2-(cPr-2,2-Cl2) 0 0 1662 Cl H CO2Me 2-cBu 0 0 1663 Cl H CO2Me 2-CH2CH2CH2-3 0 0 1664 Cl H CO2Me 2-CHCH—O-3 0 0 1665 Cl H CO2Me 2-CH2CH2O-3 0 0 1666 Cl H CO2Me 2-OCH═CH-3 0 0 1667 Cl H CO2Me 2-OCH2CH23 0 0 1668 Cl H CO2Me 2-cPr, 5-F 0 0 1669 Cl H CO2Me 2-cPr, 5-Cl 0 0 1670 Cl H CO2Me 2-cPr, 5-Me 0 0 1671 Cl H CO2Me 2-OMe, 5-Me 0 0 1672 Cl H CO2Me 2-F, 6-iPr 0 0 1673 Cl H CO2Me 2-F, 6-cPr 0 0 1674 Cl H CO2Me 2-Cl, 6-Me 0 0 1675 Cl H CO2Me 2-Cl, 6-cPr 0 0 1676 Cl H CO2Me 2-Br, 6-Me 0 0 1677 Cl H CO2Me 2-Br, 6-Et 0 0 1678 Cl H CO2Me 2-Br, 6-cPr 0 0 1679 Cl H CO2Me 2-I, 6-Me 0 0 1680 Cl H CO2Me 2-I, 6-Et 0 0 1681 Cl H CO2Me 2,6-Me2 0 0 1682 Cl H CO2Me 2-Me, 6-Et 0 0 1683 Cl H CO2Me 2-Me, 6-cPr 0 0 1684 Cl H CO2Me 2-Et, 6-cPr 0 0 1685 Cl H CO2Me 2-iPr, 6-cPr 0 0 1686 Cl H CO2Me 2-tBu, 6-cPr 0 0 1687 Cl H CO2Me 2,6-cPr2 0 0 1688 Cl H CO2Me 2-cPr, 6-OMe 0 0 1689 Cl H CO2Me 2-Br, 3,6-Me2 0 0 1690 Cl H CO2Me 2-cPr, 3,2 0 0 1691 Cl H CO2Me 2-cPr, 4,6-Me2 0 0 1692 Cl H CO2Me 2-Br, 5,6-Me2 0 0 1693 Cl H CO2Me 2-cPr, 5,6-Me2 0 0 1694 Cl H CO2Me 2-Br, 5-CH═CH—O-6 0 0 1695 Cl H CO2Me 2-Me, 5-CH2CH2CH2-6 0 0 1696 Cl H CO2Me 2-Me, 5-CH2CH2O-6 0 0 1697 Cl H CO2Me 2-Me, 5-CHCH—O-6 0 0 1698 Cl H CO2Me 2-Et, 5-CH2CH2CH2-6 0 0 1699 Cl H CO2Me 2-cPr, 5-CH2CH2CH2-6 0 0 1700 Cl H CO2Me 2-cPr, 5-CHCH—O-6 0 0 1701 Cl H CO2Me 2-Br, 3,5,6-Me3 0 0 1702 Cl H CO2Et 2-F 0 0 1703 Cl H CO2Et 2-Cl 0 0 1704 Cl H CO2Et 2-Br 0 0 1705 Cl H CO2Et 2-I 0 0 1706 Cl H CO2Et 2-Me 0 0 1707 Cl H CO2Et 2-Et 0 0 1708 Cl H CO2Et 2-iPr 0 0 1709 Cl H CO2Et 2-tBu 0 0 1710 Cl H CO2Et 2-cPr 0 0 1711 Cl H CO2Et 2-(cPr-1-Me) 0 0 1712 Cl H CO2Et 2-(cPr-2-Me) 0 0 1713 Cl H CO2Et 2-(cPr-2,2-Cl2) 0 0 1714 Cl H CO2Et 2-cBu 0 0 1715 Cl H CO2Et 2-CH2CH2CH2-3 0 0 1716 Cl H CO2Et 2-CH═CH—O-3 0 0 1717 Cl H CO2Et 2-CH2CH2O-3 0 0 1718 Cl H CO2Et 2-OCH═CH-3 0 0 1719 Cl H CO2Et 2-OCH2CH2-3 0 0 1720 Cl H CO2Et 2-cPr, 5-F 0 0 1721 Cl H CO2Et 2-cPr, 5-Cl 0 0 1722 Cl H CO2Et 2-cPr, 5-Me 0 0 1723 Cl H CO2Et 2-OMe, 5-Me 0 0 1724 Cl H CO2Et 2-F, 6-iPr 0 0 1725 Cl H CO2Et 2-F, 6-cPr 0 0 1726 Cl H CO2Et 2-Cl, 6-Me 0 0 1727 Cl H CO2Et 2-Cl, 6-cPr 0 0 1728 Cl H CO2Et 2-Br, 6-Me 0 0 1729 Cl H CO2Et 2-Br, 6-Et 0 0 1730 Cl H CO2Et 2-Br, 6-cPr 0 0 1731 Cl H CO2Et 2-I, 6-Me 0 0 1732 Cl H CO2Et 2-I, 6-Et 0 0 1733 Cl H CO2Et 2,6-Me2 0 0 1734 Cl H CO2Et 2-Me, 6-Et 0 0 1735 Cl H CO2Et 2-Me, 6-cPr 0 0 1736 Cl H CO2Et 2-Et, 6-cPr 0 0 1737 Cl H CO2Et 2-iPr, 6-cPr 0 0 1738 Cl H CO2Et 2-tBu, 6-cPr 0 0 1739 Cl H CO2Et 2,6-cPr2 0 0 1740 Cl H CO2Et 2-cPr, 6-OMe 0 0 1741 Cl H CO2Et 2-Br, 3,6-Me2 0 0 1742 Cl H CO2Et 2-cPr, 3,5-Me2 0 0 1743 Cl H CO2Et 2-cPr, 4,6-Me2 0 0 1744 Cl H CO2Et 2-Br, 5,6-Me2 0 0 1745 Cl H CO2Et 2-cPr, 5,6-Me2 0 0 1746 Cl H CO2Et 2-Br, 5-CH═CH—O-6 0 0 1747 Cl H CO2Et 2-Me, 5-CH2CH2CH2-6 0 0 1748 Cl H CO2Et 2-Me, 5-CH2CH2O-6 0 0 1749 Cl H CO2Et 2-Me, 5-CHCH—O-6 0 0 1750 Cl H CO2Et 2-Et, 5-CH2CH2CH2-6 0 0 1751 Cl H CO2Et 2-cPr, 5-CH2CH2CH2-6 0 0 1752 Cl H CO2Et 2-cPr, 5-CHCH—O-6 0 0 1753 Cl H CO2Et 2-Br, 3,5,6-Me3 0 0 1754 Cl H CO2iBu 2-Cl 0 0 1755 Cl H CO2iBu 2-Br 0 0 1756 Cl H CO2iBu 2-I 0 0 1757 Cl H CO2iBu 2-Me 0 0 1758 Cl H CO2iBu 2-iPr 0 0 1759 Cl H CO2iBu 2-cPr 0 0 1760 Cl H CO2iBu 2-cBu 0 0 1761 Cl H CO2iBu 2-CH2CH2CH2-3 0 0 1762 Cl H CO2iBu 2-cPr, 5-Me 0 0 1763 Cl H CO2iBu 2-OMe, 5-Me 0 0 1764 Cl H CO2iBu 2-F, 6-iPr 0 0 1765 Cl H CO2iBu 2-Cl, 6-cPr 0 0 1766 Cl H CO2iBu 2-Br, 6-Me 0 0 1767 Cl H CO2iBu 2-I, 6-Me 0 0 1768 Cl H CO2iBu 2,6-Me2 0 0 1769 Cl H CO2iBu 2-Me, 6-Et 0 0 1770 Cl H CO2iBu 2-Me, 6-cPr 0 0 1771 Cl H CO2iBu 2,6-cPr2 0 0 1772 Cl H CO2iBu 2-cPr, 3,5-Me2 0 0 1773 Cl H CO2iBu 2-cPr, 5,6-Me2 0 0 1774 Cl H CO2Bu 2-Me 0 0 1775 Cl H CO2Bu 2-iPr 0 0 1776 Cl H CO2Bu 2-cPr 0 0 1777 Cl H CO2Bu 2-CH2CH2CH2-3 0 0 1778 Cl H CO2Bu 2,6-Me2 0 0 1779 Cl H CO2Bu 2-Me, 6-cPr 0 0 1780 Cl H CO2CH2Cl 2-Me 0 0 1781 Cl H CO2CH2Cl 2-iPr 0 0 1782 Cl H CO2CH2Cl 2-cPr 0 0 1783 Cl H CO2CH2Cl 2-CH2CH2CH2-3 0 0 1784 Cl H CO2CH2Cl 2,6-Me2 0 0 1785 Cl H CO2CH2Cl 2-Me, 6-cPr 0 0 1786 Cl H CO2CH2CCl3 2-Cl 0 0 1787 Cl H CO2CH2CCl3 2-Br 0 0 1788 Cl H CO2CH2CCl3 2-I 0 0 1789 Cl H CO2CH2CCl3 2-Me 0 0 1790 Cl H CO2CH2CCl3 2-iPr 0 0 1791 Cl H CO2CH2CCl3 2-cPr 0 0 1792 Cl H CO2CH2CCl3 2-cBu 0 0 1793 Cl H CO2CH2CCl3 2-CH2CH2CH2-3 0 0 1794 Cl H CO2CH2CCl3 2-cPr, 5-Me 0 0 1795 Cl H CO2CH2CCl3 2-OMe, 5-Me 0 0 1796 Cl H CO2CH2CCl3 2-F, 6-iPr 0 0 1797 Cl H CO2CH2CCl3 2-Cl, 6-cPr 0 0 1798 Cl H CO2CH2CCl3 2-Br, 6-Me 0 0 1799 Cl H CO2CH2CCl3 2-I, 6-Me 0 0 1800 Cl H CO2CH2CCl3 2,6-Me2 0 0 1801 Cl H CO2CH2CCl3 2-Me, 6-Et 0 0 1802 Cl H CO2CH2CCl3 2-Me, 6-cPr 0 0 1803 Cl H CO2CH2CCl3 2,6-cPr2 0 0 1804 Cl H CO2CH2CCl3 2-cPr, 3,5-Me2 0 0 1805 Cl H CO2CH2CCl3 2-cPr, 5,6-Me2 0 0 1806 Cl H CO2CH2CHCH2 2-Me 0 0 1807 Cl H CO2CH2CH═CH2 2-iPr 0 0 1808 Cl H CO2CH2CH═CH2 2-cPr 0 0 1809 Cl H CO2CH2CH═CH2 2-CH2CH2CH2-3 0 0 1810 Cl H CO2CH2CH═CH2 2,6-Me2 0 0 1811 Cl H CO2CH2CH═CH2 2-Me, 6-cPr 0 0 1812 Cl H CO2CH2Ph 2-Me 0 0 1813 Cl H CO2CH2Ph 2-iPr 0 0 1814 Cl H CO2CH2Ph 2-cPr 0 0 1815 Cl H CO2CH2Ph 2-CH2CH2CH2-3 0 0 1816 Cl H CO2CH2Ph 2,6-Me2 0 0 1817 Cl H CO2CH2Ph 2-Me, 6-cPr 0 0 1818 Cl H CO2CH2CH2OMe 2-Me 0 0 1819 Cl H CO2CH2CH2OMe 2-iPr 0 0 1820 Cl H CO2CH2CH2OMe 2-cPr 0 0 1821 Cl H CO2CH2CH2OMe 2-CH2CH2CH2-3 0 0 1822 Cl H CO2CH2CH2OMe 2,6-Me2 0 0 1823 Cl H CO2CH2CH2OMe 2-Me, 6-cPr 0 0 1824 Cl H CO2Ph 2-Cl 0 0 1825 Cl H CO2Ph 2-Br 0 0 1826 Cl H CO2Ph 2-I 0 0 1827 Cl H CO2Ph 2-Me 0 0 1828 Cl H CO2Ph 2-iPr 0 0 1829 Cl H CO2Ph 2-cPr 0 0 1830 Cl H CO2Ph 2-cBu 0 0 1831 Cl H CO2Ph 2-CH2CH2CH2-3 0 0 1832 Cl H CO2Ph 2-cPr, 5-Me 0 0 1833 Cl H CO2Ph 2-OMe, 5-Me 0 0 1834 Cl H CO2Ph 2-F, 6-iPr 0 0 1835 Cl H CO2Ph 2-Cl, 6-cPr 0 0 1836 Cl H CO2Ph 2-Br, 6-Me 0 0 1837 Cl H CO2Ph 2-I, 6-Me 0 0 1838 Cl H CO2Ph 2,6-Me2 0 0 1839 Cl H CO2Ph 2-Me, 6-Et 0 0 1840 Cl H CO2Ph 2-Me, 6-cPr 0 0 1841 Cl H CO2Ph 2,6-cPr2 0 0 1842 Cl H CO2Ph 2-cPr, 3,5-Me2 0 0 1843 Cl H CO2Ph 2-cPr, 5,6-Me2 0 0 1844 Cl H CO2(Ph-4-Cl) 2-Me 0 0 1845 Cl H CO2(Ph-4-Cl) 2-iPr 0 0 1846 Cl H CO2(Ph-4-Cl) 2-cPr 0 0 1847 Cl H CO2(Ph-4-Cl) 2-CH2CH2CH2-3 0 0 1848 Cl H CO2(Ph-4-Cl) 2,6-Me2 0 0 1849 Cl H CO2(Ph-4-Cl) 2-Me, 6-cPr 0 0 1850 Cl H CO2 (Ph-4-NO2) 2-Me 0 0 1851 Cl H CO2 (Ph-4-NO2) 2-iPr 0 0 1852 Cl H CO2 (Ph-4-NO2) 2-cPr 0 0 1853 Cl H CO2 (Ph-4-NO2) 2-CH2CH2CH2-3 0 0 1854 Cl H CO2 (Ph-4-NO2) 2,6-Me2 0 0 1855 Cl H CO2 (Ph-4-NO2) 2-Me, 6-cPr 0 0 1856 Cl H CO2 (1-Np) 2-Me 0 0 1857 Cl H CO2 (1-Np) 2-iPr 0 0 1858 Cl H CO2 (1-Np) 2-cPr 0 0 1859 Cl H CO2 (1-Np) 2-CH2CH2CH2-3 0 0 1860 Cl H CO2 (1-Np) 2,6-Me2 0 0 1861 Cl H CO2 (1-Np) 2-Me, 6-cPr 0 0 1862 Cl H CO2 (9-Q4) 2-Me 0 0 1863 Cl H CO2 (9-Q4) 2-iPr 0 0 1864 Cl H CO2 (9-Q4) 2-cPr 0 0 1865 Cl H CO2 (9-Q4) 2-CH2CH2CH2-3 0 0 1866 Cl H CO2 (9-Q4) 2,6-Me2 0 0 1867 Cl H CO2 (9-Q4) 2-Me, 6-cPr 0 0 1868 Cl H CO2Q5 2-Me 0 0 1869 Cl H CO2Q5 2-iPr 0 0 1870 Cl H CO2Q5 2-cPr 0 0 1871 Cl H CO2Q5 2-CH2CH2CH2-3 0 0 1872 Cl H CO2Q5 2,6-Me2 0 0 1873 Cl H CO2Q5 2-Me, 6-cPr 0 0 1874 Cl H CONMe2 2-Cl 0 0 1875 Cl H CONMe2 2-Br 0 0 1876 Cl H CONMe2 2-I 0 0 1877 Cl H CONMe2 2-Me 0 0 1878 Cl H CONMe2 2-iPr 0 0 1879 Cl H CONMe2 2-cPr 0 0 1880 Cl H CONMe2 2-cBu 0 0 1881 Cl H CONMe2 3-CF3 0 0 1882 Cl H CONMe2 2-CH2CH2CH2-3 0 0 1883 Cl H CONMe2 2-cPr, 5-Me 0 0 1884 Cl H CONMe2 2-OMe, 5-Me 0 0 1885 Cl H CONMe2 2-F, 6-iPr 0 0 1886 Cl H CONMe2 2-Cl, 6-cPr 0 0 1887 Cl H CONMe2 2-Br, 6-Me 0 0 1888 Cl H CONMe2 2-I, 6-Me 0 0 1889 Cl H CONMe2 2,6-Me2 0 0 1890 Cl H CONMe2 2-Me, 6-Et 0 0 1891 Cl H CONMe2 2-Me, 6-cPr 0 0 1892 Cl H CONMe2 2,6-cPr2 0 0 1893 Cl H CONMe2 2-cPr, 3,5-Me2 0 0 1894 Cl H CONMe2 2-cPr, 5,6-Me2 0 0 1895 Cl H CONEt2 2-Cl 0 0 1896 Cl H CONEt2 2-Br 0 0 1897 Cl H CONEt2 2-I 0 0 1898 Cl H CONEt2 2-Me 0 0 1899 Cl H CONEt2 2-iPr 0 0 1900 Cl H CONEt2 2-cPr 0 0 1901 Cl H CONEt2 2-cBu 0 0 1902 Cl H CONEt2 2-CH2CH2CH2-3 0 0 1903 Cl H CONEt2 2-cPr, 5-Me 0 0 1904 Cl H CONEt2 2-OMe, 5-Me 0 0 1905 Cl H CONEt2 2-F, 6-iPr 0 0 1906 Cl H CONEt2 2-Cl, 6-cPr 0 0 1907 Cl H CONEt2 2-Br, 6-Me 0 0 1908 Cl H CONEt2 2-I, 6-Me 0 0 1909 Cl H CONEt2 2,6-Me2 0 0 1910 Cl H CONEt2 2-Me, 6-Et 0 0 1911 Cl H CONEt2 2-Me, 6-cPr 0 0 1912 Cl H CONEt2 2,6-cPr2 0 0 1913 Cl H CONEt2 2-cPr, 3,5-Me2 0 0 1914 Cl H CONEt2 2-cPr, 5,6-Me2 0 0 1915 Cl H CON(iPr)2 2-Me 0 0 1916 Cl H CON(iPr)2 2-iPr 0 0 1917 Cl H CON(iPr)2 2-cPr 0 0 1918 Cl H CON(iPr)2 2-CH2CH2CH2-3 0 0 1919 Cl H CON(iPr)2 2,6-Me2 0 0 1920 Cl H CON(iPr)2 2-Me, 6-cPr 0 0 1921 Cl H CO-1-Pyrd 2-Cl 0 0 1922 Cl H CO-1-Pyrd 2-Br 0 0 1923 Cl H CO-1-Pyrd 2-I 0 0 1924 Cl H CO-1-Pyrd 2-Me 0 0 1925 Cl H CO-1-Pyrd 2-iPr 0 0 1926 Cl H CO-1-Pyrd 2-cPr 0 0 1927 Cl H CO-1-Pyrd 2-cBu 0 0 1928 Cl H CO-1-Pyrd 2-CH2CH2CH2-3 0 0 1929 Cl H CO-1-Pyrd 2-cPr, 5-Me 0 0 1930 Cl H CO-1-Pyrd 2-OMe, 5-Me 0 0 1931 Cl H CO-1-Pyrd 2-F, 6-iPr 0 0 1932 Cl H CO-1-Pyrd 2-Cl, 6-cPr 0 0 1933 Cl H CO-1-Pyrd 2-Br, 6-Me 0 0 1934 Cl H CO-1-Pyrd 2-I, 6-Me 0 0 1935 Cl H CO-1-Pyrd 2,6-Me2 0 0 1936 Cl H CO-1-Pyrd 2-Me, 6-Et 0 0 1937 Cl H CO-1-Pyrd 2-Me, 6-cPr 0 0 1938 Cl H CO-1-Pyrd 2,6-cPr2 0 0 1939 Cl H CO-1-Pyrd 2-cPr, 3,5-Me2 0 0 1940 Cl H CO-1-Pyrd 2-cPr, 5,6-Me2 0 0 1941 Cl H CONMePh 2-Me 0 0 1942 Cl H CONMePh 2-iPr 0 0 1943 Cl H CONMePh 2-cPr 0 0 1944 Cl H CONMePh 2-CH2CH2CH2-3 0 0 1945 Cl H CONMePh 2,6-Me2 0 0 1946 Cl H CONMePh 2-Me, 6-cPr 0 0 1947 Cl H CONPh2 2-Me 0 0 1948 Cl H CONPh2 2-iPr 0 0 1949 Cl H CONPh2 2-cPr 0 0 1950 Cl H CONPh2 2-CH2CH2CH2-3 0 0 1951 Cl H CONPh2 2,6-Me2 0 0 1952 Cl H CONPh2 2-Me, 6-cPr 0 0 1953 Cl H COSMe 2-Me 0 0 1954 Cl H COSMe 2-iPr 0 0 1955 Cl H COSMe 2-cPr 0 0 1956 Cl H COSMe 2-CH2CH2CH2-3 0 0 1957 Cl H COSMe 2,6-Me2 0 0 1958 Cl H COSMe 2-Me, 6-cPr 0 0 1959 Cl H COSC7H15 2-Me 0 0 1960 Cl H COSC7H15 2-iPr 0 0 1961 Cl H COSC7H15 2-cPr 0 0 1962 Cl H COSC7H15 2-CH2CH2CH2-3 0 0 1963 Cl H COSC7H15 2,6-Me2 0 0 1964 Cl H COSC7H15 2-Me, 6-cPr 0 0 1965 Cl H COScHx 2-Me 0 0 1966 Cl H COScHx 2-iPr 0 0 1967 Cl H COScHx 2-cPr 0 0 1968 Cl H COScHx 2-CH2CH2CH2-3 0 0 1969 Cl H COScHx 2,6-Me2 0 0 1970 Cl H COScHx 2-Me, 6-cPr 0 0 1971 Cl H COSPh 2-Me 0 0 1972 Cl H COSPh 2-iPr 0 0 1973 Cl H COSPh 2-cPr 0 0 1974 Cl H COSPh 2-CH2CH2CH2-3 0 0 1975 Cl H COSPh 2,6-Me2 0 0 1976 Cl H COSPh 2-Me, 6-cPr 0 0 1977 Cl H SO2Me 2-F 0 0 1978 Cl H SO2Me 2-Cl 0 0 1979 Cl H SO2Me 2-Br 0 0 1980 Cl H SO2Me 2-I 0 0 1981 Cl H SO2Me 2-Me 0 0 1982 Cl H SO2Me 2-Et 0 0 1983 Cl H SO2Me 2-iPr 0 0 1984 Cl H SO2Me 2-tBu 0 0 1985 Cl H SO2Me 2-cPr 0 0 1986 Cl H SO2Me 2-(cPr-1-Me) 0 0 1987 Cl H SO2Me 2-(cPr-2-Me) 0 0 1988 Cl H SO2Me 2-(cPr-2,2-Cl2) 0 0 1989 Cl H SO2Me 2-cBu 0 0 1990 Cl H SO2Me 2-CH2CH2CH2-3 0 0 1991 Cl H SO2Me 2-CH═CH—O-3 0 0 1992 Cl H SO2Me 2-CH2CH2O-3 0 0 1993 Cl H SO2Me 2-OCH═CH-3 0 0 1994 Cl H SO2Me 2OCH2CH2-3 0 0 1995 Cl H SO2Me 2-cPr, 5-F 0 0 1996 Cl H SO2Me 2-cPr, 5-Cl 0 0 1997 Cl H SO2Me 2-cPr, 5-Me 0 0 1998 Cl H SO2Me 2-OMe, 5-Me 0 0 1999 Cl H SO2Me 2-F, 6-iPr 0 0 2000 Cl H SO2Me 2-F, 6-cPr 0 0 2001 Cl H SO2Me 2-Cl, 6-Me 0 0 2002 Cl H SO2Me 2-Cl, 6-cPr 0 0 2003 Cl H SO2Me 2-Br, 6-Me 0 0 2004 Cl H SO2Me 2-Br, 6-Et 0 0 2005 Cl H SO2Me 2-Br, 6-cPr 0 0 2006 Cl H SO2Me 2-I, 6-Me 0 0 2007 Cl H SO2Me 2-I, 6-Et 0 0 2008 Cl H SO2Me 2,6-Me2 0 0 2009 Cl H SO2Me 2-Me, 6-Et 0 0 2010 Cl H SO2Me 2-Me, 6-cPr 0 0 2011 Cl H SO2Me 2-Et, 6-cPr 0 0 2012 Cl H SO2Me 2-iPr, 6-cPr 0 0 2013 Cl H SO2Me 2-tBu, 6-cPr 0 0 2014 Cl H SO2Me 2,6-cPr2 0 0 2015 Cl H SO2Me 2-cPr, 6-OMe 0 0 2016 Cl H SO2Me 2-Br, 3,6-Me2 0 0 2017 Cl H SO2Me 2-cPr, 3,5-Me2 0 0 2018 Cl H SO2Me 2-cPr, 4, 6-Me2 0 0 2019 Cl H SO2Me 2-Br, 5,6-Me2 0 0 2020 Cl H SO2Me 2-cPr, 5,6-Me2 0 0 2021 Cl H SO2Me 2-Br, 5-CH═CH—O-6 0 0 2022 Cl H SO2Me 2-Me, 5-CH2CH2CH2-6 0 0 2023 Cl H SO2Me 2-Me, 5-CH2CH2O-6 0 0 2024 Cl H SO2Me 2-Me, 5-CHCH—O-6 0 0 2025 Cl H SO2Me 2-Et, 5-CH2CH2CH2-6 0 0 2026 Cl H SO2Me 2-cPr, 5-CH2CH2CH2-6 0 0 2027 Cl H SO2Me 2-cPr, 5-CH═CH—O-6 0 0 2028 Cl H SO2Me 2-Br, 3,5,6-Me3 0 0 2029 Cl H SO2Et 2-Me 0 0 2030 Cl H SO2Et 2-iPr 0 0 2031 Cl H SO2Et 2-cPr 0 0 2032 Cl H SO2Et 2-CH2CH2CH2-3 0 0 2033 Cl H SO2Et 2,6-Me2 0 0 2034 Cl H SO2Et 2-Me, 6-cPr 0 0 2035 Cl H SO2Pr 2-Cl 0 0 2036 Cl H SO2Pr 2-Br 0 0 2037 Cl H SO2Pr 2-I 0 0 2038 Cl H SO2Pr 2-Me 0 0 2039 Cl H SO2Pr 2-iPr 0 0 2040 Cl H SO2Pr 2-cPr 0 0 2041 Cl H SO2Pr 2-cBu 0 0 2042 Cl H SO2Pr 2-CH2CH2CH2-3 0 0 2043 Cl H SO2Pr 2-cPr, 5-Me 0 0 2044 Cl H SO2Pr 2-OMe, 5-Me 0 0 2045 Cl H SO2Pr 2-F, 6-iPr 0 0 2046 Cl H SO2Pr 2-Cl, 6-cPr 0 0 2047 Cl H SO2Pr 2-Br, 6-Me 0 0 2048 Cl H SO2Pr 2-I, 6-Me 0 0 2049 Cl H SO2Pr 2,6-Me2 0 0 2050 Cl H SO2Pr 2-Me, 6-Et 0 0 2051 Cl H SO2Pr 2-Me, 6-cPr 0 0 2052 Cl H SO2Pr 2,6-cPr2 0 0 2053 Cl H SO2Pr 2-cPr, 3,5-Me2 0 0 2054 Cl H SO2Pr 2-cPr, 5,6-Me2 0 0 2055 Cl H SO2iPr 2-Me 0 0 2056 Cl H SO2iPr 2-iPr 0 0 2057 Cl H SO2iPr 2-cPr 0 0 2058 Cl H SO2iPr 2-CH2CH2CH2-3 0 0 2059 Cl H SO2iPr 2,6-Me2 0 0 2060 Cl H SO2iPr 2-Me, 6-cPr 0 0 2061 Cl H SO2C8H17 2-Me 0 0 2062 Cl H SO2C8H17 2-iPr 0 0 2063 Cl H SO2C8H17 2-cPr 0 0 2064 Cl H SO2C8H17 2-CH2CH2CH2-3 0 0 2065 Cl H SO2C8H17 2,6-Me2 0 0 2066 Cl H SO2C8H17 2Me, 6-cPr 0 0 2067 Cl H SO2CH2Cl 2-Me 0 0 2068 Cl H SO2CH2Cl 2-iPr 0 0 2069 Cl H SO2CH2Cl 2-cPr 0 0 2070 Cl H SO2CH2Cl 2-CH2CH2CH2-3 0 0 2071 Cl H SO2CH2Cl 2,6-Me2 0 0 2072 Cl H SO2CH2Cl 2-Me, 6-cPr 0 0 2073 Cl H SO2CF3 2-F 0 0 2074 Cl H SO2CF3 2-Cl 0 0 2075 Cl H SO2CF3 2-Br 0 0 2076 Cl H SO2CF3 2-I 0 0 2077 Cl H SO2CF3 2-Me 0 0 2078 Cl H SO2CF3 2-Et 0 0 2079 Cl H SO2CF3 2-iPr 0 0 2080 Cl H SO2CF3 2-tBu 0 0 2081 Cl H SO2CF3 2-cPr 0 0 2082 Cl H SO2CF3 2-(cPr-1-Me) 0 0 2083 Cl H SO2CF3 2-(cPr-2-Me) 0 0 2084 Cl H SO2CF3 2-(cPr-2,2-Cl2) 0 0 2085 Cl H SO2CF3 2-cBu 0 0 2086 Cl H SO2CF3 2-CH2CH2CH2-3 0 0 2087 Cl H SO2CF3 2-CH═CH—O-3 0 0 2088 Cl H SO2CF3 2-CH2CH2O-3 0 0 2089 Cl H SO2CF3 2-OCH═CH-3 0 0 2090 Cl H SO2CF3 2-OCH2CH2-3 0 0 2091 Cl H SO2CF3 2-cPr, 5-F 0 0 2092 Cl H SO2CF3 2-cPr, 5-Cl 0 0 2093 Cl H SO2CF3 2-cPr, 5-Me 0 0 2094 Cl H SO2CF3 2-OMe, 5-Me 0 0 2095 Cl H SO2CF3 2-F, 6-iPr 0 0 2096 Cl H SO2CF3 2-F, 6-cPr 0 0 2097 Cl H SO2CF3 2-Cl, 6-Me 0 0 2098 Cl H SO2CF3 2-Cl, 6-cPr 0 0 2099 Cl H SO2CF3 2-Br, 6-Me 0 0 2100 Cl H SO2CF3 2-Br, 6-Et 0 0 2101 Cl H SO2CF3 2-Br, 6-cPr 0 0 2102 Cl H SO2CF3 2-I, 6-Me 0 0 2103 Cl H SO2CF3 2-I, 6-Et 0 0 2104 Cl H SO2CF3 2,6-Me2 0 0 2105 Cl H SO2CF3 2-Me, 6-Et 0 0 2106 Cl H SO2CF3 2-Me, 6-cPr 0 0 2107 Cl H SO2CF3 2-Et, 6-cPr 0 0 2108 Cl H SO2CF3 2-iPr, 6-cPr 0 0 2109 Cl H SO2CF3 2-tBu, 6-cPr 0 0 2110 Cl H SO2CF3 2,6-cPr2 0 0 2111 Cl H SO2CF3 2-cPr, 6-OMe 0 0 2112 Cl H SO2CF3 2-Br, 3,6-Me2 0 0 2113 Cl H SO2CF3 2-cPr, 3,5-Me2 0 0 2114 Cl H SO2CF3 2-cPr, 4, 6-Me2 0 0 2115 Cl H SO2CF3 2-Br, 5,6-Me2 0 0 2116 Cl H SO2CF3 2-cPr, 5,6-Me2 0 0 2117 Cl H SO2CF3 2-Br, 5-CH═CH—O-6 0 0 2118 Cl H SO2CF3 2-Me, 5-CH2CH2CH2-6 0 0 2119 Cl H SO2CF3 2-Me, 5-CH2CH2O-6 0 0 2120 Cl H SO2CF3 2-Me, 5-CHCH—O-6 0 0 2121 Cl H SO2CF3 2-Et, 5-CH2CH2CH2-6 0 0 2122 Cl H SO2CF3 2-cPr, 5-CH2CH2CH2-6 0 0 2123 Cl H SO2CF3 2-cPr, 5-CH═CH—O-6 0 0 2124 Cl H SO2CF3 2-Br, 3,5,6-Me3 0 0 2125 Cl H SO2CCl3 2-Me 0 0 2126 Cl H SO2CCl3 2-iPr 0 0 2127 Cl H SO2CCl3 2-cPr 0 0 2128 Cl H SO2CCl3 2-CH2CH2CH2-3 0 0 2129 Cl H SO2CCl3 2,6-Me2 0 0 2130 Cl H SO2CCl3 2-Me, 6-cPr 0 0 2131 Cl H SO2CH2CF3 2-Me 0 0 2132 Cl H SO2CH2CF3 2-iPr 0 0 2133 Cl H SO2CH2CF3 2-cPr 0 0 2134 Cl H SO2CH2CF3 2-CH2CH2CH2-3 0 0 2135 Cl H SO2CH2CF3 2,6-Me2 0 0 2136 Cl H SO2CH2CF3 2-Me, 6-cPr 0 0 2137 Cl H SO2CH2CH2CH2Cl 2-Me 0 0 2138 Cl H SO2CH2CH2CH2Cl 2-iPr 0 0 2139 Cl H SO2CH2CH2CH2Cl 2-cPr 0 0 2140 Cl H SO2CH2CH2CH2Cl 2-CH2CH2CH2-3 0 0 2141 Cl H SO2CH2CH2CH2Cl 2,6-Me2 0 0 2142 Cl H SO2CH2CH2CH2Cl 2-Me, 6-cPr 0 0 2143 Cl H SO2Ph 2-F 0 0 2144 Cl H SO2Ph 2-Cl 0 0 2145 Cl H SO2Ph 2-Br 0 0 2146 Cl H SO2Ph 2-I 0 0 2147 Cl H SO2Ph 2-Me 0 0 2148 Cl H SO2Ph 2-Et 0 0 2149 Cl H SO2Ph 2-iPr 0 0 2150 Cl H SO2Ph 2-tBu 0 0 2151 Cl H SO2Ph 2-cPr 0 0 2152 Cl H SO2Ph 2-(cPr-1-Me) 0 0 2153 Cl H SO2Ph 2-(cPr-2-Me) 0 0 2154 Cl H SO2Ph 2-(cPr-2,2-Cl2) 0 0 2155 Cl H SO2Ph 2-cBu 0 0 2156 Cl H SO2Ph 2-CH2CH2CH2-3 0 0 2157 Cl H SO2Ph 2-CH═CHO-3 0 0 2158 Cl H SO2Ph 2-CH2CH2O-3 0 0 2159 Cl H SO2Ph 2-OCH═CH-3 0 0 2160 Cl H SO2Ph 2-OCH2CH2-3 0 0 2161 Cl H SO2Ph 2-cPr, 5-F 0 0 2162 Cl H SO2Ph 2-cPr, 5-Cl 0 0 2163 Cl H SO2Ph 2-cPr, 5-Me 0 0 2164 Cl H SO2Ph 2-OMe, 5-Me 0 0 2165 Cl H SO2Ph 2-F, 6-iPr 0 0 2166 Cl H SO2Ph 2-F, 6-cPr 0 0 2167 Cl H SO2Ph 2-Cl, 6-Me 0 0 2168 Cl H SO2Ph 2-Cl, 6-cPr 0 0 2169 Cl H SO2Ph 2-Br, 6-Me 0 0 2170 Cl H SO2Ph 2-Br, 6-Et 0 0 2171 Cl H SO2Ph 2-Br, 6-cPr 0 0 2172 Cl H SO2Ph 2-I, 6-Me 0 0 2173 Cl H SO2Ph 2-I, 6-Et 0 0 2174 Cl H SO2Ph 2,6-Me2 0 0 2175 Cl H SO2Ph 2-Me, 6-Et 0 0 2176 Cl H SO2Ph 2-Me, 6-cPr 0 0 2177 Cl H SO2Ph 2-Et, 6-cPr 0 0 2178 Cl H SO2Ph 2-iPr, 6-cPr 0 0 2179 Cl H SO2Ph 2-tBu, 6-cPr 0 0 2180 Cl H SO2Ph 2,6-cPr2 0 0 2181 Cl H SO2Ph 2-cPr, 6-OMe 0 0 2182 Cl H SO2Ph 2-Br, 3,6-Me2 0 0 2183 Cl H SO2Ph 2-cPr, 3,5-Me2 0 0 2184 Cl H SO2Ph 2-cPr, 4, 6-Me2 0 0 2185 Cl H SO2Ph 2-Br, 5,6-Me2 0 0 2186 Cl H SO2Ph 2-cPr, 5,6-Me2 0 0 2187 Cl H SO2Ph 2-Br, 5-CHCH—O-6 0 0 2188 Cl H SO2Ph 2-Me, 5-CH2CH2CH2-6 0 0 2189 Cl H SO2Ph 2-Me, 5-CH2CH2O-6 0 0 2190 Cl H SO2Ph 2-Me, 5-CH═CH—O-6 0 0 2191 Cl H SO2Ph 2-Et, 5-CH2CH2CH2-6 0 0 2192 Cl H SO2Ph 2-cPr, 5-CH2CH2CH2-6 0 0 2193 Cl H SO2Ph 2-cPr, 5-CH═CH—O-6 0 0 2194 Cl H SO2Ph 2-Br, 3,5,6-Me3 0 0 2195 Cl H SO2 (Ph-4-Cl) 2-Cl 0 0 2196 Cl H SO2 (Ph-4-Cl) 2-Br 0 0 2197 Cl H SO2 (Ph-4-cl) 2-I 0 0 2198 Cl H SO2 (Ph-4-Cl) 2-Me 0 0 2199 Cl H SO2 (Ph-4-Cl) 2-iPr 0 0 2200 Cl H SO2 (Ph-4-Cl) 2-tBu 0 0 2201 Cl H SO2 (Ph-4-Cl) 2-cPr 0 0 2202 Cl H SO2 (Ph-4-Cl) 2-cBu 0 0 2203 Cl H SO2 (Ph-4-Cl) 2-CH2CH2CH2-3 0 0 2204 Cl H SO2 (Ph-4-Cl) 2-cPr, 5-Me 0 0 2205 Cl H SO2 (Ph-4-Cl) 2-OMe, 5-Me 0 0 2206 Cl H SO2 (Ph-4-Cl) 2-F, 6-iPr 0 0 2207 Cl H SO2 (Ph-4-Cl) 2-Cl, 6-cPr 0 0 2208 Cl H SO2 (Ph-4-Cl) 2-Br, 6-Me 0 0 2209 Cl H SO2 (Ph-4-Cl) 2-I, 6-Me 0 0 2210 Cl H SO2 (Ph-4-Cl) 2,6-Me2 0 0 2211 Cl H SO2 (Ph-4-Cl) 2-Me, 6-Et 0 0 2212 Cl H SO2 (Ph-4-Cl) 2-Me, 6-cPr 0 0 2213 Cl H SO2 (Ph-4-Cl) 2,6-cPr2 0 0 2214 Cl H SO2 (Ph-4-Cl) 2-cPr, 3,5-Me2 0 0 2215 Cl H SO2 (Ph-4-Cl) 2-cPr, 5,6-Me2 0 0 2216 Cl H SO2 (Ph-4-Me) 2-F 0 0 2217 Cl H SO2 (Ph-4-Me) 2-Cl 0 0 2218 Cl H SO2 (Ph-4-Me) 2-Br 0 0 2219 Cl H SO2 (Ph-4-Me) 2-I 0 0 2220 Cl H SO2 (Ph-4-Me) 2-Me 0 0 2221 Cl H SO2 (Ph-4-Me) 2-Et 0 0 2222 Cl H SO2 (Ph-4-Me) 2-iPr 0 0 2223 Cl H SO2 (Ph-4-Me) 2-sBu 0 0 2224 Cl H SO2 (Ph-4-Me) 2-tBu 0 0 2225 Cl H SO2 (Ph-4-Me) 2-cPr 0 0 2226 Cl H SO2 (Ph-4-Me) 2-(cPr-1-Me) 0 0 2227 Cl H SO2 (Ph-4-Me) 2-(cPr-2-Me) 0 0 2228 Cl H SO2 (Ph-4-Me) 2-(cPr-2,2-Cl2) 0 0 2229 Cl H SO2 (Ph-4-Me) 2-cBu 0 0 2230 Cl H SO2 (Ph-4-Me) 2-cHic 0 0 2231 Cl H SO2 (Ph-4-Me) 2-Ph 0 0 2232 Cl H SO2 (Ph-4-Me) 2-OMe 0 0 2233 Cl H SO2 (Ph-4-Me) 2-OSO2 (Ph-4-Me) 0 0 2234 Cl H SO2 (Ph-4-Me) 3-Cl 0 0 2235 Cl H SO2 (Ph-4-Me) 3-tBu 0 0 2236 Cl H SO2 (Ph-4-Me) 3-CF3 0 0 2237 Cl H SO2 (Ph-4-Me) 3-CN 0 0 2238 Cl H SO2 (Ph-4-Me) 3-OMe 0 0 2239 Cl H SO2 (Ph-4-Me) 2-CH2CH2CH2-3 0 0 2240 Cl H SO2 (Ph-4-Me) 2-CH═CHCH═CH-3 0 0 2241 Cl H SO2 (Ph-4-Me) 2-CH═CH—O-3 0 0 2242 Cl H SO2 (Ph-4-Me) 2-CH2CH2O-3 0 0 2243 Cl H SO2 (Ph-4-Me) 2-OCH═CH-3 0 0 2244 Cl H SO2 (Ph-4-Me) 2-OCH2CH2-3 0 0 2245 Cl H SO2 (Ph-4-Me) 2-Br, 4-tBu 0 0 2246 Cl H SO2 (Ph-4-Me) 2-Me, 4-Cl 0 0 2247 Cl H SO2 (Ph-4-Me) 2, 4-Me2 0 0 2248 Cl H SO2 (Ph-4-Me) 2-iPr, 4-Br 0 0 2249 Cl H SO2 (Ph-4-Me) 2-iPr, 5-Me 0 0 2250 Cl H SO2 (Ph-4-Me) 2-cPr, 5-F 0 0 2251 Cl H SO2 (Ph-4-Me) 2-cPr, 5-Cl 0 0 2252 Cl H SO2 (Ph-4-Me) 2-cPr, 5-Me 0 0 2253 Cl H SO2 (Ph-4-Me) 2-OMe, 5-Me 0 0 2254 Cl H SO2 (Ph-4-Me) 2-F, 6-iPr 0 0 2255 Cl H SO2 (Ph-4-Me) 2-F, 6-cPr 0 0 2256 Cl H SO2 (Ph-4-Me) 2-Cl, 6-Me 0 0 2257 Cl H SO2 (Ph-4-Me) 2-Cl, 6-cPr 0 0 2258 Cl H SO2 (Ph-4-Me) 2-Br, 6-Me 0 0 2259 Cl H SO2 (Ph-4-Me) 2-Br, 6-Et 0 0 2260 Cl H SO2 (Ph-4-Me) 2-Br, 6-cPr 0 0 2261 Cl H SO2 (Ph-4-Me) 2-I, 6-Me 0 0 2262 Cl H SO2 (Ph-4-Me) 2-I, 6-Et 0 0 2263 Cl H SO2 (Ph-4-Me) 2,6-Me2 0 0 2264 Cl H SO2 (Ph-4-Me) 2-Me, 6-Et 0 0 2265 Cl H SO2 (Ph-4-Me) 2-Me, 6-cPr 0 0 2266 Cl H SO2 (Ph-4-Me) 2-Et, 6-cPr 0 0 2267 Cl H SO2 (Ph-4-Me) 2-iPr, 6-cPr 0 0 2268 Cl H SO2 (Ph-4-Me) 2-tBu, 6-cPr 0 0 2269 Cl H SO2 (Ph-4-Me) 2,6-cPr2 0 0 2270 Cl H SO2 (Ph-4-Me) 2-cPr, 6-OMe 0 0 2271 Cl H SO2 (Ph-4-Me) 2-Br, 3,6-Me2 0 0 2272 Cl H SO2 (Ph-4-Me) 2-cPr, 3,5-Me2 0 0 2273 Cl H SO2 (Ph-4-Me) 2-cPr, 4, 6-Me2 0 0 2274 Cl H SO2 (Ph-4-Me) 2-Br, 5,6-Me2 0 0 2275 Cl H SO2 (Ph-4-Me) 2-cPr, 5,6-Me2 0 0 2276 Cl H SO2 (Ph-4-Me) 2-Br, 5-CH═CH—O-6 0 0 2277 Cl H SO2 (Ph-4-Me) 2-Me, 5-CH2CH2CH2-6 0 0 2278 Cl H SO2 (Ph-4-Me) 2-Me, 5-CH2CH2O-6 0 0 2279 Cl H SO2 (Ph-4-Me) 2-Me, 5-CH═CH—O-6 0 0 2280 Cl H SO2 (Ph-4-Me) 2-Et, 5-CH2CH2CH2-6 0 0 2281 Cl H SO2 (Ph-4-Me) 2-cPr, 5-CH2CH2CH2-6 0 0 2282 Cl H SO2 (Ph-4-Me) 2-cPr, 5-CHCH—O-6 0 0 2283 Cl H SO2 (Ph-4-Me) 2-Br, 3,5,6-Me3 0 0 2284 Cl H SO2 (Ph-4-No2) 2-Cl 0 0 2285 Cl H SO2 (Ph-4-NO2) 2-Br 0 0 2286 Cl H SO2 (Ph-4-NO2) 2-I 0 0 2287 Cl H SO2 (Ph-4-NO2) 2-Me 0 0 2288 Cl H SO2 (Ph-4-NO2) 2-iPr 0 0 2289 Cl H SO2 (Ph-4-NO2) 2-cPr 0 0 2290 Cl H SO2 (Ph-4-NO2) 2-cBu 0 0 2291 Cl H SO2 (Ph-4-NO2) 2-CH2CH2CH2-3 0 0 2292 Cl H SO2 (Ph-4-NO2) 2-cPr, 5-Me 0 0 2293 Cl H SO2 (Ph-4-NO2) 2-OMe, 5-Me 0 0 2294 Cl H SO2 (Ph-4-NO2) 2-F, 6-iPr 0 0 2295 Cl H SO2 (Ph-4-NO2) 2-Cl, 6-cPr 0 0 2296 Cl H SO2 (Ph-4-NO2) 2-Br, 6-Me 0 0 2297 Cl H SO2 (Ph-4-NO2) 2-I, 6-Me 0 0 2298 Cl H SO2 (Ph-4-NO2) 2,6-Me2 0 0 2299 Cl H SO2 (Ph-4-NO2) 2-Me, 6-Et 0 0 2300 Cl H SO2 (Ph-4-NO2) 2-Me, 6-cPr 0 0 2301 Cl H SO2 (Ph-4-NO2) 2,6-cPr2 0 0 2302 Cl H SO2 (Ph-4-NO2) 2-cPr, 3,5-Me2 0 0 2303 Cl H SO2 (Ph-4-NO2) 2-cPr, 5,6-Me2 0 0 2304 Cl H SO2 (Ph-4-OMe) 2-Me 0 0 2305 Cl H SO2 (Ph-4-OMe) 2-iPr 0 0 2306 Cl H SO2 (Ph-4-OMe) 2-cPr 0 0 2307 Cl H SO2 (Ph-4-OMe) 2-CH2CH2CH2-3 0 0 2308 Cl H SO2 (Ph-4-OMe) 2,6-Me2 0 0 2309 Cl H SO2 (Ph-4-OMe) 2-Me, 6-cPr 0 0 2310 Cl H SO2 (Ph-2,4,6-Me3) 2-Me 0 0 2311 Cl H SO2 (Ph-2,4,6-Me3) 2-iPr 0 0 2312 Cl H SO2 (Ph-2,4,6-Me3) 2-cPr 0 0 2313 Cl H SO2 (Ph-2,4,6-Me3) 2-CH2CH2CH2-3 0 0 2314 Cl H SO2 (Ph-2,4,6-Me3) 2,6-Me2 0 0 2315 Cl H SO2 (Ph-2,4,6-Me3) 2-Me, 6-cPr 0 0 2316 Cl H SO2 (Ph-2,4,6-iPr3) 2-Me 0 0 2317 Cl H SO2 (Ph-2,4,6-iPr3) 2-iPr 0 0 2318 Cl H SO2 (Ph-2,4,6-iPr3) 2-cPr 0 0 2319 Cl H SO2 (Ph-2,4,6-iPr3) 2-CH2CH2CH2-3 0 0 2320 Cl H SO2 (Ph-2,4,6-iPr3) 2,6-Me2 0 0 2321 Cl H SO2 (Ph-2,4,6-iPr3) 2-Me, 6-cPr 0 0 2322 Cl H SO2 (Ph-2-SO2OQ5) 2-Me 0 0 2323 Cl H SO2 (Ph-2-SO2OQ5) 2-iPr 0 0 2324 Cl H SO2 (Ph-2-SO2OQ5) 2-cPr 0 0 2325 Cl H SO2 (Ph-2-SO2OQ5) 2-CH2CH2CH2-3 0 0 2326 Cl H SO2 (Ph-2-SO2OQ5) 2,6-Me2 0 0 2327 Cl H SO2 (Ph-2-SO2OQ5) 2-Me, 6-cPr 0 0 2328 Cl H SO2 (Ph-3-SO2OQ5) 2-Me 0 0 2329 Cl H SO2 (Ph-3-SO2OQ5) 2-iPr 0 0 2330 Cl H SO2 (Ph-3-SO2OQ5) 2-cPr 0 0 2331 Cl H SO2 (Ph-3-SO2OQ5) 2-CH2CH2CH2-3 0 0 2332 Cl H SO2 (Ph-3-SO2OQ5) 2,6-Me2 0 0 2333 Cl H SO2 (Ph-3-SO2OQ5) 2-Me, 6-cPr 0 0 2334 Cl H SO2 (Ph-4-SO2OQ5) 2-Me 0 0 2335 Cl H SO2 (Ph-4-SO2OQ5) 2-iPr 0 0 2336 Cl H SO2 (Ph-4-SO2OQ5) 2-cPr 0 0 2337 Cl H SO2 (Ph-4-SO2OQ5) 2-CH2CH2CH2-3 0 0 2338 Cl H SO2 (Ph-4-SO2OQ5) 2,6-Me2 0 0 2339 Cl H SO2 (Ph-4-SO2OQ5) 2-Me, 6-cPr 0 0 2340 Cl H SO2OQ5 2-Me 0 0 2341 Cl H SO2OQ5 2-iPr 0 0 2342 Cl H SO2OQ5 2-cPr 0 0 2343 Cl H SO2OQ5 2-CH2CH2CH2-3 0 0 2344 Cl H SO2OQ5 2,6-Me2 0 0 2345 Cl H SO2OQ5 2-Me, 6-cPr 0 0 2346 Cl H SO2NMe2 2-Cl 0 0 2347 Cl H SO2NMe2 2-Br 0 0 2348 Cl H SO2NMe2 2-I 0 0 2349 Cl H SO2NMe2 2-Me 0 0 2350 Cl H SO2NMe2 2-iPr 0 0 2351 Cl H SO2NMe2 2-cPr 0 0 2352 Cl H SO2NMe2 2-cBu 0 0 2353 Cl H SO2NMe2 2-CH2CH2CH2-3 0 0 2354 Cl H SO2NMe2 2-cPr, 5-Me 0 0 2355 Cl H SO2NMe2 2-OMe, 5-Me 0 0 2356 Cl H SO2NMe2 2-F, 6-iPr 0 0 2357 Cl H SO2NMe2 2-Cl, 6-cPr 0 0 2358 Cl H SO2NMe2 2-Br, 6-Me 0 0 2359 Cl H SO2NMe2 2-I, 6-Me 0 0 2360 Cl H SO2NMe2 2,6-Me2 0 0 2361 Cl H SO2NMe2 2-Me, 6-Et 0 0 2362 Cl H SO2NMe2 2-Me, 6-cPr 0 0 2363 Cl H SO2NMe2 2,6-cPr2 0 0 2364 Cl H SO2NMe2 2-cPr, 3,5-Me2 0 0 2365 Cl H SO2NMe 2-cPr, 5,6-Me2 0 0 2366 Cl H SO2OEt 2-Me 0 0 2367 Cl H SO2OEt 2-iPr 0 0 2368 Cl H SO2OEt 2-cPr 0 0 2369 Cl H SO2OEt 2-CH2CH2CH2-3 0 0 2370 Cl H SO2OEt 2,6-Me2 0 0 2371 Cl H SO2OEt 2-Me, 6-cPr 0 0 2372 Cl Me H 2-Me 0 0 2373 Cl Me H 2-iPr 0 0 2374 Cl Me H 2-cPr 0 0 2375 Cl Me H 2-CH2CH2CH2-3 0 0 2376 Cl Me H 2,6-Me2 0 0 2377 Cl Me H 2-Me, 6-cPr 0 0 2378 Cl CH2OMe H 2-Me 0 0 2379 Cl CH2OMe H 2-iPr 0 0 2380 Cl CH2OMe H 2-cPr 0 0 2381 Cl CH2OMe H 2-CH2CH2CH2-3 0 0 2382 Cl CH2OMe H 2,6-Me2 0 0 2383 Cl CH2OMe H 2-Me, 6-cPr 0 0 2384 Cl CO2Et H 2-Me 0 0 2385 Cl CO2Et H 2-iPr 0 0 2386 Cl CO2Et H 2-tBu 0 0 2387 Cl CO2Et H 2-cPr 0 0 2388 Cl CO2Et H 2-CH2CH2CH2-3 0 0 2389 Cl CO2Et H 2,6-Me2 0 0 2390 Cl CO2Et H 2-Me, 6-cPr 0 0 2391 Cl CO(Ph-2-F) H 2-tBu 0 0 2392 Cl OMe H 2-Me 0 0 2393 Cl O(Ph-2,4-F2) H 2,4-F2 0 0 2394 Cl O(Ph-2,6-F2) H 2,6-F2 0 0 2395 Cl O(Ph-2-Me) H 2-Me 0 0 2396 Cl O(Ph-2-Me) H 2-iPr 0 0 2397 Cl O(Ph-2-Me) H 2-cPr 0 0 2398 Cl O(Ph-2-Me) H 2-CH2CH2CH2-3 0 0 2399 Cl O(Ph-2-Me) H 2,6-Me2 0 0 2400 Cl O(Ph-2-Me) H 2-Me, 6-cPr 0 0 2401 Cl SPh H 2-Me 0 0 2402 Cl SiMe3 H H 0 0 2403 Cl SiMe3 H 2-Me 0 0 2404 Cl SiMe3 H 2-iPr 0 0 2405 Cl SiMe3 H 2-tBu 0 0 2406 Cl SiMe3 H 2-cPr 0 0 2407 Cl SiMe3 H 2-CH2CH2CH2-3 0 0 2408 Cl SiMe3 H 2,6-Me2 0 0 2409 Cl SiMe3 H 2-Me, 6-cPr 0 0 2410 Br H H 2-Cl 0 0 2411 Br H H 2-Me 0 0 2412 Br H H 2-iPr 0 0 2413 Br H H 2-cPr 0 0 2414 Br H H 2-CH2CH2CH2-3 0 0 2415 Br H H 2,6-Me2 0 0 2416 Br H H 2-Me, 6-cPr 0 0 2417 Me H H 2-Me 0 0 2418 Me H H 2-iPr 0 0 2419 Me H H 2-cPr 0 0 2420 Me H H 2-CH2CH2CH2-3 0 0 2421 Me H H 2,6-Me2 0 0 2422 Me H H 2-Me, 6-cPr 0 0 2423 cPr H H 2-Me 0 0 2424 cPr H H 2-iPr 0 0 2425 cPr H H 2-cPr 0 0 2426 cPr H H 2-CH2CH2CH2-3 0 0 2427 cPr H H 2,6-Me2 0 0 2428 cPr H H 2-Me, 6-cPr 0 0 2429 CF3 H H 2-Cl 0 0 2430 CF3 H H 2-Me 0 0 2431 CF3 H H 2-iPr 0 0 2432 CF3 H H 2-cPr 0 0 2433 CF3 H H 2-CH2CH2CH2-3 0 0 2434 CF3 H H 2,6-Me2 0 0 2435 CF3 H H 2-Me, 6-cPr 0 0 2436 CH═CH2 H H 2-Me 0 0 2437 CH═CH2 H H 2-iPr 0 0 2438 CH═CH2 H H 2-cPr 0 0 2439 CH═CH2 H H 2-CH2CH2CH2-3 0 0 2440 CH═CH2 H H 2,6-Me2 0 0 2441 CH═CH2 H H 2-Me, 6-cPr 0 0 2442 CH═CHMe H H 2-Me 0 0 2443 CH═CHMe H H 2-iPr 0 0 2444 CH═CHMe H H 2-cPr 0 0 2445 CH═CHMe H H 2-CH2CH2CH2-3 0 0 2446 CH═CHMe H H 2,6-Me2 0 0 2447 CH═CHMe H H 2-Me, 6-cPr 0 0 2448 CH2CH═CH2 H H 2-Me 0 0 2449 CN H H 2-Me 0 0 2450 CN H H 2-iPr 0 0 2451 CN H H 2-cPr 0 0 2452 CN H H 2-CH2CH2CH2-3 0 0 2453 CN H H 2,6-Me2 0 0 2454 CN H H 2-Me, 6-cPr 0 0 2455 COMe H H 2-Me 0 0 2456 COMe H H 2-iPr 0 0 2457 COMe H H 2-cPr 0 0 2458 COMe H H 2-CH2CH2CH2-3 0 0 2459 COMe H H 2,6-Me2 0 0 2460 COMe H H 2-Me, 6-cPr 0 0 2461 COBu H H 2,6-Me2 0 0 2462 CONMe2 H H 2,6-Me2 0 0 2463 CONMe2 SiMe3 H 2,6-Me2 0 0 2464 Ph H H 2-Me 0 0 2465 Ph H H 2-iPr 0 0 2466 Ph H H 2-cPr 0 0 2467 Ph H H 2-CH2CH2CH2-3 0 0 2468 Ph H H 2,6-Me2 0 0 2469 Ph H H 2-Me, 6-cPr 0 0 2470 Ph H H 3-CN 0 0 2471 Ph-3-CF3 H H 2-Me 0 0 2472 Ph-3-CN H H 2-iPr 0 0 2473 Ph-3-CN H H 2-cPr 0 0 2474 Ph-3-CN H H 2-CH2CH2CH2-3 0 0 2475 Ph-3-CN H H 2,6-Me2 0 0 2476 Ph-3-CN H H 2-Me, 6-cPr 0 0 2477 2-Fur H H 2-Me 0 0 2478 2-Thi H H 2-Me 0 0 2479 2-Thi H H 2-iPr 0 0 2480 2-Thi H H 2-cPr 0 0 2481 2-Thi H H 2-CH2CH2CH2-3 0 0 2482 2-Thi H H 2,6-Me2 0 0 2483 2-Thi H H 2-Me, 6-cPr 0 0 2484 OMe H H 2-Me 0 0 2485 O(Ph-2-F) H H 2-F 0 0 2486 O(Ph-2-F) H H 2-Me 0 0 2487 O(Ph-2-F) H H 2-iPr 0 0 2488 O(Ph-2-F) H H 2-cPr 0 0 2489 O(Ph-2-F) H H 2-CH2CH2CH2-3 0 0 2490 O(Ph-2-F) H H 2,6-Me2 0 0 2491 O(Ph-2-F) H H 2-Me, 6-cPr 0 0 2492 O(Ph-2-Me) H H 2-Me 0 0 2493 O(Ph-2-Me) H H 2-iPr 0 0 2494 O(Ph-2-Me) H H 2-cPr 0 0 2495 O(Ph-2-Me) H H 2-CH2CH2CH2-3 0 0 2496 O(Ph-2-Me) H H 2,6-Me2 0 0 2497 O(Ph-2-Me) H H 2-Me, 6-cPr 0 0 2498 O(Ph-2-Me) CO2Et H 2-Me 0 0 2499 O(Ph-4-tBu) H H 4-tBu 0 0 2500 O(Ph-2-iPr-5-Me) H H 2-iPr, 5-Me 0 0 2501 O(Ph-2,3,5-Me3) H H 2,3,5-Me3 0 0 2502 O(Ph-2,4,6-Me3) H H 2,4,6-Me3 0 0 2503 O(Ph-2-cHx) H H 2-cHx 0 0 2504 O(Ph-3-cN) H H 3-CN 0 0 2505 O(Ph-4-SiMe3) H H 4-SiMe3 0 0 2506 OQ5 H H 2-Me 0 0 2507 OQ5 H H 2-iPr 0 0 2508 OQ5 H H 2-cPr 0 0 2509 OQ5 H H 2-CH2CH2CH2-3 0 0 2510 OQ5 H H 2,6-Me2 0 0 2511 OQ5 H H 2-Me, 6-cPr 0 0 2512 Cl H H 2-(cPr-1-F-2-F) 0 0 2513 Cl H H 2-(cPr-1-F-2-Cl) 0 0 2514 Cl H H 2-(cPr-1,2-Cl2) 0 0 2515 Cl H H 2-(cPr-1-Cl-2-Br) 0 0 2516 Cl H H 2-(cPr-1,2-Br2) 0 0 2517 Cl H H 2-(cPr-1-Me-2-Cl) 0 0 2518 Cl H H 2-(cPr-1-Me-2-Br) 0 0 2519 Cl H H 2-(cPr-2-F-2-Cl) 0 0 2520 Cl H H 2-(cPr-2-F-2-Br) 0 0 2521 Cl H H 2-(cPr-2-Cl-2-Br) 0 0 2522 Cl H H 2-(cPr-1-Me-2,2-Cl2) 0 0 2523 Cl H H 2-(cPr-1-Me-2,2-Br2) 0 0 2524 Cl H H 2-(cPr-1-Me-2-F-2-Cl) 0 0 2525 Cl H H 2-C(F)═CH2 0 0 2526 Cl H H 2-C(Cl)═CH2 0 0 2527 Cl H H 2-C(Br)═CH2 0 0 2528 Cl H H 2-C(Et)═CH2 0 0 2529 Cl H H 2-C(iPr)═CH2 0 0 2530 Cl H H 2-C(tBu)═CH2 0 0 2531 Cl H H 2-C(CN)═CH2 0 0 2532 Cl H H 2-CH═CHF 0 0 2533 Cl H H 2-CH═CHCl 0 0 2534 Cl H H 2-CH═CHBr 0 0 2535 Cl H H 2-CCl═CHC 0 0 2536 Cl H H 2-CMe═CHCl 0 0 2537 Cl H H 2-CH═CF2 0 0 2538 Cl H H 2-CH═CCl2 0 0 2539 Cl H H 2-CH═CBr2 0 0 2540 Cl H H 2-CH═CMe2 0 0 2541 Cl H H 2-CCl═CCl2 0 0 2542 Cl H H 2-CMe═CMe2 0 0 2543 Cl H H 2-CH═C(CN)2 0 0 2544 Cl H H 3-OH 0 0 2545 Cl H H 4-OH 0 0 2546 Cl H H 2-OCH2Ph 0 0 2547 Cl H H 3-OCH2Ph 0 0 2548 Cl H H 4-OCH2Ph 0 0 2549 Cl H H 2-I, 3-F 0 0 2550 Cl H H 2-I, 3-Me 0 0 2551 Cl H H 2-I, 3-OMe 0 0 2552 Cl H H 2-CHMeCH2-3 0 0 2553 Cl H H 2-CMe2CH2-3 0 0 2554 Cl H H 2-CH2CHMe-3 0 0 2555 Cl H H 2-CH2CH{(CH2)3OH}-3 0 0 2556 Cl H H 2-CH2CMe2-3 0 0 2557 Cl H H 2-CH(CH2)CH-3 0 0 2558 Cl H H 2-CH(—CH2CH2—)CH2-3 0 0 2559 Cl H H 2-CHOMeCH2-3 0 0 2560 Cl H H 2-C(═O)CH2-3 0 0 2561 Cl H H 2-CH2C(═O)-3 0 0 2562 Cl H H 2-C(═O)C(═O)-3 0 0 2563 Cl H H 2-CH2CH2NMe-3 0 0 2564 Cl H H 2-CH═CHNH-3 0 0 2565 Cl H H 2-CH═CHNMe-3 0 0 2566 Cl H H 2-NMeCH2CH2-3 0 0 2567 Cl H H 2-NHCH═CH-3 0 0 2568 Cl H H 2-NMeCH═CH-3 0 0 2569 Cl H H 2-N(COMe)CH═CH-3 0 0 2570 Cl H H 2-Me, 4-COMe 0 0 2571 Cl H H 2-Me, 4-C(NOMe)Me 0 0 2572 Cl H H 2-Me, 4-OCOMe 0 0 2573 Cl H H 2-Me, 4-OCOPh 0 0 2574 Cl H H 2-OMe, 5-CO2Me 0 0 2575 Cl H H 2-Me, 6-CH2F 0 0 2576 Cl H H 2-Me, 6-CHF2 0 0 2577 Cl H H 2-Me, 6-CMe═CH2 0 0 2578 Cl H H 2-Me, 6-COMe 0 0 2579 Cl H H 2-Me, 6-C(═NOMe)Me 0 0 2580 Cl H H 2-OMe, 6-CO2Me 0 0 2581 Cl H H 2-Me, 6-OCOMe 0 0 2582 Cl H H 2-Me, 6-OCOPh 0 0 2583 Cl H H 3-Me, 4-F 0 0 2584 Cl H H 3-CH2CH2CH2-4 0 0 2585 Cl H H 3-CH2CH2CMe2-4 0 0 2586 Cl H H 2,6-Me2, 3-Br 0 0 2587 Cl H H 2-Me, 3-Br, 6-cPr 0 0 2588 Cl H H 2,6-Me2, 3-NO2 0 0 2589 Cl H H 2-Me, 3-NO2,6-cPr 0 0 2590 Cl H H 6-Cl, 2-CH2OCH2-3 0 0 2591 Cl H H 6-Br, 2-CH2OCH2-3 0 0 2592 Cl H H 6-Me, 2-CH2OCH2-3 0 0 2593 Cl H H 6-Et, 2-CH2OCH2-3 0 0 2594 Cl H H 6-iPr, 2-CH2OCH2-3 0 0 2595 Cl H H 6-cPr, 2-CH2OCH2-3 0 0 2596 Cl H H 2,4-Br2, 5-SEt 0 0 2597 Cl H H 2-F, 3,5,6-Me3 0 0 2598 Cl H H 2,3,5,6-Cl4 0 0 2599 Cl H H 2-Cl, 3,5,6-Me3 0 0 2600 Cl H H 2-I, 3,5,6-Me3 0 0 2601 Cl H H 2,3,3,6-Et 0 0 2602 Cl H H 2,3, ═, 6-iPr 0 0 2603 Cl H H 2,3,5-Me3, 6-CH═CH2 0 0 2604 Cl H H 2,3,5-Me3, 6-CCl═CH2 0 0 2605 Cl H H 2,3,5-Me3, 6-CMe═CH2 0 0 2606 Cl H H 2,3,5-Me3, 6-CH(SEt)Me 0 0 2607 Cl H H 2,3,5-Me3, 6-COMe 0 0 2608 Cl H H 2,3,5-Me3, 6-NO2 0 0 2609 Cl H H 2,4-Cl2, 3,5,6-Me3 0 0 2610 Cl H H 2,3,4,5,6-F5 0 0 2611 Cl H H 2,3,4,5,6-Cl5 0 0 2612 Cl H H 2-Cl, 3,4,5,6-Me4 0 0 2613 Cl H H 2-Br, 3,4,5,6-Me4 0 0 2614 Cl H H 2,3,4,5,6-Me5 0 0 2615 Cl H H 2,3,4,4,6-Et 0 0 2616 Cl H H 2,3,4,5-Me4, 6-iPr 0 0 2617 Cl H H 2,3,4,5-Me4, 6-cPr 0 0 2618 Cl H COEt 2-Cl 0 0 2619 Cl H COEt 2-Br 0 0 2620 Cl H COEt 2-I 0 0 2621 Cl H COEt 2-cBu 0 0 2622 Cl H COEt 2-cPr, 5-Me 0 0 2623 Cl H COEt 2-OMe, 5-Me 0 0 2624 Cl H COEt 2-F, 6-iPr 0 0 2625 Cl H COEt 2-Cl, 6-cPr 0 0 2626 Cl H COEt 2-Br, 6-Me 0 0 2627 Cl H COEt 2-I, 6-Me 0 0 2628 Cl H COEt 2-Me, 6-Et 0 0 2629 Cl H COEt 2,6-cPr2 0 0 2630 Cl H COEt 2-cPr, 3,5-Me2 0 0 2631 Cl H COEt 2-cPr, 3,6-Me2 0 0 2632 Cl H COiPr 2-Cl 0 0 2633 Cl H COiPr 2-Br 0 0 2634 Cl H COiPr 2-I 0 0 2635 Cl H COiPr 2-cBu 0 0 2636 Cl H COiPr 2-cPr, 5-Me 0 0 2637 Cl H COiPr 2-OMe, 5-Me 0 0 2638 Cl H COiPr 2-F, 6-iPr 0 0 2639 Cl H COiPr 2-Cl, 6-cPr 0 0 2640 Cl H COiPr 2-Br, 6-Me 0 0 2641 Cl H COiPr 2-I, 6-Me 0 0 2642 Cl H COiPr 2-Me, 6-Et 0 0 2643 Cl H COiPr 2,6-cPr2 0 0 2644 Cl H COiPr 2-cPr, 3,5-Me2 0 0 2645 Cl H COiPr 2-cPr, 3,6-Me2 0 0 2646 Cl H COneoPen 2-Cl 0 0 2647 Cl H COneoPen 2-Br 0 0 2648 Cl H COneoPen 2-I 0 0 2649 Cl H COneoPen 2-Me 0 0 2650 Cl H COneoPen 2-iPr 0 0 2651 Cl H COneoPen 2-cPr 0 0 2652 Cl H COneoPen 2-cBu 0 0 2653 Cl H COneoPen 2-CH2CH2CH2-3 0 0 2654 Cl H COneoPen 2-cPr, 5-Me 0 0 2655 Cl H COneoPen 2-OMe, 5-Me 0 0 2656 Cl H COneoPen 2-F, 6-iPr 0 0 2657 Cl H COneoPen 2-Cl, 6-cPr 0 0 2658 Cl H COneoPen 2-Br, 6-Me 0 0 2659 Cl H COneoPen 2-I, 6-Me 0 0 2660 Cl H COneoPen 2,6-Me2 0 0 2661 Cl H COneoPen 2-Me, 6-Et 0 0 2662 Cl H COneoPen 2-Me, 6-cPr 0 0 2663 Cl H COneoPen 2,6-cPr2 0 0 2664 Cl H COneoPen 2-cPr, 3,5-Me2 0 0 2665 Cl H COneoPen 2-cPr, 3,6-Me2 0 0 2666 Cl H CO(1-Ad) 2-Me 0 0 2667 Cl H CO(1-Ad) 2-iPr 0 0 2668 Cl H CO(1-Ad) 2-cPr 0 0 2669 Cl H CO(1-Ad) 2-CH2CH2CH2-3 0 0 2670 Cl H CO(1-Ad) 2,6-Me2 0 0 2671 Cl H CO(1-Ad) 2-Me, 6-cPr 0 0 2672 Cl H COCMe═CH2 2-Me 0 0 2673 Cl H COCMe═CH2 2-iPr 0 0 2674 Cl H COCMe═CH2 2-cPr 0 0 2675 Cl H COCMe═CH2 2-CH2CH2CH2-3 0 0 2676 Cl H COCMe═CH2 2,6-Me2 0 0 2677 Cl H COCMe═CH2 2-Me, 6-cPr 0 0 2678 Cl H COCH═CMe2 2-Cl 0 0 2679 Cl H COCH═CMe2 2-Br 0 0 2680 Cl H COCH═CMe2 2-I 0 0 2681 Cl H COCH═CMe2 2-cBu 0 0 2682 Cl H COCH═CMe2 2-cPr, 5-Me 0 0 2683 Cl H COCH═CMe2 2-OMe, 5-Me 0 0 2684 Cl H COCH═CMe2 2-F, 6-iPr 0 0 2685 Cl H COCH═CMe2 2-Cl, 6-cPr 0 0 2686 Cl H COCH═CMe2 2-Br, 6-Me 0 0 2687 Cl H COCH═CMe2 2-I, 6-Me 0 0 2688 Cl H COCH═CMe2 2-Me, 6-Et 0 0 2689 Cl H COCH═CMe2 2,6-cPr2 0 0 2690 Cl H COCH═CMe2 2-cPr, 3,5-Me2 0 0 2691 Cl H COCH═CMe2 2-cPr, 3,2 0 0 2692 Cl H COCMe2Br 2-Me 0 0 2693 Cl H COCMe2Br 2-iPr 0 0 2694 Cl H COCMe2Br 2-cPr 0 0 2695 Cl H COCMe2Br 2-CH2CH2CH2-3 0 0 2696 Cl H COCMe2Br 2,6-Me2 0 0 2697 Cl H COCMe2Br 2-Me, 6-cPr 0 0 2698 Cl H COCMe2CH2Cl 2-Me 0 0 2699 Cl H COCMe2CH2Cl 2-iPr 0 0 2700 Cl H COCMe2CH2Cl 2-cPr 0 0 2701 Cl H COCMe2CH2Cl 2-CH2CH2CH2-3 0 0 2702 Cl H COCMe2CH2Cl 2,6-Me2 0 0 2703 Cl H COCMe2CH2Cl 2-Me, 6-cPr 0 0 2704 Cl H COCH2CH2CH2CH2Br 2-Me 0 0 2705 Cl H COCH2CH2CH2CH2Br 2-iPr 0 0 2706 Cl H COCH2CH2CH2CH2Br 2-cPr 0 0 2707 Cl H COCH2CH2CH2CH2Br 2-CH2CH2CH2-3 0 0 2708 Cl H COCH2CH2CH2CH2Br 2,6-Me2 0 0 2709 Cl H COCH2CH2CH2CH2Br 2-Me, 6-cPr 0 0 2710 Cl H COCHMePh 2-Me 0 0 2711 Cl H COCHMePh 2-iPr 0 0 2712 Cl H COCHMePh 2-cPr 0 0 2713 Cl H COCHMePh 2-CH2CH2CH2-3 0 0 2714 Cl H COCHMePh 2,6-Me2 0 0 2715 Cl H COCHMePh 2-Me, 6-cPr 0 0 2716 Cl H COCH2 (Ph-4-OMe) 2-Me 0 0 2717 Cl H COCH2 (Ph-4-OMe) 2-iPr 0 0 2718 Cl H COCH2 (Ph-4-OMe) 2-cPr 0 0 2719 Cl H COCH2 (Ph-4-OMe) 2-CH2CH2CH2-3 0 0 2720 Cl H COCH2 (Ph-4-OMe) 2,6-Me2 0 0 2721 Cl H COCH2 (Ph-4-OMe) 2-Me, 6-cPr 0 0 2722 Cl H COCH2CH2CO2Et 2-Me 0 0 2723 Cl H COCH2CH2CO2Et 2-iPr 0 0 2724 Cl H COCH2CH2CO2Et 2-cPr 0 0 2725 Cl H COCH2CH2CO2Et 2-CH2CH2CH2-3 0 0 2726 Cl H COCH2CH2CO2Et 2,6-Me2 0 0 2727 Cl H COCH2CH2CO2Et 2-Me, 6-cPr 0 0 2728 Cl H CO(CH2)2CO2Q6 2-Me 0 0 2729 Cl H CO(CH2)2CO2Q7 2-iPr 0 0 2730 Cl H CO(CH2)2CO2Q8 2-cPr 0 0 2731 Cl H CO(CH2)2CO2Q9 2-CH2CH2CH2-3 0 0 2732 Cl H CO(CH2)2CO2Q10 2,6-Me2 0 0 2733 Cl H CO(CH2)2CO2Q11 2-Me, 6-cPr 0 0 2734 Cl H CO(CH2)3CO2Q5 2-Me 0 0 2735 Cl H CO(CH2)3CO2Q5 2-iPr 0 0 2736 Cl H CO(CH2)3CO2Q5 2-cPr 0 0 2737 Cl H CO(CH2)3CO2Q5 2-CH2CH2CH2-3 0 0 2738 Cl H CO(CH2)3CO2Q5 2,6-Me2 0 0 2739 Cl H CO(CH2)3CO2Q5 2-Me, 6-cPr 0 0 2740 Cl H CO(CH2)3CO2Q12 2-Me, 6-cPr 0 0 2741 Cl H CO(CH2)3CO2Q13 2-Me, 6-cPr 0 0 2742 Cl H CO(CH2)3CO2Q14 2-Me, 6-cPr 0 0 2743 Cl H CO(CH2)3CO2Q15 2-Me, 6-cPr 0 0 2744 Cl H CO(CH2)3CO2Q16 2-Me, 6-cPr 0 0 2745 Cl H CO(CH2)3CO2Q17 2-Me, 6-cPr 0 0 2746 Cl H CO(CH2)3CO2Q11 2-Me, 6-cPr 0 0 2747 Cl H COCH2OMe 2-Me 0 0 2748 Cl H COCH2OMe 2-iPr 0 0 2749 Cl H COCH2OMe 2-cPr 0 0 2750 Cl H COCH2OMe 2-CH2CH2CH2-3 0 0 2751 Cl H COCH2OMe 2,6-Me2 0 0 2752 Cl H COCH2OMe 2-Me, 6-cPr 0 0 2753 Cl H COCH2OPh 2-Me 0 0 2754 Cl H COCH2OPh 2-iPr 0 0 2755 Cl H COCH2OPh 2-cPr 0 0 2756 Cl H COCH2OPh 2-CH2CH2CH2-3 0 0 2757 Cl H COCH2OPh 2,6-Me2 0 0 2758 Cl H COCH2OPh 2-Me, 6-cPr 0 0 2759 Cl H COCH(Me)OPh 2-Me 0 0 2760 Cl H COCH(Me)OPh 2-iPr 0 0 2761 Cl H COCH(Me)OPh 2-cPr 0 0 2762 Cl H COCH(Me)OPh 2-CH2CH2CH2-3 0 0 2763 Cl H COCH(Me)OPh 2,6-Me2 0 0 2764 Cl H COCH(Me)OPh 2-Me, 6-cPr 0 0 2765 Cl H COCH(OMe)Ph 2-Me 0 0 2766 Cl H COCH(OMe)Ph 2-iPr 0 0 2767 Cl H COCH(OMe)Ph 2-cPr 0 0 2768 Cl H COCH(OMe)Ph 2-CH2CH2CH2-3 0 0 2769 Cl H COCH(OMe)Ph 2,6-Me2 0 0 2770 Cl H COCH(OMe)Ph 2-Me, 6-cPr 0 0 2771 Cl H COCH2CH2SMe 2-Me 0 0 2772 Cl H COCH2CH2SMe 2-iPr 0 0 2773 Cl H COCH2CH2SMe 2-cPr 0 0 2774 Cl H COCH2CH2SMe 2-CH2CH2CH2-3 0 0 2775 Cl H COCH2CH2SMe 2,6-Me2 0 0 2776 Cl H COCH2CH2SMe 2-Me, 6-cPr 0 0 2777 Cl H COCO(2-Thi) 2-Me 0 0 2778 Cl H COCO(2-Thi) 2-iPr 0 0 2779 Cl H COCO(2-Thi) 2-cPr 0 0 2780 Cl H COCO(2-Thi) 2-CH2CH2CH2-3 0 0 2781 Cl H COCO(2-Thi) 2,6-Me2 0 0 2782 Cl H COCO(2-Thi) 2-Me, 6-cPr 0 0 2783 Cl H CO(Ph-2-F) 2-Me 0 0 2784 Cl H CO(Ph-2-F) 2-iPr 0 0 2785 Cl H CO(Ph-2-F) 2-cPr 0 0 2786 Cl H CO(Ph-2-F) 2-CH2CH2CH2-3 0 0 2787 Cl H CO(Ph-2-F) 2,6-Me2 0 0 2788 Cl H CO(Ph-2-F) 2-Me, 6-cPr 0 0 2789 Cl H CO(Ph-2-Br) 2-Cl 0 0 2790 Cl H CO(Ph-2-Br) 2-Br 0 0 2791 Cl H CO(Ph-2-Br) 2-I 0 0 2792 Cl H CO(Ph-2-Br) 2-Me 0 0 2793 Cl H CO(Ph-2-Br) 2-iPr 0 0 2794 Cl H CO(Ph-2-Br) 2-cPr 0 0 2795 Cl H CO(Ph-2-Br) 2-cBu 0 0 2796 Cl H CO(Ph-2-Br) 2-CH2CH2CH2-3 0 0 2797 Cl H CO(Ph-2-Br) 2-cPr, 5-Me 0 0 2798 Cl H CO(Ph-2-Br) 2-OMe, 5-Me 0 0 2799 Cl H CO(Ph-2-Br) 2-F, 6-iPr 0 0 2800 Cl H CO(Ph-2-Br) 2-Cl, 6-cPr 0 0 2801 Cl H CO(Ph-2-Br) 2-Br, 6-Me 0 0 2802 Cl H CO(Ph-2-Br) 2-I, 6-Me 0 0 2803 Cl H CO(Ph-2-Br) 2,6-Me2 0 0 2804 Cl H CO(Ph-2-Br) 2-Me, 6-Et 0 0 2805 Cl H CO(Ph-2-Br) 2-Me, 6-cPr 0 0 2806 Cl H CO(Ph-2-Br) 2,6-cPr2 0 0 2807 Cl H CO(Ph-2-Br) 2-cPr, 3,5-Me2 0 0 2808 Cl H CO(Ph-2-Br) 2-cPr, 3,6-Me2 0 0 2809 Cl H CO(Ph-2-I) 2-Me 0 0 2810 Cl H CO(Ph-2-I) 2-iPr 0 0 2811 Cl H CO(Ph-2-I) 2-cPr 0 0 2812 Cl H CO(Ph-2-I) 2-CH2CH2CH2-3 0 0 2813 Cl H CO(Ph-2-I) 2,6-Me2 0 0 2814 Cl H CO(Ph-2-I) 2-Me, 6-cPr 0 0 2815 Cl H CO(Ph-2-CF3) 2-Me 0 0 2816 Cl H CO(Ph-2-CF3) 2-iPr 0 0 2817 Cl H CO(Ph-2-CF3) 2-cPr 0 0 2818 Cl H CO(Ph-2-CF3) 2-CH2CH2CH2-3 0 0 2819 Cl H CO(Ph-2-CF3) 2,6-Me2 0 0 2820 Cl H CO(Ph-2-CF3) 2-Me, 6-cPr 0 0 2821 Cl H CO(Ph-2-CH2Ph) 2-Me 0 0 2822 Cl H CO(Ph-2-CH2Ph) 2-iPr 0 0 2823 Cl H CO(Ph-2-CH2Ph) 2-cPr 0 0 2824 Cl H CO(Ph-2-CH2Ph) 2-CH2CH2CH2-3 0 0 2825 Cl H CO(Ph-2-CH2Ph) 2,6-Me2 0 0 2826 Cl H CO(Ph-2-CH2Ph) 2-Me, 6-cPr 0 0 2827 Cl H CO(Ph-2-CO2Q6) 2-Me 0 0 2828 Cl H CO(Ph-2-CO2Q12) 2-Me 0 0 2829 Cl H CO(Ph-2-CO2Q13) 2-Me 0 0 2830 Cl H CO(Ph-2-CO2Q14) 2-Me 0 0 2831 Cl H CO(Ph-2-CO2Q15) 2-Me 0 0 2832 Cl H CO(Ph-2-CO2Q16) 2-Me 0 0 2833 Cl H CO(Ph-2-CO2Q17) 2-Me 0 0 2834 Cl H CO(Ph-2-CO2Q7) 2-iPr 0 0 2835 Cl H CO(Ph-2-CO2Q8) 2-cPr 0 0 2836 Cl H CO(Ph-2-CO2Q9) 2-CH2CH2CH2-3 0 0 2837 Cl H CO(Ph-2-CO2Q10) 2,6-Me2 0 0 2838 Cl H CO(Ph-2-CO2Q11) 2-Me, 6-cPr 0 0 2839 Cl H CO(Ph-2-CO2Q12) 2-Me, 6-cPr 0 0 2840 Cl H CO(Ph-2-CO2Q13) 2-Me, 6-cPr 0 0 2841 Cl H CO(Ph-2-CO2Q14) 2-Me, 6-cPr 0 0 2842 Cl H CO(Ph-2-CO2Q15) 2-Me, 6-cPr 0 0 2843 Cl H CO(Ph-2-CO2Q16) 2-Me, 6-cPr 0 0 2844 Cl H CO(Ph-2-CO2Q17) 2-Me, 6-cPr 0 0 2845 Cl H CO(Ph-2-NO2) 2-Me 0 0 2846 Cl H CO(Ph-2-NO2) 2-iPr 0 0 2847 Cl H CO(Ph-2-NO2) 2-cPr 0 0 2848 Cl H CO(Ph-2-NO2) 2-CH2CH2CH2-3 0 0 2849 Cl H CO(Ph-2-NO2) 2,6-Me2 0 0 2850 Cl H CO(Ph-2-NO2) 2-Me, 6-cPr 0 0 2851 Cl H CO(Ph-2-OPh) 2-Me 0 0 2852 Cl H CO(Ph-2-OPh) 2-iPr 0 0 2853 Cl H CO(Ph-2-OPh) 2-cPr 0 0 2854 Cl H CO(Ph-2-OPh) 2-CH2CH2CH2-3 0 0 2855 Cl H CO(Ph-2-OPh) 2,6-Me2 0 0 2856 Cl H CO(Ph-2-OPh) 2-Me, 6-cPr 0 0 2857 Cl H CO(Ph-3-F) 2-Me 0 0 2858 Cl H CO(Ph-3-F) 2-iPr 0 0 2859 Cl H CO(Ph-3-F) 2-cPr 0 0 2860 Cl H CO(Ph-3-F) 2-CH2CH2CH2-3 0 0 2861 Cl H CO(Ph-3-F) 2,6-Me2 0 0 2862 Cl H CO(Ph-3-F) 2-Me, 6-cPr 0 0 2863 Cl H CO(Ph-3-Cl) 2-Me 0 0 2864 Cl H CO(Ph-3-Cl) 2-iPr 0 0 2865 Cl H CO(Ph-3-Cl) 2-cPr 0 0 2866 Cl H CO(Ph-3-Cl) 2-CH2CH2CH2-3 0 0 2867 Cl H CO(Ph-3-Cl) 2,6-Me2 0 0 2868 Cl H CO(Ph-3-Cl) 2-Me, 6-cPr 0 0 2869 Cl H CO(Ph-3-Br) 2-Me 0 0 2870 Cl H CO(Ph-3-Br) 2-iPr 0 0 2871 Cl H CO(Ph-3-Br) 2-cPr 0 0 2872 Cl H CO(Ph-3-Br) 2-CH2CH2CH2-3 0 0 2873 Cl H CO(Ph-3-Br) 2,6-Me2 0 0 2874 Cl H CO(Ph-3-Br) 2-Me, 6-cPr 0 0 2875 Cl H CO(Ph-3-I) 2-Me 0 0 2876 Cl H CO(Ph-3-I) 2-iPr 0 0 2877 Cl H CO(Ph-3-I) 2-cPr 0 0 2878 Cl H CO(Ph-3-I) 2-CH2CH2CH2-3 0 0 2879 Cl H CO(Ph-3-I) 2,6-Me2 0 0 2880 Cl H CO(Ph-3-I) 2-Me, 6-cPr 0 0 2881 Cl H CO(Ph-3-Me) 2-Cl 0 0 2882 Cl H CO(Ph-3-Me) 2-Br 0 0 2883 Cl H CO(Ph-3-Me) 2-I 0 0 2884 Cl H CO(Ph-3-Me) 2-cBu 0 0 2885 Cl H CO(Ph-3--Me) 2-cPr, 5-Me 0 0 2886 Cl H CO(Ph-3-Me) 2-OMe, 5-Me 0 0 2887 Cl H CO(Ph-3-Me) 2-F, 6-iPr 0 0 2888 Cl H CO(Ph-3-Me) 2-Cl, 6-cPr 0 0 2889 Cl H CO(Ph-3-Me) 2-Br, 6-Me 0 0 2890 Cl H CO(Ph-3-Me) 2-I, 6-Me 0 0 2891 Cl H CO(Ph-3-Me) 2-Me, 6-Et 0 0 2892 Cl H CO(Ph-3-Me) 2,6-cPr2 0 0 2893 Cl H CO(Ph-3-Me) 2-cPr, 3,5-Me2 0 0 2894 Cl H CO(Ph-3-Me) 2-cPr, 3,6-Me2 0 0 2895 Cl H CO(Ph-3-CF3) 2-Me 0 0 2896 Cl H CO(Ph-3-CF3) 2-iPr 0 0 2897 Cl H CO(Ph-3-CF3) 2-cPr 0 0 2898 Cl H CO(Ph-3-CF3) 2-CH2CH2CH2-3 0 0 2899 Cl H CO(Ph-3-CF3) 2,6-Me2 0 0 2900 Cl H CO(Ph-3-CF3) 2-Me, 6-cPr 0 0 2901 Cl H CO(Ph-3-CO2Q6) 2-Me 0 0 2902 Cl H CO(Ph-3-CO2Q7) 2-iPr 0 0 2903 Cl H CO(Ph-3-CO2Q8) 2-cPr 0 0 2904 Cl H CO(Ph-3-CO2Q9) 2-CH2CH2CH2-3 0 0 2905 Cl H CO(Ph-3-CO2Q10) 2,6-Me2 0 0 2906 Cl H CO(Ph-3-CO2Q11) 2-Me, 6-cPr 0 0 2907 Cl H CO(Ph-3-CO2Q12) 2-Me, 6-cPr 0 0 2908 Cl H CO(Ph-3-CO2Q13) 2-Me, 6-cPr 0 0 2909 Cl H CO(Ph-3-CO2Q14) 2-Me, 6-cPr 0 0 2910 Cl H CO(Ph-3-CO2Q15) 2-Me, 6-cPr 0 0 2911 Cl H CO(Ph-3-CO2Q16) 2-Me, 6-cPr 0 0 2912 Cl H CO(Ph-3-CO2Q17) 2-Me., 6-cPr 0 0 2913 Cl H CO(Ph-3-NO2) 2-Me 0 0 2914 Cl H CO(Ph-3-NO2) 2-iPr 0 0 2915 Cl H CO(Ph-3-NO2) 2-cPr 0 0 2916 Cl H CO(Ph-3-NO2) 2-CH2CH2CH2-3 0 0 2917 Cl H CO(Ph-3-NO2) 2,6-Me2 0 0 2918 Cl H CO(Ph-3-NO2) 2-Me, 6-cPr 0 0 2919 Cl H CO(Ph-3-OPh) 2-Me 0 0 2920 Cl H CO(Ph-3-OPh) 2-iPr 0 0 2921 Cl H CO(Ph-3-OPh) 2-cPr 0 0 2922 Cl H CO(Ph-3-OPh) 2-CH2CH2CH2-3 0 0 2923 Cl H CO(Ph-3-OPh) 2,6-Me2 0 0 2924 Cl H CO(Ph-3-OPh) 2-Me, 6-cPr 0 0 2925 Cl H CO(Ph-4-F) 2-Me 0 0 2926 Cl H CO(Ph-4-F) 2-iPr 0 0 2927 Cl H CO(Ph-4-F) 2-cPr 0 0 2928 Cl H CO(Ph-4-F) 2-CH2CH2CH2-3 0 0 2929 Cl H CO(Ph-4-F) 2,6-Me2 0 0 2930 Cl H CO(Ph-4-F) 2-Me, 6-cPr 0 0 2931 Cl H CO(Ph-4-Br) 2-Cl 0 0 2932 Cl H CO(Ph-4-Br) 2-Br 0 0 2933 Cl H CO(Ph-4-Br) 2-I 0 0 2934 Cl H CO(Ph-4-Br) 2-cBu 0 0 2935 Cl H CO(Ph-4-Br) 2-cPr, 5-Me 0 0 2936 Cl H CO(Ph-4-Br) 2-OMe, 5-Me 0 0 2937 Cl H CO(Ph-4-Br) 2-F, 6-iPr 0 0 2938 Cl H CO(Ph-4-Br) 2-Cl, 6-cPr 0 0 2939 Cl H CO(Ph-4-Br) 2-Br, 6-Me 0 0 2940 Cl H CO(Ph-4-Br) 2-I, 6-Me 0 0 2941 Cl H CO(Ph-4-Br) 2-Me, 6-Et 0 0 2942 Cl H CO(Ph-4-Br) 2,6-cPr2 0 0 2943 Cl H CO(Ph-4-Br) 2-cPr, 3,5-Me2 0 0 2944 Cl H CO(Ph-4-Br) 2-cPr, 3,6-Me2 0 0 2945 Cl H CO(Ph-4-Et) 2-Cl 0 0 2946 Cl H CO(Ph-4-Et) 2-Br 0 0 2947 Cl H CO(Ph-4-Et) 2-I 0 0 2948 Cl H CO(Ph-4-Et) 2-Me 0 0 2949 Cl H CO(Ph-4-Et) 2-iPr 0 0 2950 Cl H CO(Ph-4-Et) 2-cPr 0 0 2951 Cl H CO(Ph-4-Et) 2-cBu 0 0 2952 Cl H CO(Ph-4-Et) 2-CH2CH2CH2-3 0 0 2953 Cl H CO(Ph-4-Et) 2-cPr, 5-Me 0 0 2954 Cl H CO(Ph-4-Et) 2-OMe, 5-Me 0 0 2955 Cl H CO(Ph-4-Et) 2-F, 6-iPr 0 0 2956 Cl H CO(Ph-4-Et) 2-Cl, 6-cPr 0 0 2957 Cl H CO(Ph-4-Et) 2-Br, 6-Me 0 0 2958 Cl H CO(Ph-4-Et) 2-I, 6-Me 0 0 2959 Cl H CO(Ph-4-Et) 2,6-Me2 0 0 2960 Cl H CO(Ph-4-Et) 2-Me, 6-Et 0 0 2961 Cl H CO(Ph-4-Et) 2-Me, 6-cPr 0 0 2962 Cl H CO(Ph-4-Et) 2,6-cPr2 0 0 2963 Cl H CO(Ph-4-Et) 2-cPr, 3,5-Me2 0 0 2964 Cl H CO(Ph-4-Et) 2-cPr, 3,6-Me2 0 0 2965 Cl H CO(Ph-4-Pr) 2-Me 0 0 2966 Cl H CO(Ph-4-Pr) 2-iPr 0 0 2967 Cl H CO(Ph-4-Pr) 2-cPr 0 0 2968 Cl H CO(Ph-4-Pr) 2-CH2CH2CH2-3 0 0 2969 Cl H CO(Ph-4-Pr) 2,6-Me2 0 0 2970 Cl H CO(Ph-4-Pr) 2-Me, 6-cPr 0 0 2971 Cl H CO(Ph-4-iPr) 2-Me 0 0 2972 Cl H CO(Ph-4-iPr) 2-iPr 0 0 2973 Cl H CO(Ph-4-iPr) 2-cPr 0 0 2974 Cl H CO(Ph-4-iPr) 2-CH2CH2CH2-3 0 0 2975 Cl H CO(Ph-4-iPr) 2,6-Me2 0 0 2976 Cl H CO(Ph-4-iPr) 2-Me, 6-cPr 0 0 2977 Cl H CO(Ph-4-Bu) 2-Me 0 0 2978 Cl H CO(Ph-4-Bu) 2-iPr 0 0 2979 Cl H CO(Ph-4-Bu) 2-cPr 0 0 2980 Cl H CO(Ph-4-Bu) 2-CH2CH2CH2-3 0 0 2981 Cl H CO(Ph-4-Bu) 2,6-Me2 0 0 2982 Cl H CO(Ph-4-Bu) 2-Me, 6-cPr 0 0 2983 Cl H CO(Ph-4-CF3) 2-Me 0 0 2984 Cl H CO(Ph-4-CF3) 2-iPr 0 0 2985 Cl H CO(Ph-4-CF3) 2-cPr 0 0 2986 Cl H CO(Ph-4-CF3) 2-CH2CH2CH2-3 0 0 2987 Cl H CO(Ph-4-CF3) 2,6-Me2 0 0 2988 Cl H CO(Ph-4-CF3) 2-Me, 6-cPr 0 0 2989 Cl H CO(Ph-4-CN) 2-Me 0 0 2990 Cl H CO(Ph-4-CN) 2-iPr 0 0 2991 Cl H CO(Ph-4-CN) 2-cPr 0 0 2992 Cl H CO(Ph-4-CN) 2-CH2CH2CH2-3 0 0 2993 Cl H CO(Ph-4-CN) 2,6-Me2 0 0 2994 Cl H CO(Ph-4-CN) 2-Me, 6-cPr 0 0 2995 Cl H CO(Ph-4-CO2Q5) 2-Cl, 6-cPr 0 0 2996 Cl H CO(Ph-4-CO2Q6) 2-Me 0 0 2997 Cl H CO(Ph-4-CO2Q7) 2-iPr 0 0 2998 Cl H CO(Ph-4-CO2Q8) 2-cPr 0 0 2999 Cl H CO(Ph-4-CO2Q9) 2-CH2CH2CH2-3 0 0 3000 Cl H CO(Ph-4-CO2Q10) 2,6-Me2 0 0 3001 Cl H CO(Ph-4-CO2Q11) 2-Me, 6-cPr 0 0 3002 Cl H CO(Ph-4-CO2Q12) 2-Me, 6-cPr 0 0 3003 Cl H CO(Ph-4-CO2Q13) 2-Me, 6-cPr 0 0 3004 Cl H CO(Ph-4-CO2Q14) 2-Me, 6-cPr 0 0 3005 Cl H CO(Ph-4-CO2Q15) 2-Me, 6-cPr 0 0 3006 Cl H CO(Ph-4-CO2Q16) 2-Me, 6-cPr 0 0 3007 Cl H CO(Ph-4-CO2Q17) 2-Me, 6-cPr 0 0 3008 Cl H CO(Ph-2-SO2OQ5) 2-Me, 6-cPr 0 0 3009 Cl H CO(Ph-3-SO2OQ5) 2-Me, 6-cPr 0 0 3010 Cl H CO(Ph-4-SO2OQ5) 2-Me, 6-cPr 0 0 3011 Cl H CO(Ph-4-Ph) 2-Me 0 0 3012 Cl H CO(Ph-4-Ph) 2-iPr 0 0 3013 Cl H CO(Ph-4-Ph) 2-cPr 0 0 3014 Cl H CO(Ph-4-Ph) 2-CH2CH2CH2-3 0 0 3015 Cl H CO(Ph-4-Ph) 2,6-Me2 0 0 3016 Cl H CO(Ph-4-Ph) 2-Me, 6-cPr 0 0 3017 Cl H CO(Ph-4-OCF3) 2-Me 0 0 3018 Cl H CO(Ph-4-OCF3) 2-iPr 0 0 3019 Cl H CO(Ph-4-OCF3) 2-cPr 0 0 3020 Cl H CO(Ph-4-OCF3) 2-CH2CH2CH2-3 0 0 3021 Cl H CO(Ph-4-OCF3) 2,6-Me2 0 0 3022 Cl H CO(Ph-4-OCF3) 2-Me, 6-cPr 0 0 3023 Cl H CO(Ph-4-OCH2Ph) 2-Me 0 0 3024 Cl H CO(Ph-4-OCH2Ph) 2-iPr 0 0 3025 Cl H CO(Ph-4-OCH2Ph) 2-cPr 0 0 3026 Cl H CO(Ph-4-OCH2Ph) 2-CH2CH2CH2-3 0 0 3027 Cl H CO(Ph-4-OCH2Ph) 2,6-Me2 0 0 3028 Cl H CO(Ph-4-OCH2Ph) 2-Me, 6-cPr 0 0 3029 Cl H CO(Ph-2,3-F2) 2-Me 0 0 3030 Cl H CO(Ph-2,3-F2) 2-iPr 0 0 3031 Cl H CO(Ph-2,3-F2) 2-cPr 0 0 3032 Cl H CO(Ph-2,3-F2) 2-CH2CH2CH2-3 0 0 3033 Cl H CO(Ph-2,3-F2) 2,6-Me2 0 0 3034 Cl H CO(Ph-2,3-F2) 2-Me, 6-cPr 0 0 3035 Cl H CO(Ph-2-F-3-CF3) 2-Me 0 0 3036 Cl H CO(Ph-2-F-3-CF3) 2-iPr 0 0 3037 Cl H CO(Ph-2-F-3-CF3) 2-cPr 0 0 3038 Cl H CO(Ph-2-F-3-CF3) 2-CH2CH2CH2-3 0 0 3039 Cl H CO(Ph-2-F-3-CF3) 2,6-Me2 0 0 3040 Cl H CO(Ph-2-F-3-CF3) 2-Me, 6-cPr 0 0 3041 Cl H CO(Ph-2,3-Me2) 2-Me 0 0 3042 Cl H CO(Ph-2,3-Me2) 2-iPr 0 0 3043 Cl H CO(Ph-2,3-Me2) 2-cPr 0 0 3044 Cl H CO(Ph-2,3-Me2) 2-CH2CH2CH2-3 0 0 3045 Cl H CO(Ph-2,3-Me2) 2,6-Me2 0 0 3046 Cl H CO(Ph-2,3-Me2) 2-Me, 6-cPr 0 0 3047 Cl H CO(Ph-2-Me-3-Cl) 2-Me 0 0 3048 Cl H CO(Ph-2-Me-3-Cl) 2-iPr 0 0 3049 Cl H CO(Ph-2-Me-3-Cl) 2-cPr 0 0 3050 Cl H CO(Ph-2-Me-3-Cl) 2-CH2CH2CH2-3 0 0 3051 Cl H CO(Ph-2-Me-3-Cl) 2,6-Me2 0 0 3052 Cl H CO(Ph-2-Me-3-Cl) 2-Me, 6-cPr 0 0 3053 Cl H CO(Ph-2,4-F2) 2-Me 0 0 3054 Cl H CO(Ph-2,4-F2) 2-iPr 0 0 3055 Cl H CO(Ph-2,4-F2) 2-cPr 0 0 3056 Cl H CO(Ph-2,4-F2) 2-CH2CH2CH2-3 0 0 3057 Cl H CO(Ph-2,4-F2) 2,6-Me2 0 0 3058 Cl H CO(Ph-2,4-F2) 2-Me, 6-cPr 0 0 3059 Cl H CO(Ph-2-F-4-Cl) 2-Me 0 0 3060 Cl H CO(Ph-2-F-4-Cl) 2-iPr 0 0 3061 Cl H CO(Ph-2-F-4-Cl) 2-cPr 0 0 3062 Cl H CO(Ph-2-F-4-Cl) 2-CH2CH2CH2-3 0 0 3063 Cl H CO(Ph-2-F-4-Cl) 2,6-Me2 0 0 3064 Cl H CO(Ph-2-F-4-Cl) 2-Me, 6-cPr 0 0 3065 Cl H CO(Ph-2-F-4-CF3) 2-Me 0 0 3066 Cl H CO(Ph-2-F-4-CF3) 2-iPr 0 0 3067 Cl H CO(Ph-2-F-4-CF3) 2-cPr 0 0 3068 Cl H CO(Ph-2-F-4-CF3) 2-CH2CH2CH2-3 0 0 3069 Cl H CO(Ph-2-F-4-CF3) 2,6-Me2 0 0 3070 Cl H CO(Ph-2-F-4-CF3) 2-Me, 6-cPr 0 0 3071 Cl H CO(Ph-2-Cl-4-F) 2-Me 0 0 3072 Cl H CO(Ph-2-Cl-4-F) 2-iPr 0 0 3073 Cl H CO(Ph-2-Cl-4-F) 2-cPr 0 0 3074 Cl H CO(Ph-2-Cl-4-F) 2-CH2CH2CH2-3 0 0 3075 Cl H CO(Ph-2-Cl-4-F) 2,6-Me2 0 0 3076 Cl H CO(Ph-2-Cl-4-F) 2-Me, 6-cPr 0 0 3077 Cl H CO(Ph-2-Cl-4-Br) 2-Me 0 0 3078 Cl H CO(Ph-2-Cl-4-Br) 2-iPr 0 0 3079 Cl H CO(Ph-2-Cl-4-Br) 2-cPr 0 0 3080 Cl H CO(Ph-2-Cl-4-Br) 2-CH2CH2CH2-3 0 0 3081 Cl H CO(Ph-2-Cl-4-Br) 2,6-Me2 0 0 3082 Cl H CO(Ph-2-Cl-4-Br) 2-Me, 6-cPr 0 0 3083 Cl H CO(Ph-2-Me-4-Br) 2-Me 0 0 3084 Cl H CO(Ph-2-Me-4-Br) 2-iPr 0 0 3085 Cl H CO(Ph-2-Me-4-Br) 2-cPr 0 0 3086 Cl H CO(Ph-2-Me-4-Br) 2-CH2CH2CH2-3 0 0 3087 Cl H CO(Ph-2-Me-4-Br) 2,6-Me2 0 0 3088 Cl H CO(Ph-2-Me-4-Br) 2-Me, 6-cPr 0 0 3089 Cl H CO(Ph-2,4-Me2) 2-Me 0 0 3090 Cl H CO(Ph-2,4-Me2) 2-iPr 0 0 3091 Cl H CO(Ph-2,4-Me2) 2-cPr 0 0 3092 Cl H CO(Ph-2,4-Me2) 2-CH2CH2CH2-3 0 0 3093 Cl H CO(Ph-2,4-Me2) 2,6-Me2 0 0 3094 Cl H CO(Ph-2,4-Me2) 2-Me, 6-cPr 0 0 3095 Cl H CO(Ph-2,5-Cl2) 2-Me 0 0 3096 Cl H CO(Ph-2,5-Cl2) 2-iPr 0 0 3097 Cl H CO(Ph-2,5-Cl2) 2-cPr 0 0 3098 Cl H CO(Ph-2,5-Cl2) 2-CH2CH2CH2-3 0 0 3099 Cl H CO(Ph-2,5-Cl2) 2,6-Me2 0 0 3100 Cl H CO(Ph-2,5-Cl2) 2-Me, 6-cPr 0 0 3101 Cl H CO(Ph-2-Cl-5-Br) 2-Me 0 0 3102 Cl H CO(Ph-2-Cl-5-Br) 2-iPr 0 0 3103 Cl H CO(Ph-2-Cl-5-Br) 2-cPr 0 0 3104 Cl H CO(Ph-2-Cl-5-Br) 2-CH2CH2CH2-3 0 0 3105 Cl H CO(Ph-2-Cl-5-Br) 2,6-Me2 0 0 3106 Cl H CO(Ph-2-Cl-5-Br) 2-Me, 6-cPr 0 0 3107 Cl H CO(Ph-2-Br-5-OMe) 2-Me 0 0 3108 Cl H CO(Ph-2-Br-5-OMe) 2-iPr 0 0 3109 Cl H CO(Ph-2-Br-5-OMe) 2-cPr 0 0 3110 Cl H CO(Ph-2-Br-5-OMe) 2-CH2CH2CH2-3 0 0 3111 Cl H CO(Ph-2-Br-5-OMe) 2,6-Me2 0 0 3112 Cl H CO(Ph-2-Br-5-OMe) 2-Me, 6-cPr 0 0 3113 Cl H CO(Ph-2,5-Me2) 2-Cl 0 0 3114 Cl H CO(Ph-2,5-Me2) 2-Br 0 0 3115 Cl H CO(Ph-2,5-Me2) 2-I 0 0 3116 Cl H CO(Ph-2,5-Me2) 2-Me 0 0 3117 Cl H CO(Ph-2,5-Me2) 2-iPr 0 0 3118 Cl H CO(Ph-2,5-Me2) 2-cPr 0 0 3119 Cl H CO(Ph-2,5-Me2) 2-cBu 0 0 3120 Cl H CO(Ph-2,5-Me2) 2-CH2CH2CH2-3 0 0 3121 Cl H CO(Ph-2,5-Me2) 2-cPr, 5-Me 0 0 3122 Cl H CO(Ph-2,5-Me2) 2-OMe, 5-Me 0 0 3123 Cl H CO(Ph-2,5-Me2) 2-F, 6-iPr 0 0 3124 Cl H CO(Ph-2,5-Me2) 2-Cl, 6-cPr 0 0 3125 Cl H CO(Ph-2,5-Me2) 2-Br, 6-Me 0 0 3126 Cl H CO(Ph-2,5-Me2) 2-I, 6-Me 0 0 3127 Cl H CO(Ph-2,5-Me2) 2,6-Me2 0 0 3128 Cl H CO(Ph-2,5-Me2) 2-Me, 6-Et 0 0 3129 Cl H CO(Ph-2,5-Me2) 2-Me, 6-cPr 0 0 3130 Cl H CO(Ph-2,5-Me2) 2,6-cPr2 0 0 3131 Cl H CO(Ph-2,5-Me2) 2-cPr, 3,5-Me2 0 0 3132 Cl H CO(Ph-2,5-Me2) 2-cPr, 3,6-Me2 0 0 3133 Cl H CO(Ph-2,6-F2) 2-Me 0 0 3134 Cl H CO(Ph-2,6-F2) 2-iPr 0 0 3135 Cl H CO(Ph-2,6-F2) 2-cPr 0 0 3136 Cl H CO(Ph-2,6-F2) 2-CH2CH2CH2-3 0 0 3137 Cl H CO(Ph-2,6-F2) 2,6-Me2 0 0 3138 Cl H CO(Ph-2,6-F2) 2-Me, 6-cPr 0 0 3139 Cl H CO(Ph-2-F-6-Cl) 2-Me 0 0 3140 Cl H CO(Ph-2-F-6-Cl) 2-iPr 0 0 3141 Cl H CO(Ph-2-F-6-Cl) 2-cPr 0 0 3142 Cl H CO(Ph-2-F-6-Cl) 2-CH2CH2CH2-3 0 0 3143 Cl H CO(Ph-2-F-6-Cl) 2,6-Me2 0 0 3144 Cl H CO(Ph-2-F-6-Cl) 2-Me, 6-cPr 0 0 3145 Cl H CO(Ph-2,6-Cl2) 2-Me 0 0 3146 Cl H CO(Ph-2,6-Cl2) 2-iPr 0 0 3147 Cl H CO(Ph-2,6-Cl2) 2-cPr 0 0 3148 Cl H CO(Ph-2,6-Cl2) 2-CH2CH2CH2-3 0 0 3149 Cl H CO(Ph-2,6-Cl2) 2,6-Me2 0 0 3150 Cl H CO(Ph-2,6-Cl2) 2-Me, 6-cPr 0 0 3151 Cl H CO(Ph-2,6-Me2) 2-Me 0 0 3152 Cl H CO(Ph-2,6-Me2) 2-iPr 0 0 3153 Cl H CO(Ph-2,6-Me2) 2-cPr 0 0 3154 Cl H CO(Ph-2,6-Me2) 2-CH2CH2CH2-3 0 0 3155 Cl H CO(Ph-2,6-Me2) 2,6-Me2 0 0 3156 Cl H CO(Ph-2,6-Me2) 2-Me, 6-cPr 0 0 3157 Cl H CO{Ph-2,6-(OMe)2} 2-Me 0 0 3158 Cl H CO{Ph-2,6-(OMe)2} 2-iPr 0 0 3159 Cl H CO{Ph-2,6-(OMe)2} 2-cPr 0 0 3160 Cl H CO{Ph-2,6-(OMe)2} 2-CH2CH2CH2-3 0 0 3161 Cl H CO{Ph-2,6-(OMe)2} 2,6-Me2 0 0 3162 Cl H CO{Ph-2,6-(OMe)2} 2-Me, 6-cPr 0 0 3163 Cl H CO(Ph-3,4-F2) 2-Me 0 0 3164 Cl H CO(Ph-3,4-F2) 2-iPr 0 0 3165 Cl H CO(Ph-3,4-F2) 2-cPr 0 0 3166 Cl H CO(Ph-3,4-F2) 2-CH2CH2CH2-3 0 0 3167 Cl H CO(Ph-3,4-F2) 2,6-Me2 0 0 3168 Cl H CO(Ph-3,4-F2) 2-Me, 6-cPr 0 0 3169 Cl H CO(Ph-3-F-4-Me) 2-Cl 0 0 3170 Cl H CO(Ph-3-F-4-Me) 2-Br 0 0 3171 Cl H CO(Ph-3-F-4-Me) 2-I 0 0 3172 Cl H CO(Ph-3-F-4-Me) 2-Me 0 0 3173 Cl H CO(Ph-3-F-4-Me) 2-iPr 0 0 3174 Cl H CO(Ph-3-F-4-Me) 2-cPr 0 0 3175 Cl H CO(Ph-3-F-4-Me) 2-cBu 0 0 3176 Cl H CO(Ph-3-F-4-Me) 2-CH2CH2CH2-3 0 0 3177 Cl H CO(Ph-3-F-4-Me) 2-cPr, 5-Me 0 0 3178 Cl H CO(Ph-3-F-4-Me) 2-OMe, 5-Me 0 0 3179 Cl H CO(Ph-3-F-4-Me) 2-F, 6-iPr 0 0 3180 Cl H CO(Ph-3-F-4-Me) 2-Cl, 6-cPr 0 0 3181 Cl H CO(Ph-3-F-4-Me) 2-Br, 6-Me 0 0 3182 Cl H CO(Ph-3-F-4-Me) 2-I, 6-Me 0 0 3183 Cl H CO(Ph-3-F-4-Me) 2,6-Me2 0 0 3184 Cl H CO(Ph-3-F-4-Me) 2-Me, 6-Et 0 0 3185 Cl H CO(Ph-3-F-4-Me) 2-Me, 6-cPr 0 0 3186 Cl H CO(Ph-3-F-4-Me) 2,6-cPr2 0 0 3187 Cl H CO(Ph-3-F-4-Me) 2-cPr, 3,5-Me2 0 0 3188 Cl H CO(Ph-3-F-4-Me) 2-cPr, 3,6-Me2 0 0 3189 Cl H CO(Ph-3,4-Cl2) 2-Me 0 0 3190 Cl H CO(Ph-3,4-Cl2) 2-iPr 0 0 3191 Cl H CO(Ph-3,4-Cl2) 2-cPr 0 0 3192 Cl H CO(Ph-3,4-Cl2) 2-CH2CH2CH2-3 0 0 3193 Cl H CO(Ph-3,4-Cl2) 2,6-Me2 0 0 3194 Cl H CO(Ph-3,4-Cl2) 2-Me, 6-cPr 0 0 3195 Cl H CO(Ph-3-NO2-4-Cl) 2-Me 0 0 3196 Cl H CO(Ph-3-NO2-4-Cl) 2-iPr 0 0 3197 Cl H CO(Ph-3-NO2-4-Cl) 2-cPr 0 0 3198 Cl H CO(Ph-3-NO2-4-Cl) 2-CH2CH2CH2-3 0 0 3199 Cl H CO(Ph-3-NO2-4-Cl) 2,6-Me2 0 0 3200 Cl H CO(Ph-3-NO2-4-Cl) 2-Me, 6-cPr 0 0 3201 Cl H CO(Ph-3,5-F2) 2-Cl 0 0 3202 Cl H CO(Ph-3,5-F2) 2-Br 0 0 3203 Cl H CO(Ph-3,5-F2) 2-I 0 0 3204 Cl H CO(Ph-3,5-F2) 2-Me 0 0 3205 Cl H CO(Ph-3,5-F2) 2-iPr 0 0 3206 Cl H CO(Ph-3,5-F2) 2-cPr 0 0 3207 Cl H CO(Ph-3,5-F2) 2-cBu 0 0 3208 Cl H CO(Ph-3,5-F2) 2-CH2CH2CH2-3 0 0 3209 Cl H CO(Ph-3,5-F2) 2-cPr, 5-Me 0 0 3210 Cl H CO(Ph-3,5-F2) 2-OMe, 5-Me 0 0 3211 Cl H CO(Ph-3,5-F2) 2-F, 6-iPr 0 0 3212 Cl H CO(Ph-3,5-F2) 2-Cl, 6-cPr 0 0 3213 Cl H CO(Ph-3,5-F2) 2-Br, 6-Me 0 0 3214 Cl H CO(Ph-3,5-F2) 2-I, 6-Me 0 0 3215 Cl H CO(Ph-3,5-F2) 2,6-Me2 0 0 3216 Cl H CO(Ph-3,5-F2) 2-Me, 6-Et 0 0 3217 Cl H CO(Ph-3,5-F2) 2-Me, 6-cPr 0 0 3218 Cl H CO(Ph-3,5-F2) 2,6-cPr2 0 0 3219 Cl H CO(Ph-3,5-F2) 2-cPr, 3,5-Me2 0 0 3220 Cl H CO(Ph-3,5-F2) 2-cPr, 3,6-Me2 0 0 3221 Cl H CO(Ph-3,5-Cl2) 2-Me 0 0 3222 Cl H CO(Ph-3,5-Cl2) 2-iPr 0 0 3223 Cl H CO(Ph-3,5-Cl2) 2-cPr 0 0 3224 Cl H CO(Ph-3,5-Cl2) 2-CH2CH2CH2-3 0 0 3225 Cl H CO(Ph-3,5-Cl2) 2,6-Me2 0 0 3226 Cl H CO(Ph-3,5-Cl2) 2-Me, 6-cPr 0 0 3227 Cl H CO(Ph-3,5-Me2) 2-Cl 0 0 3228 Cl H CO(Ph-3,5-Me2) 2-Br 0 0 3229 Cl H CO(Ph-3,5-Me2) 2-I 0 0 3230 Cl H CO(Ph-3,5-Me2) 2-Me 0 0 3231 Cl H CO(Ph-3,5-Me2) 2-iPr 0 0 3232 Cl H CO(Ph-3,5-Me2) 2-cPr 0 0 3233 Cl H CO(Ph-3,5-Me2) 2-cBu 0 0 3234 Cl H CO(Ph-3,5-Me2) 2-CH2CH2CH2-3 0 0 3235 Cl H CO(Ph-3,5-Me2) 2-cPr, 5-Me 0 0 3236 Cl H CO(Ph-3,5-Me2) 2-OMe, 5-Me 0 0 3237 Cl H CO(Ph-3,5-Me2) 2-F, 6-iPr 0 0 3238 Cl H CO(Ph-3,5-Me2) 2-Cl, 6-cPr 0 0 3239 Cl H CO(Ph-3,5-Me2) 2-Br, 6-Me 0 0 3240 Cl H CO(Ph-3,5-Me2) 2-I, 6-Me 0 0 3241 Cl H CO(Ph-3,5-Me2) 2,6-Me2 0 0 3242 Cl H CO(Ph-3,5-Me2) 2-Me, 6-Et 0 0 3243 Cl H CO(Ph-3,5-Me2) 2-Me, 6-cPr 0 0 3244 Cl H CO(Ph-3,5-Me2) 2,6-cPr2 0 0 3245 Cl H CO(Ph-3,5-Me2) 2-cPr, 3,5-Me2 0 0 3246 Cl H CO(Ph-3,5-Me2) 2-cPr, 3,6-Me2 0 0 3247 Cl H CO{Ph-3,5-(OMe)2} 2-Me 0 0 3248 Cl H CO{Ph-3,5-(OMe)2} 2-iPr 0 0 3249 Cl H CO{Ph-3,5-(OMe)2} 2-cPr 0 0 3250 Cl H CO{Ph-3,5-(OMe)2} 2-CH2CH2CH2-3 0 0 3251 Cl H CO{Ph-3,5-(OMe)2} 2,6-Me2 0 0 3252 Cl H CO{Ph-3,5-(OMe)2} 2-Me, 6-cPr 0 0 3253 Cl H CO(Ph-2,4,6-Cl3) 2-Me 0 0 3254 Cl H CO(Ph-2,4,6-Cl3) 2-iPr 0 0 3255 Cl H CO(Ph-2,4,6-Cl3) 2-cPr 0 0 3256 Cl H CO(Ph-2,4,6-Cl3) 2-CH2CH2CH2-3 0 0 3257 Cl H CO(Ph-2,4,6-Cl3) 2,6-Me2 0 0 3258 Cl H CO(Ph-2,4,6-Cl3) 2-Me, 6-cPr 0 0 3259 Cl H CO{Ph-3,4,5-(OMe)3} 2-Me 0 0 3260 Cl H CO{Ph-3,4,5-(OMe)3} 2-iPr 0 0 3261 Cl H CO{Ph-3,4,5-(OMe)3} 2-cPr 0 0 3262 Cl H CO{Ph-3,4,5-(OMe)3} 2-CH2CH2CH2-3 0 0 3263 Cl H CO{Ph-3,4,5-(OMe)3} 2,6-Me2 0 0 3264 Cl H CO{Ph-3,4,5-(OMe)3} 2-Me, 6-cPr 0 0 3265 Cl H CO(1-Np) 2-Me 0 0 3266 Cl H CO(1-Np) 2-iPr 0 0 3267 Cl H CO(1-Np) 2-cPr 0 0 3268 Cl H CO(1-Np) 2-CH2CH2CH2-3 0 0 3269 Cl H CO(1-Np) 2,6-Me2 0 0 3270 Cl H CO(1-Np) 2-Me, 6-cPr 0 0 3271 Cl H CO(2-Np) 2-Me 0 0 3272 Cl H CO(2-Np) 2-iPr 0 0 3273 Cl H CO(2-Np) 2-cPr 0 0 3274 Cl H CO(2-Np) 2-CH2CH2CH2-3 0 0 3275 Cl H CO(2-Np) 2,6-Me2 0 0 3276 Cl H CO(2-Np) 2-Me, 6-cPr 0 0 3277 Cl H CO(2-Pyrr-1-Me) 2-Me 0 0 3278 Cl H CO(2-Pyrr-1-Me) 2-iPr 0 0 3279 Cl H CO(2-Pyrr-1-Me) 2-cPr 0 0 3280 Cl H CO(2-Pyrr-1-Me) 2-CH2CH2CH2-3 0 0 3281 Cl H CO(2-Pyrr-1-Me) 2,6-Me2 0 0 3282 Cl H CO(2-Pyrr-1-Me) 2-Me, 6-cPr 0 0 3283 Cl H CO(2-Fur-5-Br) 2-Me 0 0 3284 Cl H CO(2-Fur-5-Br) 2-iPr 0 0 3285 Cl H CO(2-Fur-5-Br) 2-cPr 0 0 3286 Cl H CO(2-Fur-5-Br) 2-CH2CH2CH2-3 0 0 3287 Cl H CO(2-Fur-5-Br) 2,6-Me2 0 0 3288 Cl H CO(2-Fur-5-Br) 2-Me, 6-cPr 0 0 3289 Cl H CO(3-Fur) 2-Me 0 0 3290 Cl H CO(3-Fur) 2-iPr 0 0 3291 Cl H CO(3-Fur) 2-cPr 0 0 3292 Cl H CO(3-Fur) 2-CH2CH2CH2-3 0 0 3293 Cl H CO(3-Fur) 2,6-Me2 0 0 3294 Cl H CO(3-Fur) 2-Me, 6-cPr 0 0 3295 Cl H CO(3-Fur-2-Me-5-tBu) 2-Me 0 0 3296 Cl H CO(3-Fur-2-Me-5-tBu) 2-iPr 0 0 3297 Cl H CO(3-Fur-2-Me-5-tBu) 2-cPr 0 0 3298 Cl H CO(3-Fur-2-Me-5-tBu) 2-CH2CH2CH2-3 0 0 3299 Cl H CO(3-Fur-2-Me-5-tBu) 2,6-Me2 0 0 3300 Cl H CO(3-Fur-2-Me-5-tBu) 2-Me, 6-cPr 0 0 3301 Cl H CO(3-Fur-2-CF3-5-Me) 2-Me 0 0 3302 Cl H CO(3-Fur-2-CF3-5-Me) 2-iPr 0 0 3303 Cl H CO(3-Fur-2-CF3-5-Me) 2-cPr 0 0 3304 Cl H CO(3-Fur-2-CF3-5-Me) 2-CH2CH2CH2-3 0 0 3305 Cl H CO(3-Fur-2-CF3-5-Me) 2,6-Me2 0 0 3306 Cl H CO(3-Fur-2-CF3-5-Me) 2-Me, 6-cPr 0 0 3307 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2-Me 0 0 3308 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2-iPr 0 0 3309 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2-cPr 0 0 3310 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2-CH2CH2CH2-3 0 0 3311 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2,6-Me2 0 0 3312 Cl H CO{3-Fur-2-CF3-5-(Ph-4-Cl)} 2-Me, 6-cPr 0 0 3313 Cl H CO(2-Thi-3-Cl) 2-Me 0 0 3314 Cl H CO(2-Thi-3-Cl) 2-iPr 0 0 3315 Cl H CO(2-Thi-3-Cl) 2-cPr 0 0 3316 Cl H CO(2-Thi-3-Cl) 2-CH2CH2CH2-3 0 0 3317 Cl H CO(2-Thi-3-Cl) 2,6-Me2 0 0 3318 Cl H CO(2-Thi-3-Cl) 2-Me, 6-cPr 0 0 3319 Cl H CO(2-Thi-3-Me) 2-Me 0 0 3320 Cl H CO(2-Thi-3-Me) 2-iPr 0 0 3321 Cl H CO(2-Thi-3-Me) 2-cPr 0 0 3322 Cl H CO(2-Thi-3-Me) 2-CH2CH2CH2-3 0 0 3323 Cl H CO(2-Thi-3-Me) 2,6-Me2 0 0 3324 Cl H CO(2-Thi-3-Me) 2-Me, 6-cPr 0 0 3325 Cl H CO(2-Thi-3-OEt) 2-Me 0 0 3326 Cl H CO(2-Thi-3-OEt) 2-iPr 0 0 3327 Cl H CO(2-Thi-3-OEt) 2-cPr 0 0 3328 Cl H CO(2-Thi-3-OEt) 2-CH2CH2CH2-3 0 0 3329 Cl H CO(2-Thi-3-OEt) 2,6-Me2 0 0 3330 Cl H CO(2-Thi-3-OEt) 2-Me, 6-cPr 0 0 3331 Cl H CO(2-Thi-5-Cl) 2-Me 0 0 3332 Cl H CO(2-Thi-5-Cl) 2-iPr 0 0 3333 Cl H CO(2-Thi-5-Cl) 2-cPr 0 0 3334 Cl H CO(2-Thi-5-Cl) 2-CH2CH2CH2-3 0 0 3335 Cl H CO(2-Thi-5-Cl) 2,6-Me2 0 0 3336 Cl H CO(2-Thi-5-Cl) 2-Me, 6-cPr 0 0 3337 Cl H CO(2-Thi-5-Br) 2-Me 0 0 3338 Cl H CO(2-Thi-5-Br) 2-iPr 0 0 3339 Cl H CO(2-Thi-5-Br) 2-cPr 0 0 3340 Cl H CO(2-Thi-5-Br) 2-CH2CH2CH2-3 0 0 3341 Cl H CO(2-Thi-5-Br) 2,6-Me2 0 0 3342 Cl H CO(2-Thi-5-Br) 2-Me, 6-cPr 0 0 3343 Cl H CO(2-Thi-5-Me) 2-Me 0 0 3344 Cl H CO(2-Thi-5-Me) 2-iPr 0 0 3345 Cl H CO(2-Thi-5-Me) 2-cPr 0 0 3346 Cl H CO(2-Thi-5-Me) 2-CH2CH2CH2-3 0 0 3347 Cl H CO(2-Thi-5-Me) 2,6-Me2 0 0 3348 Cl H CO(2-Thi-5-Me) 2-Me, 6-cPr 0 0 3349 Cl H CO(2-Thi-5-COMe) 2-Me 0 0 3350 Cl H CO(2-Thi-5-COMe) 2-iPr 0 0 3351 Cl H CO(2-Thi-5-COMe) 2-cPr 0 0 3352 Cl H CO(2-Thi-5-COMe) 2-CH2CH2CH2-3 0 0 3353 Cl H CO(2-Thi-5-COMe) 2,6-Me2 0 0 3354 Cl H CO(2-Thi-5-COMe) 2-Me, 6-cPr 0 0 3355 Cl H CO(3-Thi-5-NO2) 2-Me 0 0 3356 Cl H CO(3-Thi-5-NO2) 2-iPr 0 0 3357 Cl H CO(3-Thi-5-NO2) 2-cPr 0 0 3358 Cl H CO(3-Thi-5-NO2) 2-CH2CH2CH2-3 0 0 3359 Cl H CO(3-Thi-5-NO2) 2,6-Me2 0 0 3360 Cl H CO(3-Thj-5-NO2) 2-Me, 6-cPr 0 0 3361 Cl H CO(2-Thi-4,5-Br2) 2-Me 0 0 3362 Cl H CO(2-Thi-4,5-Br2) 2-iPr 0 0 3363 Cl H CO(2-Thi-4,5-Br2) 2-cPr 0 0 3364 Cl H CO(2-Thi-4,5-Br2) 2-CH2CH2CH2-3 0 0 3365 Cl H CO(2-Thi-4,5-Br2) 2,6-Me2 0 0 3366 Cl H CO(2-Thi-4,5-Br2) 2-Me, 6-cPr 0 0 3367 Cl H CO(3-Thi) 2-Me 0 0 3368 Cl H CO(3-Thi) 2-iPr 0 0 3369 Cl H CO(3-Thi) 2-cPr 0 0 3370 Cl H CO(3-Thi) 2-CH2CH2CH2-3 0 0 3371 Cl H CO(3-Thi) 2,6-Me2 0 0 3372 Cl H CO(3-Thi) 2-Me, 6-cPr 0 0 3373 Cl H CO(3-Thi-4-OMe) 2-Me 0 0 3374 Cl H CO(3-Thi-4-OMe) 2-iPr 0 0 3375 Cl H CO(3-Thi-4-OMe) 2-cPr 0 0 3376 Cl H CO(3-Thi-4-OMe) 2-CH2CH2CH2-3 0 0 3377 Cl H CO(3-Thi-4-OMe) 2,6-Me2 0 0 3378 Cl H CO(3-Thi-4-OMe) 2-Me, 6-cPr 0 0 3379 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2-Me 0 0 3380 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2-iPr 0 0 3381 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2-cPr 0 0 3382 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2-CH2CH2CH2-3 0 0 3383 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2,6-Me2 0 0 3384 Cl H CO(5-Pyza-1-CH2Ph-3-tBu) 2-Me, 6-cPr 0 0 3385 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2-Me 0 0 3386 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2-iPr 0 0 3387 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2-cPr 0 0 3388 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2-CH2CH2CH2-3 0 0 3389 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2,6-Me2 0 0 3390 Cl H CO(4-Pyza-1,3-Me2-5-Cl) 2-Me, 6-cPr 0 0 3391 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2-Me 0 0 3392 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2-iPr 0 0 3393 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2-cPr 0 0 3394 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2-CH2CH2CH2-3 0 0 3395 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2,6-Me2 0 0 3396 Cl H CO{4-Ioxa-5-Me-3-(Ph-2-Cl)} 2-Me, 6-cPr 0 0 3397 Cl H CO(5-Tdia-4-Me) 2-Me 0 0 3398 Cl H CO(5-Tdia-4-Me) 2-iPr 0 0 3399 Cl H CO(5-Tdia-4-Me) 2-cPr 0 0 3400 Cl H CO(5-Tdia-4-Me) 2-CH2CH2CH2-3 0 0 3401 Cl H CO(5-Tdia-4-Me) 2,6-Me2 0 0 3402 Cl H CO(5-Tdia-4-Me) 2-Me, 6-cPr 0 0 3403 Cl H CO(2-Pyr-6-Me) 2-Me 0 0 3404 Cl H CO(2-Pyr-6-Me) 2-iPr 0 0 3405 Cl H CO(2-Pyr-6-Me) 2-cPr 0 0 3406 Cl H CO(2-Pyr-6-Me) 2-CH2CH2CH2-3 0 0 3407 Cl H CO(2-Pyr-6-Me) 2,6-Me2 0 0 3408 Cl H CO(2-Pyr-6-Me) 2-Me, 6-cPr 0 0 3409 Cl H CO(2-Pyr-5-Bu) 2-Me 0 0 3410 Cl H CO(2-Pyr-5-Bu) 2-iPr 0 0 3411 Cl H CO(2-Pyr-5-Bu) 2-cPr 0 0 3412 Cl H CO(2-Pyr-5-Bu) 2-CH2CH2CH2-3 0 0 3413 Cl H CO(2-Pyr-5-Bu) 2,6-Me2 0 0 3414 Cl H CO(2-Pyr-5-Bu) 2-Me, 6-cPr 0 0 3415 Cl H CO(3-Pyr) 2-Me 0 0 3416 Cl H CO(3-Pyr) 2-iPr 0 0 3417 Cl H CO(3-Pyr) 2-cPr 0 0 3418 Cl H CO(3-Pyr) 2-CH2CH2CH2-3 0 0 3419 Cl H CO(3-Pyr) 2,6-Me2 0 0 3420 Cl H CO(3-Pyr) 2-Me, 6-cPr 0 0 3421 Cl H CO(3-Pyr-2-Cl) 2-Me 0 0 3422 Cl H CO(3-Pyr-2-Cl) 2-iPr 0 0 3423 Cl H CO(3-Pyr-2-Cl) 2-cPr 0 0 3424 Cl H CO(3-Pyr-2-Cl) 2-CH2CH2CH2-3 0 0 3425 Cl H CO(3-Pyr-2-Cl) 2,6-Me2 0 0 3426 Cl H CO(3-Pyr-2-Cl) 2-Me, 6-cPr 0 0 3427 Cl H CO(3-Pyr-2-Me) 2-Me 0 0 3428 Cl H CO(3-Pyr-2-Me) 2-iPr 0 0 3429 Cl H CO(3-Pyr-2-Me) 2-cPr 0 0 3430 Cl H CO(3-Pyr-2-Me) 2-CH2CH2CH2-3 0 0 3431 Cl H CO(3-Pyr-2-Me) 2,6-Me2 0 0 3432 Cl H CO(3-Pyr-2-Me) 2-Me, 6-cPr 0 0 3433 Cl H CO(3-Pyr-2-OPh) 2-Me 0 0 3434 Cl H CO(3-Pyr-2-OPh) 2-iPr 0 0 3435 Cl H CO(3-Pyr-2-OPh) 2-cPr 0 0 3436 Cl H CO(3-Pyr-2-OPh) 2-CH2CH2CH2-3 0 0 3437 Cl H CO(3-Pyr-2-OPh) 2,6-Me2 0 0 3438 Cl H CO(3-Pyr-2-OPh) 2-Me, 6-cPr 0 0 3439 Cl H CO(3-Pyr-2-SMe) 2-Me 0 0 3440 Cl H CO(3-Pyr-2-SMe) 2-iPr 0 0 3441 Cl H CO(3-Pyr-2-SMe) 2-cPr 0 0 3442 Cl H CO(3-Pyr-2-SMe) 2-CH2CH2CH2-3 0 0 3443 Cl H CO(3-Pyr-2-SMe) 2,6-Me2 0 0 3444 Cl H CO(3-Pyr-2-SMe) 2-Me, 6-cPr 0 0 3445 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2-Me 0 0 3446 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2-iPr 0 0 3447 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2-cPr 0 0 3448 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2-CH2CH2CH2-3 0 0 3449 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2,6-Me2 0 0 3450 Cl H CO(3-Pyr-2-SCH2CH═CH2) 2-Me, 6-cPr 0 0 3451 Cl H CO(3-Pyr-2-SPh) 2-Me 0 0 3452 Cl H CO(3-Pyr-2-SPh) 2-iPr 0 0 3453 Cl H CO(3-Pyr-2-SPh) 2-cPr 0 0 3454 Cl H CO(3-Pyr-2-SPh) 2-CH2CH2CH2-3 0 0 3455 Cl H CO(3-Pyr-2-SPh) 2,6-Me2 0 0 3456 Cl H CO(3-Pyr-2-SPh) 2-Me, 6-cPr 0 0 3457 Cl H CO(3-Pyr-4-CF3) 2-Me 0 0 3458 Cl H CO(3-Pyr-4-CF3) 2-iPr 0 0 3459 Cl H CO(3-Pyr-4-CF3) 2-cPr 0 0 3460 Cl H CO(3-Pyr-4-CF3) 2-CH2CH2CH2-3 0 0 3461 Cl H CO(3-Pyr-4-CF3) 2,6-Me2 0 0 3462 Cl H CO(3-Pyr-4-CF3) 2-Me, 6-cPr 0 0 3463 Cl H CO(3-Pyr-6-Cl) 2-Me 0 0 3464 Cl H CO(3-Pyr-6-Cl) 2-iPr 0 0 3465 Cl H CO(3-Pyr-6-Cl) 2-cPr 0 0 3466 Cl H CO(3-Pyr-6-Cl) 2-CH2CH2CH2-3 0 0 3467 Cl H CO(3-Pyr-6-Cl) 2,6-Me2 0 0 3468 Cl H CO(3-Pyr-6-Cl) 2-Me, 6-cPr 0 0 3469 Cl H CO(3-Pyr-2,6-Cl2) 2-Me 0 0 3470 Cl H CO(3-Pyr-2,6-Cl2) 2-iPr 0 0 3471 Cl H CO(3-Pyr-2,6-Cl2) 2-cPr 0 0 3472 Cl H CO(3-Pyr-2,6-Cl2) 2-CH2CH2CH2-3 0 0 3473 Cl H CO(3-Pyr-2,6-Cl2) 2,6-Me2 0 0 3474 Cl H CO(3-Pyr-2,6-Cl2) 2-Me, 6-cPr 0 0 3475 Cl H CO(3-Pyr-2-Cl-6-Me) 2-Me 0 0 3476 Cl H CO(3-Pyr-2-Cl-6-Me) 2-iPr 0 0 3477 Cl H CO(3-Pyr-2-Cl-6-Me) 2-cPr 0 0 3478 Cl H CO(3-Pyr-2-Cl-6-Me) 2-CH2CH2CH2-3 0 0 3479 Cl H CO(3-Pyr-2-Cl-6-Me) 2,6-Me2 0 0 3480 Cl H CO(3-Pyr-2-Cl-6-Me) 2-Me, 6-cPr 0 0 3481 Cl H CO(3-Pyr-5,6-Cl2) 2-Me 0 0 3482 Cl H CO(3-Pyr-5,6-Cl2) 2-iPr 0 0 3483 Cl H CO(3-Pyr-5,6-Cl2) 2-cPr 0 0 3484 Cl H CO(3-Pyr-5,6-Cl2) 2-CH2CH2CH2-3 0 0 3485 Cl H CO(3-Pyr-5,6-Cl2) 2,6-Me2 0 0 3486 Cl H CO(3-Pyr-5,6-Cl2) 2-Me, 6-cPr 0 0 3487 Cl H CO(4-Pyr-2-Cl) 2-Me 0 0 3488 Cl H CO(4-Pyr-2-Cl) 2-iPr 0 0 3489 Cl H CO(4-Pyr-2-Cl) 2-cPr 0 0 3490 Cl H CO(4-Pyr-2-Cl) 2-CH2CH2CH2-3 0 0 3491 Cl H CO(4-Pyr-2-Cl) 2,6-Me2 0 0 3492 Cl H CO(4-Pyr-2-Cl) 2-Me, 6-cPr 0 0 3493 Cl H CO(2-Bfur) 2-Me 0 0 3494 Cl H CO(2-Bfur) 2-iPr 0 0 3495 Cl H CO(2-Bfur) 2-cPr 0 0 3496 Cl H CO(2-Bfur) 2-CH2CH2CH2-3 0 0 3497 Cl H CO(2-Bfur) 2,6-Me2 0 0 3498 Cl H CO(2-Bfur) 2-Me, 6-cPr 0 0 3499 Cl H CO(2-Bthi) 2-Me 0 0 3500 Cl H CO(2-Bthi) 2-iPr 0 0 3501 Cl H CO(2-Bthi) 2-cPr 0 0 3502 Cl H CO(2-Bthi) 2-CH2CH2CH2-3 0 0 3503 Cl H CO(2-Bthi) 2,6-Me2 0 0 3504 Cl H CO(2-Bthi) 2-Me, 6-cPr 0 0 3505 Cl H CO(6-Bthia) 2-Me 0 0 3506 Cl H CO(6-Bthia) 2-iPr 0 0 3507 Cl H CO(6-Bthia) 2-cPr 0 0 3508 Cl H CO(6-Bthia) 2-CH2CH2CH2-3 0 0 3509 Cl H CO(6-Bthia) 2,6-Me2 0 0 3510 Cl H CO(6-Bthia) 2-Me, 6-cPr 0 0 3511 Cl H CO(5-Boxaz) 2-Me 0 0 3512 Cl H CO(5-Boxaz) 2-iPr 0 0 3513 Cl H CO(5-Boxaz) 2-cPr 0 0 3514 Cl H CO(5-Boxaz) 2-CH2CH2CH2-3 0 0 3515 Cl H CO(5-Boxaz) 2,6-Me2 0 0 3516 Cl H CO(5-Boxaz) 2-Me, 6-cPr 0 0 3517 Cl H CO(1-Iqu) 2-Me 0 0 3518 Cl H CO(1-Iqu) 2-iPr 0 0 3519 Cl H CO(1-Iqu) 2-cPr 0 0 3520 Cl H CO(1-Iqu) 2-CH2CH2CH2-3 0 0 3521 Cl H CO(1-Iqu) 2,6-Me2 0 0 3522 Cl H CO(1-Iqu) 2-Me, 6-cPr 0 0 3523 Cl H CONMe(tBu) 2-Me 0 0 3524 Cl H CONMe(tBu) 2-iPr 0 0 3525 Cl H CONMe(tBu) 2-cPr 0 0 3526 Cl H CONMe(tBu) 2-CH2CH2CH2-3 0 0 3527 Cl H CONMe(tBu) 2,6-Me2 0 0 3528 Cl H CONMe(tBu) 2-Me, 6-cPr 0 0 3529 Cl H CONBu2 2-Me 0 0 3530 Cl H CONBu2 2-iPr 0 0 3531 Cl H CONBu2 2-cPr 0 0 3532 Cl H CONBu2 2-CH2CH2CH2-3 0 0 3533 Cl H CONBu2 2,6-Me2 0 0 3534 Cl H CONBu2 2-Me, 6-cPr 0 0 3535 Cl H CONMe(CH2Ph) 2-Me 0 0 3536 Cl H CONMe(CH2Ph) 2-iPr 0 0 3537 Cl H CONMe(CH2Ph) 2-cPr 0 0 3538 Cl H CONMe(CH2Ph) 2-CH2CH2CH2-3 0 0 3539 Cl H CONMe(CH2Ph) 2,6-Me2 0 0 3540 Cl H CONMe(CH2Ph) 2-Me, 6-cPr 0 0 3541 Cl H CONMe(CH2CN) 2-Me 0 0 3542 Cl H CONMe(CH2CN) 2-iPr 0 0 3543 Cl H CONMe(CH2CN) 2-cPr 0 0 3544 Cl H CONMe(CH2CN) 2CH2CH2CH2-3 0 0 3545 Cl H CONMe(CH2CN) 2,6-Me2 0 0 3546 Cl H CONMe(CH2CN) 2-Me, 6-cPr 0 0 3547 Cl H CONMe(CH2CO2Et) 2-Me 0 0 3548 Cl H CONMe(CH2CO2Et) 2-iPr 0 0 3549 Cl H CONMe(CH2CO2Et) 2-cPr 0 0 3550 Cl H CONMe(CH2CO2Et) 2-CH2CH2CH2-3 0 0 3551 Cl H CONMe(CH2CO2Et) 2,6-Me2 0 0 3552 Cl H CONMe(CH2CO2Et) 2-Me, 6-cPr 0 0 3553 Cl H CONMe(2-Pyr) 2-Me 0 0 3554 Cl H CONMe(2-Pyr) 2-iPr 0 0 3555 Cl H CONMe(2-Pyr) 2-cPr 0 0 3556 Cl H CONMe(2-Pyr) 2-CH2CH2CH2-3 0 0 3557 Cl H CONMe(2-Pyr) 2,6-Me2 0 0 3558 Cl H CONMe(2-Pyr) 2-Me, 6-cPr 0 0 3559 Cl H CONMe(OMe) 2-Me 0 0 3560 Cl H CONMe(OMe) 2-iPr 0 0 3561 Cl H CONMe(OMe) 2-cPr 0 0 3562 Cl H CONMe(OMe) 2-CH2CH2CH2-3 0 0 3563 Cl H CONMe(OMe) 2,6-Me2 0 0 3564 Cl H CONMe(OMe) 2-Me, 6-cPr 0 0 3565 Cl H CON(CH2CH2Cl)2 2-Me 0 0 3566 Cl H CON(CH2CH2Cl)2 2-iPr 0 0 3567 Cl H CON(CH2CH2Cl)2 2-cPr 0 0 3568 Cl H CON(CH2CH2Cl)2 2-CH2CH2CH2-3 0 0 3569 Cl H CON(CH2CH2Cl)2 2,6-Me2 0 0 3570 Cl H CON(CH2CH2Cl)2 2-Me, 6-cPr 0 0 3571 Cl H CON(CH2CH═CH2)2 2-Me 0 0 3572 Cl H CON(CH2CH═CH2)2 2-iPr 0 0 3573 Cl H CON(CH2CH═CH2)2 2-cPr 0 0 3574 Cl H CON(CH2CH═CH2)2 2-CH2CH2CH2-3 0 0 3575 Cl H CON(CH2CH═CH2)2 2,6-Me2 0 0 3576 Cl H CON(CH2CH═CH2)2 2-Me, 6-cPr 0 0 3577 Cl H CON(CH2CN)2 2-Me 0 0 3578 Cl H CON(CH2CN)2 2-iPr 0 0 3579 Cl H CON(CH2CN)2 2-cPr 0 0 3580 Cl H CON(CH2CN)2 2-CH2CH2CH2-3 0 0 3581 Cl H CON(CH2CN)2 2,6-Me2 0 0 3582 Cl H CON(CH2CN)2 2-Me, 6-cPr 0 0 3583 Cl H CON(CH2CH2CN)2 2-Me 0 0 3584 Cl H CON(CH2CH2CN)2 2-iPr 0 0 3585 Cl H CON(CH2CH2CN)2 2-cPr 0 0 3586 Cl H CON(CH2CH2CN)2 2-CH2CH2CH2-3 0 0 3587 Cl H CON(CH2CH2CN)2 2,6-Me2 0 0 3588 Cl H CON(CH2CH2CN)2 2-Me, 6-cPr 0 0 3589 Cl H CON(CH2CO2Et)2 2-Me 0 0 3590 Cl H CON(CH2CO2Et)2 2-iPr 0 0 3591 Cl H CON(CH2CO2Et)2 2-cPr 0 0 3592 Cl H CON(CH2cO2Et)2 2-CH2CH2CH2-3 0 0 3593 Cl H CON(CH2CO2Et)2 2,6-Me2 0 0 3594 Cl H CON(CH2CO2Et)2 2-Me, 6-cPr 0 0 3595 Cl H CON(CH2CH2OMe)2 2-Me 0 0 3596 Cl H CON(CH2CH2OMe)2 2-iPr 0 0 3597 Cl H CON(CH2CH2OMe)2 2-cPr 0 0 3598 Cl H CON(CH2CH2OMe)2 2-CH2CH2CH2-3 0 0 3599 Cl H CON(CH2CH2OMe)2 2,6-Me2 0 0 3600 Cl H CON(CH2CH2OMe)2 2-Me, 6-cPr 0 0 3601 Cl H CON(CH2CH2OEt)2 2-Me 0 0 3602 Cl H CON(CH2CH2OEt)2 2-iPr 0 0 3603 Cl H CON(CH2CH2OEt)2 2-cPr 0 0 3604 Cl H CON(CH2CH2OEt)2 2-CH2CH2CH2-3 0 0 3605 Cl H CON(CH2CH2OEt)2 2,6-Me2 0 0 3606 Cl H CON(CH2CH2OEt)2 2-Me, 6-cPr 0 0 3607 Cl H CO(1-Azet) 2-Me 0 0 3608 Cl H CO(1-Azet) 2-iPr 0 0 3609 Cl H CO(1-Azet) 2-cPr 0 0 3610 Cl H CO(1-Azet) 2-CH2CH2CH2-3 0 0 3611 Cl H CO(1-Azet) 2,6-Me2 0 0 3612 Cl H CO(1-Azet) 2-Me, 6-cPr 0 0 3613 Cl H CO(1-Pyrd-2-CO2Me) 2-Me 0 0 3614 Cl H CO(1-Pyrd-2-CO2Me) 2-iPr 0 0 3615 Cl H CO(1-Pyrd-2-CO2Me) 2-cPr 0 0 3616 Cl H CO(1-Pyrd-2-CO2Me) 2-CH2CH2CH2-3 0 0 3617 Cl H CO(1-Pyrd-2-CO2Me) 2,6-Me2 0 0 3618 Cl H CO(1-Pyrd-2-CO2Me) 2-Me, 6-cPr 0 0 3619 Cl H CO(1-Pyrd-3-OH) 2-Me 0 0 3620 Cl H CO(1-Pyrd-3-OH) 2-iPr 0 0 3621 Cl H CO(1-Pyrd-3-OH) 2-cPr 0 0 3622 Cl H CO(1-Pyrd-3-OH) 2-CH2CH2CH2-3 0 0 3623 Cl H CO(1-Pyrd-3-OH) 2,6-Me2 0 0 3624 Cl H CO(1-Pyrd-3-OH) 2-Me, 6-cPr 0 0 3625 Cl H CO(1-Pyrr-2,5-Me2) 2-Me 0 0 3626 Cl H CO(1-Pyrr-2,5-Me2) 2-iPr 0 0 3627 Cl H CO(1-Pyrr-2,5-Me2) 2-cPr 0 0 3628 Cl H CO(1-Pyrr-2,5-Me2) 2-CH2CH2CH2-3 0 0 3629 Cl H CO(1-Pyrr-2,5-Me2) 2,6-Me2 0 0 3630 Cl H CO(1-Pyrr-2,5-Me2) 2-Me, 6-cPr 0 0 3631 Cl H CO(1-Ppri) 2-Me 0 0 3632 Cl H CO(1-Ppri) 2-iPr 0 0 3633 Cl H CO(1-Ppri) 2-cPr 0 0 3634 Cl H CO(1-Ppri) 2-CH2CH2CH2-3 0 0 3635 Cl H CO(1-Ppri) 2,6-Me2 0 0 3636 Cl H CO(1-Ppri) 2-Me, 6-cPr 0 0 3637 Cl H CO(1-Ppri-2-CO2Me) 2-Me 0 0 3638 Cl H CO(1-Ppri-2-CO2Me) 2-iPr 0 0 3639 Cl H CO(1-Ppri-2-CO2Me) 2-cPr 0 0 3640 Cl H CO(1-Ppri-2-CO2Me) 2-CH2CH2CH2-3 0 0 3641 Cl H CO(1-Ppri-2-CO2Me) 2,6-Me2 0 0 3642 Cl H CO(1-Ppri-2-CO2Me) 2-Me, 6-cPr 0 0 3643 Cl H CO(1-Ppri-4-Br) 2-Me 0 0 3644 Cl H CO(1-Ppri-4-Br) 2-iPr 0 0 3645 Cl H CO(1-Ppri-4-Br) 2-cPr 0 0 3646 Cl H CO(1-Ppri-4-Br) 2-CH2CH2CH2-3 0 0 3647 Cl H CO(1-Ppri-4-Br) 2,6-Me2 0 0 3648 Cl H CO(1-Ppri-4-Br) 2-Me, 6-cPr 0 0 3649 Cl H CO(1-Ppri-4-Me) 2-Me 0 0 3650 Cl H CO(1-Ppri-4-Me) 2-iPr 0 0 3651 Cl H CO(1-Ppri-4-Me) 2-cPr 0 0 3652 Cl H CO(1-Ppri-4-Me) 2-CH2CH2CH2-3 0 0 3653 Cl H CO(1-Ppri-4-Me) 2,6-Me2 0 0 3654 Cl H CO(1-Ppri-4-Me) 2-Me, 6-cPr 0 0 3655 Cl H CO(1-Ppri-4-CO2Me) 2-Me 0 0 3656 Cl H CO(1-Ppri-4-CO2Me) 2-iPr 0 0 3657 Cl H CO(1-Ppri-4-CO2Me) 2-cPr 0 0 3658 Cl H CO(1-Ppri-4-CO2Me) 2-CH2CH2CH2-3 0 0 3659 Cl H CO(1-Ppri-4-CO2Me) 2,6-Me2 0 0 3660 Cl H CO(1-Ppri-4-CO2Et) 2-Me, 6-cPr 0 0 3661 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2-Me 0 0 3662 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2-iPr 0 0 3663 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2-cPr 0 0 3664 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2-CH2CH2CH2-3 0 0 3665 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2,6-Me2 0 0 3666 Cl H CO(1-Ppri-4-OCH2CH2O-4) 2-Me, 6-cPr 0 0 3667 Cl H CO(1-Ppri-2,2,6,6-Me4) 2-Me 0 0 3668 Cl H CO(1-Ppri-2,2,6,6-Me4) 2-iPr 0 0 3669 Cl H CO(1-Ppri-2,2,6,6-Me4) 2-cPr 0 0 3670 Cl H CO(1-Ppri-2,2,6,6-Me4) 2-CH2CH2CH2-3 0 0 3671 Cl H CO(1-Ppri-2,2,6,6-Me4) 2,6-Me2 0 0 3672 Cl H CO(1-Ppri-2,2,6,6-Me4) 2-Me, 6-cPr 0 0 3673 Cl H CO(1-Ppra-4-Me) 2-Me 0 0 3674 Cl H CO(1-Ppra-4-Me) 2-iPr 0 0 3675 Cl H CO(1-Ppra-4-Me) 2-cPr 0 0 3676 Cl H CO(1-Ppra-4-Me) 2-CH2CH2CH2-3 0 0 3677 Cl H CO(1-Ppra-4-Me) 2,6-Me2 0 0 3678 Cl H CO(1-Ppra-4-Me) 2-Me, 6-cPr 0 0 3679 Cl H CO(1-Ppra-4-Ph) 2-Me 0 0 3680 Cl H CO(1-Ppra-4-Ph) 2-iPr 0 0 3681 Cl H CO(1-Ppra-4-Ph) 2-cPr 0 0 3682 Cl H CO(1-Ppra-4-Ph) 2-CH2CH2CH2-3 0 0 3683 Cl H CO(1-Ppra-4-Ph) 2,6-Me2 0 0 3684 Cl H CO(1-Ppra-4-Ph) 2-Me, 6-cPr 0 0 3685 Cl H CO-4-Morp 2-Me 0 0 3686 Cl H CO-4-Morp 2-iPr 0 0 3687 Cl H CO-4-Morp 2-cPr 0 0 3688 Cl H CO-4-Morp 2-CH2CH2CH2-3 0 0 3689 Cl H CO-4-Morp 2,6-Me2 0 0 3690 Cl H CO-4-Morp 2-Me, 6-cPr 0 0 3691 Cl H CO(4-Morp-2,6-Me2) 2-Me 0 0 3692 Cl H CO(4-Morp-2,6-Me2) 2-iPr 0 0 3693 Cl H CO(4-Morp-2,6-Me2) 2-cPr 0 0 3694 Cl H CO(4-Morp-2,6-Me2) 2-CH2CH2CH2-3 0 0 3695 Cl H CO(4-Morp-2,6-Me2) 2,6-Me2 0 0 3696 Cl H CO(4-Morp-2,6-Me2) 2-Me, 6-cPr 0 0 3697 Cl H CO-4-Trnor 2-Me 0 0 3698 Cl H CO-4-Tnior 2-iPr 0 0 3699 Cl H CO-4-Tmor 2-cPr 0 0 3700 Cl H CO-4-Tmor 2-CH2CH2CH2-3 0 0 3701 Cl H CO-4-Tmor 2,6-Me2 0 0 3702 Cl H CO-4-Tmor 2-Me, 6-cPr 0 0 3703 Cl H COQ18 2-Me 0 0 3704 Cl H COQ18 2-iPr 0 0 3705 Cl H COQ18 2-cPr 0 0 3706 Cl H COQ18 2-CH2CH2CH2-3 0 0 3707 Cl H COQ18 2,6-Me2 0 0 3708 Cl H COQ18 2-Me, 6-cPr 0 0 3709 Cl H CO(9-Carb) 2-Me 0 0 3710 Cl H CO(9-Carb) 2-iPr 0 0 3711 Cl H CO(9-Carb) 2-cPr 0 0 3712 Cl H CO(9-Carb) 2-CH2CH2CH2-3 0 0 3713 Cl H CO(9-Carb) 2,6-Me2 0 0 3714 Cl H CO(9-Carb) 2-Me, 6-cPr 0 0 3715 Cl H CO(10-Pthia) 2-Me 0 0 3716 Cl H CO(10-Pthia) 2-iPr 0 0 3717 Cl H CO(10-Pthia) 2-cPr 0 0 3718 Cl H CO(10-Pthia) 2-CH2CH2CH2-3 0 0 3719 Cl H CO(10-Pthia) 2,6-Me2 0 0 3720 Cl H CO(10-Pthia) 2-Me, 6-cPr 0 0 3721 Cl H SO2 (Ph-2-CO2Q5) 2-Me, 6-cPr 0 0 3722 Cl H SO2 (Ph-3-CO2Q5) 2-Me, 6-cPr 0 0 3723 Cl H SO2 (Ph-4-CO2Q5) 2-Me, 6-cPr 0 0 3724 Cl H SO2 (Ph-4-OMe) 2-Cl 0 0 3725 Cl H SO2 (Ph-4-OMe) 2-Br 0 0 3726 Cl H SO2 (Ph-4-OMe) 2-I 0 0 3727 Cl H SO2 (Ph-4-OMe) 2-cBu 0 0 3728 Cl H SO2 (Ph-4-OMe) 2-cPr, 5-Me 0 0 3729 Cl H SO2 (Ph-4-OMe) 2-OMe, 5-Me 0 0 3730 Cl H SO2 (Ph-4-OMe) 2-F, 6-iPr 0 0 3731 Cl H SO2 (Ph-4-OMe) 2-Cl, 6-cPr 0 0 3732 Cl H SO2 (Ph-4-OMe) 2-Br, 6-Me 0 0 3733 Cl H SO2 (Ph-4-OMe) 2-I, 6-Me 0 0 3734 Cl H SO2 (Ph-4-OMe) 2-Me, 6-Et 0 0 3735 Cl H SO2 (Ph-4-OMe) 2,6-cPr2 0 0 3736 Cl H SO2 (Ph-4-OMe) 2-cPr, 3,5-Me2 0 0 3737 Cl H SO2 (Ph-4-OMe) 2-cPr, 3,6-Me2 0 0 3738 Cl H SO2 (Ph-2-SO2OQ6) 2-Me 0 0 3739 Cl H SO2 (Ph-2-SO2OQ7) 2-iPr 0 0 3740 Cl H SO2 (Ph-2-SO2OQ8) 2-cPr 0 0 3741 Cl H SO2 (Ph-2-SO2OQ9) 2-CH2CH2CH2-3 0 0 3742 Cl H SO2 (Ph-2-SO2OQ10) 2,6-Me2 0 0 3743 Cl H SO2 (Ph-2-SO2OQ11) 2-Me, 6-cPr 0 0 3744 Cl H SO2 (Ph-2-SO2OQ12) 2-Me, 6-cPr 0 0 3745 Cl H SO2 (Ph-2-SO2OQ13) 2-Me, 6-cPr 0 0 3746 Cl H SO2 (Ph-2-SO2OQ14) 2-Me, 6-cPr 0 0 3747 Cl H SO2 (Ph-2-SO2OQ15) 2-Me, 6-cPr 0 0 3748 Cl H SO2 (Ph-2-SO2OQ16) 2-Me, 6-cPr 0 0 3749 Cl H SO2 (Ph-2-SO2OQ17) 2-Me, 6-cPr 0 0 3750 Cl H SO2 (Ph-3-SO2OQ6) 2-Me 0 0 3751 Cl H SO2 (Ph-3-SO2OQ7) 2-iPr 0 0 3752 Cl H SO2 (Ph-3-SO2OQ8) 2-cPr 0 0 3753 Cl H SO2 (Ph-3-SO2OQ9) 2-CH2CH2CH2-3 0 0 3754 Cl H SO2 (Ph-3-SO2OQ10) 2,6-Me2 0 0 3755 Cl H SO2 (Ph-3-SO2OQ11) 2-Me, 6-cPr 0 0 3756 Cl H SO2 (Ph-3-SO2OQ12) 2-Me, 6-cPr 0 0 3757 Cl H SO2 (Ph-3-SO2OQ13) 2-Me, 6-cPr 0 0 3758 Cl H SO2 (Ph-3-SO2OQ14) 2-Me, 6-cPr 0 0 3759 Cl H SO2 (Ph-3-SO2OQ15) 2-Me, 6-cPr 0 0 3760 Cl H SO2 (Ph-3-SO2OQ16) 2-Me, 6-cPr 0 0 3761 Cl H SO2 (Ph-3-SO2OQ17) 2-Me, 6-cPr 0 0 3762 Cl H SO2 (Ph-4-SO2OQ5) 2-Cl, 6-cPr 0 0 3763 Cl H SO2 (Ph-4-SO2OQ6) 2-Me 0 0 3764 Cl H SO2 (Ph-4-SO2OQ7) 2-iPr 0 0 3765 Cl H SO2 (Ph-4-SO2OQ8) 2-cPr 0 0 3766 Cl H SO2 (Ph-4-SO2OQ9) 2-CH2CH2CH2-3 0 0 3767 Cl H SO2 (Ph-4-SO2OQ10) 2,6-Me2 0 0 3768 Cl H SO2 (Ph-4-SO2OQ11) 2-Me, 6-cPr 0 0 3769 Cl H SO2 (Ph-4-SO2OQ12) 2-Me, 6-cPr 0 0 3770 Cl H SO2 (Ph-4-SO2OQ13) 2-Me, 6-cPr 0 0 3771 Cl H SO2 (Ph-4-SO2OQ14) 2-Me, 6-cPr 0 0 3772 Cl H SO2 (Ph-4-SO2OQ15) 2-Me, 6-cPr 0 0 3773 Cl H SO2 (Ph-4-SO2OQ16) 2-Me, 6-cPr 0 0 3774 Cl H SO2 (Ph-4-SO2OQ17) 2-Me, 6-cPr 0 0 3775 Cl H SO2 (Ph-2,5-Cl2) 2-Me 0 0 3776 Cl H SO2 (Ph-2,5-Cl2) 2-iPr 0 0 3777 Cl H SO2 (Ph-2,5-Cl2) 2-cPr 0 0 3778 Cl H SO2 (Ph-2,5-Cl2) 2-CH2CH2CH2-3 0 0 3779 Cl H SO2 (Ph-2,5-Cl2) 2,6-Me2 0 0 3780 Cl H SO2 (Ph-2,5-Cl2) 2-Me, 6-cPr 0 0 3781 Cl H SO2 (Ph-3-NO2-4-Cl) 2-Me 0 0 3782 Cl H SO2 (Ph-3-NO2-4-Cl) 2-iPr 0 0 3783 Cl H SO2 (Ph-3-NO2-4-Cl) 2-cPr 0 0 3784 Cl H SO2 (Ph-3-NO2-4-Cl) 2-CH2CH2CH2-3 0 0 3785 Cl H SO2 (Ph-3-NO2-4-Cl) 2,6-Me2 0 0 3786 Cl H SO2 (Ph-3-NO2-4-Cl) 2-Me, 6-cPr 0 0 3787 Cl H SO2 (2-Thi) 2-Me 0 0 3788 Cl H SO2 (2-Thi) 2-iPr 0 0 3789 Cl H SO2 (2-Thi) 2-cPr 0 0 3790 Cl H SO2 (2-Thi) 2-CH2CH2CH2-3 0 0 3791 Cl H SO2 (2-Thi) 2,6-Me2 0 0 3792 Cl H SO2 (2-Thi) 2-Me, 6-cPr 0 0 3793 Cl H N(Bu)4 2-Me 0 0 3794 Cl H N(Bu)4 2-iPr 0 0 3795 Cl H N(Bu)4 2-cPr 0 0 3796 Cl H N(Bu)4 2-CH2CH2CH2-3 0 0 3797 Cl H N(Bu)4 2,6-Me2 0 0 3798 Cl H N(Bu)4 2-Me, 6-cPr 0 0 3799 Cl H Li 2-Me, 6-cPr 0 0 3800 Cl H Na 2-Me 0 0 3801 Cl H Na 2-iPr 0 0 3802 Cl H Na 2-cPr 0 0 3803 Cl H Na 2CH2CH2CH2-3 0 0 3804 Cl H Na 2,6-Me2 0 0 3805 Cl H Na 2-Me, 6-cPr 0 0 3806 Cl H K 2-Me 0 0 3807 Cl H K 2-iPr 0 0 3808 Cl H K 2-cPr 0 0 3809 Cl H K 2-CH2CH2CH2-3 0 0 3810 Cl H K 2,6-Me2 0 0 3811 Cl H K 2-Me, 6-cPr 0 0 3812 Cl H Rb 2-Me, 6-cPr 0 0 3813 Cl H Cs 2-Me, 6-cPr 0 0 3814 Cl H Mg 2-Me, 6-cPr 0 0 3815 Cl H Ca 2-Me, 6-cPr 0 0 3816 Cl H Ba 2-Me, 6-cPr 0 0 3817 Cl H Sc 2-Me, 6-cPr 0 0 3818 Cl H Ti 2-Me, 6-cPr 0 0 3819 Cl H Mn 2-Me, 6-cPr 0 0 3820 Cl H Fe 2-Me, 6-cPr 0 0 3821 Cl H Cu 2-Me, 6-cPr 0 0 3822 Cl H Ag 2-Me, 6-cPr 0 0 3823 Cl H Au 2-Me, 6-cPr 0 0 3824 Cl H Zn 2-Me, 6-cPr 0 0 3825 Cl H Al 2-Me, 6-cPr 0 0 3826 Cl F H 2-Me 0 0 3827 Cl F H 2-iPr 0 0 3828 Cl F H 2-cPr 0 0 3829 Cl F H 2-CH2CH2CH2-3 0 0 3830 Cl F H 2,6-Me2 0 0 3831 Cl F H 2-Me, 6-cPr 0 0 3832 Cl Cl H 2-Me 0 0 3833 Cl Cl H 2-iPr 0 0 3834 Cl Cl H 2-cPr 0 0 3835 Cl Cl H 2-CH2CH2CH2-3 0 0 3836 Cl Cl H 2,6-Me2 0 0 3837 Cl Cl H 2-Me, 6-cPr 0 0 3838 Cl Br H 2-Me 0 0 3839 Cl Br H 2-iPr 0 0 3840 Cl Br H 2-cPr 0 0 3841 Cl Br H 2-CH2CH2CH2-3 0 0 3842 Cl Br H 2,6-Me2 0 0 3843 Cl Br H 2-Me, 6-cPr 0 0 3844 Cl I H 2-Me 0 0 3845 Cl I H 2-iPr 0 0 3846 Cl I H 2-cPr 0 0 3847 Cl I H 2-CH2CH2CH2-3 0 0 3848 Cl I H 2,6-Me2 0 0 3849 Cl I H 2-Me, 6-cPr 0 0 3850 Cl H OCOPh 2-Me, 4-OCOPh 0 0 3851 Cl H CO-4-Thpy 2-Me 0 0 3852 Cl H CO-4-Thpy 2-iPr 0 0 3853 Cl H CO-4-Thpy 2-cPr 0 0 3854 Cl H CO-4-Thpy 2-CH2CH2CH2-3 0 0 3855 Cl H CO-4-Thpy 2,6-Me2 0 0 3856 Cl H CO-4-Thpy 2-Me, 6-cPr 0 0 Among the above-mentioned exemplary compounds, preferred compounds are Compounds Nos. 124, 125, 126, 127, 128, 130, 131, 132, 134, 136, 139, 140, 144, 145, 151, 163, 173, 202, 207, 217, 226, 249, 264, 265, 266, 267, 269, 270, 271, 272, 273, 279, 280, 284, 287, 292, 300, 304, 305, 306, 307, 308, 309, 311, 330, 334, 336, 339, 344, 359, 361, 362, 364, 365, 370, 377, 385, 386, 387, 390, 391, 400, 401, 403, 410, 412, 413, 417, 422, 426, 437, 438, 441, 443, 446, 450, 456, 459, 472, 478, 498, 505, 506, 507, 514, 515, 516, 521, 527, 528, 529, 531, 532, 534, 535, 539, 541, 544, 547, 557, 562, 566, 571, 614, 618, 621, 623, 629, 640, 642, 658, 659, 662, 663, 664, 667, 700, 701, 702, 704, 707, 708, 710, 711, 712, 716, 717, 719, 728, 732, 733, 734, 735, 736, 737, 738, 740, 756, 758, 759, 760, 761, 762, 775, 778, 780, 781, 782, 801, 802, 803, 804, 805, 806, 827, 834, 844, 845, 846, 850, 890, 894, 896, 911, 914, 931, 964, 965, 979, 982, 987, 998, 1000, 1007, 1009, 1013, 1016, 1020, 1023, 1027, 1040, 1050, 1052, 1053, 1055, 1058, 1060, 1061, 1063, 1064, 1066, 1069, 1073, 1083, 1086, 1088, 1089, 1091, 1096, 1099, 1100, 1102, 1109, 1115, 1118, 1119, 1120, 1122, 1123, 1124, 1125, 1126, 1128, 1129, 1133, 1140, 1151, 1160, 1172, 1178, 1184, 1207, 1251, 1260, 1266, 1286, 1298, 1334, 1340, 1358, 1364, 1382, 1387, 1391, 1417, 1441, 1446, 1448, 1456, 1459, 1461, 1481, 1509, 1522, 1531, 1537, 1543, 1549, 1553, 1554, 1566, 1575, 1593, 1599, 1603, 1616, 1620, 1625, 1631, 1643, 1649, 1658, 1706, 1710, 1757, 1770, 1789, 1811, 1840, 1877, 1879, 1891, 1898, 1911, 1920, 1924, 1937, 1946, 1952, 1958, 1981, 1985, 2010, 2034, 2038, 2040, 2042, 2051, 2060, 2066, 2072, 2081, 2106, 2136, 2147, 2151, 2176, 2198, 2199, 2200, 2212, 2220, 2221, 2222, 2224, 2225, 2263, 2265, 2287, 2289, 2300, 2309, 2315, 2321, 2327, 2333, 2411, 2431, 2453, 2519, 2529, 2540, 2542, 2547, 2548, 2551, 2555, 2556, 2565, 2568, 2570, 2571, 2572, 2574, 2576, 2577, 2585, 2587, 2589, 2592, 2596, 2597, 2599, 2600, 2601, 2603, 2605, 2606, 2607, 2608, 2609, 2614, 2662, 2671, 2677, 2697, 2703, 2709, 2715, 2721, 2727, 2733, 2739, 2746, 2752, 2758, 2764, 2770, 2776, 2782, 2788, 2805, 2814, 2820, 2826, 2827, 2838, 2850, 2856, 2862, 2868, 2874, 2880, 2900, 2906, 2918, 2924, 2930, 2961, 2970, 2976, 2982, 2988, 2994, 3001, 3016, 3022, 3028, 3034, 3040, 3046, 3052, 3058, 3064, 3070, 3076, 3082, 3088, 3094, 3100, 3106, 3112, 3129, 3138, 3144, 3150, 3156, 3162, 3168, 3185, 3194, 3200, 3217, 3226, 3243, 3252, 3258, 3264, 3270, 3276, 3282, 3288, 3294, 3300, 3306, 3312, 3318, 3324, 3330, 3336, 3342, 3348, 3354, 3360, 3366, 3372, 3378, 3384, 3390, 3396, 3402, 3408, 3414, 3420, 3426, 3432, 3438, 3444, 3450, 3456, 3462, 3468, 3474, 3480, 3486, 3492, 3498, 3504, 3510, 3516, 3522, 3528, 3534, 3540, 3546, 3552, 3558, 3564, 3570, 3576, 3582, 3588, 3594, 3600, 3606, 3612, 3618, 3624, 3630, 3636, 3642, 3648, 3654, 3660, 3666, 3672, 3678, 3684, 3690, 3696, 3702, 3708, 3714, 3720, 3755, 3780, 3786, 3792, 3798, 3805, 3811, 3837, 3843 or 3849, more preferably compounds of Compounds Nos. 124, 125, 126, 127, 128, 130, 132, 136, 139, 140, 144, 145, 151, 163, 173, 202, 217, 249, 264, 265, 266, 267, 269, 270, 271, 284, 287, 300, 304, 308, 309, 311, 334, 336, 339, 361, 362, 377, 385, 386, 387, 390, 391, 401, 437, 438, 459, 472, 505, 506, 507, 515, 516, 521, 528, 529, 531, 532, 534, 539, 541, 544, 547, 571, 621, 658, 659, 662, 663, 664, 667, 700, 701, 702, 704, 707, 708, 711, 712, 717, 719, 732, 733, 734, 735, 736, 737, 738, 740, 756, 758, 759, 760, 762, 775, 778, 780, 781, 782, 801, 802, 803, 806, 827, 834, 845, 846, 850, 896, 914, 931, 964, 965, 998, 1013, 1016, 1023, 1040, 1050, 1052, 1053, 1055, 1058, 1060, 1061, 1063, 1064, 1066, 1069, 1073, 1086, 1088, 1089, 1091, 1096, 1099, 1100, 1102, 1109, 1115, 1118, 1119, 1120, 1123, 1124, 1125, 1126, 1129, 1133, 1140, 1151, 1160, 1172, 1178, 1184, 1207, 1260, 1266, 1286, 1298, 1334, 1340, 1358, 1364, 1382, 1387, 1391, 1417, 1441, 1446, 1448, 1481, 1522, 1531, 1537, 1543, 1549, 1566, 1575, 1593, 1599, 1616, 1620, 1625, 1631, 1643, 1649, 1658, 1710, 1770, 1789, 1811, 1840, 1879, 1891, 1911, 1937, 1946, 1958, 1981, 1985, 2010, 2034, 2038, 2040, 2042, 2051, 2060, 2066, 2072, 2081, 2106, 2136, 2151, 2176, 2200, 2212, 2220, 2225, 2265, 2289, 2300, 2309, 2327, 2333, 2411, 2519, 2529, 2540, 2542, 2556, 2565, 2568, 2576, 2577, 2587, 2597, 2599, 2600, 2601, 2605, 2609, 2614, 2662, 2671, 2677, 2697, 2703, 2709, 2715, 2721, 2727, 2733, 2739, 2746, 2752, 2758, 2764, 2770, 2776, 2782, 2788, 2805, 2814, 2820, 2826, 2850, 2856, 2862, 2868, 2874, 2880, 2900, 2906, 2918, 2924, 2930, 2961, 2970, 2976, 2982, 2988, 2994, 3022, 3028, 3034, 3040, 3046, 3052, 3058, 3064, 3070, 3076, 3082, 3088, 3094, 3100, 3106, 3112, 3129, 3138, 3144, 3162, 3168, 3185, 3194, 3200, 3217, 3226, 3243, 3252, 3258, 3264, 3270, 3276, 3282, 3288, 3294, 3300, 3306, 3312, 3318, 3324, 3330, 3336, 3342, 3348, 3354, 3360, 3366, 3372, 3378, 3384, 3390, 3396, 3402, 3408, 3414, 3420, 3426, 3432, 3438, 3444, 3450, 3456, 3462, 3468, 3474, 3480, 3486, 3492, 3498, 3504, 3510, 3516, 3528, 3534, 3540, 3546, 3552, 3558, 3564, 3570, 3576, 3582, 3588, 3594, 3600, 3606, 3612, 3618, 3624, 3630, 3636, 3642, 3648, 3654, 3660, 3666, 3672, 3678, 3684, 3690, 3696, 3702, 3708, 3714, 3720, 3755, 3780, 3786, 3792, 3798, 3805, 3811, 3837, 3843 or 3849, still further preferably compounds of Compounds Nos. 125, 126, 127, 128, 130, 132, 139, 140, 144, 145, 151, 163, 217, 249, 264, 265, 266, 284, 304, 308, 387, 390, 391, 459, 472, 506, 507, 515, 516, 531, 539, 541, 621, 658, 659, 662, 700, 701, 702, 704, 711, 717, 719, 733, 734, 735, 740, 758, 759, 762, 775, 780, 781, 801, 802, 803, 806, 827, 834, 846, 850, 931, 964, 965, 1023, 1040, 1050, 1052, 1053, 1055, 1058, 1061, 1064, 1066, 1069, 1073, 1088, 1089, 1091, 1096, 1099, 1100, 1102, 1109, 1119, 1124, 1125, 1126, 1129, 1133, 1151, 1160, 1172, 1178, 1184, 1207, 1260, 1286, 1298, 1334, 1340, 1358, 1382, 1417, 1441, 1481, 1522, 1531, 1537, 1543, 1549, 1566, 1593, 1599, 1616, 1625, 1631, 1643, 1649, 1770, 1811, 1891, 1958, 2034, 2051, 2060, 2072, 2136, 2176, 2212, 2265, 2309, 2327, 2333, 2519, 2556, 2577, 2587, 2597, 2599, 2600, 2601, 2609, 2614, 2662, 2677, 2697, 2709, 2715, 2721, 2727, 2733, 2739, 2746, 2752, 2758, 2764, 2770, 2776, 2782, 2788, 2805, 2814, 2820, 2826, 2850, 2862, 2868, 2874, 2900, 2918, 2924, 2930, 2961, 2970, 2988, 2994, 3022, 3034, 3046, 3058, 3064, 3076, 3082, 3094, 3106, 3112, 3129, 3144, 3162, 3168, 3185, 3217, 3243, 3252, 3264, 3282, 3288, 3294, 3306, 3324, 3330, 3336, 3354, 3378, 3390, 3396, 3402, 3408, 3414, 3420, 3426, 3432, 3438, 3450, 3462, 3468, 3474, 3486, 3492, 3510, 3516, 3546, 3552, 3564, 3582, 3588, 3594, 3600, 3606, 3612, 3618, 3624, 3642, 3654, 3660, 3678, 3690, 3696, 3702, 3780, 3786, 3798, 3805, 3811, 3837, 3843 or 3849, particularly preferably compounds of Compounds Nos. 127, 128, 132, 139, 144, 217, 265, 284, 304, 391, 472, 506, 507, 515, 516, 539, 541, 621, 658, 659, 662, 704, 711, 717, 719, 733, 735, 740, 758, 759, 762, 780, 781, 801, 802, 803, 806, 827, 846, 850, 931, 964, 965, 1023, 1040, 1052, 1058, 1061, 1088, 1089, 1091, 1096, 1099, 1100, 1102, 1109, 1124, 1125, 1151, 1160, 1172, 1184, 1207, 1286, 1298, 1334, 1358, 1417, 1441, 1481, 1522, 1531, 1537, 1543, 1566, 1593, 1599, 1616, 1625, 1631, 1643, 1770, 1811, 1891, 1958, 2034, 2051, 2176, 2212, 2265, 2309, 2327, 2333, 2597, 2599, 2614, 2662, 2677, 2727, 2733, 2739, 2746, 2752, 2805, 2814, 2850, 2900, 2918, 2961, 2994, 3022, 3046, 3064, 3094, 3129, 3144, 3168, 3185, 3217, 3243, 3264, 3288, 3402, 3408, 3426, 3432, 3450, 3462, 3546, 3552, 3564, 3582, 3588, 3594, 3600, 3606, 3612, 3618, 3624, 3642, 3654, 3660, 3678, 3690, 3696, 3702, 3805 or 3811, most preferably compounds of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128), 6-chloro-3-(2-isopropylphenoxy)-4-pyridazinol (Compound No. 132), 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139), 6-chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 265), 6-chloro-3-(2,3-dihydro-1H-inden-4-yloxy)-4-pyridazinol (Compound No. 506), 6-chloro-3-(2-cyclopropyl-5-methylphenoxy)-4-pyridazinol (Compound No. 662), 6-chloro-3-(2-fluoro-6-isopropylphenoxy)-4-pyridazinol (Compound No. 717), 6-chloro-3-(2-chloro-6-cyclopropylphenoxy)-4-pyridazinol (Compound No. 740), 6-chloro-3-(2,6-dimethylphenoxy)-4-pyridazinol (Compound No. 801), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 806), 6-chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 827), 6-chloro-3-(2-cyclopropyl-3,5-dimethylphenoxy)-4-pyridazinol (Compound No. 1023), 6-chloro-3-(6-cyclopropyl-3-fluoro-2-methylphenoxy)-4-pyridazinol (Compound No. 1052), 6-chloro-3-(6-cyclopropyl-2,3-dimethylphenoxy)-4-pyridazinol (Compound No. 1061), 6-chloro-3-(2,3,5,6-tetramethylphenoxy)-4-pyridazinol (Compound No. 1125), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl acetate (Compound No. 1151), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl propionate (Compound No. 1160), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylpropanoate (Compound No. 1172), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl pivalate (Compound No. 1207), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methyl-2-butenoate (Compound No. 1358), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl benzoate (Compound No. 1417), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1481), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methoxybenzoate (Compound No. 1522), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methylbenzoate (Compound No. 1531), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-bromobenzoate (Compound No. 1543), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methylbenzoate (Compound No. 1566), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1625), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl isophthalate (Compound No. 1631), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl isobutylcarbonate (Compound No. 1770), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl dimethylcarbamate (Compound No. 1891), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-propanesulfonate (Compound No. 2051), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl benzene sulfonate (Compound No. 2176), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chlorobenzene sulfonate (Compound No. 2212), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methylbenzene sulfonate (Compound No. 2265), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methoxybenzene sulfonate (Compound No. 2309), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazoyl-5-yl 1,2-benzene disulfonate (Compound No. 2327), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl 1,3-benzene disulfonate (Compound No. 2333), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,3-dimethylbutanoate (Compound No. 2662), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl ethyl succinate (Compound No. 2727), bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] succinate (Compound No. 2733), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl pentanedioate (Compound No. 2739), bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] pentanedioate (Compound No. 2746), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-bromobenzoate (Compound No. 2805), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-ethylbenzoate (Compound No. 2961), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dimethylbenzoate (Compound No. 3129), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-fluoro-4-methylbenzoate (Compound No. 3185), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-difluorobenzoate (Compound No. 3217), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-dimethylbenzoate (Compound No. 3243), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxy(methyl)carbamate (Compound No. 3564), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(2-methoxyethyl)carbamate (Compound No. 3600), 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-azetizincarboxylate (Compound No. 3612) or 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-morpholinecarboxylate (Compound No. 3690). The 3-phenoxy-4-pyridazinol compound and its ester derivative of the present invention can be produced by the methods described in the following Steps A to N. In the above formula, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as defined in the above, L represents a leaving group, and for example, it may be a halogen atom, a C1 to C6 alkylsulfonyloxy group or a phenylsulfonyloxy group (the phenylsulfonyloxy group may be substituted by the same or different 1 to 5 halogen atom(s) or C1 to C6 alkyl group(s).), X repersents a hydrogen atom or an acyl group, Y represents, in addition to X, other protective groups for the hydroxyl group, and for example, it may be a methyl group, a methoxymethyl group, a methoxyethoxymethyl group or a benzyl group. Step A is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting a phenol compound represented by the formula (III) with a pyridazine compound represented by the formula (II), then, chlorinating the resulting compound, and futher reacting an oxygen nucleophilic agent, and further a step to produce Compound (Ib) of the present invention by removing the protective group of Compound (VII). (Step A-1) Step A-1 is a step to produce a phenoxypyridazine compound represented by the formula (IV) by reacting Compound (II) with Compound (III) in the presence or absence of a solvent, and if necessary, in the presence of a base. The base to be used is not specifically limited so long as it is a base showing generally a pH of 8 or more, and for example, it may be alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; alkali metals such as sodium, potassium, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo[2.2.2]-octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; organic metal bases such as n-butyl lithiums, s-butyl lithium, lithium diisopropylamide, sodium bis(trimehylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably alkali metal hydroxides, alkali metal carbonates, metal alkoxides, alkali metal hydrides or alkali metals, more preferably potassium carbonate, potassium t-butoxide, sodium hydride or sodium. An amount of the base to be used is generally 0.5 to 5 mol, preferably 1 to 3 mol based on 1 mol of the compound (II). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably nitriles, halogenated hdyrocarbons, ethers, aromatic hydrocarbons, amides or sulfoxides, more preferably dioxane, toluene, dimethylformamide or dimethylsulfoxide. The reaction temperature may vary depending on the starting compounds, reaction reagents and solvent, etc., and is generally −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. (Step A-2) Step A-2 is a step to producing a compound represented by the formula (V) in which a chlorine atom is introduced into the 4-position of a pyridazine ring by chlorinating Compound (IV) with a chlorinating agent in the presence or absence of a solvent. As the chlorinating agent to be used, it is not specifically limited so long as it can chlorinate an aromatic ring, and for example, it may be chlorine, chlorine-iron chloride, sulfuryl chloride, copper chloride, N-chlorosuccinimide or phosphorus pentachloride, preferably chlorine. An amount of the chlorinating agent to be used is generally 0.5 to 10 mol, preferably 1 to 2 mol based on 1 mol of the compound (IV). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be phosphorus oxychloride; water; alcohols such as methanol, ethanol, t-butanol, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc.; or a mixed solvent of the above, preferably phosphorus oxychloride, water, halogenated hdyrocarbons or ethers, more preferably phosphorus oxychloride. The reaction temperature may vary depending on the starting compounds, reaction reagents and a kind of the solvent to be used, etc., and is generally −90° C. to 200° C., preferably 0° C. to 50° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours. (Step A-3) Step A-3 is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting Compound (V) with an oxygen nucleophilic agent represented by the formula (VI) in the presence or absence of a solvent, and if necessary, in the presence of a base. The base to be used is not specifically limited so long as it is a base showing generally a pH of 8 or more, and for example, it may be alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal salts of an organic acid such as sodium acetate, potassium acetate, sodium formate, potassium formate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; alkali metals such as sodium, potassium, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo-[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; organic metal bases such as n-butyl lithiums, s-butyl lithium, lithium diisopropylamide, sodium bis(trimehylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably alkali metal hydroxides, alkali metal carbonates, metal alkoxide, alkali metal salts of an organic acid, alkali metal hydrides or alkali metals, more preferably sodium hydroxide, potassium hydroxide, potassium carbonate, potassium t-butoxide, sodium acetate, sodium formate, sodium hydride or sodium. The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, for example, water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably water, alcohols, nitriles, ethers, amides or sulfoxides, more preferably water, methanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide. The reaction temperature may vary depending on the starting compounds, reaction reagents and a kind of the solvent to be used, etc., and is generally −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and is usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours. Incidentally, in the present step, the compound (VI) may be used in the present step after making a salt by previously reacting with a base. (Step A-4) Step A-4 is a step to produce Compound (Ib) of the present invention by removing the protective group for a hydroxyl group of Compound (VII). The protective group to be used in the present step is not specifically limited so long as it can selectively removed from Compound (VII) to provide Compound (Ib), and for example, it may be a methyl group, methoxymethyl group, benzyloxymethyl group, methoxyethoxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, methylthiomethyl group, phenylthiomethyl group, 2,2-dichloro-1,1-difluoroethyl group, tetrahydropyranyl group, phenacyl group, p-bromophenacyl group, cyclopropylmethyl group, allyl group, isopropyl group, cyclohexyl group, t-butyl group, benzyl group, 2,6-dimethylbenzyl group, 4-methoxybenzyl group, 2-nitrobenzyl group, 2,6-dichlorobenzyl group, 4-(dimethylaminocarbonyl)benzyl group, 9-anthrylmethyl group, 4-picolyl group, heptafluoro-p-tolyl group or tetrafluoro-4-pyridyl group, preferably a methyl group, methoxymethyl group, methoxyethoxymethyl group, methylthiomethyl group, tetrahydropyranyl group, phenacyl group, allyl group or benzyl group, more preferably a methyl group. A method for removing the protective group to be used in the present step is not specifically limited so long as it can selectively remove the protective group for a hydroxyl group, and it can be carried out by the conventionally known method (for example, a method described in Protective Groups in Organic Synthesis, 13th Edition, written by Theodora W. Greene and Peter G. M. Wuts, JOHN WILEY & SONS, INC.) with regard to the respective protecttive groups or in accordance with these methods. For example, when the protective group is a methyl group, removal of the methyl group can be carried out, for example, by reacting with a potassium salt or sodium salt of 2-hydroxypyridine in dimethylsulfoxide, a sodium salt of ethanethiol in dimethylformamide, or boron tribromide in methylene chloride. For example, when the protective group is a methoxymethyl group, removal of the methoxymethyl group can be carried out, for example, by reacting with trifluoroacetic acid. For example, when the protective group is a methoxyethoxymethyl group, removal of the methoxyethoxymethyl group can be carried out, for example, by reacting with trifluoroacetic acid. Also, for example, when the protective group is a benzyl group, removal of the benzyl group can be carried out by catalytic hydrogenation. In the above formula, R1, R2, R3, R4, R5, R6, R7, L, X and Y have the same meanings as defined in the above. Step B is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by oxidizing a pyridazine compound represented by the formula (II), reacting a phenol compound represented by the formula (III) to the resulting compound, then chlorinating the resulting compound, and further reacting an oxygen nucleophilic agent, or a step to produce Compound (Ib) of the present invention by removing the protective group of Compound (VII). (Step B-1) Step B-1 is a step to produce Pyridazine N-oxide represented by the formula (VIII) by oxidizing Compound (II) with an oxidizing agent in the presence or absence of a solvent. The oxidizing agent to be used is not specifically limited so long as it can convert an amine into an N-oxide, and for example, it may be peroxides such as m-chloroperbenzoic acid (mcpba), peracetic acid, pertrifluoroacetic acid, trifluoroacetic anhydride-hydrogen peroxide, peroxydichloromaleic acid, dichloromaleic acid-hydrogen peroxide, peroxymaleic acid, maleic acid-hydrogen peroxide, t-butylhydroperoxide, t-butylhydroperoxide-vanadium oxyacetylacetonate, t-butylhydroperoxide-molybdenum chloride, hydrogen peroxide, etc.; ozone; or oxygen, preferably m-chloroperbenzoic acid (mcpba), trifluoroacetic anhydride-hydrogen peroxide or dichloromaleic acid-hydrogen peroxide. An amount of the oxidizing agent to be used in the reaction is usually 0.5 to 100 mol, preferably 1 to 2 mol based on 1 mol of Compound (II). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably halogenated hdyrocarbons, more preferably methylene chloride. The reaction temperature may vary depending on the starting compounds, reaction reagents and solvents, etc., and is generally −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours. According to the present step, an isomer in which other nitrogen atom is oxidized may be by-produced in some cases, and an objective Pyridazine N-oxide can be obtained by purifying the resulting materials after completion of the present step, or carrying out the subsequent steps in a state of admixture and by purifying the resulting materials after completion of the step. (Step B-2) Step B-2 is a step to produce a phenoxypyridazine compound represented by the formula (IX) by reacting Compound (VIII) with Compound (III) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step can be carried out in accordance with Step A-1. (Step B-3) Step B-3 is a step to produce Compound (V) by reacting Compound (IX) with phosphorus oxychloride in the presence or absence of a solvent. An amount of the phosphorus oxychloride to be used in the present step is generally 0.5 to 100 mol, preferably 1 to 5 mol based on 1 mol of Compound (IX). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; or a mixed solvent of the above, preferably halogenated hdyrocarbons, more preferably methylene chloride or chloroform. The reaction temperature may vary depending on the starting compounds, reaction reagents and solvents, etc., and is generally −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. (Step B-4) Step B-4 is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting Compound (V) with an oxygen nucleophilic agent represented by the formula (VI) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step is similar to Step A-3. (Step B-5) Step B-5 is a step to produce Compound (Ib) of the present invention by removing the protective group for a hydroxyl group of Compound (VII). The present step is similar to Step A-4. In the above formula, R1, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined in the above. Step C is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by oxidizing Compound (IV), then chlorinating the resulting material, and then reacting the same with an oxygen nucleophilic agent, and further a step to produce Compound (Ib) of the present invention by removing the protective group of Compound (VII). (Step C-1) Step C-1 is a step to produce Pyridazine N-oxide represented by the formula (IX) by oxidizing Compound (IV) with an oxidizing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step B-1. (Step C-2) Step C-2 is a step to produce Compound (V) by reacting Compound (IX) with phosphorus oxychloride in the presence or absence of a solvent. The present step is similar to Step B-3. (Step C-3) Step C-3 is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting Compound (V) with an oxygen nucleophilic agent represented by the formula (VI) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step is similar to Step A-3 or B-4. (Step C-4) Step C-4 is a step to produce Compound (Ib) of the present invention by removing the protective group for a hydroxyl group of Compound (VII). The present step is similar to Step A-4 or B-5. In the above formula, R1, R2, R3, R4, R5, R6, R7, L, X and Y have the same meanings as defined above. Step D is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting a pyridazine compound represented by the formula (X), into which an oxygen functional group has previously been substituted, with a phenol represented by the formula (III), and further a step to produce Compound (Ib) of the present invention by removing the protective group of Compound (VII). (Step D-1) Step D-1 is a step to produce Compound (Ia) of the present invention or a compound represented by the formula (VII), in which a hydroxyl group is protected, by reacting Compound (X) with Compound (III) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step can be carried out in accordance with Step A-1 or B-2. (Step D-2) Step D-2 is a step to produce Compound (Ib) of the present invention by removing the protective group for a hydroxyl group for Compound (VII). The present step is similar to Step A-4, B-5 or C-4. In the above formula, R1, R2, R3, R4, R5, R6, R7, L, X and Y have the same meanings as defined above, m′ and n′ each represent 0 or 1, provided that m′ and n′ are not simultaneously 0. Step E is a step to produce Compound (Ic) of the present invention or a compound represented by the formula (XII), in which a hydroxyl group is protected, by oxidizing a pyridazine compound to which an oxygen functional group has previously been substituted represented by the formula (X), and then reacting a phenol represented by the formula (III), and further a step to produce Compound (Id) of the present invention by removing the protective group of Compound (XII). (Step E-1) Step E-1 is a step to produce Pyridazine N-oxide represented by the formula (XI) by oxidizing Compound (X) with an oxidizing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step B-1 or C-1 in the case where m′=0 or n′=0, and when m′=n′=1, it can be carried out under severer conditions by making an amount of the oxidizing agent in excessive, by using an oxidizing agent having higher reactivity to carry out the oxidation, and the like. (Step E-2) Step E-2 is a step to produce Compound (Ic) of the present invention or a compound represented by the formula (XII), in which a hydroxyl group is protected, by reacting Compound (XI) with Compound (III) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step can be carried out in accordance with Step A-1, B-2 or D-1. (Step E-3) Step E-3 is a step to produce Compound (Id) of the present invention by removing the protective group for a hydroxyl group of Compound (XII). The present step is similar to Step A-4, B-5, C-4 or D-2. In the above formula, R1, R2, R3, R4, R5, R6, R7, X, Y, m′ and n′ have the same meanings as defined above. Step F is a step to produce Compound (Ic) of the present invention or a compound represented by the formula (XII), in which a hydroxyl group is protected, by oxidizing Compound (Ia) of the present invention or a compound represented by the formula (VII) in which a hydroxyl group is protected, and further is a step to produce Compound (Id) of the present invention by removing the protective group of Compound (XII). (Step F-1) Step F-1 is a step to produce Compound (Ic) of the present invention or a compound represented by the formula (XII), in which a hydroxyl group is protected, by oxidizing Compound (Ia) of the present invention or Compound (VII) with an oxidizing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step E-1. (Step F-2) Step F-2 is a step to produce Compound (Id) of the present invention by removing the protective group for a hydroxyl group of Compound (XII). The present step is similar to Step A-4, B-5, C-4, D-2 or E-3. In the above formula, R1, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above, R2a has the same meaning as R2 except for removing a hydrogen atom. Step G is a step to produce Compound (If) of the present invention or a compound represented by the formula (XIV), in which a hydroxyl group is protected, by subjecting the 5-position of the pyridazine ring of Compound (Ie) of the present invention or a compound represented by the formula (XIII), in which a hydroxyl group is protected, to metalation, and then reacting an electrophilic agent to the resulting material, and further is a step to produce Compound (Ig) of the present invention by removing the protective group of Compound (XIV). (Step G-1) Step G-1 is a step to produce Compound (If) of the present invention or a compound represented by the formula (XIV), in which a hydroxyl group is protected, by reacting Compound (Ie) of the present invention or a compound represented by the formula (XIII), in which a hydroxyl group is protected, with a metalating agent in the presence or absence of a solvent, and then, reacting with an electrophilic agent. The metalating agent to be used is not specifically limited so long as it can metalate an aromatic ring, and for example, it may be organic lithium compounds such as methyl lithium, butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, etc.; organic magnesium compounds such as methylmagnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, phenylmagnesium bromide, etc.; organometal amides such as lithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; alkali metals such as lithium, sodium, potassium, etc.; alkaline earth metals such as magnesium, etc., preferably organic lithium compounds, more preferably butyl lithium. An amount of the metalating agent to be used in the reaction is generally 0.5 to 10 mol, preferably 1 to 2 mol based on 1 mol of Compound (Ie) or Compound (XIII). The electrophilic agent to be used in the reaction is not specifically limited so long as it can be a nucleophilic agent capable of reacting with an organometallic compound, and for example, it may be silylating agents such as trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, trimethylsilyl trifluoromethane sulfonate, etc.; acylating agents such as acetyl chloride, benzoyl chloride, ethyl chlorocarbonate, methyl chlorocarbonate, N,N-dimethylformamide, methyl formate, etc.; carbonyl compounds such as acetaldehyde, benzaldehyde, acetone, cyclohexanone, etc.; alkylating agents such as methyl iodide, methyl bromide, benzyl bromide, etc.; halogenating agents such as fluorine, chlorine, bromine, iodine, N-fluorobenzene sulfonamide, 1-fluoro-2,6-dichloropyridinium triflate, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), etc.; or carbon dioxide, preferably a silylating agent, acylating agent, alkylating agent or halogenating agent, more preferably trimethylsilyl chloride, benzoyl chloride, ethyl chlorocarbonate or methyl iodide. An amount of the electrophilic agent to be used in the reaction is generally 0.5 to 10 mol, preferably 1 to 3 mol based on 1 mol of Compound (Ie) or Compound (XIII). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; or a mixed solvent of the above, preferably ethers, more preferably tetrahydrofuran. The reaction temperature may vary depending on starting materials, reaction reagents and a kind of the solvent to be used, etc., and usually −90° C. to 100° C., preferably −70° C. to 30° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 24 hours, preferably 30 minutes to 12 hours. (Step G-2) Step G-2 is a step to produce Compound (Ig) of the present invention by removing the protective group for a hydroxyl group of Compound (XIV). The present step is similar to Step A-4, B-5, C-4, D-2, E-3 or F-2. In the above formula, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as defined above, Xa represents the same meanings as X except for removing a hydrogen atom. Step H is a step to convert an ester derivative represented by the formula (Ih) of the present invention into a hydroxy compound represented by the formula (Ib) of the present invention. (Step H-1) Step H-1 is a step to produce Compound (Ib) of the present invention by reacting Compound (Ih) of the present invention with a nucleophilic agent in the presence or absence of a solvent. The nucleophilic agent to be used is not specifically limited so long as it can nucleophilically attack an ester derivative, and cleave the ester bonding to an acid portion and an alcohol portion, and for example, it may be water; hydroxides of an alkali metal such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; hydroxides of an alkaline earth metal such as magnesium hydroxide, calcium hydroxide, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, 2-hydroxypyridine potassium salt, 2-hydroxypyridine sodium salt, etc.; alkali metal salts of an organic acid such as sodium acetate, potassium acetate, sodium formate, potassium formate, etc.; fluorides such as tetrabutylammonium fluoride, potassium fluoride, etc.; chlorides such as lithium chloride, sodium chloride, etc.; bromides such as lithium bromide, sodium bromide, etc.; iodides such as sodium iodide, potassium iodide, etc.; or metal salts of a sulfur compound such as methanethiol sodium salt, ethanethiol sodium salt, etc., preferably water, hydroxides of an alkali metal, metal alkoxides or alkali metal salts of an organic acid, more preferably water, sodium hydroxide, potassium hydroxide or sodium acetate. An amount of the nucleophilic agent to be used is generally 1 to 10 mol, preferably 1 to 5 mol based on 1 mol of Compound (Ih). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitrites such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably water, alcohols, nitrites, ethers, amides or sulfoxides, more preferably water, methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide or dimethylsulfoxide. The reaction temperature may vary depending on starting materials, reaction reagents and a kind of the solvent to be used, etc., and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. Incidentally, in the present step, a conventionally known method can be employed as usual deprotection of a hydroxyl group. In the above formula, R1, R2, R3, R4, R5, R6, R7 and Xa have the same meanings as defined above. Step I is a step to convert the hydroxy compound represented by the formula (Ib) of the present invention tinot an ester derivative represented by the formula (Ih) of the present invention. (Step I-1) Step I-1 is a step to produce Compound (Ih) of the present invention by reacting Compound (Ib) of the present invention with an esterifyng agent in the presence or absence of a solvent. The esterifying agent to be used is not specifically limited so long as it can esterify a hydroxyl group, and for example, it may be acylating agents such as acetyl chloride, acetyl bromide, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, methyl chlorocarbonate, ethyl chlorocarbonate, N,N-dimethylcarbamoyl chloride, methyl chlorothioformate, etc.; or sulfonylating agents such as methanesulfonyl chloride, propanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic acid anhydride, N,N-dimethylsulfamoyl chloride, etc., preferably acetyl chloride, acetic anhydride, trifluoroacetic anhydride, benzoyl chloride, methyl chlorocarbonate, ethyl chlorocarbonate, methanesulfonyl chloride, propanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic acid anhydride, more preferably benzoyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic acid anhydride. An amount of the esterifying agent to be used in the reaction is generally 0.5 to 10 mols, preferably 1 to 3 mols based on 1 mol of Compound (Ib). The reaction is preferably carried out in the presence of a base. The base to be used is not specifically limited so long as it is a base showing a pH of 8 or more, and for example, it may be alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo-[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; or organic metal bases such as n-butyl lithiums, s-butyl lithium, lithium diisopropylamide, sodium bis(trimehylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably aliphatic tertiary amines, aliphatic cyclic tertiary amines or pyridines, more preferably triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine or 4-(N,N-dimethylamino)pyridine. An amount of the base to be used in the reaction is generally 0.5 to 20 mols, preferably 1 to 5 mols based on 1 mol of Compound (Ib). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be ketones such as acetone, methyl isobutyl ketone, etc.; nitrites such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably nitriles, halogenated hdyrocarbons or ethers, more preferably acetonitrile or methylene chloride. The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. Incidentally, in the present step, a conventionally known method can be employed as usual protection of a hydroxyl group. In the above formula, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above, R1a represents the same meaning as R1 except for removing a hydrogen atom. Step J is a step to produce Compound (Ii) of the present invention or a compound represented by the formula (XVIII), in which a hydroxyl group is protected, by reducing, oxidizing and then metalating a 6-chloropyridazine derivative represented by the formula (IVa), and reacting the resulting material with an electrophilic agent to introduce a substituent on the 6-position of a pyridazine ring, and further subjecting to chlorination, and substitution reaction with an oxygen nucleophilic agent, and further, a step to produce Compound (Ij) of the present invention by removing the protective group of Compound (XVIII). (Step J-1) Step J-1 is a step to produce Compound (IVb) in which R1 in Compound (IV) is a hydrogen atom by reacting Compound (IVa) in which R1 in Compound (IV) is a chlorine atom with a reducing agent in the presence or absence of a solvent. The reducing agent to be used in the reaction is not specifically limited so long as it can reduce a chlorine atom on an aromatic ring, and for example, it may be a reducing agent to be used in a usual hydrogenation reaction, preferably hydrogen-palladium catalyst. When the hydrogenation reaction is carried out in the present step, a hydrogen pressure is generally 1 atm to 100 atms, preferably 1 to 3 atms. An amount of the palladium to be used in the hydrogenation reaction is generally 0.001 to 10 mols, preferably 0.01 to 1 mol based on 1 mol of Compound (IVa). The hydrogenation reaction is preferably carried out in the presence of a base. The base to be used is not specifically limited so long as it is a base showing a pH of generally 8 or more, and for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; aqueous ammonia; aliphatic tertiary amines such as triethylamine, tri-n-butylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; or organometallic bases such as butyl lithium, s-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably aqueous ammonia or aliphatic tertiary amines, more preferably aqueous ammonia or triethylamine. An amount of the base to be used in the reaction is generally 0.1 to 100 mols, preferably 1 to 3 mols based on 1 mol of Compound (IVa). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; or a mixed solvent of the above, preferably alcohols, more preferably methanol or ethanol. The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. (Step J-2) Step J-2 is a step to produce Pyridazine N-oxide represented by the formula (XV) by oxidizing Compound (IVb) with an oxidizing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step B-1 or C-1. (Step J-3) Step J-3 is a step to produce Compound (XVI) of the present invention by reacting Compound (XV) with a metalating agent in the presence or absence of a solvent, and then, reacting with an electrophilic agent. The present step can be carried out in accordance with Step G-1. (Step J-4) Step J-4 is a step to produce Compound (XVII) by reacting Compound (XVI) with phosphorus oxychloride in the presence or absence of a solvent. The present step is similar to Step B-3 or C-2. (Step J-5) Step J-5 is a step to produce Compound (Ii) of the present invention or a compound represented by the formula (XVIII), in which a hydroxyl group is protected, by reacting Compound (XVII) with an oxygen nucleophilic agent represented by the formula (VI) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step is similar to Step A-3, B-4 or C-3. (Step J-6) Step J-6 is a step to produce Compound (Ij) of the present invention by removing the protective group for a hydroxyl group of Compound (XVIII). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2 or G-2. In the above formula, R1a, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above. Step K is a step to produce Compound (Ii) of the present invention or a compound represented by the formula (XVIII), in which a hydroxyl group is protected, by oxidizing, dechlorinating and then metalating 6-chloropyridazine derivative represented by the formula (Ik) of the present invention or a 6-chloropyridazine derivative represented by the formula (XIX) in which a hydroxyl group is protected, then introducing an electrophilic agent and finally reducing the resulting material, and further a step to produce Compound (Ij) of the present invention by removing the protective group of Compound (XVIII). (Step K-1) Step K-1 is a step to produce a N-oxypyridazine compound represented by the formula (Il) or (XX) by oxidizing Compound (Ik) or Compound (XIX) with an oxidizing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step B-1, C-1 or J-2. (Step K-2) Step K-2 is a step to produce a N-oxide compound (Im) or (XXI), in which the 6-position of the pyridazine ring is a hydrogen atom, by reacting a N-oxide compound (Il) or (XX), in which the 6-position of the pyridazine ring is a chlorine atom, with a reducing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step J-1. (Step K-3) Step K-3 is a step to produce Compound (In) of the present invention or a compound represented by the formula (XXII), in which a hydroxyl group is protected, by reacting Compound (Im) or (XXI) with a metalating agent in the presence or absence of a solvent, and then, reacting with an electrophilic agent. The present step can be carried out in accordance with Step G-1 or J-3. (Step K-4) Step K-4 is a step to produce Compound (Ii) of the present invention or a compound represented by the formula (XVIII), in which a hydroxyl group is protected, by reacting a N-oxide derivative represented by the formula (In) or (XXII) with phosphorus trichloride or phosphorus tribromide in the presence or absence of a solvent. An amount of the phosphorus trichloride or phosphorus tribromide to be used is generally 0.5 to 100 mols, preferably 1 to 20 mols based on 1 mol of Compound (In) or (XXII). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, heptane, etc.; or a mixed solvent of the above, preferably halogenated hydrocarbons, more preferably chloroform. The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours. (Step K-5) Step K-5 is a step to produce Compound (Ij) of the present invention by removing the protective group for a hydroxyl group of Compound (XVIII). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2, G-2 or J-6. In the above formula, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above, R1b represents the same meaning as R1 except for removing a hydrogen atom and a halogen atom. Step L is a step to produce Compound (Io) or a compound represented by the formula (XXIII), in which a hydroxyl group is protected, by reacting a 6-chloropyridazine derivative represented by the formula (Ik) or (XIX) with an organometallic compound, and further a step to produce Compound (Ip) of the present invention by removing the protective group of Compound (XXIII). (Step L-1) Step L-1 is a step to produce Compound (Io) of the present invention or a compound represented by the formula (XXIII), in which a hydroxyl group is protected, by reacting Compound (Ik) or (XIX) with an organometallic compound in the presence or absence of a solvent and in the presence of a metal catalyst. The organometallic compound to be used is not specifically limited so long as it is used for a cross-coupling reaction in which a R1b group is substituted by a chlorine atom, and for example, it may be organic magnesium compounds such as methyl magnesium chloride, ethyl magnesium bromide, phenylmagnesium chloride, etc.; organic zinc compounds such as phenyl zinc chloride, etc.; organic aluminum compounds such as (diisobutyl)(1-hexenyl)aluminum, etc.; organic tin compounds such as (vinyl)trimethyl tin, (1-ethoxyvinyl)tributyltin, (2-furyl)tributyltin, (2-thienyl)tributyltin, etc.; organic boron compounds such as phenylboronic acid, etc.; organic silicate compounds such as trimethylvinylsilicon-tris(dimethylamino)sulfonium difluorotrimethyl silicate, etc.; potassium cyanide, and acetylene compounds such as trimethylsilyl acetylene, phenyl acetylene, etc. may be used similarly in the presence of amines such as triethylamine, etc., as in the above-mentioned organometallic compounds, preferably organic tin compounds or organic boron compounds. An amount of the organometallic compound to be used in the reaction is generally 0.5 to 10 mols, preferably 1 to 2 mols based on 1 mol of Compound (Ik) or (XIX). The metal catalyst to be used in the present step is not specifically limited so long as it can be used in a cross-coupling reaction, and for example, it may be a nickel catalyst or a palladium catalyst. An amount of the metal catalyst to be used in the reaction is generally 0.0001 to 10 mols, preferably 0.01 to 0.5 mol based on 1 mol of Compound (Ik) or (XIX). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitrites such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; organic amines such as triethylamine, pyridine, etc.; or a mixed solvent of the above, preferably ethers, aromatic hydrocarbons or amides, more preferably ether, tetrahydrofuran, toluene or dimethylformamide. The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 130° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 24 hours. (Step L-2) Step L-2 is a step to produce Compound (Ip) of the present invention by removing the protective group for a hydroxyl group of Compound (XXIII). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2, G-2, J-6 or K-5. In the above formula, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above. Step M is a step to produce Compound (Iq) of the present invention or a compound represented by the formula (XXIV), in which a hydroxyl group is protected, by cyanation of 6-position unsubstituted Pyridazine N-oxide derivative represented by the formula (Im) or (XXI), and also a step to produce Compound (Ir) of the present invention by removing the protective group of Compound (XXIV). (Step M-1) Step M-1 is a step to produce Compound (Iq) of the present invention or a compound represented by the formula (XXIV), in which a hydroxyl group is protected, by reacting Compound (Im) or (XXI) with a cyanation reagent in the presence or absence of a solvent. The present step can be carried out in accordance with the conventionally known Reissert-Henze reaction (JOC, 48, 1983, 1375 to 1377; Heterocycles, 15, 1981, 981 to 984; Synthesis, 1983, 316 to 319, etc.). (Step M-2) Step M-2 is a step to produce Compound (Ir) of the present invention by removing the protective group for a hydroxyl group of Compound (XXIV). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2, G-2, J-6, K-5 or L-2. In the above formula, R2, R3, R4, R5, R6, R7, X and Y have the same meanings as defined above. Step N is a step to produce Compound (Is) of the present invention or a compound represented by the formula (XXV), in which a hydroxyl group is protected, by dechlorinating a 6-chloropyridazine derivative represented by the formula (Ik) or (XIX), and further a step to produce Compound (It) of the present invention by removing the protective group of Compound (XXV). (Step N-1) Step N-1 is a step to produce Compound (Is) of the present invention or a compound represented by the formula (XXV), in which a hydroxyl group is protected, by reacting Compound (Ik) or (XIX) with a reducing agent in the presence or absence of a solvent. The present step can be carried out in accordance with Step J-1 or K-2. (Step N-2) Step N-2 is a step to produce Compound (It) of the present invention by removing the protective group for a hydroxyl group of Compound (XXV). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2, G-2, J-6, K-5, L-2 or M-2. In the above formula, R1, R2, R4, R5, R6 and R7 have the same meanings as defined above. Step O is a step to produce Compound (Iu) of the present invention by reacting a 3,4-dichloropyridazine derivative represented by the formula (XXVI) with a catechol derivative represented by the formula (XXVII) and then subjecting the resulting material to hydrolysis. (Step O-1) Step O-1 is a step to produce a condensed compound represented by the formula (XXVIII) by reacting Compound (XXVI) with Compound (XXVII) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step can be carried out in accordance with Step A-1, B-2, D-1 or E-2, and an amount of the base to be used is generally 1 to 10 mols, preferably 2 to 6 mols based on 1 mol of Compound (XXVI). (Step O-2) Step O-2 is a step to produce Compound (Iu) of the present invention by subjecting Compound (XXVIII) to hydrolysis. The present step can be carried out in accordance with the case where Y is a hydrogen atom in Step A-3, B-4 or C-3, and a reaction temperature is preferably 80° C. to 100° C. In the above formula, R2, R3, R4, R5, R6 and R7 have the same meanings as defined above. Step P is a step to produce Compound (Iv) of the present invention or a compound represented by the formula (XXXI), in which a hydroxyl group is protected, by selectively subjecting 6-position of a 4,6-dichloropyridazine derivative represented by the formula (Va) to hydrolysis to prepare Compound (XXIX), then, brominating 4,6-positions thereof with phosphorus oxybromide, and then selectively reacting an oxygen nucleophilic agent at 4-position thereof, and a step to produce Compound (Iw) of the present invention by removing the protective group of Compound (XXXI). (Step P-1) Step P-1 is a step to produce a compound represented by the formula (XXIX) by subjecting Compound (Va) to hydrolysis in the presence or absence of a solvent and in the presence of an acid to selectively convert a chlorine atom at the 6-position into a hydroxyl group. An acid to be used is not specifically limited so long as it is an acid showing a pH of 6 or less, and for example, it may be organic acids such as formic acid, acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, fumalic acid, benzoic acid, etc.; mineral acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or Lewis acids such as aluminum chloride, iron chloride, titanium chloride, boron trifluoride, etc., preferably organic acids, more preferably formic acid or acetic acid. The present step is carried out preferably in the presence of a metal salt of an acid. The metal salt of an acid to be used may inclide, for example, alkali metal salts of an organic acid such as sodium formate, potassium formate, lithium acetate, sodium acetate, potassium acetate, cesium acetate, sodium benzoate, etc.; alkaline earth metal salts of an organic acid such as magnesium formate, calcium formate, magnesium acetate, calcium acetate, magnesium benzoate, etc.; alkali metal salts or alkaline earth metal salts of carbonic acid such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.; or alkali metal salts or alkaline earth metal salts of a mineral acid such as sodium fluoride, potassium fluoride, sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, sodium sulfate, sodium hydrogen sulfate, potassium sulfate, potassium hydrogen sulfate, magnesium sulfate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc., preferably alkali metal salts of an organic acid, more preferably sodium formate, potassium formate, sodium acetate or potassium acetate. The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; organic acids such as formic acid, acetic acid, propionic acid, etc.; or a mixed solvent of the above, preferably water, nitriles, ethers, amides, sulfoxides or organic acids, more preferably water, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, formic acid or acetic acid. The reaction temperature may vary depending on the starting compounds, reaction reagents and a kind of the solvent to be used, etc., and is generally −90° C. to 200° C., preferably 0° C. to 150° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually, 5 minutes to 24 hours, preferably 15 minutes to 12 hours. (Step P-2) Step P-2 is a step to produce Compound (XXX) by reacting Compound (XXIX) with phosphorus oxybromide in the presence or absence of a solvent. An amount of the phosphorus oxybromide to be used in the present step is generally 0.5 to 100 mols, preferably 1 to 10 mols based on 1 mol of Compound (XXIX). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; or a mixed solvent of the above, preferably halogenated hydrocarbons, more preferably methylene chloride, chloroform. The reaction temperature may vary depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 72 hours, preferably 30 minutes to 24 hours. (Step P-3) Step P-3 is a step to produce Compound (Iv) of the present invention or a compound represented by the formula (XXXI), in which a hydroxyl group is protected, by reacting Compound (XXX) with an oxygen nucleophilic agent represented by the formula (VI) in the presence or absence of a solvent, and if necessary, in the presence of a base. The present step is similar to Step A-3, B-4, C-3 or J-5. (Step P-4) Step P-4 is a step to produce Compound (Iw) of the present invention by removing the protective group for a hydroxyl group of Compound (XXXI). The present step is similar to Step A-4, B-5, C-4, D-2, E-3, F-2, G-2, J-6, K-5, L-2, M-2 or N-2. In the above formula, R1, R2, R3, R4, R5, R6 and R7 have the same meanings as defined above, a compound represented by the formula (XXXII) represents an oxygen nucleophilic agent, a sulfur nucleophilic agent or a nitrogen nucleophilic agent, Z represents a substituent in which a proton is removed from the oxygen nucleophilic agent, the sulfur nucleophilic agent or the nitrogen nucleophilic agent, and for example, it may be an alkoxy group, a thioalkoxy group, a dialkylamino group, etc. Step Q is a step to convert a hydroxy isomer represented by the formula (Ib) of the present invention into an ester derivative represented by the formula (Iy) of the present invention. (Step Q-1) Step Q-1 is a step to produce Compound (Ix) of the present invention by reacting Compound (Ib) of the present invention with phosgene in the presence or absence of a solvent. An amount of the phosgene to be used in the reaction is generally 0.5 to 10 mols, preferably 1 to 3 mols based on 1 mol of Compound (Ib). The reaction is preferably carried out in the presence of a base. The base to be used is not specifically limited so long as it is a base generally showing a pH of 8 or more, and for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo-[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; or, organic metal bases such as n-butyl lithiums, s-butyl lithium, lithium diisopropylamide, sodium bis(trimehylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably aliphatic tertiary amines, aliphatic cyclic tertiary amines or pyridines, more preferably triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine or 4-(N,N-dimethylamino)pyridine. An amount of the base to be used in the reaction is generally 0.5 to 20 mols, preferably 1 to 5 mols based on 1 mol of Compound (Ib). The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably nitriles, halogenated hydrocarbons or ethers, more preferably acetonitrile or methylene chloride. The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. (Step Q-2) Step Q-2 is a step to produce Compound (Iy) of the present invention by reacting Compound (Ix) of the present invention with a nucleophilic agent represented by the formula (XXXII) in the presence or absence of a solvent, and if necessary, in the presence of a base. The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, and for example, it may be ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; aliphatic hydrocarbons such as hexane, cyclohexane, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above, preferably nitriles, halogenated hydrocarbons or ethers., more preferably acetonitrile or methylene chloride. The base to be used is not specifically limited so long as it is a base generally showing a pH of 8 or more, and for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo-[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; or organic metal bases such as n-butyl lithiums, s-butyl lithium, lithium diisopropylamide, sodium bis(trimehylsilyl)amide, lithium bis(trimethylsilyl)amide, etc., preferably aliphatic tertiary amines, aliphatic cyclic tertiary amines or pyridines, more preferably triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), pyridine or 4-(N,N-dimethylamino)pyridine. An amount of the base to be used in the reaction is generally 0.5 to 20 mols, preferably 1 to 5 mols based on 1 mol of Compound (Ix). The nucleophilic agent (XXXII) to be used in the reaction is not specifically limited so long as it can substitute a chlorine atom of chlorocarbonic acid ester (Ix), and the oxygen nucleophilic agent may include, for example, alcohols such as methanol, ethanol, propanol, etc.; or phenols such as phenol, 4-chlorophenol, etc., also, the sulfur nucleophilic agent may include, for example, thiols such as methanethiol, ethanethiol, propanethiol, etc.; or thiophenols such as thiophenol, etc., and, the nitrogen nucleophilic agent may include, for example, aliphatic linear amines such as methylamine, dimethylamine, diethylamine, methyl(t-butyl)amine, methyl(cyanomethyl)amine, methyl(ethoxycarbonylmethyl)amine, bis(cyanomethyl)amine, bis(2-cyanoethyl)amine, bis(ethoxycarbonylmethyl)amine, bis(2-methoxyethyl)amine, bis(2-ethoxyethyl)amine, bis(2-chloroethyl)amine, N,O-dimethylhydroxylamine, etc.; aromatic amines such as methyl(phenyl)amine, methyl(pyridyl)amine, etc.; aliphatic cyclic amines such as aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, N-methylpiperazine, N-phenylpiperazine, 2-methoxycarbonylpyrrolidine, 3-hydroxypyrrolidine, 4-bromopiperidine, 4-methylpiperidine, 2,2,6,6-tetramethylpiperidine, 2-ethoxycarbonylpiperidine, 4-ethoxycarbonylpiperidine, 2,6-dimethyl morpholine, 1,2,3,4-tetrahydroisoquinoline, etc.; aromatic cyclic amines such as carbazole, 2,5-dimethylpyrrole, etc., preferably methanol, ethanol, methanethiol, ethanethiol, methylamine, dimethylamine, methyl(cyanomethyl)amine, methyl(ethoxycarbonylmethyl)amine, bis(cyanomethyl)amine, bis(2-cyanoethyl)amine, bis(ethoxycarbonylmethyl)amine, bis(2-methoxyethyl)amine, bis(2-ethoxyethyl)amine, bis(2-chloroethyl)amine, N,O-dimethylhydroxylamine, methyl(pyridyl)amine, azetidine, pyrrolidine, piperidine, morpholine, thio morpholine, N-methylpiperazine, 2-methoxycarbonylpyrrolidine, 3-hydroxypyrrolidine, 2-ethoxycarbonylpiperidine, 4-ethoxycarbonylpiperidine, 2,6-dimethyl morpholine, 2,5-dimethylpyrrole, more preferably dimethylamine, methyl(cyanomethyl)amine, methyl(ethoxycarbonylmethyl)amine, bis(cyanomethyl)amine, bis(ethoxycarbonylmethyl)amine, bis(2-methoxyethyl)amine, bis(2-ethoxyethyl)amine, N,O-dimethylhydroxylamine, azetidine, morpholine, thiomorpholine, N-methylpiperazine, 2-methoxycarbonylpyrrolidine, 3-hydroxypyrrolidine, 2-ethoxycarbonylpiperidine, 4-ethoxycarbonylpiperidine, 2,6-dimethyl morpholine. An amount of the nucleophilic agent to be used in the reaction is generally 0.5 to 20 mols, preferably 1 to 5 mols based on 1 mol of Compound (Ix). The reaction temperature may vary mainly depending on starting materials, reaction reagents and a kind of the solvent to be used, and usually −90° C. to 200° C., preferably 0° C. to 100° C. The reaction time may vary mainly depending on a reaction temperature, starting materials, reaction reagents and a kind of the solvent to be used, and usually 5 minutes to 48 hours, preferably 15 minutes to 12 hours. Incidentally, after completion of the above-mentioned respective steps, and before the steps subsequent thereto, the functional group(s) in R1 to R7 of the desired compound of the respective steps can be converted to the other functional group so long as it is within the definitions for R1 to R7. Also, in Steps A-1, B-2, D-1 and E-2, when at least one of R1 and R2 is a chlorine atom, depending on the reaction conditions, in the Step, a chlorine atom of R1 or R2 is substituted by the group in some cases, and further, in Steps A-3, B-4, C-3 and J-5, when at least either one of R1 and R2 is a chlorine atom, depending on the reaction conditions, in the Step, a chlorine atom of R1 or R2 is substituted by the group OY in some cases, and further, in Step P-3, a bromine atom at the 6-position of the pyridazine ring or a chlorine atom of R2 when R2 is a chlorine atom is substituted by the group OY in some cases. Starting Compound (II) in Step A and B may be used those commercially available, or may be produced by the method disclosed in, for example, Kogyo Kagaku Zasshi (Journal of Industrial Chemistry), 1971, vol. 74, No. 7, pp. 1490-1491; Tetrahedron, 1999, vol. 55, No. 52, pp. 15067 to 15070; The Journal of Organic Chemistry, 1963, vol. 28, pp. 218 to 221 or in accordance with these methods. The starting Compound (X) of Steps D and E can be produced by the method disclosed in, for example, Helvetica Chimica Acta, 1956, vol. 39, pp. 1755 to 1764; Monatshefte fur Chemie, 1968, vol. 99, pp. 15-81 (in the present specification, the letter u in Monatshefte fur Chemie represents u-umlaut.); German Patent 1,912,472, Nov. 12, 1970 (filed on Apr. 12, 1969) (Ger. Offen. 1, 912, 472, 12 Nov. 1970, Appl.12 March 1969), or in accordance with these methods. The phenol Compound (III) to be used in Steps A, B, D and E may be used those commercially available, or may be produced by using the conventionally known method or in accordance with these methods. 2-Isobutylphenol can be produced by the method disclosed in, for example, Canadian Journal of Chemistry, 1956, vol. 34, pp. 851-854. 2-Pentylphenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1989, vol. 30, No. 35, pp. 4741-4744. 2-Hexylphenol can be produced by the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 2000, vol. 7, pp. 1109-1116 (coversion of vinyl group into hexyl group), and Journal of Medicinal Chemistry, 1977, vol. 20, No. 10, pp. 1317-1323 (conversion of phenylmethyl ether into phenol, demethylation reaction) from commercially available 1-methoxy-2-vinylbenzene. 2-Cyclopropylphenol can be produced by the method disclosed in, for example, Bioorganic & Medicinal Chemistry, 1997, vol. 5, No. 10, pp. 1959-1968. 2-(1-Methylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(2-methoxyphenyl)ethanone, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and by the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(1-Ethylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(2-methoxyphenyl)-1-propanone, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and by the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(1-Cyclopropylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction) from cyclopropyl(2-hydroxyphenyl)methanone produced by the method disclosed in Journal of the Chemical Society: Parkin transaction I, 1990, pp. 689-693 from commercially available 2,3-dihydro-4H-chromen-4-one. 1-(2-Hydroxyphenyl)cyclopropanecarbonitrile can be produced by producing 1-(2-methoxyphenyl)cyclopropanecarbonitrile in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 2000, vol. 122, No. 4, pp. 712-713, and by the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(1-Phenylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(2-methoxyphenyl)(phenyl)methanone, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and by the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(2-Methylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(2,2-Dimethylcyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Cis-2,cis-3-dimethyl)-ref-1-cyclopropyl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Cis-2,trans-3-dimethyl)-ref-1-cyclopropyl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Trans-2,trans-3-dimethyl)-ref-1-cyclopropyl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Ref-1,cis-5,cis-6)-bicyclo[3.1.0]hexa-6-yl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Ref-1,cis-5,trans-6)-bicyclo[3.1.0]hexa-6-yl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Ref-1,cis-6,cis-7)-bicyclo[4.1.0]hept-7-yl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(Ref-1,cis-6,trans-7)-bicyclo[4.1.0]hept-7-yl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(2,2,Cis-3-trimethyl)-ref-1-cyclopropyl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[(2,2,trans-3-trimethyl)-ref-1-cyclopropyl]phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(chloromethyl)-2-methoxybenzene, Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclobutylphenol can be produced by the method disclosed in, for example, German Patent DE-2825388. 1-(2-Hydroxyphenyl)cyclobutancarbonitrile can be produced by the method disclosed in, for example, Pharmaceutical Chemistry Journal (English Translation), 1980, vol. 14, No. 2, pp. 114-118. 1-(2-Hydroxyphenyl)cyclobutanecarboxylic acid can be produced by the method disclosed in, for example, Pharmaceutical Chemistry Journal (English Translation), 1980, vol. 14, No. 2, pp. 114-118. 2-(1-Propynyl)phenol can be produced by the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 1998, pp. 477-484. 2-(Cyclopropylmethyl)phenol can be produced in accordance with the method disclosed in, for example, Organic Reactions, 1941, vol, 1, p. 155 (Clemmensen reduction) from cyclopropyl(2-hydroxyphenyl)methanone which can be produced by the method disclosed in Journal of the Chemical Society: Parkin transaction I, 1990, pp. 689-693 from commercially available 2,3-dihydro-4H-chromen-4-one. 2-(Methoxymethyl)phenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1999, vol. 40, p. 6049. 2-(Ethoxymethyl)phenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1999, vol. 40, p. 6049. 2-(1,3-Dioxolan-2-yl)phenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1989, vol. 30, No. 13, pp. 1609-1612. 1-(2-Hydroxyphenyl)ethanone O-methyloxime can be produced in accordance with the method disclosed in, for example, commercially available 1-(2-hydroxyphenyl)ethanone, Journal of the American Chemical Society, 1986, vol. 108, pp. 6016-6023. 3′-(Trifluoromethyl)[1,1′-biphenyl]-2-ol can be produced in accordance with the method disclosed in, for example, from commercially available 2-iodophenol and 3-(trifluoromethyl)phenylboronic acid, Chemical Reviews, 1995, vol. 95, pp. 2457-2483 (phenylation reaction, Suzuki-Miyaura coupling reaction). 2-(1H-pyrrole-1-yl)phenol can be produced by the method disclosed in, for example, The Journal of Antibiotics, 1994, vol. 47, No. 5, pp. 602-605. 2-(2-Thienyl)phenol can be produced by the method disclosed in, for example, Journal of Heterocyclic Chemistry, 1985, vol. 22, pp. 1667-1669. 2-(3-Thienyl)phenol can be produced by the method disclosed in, for example, Journal of Heterocyclic Chemistry, 1985, vol. 22, pp. 1667-1669. 2-(1H-pyrazol-1-yl)phenol can be produced by the method disclosed in, for example, Canadian Journal of Chemistry, 1963, vol. 41, pp. 2086-2092. 2-(3,5-Dimethyl-1H-pyrazol-1-yl)phenol can be produced by the method disclosed in, for example, Heterocycles, 1982, vol. 19, No. 8, pp. 1487-1495. 2-[3-(Trifluoromethyl)-1H-pyrazol-1-yl]phenol can be produced, for example, by preparing 1-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol from commercially available 1-(2-methoxyphenyl)hydrazine hydrochloride by the method disclosed in Journal of Fluorine Chemistry 1998, vol. 92, p. 23, and in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[4-(Trifluoromethyl)-1H-pyrazol-1-yl]phenol can be produced, for example, by preparing 1-(2-methoxyphenyl)-4-(trifluoromethyl)-1H-pyrazole from commercially available 1-(2-methoxyphenyl)hydrazine hydrochloride by the method disclosed in Tetrahedron Letters, 1996, vol. 37, No. 11, p. 1829, and in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-[5-(Trifluoromethyl)-1H-pyrazol-1-yl]phenol can be produced, for example, by preparing 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole from commercially available 1-(2-methoxyphenyl)hydrazine hydrochloride by the method disclosed in Journal of Fluorine Chemistry, 1998, vol. 92, p. 23, and in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 5-(2-Hydroxyphenyl)-N,N-dimethyl-1H-pyrazol-1-sulfonamide can be produced, for example, from 5-(5-chloro-2-hydroxyphenyl)-N,N-dimethyl-1H-pyrazol-1-sulfonamide, which can be produced from commercially available 4-chloro-2-(1H-pyrazol-5-yl)phenol in accordance with the method disclosed in Journal of Medicinal Chemistry, 1998, vol. 41, No. 12, pp. 2019-2028, in accordance with the method disclosed in, Jikken Kagaku Koza (Experimental Chemistry Lecture), 4th Edition, vol. 26, pp. 251-266 (catalytic hydrogenation reaction). 3-(2-Hydroxyphenyl)-N,N-dimethyl-1H-pyrazol-1-sulfonamide can be produced, for example, from 3-(5-chloro-2-hydroxyphenyl)-N,N-dimethyl-1H-pyrazol-1-sulfonamide, which can be produced from commercially available 4-chloro-2-(1H-pyrazol-5-yl)phenol in accordance with the method disclosed in Journal of Medicinal Chemistry, 1998, vol. 41, No. 12, pp. 2019-2028, in accordance with the method disclosed in, Jikken Kagaku Koza (Experimental Chemistry Lecture), 4th Edition, vol. 26, pp. 251-266 (catalytic hydrogenation reaction). 2-(4-Methyl-1,3-thiazol-2-yl)phenol can be produced by the method disclosed in, for example, from commercially available 2-hydroxybenzonitrile, Japanese Provisional Patent Publication No. 11-60552 (thioamidation reaction of a cyano group), and the method disclosed in Liebigs Annalen der Chemie, 1890, vol. 259, p. 236. 2-(1,3-Benzothiazol-2-yl)phenol can be produced by the method disclosed in, for example, The Journal of Organic Chemistry, 1970, vol. 35, pp. 3147-3149. 2-(Dimethylamino)phenol can be produced by the method disclosed in, for example, Journal of Medicinal Chemistry, 1998, vol. 41, pp. 4800-4818. 2-(2-Methoxyethoxy)phenol can be produced in accordance with the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 1980, pp. 756-758 from commercially available pyrocatechol. 2-(Isopropylsulfanyl)phenol can be produced by the method disclosed in, for example, Tetrahedron, 1970, vol. 26, pp. 4449-4471. 3-Cyclopropylphenol can be produced by the method disclosed in, for example, from commercially available 1-bromo-3-methoxybenzene, Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and in accordance with the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-(2-Furyl)phenol can be produced, for example, by producing 2-(3-methoxyphenyl)furan by the method disclosed in The Journal of Organic Chemistry, 1993, vol. 58, No. 17, pp. 4722-4726, and in accordance with the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 4-Cyclopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-bromo-4-methoxybenzene, Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and by the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Bromo-3-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-methoxy-6-methylaniline, Organic Synthesis, Collective Volume, vol. 3, pp. 185-187 or the method disclosed in The Journal of Organic Chemistry, 1977, vol. 42, pp. 2426-2430 (conversion of anilines into bromobenzene, Sandmeyer reaction, etc.) and, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-Fluoro-2-methylphenol can be produced in accordance with the method disclosed in Journal of the Chemical Society: Parkin transaction I, 1974, p. 1353 from commercially available 3-fluoro-2-methylbenzaldehyde. 3-Chloro-2-methylphenol can be produced in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction) from commercially available 1-chloro-3-methoxy-2-methylbenzene. 3-Methoxy-2-methylphenol can be produced in accordance with the method disclosed in, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction) from commercially available 2-methyl-1,3-benzene diol. 2-Cyclopropyl-3-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-methoxy-6-methylaniline, Organic Synthesis, Collective Volume, vol. 3, pp. 185-187 or the method disclosed in The Journal of Organic Chemistry, 1977, vol. 42, pp. 2426-2430 (conversion of anilines into bromobenzene, Sandmeyer reaction, etc.), and the method disclosed in Tetrahedron Letters, 1979, vol. 20, pp. 4159-4162 or the method disclosed in Tetrahedron, 1997, vol. 53, No. 43, pp. 14599-14614 or the method disclosed in Bulletin of the Chemical Society of Japan, 1971, vol. 44, pp. 2237-2248 (conversion reaction of aromatic bromide into aromatic aldehyde ), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 2.8, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, 3428 or the method disclosed in Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-3-methoxyphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2,6-dimethoxybenzaldehyde, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 4-indanol can be produced in accordance with the method disclosed in, for example, Organic Reactions, 1941, vol. 1, p. 155 (Clemmensen reduction) from commercially available 4-hydroxy-1-indanone. 3-methyl-4-indanol can be produced by the method disclosed in, for example, Journal of Applied Chemistry, 1959, vol. 9, pp. 629 and 637. 1-Methyl-4-indanol can be produced by the method disclosed in, for example, Journal of the Chemical Society, 1961, pp. 2773-2777. 2,2-Dimethyl-4-indanol can be produced by the method disclosed in, for example, Journal of Chemical Research Miniprint, 1985, vol. 8, pp. 2724-2747. Spiro[cyclopropane-1,3′-(2′,3′-dihydro-1′H-inden-4′-ol)] can be produced in accordance with the method disclosed in, for example, from commercially available 2,3-dihydro-4H-chromen-4-ol, Bioorganic and Medicinal Chemistry, 1999, vol. 7, No. 12, pp. 2801-2810 (synthesis of 7-hydroxy-1-indanone), and the method disclosed in Organic Synthesis, Collective Volume vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 7-hydroxy-2,3-dihydro-1H-inden-1-one O-methyloxime can be produced in accordance with the method disclosed in, for example, from commercially available 2,3-dihydro-4H-chromen-4-ol, Bioorganic and Medicinal Chemistry, 1999, vol. 7, No. 12, pp. 2801-2810 (synthesis of 7-hydroxy-1-indanone), and the method disclosed in Organic Synthesis, Collective Volume vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Chemical Pharmaceutical Bulletin, 1988, vol. 36, No. 8, pp.3134-3137 (conversion of carbonyl group into oxime), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2,3-Dihydro-1-benzofuran-4-ol can be produced by the method disclosed in, for example, Journal of the Chemical Society, 1948, p. 894 (reduction of olefin) from 1-benzofuran-4-ol which is obtained by the method disclosed in Helvetica Chimica Acta, 1933, vol. 16, pp. 121-129. 3-Methyl-2,3-dihydro-1-benzofuran-4-ol can be produced in accordance with the method disclosed in, for example, Journal of the Chemical Society, 1948, p. 894 (reduction of olefin) from 3-methyl-1-benzofuran-4-ol which is obtained by the method disclosed in Journal of the Chemical Society, 1951, pp. 3229-3234. 1-Benzofuran-4-ol can be produced by the method disclosed in, for example, Helvetica Chimica Acta, 1933, vol. 16, pp. 121-129. 3-Methyl-1-benzofuran-4-ol can be produced by the method disclosed in, for example, Journal of the Chemical Society, 1951, pp. 3229-3234. 1-Benzothiophen-4-ol can be produced by the method disclosed in, for example, Journal of the American Chemical Society, 1935, vol. 57, pp. 1611-1615. 2-Methyl-1,3-benzoxazol-4-ol can be produced in accordance with the method disclosed in, for example, Journal of Medicinal Chemistry, 1987, vol. 30, No. 1, pp. 62-67. 2,3-Dihydro-1-benzofuran-7-ol can be produced in accordance with the method disclosed in, for example, from commercially available 7-methoxy-1-benzofuran, Journal of the Chemical Society, 1948, p. 894 (hydrogenation reaction of benzofuran), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 1-Benzofuran-7-ol can be produced in accordance with the method disclosed in, for example, from commercially available 7-methoxy-1-benzofuran, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 1,3-Benzodioxol-4-ol can be produced by the method disclosed in, for example, Chemical Pharmaceutical Bulletin, 1981, vol. 29, No. 10, pp. 2893-2898 from commercially available 1,2,3-benzene triol. 2,3-Dihydro-1,4-benzodioxyn-5-ol can be produced by the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 1988, pp. 511 to 520 from commercially available 1,2,3-benzene triol. 2-Methyl-1,3-benzoxazol-7-ol can be produced in accordance with the method disclosed in, for example, Liebigs Annalen der Chemie, 1957, vol. 608, p. 128 (reduction of a nitro group into an amino group), and the method disclosed in Journal of Medicinal Chemistry, 1987, vol. 30, No. 1, pp. 62-67 from commercially available 3-nitro-1,2-benzene diol. 2-Bromo-4-tert-butylphenol can be produced by the method disclosed in, for example, Tetrahedron, 1999, vol. 55, No. 28, pp. 8377-8384. 2-Ethyl-4-iodophenol can be produced by the method disclosed in, The Journal of Organic Chemistry, 1951, vol. 16, pp. 1117-1120 from commercially available 2-ethylphenol. 4-Bromo-2-isopropylphenol can be produced by the method disclosed in, for example, Journal of Medicinal Chemistry, 1971, vol. 14, No. 9, pp. 789-792. 3-Cyclopropyl-4-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-bromo-1-methoxy-4-methylbenzene, Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction) and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 5-(Dimethylamino)-2-methylphenol can be produced by the method disclosed in, for example, Journal of the Chemical Society, 1947, pp. 182-191. 5-Methoxy-2-methylphenol can be produced by the method disclosed in, for example, Chemical Abstracts, 1938, p. 2519. 2-Ethyl-5-methoxyphenol can be produced by the method disclosed in, for example, Chemical and Pharmaceutical Bulletin, 1979, vol. 27, No. 6, pp. 1490-1494. 2,5-Diisopropylphenol can be produced by the method disclosed in, for example, The Journal of Organic Chemistry, 1980, vol. 45, No. 22, pp. 4326-4329. 2-Cyclopropyl-5-fluorophenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-bromo-5-fluorophenol, Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 5-Chloro-2-cyclopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 4-chloro-2-methoxyphenol, The Journal of Organic Chemistry, 1997, vol. 62, No. 2, pp. 261-274 (trifluoromethanesulfonylation of phenol), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-5-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-methoxy-4-methylphenol, The Journal of Organic Chemistry, 1997, vol. 62, No. 2, pp. 261-274 (trifluoromethanesulfonylation of phenol), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-5-ethylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 4-ethyl-2-methoxyphenol, The Journal of Organic Chemistry, 1997, vol. 62, No. 2, pp. 261-274 (trifluoromethanesulfonylation of phenol), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-5-isopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 3-isopropylphenol, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 4-Cyclopropyl-3-hydroxybenzonitrile can be produced in accordance with the method disclosed in, for example, from commercially available 4-hydroxy-3-methoxybenzonitrile, The Journal of Organic Chemistry, 1997, vol. 62, No. 2, pp. 261-274 (trifluoromethanesulfonylation of phenol), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 5-Fluoro-2-[(1E)-1-propenyl]phenol can be produced in accordance with the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 1994, pp. 1823-1831 (synthesis of 4-fluoro-2-hydroxybenzaldehyde), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 5-Chloro-2-[(1E)-1-propenyl]phenol can be produced in accordance with the method disclosed in, for example, The Journal of Organic Chemistry, 1964, vol. 29, pp. 2693-2698 (synthesis of 4-chloro-2-hydroxybenzaldehyde), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), the method disclosed in Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 4-(Dimethylamino)-2-hydroxybenzaldehyde can be produced by the method disclosed in, for example, German Patent (DE 105103). 5-Chloro-2-methoxyphenol can be produced in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 2, pp. 130-133 (conversion of anilines into chlorobenzene, Sandmeyer reaction, etc.) from commercially available 5-amino-2-methoxyphenol. 5-Bromo-2-methoxyphenol can be produced in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 3, pp. 185-187 or the method disclosed in The Journal of Organic Chemistry, 1977, vol. 42, pp. 2426-2430 (conversion of anilines into bromobenzene, Sandmeyer reaction, etc.) from commercially available 5-amino-2-methoxyphenol. 3-Hydroxy-4-methoxybenzonitrile can be produced by the method disclosed in, for example, Synthesis, 1998, pp. 329-332 from commercially available methyl 3,4-dimethoxybenzoate. 2,5-Dimethoxyphenol can be produced by the method disclosed in., for example, The Journal of Organic Chemistry, 1987, vol. 57, p. 4485. 2-Bromo-6-fluorophenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2-fluorophenol. 2-Fluoro-6-propylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-fluorophenol, Organic Reactions, 1949, vol. 2, pp. 1-48 (allyllation of phenol, Claisen transition reaction), and the method disclosed in Journal of the American Chemical Society, 1951, vol. 73, pp. 4152-4156 (conversion of an allyl group into a propyl group, hydrogenation reaction). 2-Fluoro-6-isopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-isopropyl-6-nitrophenol, Organic Synthesis, Collective Volume vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), the method disclosed in Liebigs Annalen der Chemie, 1975, vol. 608, p. 128 (Reduction of a nitro group into an amino group), the method disclosed in Synthesis, 1989, p. 905 (conversion reaction of an amino group into a fluorine atom), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-6-fluorophenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-fluorophenol, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chemica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Chloro-6-iodophenol can be produced by the method disclosed in, for example, The Journal of Organic Chemistry, 1988, vol. 53, No. 22, pp. 5281-5287. 2-Chloro-6-ethylphenol can be produced by the method disclosed in, for example, Journal of Chemical and Engineering Data, 1969, vol. 14, p. 392. 2-Chloro-6-cyclopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-chlorophenol, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Chloro-6-(2-methyl-2-propenyl)phenol can be produced in accordance with the method disclosed in, for example, Organic Reactions, 1949, vol. 2, pp. 1-48 (allylation of phenol, Claisen transition reaction) from commercially available 2-chlorophenol. 2-Bromo-6-methylphenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947. 2-Bromo-6-ethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2-ethylphenol. 2-Bromo-6-cyclopropylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2,6-dibromophenol, Organic Synthesis, Collective Volume vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-Bromo-2-hydroxybenzonitrile can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2-hydroxybenzonitrile. 2-Bromo-6-methoxyphenol can be produced by the method disclosed in, for example, Synthesis, 1999, vol. 7, pp. 1127-1134. 2-Iodo-6-methylphenol can be produced by the method disclosed in, for example, Australian Journal of Chemistry, 1997, vol. 50, No. 7, pp. 767-770. 2-Ethyl-6-iodophenol can be produced in accordance with the method disclosed in, Australian Journal of Chemistry, 1997, vol. 50, No. 7, pp. 767-770 (iodation reaction of phenol) from commercially available 2-ethylphenol. 2-Iodo-6-isopropylphenol can be produced in accordance with the method disclosed in, Australian Journal of Chemistry, 1997, vol. 50, No. 7, pp. 767-770 (iodation reaction of phenol) from commercially available 2-isopropylphenol. 2-Isopropyl-6-methylphenol can be produced by the method disclosed in, for example, Bulletin de la Societe Chemique de France, 1962, pp. 1700-1705. 2-s-Butyl-6-methylphenol can be produced by the method disclosed in, for example, Angewandte Chemie, 1957, vol. 69, p. 699, p. 703. Also, for example, it can be produced in accordance with the method disclosed in Organic Reactions, 1949, vol. 2, pp. 1-48 (allylation of phenol, Claisen transition reaction), and Journal of the American Chemical Society, 1951, vol. 73, pp. 4152-4156 (conversion of allyl group into propyl group, hydrogenation reaction) from commercially available 2-methylphenol. 2-Cyclopropyl-6-methylphenol can be produced from commercially available 2-hydroxy-3-methylbenzaldehyde in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and The Journal of Organic Chemistry, 1963, vol. 28, 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Methoxy-6-methylphenol can be produced by the method disclosed in, for example, Synthetic Communications, 1996, vol. 26, No. 1, pp. 49-62 from commercially available 1,2-dimethoxy-3-methylbenzene. 2,6-Diethylphenol can be produced by the method disclosed in, for example, Journal of Medicinal Chemistry, 1960, vol. 2, pp. 201-212. 2-Cyclopropyl-6-ethylphenol can be produced from commercially available 2-ethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2,6-Dipropylphenol can be produced by the method disclosed in, for example, Liebigs Annalen der Chemie, 1919, vol. 418, pp. 90-91 (synthesis of 2,6-diallylphenol), and Bulletin de la Societe Chemique de France, 1937, vol. 5, No. 4, pp. 1080-1083 (conversion of allyl group into propyl group, hydrogenation reaction). 3-Cyclopropyl-6-isopropylphenol can be produced in accordance with the method disclosed in, for example, Journal of the Chemical Society: Parkin transaction I, 1980, pp. 1862-1865 (synthesis of 2-hydroxy-3-isopropylbenzaldehyde), and Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-tert-Butyl-6-cyclopropylphenol can be produced in accordance with the method disclosed in, for example, commercially available 3-tert-butyl-2-hydroxybenzaldehyde , Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2,6-Dicyclopropylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1997, vol. 38, No. 17, pp. 3111-3114 (synthesis of 2-hydroxyisophthalaldehyde), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Cyclopropyl-6-methoxyphenol can be produced from commercially available 2-hydroxy-3-methoxybenzaldehyde in accordance with the method disclosed in, for example, Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Cyclopropyl-6-ethoxyphenol can be produced from commercially available 3-ethoxy-2-hydroxybenzaldehyde in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2,6-Di[(1E)-1-propenyl]phenol can be produced by the method disclosed in, for example, Liebigs Annalen der Chemie, 1919, vol. 418, pp. 90-91 (synthesis of 2,6-diallylphenol), and the method disclosed in Journal of the American Chemical Society, 1956, vol. 78, pp. 1709-1713(isomerization reaction). 2,6-Diallylphenol can be produced by the method disclosed in, for example, Liebigs Annalen der Chemie, 1919, vol. 418, pp. 90-91. 3,5-Diisopropylphenol can be produced by the method disclosed in, for example, U.S. Patent (U.S. Pat. No. 2,790,010). 2-Bromo-3,5-dimethylphenol can be produced in accordance with the method disclosed in, Bulletin of the Chemical Society of Japan, 1993, vol. 66, p. 1576 (brominetion reaction of phenol) from commercially available 3,5-dimethylphenol. 3,5-Dimethyl-2-propylphenol can be produced by the method disclosed in, for example, Bulletin of the Chemical Society of Japan, 1968, vol. 41, No. 3, pp. 745-746. 2-Cyclopropyl-3,5-dimethylphenol can be produced from commercially available 3,5-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and Organic Synthesis, Collective Volume vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Tetrahedron Letters, 1979, vol. 20, pp. 4159-4162 or the method disclosed in Tetrahedron, 1997, vol. 53, No. 43, pp. 14599-14614 or the method disclosed in Bulletin of the Chemical Society of Japan, 1971, vol. 44, pp. 2237-2248 (conversion reaction of aromatic bromide into aromatic aldehyde ), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3,5-Dimethyl-2-(methylsulfanyl)phenol can be produced by the method disclosed in, for example, Tetrahedron Letters, 1999, vol. 40, No. 35, pp. 6357-6358. 2-Bromo-3,6-dimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 3,6-dimethylphenol. 6-Bromo-3-fluoro-2-methylphenol can be produced, from 3-fluoro-2-methylphenol which can be produced from commercially available 3-fluoro-2-methylbenzaldehyde in accordance with the method disclosed in Journal of the Chemical Society: Parkin transaction I, 1974, p. 1353, in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol). 6-Bromo-3-chloro-2-methylphenol can be produced in accordance with the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from 3-chloro-2-methylphenol which can be produced from commercially available 1-chloro-3-methoxy-2-methylbenzene in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-Chloro-6-cyclopropyl-2-methylphenol can be produced from 3-chloro-2-methylphenol which can be produced from commercially available 1-chloro-3-methoxy-2-methylbenzene in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction), in accordance with the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947. (bromination reaction of phenol) and Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 6-Bromo-2,3-dimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2,3-dimethylphenol. 6-Cyclopropyl-2,3-dimethylphenol can be produced from commercially available 2,3-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Hydroxy-3,4-dimethylbenzaldehyde O-methyloxime can be produced from commercially available 2,3-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 1979, vol. 20, pp. 4159-4162 or the method disclosed in Tetrahedron, 1997, vol. 53, No. 43, pp. 14599-14614 or the method disclosed in Bulletin of the Chemical Society of Japan, 1971, vol. 44, pp. 2237-2248 (conversion reaction of aromatic bromide into aromatic aldehyde), and the method disclosed in Journal of the Chemical Society: Perkin transactions I, 1979, pp. 643-645 (oximation reaction), and Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 6-Methoxy-2,3-dimethylphenol can be produced from commercially available 3,4-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) and the method disclosed in Tetrahedron Letters, 1979, vol. 20, pp. 4159-4162 or the method disclosed in Tetrahedron, 1997, vol. 53, No. 43, pp. 14599-14614 or the method disclosed in Bulletin of the Chemical Society of Japan, 1971, vol. 44, pp. 2237-2248 (conversion reaction of aromatic bromide into aromatic aldehyde ), and the method disclosed in Journal of the Chemical Society: Parkin transaction I, 1974, p. 1353. 6-Bromo-3-methoxy-2-methylphenol can be produced in accordance with the method disclosed in, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from 3-methoxy-2-methylphenol which can be produced from commercially available 2-methyl-1,3-benzene diol in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction). 6-Cyclopropyl-3-methoxy-2-methylphenol can be produced from 3-methoxy-2-methylphenol which can be produced from commercially available 2-methyl-1,3-benzene diol in accordance with the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), in accordance with the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Cyclopropyl-3,6-dimethylphenol can be produced from commercially available 2,5-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Tetrahedron Letters, 1979, vol. 20, pp. 4159-4162 or the method disclosed in Tetrahedron, 1997, vol. 53, No. 43, pp. 14599-14614 or the method disclosed in Bulletin of the Chemical Society of Japan, 1971, vol. 44, pp. 2237-2248 (conversion reaction of aromatic bromide into aromatic aldehyde ), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittg reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Allyl-6-ethyl-3-methoxyphenol can be produced from 2-ethyl-5-methoxyphenol which can be produced in accordance with the method disclosed in Chemical and Pharmaceutical Bulletin, 1979, vol. 27, No. 6, pp. 1490-1494, in accordance with the method disclosed in, for example, Organic Reactions, 1949, vol. 2, pp. 1-48 (allylation reaction of phenol, Claisen transition). 3,6-Dimethyl-2-[(methylsulfanyl)methyl]phenol can be produced by the method disclosed in, for example, Journal of the American Chemical Society, 1966, vol. 88, No. 24, pp. 5855-5864. 5-Bromo-4-indanol can be produced in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1946, vol. 68, p. 2487 (reduction of carbonyl group, Wolff-Kishner Reduction), and Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 4-hydroxy-1-indanone. 5-Methyl-4-indanol can be produced from commercially available 4-hydroxy-1-indanone in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1946, vol. 68, p. 2487 (reduction of carbonyl group, Wolff-Kishner Reduction), and the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1990, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Helvetica Chimica Acta, 1990, vol. 73, pp. 417-425 (conversion reaction of bromo group into methyl group), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 5-Ethyl-4-indanol can be produced from commercially available 4-hydroxy-1-indanone in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1946, vol. 68, p. 2487 (reduction of carbonyl group, Wolff-Kishner Reduction), and the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Helvetica Chimica Acta, 1990, vol. 73, pp. 417-425 (conversion reaction of bromo group into ethyl group), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 5-Cyclopropyl-4-indanol can be produced from commercially available 4-hydroxy-1-indanone in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1946, vol. 68, p. 2487 (reduction of carbonyl group, Wolff-Kishner Reduction), and the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 6-Methyl-2,3-dihydro-1-benzofuran-7-ol can be produced in accordance with the method disclosed in, for example, Journal of the Chemical Society, 1948, p. 894 (reduction of olefin) from 6-methyl-1-benzofuran-7-ol. 6-Methyl-1-benzofuran-7-ol can be produced, for example, from 2-methoxy-3-methylphenol which can be produced by the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947, in accordance with the method disclosed in Journal of the Chemical Society: Perkin transactions I, 1988, p. 3029 (construction of benzofuran ring), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 6-Bromo-1-benzofuran-7-ol can be produced from commercially available 7-methoxy-1-benzofuran in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction), and Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol). 6-Methyl-1-benzofuran-7-ol can be produced from 2-methoxy-3-methylphenol which can be produced by the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947, in accordance with the method disclosed in, for example, Journal of the Chemical Society: Perkin transactions I, 1988, p. 3029 (construction of benzofuran ring), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 6-Cyclopropyl-1-benzofuran-7-ol can be produced from commercially available 7-methoxy-1-benzofuran in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction), and the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2,4-Dicyclopropyl-6-fluorophenol can be produced from commercially available 2-fluorophenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2,4-Dibromo-3,6-dimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 3,6-dimethylphenol. 2-Bromo-4,6-dimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2,4-dimethylphenol. 2-Ethyl-4,6-diiodophenol can be produced in accordance with the method disclosed in, Australian Journal of Chemistry, 1997, vol. 50, No. 7, pp. 767-770 (iodation reaction of phenol) from commercially available 2-ethylphenol. 2-Cyclopropyl-4,6-dimethylphenol can be produced from commercially available 2,4-dimethylphenol in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-Bromo-3,5,6-trimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2,3,5-trimethylphenol. 5,6-Dimethyl-4-indanol can be produced from commercially available 7-methyl-2H-chromen-2-one in accordance with the method disclosed in, for example, Nihon Kagakukaishi (Journal of Japan Chemical Association), 1974, pp. 136-146, and the method disclosed in Organic Reactions, 1941, vol. 1, p. 155 (Clemmensen reduction). 1,2,3,5,6,7-Hexahydro-s-indacen-4-ol can be produced from commercially available indane by the method disclosed in, for example, Journal of the American Chemical Society, 1977, vol. 99, pp. 8007-8014, and the method disclosed in Organic Reactions, 1941, vol. 1, p. 155 (Clemmensen reduction), and the method disclosed in The Journal of Organic Chemistry, 1977, vol. 42, pp. 3260-3264. 3-(1,3-Dioxolan-2-yl)phenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1989, vol. 30, No. 13, pp. 1609-1612 from 3-hydroxybenzaldehyde. 3′-(Trifluoromethyl)[1,1′-biphenyl]-3-ol can be produced in accordance with the method disclosed in, for example, Chemical Reviews, 1995, vol. 95, pp. 2457-2483 (phenylation reaction, Suzuki-Miyaura coupling reaction) from commercially available 3-iodophenol and 3-(trifluoromethyl)phenylboronic acid. 3-Hydroxy-4-methylbenzonitrile can be produced by the method disclosed in, for example, Monatshefte fur Chemie, 1957, vol. 88, pp. 228, 230. Ethyl 3-hydroxy-4-methylbenzoate can be produced by the method disclosed in, for example, The Journal of Organic Chemistry, 1961, vol. 26, pp. 1732-1734. 3-Hydroxy-4-methylbenzamide can be produced in accordance with the method disclosed in, for example, Phosphorus and Sulfur, 1980, vol. 9, pp. 155-164 from commercially available 3-hydroxy-4-methylbenzoic acid. 3,6-Dimethyl-2-propylphenol can be produced by the method disclosed in, for example, Journal of Polymer Science, 1948, vol. 3, p. 448, p. 452. 2-Hydroxy-3,4,6-trimethylbenzaldehyde can be produced by the method disclosed in, for example, Liebigs Annalen der Chemie, 1906, vol. 347, p. 379. 2-Hydroxy-3,4,6-trimethylbenzaldehyde O-methyloxime can be produced in accordance with the method disclosed in, for example, Liebigs Annalen der Chemie, 1906, vol. 347, p. 379 (synthesis of 2-hydroxy-3,4,6-trimethylbenzaldehyde), and in accordance with the method disclosed in Chemical Pharmaceutical Bulletin, 1988, vol. 36, No. 8, pp.3134-3137. 2-[1-(Methoxymethyl)cyclopropyl]phenol can be produced from 2-methoxy-1-(2-methoxyphenyl)ethanone which can be obtained by the method disclosed in The Journal of Organic Chemistry, 1942, vol. 7, pp. 444-456, in accordance with the method disclosed in, for example, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(1-Methoxycyclopropyl)phenol can be produced from 1-methoxy-2-(1-methoxyvinyl)benzene which can be produced by the method disclosed in The Journal of Organic Chemistry, 1998, vol. 63, pp. 4632-4635, in accordance with the method disclosed in, for example, Organic Reactions, 1973, vol. 20, pp. 1-131 or Journal of the American Chemical Society, 1975, vol. 97, p. 3428 or Tetrahedron Letters, 1998, vol. 39, pp. 8621-8624 (construction of cyclopropyl group, Simmons-Smith reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(2-Hydroxyphenyl)cyclopropanecarbonitrile can be produced from 3-(2-methoxyphenyl)acrylonitrile which can be produced by the method disclosed in Journal of Medicinal Chemistry, 1988, vol. 31, No. 1, pp. 37-54, in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction), and the method disclosed in Helvetica Chimica Acta, 1992, vol. 75, p. 457 (conversion of phenol into phenylmethoxymethyl ether, methoxymethylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1973, vol. 38, pp. 1793-1797 or The Journal of Organic Chemistry, 1970, vol. 35, pp. 374-379 (cyclopropanation reaction), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction). 2-(2-Ethoxycyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, The Journal of Organic Chemistry, 1981, vol. 46, pp. 5143-5147 (conversion of benzyl alcohol into benzyl chloride), and the method disclosed in Journal of the American Chemical Society, 1973, vol. 95, No. 2, pp. 581-582 (construction of cyclopropyl group), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction) from [2-(methoxymethoxy)phenyl]methanol which can be produced by the method disclosed in Heterocycles, 1998, vol. 48, No. 7, pp. 1373-1394. 2-(2,2-Difluorocyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, The Journal of Organic Chemistry, 1973, vol. 38, pp. 1793-1797 or The Journal of Organic Chemistry, 1970, vol. 35, pp. 374-379 (cyclopropanization reaction), and the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction) from 1-(2,2-difluorovinyl)-2-methoxybenzene which can be produced by the method disclosed in Bulletin de la Societe Chemique de France, 1995, pp. 850-856. 2-(2,2-Dichlorocyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Synthetic Communications, 1999, vol. 29, No. 23, pp. 4101-4112 (conversion of olefin into dichlorocyclopropane), and the method disclosed in Tetrahedron, 1998, vol. 54, pp. 15861-15869 (conversion of phenylmethoxymethyl ether into phenol, demethoxymethylation reaction) from 2-(methoxymethoxy)benzaldehyde which can be produced by the method disclosed in Heterocycles, 1998, vol. 48, No. 7, pp. 1373-1394. 2-(2,2-Dibromocyclopropyl)phenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-methoxy-2-vinylbenzene, Synthetic Communications, 1999, vol. 29, No. 23, pp. 4101-4112 (using bromoform in place of chloroform. Conversion of olefin into dibromocyclopropane), and the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Isopropenylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 1-(2-methoxyphenyl)ethanone, The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-(2-Hydroxyphenyl)acrylonitrile can be produced in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction) from 3-(2-methoxyphenyl)acrylonitrile which can be produced by the method disclosed in Journal of Medicinal Chemistry, 1988, vol. 31, No. 1, pp. 37-54. 2-Ethynylphenol can be produced by the method disclosed in, for example, Canadian Journal of Chemistry, 1997, vol. 75, No. 9, pp. 1256-1263 from commercially available 1-benzofuran. Bicyclo[4.2.0]octa-1,3,5-trien-2-ol can be produced in accordance with the method disclosed in, for example, Organic Reactions, 1941, vol. 1, p. 155 (Clemmensen reduction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 or Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction) from 5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one which can be produced by the method disclosed in The Journal of Organic Chemistry, 1982, vol. 47, pp. 2393-2396. 2-Bromo-6-chlorophenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2-chlorophenol. 3-Bromo-2-hydroxybenzonitrile can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol) from commercially available 2-hydroxybenzonitrile. 2-(2,2-Dichlorocyclopropyl)-6-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 2-hydroxy-3-methylbenzaldehyde, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Synthetic Communications, 1999, vol. 29, No. 23, pp. 4101-4112 (conversion of olefin into dichlorocyclopropane), and the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Methyl-6-vinylphenol can be produced in accordance with the method disclosed in, for example, for example, from commercially available 2-hydroxy-3-methylbenzaldehyde, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 6-Cyclopropyl-3-fluoro-2-methylphenol can be produced in accordance with the method disclosed in, for example, from commercially available 3-fluoro-2-methylbenzaldehyde, The Journal of Organic Chemistry, 1999, vol. 64, pp. 7921-7928 or Journal of the Chemical Society: Parkin transaction I) 1974, p. 1353 (Baeyer-Villiger oxidation, convertion of an aromatic aldehyde into phenol), and the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction) and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 5-Methyl-1-benzofuran-4-ol can be produced from methyl 4-hydroxy-1-benzofuran-5-carboxylate which can be produced by the method disclosed in Tetrahedron, 1995, vol. 51, pp. 4009-4022, in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 2001, vol. 66, pp. 4965-4972 (reduction of ester to alcohol), and the method disclosed in Journal of Medicinal Chemistry, 1999, vol. 42, No. 6, pp. 1007-1017 (conversion of benzyl alcohol into benzylmethanesulfonyl ester), and the method disclosed in The Journal of Organic Chemistry, 1969, vol. 34, p. 3923 or Synthetic Communications, 2001, vol. 31, No. 9, pp. 1373-1382 (reduction of halogen compound, tosylate, and mesylate), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-(2-Chloro-2-fluorocyclopropyl)phenol can be produced from 2-(methoxymethoxy)benzaldehyde which can be produced by the method disclosed in Heterocycles, 1998, vol. 48, No. 7, pp. 1373-1394, in accordance with the method disclosed in, for example, Journal of Fluorine Chemistry, 1983, vol. 23, pp. 339-357 (conversion of carbonyl group into chlorofluoroolefin), and the method disclosed in The Journal of Organic Chemistry, 1973, vol. 38, pp. 1793-1797 or The Journal of Organic Chemistry, 1970, vol. 35, pp. 374-379 (cyclopropanation reaction), and the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 3-(Benzyloxy)phenol can be produced by the method disclosed in, for example, The Journal of Organic Chemistry, 1997, vol. 62, No. 10, pp. 3062-3075. 1-Methyl-1H-indol-4-ol can be produced in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction) from commercially available 4-methoxy-1-methyl-1H-indole. 1-Methyl-1H-indol-7-ol can be produced in accordance with the method disclosed in, for example, Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction) from 7-methoxy-1-methyl-1H-indole which can be produced by the method disclosed in Journal of Medicinal Chemistry, 1992, vol. 35, No. 1, pp. 177-184. 1-(4-Hydroxy-3-methylphenyl)ethanone O-methyloxime can be produced in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1986, vol. 108, pp. 6016-6023 from commercially available 1-(4-hydroxy-3-methylphenyl)ethanone. 2-Isopropenyl-6-methylphenol can be produced from 1-(2-hydroxy-3-methylphenyl)ethanone which can be produced by the method disclosed in Chemische Berichte, 1925, vol. 58, p. 41, in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 1,1-Dimethyl-5-indanol can be produced in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction) from 5-methoxy-1,1-dimethylindane which can be produced by the method disclosed in Bulletin of the Chemical Society of Japan, 2000, vol. 73, No. 12, pp. 2779-2782. 3-Bromo-6-cyclopropyl-2-methylphenol can be produced from commercially available 2-methyl-3-nitrophenol, in accordance with the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the modified method of the method disclosed in Organic Synthesis, Collective Volume, vol. 1, pp. 445-447 (reduction of nitrophenol to aniline; 8.5 equivalents of zinc powder and 25 equivalents of ammonium chloride are used based on nitrophenol, reaction is carried out at room temperature), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Organic Synthesis, Collective Volume, vol. 3, pp. 185-187 or the method disclosed in The Journal of Organic Chemistry, 1977, vol. 42, pp. 2426-2430 (conversion of anilines into bromobenzene, Sandmeyer reaction, etc.) and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 6-Cyclopropyl-2-methyl-3-nitrophenol can be produced from commercially available 2-methyl-3-nitrophenol, in accordance with the method disclosed in Tetrahedron Letters, 1998, vol. 39, p. 2947 (bromination reaction of phenol), and the method disclosed in Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the modified method of the method disclosed in Organic Synthesis, Collective Volume, vol. 1, pp. 445-447 (reduction of nitrophenol to aniline; 8.5 equivalents of zinc powder and 25 equivalents of ammonium chloride are used based on nitrophenol, reaction is carried out at room temperature), and the method disclosed in Tetrahedron Letters, 2000, vol. 41, pp. 4251-4255 (construction of cyclopropyl group, Suzuki-Miyaura coupling reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction), and the method disclosed in Tetrahedron, 1987, vol. 43, No. 8, pp. 1753-1758 (conversion of aniline derivative into nitrobenzene). 5-Methyl-1,3-dihydro-2-benzofuran-4-ol can be produced in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 2000, vol. 122, pp. 11553-11554. 2-Fluoro-3,5,6-trimethylphenol can be produced from 2,3,5-trimethyl-6-nitrophenol which can be produced by the method disclosed in Chemische Berichte, 1922, vol. 55, p. 2384, in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in Liebigs Annalen der Chemie, 1957, vol. 608, p. 128, or the method disclosed in Organic Synthesis, Collective Volume, vol. 5, 829-833 (Reduction of a nitro group into an amino group), and the method disclosed in Synthesis, 1989, pp. 905-908 (conversion of aromatic amine into aromatic fluoride), and the method disclosed in Organic Synthesis, Collective Volume, vol. 5, pp. 412-414 (conversion of phenylmethyl ether into phenol, demethylation reaction). 2-Chloro-3,5,6-trimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (chlorication reaction of phenol; using N-chlorosuccinimide in place of N-bromosuccinimide) from commercially available 2,3,5-trimethylphenol. 2-Iodo-3,5,6-trimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (iodation reaction of phenol; using N-iodosuccinimide in place of N-bromosuccinimide) from commercially available 2,3,5-trimethylphenol. 2-Ethyl-3,5,6-trimethylphenol can be produced in accordance with the method disclosed in, for example, Journal of the American Chemical Society, 1946, vol. 68, p. 2487 (reduction of carbonyl group, Wolff-Kishner reduction) from 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone which can be produced by the method disclosed in Chemical Research in Toxicology, 1997, vol. 10, No. 3, pp. 335-343. 2-Isopropenyl-3,5,6-trimethylphenol can be produced from 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone which can be produced by the method disclosed in Chemical Research in Toxicology, 1997, vol. 10, No. 3, pp. 335-343, in accordance with the method disclosed in, for example, Organic Synthesis, Collective Volume, vol. 4, pp. 836-838 (conversion of phenol into phenyl methyl ether, methylation reaction), and the method disclosed in The Journal of Organic Chemistry, 1963, vol. 28, p. 1128 or Synthetic Communications, 1985, vol. 15, No. 10, pp. 855-864 (conversion of carbonyl group into olefin, Wittig reaction), and the method disclosed in Bioscience, Biotechnology, and Biochemistry, 1993, vol. 57, No. 9, pp. 1572-1574 or Japanese Provisional Patent Publication No. 11-322755 (conversion of phenylmethyl ether into phenol, demethylation reaction). 1-(2-Hydroxy-3,4,6-trimethylphenyl)ethanone can be produced by the method disclosed in, for example, Chemical Research in Toxicology, 1997, vol. 10, No. 3, pp. 335-343. 2,3,5-Trimethyl-6-nitrophenol can be produced by the method disclosed in, for example, Chemische Berichte, 1922, vol. 55, p. 2384. 2,4-Dichloro-3,5,6-trimethylphenol can be produced in accordance with the method disclosed in, for example, Tetrahedron Letters, 1998, vol. 39, p. 2947 (chlorination reaction of phenol; using N-chlorosuccinimide in place of N-bromosuccinimide) from commercially available 2,3,5-trimethylphenol. Pentamethylphenol can be produced by the method disclosed in, for example, Journal of the Chemical Society, 1949, p. 624. After completion of the above-mentioned respective reaction steps, the objective compounds of the respective steps can be collected from the reaction mixture according to the conventional manner. For example, the reaction mixture is optionally neutralized, and also, after removing insoluble materials by filtration when insoluble materials exist, an organic solvent which is immiscible with water is added to the mixture, and after washing with water, it can be obtained by distillation of the solvent. The obtained desired compound can be further purified according to the conventional manner, if necessary, for example, recrystallization, reprecipitation or chromatography, etc. Compound (I) of the present invention can be made a salt. These salts are included in the present invention so long as they can be used as an agricultural and horticultural herbicide. A salt of Compound (I) of the present invention may include, for example, alkali metal salts such as lithium, sodium, potassium, etc.; alkaline earth metal salts such as magnesium, calcium, etc.; aluminum salts; transition metal salts such as iron, copper, etc.; amine salts such as ammonium, trimethyl ammonium, triethyl ammonium, tetramethyl ammonium, pyridinium, etc.; inorganic mineral acid salts such as hydrochloride, sulfate, phosphate, etc.; or organic acid salts such as formate, acetate, toluenesulfonate, oxalate, etc. When a pyridazine derivative is an acid component of the salt, the salt can be produced by, for example, mixing the pyridazine derivative and a base in the presence or absence of a solvent, and removing the solvent. The base to be used is not specifically limited so long as it is a base generally showing a pH 8 or more, and for example, it may be alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.; alkali metal salts of an organic acid such as sodium acetate, potassium acetate, sodium formate, potassium formate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; alkali metals such as sodium, potassium, etc.; aliphatic tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, etc.; aliphatic cyclic tertiary amines such as 1,4-diazabicyclo-[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undece-7-ene (DBU), etc.; pyridines such as pyridine, collidine, 4-(N,N-dimethylamino)pyridine, etc.; metal amides such as lithium amide, sodium amide, etc.; or organometallic bases such as butyl lithium, s-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc. The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, for example, water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above. When the pyridazine derivative is a base component of a salt, the salt can be prepared by, for example, mixing the pyridazine derivative and an acid in the presence or absence of a solvent, and removing the solvent. The acid to be used is not specifically limited so long as it is an acid generally showing a pH of 6 or less, and for example, it may be inorganic mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as formic acid, acetic acid, toluenesulfonic acid, oxalic acid, benzoic acid, etc. The solvent to be used is not specifically limited so long as it does not inhibit the reaction, and dissolves starting material(s) with a certain extent, for example, water; alcohols such as methanol, ethanol, t-butanol, etc.; ketones such as acetone, methyl isobutyl ketone, etc.; nitriles such as acetonitrile, etc.; esters such as ethyl acetate, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; aromatic hydrocarbons such as toluene, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; sulfoxides such as dimethylsulfoxide, etc.; or a mixed solvent of the above. The composition of the present invention shows herbicidal activity against various kinds of weeds which cause problems in a paddy field, for example, broad-leaved weeds such as Lindernia spp., Vandellia angustifolia Benth., Rotala indica, Elatine triandra, Dopatirum junceum (Roxb.) Hamilt, Ammannia coccinea (Rottb.), Monochoria vaginaris, etc.; Cyperaceous weeds such as smallflower umbrella sedge, Scirpus juncoides, needle spikerush, Cyperus serotinus, Scirpus nipponicus Makino etc.; and Arrowhead plant weeds such as Sagittaria pygmaea, arrowhead, Alisma canaliculatum, and shows no crop injury, which causes any problem, to rice. The composition of the present invention shows herbicidal activities both by foliar application and soil application against valious kinds of weeds, which are troublesome in upland fields, including, for example, broad-leaved weeds such as Common purslane, Common chickweed, Common lambsquarters, Amaranthus retroflexus L.i, Sinapis arvensis, shepherdspurse, velvetleaf, Sida spinosa, field pansy, Cleavers, Lamium purpureum, henbit, Datura stramonium L., Solanum nigrum L., Persian speedwell, Matricaria indora, etc.; Commelinaceae weeds such as asiatic dayflower; and Cyperaceous weeds such as Cyperus iria, Cyperus rotundus, etc., and shows no crop injury which causes a problem, against corn, wheat, soybean, etc. The composition of the present invention can be used not only in an upland and a paddy field, but also in an orchard, a mulberry field and a non-crop land. Synergistic effects of the present invention can be admitted in a wide range of a mixing ratio, and when the second herbicidally active compound is Compound A, B or C, the second herbicidally active compound is mixed with a ratio of, in general, 0.1 to 50 parts by weight based on 1 part by weight of Compound (I) to prepare a useful herbicidal composition, and the ratio is preferably 0.2 to 20 parts by weight, more preferably 0.5 to 10 parts by weight, and when the second herbicidally active compound is Compound D, E, F or G, the second herbicidally active compound is mixed with a ratio of, in general, 0.01 to 100 parts by weight based on 1 part by weight of Compound (I) to prepare a useful herbicidal composition, and the ratio is preferably 0.02 to 50 parts by weight, more preferably 0.1 to 10 parts by weight. The thus accomplished herbicidal composition of the present invention gives high herbicidal effects by applying it before germination of weeds and subjecting to a soil treatment or a foliar treatment after germination. In the present invention, 3-phenoxy-4-pyridazinol derivatives and the second herbicidally active compound may be mixed and spread as a preparation, may be spread simultaneously without mixing both effective ingredients, or may be spread one of these effective ingredients firstly and then spread the remaining effective ingredient later. Also, an order of spreading may be optional. The composition of the present invention may be spread a raw material itself, or may be used by mixing with a carrier and, if necessary, with the other auxiliaries, and prepared in a preparation form which is generally used as a herbicidal composition, for example, dust powder, coarse dust powder, fine dust powder, granules, wettable powder, emulsifiable concentrate, aqueous suspension, water dispersible granules, suspension concentrate in water or oil, Jumbo (Throw-in Packed) formulation, etc. The compound of the present invention is used by mixing with a carrier and, if necessary, with the other auxiliaries (a surfactant, etc.), and prepared in a preparation form which is generally used as a herbicidal composition, for example, dust powder, coarse dust powder, granules, fine granules, wettable powder, water-soluble agent, emulsifiable concentrate, liquid agent, etc. The carrier herein mentioned means a synthetic or natural inorganic or organic substance which is mixed in the herbicidal composition to aid reachability of the effective ingredient compound to plants or to make storage, transportation or handling of the effective ingredient easy. A suitable solid carrier may be, for example, clays represented by kaolinite group, montmorllironite group, attapulgite group, etc.; inorganic substances such as talc, mica, pyrophyllite, pumice, vermiculite, gypsum, dolomite, diatomaceous earth, magnesium lime, phosphorus lime, zeolite, silicic acid anhydride, synthetic calcium silicate, kaolin, bentonite, calcium carbonate, etc.; vegetable organic substances such as soybean powder, tobacco powder, walnut powder, wheat flour, wood powder, starch powder, crystalline cellulose, etc.; synthetic or natural polymer compounds such as coumarone resin, petroleum resin, alkyd resin, polyvinyl chloride, polyalkylene glycol, ketone resin, ester gum, copal gum, dammar gum, etc.; waxes such as carnauba wax, paraffin wax, bees wax, etc.; or urea. Suitable liquid carriers may include, for example, paraffin series or naphthene series hydrocarbons such as kerosine, mineral oil, spindle oil, white oil, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, cumene, methylnaphthalene, etc.; chlorinated hydrocarbons such as carbon tetrachloride, chloroform, trichloroethylene, monochlorobenzene, chlorotoluene, etc.; ethers such as dioxane, tetrahydrofuran, etc.; ketones such as acetone, methylethylketone, diisobutylketone, cyclohexanone, acetophenone, isophorone, etc.; esters such as ethyl acetate, amyl acetate, ethylene glycol acetate, diethylene glycol acetate, dibutyl maleate, diethyl succinate, etc.; alcohols such as methanol, hexanole, ethylene glycol, diethylene glycol, cyclohexanol, benzyl alcohol, etc.; ether alcohols such as ethylene glycol ethyl ether, ethylene glycol phenyl ether, diethylene glycol ethyl ether, diethylene glycol butyl ether, etc.; polar solvents such as dimethylformamide, dimethylsulfoxide, etc.; or water. A surfactant which is used for the purpose of emulsification, dispersion, wetting, spreading, binding, controlling disintegration, stabilization of effective ingredient(s), improvement in fluidity, antirust, promotion of absorption into plants, etc., may be ionic or nonionic one. Suitable nonionic surfactants may include, for example, sucrose ester of aliphatic acid, ethylene oxide polymerized adducts of higher fatty acids such as lauryl alcohol, stearyl alcohol, oleyl alcohol, etc., ethylene oxide polymerized adducts of alkylphenols such as isooctylphenol, nonylphenol, etc., ethylene oxide polymerized adducts of alkyl naphthol such as butylnaphthol, octylnaphthol, etc., ethylene oxide polymerized adducts of higher fatty acids such as palmitic acid, stearic acid, oleic acid, etc., ethylene oxide polymerized adducts of mono- or dialkylphosphates such as stearyl phosphate, dilauryl phosphate, etc., ethylene oxide polymerized adducts of higher fatty amines such as dodecylamine, stearic amide, etc., higher fatty acid esters of polyvalent alcohols such as sorbitan, etc. and their ethylene oxide polymerized adducts and copolymers of ethylene oxide and propylene oxide, and the like. Suitable anionic surfactants may include, for example, alkylsulfuric acid ester salts such as sodium lauryl sulfate, oleyl alcohol sulfuric acid ester amine salt, etc., aliphatic acid salts such as sodium sulfosuccinate dioctyl ester, sodium oleate, sodium stearate, etc., alkylarylsulfonic acid salts such as sodium isopropylnaphthalene sulfonate, sodium methylenebisnaphthalene sulfonate, sodium lignosulfonate, sodium dodecylbenzenesulfonate, etc. Suitable cationic surfactants may include, for example, higher aliphatic amines, quaternary ammonium salts, alkylpyridinium salts, etc. Moreover, in the herbicide of the present invention, A surfactant which is used for the purpose of emulsification, dispersion, wetting, spreading, binding, controlling disintegration, stabilization of effective ingredient(s), improvement in fluidity, antirust, promotion of absorption into plants, etc., may be ionic or nonionic one. Suitable nonionic surfactants may include, for example, sucrose ester of aliphatic acid, ethylene oxide polymerized adducts of higher fatty acids such as lauryl alcohol, stearyl alcohol, oleyl alcohol, etc., ethylene oxide polymerized adducts of alkylphenols such as isooctylphenol, nonylphenol, etc., ethylene oxide polymerized adducts of alkyl naphthol such as butylnaphthol, octylnaphthol, etc., ethylene oxide polymerized adducts of higher fatty acids such as palmitic acid, stearic acid, oleic acid, etc., ethylene oxide polymerized adducts of mono- or dialkylphosphates such as stearyl phosphate, dilauryl phosphate, etc., ethylene oxide polymerized adducts of higher fatty amines such as dodecylamine, stearic amide, etc., higher fatty acid esters of polyvalent alcohols such as sorbitan, etc. and their ethylene oxide polymerized adducts and copolymers of ethylene oxide and propylene oxide, and the like. Suitable anionic surfactants may include, for example, alkylsulfuric acid ester salts such as sodium lauryl sulfate, oleyl alcohol sulfuric acid ester amine salt, etc., aliphatic acid salts such as sodium sulfosuccinate dioctyl ester, sodium oleate, sodium stearate, etc., alkylarylsulfonic acid salts such as sodium isopropylnaphthalene sulfonate, sodium methylenebisnaphthalene sulfonate, sodium lignosulfonate, sodium dodecylbenzenesulfonate, etc. Suitable cationic surfactants may include, for example, higher aliphatic amines, quaternary ammonium salts, alkylpyridinium salts, etc. Moreover, in the herbicide of the present invention, for the purpose of improving characteristics of the preparation and heightening biological effects, for example, polymer compounds such as gelatin, Gum Arabic, caseine, albumin, glue, sodium arginate, polyvinyl alcohol, carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, etc., thixotropic agents such as sodium polyphosphate, bentonite, etc. and other auxiliaries may be contained as other components. Dust powder or crude dust powder generally contans, for example, 0.1 to 25 parts by weight of an effective ingredient, and the reminder is a solid carrier. Wettable powder or granular wettable powder generally contans, for example, 1 to 90 parts by weight of an effective ingredient, and the reminder is a solid carrier and a dispersing or wetting agent, and a protective colloidal agent, thixotropic agent and defoaming agent are added depending on necessity. These preparations are suspended and dispersed when they are thrown into water and stirred. Granules or fine dust powder generally contain(s), for example, 0.1 to 35 parts by weight of an effective ingredient, and the reminder is a solid carrier in almost all the part. The effective ingredient compound is uniformly mixed with a solid carrier, or firmly fixed or adsorbed on the surface of the solid carrier, and a size of the grain is generally 0.2 to 1.5 mm. Emulsifiable concentrate generally contans, for example, 1 to 70 parts by weight of an effective ingredient compound, and further 5 to 20 parts by weight of an emulsifying agent is contained therein, and the reminder is a liquid carrier, and other auxiliaries such as a rust proof agent, etc. may be added if necessary. Aqueous suspension or oil suspension is one in which the effective ingredient is suspended or emulsified and dispersed in water or an organic solvent with a high boiling point by using a suitable surfactant, and stability with a lapse of time is maintained by adding a thickening agent, etc., if necessary. The Jumbo (Throw-in Packed) formulation can be prepared by making an active ingredient suitable preparation forms, for example, dust powder, granule, tablet, emulsifiable concentrate, clumpy tablet, etc., and if necessary, they are dividedly packed in a water-soluble film or a container, and at the time of use, they are directry thrown into a paddy field with several to several hundred preparations. The compound of the present invention thus prepared in various types of formulations may be applied, for example, at dosage of 1 g to 1000 g, preferably 10 g to 300 g of an active ingredient per 10 are when it is subjected to soil treatment in a paddy field before or after germination of weeds, whereby weeds can be effectively eliminated. As a method for treating the compound of the present invention, it can be applied, generally by preparing a formulation, as a soil treatment, a foliar treatment or a submerged treatment at pre-emergence or post-emergence within about one month after germination of weeds. In the soil treatment, there are soil surface treatment, soil incorporation, etc., in the foliar treatment, in addition to a treatment from upward of a plant canopy, there is a directed treatment in which weeds alone are treated so that the compound is not adhered to crops, etc., and in the submerged treatment, there are spreading or injection treatment of granules or flowable agent to water surface, etc. Into the herbicidal composition of the present invention, other herbicides may be added to broaden weeding spectrum. The herbicidal composition of the present invention can be used by mixing with, for example, a plant growth regulator, fungicide, insecticide, acaricide, nematocide or fertilizer, etc. BEST MODE FOR CARRYING OUT THE INVENTION In the following, Examples, Preparation examples and Test examples of the present invention are shown to explain the invention more specifically, but the present invention is not limited by these. Incidentally, in the following Preparation examples, “%” means % by weight. EXAMPLE 1 6-Chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128) (1) 3-Chloro-6-(2-methylphenoxy)pyridazine (Step A-1) A mixture of 278.7 g (1.87 mol) of 3,6-dichloropyridazine, 202.3 g (1.87 mol) of 2-methylphenol and 259 g (1.87 mol) of potassium carbonate was stirred at 160° C. for 6 hours. The reaction mixture was cooled to 70° C. and 2 L of ethyl acetate was added. This mixture was washed successively with 1 mol/L sodium hydroxide aqueous solution (4×500 mL), water (4×500 mL) and brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was removed, and isopropyl ether was added to the residue to form crystal. The crystal was collected by filtration to obtain 234.2 g (1.06 mol, Yield: 56.7%) of 3-chloro-6-(2-methylphenoxy)pyridazine. (2) 4,6-Dichloro-3-(2-methylphenoxy)pyridazine(Step A-2) In phosphorus oxychloride (1.85 L) was dissolved 6-chloro-3-(2-methylphenoxy)pyridazine (234.2 g, 1.06 mol) obtained in (1), and 76.7 g (1.08 mol) of a chlorine gas was passed into the solution over 4 hours. A nitrogen gas was passed into the reaction mixture to remove excess chlorine gas, and then phosphorus oxychloride was removed. The residue was dissolved in ethyl acetate (1.5 L), washed successively with water (4×500 mL) and brine(200 mL), and dried over anhydrous magnesium sulfate. The solvent was removed, and the resulting residue was washed with 500 mL of hexane to obtain 193.1 g of a crude product. This crude product was recrystallized form a mixed solvent of hexaneethyl acetate (400 mL-240 mL) to obtain 114.4 g (0.448 mol, Yield: 42.3%) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine. (3) 6-Chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128, Step A-3) In 1,4-dioxane (1 L) was dissolved 100.0 g (0.392 mol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in (2), and to the solution were added an aqueous solution (400 mL of water) containing sodium hydroxide (purity 96%, 19.6 g, 0.470 mol) and 1.09 g (4.78 mmol) of tetrabutylammonium chloride, and the resulting mixture was stirred for 4 hours under reflux. The reaction mixture was concentrated under reduced pressure, and the total amount was made about 100 mL. To the residue were added an aqueous sodium hydroxide solution (13.1 g of sodium hydroxide was dissolved in 1.4 L of water) and 500 mL of ethyl acetate. The aqueous layer was washed with ethyl acetate (3×200 mL), cooled in an ice-bath, and then conc. hydrochloric acid was added to adjust the pH thereof to 5. Precipitated solid was collected by suction filtration, washed with 1 L of water and air dried. The resulting solid was recrystallized from acetonitrile to obtain 34.4 g (0.145 mol, Yield: 37.0%) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128). Also, the organic layer was dried over magnesium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (YMC GEL, SIL60, 350/250 mesh, hexane-ethyl acetate, gradient) to obtain 13.5 g (0.0414 mol, Yield: 10.5%) of 6-chloro-3,4-bis(2-methylphenoxy)pyridazine. 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35-7.08 (4H, m), 6.84 (1H, brs), 2.11 (3H, s). Melting point (° C.): 211-213. EXAMPLE 2 3-(2-Methylphenoxy)-4-pyridazinol (Compound No. 5) (1) 6-Chloro-4-methoxy-3-(2-methylphenoxy)pyridazine (Step A-3) In methanol (60 mL) was dissolved 3.00 g (11.8 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), 1.00 g (17.6 mmol) of 95% sodium methoxide was added to the solution at room temperature and the mixture was stirred at 60° C. for 4 hours. Moreover, 1.00 g (17.6 mmol) of 95% sodium methoxide was further added and after stirring the mixture at 60° C. for 1 hour, it was allowed to stand at room temperature overnight. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was successively washed with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=4:1) to obtain 2.75 g (11.0 mmol, Yield: 93.2%) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine. (2) 4-Methoxy-3-(2-methylphenoxy)pyridazine (Step N-1) In methanol (40 mL) was dissolved 2.00 g (7.98 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in (1), 0.20 g of 5% palladium-carbon was added to the solution and the mixture was stirred under hydrogen atmosphere (1 atm) for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with ethyl acetate and then dichloromethane: methanol=5:1) to obtain 1.59 g (7.36 mmol, Yield: 92.2%) of 4-methoxy-3-(2-methylphenoxy)pyridazine. (3) 3-(2-Methylphenoxy)-4-pyridazinol (Compound No. 5, Step N-2) A mixture comprising 1.08 g (5.00 mmol) of 4-methoxy-3-(2-methylphenoxy)pyridazine obtained in (2), 0.24 g (6.0 mmol) of sodium hydroxide, water (5 mL) and 1,4-dioxane (5 mL) was stirred overnight. The reaction mixture was washed with ethyl acetate, the aqueous layer was made acidic with hydrochloric acid, and extracted with ethyl acetate. The solvent was removed to obtain 0.21 g (10 mmol, Yield: 20%) of 3-(2-methylphenoxy)-4-pyridazinol (Compound No. 5). 1H-NMR (60 MHz, DMF-d7) δ ppm: 8.30 (1H, d, J=7.2 Hz), 7.43-7.00 (5H, m), 6.43 (1H, d, J=7.2 Hz), 2.18 (3H, s). Melting point (° C.): 169-171. EXAMPLE 3 5-Chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 45) (1) 4,5-Dichloro-3-(2-methylphenoxy)pyridazine 16.4 g (88.2 mmol) of 3-(2-methylphenoxy)pyridazine {which can be produced by the method described in Agricultural and Biological Chemistry, 1968, vol. 32, p. 1376 and Agricultural and Biological Chemistry, 1969, vol. 33, p. 96.} and phosphorus oxychloride (200 mL) were mixed, the mixture was heated to 80° C., and 8.5 g (120 mmol) of a chlorine gas was introduced therein. Phosphorus oxychloride was removed from the reaction mixture by distillation, the residue was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (available from Merck Co., 9385, hexane:ethyl acetate gradient) to obtain 6.61 g (25.9 mmol, Yield: 29.4%) of 4,5-dichloro-3-(2-methylphenoxy)pyridazine, 8.14 g (36.9 mmol, Yield: 41.8%) of 5-chloro-3-(2-methylphenoxy)pyridazine and 1.20 g (5.44 mmol, Yield: 6.17%) of 4-chloro-3-(2-methylphenoxy)pyridazine. (2) 5-Chloro-4-methoxy-3-(2-methylphenoxy)pyridazine (Step A-3) 5.10 g (20.0 mmol) of 4,5-dichloro-3-(2-methylphenoxy)pyridazine obtained in (1) and methanol (70 mL) were mixed, and 0.46 g (20 mmol) of sodium was added to the mixture at −8° C., and the resulting mixture was stirred at −8° C. for 30 minutes, and in an ice bath for 8 hours and 30 minutes. Ice-cold water was added to the reaction mixture, pH was made 3 with hydrochloric acid, and then the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (available from Merck Co., 9385, hexane:ethyl acetate, gradient) to obtain 1.15 g (4.58 mmol, Yield: 22.9%) of 5-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine and 3.27 g (13.0 mmol, Yield: 65%) of 4-chloro-5-methoxy-3-(2-methylphenoxy)pyridazine. (3) 5-Chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 45, Step A-4, etc.) 750 mg (2.99 mmol) of 5-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in (2), 156 mg (3.9 mmol) of sodium hydroxide, 1,4-dioxane (5 mL) and water (10 mL) were mixed, and the mixture was refluxed with stirring for 2 hours and 30 minutes. The reaction mixture was poured into ice-cold water, and made acidic with hydrochloric acid. The precipitated solid was collected by filtration, and washed with water and then with hexane. 525 mg (2.22 mmol, Yield: 74.2%) of 5-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 45) was obtained. 1H-NMR (60 MHz, DMF-d7) δ ppm: 8.68 (1H, s), 7.38-6.80 (4H, m), 5.32 (1H, brs), 2.13 (3H, s). Melting point (° C.): 238-243. EXAMPLE 4 5-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-methylbenzene sulfonate (Compound No. 66, Step I-1) 237 mg (1.00 mmol) of 5-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 45) obtained in Example 3 and acetonitrile (8 mL) were mixed, and 112 mg (1.00 mmol) of 1,4-diazabicyclo[2,2,2]octane was added to the mixture with stirring, and then, 191 mg (1.00 mmol) of 4-methylbenzene sulfonyl chloride was added thereto, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. Water was added to the reaction mixture, the mixture was made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate=3:1) to obtain 379 mg (0.969 mmol, Yield: 96.9%) of 5-chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-methylbenzene sulfonate (Compound No. 66). 1H-NMR (60 MHz, CDCl3) δ ppm: 8.80 (1H, s), 7.77-6.75 (8H, m), 2.47 (3H, s), 1.98 (3H, s). Melting point (° C.): 140-143. EXAMPLE 5 6-Chloro-3-(2-methylphenoxy)-4-pyridazinol 1-oxide (Compound No. 129, Step F-1) 135 mg (0.572 mmol) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128) obtained in Example 1 and methylene chloride (6 mL) were mixed, 247 mg (purity 80%, 1.14 mmol) of m-chloroperbenzoic acid was added to the mixture and the resulting mixture was refluxed for 16 hours with stirring. The mixture was allowed to stand at room temperature for 2 days, the reaction mixture was poured in a saturated aqueous sodium sulfite solution, and washed with methylene chloride. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, then washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (YMC GEL, SIL60, 350/250 mesh, eluted with ethyl acetate) to obtain 32.6 mg (0.129 mmol, Yield: 22.6%) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol 1-oxide (Compound No. 129). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.34 (1H, s), 7.34-7.10 (4H, m), 2.20 (3H, s). Melting point (° C.): 194-196. EXAMPLE 6 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139) (1) Mixture of 6-chloro-3-(2-cyclopropylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropylphenoxy)pyridazine 1-oxide (Step B-2) 25.3 g (189 mmol) of 2-cyclopropylphenol, 1,4-dioxane (120 mL) and dimethylsulfoxide (120 mL) were mixed, 23.2 g (207 mmol) of potassium tert-butoxide was added to the mixture in an ice bath and the resulting mixture was stirred for 10 minutes. To the mixture was added 32.0 g (194 mmol) of 3,6-dichloropyridazine 1-oxide which is a known compound, and the mixture was allowed to stand at room temperature for 5 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successsively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 43.3 g (165 mmol, Yield: 87.3%) of a mixture of 6-chloro-3-(2-cyclopropylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropylphenoxy)pyridazine 1-oxide. (2) 4,6-Dichloro-3-(2-cyclopropylphenoxy)pyridazine (Step B-3) 43.3 g (165 mmol) of a mixture of 6-chloro-3-(2-cyclopropylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropylphenoxy)pyridazine 1-oxide obtained in (1), chloroform (30 mL) and 18.0 mL (194 mmol) of phosphorus oxychloride were mixed, and the mixture was heated to 60° C. and dissolved. The solution was stirred at room temperature overnight, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 32.5 g (116 mmol, Yield: 70.3%) of 4,6-dichloro-3-(2-cyclopropylphenoxy)pyridazine. (3) 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139, Step B-4) In dimethylsulfoxide (500 mL) was dissolved 32.5 g (116 mmol) of 4,6-dichloro-3-(2-cyclopropylphenoxy)pyridazine obtained in (2), 84 mL (210 mmol) of 10% (w/v) aqueous sodium hydroxide solution was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ether. The aqueous layer was made acidic with hydrochloric acid, the precipitated solid was collected by filtration, and washed with water. To the resulting solid was added acetonitrile and the mixture was heated. The mixture was cooled overnight by allowing to stand, and crystals (14.04 g) were collected by filtration. The filtrate was concentrated, the residue was recrystallized from ethanol to obtain 2.64 g of crystals. These crystals were combined to obtain 16.7 g (63.5 mmol, Yield: 54.7%) of 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.28-6.97 (4H, m), 6.82 (1H, s), 1.89-1.77 (1H, m), 0.87-0.73 (2H, m), 0.73-0.58 (2H, m). Melting point (° C.): 229-231. EXAMPLE 7 6-Chloro-3-[2-(1-fluorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 140) (1) 2-(Methoxymethoxy)benzaldehyde In N,N-dimethylformamide (20 mL) was dissolved 5.01 g (41.1 mmol) of commercially available salicylaldehyde, 1.80 g (45.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and after stirring the mixture in an ice bath for 10 minutes, 3.43 mL (45.2 mmol) of chloro(methoxy)methane was gradually added dropwise to the mixture and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 6.54 g (39.4 mmol, Yield: 95.9%) of 2-(methoxymethoxy)benzaldehyde. (2) 1-(Methoxymethoxy)-2-vinylbenzene Under nitrogen atmosphere, 877 mg (21.9 mmol) of 60% sodium hydride washed with hexane was suspended in dry dimethylsulfoxide (10 mL), the suspension was heated at 85° C. for 30 minutes with stirring, cooled to room temperature, and then, in an ice bath, a dry dimethylsulfoxide (20 mL) solution containing 7.83 g (21.9 mmol) of methyl(triphenyl)phosphonium bromide was gradually added dropwise thereto. After stirring at room temperature for 15 minutes, a dry dimethylsulfoxide (9 mL) solution containing 3.02 g (18.2 mmol) of 2-(methoxymethoxy)benzaldehyde obtained in (1) was added dropwise thereto, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, and extracted with diethyl ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 2.54 g (15.5 mmol, Yield: 85.2%) of 1-(methoxymethoxy)-2-vinylbenzene. (3) 1-(2-Bromo-1-fluoroethyl)-2-(methoxymethoxy)benzene To a methylene chloride (10 mL) solution containing 1.47 g (9.13 mmol) of N,N,N-triethylamine hydrotrifluoric acid (MEC-82) was added dropwise a methylene chloride (5 mL) solution containing 1.00 g (6.09 mmol) of 1-(methoxymethoxy)-2-vinylbenzene obtained in (2), and 1.19 g (6.70 mmol) of N-bromosuccinimide was added thereto in an ice bath. The mixture was stirred in an ice bath as such for 2 hours, it was warmed to room temperature and stirred for further 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was successively washed with diluted hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 4 plates were used, developed by ethyl acetate:hexane=4:1), and then, purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 4 plates were used, developed by ethyl acetate:hexane=10:1) to obtain 1.24 g of a crude product of 1-(2-bromo-1-fluoroethyl)-2-(methoxymethoxy)benzene. (4) 1-(1-Fluorovinyl)-2-(methoxymethoxy)benzene In dry dimethylsulfoxide (10 mL) was added 736.2 mg (11.15 mmol) of 85% potassium hydroxide, the mixture was stirred at room temperature for 1 hour and 30 minutes, a dry dimethylsulfoxide (6 mL) solution containing 978.2 mg of a crude purified product of 1-(2-bromo-1-fluoroethyl)-2-(methoxymethoxy)benzene obtained in (3) was added dropwise to the mixture, and the resulting mixture was stirred for 2 hours and then stirred at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with hexane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 632.7 mg of a crude product of 1-(1-fluorovinyl)-2-(methoxymethoxy)benzene. (5) 1-(1-Fluorocyclopropyl)-2-(methoxymethoxy)benzene Under nitrogen atmosphere, dry diethyl ether (5 mL) was charged in a dry flask, 1.97 mL (1.97 mmol) of diethylzinc (1M hexane solution) was added dropwise thereto, and then, a dry diethyl ether (3 mL) solution containing 143.6 mg of a crude product of 1-(1-fluorovinyl)-2-(methoxymethoxy)benzene obtained in (4) was added dropwise thereto. After stirring at room temperature for 10 minutes, 0.19 mL (2.3 mmol) of diiodomethane was added dropwise to the mixture and the resulting mixture was refluxed for 4 hours and 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, then, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was stirred for a while, and extracted with diethyl ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=4:1) to obtain 80.5 mg of a crude product of 1-(1-fluorocyclopropyl)-2-(methoxymethoxy)benzene. (6) 2-(1-Fluorocyclopropyl)phenol Conc. hydrochloric acid (0.3 mL) was added dropwise to a methanol (6 mL) solution containing 43.8 mg of a crude product of 1-(1-fluorocyclopropyl)-2-(methoxymethoxy)benzene obtained in (5), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 42.8 mg of a crude product of 2-(1-fluorocyclopropyl)phenol. (7) 6-Chloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane(3 mL) and dimethylsulfoxide (3 mL) was dissolved 42.8 mg of a crude product of 2-(1-fluorocyclopropyl)phenol obtained in (6), 34.7 mg (0.310 mmol) of potassium tert-butoxide was added to the solution, and then, 46.4 mg.(0.281 mmol) of 3,6-dichloropyridazine 1-oxide was added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 28.0 mg (0.0996 mmol) of 6-chloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine 1-oxide. (8) 4,6-Dichloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine (Step B-3) In phosphorus oxychloride (1 mL) was dissolved 28.0 mg (0.0996 mmol) of 6-chloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine 1-oxide obtained in (7), and the solution was stirred at room temperature overnight. To the mixture were added water and methylene chloride, and after stirring for 30 minutes, the mixture was extracted with methylene chloride. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 5.1 mg (0.017 mmol, Yield: 17%) of 4,6-dichloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine. (9) 6-Chloro-3-[2-(1-fluorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 140, Step B-4) In a mixed solvent of 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) was dissolved 5.1 mg (0.017 mmol) of 4,6-dichloro-3-[2-(1-fluorocyclopropyl)phenoxy]pyridazine obtained in (8), and to the solution was added 0.1 mL of 2 mol/L of aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, diluted hydrochloric acid was added to the mixture to adjust pH 2, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by ethyl acetate) to obtain 4.0 mg (0.014 mmol, Yield: 82%) of 6-chloro-3-[2-(1-fluorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 140). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.57-7.52 (1H, m), 7.39-7.31 (1H, m), 7.22-7.13 (1H, m), 7.00 (1H, d, J=8.1 Hz), 6.48 (1H, s), 1.32-1.22 (2H, m), 1.16-1.08 (2H, m). Melting point (° C.): 152-157. EXAMPLE 8 6-Chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 207) (1) 1-Methoxy-2-vinylbenzene Under nitrogen atmosphere, in dry dimethylsulfoxide (15 mL) was suspended 1.92 g (48.0 mmol) of 60% sodium hydride washed with hexane, after stirring the suspension at 85° C. for 30 minutes, it was cooled to room temperature and then, in an ice bath, a dry dimethylsulfoxide (35 mL) solution containing 17.2 g (48.2 mmol) of methyl(triphenyl)phosphonium bromide was gradually added dropwise thereto. After stirring at room temperature for 20 minutes, 4.83 mL (40.1 mmol) of commercially available 2-methoxybenzaldehyde was added dropwise thereto, and the resulting mixture was stirred at room temperature for 1 hour and then at 65° C. for 3 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.29 g (24.5 mmol, Yield: 61.1%) of 1-methoxy-2-vinylbenzene. (2) 1-(2-Bromo-1-fluoroethyl)-2-methoxybenzene To a methylene chloride (20 mL) solution containing 3.60 g (22.4 mmol) of N,N,N-triethylamine hydrotrifluoric acid (MEC-82) was added dropwise a methylene chloride (6 mL) solution containing 2.01 g (15.0 mmol) of 1-methoxy-2-vinylbenzene obtained in (1), and 2.92 g (16.4 mmol) of N-bromosuccinimide was added in an ice bath. Stirring was continued in an ice bath for 25 minutes, and the mixture was warmed to room temperature and further stirred for 1 hour and 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with methylene chloride. The organic layer was successively washed with diluted hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.39 g of a crude product of 1-(2-bromo-1-fluoroethyl)-2-methoxybenzene. (3) 1-(1-Fluorovinyl)-2-methoxybenzene To dry dimethylsulfoxide (10 mL) was added 1.28 g (19.4 mmol) of 85% potassium hydroxide, the mixture was stirred at room temperature for 30 minutes, and then, a dry dimethylsulfoxide (10 mL) solution containing 1.50 g of a crude product of 1-(2-bromo-1-fluoroethyl)-2-methoxybenzene obtained in (2) was added dropwise thereto, and the mixture was stirred overnight. The reaction mixture was poured into water and extracted with hexane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.21 g of a crude product of 1-(1-fluorovinyl)-2-methoxybenzene. (4) 1-(1-Fluorocyclopropyl)-2-methoxybenzene Under nitrogen atmosphere, dry diethyl ether (8 mL) was charged in a dry flask, 19.88 mL (19.88 mmol) of diethylzinc (1 mol/L hexane solution) was added dropwise thereto, and a dry diethyl ether (8 mL) solution containing 1.21 g of a crude product of 1-(1-fluorovinyl)-2-methoxybenzene obtained in (3) was added dropwise thereto. After stirring at room temperature for 10 minutes, 1.92 mL (23.86 mmol) of diiodomethane was added dropwise thereto, and the mixture was refluxed for 6 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into a saturated aqueous ammonium chloride solution, and then, a saturated aqueous sodium hydrogen carbonate solution was added thereto and the mixture was stirred for a while, and extracted with diethyl ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.06 g of a crude product of 1-(1-fluorocyclopropyl)-2-methoxybenzene. (5) 2-[1-(ethylsulfanyl)cyclopropyl]phenol Under nitrogen atmosphere, in dry N,N-dimethylformamide (8 mL) was suspended 765.3 mg (19.1 mmol) of 60% sodium hydride, and to the suspension was gradually added dropwise 1.46 mL (19.8 mmol) of ethanethiol and after stirring for 15 minutes, a dry N,N-dimethylformamide (5 mL) solution containing 1.06 g of a crude product of 1-(1-fluorocyclopropyl)-2-methoxybenzene obtained in (4) was added dropwise thereto and the resulting mixture was stirred at 160° C. for 5 hours. After cooling by allowing to stand, 1 mol/L of aqueous potassium hydroxide solution and diethyl ether were added to the reaction mixture. The aqueous layer was separated, and washed with diethyl ether. To the mixture was added diluted hydrochloric acid to adjust pH to 2, and extracted with diethyl ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexaneethyl acetate, gradient) to obtain 0.26 g of a crude product of 2-[1-(ethylsulfanyl)cyclopropyl]phenol. (6) 6-Chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was dissolved 0.26 g of a crude product of 2-[1-(ethylsulfanyl)cyclopropyl]phenol obtained in (5), 265.5 mg (2.37 mmol) of potassium tert-butoxide was added to the solution, and then, 390.3 mg (2.37 mmol) of 3,6-dichloropyridazine 1-oxide was added to the same, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 138.4 mg (0.428 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine 1-oxide. (7) 4,6-Dichloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine (Step B-3) In phosphorus oxychloride (1 mL) was dissolved 138.4 mg (0.428 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine 1-oxide obtained in (6), and the solution was stirred at room temperature overnight. To the reaction mixture were added water and methylene chloride, and the mixture was stirred for 30 minutes and extracted with methylene chloride. The organic layer was successsively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate:hexane=4:1) to obtain 94.4 mg (0.277 mmol, Yield: 64.7%) of 4,6-dichloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine. (8) 6-Chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 207, Step B-4) In a mixed solvent of 1,4-dioxane (1 mL) and dimethylsulfoxide (1 mL) was dissolved 94.4 mg (0.277 mmol) of 4,6-dichloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}pyridazine obtained in (7), 0.69 mL (1.38 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and ethyl acetate, the aqueous layer was separated and washed with ethyl acetate. Diluted hydrochloric acid was added thereto to adjust pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate) to obtain 47.5 mg (0.147 mmol, Yield: 53.1%) of 6-chloro-3-{2-[1-(ethylsulfanyl)cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 207). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.45-7.07 (4H, m), 6.69 (1H, s), 2.46 (2H, q, J=7.3 Hz), 1.28-1.02 (9H, m). Melting point (° C.): 88. EXAMPLE 9 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 265) (1) 1-(2,2-dichlorocyclopropyl)-2-(methoxymethoxy)benzene In chloroform (12 mL) was dissolved 305 mg (1.86 mmol) of 1-(methoxymethoxy)-2-vinylbenzene obtained in Example 7(2), 5 mL (63 mmol) of 50% aqueous sodium hydroxide solution was added dropwise to the solution, and then, 54.1 mg (0.237 mmol) of benzyl(triethyl)ammonium chloride was added to the same and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=1:2) to obtain 387 mg (1.57 mmol, Yield: 84.4%) of 1-(2,2-dichlorocyclopropyl)-2-(methoxymethoxy)benzene. (2) 2-(2,2-Dichlorocyclopropyl)phenol In methanol (5 mL) was dissolved 203 mg (0.822 mmol) of 1-(2,2-dichlorocyclopropyl)-2-(methoxymethoxy)benzene obtained in (1), 0.1 mL of conc. hydrochloric acid was added to the solution, and the resulting mixture was stirred at 60° C. for 2 hours. After confirming disappearance of the starting materials by thin layer chromatography, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 194 mg of a crude product of 2-(2,2-dichlorocyclopropyl)phenol. (3) 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was mixed 194 mg of a crude product of 2-(2,2-dichlorocyclopropyl)phenol obtained in (2), 118 mg (1.05 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 157 mg (0.952 mmol) of 3,6-dichloropyridazine 1-oxide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=1:2) to obtain 268 mg of a crude product of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine 1-oxide. (4) 4,6-Dichloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine (Step B-3) 268 mg of a crude product of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine 1-oxide obtained in (3) and 3 mL of phosphorus oxychloride were mixed, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and dichloromethane, and the resulting mixture was stirred for 30 minutes. The mixture was separated, and the organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=1:2) to obtain 162 mg (0.463 mmol, Yield with 3 steps from 1-(2,2-dichlorocyclopropyl)-2-(methoxymethoxy)benzene: 56.3%) of 4,6-dichloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine. (5) 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 265, Step B-4) 162 mg (0.463 mmol) of 4,6-dichloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]pyridazine obtained in (4), 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, to the mixture was added 1.15 mL (2.30 mmol) of 2 mol/L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and made acidic with diluted hydrochloric acid. The mixture was extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 50.0 mg (0.151 mmol, Yield: 32.6%) of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 265). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55-7.15 (4H, m), 6.69 (1H, s), 2.90 (1H, dd, J=10.6, 8.8 Hz), 2.07-1.89 (2H, m). Melting point (° C.): 158-163. EXAMPLE 10 6-Chloro-3-(2-hydroxyphenoxy)-4-pyridazinol (Compound No. 384) (1) 3-Chloro[1,4]benzodioxino[2,3-c]pyridazine(Step O-1) In 1,4-dioxane (30 mL) was suspended 3.49 g (80.0 mmol) of 55% sodium hydride, and to the suspension were added a 1,4-dioxane (30 mL) solution containing 4.40 g (40 mmol) of pyrocatechol, then a 1,4-dioxane (30 mL) solution containing 7.30 g (39.9 mmol) of 3,4,6-trichloropyridazine {described in The Journal of Organic Chemistry, 1963, vol. 28, pp. 218 to 221}, and the mixture was refluxed for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L sodium hydroxide and water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was recrystallized from methyl isobutyl ketone to obtain 6.15 g (27.8 mmol, Yield: 69.7%) of 3-chloro[1,4]benzodioxino[2,3-c]pyridazine. (2) 6-Chloro-3-(2-hydroxyphenoxy)-4-pyridazinol (Compound No. 384, Step O-2) A mixture comprising 5.52 g (25.0 mmol) of 3-chloro[1,4]benzodioxino[2,3-c]pyridazine obtained in (1), 1.30 g (31.2 mmol) of 96% sodium hydroxide, dimethylsulfoxide (55 mL) and water (15 mL) was stirred at 90° C. for 1 hour. The reaction mixture was poured into ice-cold water, made acidic with hydrochloric acid, and extracted with ethyl acetate. The solvent was removed, and the residue was washed with isopropyl ether to obtain 4.90 g (20.5 mmol, Yield: 82.0%) of 6-chloro-3-(2-hydroxyphenoxy)-4-pyridazinol (Compound No. 384). 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.25-6.40 (5H, m). Melting point (° C.): 216-219. EXAMPLE 11 6-Chloro-3-[2-(methylsulfinyl)phenoxy]-4-pyridazinol (Compound No. 404) (1) 6-Chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) was dissolved 454 mg (3.24 mmol) of 2-(methylsulfanyl)phenol, to the solution was added 519 mg (4.63 mmol) of potassium tert-butoxide and the mixture was stirred for 35 minutes. To the mixture was added 424 mg (2.57 mmol) of 3,6-dichloropyridazine 1-oxide and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, eluted with hexane:ethyl acetate=3:1) to obtain 391 mg (1.46 mmol, Yield: 56.8%) of 6-chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide. (2) 4,6-Dichloro-3-[2-(methylsulfanyl)phenoxy]pyridazine (Step B-3) 288 mg (1.07 mmol) of 6-chloro-3-[2-(methylsulfanyl)-phenoxy]pyridazine 1-oxide obtained in (1) and 1.00 mL (10.8 mmol) of phosphorus oxychloride were mixed, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane/ethyl acetate=3/1) to obtain 118 mg (0.411 mmol, Yield: 38.4%) of 4,6-dichloro-3-[2-(methylsulfanyl)phenoxy]pyridazine. (3) 4,6-Dichloro-3-[2-(methylsulfinyl)phenoxy]pyridazine In 1,2-dichloroethane (4 mL) was dissolved 118 mg (0.411 mmol) of 4,6-dichloro-3-[2-(methylsulfanyl)phenoxy]pyridazine obtained in (2), 96.3 mg (purity 80%, 0.446 mmol) of m-chloroperbenzoic acid was added to the solution and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 10% aqueous sodium sulfite solution, extracted with ethyl acetate, then washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane:ethyl acetate=1:1, then, 3:1, and then, 1:1) to obtain 21.1 mg (0.0696 mmol, Yield: 16.9%) of 4,6-dichloro-3-[2-(methylsulfinyl)phenoxy]pyridazine. (4) 6-Chloro-3-[2-(methylsulfinyl)phenoxy]-4-pyridazinol (Compound No. 404, Step B-4) In 1,4-dioxane (0.5 mL) was dissolved 21.1 mg (0.0696 mmol) of 4,6-dichloro-3-[2-(methylsulfinyl)phenoxy]pyridazine obtained in (3), 0.12 mL (0.36 mmol) of 3 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred for 45 minutes. To the mixture was added dimethylsulfoxide (0.5 mL), and after stirring for 3 hours, the reaction mixture was poured into 10% hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, chloroform:methanol=10:1) to obtain 2.1 mg (0.0074 mmol, Yield: 11%) of 6-chloro-3-[2-(methylsulfinyl)phenoxy]-4-pyridazinol (Compound No. 404). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.90-7.84 (1H, m), 7.60-7.42 (2H, m), 7.14 (1H, dd, J=9.2, 1.1 Hz), 6.62 (1H, s), 2.92 (3H, s). Appearance: amorphous. EXAMPLE 12 6-Chloro-3-[2-(methylsulfonyl)phenoxy]-4-pyridazinol (Compound No. 406) (1) 6-Chloro-3-[2-(methylsulfonyl)phenoxy]pyridazine 1-oxide In 1,2-dichloroethane (5 mL) was dissolved 208 mg (0.774 mmol) of 6-chloro-3-[2-(methylsulfanyl)phenoxy]pyridazine 1-oxide obtained in Example 11 (1), 829 mg (3.84 mmol) of 80% m-chloroperbenzoic acid was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane:ethyl acetate=1:1) to obtain 132 mg (0.439 mmol, Yield: 56.7%) of 6-chloro-3-[2-(methylsulfonyl)phenoxy]pyridazine 1-oxide. (2) 4,6-Dichloro-3-[2-(methylsulfonyl)phenoxy]pyridazine (Step B-3) 111 mg (0.369 mmol) of 6-chloro-3-[2-(methylsulfonyl)phenoxy]pyridazine 1-oxide obtained in (1) and 1.00 mL (10.8 mmol) of phosphorus oxychloride were mixed, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with a saturated sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane:ethyl acetate=1:1) to obtain 70.8 mg (0.222 mmol, Yield: 60.2%) of 4,6-dichloro-3-[2-(methylsulfonyl)phenoxy]pyridazine. (3) 6-Chloro-3-[2-(methylsulfonyl)phenoxy]-4-pyridazinol (Compound No. 406, Step B-4) In 1,4-dioxane (2.0 mL) was dissolved 70.8 mg (0.222 mmol) of 4,6-dichloro-3-[2-(methylsulfonyl)phenoxy]pyridazine obtained in (2), 0.45 mL (1.4 mmol) of 3 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred for 30 minutes. To the mixture was added dimethylsulfoxide (2.0 mL), the mixture was stirred overnight, poured into water and washed with a mixed solvent of hexane-ethyl acetate. To the aqueous layer was added 10% hydrochloric acid to make it acidic, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by chloroform:methanol=10:1) to obtain 18.0 mg (0.0599 mmol, Yield: 27.0%) of 6-chloro-3-[2-(methylsulfonyl)phenoxy]-4-pyridazinol (Compound No. 406). 1H-NMR (200 MHz, CD3OD) δ ppm: 8.00 (1H, dd, J=7.7, 1.8 Hz), 7.71 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.43 (1H, ddd, J=7.7, 7.7, 1.1 Hz), 7.32 (1H, br.d, J=7.7 Hz), 6.62 (1H, s), 3.36 (3H, s). Appearance: amorphous. EXAMPLE 13 6-Chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-pyridazinol (Compound No. 478) (1) 6-Chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine (Step D-1) In a mixed solvent of 1,4-dioxane (2.5 mL) and dimethylsulfoxide (2.5 mL) was dissolved 190 mg (1.16 mmol) of 2-cyclopropyl-3-methoxyphenol, 146 mg (1.30 mmol) of potassium tert-butoxide was added to the solution and the resulting mixture was stirred for 10 minutes. To the mixture was added 170 mg (0.950 mmol) of 3,6-dichloro-4-methoxypyridazine and the resulting mixture was stirred overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 90.1 mg (0.293 mmol, Yield: 30.8%) of 6-chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine and 114 mg (0.371 mmol, Yield: 39.1%) of 3-chloro-6-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine. (2) 6-Chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-pyridazinol (Compound No. 478, Step D-2) In dry N,N-dimethylformamide (DMF, 2 mL) was suspended 24 mg (0.60 mmol) of 60% sodium hydride, 0.05 mL (0.7 mmol) of ethanethiol was added dropwise to the suspension in an ice bath and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dry N,N-dimethylformamide (DMF, 1.5 mL) solution containing 60.0 mg (0.195 mmol,) of 6-chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-methoxypyridazine obtained in (1), and the resulting mixture was refluxed for 2 hours. The reaction mixture was cooled, and poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. Ice-cold conc. hydrochloric acid was added to the aqueous layer to adjust pH to 4, and the mixture was extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=1:1) to obtain 15.2 mg (0.0519 mmol, Yield: 26.6%) of 6-chloro-3-(2-cyclopropyl-3-methoxyphenoxy)-4-pyridazinol (Compound No. 478). 1H-NMR (200 MHz, CDCl3) δ ppm: 7.19 (1H, dd, J=8.1, 8.4 Hz), 6.76 (1H, d, J=8.1 Hz), 6.69 (1H, d, J=8.4 Hz), 6.60 (1H, s), 3.85 (3H, s), 1.55-1.35 (1H, m), 0.85-0.60 (4H, m). Melting point (° C.): 184-185. EXAMPLE 14 3-(1,1a,6,6a-Tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloro-4-pyridazinol (Compound No. 515) (1) 7-hydroxy-1-indanone 37.0 g (278 mmol) of aluminum chloride was mixed with 3.70 g (61.3 mmol) of sodium chloride, the mixture was dissolved at 150° C. under heating, 6.40 g (43.2 mmol) of commercially available 2,3-dihydro-4H-chromen-4-one dissolved by heating (50° C.) was added to the mixture and the resulting mixture was stirred at 200° C. for 20 minutes. The reaction mixture (gum state) was cooled, and added to ice-cold hydrochloric acid (100 ml of conc. hydrochloric acid and ice were combined to make them 200 ml) little by little and stirred for 30 minutes. Methylene chloride was added to the mixture and the mixture was separated. The aqueous layer was filtered, and the filtrate was extracted with methylene chloride. The organic layers were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 4.82 g (32.6 mmol, Yield: 75.2%) of 7-hydroxy-1-indanone. (2) 7-(Methoxymethoxy)-1-indanone In N,N-dimethylformamide (DMF, 33 mL) was dissolved 1.00 g (6.76 mmol) of 7-hydroxy-1-indanone obtained in (1), the solution was cooled in an ice bath, and 0.330 g (8.25 mmol) of 60% sodium hydride was added by dividing into four times and the resulting mixture was stirred for 30 minutes. To the mixture was added dropwise 0.80 mL (11 mmol) of chloromethoxymethane, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an ice-cold saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate. The organic layer was washed successively with water and and brine, dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 1.04 g (5.42 mmol, Yield: 80.2%) of 7-(methoxymethoxy)-1-indanone. (3) 7-(Methoxymethoxy)-1-indanol In methanol(20 mL) was dissolved 1.04 g (5.42 mmol) of 7-methoxymethoxy-1-indanone obtained in (2), the solution was cooled in an ice bath, and 164 mg (4.34 mmol) of sodium borohydride was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 1.05 g (5.42 mmol, Yield: 100%) of 7-(methoxymethoxy)-1-indanol. (4) Mixture of 4-(methoxymethoxy)-1H-indene and 7-(methoxymethoxy)-1H-indene In methylene chloride (3 mL) was dissolved 500 mg (2.58 mmol) of 7-(methoxymethoxy)-1-indanol obtained in (3), the solution was cooled in an ice bath, and 0.50 mL (3.7 mmol) of triethylamine and 0.25 mL (3.3 mmol) of methanesulfonyl chloride were added to the solution and the resulting mixture was stirred for 2 hours. To the mixture was added 0.80 mL (5.7 mmol) of triethylamine and the mixture was stirred for 1 hour, then the mixture was poured into water and extracted with methylene chloride. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the resulting residue was dissolved in pyridine (3 mL), and the mixture was refluxed for 4 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 280 mg (1.59 mmol, Yield: 61.6%) of a mixture of 4-(methoxymethoxy)-1H-indene and 7-(methoxymethoxy)-1H-indene. (5) Mixture of (2-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene and 5-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene In 30 mL of eggplant type flask was charged dry diethyl ether (5 mL) under nitrogen atmosphere, and cooled in an ice bath. To the solution were successively added dropwise 6.3 mL (6.3 mmol) of diethylzinc (1.0 mol/L hexane solution), and 0.70 mL (8.5 mmol) of diiodomethane, and the mixture was stirred for 10 minutes. To the mixture was gradually added dropwise an ether solution (9 mL) containing 250 mg (1.42 mmol) of a mixture comprising 4-(methoxymethoxy)-1H-indene and 7-(methoxymethoxy)-1H-indene obtained in (4). The resulting mixture was refluxed for 4 hours. The reaction mixture was cooled, and poured into a saturated aqueous ammonium chloride solution. To the mixture was added the same volume of a saturated aqueous sodium hydrogen carbonate solution, and then, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 150 mg (0.789 mmol, Yield: 55.6%) of a mixture of 2-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene and 5-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]-indene. (6) Mixture of 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-ol and 1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-ol In methanol (6 mL) was dissolved 150 mg (0.789 mmol) of a mixture of 2-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene and 5-(methoxymethoxy)-1,1a,6,6a-tetrahydrocyclopropa[a]indene obtained in (5), two drops of conc. hydrochloric acid were added to the solution and the resulting mixture was stirred at room temperature for 1 hour and then at 60° C. for 20 minutes. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 80.0 mg (0.548 mmol, Yield: 69.5%) of a mixture of 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-ol and 1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-ol. (7) Mixture of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloropyridazine 1-oxide and 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloropyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) was dissolved 80.0 mg (0.548 mmol) of a mixture of 1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-ol and 1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-ol obtained in (6), and 85 mg (0.76 mmol) of potassium tert-butoxide was added to the solution and the mixture was stirred for 10 minutes. To the mixture was added 82 mg (0.50 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 4 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 75.0 mg (0.273 mmol, Yield: 49.8%) of a mixture of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloropyridazine 1-oxide and 3-(1,1a,6,6a-tetrahydrocyclopropa-[a]inden-5-yloxy)-6-chloropyridazine 1-oxide. (8) 3-(1,1a,6,6a-Tetrahydrocyclopropa[a]inden-2-yloxy)-4,6-dichloropyridazine and 3-(1,1a,6,6a-tetrahydrocyclopropa-[a]inden-5-yloxy)-4,6-dichloropyridazine (Step B-3) 75.0 mg (0.273 mmol) of a mixture of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloropyridazine 1-oxide and 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloropyridazine 1-oxide obtained in (7) was mixed with 0.30 mL (3.2 mmol) of phosphorus oxychloride, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to remove phosphorus oxychloride, and the residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 3 plates were used, developed by hexane/ethyl acetate=9/1 four times repeatedly) to obtain 21.4 mg (0.0730 mmol, Yield: 26.7%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-4,6-dichloropyridazine and 32.6 mg (0.111 mmol, Yield: 40.7%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-4,6-dichloropyridazine. (9) 3-(1,1a,6,6a-Tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloro-4-pyridazinol (Compound No. 515, Step B-4) To a dimethylsulfoxide (3 mL) solution containing 21.4 mg (0.0730 mmol) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-4,6-dichloropyridazine obtained in (8) was added 0.1 mL (0.2 mmol) of 2 mol/L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, conc. hydrochloric acid was added thereto to adjust pH to 4 in an ice bath, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 1 plate was used, developed by chloroform:methanol=10:1) to obtain 10.3 mg (0.0375 mmol, Yield: 51.4%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-2-yloxy)-6-chloro-4-pyridazinol (Compound No. 515). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08 (1H, t, J=7.7 Hz), 6.98 (1H, d, J=7.7 Hz), 6.84 (1H, d, J=7.7 Hz), 6.59 (1H, s), 3.20 (1H, dd, J=17.2, 6.2 Hz), 2.94 (1H, d, J=17.2 Hz), 2.30-2.15 (1H, m), 1.90-1.75 (1H, m), 1.05-0.90 (1H, m). Melting point (° C.): 245-247. EXAMPLE 15 3-(1,1a,6,6a-Tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloro-4-pyridazinol (Compound No. 516, Step B-4) In dimethylsulfoxide (3 mL) was dissolved 32.6 mg (0.111 mmol) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-4,6-dichloropyridazine obtained in Example 14(8), and 0.1 mL (0.2 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was separated, conc. hydrochloric acid was added thereto to adjust pH to 4 in an ice bath, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 1 plate was used, developed by chloroform:methanol=10:1) to obtain 13.4 mg (0.0487 mmol, Yield: 43.9%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloro-4-pyridazinol (Compound No. 516). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.25-7.05 (2H, m), 6.83 (1H, dd, J=6.6, 2.6 Hz), 6.67 (1H, s), 3.00 (1H, dd, J=17.2, 6.6 Hz), 2.78 (1H, d, J=17.2 Hz), 2.50-2.35 (1H, m), 2.00-1.80 (1H, m), 1.15-1.00 (1H, m), 0.10-0.00 (1H, m). Melting point (° C.): 211-213. EXAMPLE 16 6-Chloro-3-(2-methoxy-5-methylphenoxy)-4-pyridazinol (Compound No. 704) (1) 6-Chloro-3-(2-methoxy-5-methylphenoxy)pyridazine 1-oxide (Step B-2) In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was dissolved 167.5 mg (1.21 mmol) of commercially available 2-methoxy-5-methylphenol, and 142.8 mg (1.27 mmol) of potassium tert-butoxide was added to the solution, then 202.9 mg (1.23 mmol) of 3,6-dichloropyridazine 1-oxide was added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 226.5 mg (0.849 mmol, Yield: 70.2%) of 6-chloro-3-(2-methoxy-5-methylphenoxy)pyridazine 1-oxide. (2) 4,6-Dichloro-3-(2-methoxy-5-methylphenoxy)pyridazine (Step B-3) In phosphorus oxychloride (1 mL) was dissolved 226.5 mg (0.849 mmol) of 6-chloro-3-(2-methoxy-5-methylphenoxy)-pyridazine 1-oxide obtained in (1), and the solution was stirred at room temperature overnight. To the reaction mixture were added water and methylene chloride, and after stirring for 30 minutes, it was extracted with methylene chloride. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 205.3 mg (0.720 mmol, Yield: 84.8%) of 4,6-dichloro-3-(2-methoxy-5-methylphenoxy)pyridazine. (3) 6-Chloro-3-(2-methoxy-5-methylphenoxy)-4-pyridazinol (Compound No. 704, Step B-4) In a mixed solvent of 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) was dissolved 205.3 mg (0.720 mmol) of 4,6-dichloro-3-(2-methoxy-5-methylphenoxy)pyridazine obtained in (2), and 1.8 mL (3.6 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, diluted hydrochloric acid was added thereto to adjust pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 148.1 mg (0.555 mmol, Yield: 77.1%) of 6-chloro-3-(2-methoxy-5-methylphenoxy)-4-pyridazinol (Compound No. 704). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.04-6.91 (3H, m), 6.66 (1H, s), 3.70 (3H, s), 2.27 (3H, s). Melting point (° C.): 126-134. EXAMPLE 17 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}-4-pyridazinol (Compound No. 728) (1) 3-Fluoro-2-methoxybenzaldehyde To an acetonitrile (50 mL) solution containing 3.01 g (21.5 mmol) of commercially available 3-fluoro-2-hydroxybenzaldehyde were added 5.92 g (42.8 mmol) of potassium carbonate and 6.66 mL (107 mmol) of methyl iodide, and the mixture was stirred at 90° C. for 3 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.22 g of a crude product of 3-fluoro-2-methoxybenzaldehyde. (2) 1-Fluoro-2-methoxy-3-vinylbenzene Under nitrogen atmosphere, 273.2 mg (6.83 mmol) of 60% sodium hydride washed with hexane was suspended in dry dimethylsulfoxide (3 mL), and the suspension was stirred at 85° C. for 30 minutes, cooled to room temperature and then, in an ice bath, a dry dimethylsulfoxide (8 mL) solution containing 2.44 g (6.83 mmol) of methyl(triphenyl)phosphonium bromide was gradually added dropwise. After stirring at room temperature for 30 minutes, a dry dimethylsulfoxide (5 mL) solution containing 877.4 mg of a crude product of 3-fluoro-2-methoxybenzaldehyde obtained in (1) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 0.38 g (2.5 mmol) of 1-fluoro-2-methoxy-3-vinylbenzene. (3) 1-Cyclopropyl-3-fluoro-2-methoxybenzene Under nitrogen atmosphere, dry diethyl ether (5 mL) was charged in a dry flask, 9.20 mL (9.20 mmol) of diethyl-zinc (1 mol/L hexane solution) was then added dropwise, and a dry diethyl ether (10 mL) solution containing 0.56 g (3.7 mmol) of 1-fluoro-2-methoxy-3-vinylbenzene obtained in (2) was added dropwise thereto. After stirring at room temperature for 5 minutes, 1.48 mL (18.4 mmol) of diiodomethane was added dropwise thereto, and the resulting mixture was refluxed for 5 hours. After cooling to room temperature, 9.20 mL (9.20 mmol) of diethylzinc (1 mol/L hexane solution) and 1.48 mL (18.4 mmol) of diiodomethane were additionally added, and the resulting mixture was again refluxed for 4 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into a saturated aqueous ammonium chloride solution. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution and after stirring for 30 minutes, and the mixture was extracted with diethyl ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 0.82 g of a crude product of 1-cyclopropyl-3-fluoro-2-methoxybenzene. (4) 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}pyridazine 1-oxide (Step B-2) Under nitrogen atmosphere, 288.8 mg (7.22 mmol) of 60% sodium hydride was suspended in dry N,N-dimethylformamide (3 mL), and 0.55 mL (7.5 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 15 minutes, a dry N,N-dimethylformamide (6 mL) solution containing 402.1 mg of a crude product of 1-cyclopropyl-3-fluoro-2-methoxybenzene obtained in (3) was added dropwise thereto, and the resulting mixture was stirred at 160° C. for 5 hours. After allowing to stand at room temperature overnight, 1 mol/L aqueous potassium hydroxide solution and diethyl ether were added to the reaction mixture. The aqueous layer was separated, washed with diethyl ether, and added thereto diluted hydrochloric acid to adjust pH to 2. The mixture was extracted with diethyl ether, ether extracts were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=4:1) to obtain 299.9 mg of a mixture. In a mixed solvent of 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) was dissolved 152.7 mg of the mixture, 116.1 mg (1.03 mmol) of potassium tert-butoxide was added to the solution, then 162.6 mg (0.988 mmol) of 3,6-dichloropyridazine 1-oxide was added thereto, and the resulting mixture was stirred at room temperature over-night. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 46.6 mg (0.144 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}pyridazine 1-oxide. (5) 4,6-Dichloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}pyridazine (Step B-3) A phosphorus oxychloride (0.5 mL) solution containing 46.6 mg (0.144 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)-ethyl]-6-fluorophenoxy}pyridazine 1-oxide obtained in (4) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by ethyl acetate:hexane=4:1) to obtain 9.8 mg (0.028 mmol, Yield: 19%) of 4,6-dichloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}pyridazine. (6) 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}-4-pyridazinol (Compound No. 728, Step B-4) In a mixed solvent of 1,4-dioxane (1 mL) and dimethylsulfoxide (1 mL) was dissolved 9.8 mg (0.028 mmol) of 4,6-dichloro-3-{2-[l-(ethylsulfanyl)ethyl]-6-fluorophenoxy}pyridazine obtained in (5), 0.07 mL (0.14 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, diluted hydrochloric acid was added thereto to adjust pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by ethyl acetate) to obtain 2.2 mg (0.0067 mmol, Yield: 24%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}-4-pyridazinol (Compound No. 728). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.42 (1H, d, J=8.1 Hz), 7.26-7.15 (1H, m), 7.07-6.97 (1H, m), 6.46 (1H, s), 4.33 (1H, q, J=7.0 Hz), 2.42-2.20 (2H, m), 1.43 (3H, d, J=7.0 Hz), 1.02 (3H, t, J=7.0 Hz). Appearance: amorphous. EXAMPLE 18 6-Chloro-3-(2-chloro-6-isopropylphenoxy)-4-pyridazinol (Compound No. 738) (1) 1-Isopropyl-2-[(2-methoxyethoxy)methoxy]benzene In dry tetrahydrofuran (60 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 13.6 g (100 mmol) of 2-isopropylphenol was added dropwise to the suspension at 0° C. After stirring at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise thereto. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed succeccively with 1 mol/L aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=50:1) to obtain 18.1 g (80.8 mmol, Yield: 80.8%) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene. (2) 1-Chloro-3-isopropyl-2-[(2-methoxyethoxy)methoxy]-benzene In a dry ether (100 mL) was dissolved 8.00 g (35.7 mmol) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene obtained in (1), and 34.4 mL (55.0 mmol) of n-butyl lithium-hexane solution (1.60M) was added to the solution in an ice bath (reaction solution temperature: 5-10° C.), and the mixture was stirred in an ice bath for 5 hours. To the mixture was passed through 2.51 g (35.4 mmol) of a chlorine gas while keeping the reaction solution temperature to 5-10° C. The reaction mixture was stirred in an ice bath for 1 hour, poured into 1 mol/L hydrochloric acid (300 mL), and extracted with ether. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=100:1) to obtain 4.38 g (16.9 mmol, Yield: 47.3%) of 1-chloro-3-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene. (3) 2-Chloro-6-isopropylphenol In dichloromethane (15 mL) was dissolved 4.38 g (16.9 mmol) of 1-chloro-3-isopropyl-2-[(2-methoxyethoxy)methoxy]-benzene obtained in (2), 2.70 g (23.7 mmol) of trifluoroacetic acid was added to the solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane) to obtain 2.50 g (14.7 mmol, Yield: 87.0%) of 2-chloro-6-isopropylphenol. (4) 3-Chloro-6-(2-chloro-6-isopropylphenoxy)pyridazine (Step A-1) 1.98 g (17.7 mmol) of potassium tert-butoxide, 1,4-dioxane (100 mL) and 2.50 g (14.7 mmol) of 2-chloro-6-isopropylphenol obtained in (3) were mixed, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added 2.18 g (14.6 mmol) of 3,6-dichloropyridazine and the mixture was refluxed for 4 hours. To the reaction mixture was further added 0.50 g (4.5 mmol) of potassium tert-butoxide, and the mixture was refluxed for further 3 hours. The reaction mixture was allowed to stand for cooling, poured into 1N hydrochloric acid (100 mL), and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 3.18 g (11.2 mmol, Yield: 76.2%) of 3-chloro-6-(2-chloro-6-isopropylphenoxy)pyridazine. (5) Mixture of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-pyridazine 1-oxide and 3-chloro-6-(2-chloro-6-isopropylphenoxy)pyridazine 1-oxide (Step C-1) In dry dichloromethane (90 mL) was dissolved 3.17 g (11.2 mmol) of 3-chloro-6-(2-chloro-6-isopropylphenoxy)-pyridazine obtained in (4), 2.90 g (13.4-14.3 mmol) of 80-85% m-chloroperbenzoic acid was added to the solution, and the mixture was refluxed for 13 hours. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 2.82 g (9.43 mmol, Yield: 84.2%) of a mixture of 6-chloro-3-(2-chloro-6-isopropylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-chloro-6-isopropylphenoxy)pyridazine 1-oxide. (6) Mixture of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine and 3,4-dichloro-6-(2-chloro-6-isopropylphenoxy)pyridazine (Step C-2) 2.80 g (9.36 mmol) of a mixture of 6-chloro-3-(2-chloro-6-isopropylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-chloro-6-isopropylphenoxy)pyridazine 1-oxide obtained in (5) was mixed with 17.5 mL (189 mmol) of phosphorus oxychloride, and the mixture was refluxed for 2 hours and 30 minutes. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 0.850 g (2.67 mmol, m.p.90-91° C.) of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine, and 1.78 g (5.60 mmol) of a mixture of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine and 3,4-dichloro-6-(2-chloro-6-isopropylphenoxy)pyridazine. (7) 6-Chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine and 3-chloro-6-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine (Step C-3) To methanol (10 mL) was added 0.080 g (3.5 mmol) of sodium, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 0.830 g (2.61 mmol) of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine obtained in (6), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=10:1), washed with hexane and crystallized to obtain 0.720 g (2.30 mmol, Yield: 88.1%) of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine. On the other hand, 1.78 g (5.60 mmol) of the mixture of 4,6-dichloro-3-(2-chloro-6-isopropylphenoxy)pyridazine and 3,4-dichloro-6-(2-chloro-6-isopropylphenoxy)pyridazine was reacted in the same manner as mentioned above to obtain 1.25 g (3.99 mmol, Yield: 71.3%) of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine and 0.300 g (0.958 mmol, Yield: 17.1%) of 3-chloro-6-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine. (8) 6-Chloro-3-(2-chloro-6-isopropylphenoxy)-4-pyridazinol (Compound No. 738, Step C-4) In dimethylsulfoxide (13 mL) was dissolved 1.46 g (4.66 mmol) of 6-chloro-3-(2-chloro-6-isopropylphenoxy)-4-methoxypyridazine obtained in (7), 3 mL (6.0 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water, and made acidic with hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and air dried. 6-Chloro-3-(2-chloro-6-isopropylphenoxy)-4-pyridazinol (Compound No. 738) was obtained in an amount of 1.33 g (4.45 mmol, Yield: 95.5%). 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.40-7.05 (3H, m), 6.70 (1H, s), 2.98 (1H, septet, J=6.2 Hz), 1.13 (6H, d, J=6.2 Hz). Melting point (° C.): 218-233. EXAMPLE 19 3-(2-Bromo-6-isopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 760) (1) 1-Bromo-3-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene In dry ether (100 mL) was dissolved 5.18 g (23.1 mmol) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene obtained in Example 18(1), 22.3 mL (35.7 mmol) of n-butyl lithium-hexane solution (1.60M) was added dropwise to the solution in an ice bath (reaction solution temperature: 5-10° C.), and the mixture was stirred in an ice bath for 5 hours. To the reaction mixture was added 8.20 g (69.7 mmol) of 90% cyanogen bromide while maintaining the reaction solution temperature to 5-10° C. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (300 mL), and extracted with ether. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=100:1) to obtain 3.40 g (11.2 mmol, Yield: 48.5%) of 1-bromo-3-isopropyl-2-[(2-methoxyethoxy)-methoxy]benzene. (2) 2-Bromo-6-isopropylphenol In dichloromethane (10 mL) was dissolved 3.40 g (11.2 mmol) of 1-bromo-3-isopropyl-2-[(2-methoxyethoxy)methoxy]-benzene obtained in (1), 2.50 g (21.9 mmol) of trifluoroacetic acid was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane) to obtain 2.27 g (10.6 mmol, Yield: 94.6%) of 2-bromo-6-isopropylphenol. (3) 3-(2-Bromo-6-isopropylphenoxy)-6-chloropyridazine (Step A-1) 1.52 g (13.6 mmol) of potassium tert-butoxide, 1,4-dioxane (60 mL) and 2.27 g (10.6 mmol) of 2-bromo-6-isopropylphenol obtained in (2) were mixed, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added 1.58 g (10.6 mmol) of 3,6-dichloropyridazine, and the resulting mixture was refluxed for 7 hours and 20 minutes. The reaction mixture was allowed to stand for cooling, poured into ice-cold water (110 mL), and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, the obtained residue was recrystallized (from isopropyl ether), then, purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 2.68 g (8.17 mmol, Yield: 77.1%) of 3-(2-bromo-6-isopropylphenoxy)-6-chloropyridazine. (4) Mixture of 3-(2-bromo-6-isopropylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-isopropylphenoxy)-3-chloropyridazine 1-oxide (Step C-1) In dry dichloromethane (35 mL) was dissolved 2.68 g (8.17 mmol) of 3-(2-bromo-6-isopropylphenoxy)-6-chloropyridazine obtained in (3), 2.12 g (9.80-10.4 mmol) of 80-85% m-chloroperbenzoic acid was added to the solution, and the mixture was refluxed for 12 hours and 30 minutes. The reaction mixture was poured into 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 2.26 g (6.57 mmol, Yield: 80.4%) of a mixture of 3-(2-bromo-6-isopropylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-isopropylphenoxy)-3-chloropyridazine 1-oxide. (5) Mixture of 3-(2-bromo-6-isopropylphenoxy)-4,6-dichloropyridazine and 6-(2-bromo-6-isopropylphenoxy)-3,4-dichloropyridazine (Step C-2) A mixture of 2.14 g (6.22 mmol) of 3-(2-bromo-6-isopropylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-isopropylphenoxy)-3-chloropyridazine 1-oxide obtained in (4) was mixed with 11.6 mL (125 mmol) of phosphorus oxychloride, and the resulting mixture was refluxed for 3 hours. The reaction mixture was cooled by allowing to stand, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L of an aqueous sodium hydroxide solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl .acetate=20:1) to obtain 2.22 g (6.13 mmol, Yield: 98.6%) of a mixture of 3-(2-bromo-6-isopropylphenoxy)-4,6-dichloropyridazine and 6-(2-bromo-6-isopropylphenoxy)-3,4-dichloropyridazine. (6) 3-(2-Bromo-6-isopropylphenoxy)-6-chloro-4-methoxypyridazine (Step-C-3) To methanol (20 mL) was added 0.180 g (7.8 mmol) of sodium, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 2.22 g (6.13 mmol) of a mixture of 3-(2-bromo-6-isopropylphenoxy)-4,6-dichloropyridazine and 6-(2-bromo-6-isopropylphenoxy)-3,4-dichloropyridazine obtained in (5) and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1), and washed with hexane to crystallize to obtain 1.48 g (4.13 mmol, Yield: 67.4%) of 3-(2-bromo-6-isopropylphenoxy)-6-chloro-4-methoxypyridazine. Also, 0.21 g (0.59 mmol, Yield: 9.6%) of 6-(2-bromo-6-isopropylphenoxy)-3-chloro-4-methoxypyridazine was simultaneously obtained. (7) 3-(2-Bromo-6-isopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 760, Step C-4) In dimethylsulfoxide (10 mL) was dissolved 0.72 g (2.0 mmol) of 3-(2-bromo-6-isopropylphenoxy)-6-chloro-4-methoxypyridazine obtained in (6), an aqueous sodium hydroxide solution (prepared by dissolving 100 mg of sodium hydroxide in 1.5 mL of water, 2.4 mmol) was added to the solution, and the resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was poured into water, and made acidic by hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and air-dried. Thus, 0.56 g (1.6 mmol, Yield: 80%) of 3-(2-bromo-6-isopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 760) was obtained. 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.70-7.00 (3H, m), 6.89 (1H, s), 2.94 (1H, septet, J=7.0 Hz), 1.16 (6H, d, J=7.0 Hz). Melting point (° C.): 232-253 (dec.). EXAMPLE 20 3-(2-Bromo-6-tert-butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 761) (1) tert-Butyl-2-[(2-methoxyethoxy)methoxy]benzene In dry tetrahydrofuran (25 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 15.0 g (100 mmol) of 2-tert-butylphenol was added dropwise to this suspension at 0° C. After stirring the mixture at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise to the mixture. The reaction mixture was stirred in an ice bath for 4 hours and 30 minutes, and allowed to stand at room temperature overnight. To the reaction mixture were further added 1.20 g (30 mmol) of 60% sodium hydride and 3.8 g (30 mmol) of 2-methoxyethoxymethyl chloride at 0° C., and the mixture was stirred at 0° C. for 7 hours. The reaction mixture was poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed with 2N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=20:1) to obtain 19.7 g (82.8 mmol, Yield: 82.8%) of tert-butyl-2-[(2-methoxyethoxy)methoxy]benzene. (2) 1-Bromo-3-tert-butyl-2-[(2-methoxyethoxy)methoxy]-benzene In dry ether (120 mL) was dissolved 10.0 g (42.0 mmol) of tert-butyl-2-[(2-methoxyethoxy)methoxy]benzene obtained in (1), 42.1 mL (64.4 mmol) of n-butyl lithium-hexane solution (1.53M) was added dropwise to the solution in an ice bath, and the mixture was stirred in an ice bath for 3 hours. To the mixture was added dropwise a dry ether (20 mL) solution containing 14.8 g (126 mmol) of 90% cyanogen bromide. The reaction mixture was stirred in an ice bath for 3 hours, poured into ice-cold water (300 mL), and extracted with ether. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=20:1) to obtain 8.48 g (26.8 mmol, Yield: 63.8%) of 1-bromo-3-tert-butyl-2-[(2-methoxyethoxy)methoxy]benzene. (3) 2-Bromo-6-tert-butylphenol In dichloromethane (30 mL) was dissolved 8.38 g (26.4 mmol) of 1-bromo-3-tert-butyl-2-[(2-methoxyethoxy)methoxy]-benzene obtained in (2), a dichloromethane (20 mL) solution containing 9.03 g (79.2 mmol) of trifluoroacetic acid was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold 1 mol/L of hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane) to obtain 5.68 g (24.8 mmol, Yield: 93.9%) of 2-bromo-6-tert-butylphenol. (4) 3-(2-Bromo-6-tert-butylphenoxy)-6-fluoropyridazine (Step A-1) In 1,4-dioxane (40 mL) was dissolved 4.84 g (21.1 mmol) of 2-bromo-6-tert-butylphenol obtained in (3), 3.55 g (31.7 mmol) of potassium tert-butoxide and 1,4-dioxane (40 mL) were added to the solution, and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 2.45 g (21.1 mmol) of 3,6-difluoropyridazine and the resulting mixture was refluxed for 24 hours with stirring. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, gradient) to obtain 1.70 g (5.23 mmol, Yield: 24.8%) of 3-(2-bromo-6-tert-butylphenoxy)-6-fluoropyridazine. (5) 6-(2-Bromo-6-tert-butylphenoxy)-3-pyridazinol 1.04 g (10.6 mmol) of potassium acetate was added to a mixture of acetic acid (9 mL) and 1.70 g (5.23 mmol) of 3-(2-bromo-6-tert-butylphenoxy)-6-fluoropyridazine obtained in (4), and the resulting mixture was stirred at 130-140° C. for 3 hours. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was washed with benzene to obtain 1.54 g (4.77 mmol, Yield: 91.2%, m.p.255-257° C.) of 6-(2-bromo-6-tert-butylphenoxy)-3-pyridazinol. (6) 3-(2-Bromo-6-tert-butylphenoxy)-6-chloropyridazine 1.54 g (4.77 mmol) of 6-(2-bromo-6-tert-butylphenoxy)-3-pyridazinol obtained in (5) was mixed with 15 mL (162 mmol) of phosphorus oxychloride, and the mixture was refluxed for 70 minutes. Phosphorus oxychloride was removed from the reaction mixture by distillation, the reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 1.55 g (4.53 mmol, Yield: 95.0%) of 3-(2-bromo-6-tert-butylphenoxy)-6-chloropyridazine. (7) Mixture of 3-(2-bromo-6-tert-butylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-tert-butylphenoxy)-3-chloropyridazine 1-oxide (Step C-1) In dry dichloromethane (20 mL) was dissolved 1.42 g (4.15 mmol) of 3-(2-bromo-6-tert-butylphenoxy)-6-chloropyridazine obtained in (6), a dry dichloromethane (10 mL) solution containing 1.08 g (4.99 mmol) of 80% m-chloroperbenzoic acid was added to the solution, and the mixture was refluxed for 20 hours. To the reaction mixture was additionally added 0.275 g (1.27 mmol) of 80% m-chloroperbenzoic acid, and after refluxing for 3 hours and 30 minutes, the reaction mixture was poured into 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate=10:1) to obtain 0.704 g (1.97 mmol, Yield: 47.5%) of a mixture of 3-(2-bromo-6-tert-butylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-tert-butylphenoxy)-3-chloropyridazine 1-oxide. (8) 3-(2-Bromo-6-tert-butylphenoxy)-4,6-dichloropyridazine and 6-(2-bromo-6-tert-butylphenoxy)-3,4-dichloropyridazine (Step C-2) 0.704 g (1.97 mmol) of a mixture of 3-(2-bromo-6-tert-butylphenoxy)-6-chloropyridazine 1-oxide and 6-(2-bromo-6-tert-butylphenoxy)-3-chloropyridazine 1-oxide obtained in (7) was mixed with 5 mL (54 mmol) of phosphorus oxychloride, and the resulting mixture was refluxed for 2 hours. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 0.474 g (1.26 mmol, Yield: 64.0%) of 3-(2-bromo-6-tert-butylphenoxy)-4,6-dichloropyridazine and 0.119 g (0.316 mmol, Yield: 16.0%) of 6-(2-bromo-6-tert-butylphenoxy)-3,4-dichloropyridazine. (9) 3-(2-Bromo-6-tert-butylphenoxy)-6-chloro-4-methoxypyridazine (Step C-3) In methanol (10 mL) was dissolved 0.443 g (1.18 mmol) of 3-(2-bromo-6-tert-butylphenoxy)-4,6-dichloropyridazine obtained in (8), and 0.545 g (2.83 mmol) of 28% sodium methoxide-methanol solution and methanol (5 mL) were added to the solution, and the resulting mixture was stirred at room temperature for 80 minutes. To the reaction mixture was additionally added 0.10 g (0.52 mmol) of 28% sodium methoxide-methanol solution, after stirring at room temperature for 2 hours, 0.15 g (0.78 mmol) of 28% sodium methoxide-methanol solution was further additionally added to the mixture and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 0.428 g (1.15 mmol, Yield: 97.5%) of 3-(2-bromo-6-tert-butylphenoxy)-6-chloro-4-methoxypyridazine: (10) 3-(2-Bromo-6-tert-butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 761, Step C-4) In dimethylsulfoxide (5 mL) was dissolved 0.395 g (1.06 mmol) of 3-(2-bromo-6-tert-butylphenoxy)-6-chloro-4-methoxypyridazine obtained in (9)., aqueous sodium hydroxide solution (prepared by dissolving 50.8 mg of sodium hydroxide in 3 mL of water, 1.27 mmol) was added to the solution, and the resulting mixture was stirred at 80° C. for 3 hours. Aqueous sodium hydroxide solution (prepared by dissolving 42 mg of sodium hydroxide in 3 mL of water, 1.1 mmol) and dimethylsulfoxide (10 mL) were additionally added thereto, and the mixture was further stirred at 80° C. for 5 hours. After cooling by allowing to stand, the reaction mixture was poured into ice-cold water, and made acidic by hydrochloric acid. The precipitated solid was collected by filtration, washed successively with water, hexane and isopropyl ether, and air-dried. 0.309 g (0.863 mmol, Yield: 81.4%) of 3-(2-bromo-6-tert-butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 761) was obtained. 1H-NMR (270 MHz, CDCl3) δ ppm: 9.55 (1H, brs), 7.47 (1H, dd, J=8.1, 1.7 Hz), 7.41 (1H, dd, J=8.1, 1.7 Hz), 7.08 (1H, t, J=8.1 Hz), 6.58 (1H, brs), 1.34 (9H, s). Melting point (° C.): 240-247. EXAMPLE 21 6-Chloro-3-(2,6-dimethylphenoxy)-4-pyridazinol (Compound No. 801) (1) 6-Chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide (Step B-2) 268 mg (2.20 mmol) of 2,6-dimethylphenol, 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL) were mixed, 270 mg (2.41 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 370 mg (2.24 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours and allowed to stand for 2 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, gradient) to obtain 350 mg (1.39 mmol, Yield: 63.1%) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide. (2) 4,6-Dichloro-3-(2,6-dimethylphenoxy)pyridazine (Step B-3) 330 mg (1.31 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)pyridazine 1-oxide obtained in (1) was mixed with dichloromethane (0.6 mL) and phosphorus oxychloride 0.60 mL (6.5 mmol), and the mixture was stirred for 1 hour and allowed to stand for further 5 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, gradient) to obtain 322 mg (1.20 mmol, Yield: 91.6%) of 4,6-dichloro-3-(2,6-dimethylphenoxy)-pyridazine. (3) 6-Chloro-3-(2,6-dimethylphenoxy)-4-pyridazinol (Compound No. 801, Step B-4) In dimethylsulfoxide (8 mL) was dissolved 300 mg (1.12 mmol) of 4,6-dichloro-3-(2,6-dimethylphenoxy)-pyridazine obtained in (2), 0.80 mL (2.0 mmol) of 10% (W/V) aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred at room temperature overnight. To the mixture was further added. 0.80 mL (2.0 mmol) of 10% (W/V) aqueous sodium hydroxide solution, and after disappearance of the starting materials, the reaction mixture was poured into ice-cold water. The mixture was made acidic with hydrochloric acid, and then, extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) and purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by dichloromethane: methanol=9:1) to obtain 128 mg (0.510 mmol, Yield: 45.5%) of 6-chloro-3-(2,6-dimethylphenoxy)-4-pyridazinol (Compound No. 801). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.18-7.05 (3H, m), 6.83 (1H, s), 2.05 (6H, s). Melting point (° C.): 214-215. EXAMPLE 22 3-(2-tert-Butyl-6-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 805) (1) 3-(2-tert-Butyl-6-methylphenoxy)-6-chloropyridazine (Step A-1) 17.5 g (107 mmol) of 2-tert-butyl-6-methylphenol, 11.9 g (106 mmol) of potassium tert-butoxide and 1,4-dioxane (250 mL) were mixed, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 15.0 g (101 mmol) of 2,6-dichloropyridazine and the resulting mixture was stirred at 100° C. for 3 hours and 15 minutes. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized form isopropyl ether to obtain 15.3 g (55.2 mmol, Yield: 54.6%) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine. (2) 3-(2-tert-Butyl-6-methylphenoxy)-6-chloropyridazine 1-oxide (Step C-1) 8.00 g (28.9 mmol) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine obtained in (1) was mixed with dry dichloromethane (200 mL) and 8.50 g (34.4 mmol) of 70% m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into an ice-coled saturated aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from a mixed solvent of ether-hexane or purified by silica gel column chromatography to obtain 7.04 g (24.0 mmol, Yield: 83.0%) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine 1-oxide. (3) 3-(2-tert-Butyl-6-methylphenoxy)-4,6-dichloropyridazine (Step C-2) 1.00 g (3.41 mmol) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine 1-oxide obtained in (2) was mixed with chloroform (10 mL) and 0.48 mL (5.2 mmol) of phosphorus oxychloride, and the mixture was stirred under reflux for 24 hours and at room temperature for 2 days. The reaction mixture was poured into ice-cold water, and extracted with dichloromethane. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was crystallized from a mixed solvent of ether-hexane to obtain 0.767 g (2.47 mmol, Yield: 72.4%) of 3-(2-tert-butyl-6-methylphenoxy)-4,6-dichloropyridazine. (4) 3-(2-tert-Butyl-6-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 805, Step C-3) 354 mg (1.14 mmol) of 3-(2-tert-butyl-6-methylphenoxy)-4,6-dichloropyridazine obtained in (3) was mixed with dimethylsulfoxide (10 mL) and 1.6 mL (1.6 mmol) of 1 mol/L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was poured into ice-cold water, and washed with ether. The aqueous layer was made acidic with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from a mixed solvent of ether-hexane to obtain 172 mg (0.587 mmol, Yield: 51.5%) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 805). 1H-NMR (90 MHz, CDCl3) δ ppm: 7.35-6.80 (3H, m), 6.50 (1H, s), 1.80 (3H, s), 1.18 (9H, s). Melting point (° C.): 135-136. EXAMPLE 23 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 806) (1) 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide (Step B-2) 221 mg (1.49 mmol) of 2-cyclopropyl-6-methylphenol was mixed with 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL), 184 mg (1.64 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 258 mg (1.56 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 10 hours, and then, allowed to stand for 3 days. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 222 mg (0.801 mmol, Yield: 53.8%) of a mixture of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide. (2) 4,6-Dichloro-3-(2-cyclopropyl-6-methylphenoxy)-pyridazine (Step B-3) In chloroform (1 mL) was dissolved 210 mg (0.758 mmol) of a mixture of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)pyridazine 1-oxide obtained in (1), 0.106 mL (1.14 mmol) of phosphorus oxychloride was added to the mixture, and after removing almost all the chloroform with a nitrogen-stream, the mixture was stirred at room temperature for 2 days. Further, chloroform (2 mL) and 0.150 mL (1.62 mmol) of phosphorus oxychloride were added to the mixture, and after removing almost all the chloroform with a nitrogen stream, the mixture was stirred for 3 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water, brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 167 mg (0.566 mmol, Yield: 74.7%) of 4,6-dichloro-3-(2-cyclopropyl-6-methylphenoxy)pyridazine. (3) 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 806, Step B-4) In dimethylsulfoxide (3 mL) was dissolved 150 mg (0.508 mmol) of 4,6-dichloro-3-(2-cyclopropyl-6-methylphenoxy)pyridazine obtained in (2), 0.37 mL (0.925 mmol) of 10% (W/V) aqueous sodium hydroxide solution was added to the solution, and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into an ice-coled 5% aqueous sodium hydroxide solution, and extracted with ether. The aqueous layer was made acidic with hydrochloric acid, and extracted with ether. The organic layer was dried and concentrated. The residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by dichloromethane: methanol=20:1) to obtain 114 mg (0.412 mmol, Yield: 81.1%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 806). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.13-7.03 (2H, m), 6.84-6.79 (2H, m), 2.06 (3H, s), 1.83-1.68 (1H, m), 0.82-0.72 (2H, m), 0.64-0.51 (2H, m). Melting point (° C.): 201-202. EXAMPLE 24 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 827) (1) 1-(2,2-Dichlorocyclopropyl)-2-methoxy-3-methylbenzene In chloroform (12 mL) was dissolved 304 mg (2.05 mmol) of 2-methoxy-1-methyl-3-vinylbenzene, 5 mL (63 mmol) of 50% aqueous sodium hydroxide solution was added dropwise to the solution, then, 59.9 mg (0.263 mmol) of benzyl-(triethyl)ammonium chloride was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with chloroform. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=4:1) to obtain 390 mg (1.69 mmol, Yield: 82.4%) of 1-(2,2-dichlorocyclopropyl)-2-methoxy-3-methylbenzene. (2) 2-(2,2-Dichlorocyclopropyl)-6-methylphenol In dichloromethane (5 mL) was dissolved 102 mg (0.442 mmol) of 1-(2,2-dichlorocyclopropyl)-2-methoxy-3-methylbenzene obtained in (1), the solution was cooled in an ice bath, and 0.045 mL (0.47 mmol) of boron tribromide was added dropwise to the solution with stirring. The reaction mixture was stirred in an ice bath for 2 hours, and then, poured into water and extracted with dichloromethane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 76.9 mg (0.354 mmol, Yield: 80.1%) of 2-(2,2-dichlorocyclopropyl)-6-methylphenol. (3) 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine 1-oxide (Step B-2) 198 mg (0.912 mmol) of 2-(2,2-dichlorocyclopropyl)-6-methylphenol obtained in (2) was mixed with 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL), 113 mg (1.01 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 151 mg (0.915 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1 three times) to obtain 257 mg of a crude product of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine 1-oxide. (4) 4,6-Dichloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine (Step B-3) 257 mg of a crude product of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine 1-oxide obtained in (3) was mixed with phosphorus oxychloride (3 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and dichloromethane, and the resulting mixture was stirred for 30 minutes. This mixture was separated, the organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 209 mg (0.574 mmol, Yield from 2-(2,2-dichlorocyclopropyl)-6-methylphenol with 2 Steps: 62.9%) of 4,6-dichloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine. (5) 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 827, Step B-4) 209 mg (0.574 mmol)-of 4,6-dichloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]pyridazine obtained in (4) was mixed with 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL), 1.43 mL (2.86 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at room temperature over-night. The reaction mixture was poured into water, and made acidic with diluted hydrochloric acid. This mixture was extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 120 mg (0.349 mmol, Yield: 60.8%) of 6-chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 827). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.25 (1H, br.d, J=6.3 Hz), 7.16 (1H, t, J=7.7 Hz), 6.98 (1H, d, J=7.7 Hz), 6.72 (1H, s), 2.85 (1H, dd, J=10.6, 8.8 Hz), 2.22 (3H, s), 2.05-1.86 (2H, m). Melting point (° C.): 213-215. EXAMPLE 25 6-Chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 1109) (1) 6,7-Dihydro-1-benzofuran-4(5H)-one In methanol (40 mL) was dissolved 11.2 g (0.100 mol) of 1,3-cyclohexanedione, an aqueous solution (8 mL) containing 6.60 g (0.100 mol) of 85% potassium hydroxide was added dropwise to the solution, and the resulting mixture was stirred at room temperature for 30 minutes. This mixture was cooled in an ice bath, 21.6 g (0.110 mol) of 40% chloroacetaldehyde aqueous solution was added to the mixture with stirring and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid aqueous solution, and the resulting mixture was stirred at room temperature for 30 minutes and extracted with ether. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 8.63 g (0.0635 mol, Yield: 63.5%) of 6,7-dihydro-1-benzofuran-4(5H)-one. (2) Methyl 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-5-carboxylate In dry tetrahydrofuran (10 mL) was dissolved 3.00 g (22.1 mmol) of 6,7-dihydro-1-benzofuran-4(5H)-one obtained in (1), and 48.5 mL (48.5 mmol) of lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran solution) was added dropwise to the solution under nitrogen atmosphere at −78° C. After stirring at −78° C. for 30 minutes, 1.87 mL (24.1 mmol) of methyl chlorocarbonate was added dropwise to the mixture, and the reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 3.93 g (20.3 mmol, Yield: 91.9%) of methyl 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-5-carboxylate. (3) Methyl 4-hydroxy-1-benzofuran-5-carboxylate In 1,4-dioxane (100 mL) was dissolved 3.93 g (20.3 mmol) of methyl 4-oxo-4,5,6,7-tetrahydro-1-benzofuran-5-carboxylate obtained in (2), 5.51 g (24.3 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the solution, and the resulting mixture was stirred at 120° C. for 3 hours. The reaction mixture was allowed to stand for cooling, insoluble materials were filtered off through Celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 2.04 g (10.6 mmol, Yield: 52.2%) of methyl 4-hydroxy-1-benzofuran-5-carboxylate. (4) Methyl 4-methoxy-1-benzofuran-5-carboxylate To an acetonitrile (60 mL) solution containing 2.04 g (10.6 mmol) of methyl 4-hydroxy-1-benzofuran-5-carboxylate obtained in (3) were added 2.53 g (18.3 mmol) of potassium carbonate, and then, 2.85 mL (45.8 mmol) of methyl iodide, and the resulting mixture was refluxed for 3 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 2.01 g (9.76 mmol, Yield: 92.1%) of methyl 4-methoxy-1-benzofuran-5-carboxylate. (5) (4-Methoxy-1-benzofuran-5-yl)methanol To a dry tetrahydrofuran (20 mL) solution containing 1.01 g (4.90 mmol) of methyl 4-methoxy-1-benzofuran-5-carboxylate obtained in (4), 0.479 g (12.6 mmol) of lithium aluminum hydride was added little by little to the mixture in an ice bath with stirring. The reaction mixture was stirred in an ice bath for 2 hours, and ethyl acetate was added little by little to the mixture. Subsequently, water (0.5 mL), 3N sodium hydroxide (0.5 mL), and water (1.5 mL) were successively added to the mixture and the resulting mixture was stirred for 30 minutes. This mixture was filtered through Celite, and the filtrate was concentrated to obtain 0.89 g of a crude product of (4-methoxy-1-benzofuran-5-yl)methanol. (6) 4-Methoxy-5-methyl-1-benzofuran In dichloromethane (10 mL) was dissolved 0.65 g of a crude product of (4-methoxy-1-benzofuran-5-yl)methanol obtained in (5), 0.56 mL (4.03 mmol) of triethylamine, and then, 0.31 mL (3.99 mmol) of methanesulfonyl chloride were added dropwise to the solution in an ice bath with stirring, and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, dry dimethylsulfoxide (20 mL) was added to the obtained residue, and 0.276 g (7.30 mmol) of sodium borohydride was added little by little. This mixture was stirred at room temperature for 1 hour, then poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 3 plates were used, developed by hexane:ethyl acetate=9:1) to obtain 0.284 g (1.75 mmol, Yield from methyl 4-methoxy-1-benzofuran-5-carboxylate: 48.9%) of 4-methoxy-5-methyl-1-benzofuran. (7) 5-Methyl-1-benzofuran-4-ol In dry N,N-dimethylformamide (11 mL) was suspended 268 mg (6.71 mmol) of 60% sodium hydride, 0.51 mL (6.9 mmol) of ethanethiol was added dropwise to the suspension under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a N,N-dimethylformamide (7 mL) solution containing 362 mg (2.23 mmol) of 4-methoxy-5-methyl-1-benzofuran obtained in (6), and the resulting mixture was refluxed for 1 hour and 30 minutes. The reaction mixture was allowed to stand for cooling, and 1 mol/L potassium hydroxide aqueous solution and diethyl ether were added thereto. The aqueous layer was washed with diethyl ether, and a pH thereof was adjusted by adding diluted hydrochloric acid thereto to a pH 2. The mixture was extracted with diethyl ether, the obtained organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 276 mg (1.86 mmol, Yield: 83.4%) of 5-methyl-1-benzofuran-4-ol. (8) 6-Chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]pyridazine 1-oxide (Step B-2) 121 mg (0.818 mmol) of 5-methyl-1-benzofuran-4-ol obtained in (7) was mixed with 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL), 101 mg (0.902 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 134 mg (0.812 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1 three times) to obtain 199 mg of a crude product of 6-chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]pyridazine 1-oxide. (9) 4,6-Dichloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]-pyridazine (Step B-3) 199 mg of a crude product of 6-chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]pyridazine 1-oxide obtained in (8) and 3 mL of phosphorus oxychloride were mixed, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and dichloromethane, and the resulting mixture was stirred for 30 minutes. The mixture was separated, the organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1 three times, subsequently available from MERCK CO., 1.05717, 2 plates were used, developed by hexane:ethyl acetate=2:1 three times) to obtain 120 mg (0.407 mmol, Yield from 4-hydroxy-5-methyl-1-benzofuran with 2 Steps: 49.8%) of 4,6-dichloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]pyridazine. (10) 6-Chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 1109, Step B-4) 120 mg (0.407 mmol) of 4,6-dichloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]pyridazine obtained in (9) was mixed with 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL), 1.01 mL (2.02 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and made acidic with diluted hydrochloric acid. This mixture was extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate) to obtain 70.0 mg (0.253 mmol, Yield: 62.2%) of 6-chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 1109). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.65 (1H, d, J=2.2 Hz), 7.32 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz), 6.73 (1H, s), 6.60 (1H, dd, J=2.2, 0.7 Hz), 2.23 (3H, s). Melting point (° C.): 222-225. EXAMPLE 26 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl trifluoromethanesulfonate (Compound No. 2081, Step I-1) In methylene chloride (2 mL) was dissolved 50.3 mg (0.191 mmol) of 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139) obtained in Example 6, 0.027 mL (0.19 mmol) of triethylamine was added dropwise to the solution, then, 0.031 mL (0.19 mmol) of trifluoromethanesulfonic acid anhydride was added dropwise to the same, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified as such by preparative thin-layer chromatography (available from MERCK Co., 1.05744, 2 plates were used, developed by ethyl acetate:hexane=2:1) to obtain 64.7 mg (0.164 mmol, Yield: 85.8%) of 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl trifluoromethanesulfonate (Compound No. 2081). 1H-NMR (200 MHz, CDCl3) δ ppm: 7.51 (1H, s), 7.26-7.19 (2H, m), 7.14-7.05 (2H, m), 1.89-1.81 (1H, m), 0.85-0.62 (4H, m). Melting point (° C.): 54-61. EXAMPLE 27 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl 4-methylbenzene sulfonate (Compound No. 2225, Step I-1) In acetonitrile (3 mL) was dissolved 53.4 mg (0.203 mmol) of 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 139) obtained in Example 6, 23.1 mg (0.206 mmol) of 1,4-diazabicyclo[2,2,2]octane was added to the solution, then, 39.2 mg (0.205 mmol) of 4-methylbenzene sulfonyl chloride was added to the same, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, ethyl acetate:hexane=2:1) to obtain 68.8 mg (0.165 mmol, Yield: 81.3%) of 6-chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl 4-methylbenzene sulfonate (Compound No. 2225). H1-NMR (200 MHz, CDCl3) δ ppm: 7.87 (2H, d, J=8.1 Hz), 7.58 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.26-7.11 (2H, m), 6.97-6.93 (1H, m), 6.74-6.70 (1H, m), 2.45 (3H, s), 1.67-1.59 (1H, m), 0.71-0.56 (4H, m). Appearance: oily product. EXAMPLE 28 2-[(6-Chloro-4-{[(4-methylphenyl)sulfonyl]oxy}-3-pyridazinyl)oxy]phenyl 4-methylbenzene sulfonate (Compound No. 2233, Step I-1) 0.60 g (2.5 mmol) of 6-chloro-3-(2-hydroxyphenoxy)-4-pyridazinol (Compound No. 384) obtained in Example 10, 1.06 g (5.5 mmol) of 4-methylbenzene sulfonyl chloride, 0.56 g (5.0 mmol) of 1,4-diazabicyclo[2,2,2]octane and acetonitrile (30 mL) were mixed, and the mixture was stirred under reflux for 3 hours, and at room temperature for 4 days. Acetonitrile was removed by distillation, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was washed with a mixed solvent of hexane-ethyl acetate (3:1) to obtain 1.0 g (1.8 mmol, Yield: 72%) of 2-[(6-chloro-4-{[(4-methylphenyl)sulfonyl]oxy}-3-pyridazinyl)oxy]phenyl 4-methylbenzene sulfonate (Compound No. 2233). 1H-NMR (60 MHz, CDCl3) δ ppm: 7.98-6.65 (13H, m), 2.40 (3H, s), 2.36 (3H, s). Melting point (° C.): 125.5-126.5. EXAMPLE 29 6-Chloro-5-methyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2372) (1) 3-Chloro-4-methyl-2,5-furandione and 3-chloro-4-(chloromethyl)-2,5-furandione 224 g (2.00 mol) of 3-methyl-2,5-furandione and 11.2 g (0.415 mol) of iron chloride (III) hexahydrate were mixed, and the mixture was heated to 140° C., and 346 g (4.88 mol) of a chlorine gas was passed through the mixture with stirring over 7 hours and 30 minutes. Thereafter, the mixture was heated at 175° C. for 3 hours and 30 minutes. The reaction mixture was evaporated under reduced pressure (5 mmHg) to collect fractions of 80° C. to 85° C. Thus, 223.5 g of a crude product (containing 3-chloro-4-methyl-2,5-furandione and 3-chloro-4-(chloromethyl)-2,5-furandione) was obtained. (2) 4-Chloro-5-methyl-1,2-dihydro-3,6-pyridazinedione and 4-chloro-5-(chloromethyl)-1,2-dihydro-3,6-pyridazinedione 147 g of a material (containing 3-chloro-4-methyl-2,5-furandione and 3-chloro-4-(chloromethyl)-2,5-furandione) obtained in (1) was mixed with 400 mL of water, and the mixture was refluxed to make a solution. To the solution heated at reflux was added dropwise an aqueous solution containing 116 g (1.10 mol) of hydrazine dihydrochloride (the hydrazine dihydrochloride was dissolved in 400 mL of water) over 40 minutes. Thereafter, the mixture was refluxed for 1 hour and 30 minutes, and then allowed to stand for cooling. Precipitated crystals were collected by filtration, washed with hot water, and then, with ethyl acetate, to obtain 81.8 g of 4-chloro-5-methyl-1,2-dihydro-3,6-pyridazinedione (m.p.305-310° C.). On the other hand, the filtrate was extracted with ethyl acetate, the organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and a mixture containing 8.06 g of 4-chloro-5-(chloromethyl)-1,2-dihydro-3,6-pyridazinedione was obtained as a residue. (3) 3,4,6-Trichloro-5-methylpyridazine 24.1 g (0.150 mol) of 4-chloro-5-methyl-1,2-dihydro-3,6-pyridazinedione obtained in (2) was mixed with 250 mL (2.76 mol) of phosphorus oxychloride, and the mixture was refluxed for 1 hour and 40 minutes. Excess phosphorus oxychloride was removed from the reaction mixture by distillation, and the residue was mixed with ice water. Crystals were collected by filtration, and extracted with ethyl acetate. The organic layer was washed with water, and the solvent was removed. The obtained residue was distilled under reduced pressure (0.7 mmHg) and fractions at 105° C. to 110° C. were collected to obtain 25.1 g (0.127 mol, Yield: 84.7%, m.p. 67.5-70° C.) of 3,4,6-trichloro-5-methylpyridazine. (4) 3,6-Dichloro-4-methoxy-5-methylpyridazine 7.90 g (40.1 mmol) of 3,4,6-trichloro-5-methylpyridazine obtained in (3) was mixed with methanol (100 mL), a methanol solution (50 mL) containing 0.92 g (40 mmol) of sodium was added dropwise to the mixture in an ice bath, thereafter in an ice bath, the mixture was stirred for 1 hour, and then, for 15 minutes under reflux. In an ice bath, 0.20 g (8.7 mmol) of sodium was additionally added to the mixture, and the resulting mixture was further refluxed for 15 minutes. The reaction mixture was allowed to stand for cooling, and methanol was distilled off. The residue was mixed with ice water and extracted with ethyl acetate. The organic layers were combined, washed with water, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (Wako gel C-100, eluted with hexane:ethyl acetate=5:1) to obtain 5.1 g of a crude product. This product was distilled under reduced pressure (0.07 mmHg) and fractions at 125° C. were collected to obtain 4.50 g (23.3 mmol, Yield: 58.1%) of 3,6-dichloro-4-methoxy-5-methylpyridazine. (5) Mixture of 3-chloro-5-methoxy-4-methyl-6-(2-methylphenoxy)pyridazine and 3-chloro-4-methoxy-5-methyl-6-(2-methylphenoxy)pyridazine (Step D-1) To 30.8 g (285 mmol) of 2-methylphenol was gradually added 1.66 g (38.0 mmol) of 55% sodium hydride with stirring. After stirring at room temperature for 20 minutes, the mixture was heated to 90° C. to disappear a solid of sodium hydride. This mixture was cooled to 50° C., 3.69 g (19.1 mmol) of 3,6-dichloro-4-methoxy-5-methylpyridazine obtained in (4) was added thereto, and the resulting mixture was stirred at 110° C. for 3 hours and 30 minutes. The reaction mixture was allowed to stand for cooling, water was added thereto, and then, the mixture was extracted with ethyl acetate. The organic layer was washed with 20% aqueous sodium hydroxide solution, and the solvent was removed. The obtained residue was purified by silica gel column chromatography to obtain 1.38 g (5.21 mmol, Yield: 27.3%) of a mixture of 3-chloro-5-methoxy-4-methyl-6-(2-methylphenoxy)pyridazine and 3-chloro-4-methoxy-5-methyl-6-(2-methylphenoxy)pyridazine. (6) 6-Chloro-5-methyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2372, Step D-2) 1.38 g (5.21 mmol) of a mixture of 3-chloro-5-methoxy-4-methyl-6-(2-methylphenoxy)pyridazine and 3-chloro-4-methoxy-5-methyl-6-(2-methylphenoxy)pyridazine obtained in (5) was mixed with 1,4-dioxane (8 mL), an aqueous solution (using 13 mL of water) containing 0.282 g (6.78 mmol) of 96% sodium hydroxide was added to the mixture, and the resulting mixture was stirred at 110° C. for 4.5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was made acidic with hydrochloric acid, and precipitated crystals were collected by filtration to obtain 0.249 g (0.992 mmol, Yield: 19.0%, m.p. 209-213° C.) of 6-chloro-5-methyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2372). 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.50-6.95 (4H, m), 2.28 (3H, m), 2.11 (3H, m). Melting point (° C.): 209-213. Incidentally, crystals precipitated from the filtrate were collected by filtration to obtain 0.187 g (0.745 mmol, Yield: 14.3%) of 3-chloro-5-methyl-6-(2-methylphenoxy)-4-pyridazinol. On the other hand, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed to recover 0.57 g (Recovery: 41%) of the starting material. EXAMPLE 30 6-Chloro-5-(methoxymethyl)-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2378) (1) 3,4,6-Trichloro-5-(chloromethyl)pyridazine 7.8 g of a mixture containing 4-chloro-5-(chloromethyl)-1,2-dihydro-3,6-pyridazinedione obtained in Example 29 was added 50 mL of phosphorus oxychloride, and the mixture was refluxed for 1 hour. Excess phosphorus oxychloride was distilled off from the reaction mixture, and the residue was mixed with ice water. The mixture was extracted with ethyl acetate, the organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (available from Merck Co., 9385, eluted with hexane:ethyl acetate=10:1) to obtain 3.63 g (15.6 mmol, m.p. 102-104° C.) of 3,4,6-trichloro-5-(chloromethyl)pyridazine. (2) 3,6-Dichloro-4-methoxy-5-(methoxymethyl)pyridazine In methanol (50 ml) was added 2.32 g (10.0 mmol) of 3,4,6-trichloro-5-(chloromethyl)pyridazine obtained in (1) and the mixture was heated to make a solution. Then, the solution was cooled to −60° C. and a methanol solution of sodium methoxide (prepared from 0.23 g of sodium and 5 mL of methanol, 10.0 mmol) was added dropwise to the solution. The solution was stirred at −10° C. for 2 hours and 30 minutes, and a methanol solution of sodium methoxide (prepared from 0.23 g of sodium and 5 mL of methanol, 10.0 mmol) was further added dropwise to the solution. After stirring for 2 hours at −10° C., and the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (available from Merck Co., 9385, eluted with hexane:ethyl acetate=5:1) to obtain 1.85 g (8.30 mmol, Yield: 83.0%, m.p. 28-32° C.) of 3,6-dichloro-4-methoxy-5-(methoxymethyl)pyridazine. (3) 3-Chloro-5-methoxy-4-(methoxymethyl)-6-(2-methylphenoxy)pyridazine(Step D-1) 432 mg (4.00 mmol) of 2-methylphenol, methanol (20 mL) and 92 mg (4.0 mmol) of sodium were mixed, and the mixture was stirred at room temperature until sodium was disappeared. Methanol in the mixture was distilled off, 50 mL of toluene was added to the residue and the mixture was refluxed. The mixture was cooled in an ice bath, a toluene solution (10 mL) containing 892 mg (4.00 mmol) of 3,6-dichloro-4-methoxy-5-(methoxymethyl)pyridazine obtained in (2) was added dropwise to the mixture, and the resulting mixture was refluxed for 3 hours. The reaction mixture was allowed to stand at room temperature overnight, washed with water, and then with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (First time; available from Merck Co., 9385, eluted with hexane:ethyl acetate=5:1. Second time; available from Merck Co., 9385, eluted with hexane:ethyl acetate=8:1) to obtain 0.487 g (1.65 mmol, Yield: 41.3%) of 3-chloro-5-methoxy-4-(methoxymethyl)-6-(2-methylphenoxy)pyridazine and 0.266 g (0.902 mmol, Yield: 22.6%) of 3-chloro-4-methoxy-5-(methoxymethyl)-6-(2-methylphenoxy)pyridazine. (4) 6-Chloro-5-(methoxymethyl)-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2378, Step D-2) 0.354 g (1.20 mmol) of 3-chloro-5-methoxy-4-(methoxymethyl)-6-(2-methylphenoxy)pyridazine obtained in (3), 1,4-dioxane (2 mL), 62 mg (1.49 mmol) of 96% sodium hydroxide and water (8 mL) were mixed, and the mixture was stirred at room temperature for 2 days, and further for 3 hours under reflux. Hydrochloric acid was added to the reaction mixture to make a pH 1, and then, the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 0.336 g (1.20 mmol, Yield: 100%) of 6-chloro-5-(methoxymethyl)-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2378). 1H-NMR (60 MHz, DMF-d7) δ ppm: 8.92 (1H, brs), 7.45-6.80 (4H, m), 4.39 (2H, s), 3.25 (3H, s), 2.25 (3H, s). Melting point (° C.): 123-126. EXAMPLE 31 Ethyl 6-(2-tert-butylphenoxy)-3-chloro-5-hydroxy-4-pyridazinecarboxylate (Compound No. 2386) (1) 3-(2-Tert-butylphenoxy)-6-chloro-4-methoxypyridazine 5.87 g (39.1 mmol) of 2-tert-butylphenol, dimethylsulfoxide (80 mL) and 4.38 g (39.0 mmol) of potassium t-butoxide were mixed, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added a dimethylsulfoxide solution (60 mL) containing 6.92 g (38.7 mmol) of 3,6-dichloro-4-methoxypyridazine, and the resulting mixture was stirred at room temperature for 40 minutes, and at 80° C. for 45 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layers were combined, washed with water, and then, with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (available from Merck Co., 9385, hexane:ethyl acetate, gradient) to obtain 2.66 g (9.09 mmol, Yield: 23.5%) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxypyridazine and 1.82 g (6.22 mmol, Yield: 16.1%) of 6-(2-tert-butylphenoxy)-3-chloro-4-methoxypyridazine. (2) Ethyl 6-(2-tert-butylphenoxy)-3-chloro-5-methoxy-4-pyridazinecarboxylate (Step G-1) In dry tetrahydrofuran (26 mL) was dissolved 783 mg (2.68 mmol) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxypyridazine obtained in (1). The solution was cooled to −78° C., 1.20 mL (2.80 mmol) of a n-butyl lithium-hexane solution (2.33M) was added to the solution and the resulting mixture was stirred for 20 minutes. To the mixture was added 0.330 mL (3.45 mmol) of ethyl chlorocarbonate, and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=5:1) to obtain 603 mg (1.65 mmol, Yield: 61.6%) of ethyl 6-(2-tert-butylphenoxy)-3-chloro-5-methoxy-4-pyridazinecarboxylate. (3) Eethyl 6-(2-tert-butylphenoxy)-3-chloro-5-hydroxy-4-pyridazinecarboxylate (Compound No. 2386, Step G-2) 419 mg (1.15 mmol) of ethyl 6-(2-tert-butylphenoxy)-3-chloro-5-methoxy-4-pyridazinecarboxylate obtained in (2), 1,4-dioxane, 1 mol/L aqueous sodium hydroxide solution (2.0 mL, 2.0 mmol) and dimethylsulfoxide (2.0 mL) were mixed, and the mixture was stirred at room temperature for 2 hours and 30 minutes, and at 80° C. for 4 hours and 30 minutes. After allowing to stand for cooling, the reaction mixture was made acidic with hydrochloric acid, and extracted with dichloromethane. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 337 mg (0.960 mmol, Yield: 83.5%) of ethyl 6-(2-tert-butylphenoxy)-3-chloro-5-hydroxy-4-pyridazinecarboxylate (Compound No. 2386). Appearance: amorphous. EXAMPLE 32 3,6-Bis(2-methylphenoxy)-4-pyridazinol (Compound No. 2395) (1) 3-chloro-5-methoxy-4,6-bis(2-methylphenoxy)pyridazine (Step D-1) In toluene (100 mL) was dissolved 5.32 g (49.3 mmol) of 2-methylphenol, and 1.13 g (49.1 mmol) of sodium, and then, 5.80 g (27.2 mmol) of 3,4,6-trichloro-5-methoxypyridazine were added to the solution and the resulting mixture was stirred for 4 hours under reflux. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) and recrystallized from isopropyl ether to obtain 3.0 g (8.4 mmol, Yield: 31%) of 3-chloro-5-methoxy-4,6-bis(2-methylphenoxy)pyridazine. (2) 6-Chloro-3,5-bis(2-methylphenoxy)-4-pyridazinol (Compound No. 2395, Step D-2) 0.72 g (2.0 mmol) of 3-chloro-5-methoxy-4,6-bis(2-methylphenoxy)pyridazine obtained in (1) was added to a mixture comprising 0.60 mL (4.7 mmol) of trimethylsilyl chloride, 0.60 g (4.0 mmol) of sodium iodide and acetonitrile (15ml), and the resulting mixture was stirred overnight. The reaction mixture was poured into ice-cold water, and extracted with methylene chloride. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (chloroform: methanol, gradient) to obtain 0.45 g (1.3 mmol, Yield: 65%) of 6-chloro-3,5-(2-methylphenoxy)-4-pyridazinol (Compound No. 2395). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.32-7.05 (7H, m), 6.91 (1H, br.d, J=7.3 Hz), 2.29 (3H, s), 2.19 (3H, s). Melting point (° C.): 110-115. EXAMPLE 33 3-(2-tert-Butylphenoxy)-6-chloro-5-(trimethylsilyl)-4-pyridazinol (Compound No. 2405) (1) 3-(2-tert-Butylphenoxy)-6-chloro-4-methoxy-5-(trimethylsilyl)pyridazine(Step G-1) In dry tetrahydrofuran (15 mL) was dissolved 498 mg (1.70 mmol) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxypyridazine obtained in Example 31 (1), the solution was cooled to −78° C., 1.10 mL (1.87 mmol) of a n-butyl lithium-hexane solution (1.70M) was added to the solution and the resulting mixture was stirred for 20 minutes. To the mixture was added 0.370 mL (2.91 mmol) of trimethylsilyl chloride, and the resulting mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography to obtain 596 mg (1.63 mmol, Yield: 95.9%) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxy-5-(trimethylsilyl)pyridazine. (2) 3-(2-tert-Butylphenoxy)-6-chloro-5-(trimethylsilyl)-4-pyridazinol (Compound No. 2405, Step G-2) 0.17 g (1.1 mmol) of sodium iodide, 0.14 mL (1.1 mmol) of trimethylsilyl chloride and acetonitrile (3.5 mL) were mixed, and to the mixture was added with stirring 340 mg (0.932 mmol) of 3-(2-tert-butylphenoxy)-6-chloro-4-methoxy-5-(trimethylsilyl)pyridazine obtained in (1), and the resulting mixture was stirred at room temperature for 1 hour and 35 minutes. The reaction mixture was poured into a saturated aqueous sodium sulfite solution, and ice-cold diluted hydrochloric acid was added to the mixture. The mixture was extracted with ethyl acetate, the organic layers were combined and washed with brine. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 275 mg (0.783 mmol, Yield: 84.0%) of 3-(2-tert-butylphenoxy)-6-chloro-5-(trimethylsilyl)-4-pyridazinol (Compound No. 2405). 1H-NMR (90 MHz, CDCl3) δ ppm: 10.12 (1H, brs), 7.39-6.75 (4H, m), 1.24 (9H, s), 0.31 (9H, s). Melting point (° C.): 160-163. EXAMPLE 34 6-Bromo-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2411) (1) 5-chloro-6-(2-methylphenoxy)-3-pyridazinol (Step P-1) A mixture comprising 578 mg (2.27 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2), acetic acid (10 mL) and 0.45 g (4.6 mmol) of potassium acetate was refluxed for 5 hours. The reaction mixture was allowed to stand for cooling, and after adding 50 mL of water, the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed to obtain 461 mg (1.95 mmol, Yield: 85.9%) of 5-chloro-6-(2-methylphenoxy)-3-pyridazinol. (2) 4,6-Dibromo-3-(2-methylphenoxy)pyridazine (Step P-2) 151 mg (0.637 mmol) of 5-chloro-6-(2-methylphenoxy)-3-pyridazinol obtained in (1), chloroform(3 mL) and 913 mg (3.18 mmol) of phosphorus oxybromide were mixed, and the mixture was refluxed for 5 hours. The reaction mixture was allowed to stand for cooling, water and dichloromethane were added to the mixture and the resulting mixture was stirred at room temperature for 1 hour. The mixture was extracted with dichloromethane. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography to obtain 176 mg (0.512 mmol, Yield: 80.4%) of 4,6-dibromo-3-(2-methylphenoxy)pyridazine. (3) 6-Bromo-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2411, Step P-3) In dimethylsulfoxide (3 mL) was dissolved 114 mg (0.331 mmol) of 4,6-dibromo-3-(2-methylphenoxy)pyridazine obtained in (2), 0.80 mL (1.6 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the resulting mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was washed with a mixed solvent of ethyl acetate-ether to obtain 56.0 mg (0.199 mmol, Yield: 60.1%) of 6-bromo-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2411). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35-7.05 (4H, m), 6.82 (1H, brs), 2.10 (3H, s). Melting point (° C.): 197-198. EXAMPLE 35 6-Cyclopropyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2423) (1) 6-Cyclopropyl-4-methoxy-3-(2-methylphenoxy)pyridazine (Step L-1) To a tetrahydrofuran solution (2.94 mL) containing of 9-borabicyclo[3.3.1]nonane (0.5 mol/l, 1.47 mmol) was added 87.5 mg (0.735 mmol) of propargyl bromide, and the resulting mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, 0.74 mL (2.2 mmol) of 3 mol/L aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at room temperature for 70 minutes. To the mixture were successively added 168 mg (0.669 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1) and 38.7 mg (0.00334 mmol) of tetrakis(triphenylphosphine)-palladium, and the resulting mixture was refluxed overnight. The reaction mixture was allowed to stand for cooling, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography to obtain 121 mg (0.473 mmol, Yield: 70.1%) of 6-cyclopropyl-4-methoxy-3-(2-methylphenoxy)pyridazine. (2) 6-Cyclopropyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2423, Step L-2) In dimethylsulfoxide (2 mL) was dissolved 45.6 mg (0.479 mmol) of 2-hydroxypyridine, 53.8 mg (0.480 mmol) of potassium tert-butoxide was added the solution at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 112 mg (0.438 mmol) of 6-cyclopropyl-4-methoxy-3-(2-methylphenoxy)-pyridazine obtained in (1), and the resulting mixture was stirred at 60° C. for 5 hours, and at 80° C. for 15 hours. Moreover, 45.6 mg (0.479 mmol) of 2-hydroxypyridine and then 53.8 mg (0.480 mmol) of potassium tert-butoxide were additionally added to the mixture, and the resulting mixture was stirred at 80° C. for 4 hours and 30 minutes. The reaction mixture was allowed to stand for cooling, water was added to the mixture, and and the resulting mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by ethyl acetate) to obtain 28.6 mg (0.118 mmol, Yield: 26.9%) of 6-cyclopropyl-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 2423). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.30-7.01 (4H, m), 6.19 (1H, s), 1.98-1.82 (1H, m), 1.23-1.12 (2H, m), 0.99-0.88 (2H, m). Melting point (° C.): 214-215. EXAMPLE 36 3-(2-Methylphenoxy)-6-vinyl-4-pyridazinol (Compound No. 2436) (1) 4-Methoxy-3-(2-methylphenoxy)-6-vinylpyridazine (Step L-1) In toluene (2 mL) was dissolved 123 mg (0.490 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 246 mg (0.776 mmol) of tributyl-(vinyl)tin, and then, 119 mg (0.103 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours. The reaction mixture was allowed to stand for cooling, ethyl acetate (5 mL), water (3 mL) and sodium fluoride were added to the mixture, and the resulting mixture was stirred for 30 minutes and allowed to stand at at room temperature overnight. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated and washed with brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=1:2) to obtain 105 mg (0.434 mmol, Yield: 88.6%) of 4-methoxy-3-(2-methylphenoxy)-6-vinylpyridazine. (2) 3-(2-Methylphenoxy)-6-vinyl-4-pyridazinol (Compound No. 2436, Step L-2) In dimethylsulfoxide (1 mL) was dissolved 33.7 mg (0.354 mmol) of 2-hydroxypyridine, 39.7 mg (0.354 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 85.8 mg (0.354 mmol) of 4-methoxy-3-(2-methylphenoxy)-6-vinylpyridazine obtained in (1), and the resulting mixture was stirred at room temperature overnight and at 50° C. for 4 hours and 30 minutes. The reaction mixture was allowed to stand for cooling, water was added thereto, and the resulting mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=1:4) to obtain 51.7 mg (0.227 mmol, Yield: 64.1%) of 3-(2-methylphenoxy)-6-vinyl-4-pyridazinol (Compound No. 2436). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35-7.03 (4H, m), 6.56-6.43 (2H, m), 6.16 (1H, d, J=17.9 Hz), 6.16 (1H, d, J=11.4 Hz), 2.11 (3H, s). Melting point (° C.): 195-197. EXAMPLE 37 3-(2-Methylphenoxy)-6-(1-propenyl)-4-pyridazinol (Compound No. 2442) (1) 6-Allyl-4-methoxy-3-(2-methylphenoxy)pyridazine (Step L-1) In toluene (4 mL) was dissolved 200 mg (0.797 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 305 mg (0.921 mmol) of allyl-(tributyl)tin, and then, 96.8 mg (0.0838 mmol) of tetrakis-(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, and then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, then the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 62.1 mg (0.243 mmol, Yield: 30.5%) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine. (2) 3-(2-Methylphenoxy)-6-(1-propenyl)-4-pyridazinol (Compound No. 2442, Step L-2) In dimethylsulfoxide (2 mL) was dissolved 25.3 mg (0.267 mmol) of 2-hydroxypyridine, 29.9 mg (0.267 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dimethylsulfoxide (3 mL) solution containing 62.1 mg (0.243 mmol) of 6-allyl-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in (1), and the resulting mixture was stirred at 100° C. for 8 hours and at 130° C. for 5 hours and 30 minutes. Moreover, 25.3 mg (0.267 mmol) of 2-hydroxypyridine, and then, 29.9 mg (0.267 mmol) of potassium tert-butoxide were additionally added to the mixture, and the resulting mixture was stirred at 130° C. for 5 hours. The reaction mixture was allowed to stand for cooling, and after adding water, the mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 21.3 mg (0.0880 mmol, Yield: 36.2%) of 3-(2-methylphenoxy)-6-(1-propenyl)-4-pyridazinol (Compound No. 2442). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.32-7.03 (4H, m), 6.75-6.60 (1H, m), 6.44 (1H, s), 6.22-6.10 (1H, m), 2.10 (3H s), 1.86 (3H, br.d, J=6.6 Hz). Melting point (° C.): 208-210. EXAMPLE 38 6-(2,6-Dimethylphenoxy)-5-hydroxy-3-pyridazinecarbonitrile (Compound No. 2453) (1) 6-Chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide (Step K-1) 3.42 g (12.9 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine, dichloromethane (110 mL) and 3.34 g (15.4 mmol) of 80% m-chloroperbenzoic acid were mixed, and the mixture was stirred at at room temperature for 16 days. The reaction mixture was poured into ice-cold saturated aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution , water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 2.06 g (7.33 mmol, Yield: 56.8%) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide. (2) 3-(2,6-Dimethylphenoxy)-4-methoxypyridazine 1-oxide (Step K-2) 6.00 g (21.4 mmol) of 6-chloro-3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide obtained in (1), methanol (200 mL), 3.0 mL of triethylamine, acetone (5 mL) and 0.5 g of 5% palladium carbon were mixed, and the mixture was shaked by using a Parr reducing device under a hydrogen pressure of 3.5 atm for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with chloroform. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized from an ether-dichloromethane mixed solvent to obtain 4.32 g (17.6 mmol, Yield: 82.2%) of 3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide. (3) 6-(2,6-Dimethylphenoxy)-5-methoxy-3-pyridazinecarbonitrile (Step M-1) In dry N,N-dimethylformamide (15 mL) was dissolved 0.720 g (2.92 mmol) of 3-(2,6-dimethylphenoxy)-4-methoxypyridazine 1-oxide obtained in (2), 1.10 mL (8.25 mmol) of trimethylsilylcyanide and 2.00 mL (14.4 mmol) of triethylamine were added to the solution, and the resulting mixture was stirred at 90° C. for 1 hour and 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 0.675 g (2.65 mmol, Yield: 90.8%) of 6-(2,6-dimethylphenoxy)-5-methoxy-3-pyridazinecarbonitrile. (4) 6-(2,6-Dimethylphenoxy)-5-hydroxy-3-pyridazinecarbonitrile (Compound No. 2453, Step M-2) In acetonitrile (5 mL) was dissolved 0.500 g (1.96 mmol) of 6-(2,6-dimethylphenoxy)-5-methoxy-3-pyridazinecarbonitrile obtained in (3), 0.300 mL (2.36 mmol) of trimethylsilyl chloride and 0.350 g (2.33 mmol) of sodium iodide were added to the solution, and the resulting mixture was stirred at room temperature. 5 mL of acetonitrile was additionally added and the resulting mixture was stirred for 1 hour, then, 3 mL of 1,4-dioxane was added thereto, and the resulting mixture was stirred overnight. The reaction mixture was poured into an aqueous sodium sulfite solution, and made acidic by adding 1 mol/L hydrochloric acid. The resulting mixture was extracted with dichloromethane, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography to obtain 0.121 g (0.502 mmol, Yield: 25.6%) of 6-(2,6-dimethylphenoxy)-5-hydroxy-3-pyridazinecarbonitrile (Compound No. 2453). 1H-NMR (90 MHz, CDCl3) δ ppm: 11.3 (1H, brs), 7.09-6.99 (4H, m), 1.90 (6H, s). Appearance: amorphous. EXAMPLE 39 1-[5-Hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]-ethanone (Compound No. 2455) (1) 6-(1-Ethoxyvinyl)-4-methoxy-3-(2-methylphenoxy)-pyridazine (Step L-1) In toluene (6.5 mL) was dissolved 321 mg (1.28 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), 534 mg (1.48 mmol) of (1-ethoxyvinyl)(tributyl)tin, then 155.3 mg (0.134 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the solution at room temperature, and the resulting mixture was refluxed for 3 hours and 20 minutes. The reaction mixture was allowed to stand at room temperature overnight, then, ethyl acetate, water and sodium fluoride were added to the mixture and the resulting mixture was stirred for 2 hours. The mixture was filtered through Celite, ethyl acetate was added to the filtrate, and the organic layer was separated, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 51.8 mg (0.181 mmol, Yield: 14.1%) of 6-(1-ethoxyvinyl)-4-methoxy-3-(2-methylphenoxy)pyridazine. (2) 1-[5-Hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]ethanone (Compound No. 2455, Step L-2) In dimethylsulfoxide (2 mL) was dissolved 18.4 mg (0.194 mmol) of 2-hydroxypyridine, 21.7 mg (0.194 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dimethylsulfoxide (3 mL) solution containing 50.4 mg (0.176 mmol) of 6-(1-ethoxyvinyl)-4-methoxy-3-(2-methylphenoxy)-pyridazine obtained in (1), and the resulting mixture was stirred at 100° C. for 8 hours and at 130° C. for 5 hours and 30 minutes. Moreover, 18.4 mg (0.194 mmol) of 2-hydroxypyridine, then 21.7 mg (0.194 mmol) of potassium tert-butoxide were additionally added to the mixture, and the resulting mixture was stirred at 130° C. for 2 hours. The reaction mixture was allowed to stand for cooling, and after adding water, and the mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 28.5 mg (0.117 mmol, Yield: 66.5%) of 1-[5-hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]ethanone (Compound No. 2455). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.48-7.05 (5H, m), 2.58 (3H, s), 2.10 (3H, s). Melting point (° C.): 182-185. EXAMPLE 40 3-(2-Methylphenoxy)-6-phenyl-4-pyridazinol (Compound No. 2464) (1) 4-Methoxy-3-(2-methylphenoxy)-6-phenylpyridazine (Step L-1) 210 mg (0.837 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), toluene (4 mL) and water (0.5 mL) were mixed, 161 mg (1.32 mmol) of phenylboronic acid, 365 mg (2.64 mmol) of potassium carbonate and 102 mg (0.0879 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the mixture at room temperature, and the resulting mixture was refluxed for 2 hours and 50 minutes. The reaction mixture was allowed to stand at room temperature overnight, the mixture was filtered through Celite, and ethyl acetate and water were added to the filtrate. The organic layer was separated, washed with brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=3:1) to obtain 146 mg (0.500 mmol, Yield: 59.7%) of 4-methoxy-3-(2-methylphenoxy)-6-phenylpyridazine. (2) 3-(2-Methylphenoxy)-6-phenyl-4-pyridazinol (Compound No. 2464, Step L-2) In dimethylsulfoxide (1.5 mL) was dissolved 91.9 mg (0.966 mmol) of 2-hydroxypyridine, 95.4 mg (0.850 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 82.8 mg (0.283 mmol) of 4-methoxy-3-(2-methylphenoxy)-6-phenylpyridazine obtained in (1), and the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was allowed to stand for cooling, and after adding water, the mixture was washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 3 plates were used, developed by ethyl acetate) to obtain 70.8 mg (0.255 mmol, Yield: 90.1%) of 3-(2-methylphenoxy)-6-phenyl-4-pyridazinol (Compound No. 2464). 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.78-7.66 (2H, m), 7.58-7.48 (3H, m), 7.35-7.08 (4H, m), 6.69 (1H, s), 2.15 (3H s). Melting point (° C.): 236-237. EXAMPLE 41 3,6-Bis(2-fluorophenoxy)-4-pyridazinol (Compound No. 2485) (1) 3,6-Bis(2-fluorophenoxy)pyridazine In dimethylsulfoxide (20 mL) was dissolved 2.69 g (24.0 mmol) of 2-fluorophenol, and 2.69 g (24.0 mmol) of potassium tert-butoxide was added to the solution at room temperature. To the mixture was added 1.49 g (10.0 mmol) of 2,6-dichloropyridazine, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was allowed to stand for cooling, pouted into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L aqueous sodium hydroxide solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, the obtained residue was washed with a hot hexane, and then with a hot isopropyl ether to obtain 1.71 g (5.70 mmol, Yield: 57.0%) of 3,6-bis(2-fluorophenoxy)pyridazine. (2) 3,6-Bis(2-fluorophenoxy)pyridazine 1-oxide (Step C-1) In dry dichloromethane (40 mL) was dissolved 4.14 g (13.8 mmol) of 3,6-bis(2-fluorophenoxy)pyridazine obtained in (1), 3.19 g (14.8 mmol) of 80% m-chloroperbenzoic acid was added to the solution, and the resulting mixture was stirred at room temperature for 7 days. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=3:1) to obtain 2.24 g (7.09 mmol, Yield: 51.4%) of 3,6-bis(2-fluorophenoxy)pyridazine 1-oxide. (3) 4-Chloro-3,6-bis(2-fluorophenoxy)pyridazine (Step C-2) 2.20 g (6.96 mmol) of 3,6-bis(2-fluorophenoxy)pyridazine 1-oxide obtained in (2) and 50 mL of phosphorus oxychloride were mixed, and the mixture was stirred at 90° C. for 1 hour. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L aqueous sodium hydroxide solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.95 g (5.82 mmol, Yield: 83.6%) of 4-chloro-3,6-bis(2-fluorophenoxy)pyridazine. (4) 3,6-Bis(2-fluorophenoxy)-4-methoxypyridazine (Step C-3) In methanol (20 mL) was dissolved 1.44 g (4.30 mmol) of 4-chloro-3,6-bis(2-fluorophenoxy)pyridazine obtained in (3), 0.206 g (4.72 mmol) of 55% sodium hydride was added to the solution, and the resulting mixture was stirred at 60° C. for 1 hour. The reaction mixture was allowed to stand for cooling, poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=10:1) to obtain 1.03 g (3.12 mmol, Yield: 72.6%) of 3,6-bis(2-fluorophenoxy)-4-methoxypyridazine. (5) 3,6-Bis(2-fluorophenoxy)-4-pyridazinol (Compound No. 2485, Step C-4) 450 mg (1.36 mmol) of 3,6-bis(2-fluorophenoxy)-4-methoxypyridazine obtained in (4), 77 mg (1.85 mmol) of 96% sodium hydroxide, dimethylsulfoxide (5 mL) and water (1 mL) were mixed, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was poured into ice-cold water, and made acidic with hydrochloric acid. The mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 0.380 g (1.20 mmol, Yield: 88.2%) of 3,6-bis(2-fluorophenoxy)-4-pyridazinol (Compound No. 2485). 1H-NMR. (60 MHz, DMSO-d6) δ ppm: 7.60-7.08 (8H, m), 6.34 (1H, brs). Melting point (° C.): 228. EXAMPLE 42 (2,4-Dichlorophenyl)(5-{[5-hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)methanone (Compound No. 2506) (1) (5-{[5-Chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)(2,4-dichlorophenyl)meth 109 mg (0.382 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 1.62 g (6.35 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2) and 107 mg (0.775 mmol) of potassium carbonate were mixed, and the mixture was stirred at 130° C. for 14 hours. The reaction mixture was cooled up to room temperature, and purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 155 mg (0.308 mmol, Yield: 80.6%) of (5-{[5-chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)(2,4-dichlorophenyl)methanone. (2) (2,4-Dichlorophenyl)(5-{[5-hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)met (Compound No. 2506, A-3 Step) 12.3 mg (0.0244 mmol) of (5-{[5-chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)(2,4-dichlorophenyl)methanone obtained in (1), 0.2 mL of dimethylsulfoxide and 0.012 mL of 10% (W/V) aqueous sodium hydroxide solution were mixed, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-cold water, made acidic by hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by dichloromethane:methanol=10:1) to obtain 3.2 mg (0.00784 mmol, Yield: 32%) of (2,4-dichlorophenyl)(5-{[5-hydroxy-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)methanone (Compound No. 2506) and 10.5 mg (0.0208 mmol, Yield: 85.4%) of 4-[{[5-chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-(2,4-dichlorophenyl)methylene]-2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one. 1H-NMR (200 MHz, CDCl3) δ ppm: 7.36-7.04 (7H, m), 6.20 (1H, brs), 3.64 (3H, s), 2.31 (3H, s), 2.20 (3H, s). Appearance: amorphous. Also, the following compounds were produced in accordance with the above-mentioned Examples 1 to 42 or by the methods or in accordance with the methods described in the following Examples 622 to 646. EXAMPLE 43 3-Phenoxy-4-pyridazinol (Compound No. 1) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 12.66 (1H, brs), 8.21 (1H, d, J=6.6 Hz), 7.09-7.54 (5H, m), 6.38 (1H, d, J=6.6 Hz). Melting point (° C.): 193.5. EXAMPLE 44 6-Chloro-3-{2-[1-(methoxymethyl)cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 163) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.47-7.35 (1H, m), 7.32-7.02 (3H, m), 6.71 (1H, s), 3.47 (2H, s), 3.21 (3H, s), 0.80-0.70 (4H, m). Melting point (° C.): 187-190. EXAMPLE 45 3-(2-Isopropylphenoxy)-4-pyridazinol (Compound No. 6) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 12.65 (1H, brs), 8.29 (2H, d, J=6.6 Hz), 7.49-6.98 (4H, m), 6.36 (1H, d, J=6.6 Hz), 3.20-2.89 (1H, m, J=6.6 Hz), 1.16 (6H, d, J=6.6 Hz). Melting point (° C.): 181.5-182. EXAMPLE 46 6-Chloro-3-[2-(1-methoxycyclopropyl)phenoxy]-4-pyridazinol (Compound No. 202) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.50-7.10 (4H, m), 6.67 (1H, s), 3.03 (3H, s), 1.00-0.85 (4H, m). Melting point (° C.): 157-165. EXAMPLE 47 2-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-cyclopropanecarbonitrile (Compound No. 226) Trans isomer: 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.10 (4H, m), 6.75 (1H, s), 2.65-2.50 (1H, m), 1.65-1.45 (3H, m). Melting point (° C.): 203-207. Cis isomer: 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.15 (4H, m), 6.64 (1H, s), 2.59 (1H, q, J=8.4 Hz), 2.05-1.90 (1H, m), 1.67-1.40 (2H, m). Melting point (° C.): 225-227. EXAMPLE 48 6-Chloro-3-phenoxy-4-pyridazinol (Compound No. 123) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.60-7.00 (5H, m), 6.87 (1H, s). Melting point (° C.): 222-224. EXAMPLE 49 6-Chloro-3-(2-fluorophenoxy)-4-pyridazinol (Compound No. 124) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.50-7.05 (4H, m), 6.70 (1H, s). Melting point (° C.): 210-212. EXAMPLE 50 6-Chloro-3-(2-chlorophenoxy)-4-pyridazinol (Compound No. 125) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.70-7.10 (4H, m), 6.95 (1H, s). Melting point (° C.): 208-212. EXAMPLE 51 3-(2-Bromophenoxy)-6-chloro-4-pyridazinol (Compound No. 126) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.68 (1H, dd, J=7.5, 1.8 Hz), 7.53-7.10 (3H, m), 6.73 (1H, s). Melting point (° C.): 201-203. EXAMPLE 52 6-Chloro-3-(2-iodophenoxy)-4-pyridazinol (Compound No. 127) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.89 (1H, dd, J=7.7, 1.5 Hz) 7.45 (1H, td, J=7.7, 1.5 Hz), 7.22 (1H, dd, J=7.7, 1.5 Hz), 7.04 (1H, td, J=7.7, 1.5 Hz), 6.74 (1H, s). Melting point (° C.): 216-217. EXAMPLE 53 6-Chloro-3-[2-(2-ethoxycyclopropyl)phenoxy]-4-pyridazinol (Compound No. 249) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.26-7.05 (4H, m), 6.68 (1H, s), 3.46 (1H, q, J=5.2 Hz), 3.30-3.15 (2H, m), 2.17-1.96 (1H, m), 1.10 (2H, dd, J=5.2 Hz, 8.5 Hz), 0.93 (3H, t, J=7.0 Hz). Melting point (° C.): 145-152. EXAMPLE 54 6-Chloro-3-[2-(2,2-difluorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 264) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.15 (4H, m), 6.72 (1H, s), 2.85-2.65 (1H, m), 1.90-1.65 (2H, s). Melting point (° C.): 215-216. EXAMPLE 55 6-Chloro-3-(2-ethylphenoxy)-4-pyridazinol (Compound No. 130) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.35-7.15 (3H, m), 7.10-7.02 (1H, m), 6.70 (1H, s), 2.56 (2H, q, J=7.7 Hz), 1.17 (3H, t, J=7.7 Hz). Melting point (° C.): 217-218. EXAMPLE 56 6-Chloro-3-(2-propylphenoxy)-4-pyridazinol (Compound No. 131) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.45-7.05 (4H, m), 6.90 (1H, s), 3.00-2.35 (2H, m), 1.95-1.26 (2H, m), 1.05-0.68 (3H, m). Melting point (° C.): 170-172. EXAMPLE 57 6-Chloro-3-(2-isopropylphenoxy)-4-pyridazinol (Compound No. 132) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.60-7.00 (4H, m), 6.92 (1H, s), 3.11 (1H, septet, J=7.0 Hz), 1.18 (6H, d, J=7.0 Hz). Melting point (° C.): 183. EXAMPLE 58 3-(2-Butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 133) 1H-NMR (60 MHz, CDCl3) δ ppm: 11.8 (1H, brs), 7.30-6.70 (4H, m), 6.53 (1H, s), 2.60-2.00 (2H, m), 1.80-0.60 (7H, m). Melting point (° C.): 149.5-150. EXAMPLE 59 6-Chloro-3-(2-isobutylphenoxy)-4-pyridazinol (Compound No. 134) 1H-NMR (60 MHz, CDCl3) δ ppm: 12.90 (1H, brs), 7.40-6.85 (4H, m), 6.50 (1H, s), 2.25 (2H, d, J=10.0 Hz), 2.20-1.45 (1H, m, J=10.0 Hz), 0.75 (6H, d, J=10.0 Hz). Melting point (° C.): 151.5-152.5. EXAMPLE 60 3-(2-s-Butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 135) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 7.35-6.80 (4H, m), 6.60 (1H, s), 3.05-2.50 (1H, m), 1.80-1.25 (2H, m), 1.13 (3H, d, J=6.2 Hz), 0.95-0.50 (3H, m). Melting point (° C.): 158-159. EXAMPLE 61 3-(2-tert-Butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 136) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.55-6.85 (4H, m), 6.91 (1H, s), 5.32 (1H, brs), 1.35 (9H, s). Melting point (° C.): 215-216. EXAMPLE 62 6-Chloro-3-(2-pentylphenoxy)-4-pyridazinol (Compound No. 137) 1H-NMR (60 MHz, CDCl3) δ ppm: 11.70 (1H, brs), 7.40-6.80 (4H, m), 6.50 (1H, s), 2.60-2.20 (2H, m), 1.80-0.60 (9H, m). Melting point (° C.): 151.5-152.5. EXAMPLE 63 6-Chloro-3-(2-hexylphenoxy)-4-pyridazinol (Compound No. 138) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.40-6.70 (4H, m), 6.53 (1H, s), 2.70-2.20 (2H, m), 2.00-0.60 (11H, m). Melting point (° C.): 118-118.5. EXAMPLE 64 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 265) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55-7.15 (4H, m), 6.69 (1H, s), 2.90 (1H, dd, J=11.0, 10.8 Hz), 2.05-1.85 (2H, m). Melting point (° C.): 158-163. EXAMPLE 65 6-Chloro-3-[2-(2,2-dibromocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 266) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.41-7.36 (1H, m), 7.29-7.13 (3H, m), 6.71 (1H, s), 2.97-2.87 (1H, dd, J=11.0, 8.4 Hz), 2.21-2.01 (2H, m). Melting point (° C.): 208-210 (decomposed). EXAMPLE 66 6-Chloro-3-[2-(1-methylcyclopropyl)phenoxy]-4-pyridazinol (Compound No. 144) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.40-7.35 (1H, m), 7.22-7.17 (2H, m), 6.99-6.94 (1H, m), 6.59 (1H, s), 1.25 (3H, s), 0.85-0.60 (2H, m), 0.60-0.45 (2H, m). Melting point (° C.): 196-198. EXAMPLE 67 6-Chloro-3-[2-(1-ethylcyclopropyl)phenoxy]-4-pyridazinol (Compound No. 145) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.35-7.10 (3H, m), 6.98 (1H, br.d, J=7.3 Hz), 6.59 (1H, s), 1.50 (2H, q, J=7.0 Hz), 1.26 (3H, t, J=7.0 Hz), 0.67-0.50 (4H, m). Melting point (° C.): 162-165. EXAMPLE 68 6-Chloro-3-{2-[1-(cyclopropyl)cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 151) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.35-7.29 (1H, m), 7.26-7.10 (2H m), 7.00-6.92 (1H, m), 6.58 (1H, s), 1.30-1.15 (1H, m), 0.60-0.40 (4H, m), 0.27-0.15 (2H, m), 0.07-0.00 (2H, m). Melting point (° C.): 180-182. EXAMPLE 69 1-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-cyclopropanecarbonitrile (Compound No. 173) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.55-7.15 (5H, m), 1.65-1.20 (4H, m). Melting point (° C.): 63-64. EXAMPLE 70 6-Chloro-3-[2-(1-phenylcyclopropyl)phenoxy]-4-pyridazinol (Compound No. 184) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65-7.55 (1H, m), 7.28-7.20 (2H, m), 7.17-6.95 (6H, m), 6.41 (1H, s), 1.19 (4H, s). Melting point (° C.): 172-173. EXAMPLE 71 6-Chloro-3-(2-isopropenylphenoxy)-4-pyridazinol (Compound No. 304) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.36-7.10 (4H, m), 6.66 (1H, s), 5.06 (1H, br.s), 5.02 (1H, br.s), 2.01 (3H, d, J=1.5 Hz). Melting point (° C.): 187-188. EXAMPLE 72 6-Chloro-3-[2-(2-methylcyclopropyl)phenoxy]-4-pyridazinol (Compound No. 217) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.32-6.97 (4H, m), 6.82 (1H, brs), 1.89-1.78 (0.8H, m), 1.52-1.43 (0.2H, m), 1.05-0.60 (6H, m). Melting point (° C.): 192-208. EXAMPLE 73 6-Chloro-3-[2-(2-ethoxycyclopropyl)phenoxy]-4-pyridazinol (Compound No. 249) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.30-7.05 (4H, m), 6.68 (1H, s), 3.51-3.15 (3H, m), 2.07-1.95 (1H, m), 1.13-1.06 (2H, m), 0.93 (3H, t, J=7.1 Hz). Melting point (° C.): 145-152. EXAMPLE 74 (2E)-3-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-phenyl}acrylonitrile (Compound No. 306) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.80-7.40 (3H, m), 7.35-7.15 (2H, m), 6.72 (1H, s), 6.30 (1H, d, J=6.9 Hz). Melting point (° C.): 190-192. EXAMPLE 75 6-Chloro-3-[2-(2,2-dimethylcyclopropyl)phenoxy]-4-pyridazinol (Compound No. 267) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.30-7.10 (4H, m), 1.57 (1H, dd, J=8.4, 6.2 Hz), 0.91-0.85 (1H, m), 0.85 (3H, s), 0.72-0.65 (1H, m), 0.65 (3H, s). Melting point (° C.): 187-188. EXAMPLE 76 6-Chloro-3-{2-[(cis-2, cis-3-dimethyl)-ref-1-cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 269) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.36-7.11 (4H, m), 6.68 (1H, s), 1.60 (1H, t, J=8.4 Hz), 1.09-0.93 (8H, m). Appearance: amorphous. EXAMPLE 77 6-Chloro-3-{2-[(cis-2, trans-3-dimethyl)-ref-1-cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 270) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.30-7.09 (4H, m), 6.80 (1H, brs), 1.56-1.50 (1H, m), 1.10-0.95 (1H, m), 1.03 (3H, s), 0.80-0.67 (1H, m), 0.71 (3H,s). Melting point (° C.): 157-160. EXAMPLE 78 6-Chloro-3-{2-[(trans-2, trans-3-dimethyl)-ref-1-cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 271) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.22-6.96 (4H, m), 6.70 (1H, s), 1.18-0.95 (9H, m) Melting point (° C.): 181-183. EXAMPLE 79 3-{2-[(ref-1,cis-5,cis-6)-Bicyclo[3.1.0]hex-6-yl]phenoxy}-6-chloro-4-pyridazinol (Compound No. 272) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.05 (4H, m), 6.68 (1H, s), 2.05-1.60 (5H, m), 1.53 (2H, s), 1.35-1.20 (1H, m), 0.25-0.05 (1H, m). Melting point (° C.): 215-240. EXAMPLE 80 3-{2-[(ref-1,cis-5,trans-6)-Bicyclo[3.1.0]hex-6-yl]phenoxy}-6-chloro-4-pyridazinol (Compound No. 273) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.20-7.10 (2H, m), 7.10-6.90 (2H, m), 6.58 (1H, s), 1.80-1.40 (8H, m), 1.20-1.00 (1H, m). Melting point (° C.): 137-139. EXAMPLE 81 3-{2-[(ref-1,cis-6,cis-7)-Bicyclo[4.1.0]hept-7-yl]phenoxy}-6-chloro-4-pyridazinol (Compound No. 274) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.44 (1H, br.d, J=6.3 Hz), 7.35-7.10 (3H, m), 6.66 (1H, s), 2.00-1.50 (5H, m), 1.20-1.00 (4H, m), 0.90-0.65 (2H, m). Melting point (° C.): >260. EXAMPLE 82 3-{2-[(ref-1,cis-6,trans-7)-Bicyclo[4.1.0]hept-7-yl]phenoxy}-6-chloro-4-pyridazinol (Compound No. 275) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.20-7.10 (2H, m), 7.05-6.85 (2H, m), 6.58 (1H, s), 1.90-1.70 (2H, m), 1.60-1.40 (3H, m), 1.30-1.05 (6H, m). Melting point (° C.): 191-193. EXAMPLE 83 6-Chloro-3-{2-[(2,2, cis-3-trimethyl)-ref-1-cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 279) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.30-7.00 (4H, m), 6.56 (1H, s), 1.42-1.22 (2H, m), 1.05-0.70 (9H, m). Melting point (° C.): 118-120. EXAMPLE 84 6-Chloro-3-{2-[(2,2, trans-3-trimethyl)-ref-1-cyclopropyl]phenoxy}-4-pyridazinol (Compound No. 280) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.26-7.06 (4H, m), 6.59 (1H, s), 1.70-1.50 (1H, m), 1.30-1.25 (1H, m), 1.09 (3H, s), 0.96 (3H, s), 0.75 (3H, s). Melting point .(C): 160-162. EXAMPLE 85 6-Chloro-3-(2-cyclobutylphenoxy)-4-pyridazinol (Compound No. 284) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.43-7.30 (1H, m), 7.30-7.18 (2H, m), 7.08-6.98 (1H, m), 6.69 (1H, s), 3.68-3.50 (1H, m), 2.25-1.70 (6H, m). Melting point (° C.): 188-189. EXAMPLE 86 1-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-cyclobutanecarbonitrile (Compound No. 287) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.50-7.20 (5H, m), 2.70-1.80 (6H, m) Melting point (° C.): 213-215. EXAMPLE 87 1-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-cyclobutanecarboxylicacid (Compound No. 288) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.42-7.35 (1H, m), 7.35-7.20 (2H, m), 7.08-7.03 (1H, m), 6.66 (1H, s), 2.80-2.45 (4H, m), 2.22-1.95 (1H, m), 1.90-1.70 (1H, m). Melting point (° C.): 173-175. EXAMPLE 88 6-Chloro-3-(2-cyclopentylphenoxy)-4-pyridazinol (Compound No. 292) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.41-7.35 (1H, m), 7.25-7.17 (2H, m), 7.08-7.02 (1H, m), 6.70 (1H, s), 3.14-3.06 (1H, m), 1.98-1.52 (8H, m). Melting point (° C.): 178-180. EXAMPLE 89 6-Chloro-3-(2-cyclohexylphenoxy)-4-pyridazinol (Compound No. 293) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 7.40-6.70 (4H, m), 6.55 (1H s), 2.75 (1H, brs), 2.10-0.90 (10H, m). Melting point (° C.): 158-159. EXAMPLE 90 6-Chloro-3-[2-(trifluoromethyl)phenoxy]-4-pyridazinol (Compound No. 300) 1H-NMR (90 MHz, CD30D) δ ppm: 7.76-7.27 (4H, m), 6.75 (1H, s), 5.47 (1H, s). Melting point (° C.): 188. EXAMPLE 91 6-Chloro-3-[2-(1-propenyl)phenoxy}-4-pyridazinol (Compound No. 305) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.70-6.90 (5H, m), 6.76 (1H, s), 6.50-6.20 (2H, m), 1.81 (3H, d, J=5.0 Hz). Melting point (° C.): 204-206. EXAMPLE 92 3-(2-Allylphenoxy)-6-chloro-4-pyridazinol. (Compound No. 307) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.46-7.24 (4H, m), 6.96 (1H s), 6.20-5.60 (1H, m), 5.20-4.80 (2H, m), 3.46-3.26 (2H, m). Melting point (° C.): 200-202.5. EXAMPLE 93 6-Chloro-3-[2-(1-propynyl)phenoxy]-4-pyridazinol (Compound No. 309) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.43-7.32 (2H, m), 7.23-7.16 (2H, m), 6.73 (1H, s), 1.87 (3H, s). Melting point (° C.): 182-184. EXAMPLE 94 6-Chloro-3-[2-(cyclopropylmethyl)phenoxy]-4-pyridazinol (Compound No. 311) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.45 (1H, dd, J=7.3, 1.8 Hz), 7.31-7.17 (2H, m), 7.10 (1H, dd, J=7.3, 1.8 Hz), 2.38 (2H, d, J=7.0 Hz), 1.00-0.88 (1H, m), 0.50-0.40 (2H, m), 0.22-0.11 (2H, m) Melting point (° C.): 165-168. EXAMPLE 95 3-(2-Benzylphenoxy)-6-chloro-4-pyridazinol (Compound No. 315) Melting point (° C.): 185-187. EXAMPLE 96 6-Chloro-3-[2-(methoxymethyl)phenoxy]-4-pyridazinol (Compound No. 324) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.47 (1H, br.d, J=7.7 Hz), 7.42-7.20 (2H, m), 7.15 (1H, br.d, J=7.7 Hz), 6.83 (1H, brs), 4.35 (2H, s), 3.23 (3H, s) Melting point (° C.): 211-212. EXAMPLE 97 6-Chloro-3-[2-(ethoxymethyl)phenoxy]-4-pyridazinol (Compound No. 325) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.47 (1H, br.d, J=7.7 Hz), 7.42-7.20 (2H, m), 7.16 (1H, br.d, J=7.7 Hz), 6.82 (1H, brs), 4.38 (2H, s), 3.39 (2H, q, J=7.0 Hz), 1.03 (3H, t, J=7.0 Hz). Melting point (° C.): 173-174. EXAMPLE 98 6-Chloro-3-[2-(1,3-dioxolan-2-yl)phenoxy]-4-pyridazinol (Compound No. 329) Melting point (° C.): 143-145. EXAMPLE 99 1-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-ethanone O-methyloxime (Compound No. 334) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.47 (2H, t, J=7.7 Hz), 7.31 (1H, d, J=7.7 Hz), 7.24 (1H, d, J=7.7 Hz), 6.85 (1H, brs), 3.76 (2.8H, s), 3.58 (0.2H, s), 2.02 (2.8H, s), 1.99 (0.2H, Melting point (° C.): 165-167. EXAMPLE 100 Methyl 2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-benzoate (Compound No. 339) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 8.10-7.18 (4H, m), 6.80 (1H, s), 5.75 (1H, brs), 3.70 (3H, s). Melting point (° C.): 188-191. EXAMPLE 101 3-([1,1′-Biphenyl]-2-yloxy)-6-chloro-4-pyridazinol (Compound No. 344) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.30-6.70 (10H, m), 6.25 (1H, s). Melting point (° C.): 98-100. EXAMPLE 102 6-Chloro-3-{[3′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy}-4-pyridazinol (Compound No. 348) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65-7.58 (2H, m), 7.51-7.26 (5H, m), 7.12-7.06 (1H, m), 6.41 (1H, brs). Appearance: paste state. EXAMPLE 103 6-Chloro-3-{[3′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]oxy}-4-pyridazinol (Compound No. 349) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.71-7.64 (2H, m), 7.55-7.30 (5H, m), 7.20-7.13 (1H, m), 6.43 (1H, s). Appearance: paste state. EXAMPLE 104 6-Chloro-3-[2-(1-pyrrolidinyl)phenoxy]-4-pyridazinol (Compound No. 355) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.19-6.73 (4H, m), 5.64 (1H, s), 3.32-3.25 (4H, m), 1.91-1.84 (4H, m). Appearance: amorphous. EXAMPLE 105 6-Chloro-3-[2-(1H-pyrrol-1-yl)phenoxy]-4-pyridazinol (Compound No. 356) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.41-7.27 (4H, m), 6.95-6.93 (2H, m), 6.46 (1H, m), 6.10-6.08 (2H, m). Appearance: amorphous. EXAMPLE 106 6-Chloro-3-[2-(2-thienyl)phenoxy]-4-pyridazinol (Compound No. 359) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.68-7.60 (1H, m), 7.45-7.05 (5H, m), 7.01-6.95 (1H, m), 6.52 (1H, s). Appearance: amorphous. EXAMPLE 107 6-Chloro-3-[2-(3-thienyl)phenoxy]-4-pyridazinol (Compound No. 361) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.46-7.37 (3H, m), 7.30-7.15 (4H, m). Melting point (° C.): 207-209. EXAMPLE 108 6-Chloro-3-[2-(1H-pyrazol-1-yl)phenoxy]-4-pyridazinol (Compound No. 362) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.09 (1H, d, J=2.2 Hz), 7.70 (1H, dd, J=7.5, 2.4 Hz), 7.62 (1H, d, J=2.2 Hz), 7.50-7.27 (3H, m), 6.55 (1H, s), 6.39 (1H, t, J=2.2 Hz). Appareance: amorphous. EXAMPLE 108 6-Chloro-3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)phenoxy]-4-pyridazinol (Compound No. 364) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.60-7.32 (4H, m), 6.52 (1H, s), 5.86 (1H, s), 2.17 (3H, s), 2.10 (3H, s). Appareance: amorphous. EXAMPLE 109 6-Chloro-3-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}-4-pyridazinol (Compound No. 365) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.79 (1H, brs), 7.70-7.35 (5H, m), 7.06 (1H, brs), 6.68 (1H, s). Appareance: amorphous. EXAMPLE 111 6-Chloro-3-{2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}-4-pyridazinol (Compound No. 366) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 8.75 (1H, s), 8.11 (1H, s), 7.80-7.74 (1H, m), 7.58-7.38 (3H, m), 6.77 (1H, s). Appareance: oily product. EXAMPLE 112 6-Chloro-3-{2-[5-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}-4-pyridazinol (Compound No. 367) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 8.30 (1H, brs), 7.83-7.72 (1H, m), 7.60-7.40 (3H, m), 6.91 (1H, br.d, J=2.6 Hz), 6.78 (1H, s). Appearance: amorphous. EXAMPLE 113 5-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-N,N-dimethyl-1H-pyrazole-1-sulfonamide(Compound No. 369) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.87 (1H, d, J=2.6 Hz), 7.78 (1H, dd, J=7.3, 1.8 Hz), 7.65-7.35 (3H, m), 7.20 (1H, s), 7.03 (1H, d, J=2.6 Hz), 2.86 (6H, s). Melting point (° C.): 151-152. EXAMPLE 114 3-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-N,N-dimethyl-1H-pyrazole-1-sulfonamide(Compound No. 368) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.19 (1H, d, J=2.9 Hz), 8.12 (1H, s), 7.97 (1H, dd, J=7.3, 2.2 Hz), 7.61 (1H, d, J=1.5 Hz), 7.50-7.33 (2H, m), 6.98 (1H, d, J=2.9 Hz), 2.83 (6H, s). Melting point (° C.): 210-212. EXAMPLE 115 6-Chloro-3-[2-(4-methyl-1,3-thiazol-2-yl)phenoxy]-4-pyridazinol (Compound No. 370) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.17 (1H, d, J=7.7 Hz), 7.73 (1H, d, J=7.7 Hz), 7.47 (1H, t, J=7.7 Hz), 7.28 (1H, t, J=7.7 Hz), 7.02 (1H, s), 6.98 (1H, s), 2.56 (3H, s). Appearance: amorphous. EXAMPLE 116 3-[2-(1,3-Benzoxazol-2-yl)phenoxy]-6-chloro-4-pyridazinol (Compound No. 375) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.31 (1H, dd, J=7.9, 1.6 Hz), 7.73-7.30 (7H, m), 6.78 (1H, s). Melting point (° C.): 165-167. EXAMPLE 117 35 3-[2-(1,3-Benzothiazol-2-yl)phenoxy]-6-chloro-4-pyridazinol (Compound No. 376) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.12 (1H, d, J=7.7 Hz), 8.00-7.84 (1H, m), 7.78 (1H, d, J=7.7 Hz), 7.62-7.05 (1H, brs). Melting point (° C.): 215-217. EXAMPLE 118 6-Chloro-3-[2-(dimethylamino)phenoxy]-4-pyridazinol (Compound No. 379) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.17-6.96 (4H, m), 6.61 (1H, s), 2.75 (6H, s). Appareance: amorphous. EXAMPLE 119 6-Chloro-3-(2-nitrophenoxy)-4-pyridazinol (Compound No. 383) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.16 (1H, d, J=6.0 Hz), 7.90-7.33 (3H, m), 6.78 (1H, s). Melting point (° C.): 99-100. EXAMPLE 120 6-Chloro-3-(2-ethynylphenoxy)-4-pyridazinol (Compound No. 308) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.57-7.41 (2H, m), 7.30-7.20 (2H, m), 6.71 (1H, s), 3.60 (1H,s). Melting point (° C.): 189-191. EXAMPLE 121 6-Chloro-3-(2-methoxyphenoxy)-4-pyridazinol (Compound No. 385) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 7.30-6.80 (4H, m), 6.55 (1H, s), 3.69 (3H, s) Melting point (° C.): 191-194. EXAMPLE 122 6-Chloro-3-(2-ethoxyphenoxy)-4-pyridazinol (Compound No. 386) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.26-7.02 (2H, m), 6.98-6.85 (2H, m), 6.57 (1H, s), 5.35 (1H, brs), 3.92 (2H, q, J=7.0 Hz), 1.18 (t, 3H, J=7.0 Hz). Melting point (° C.): 155-175. EXAMPLE 123 6-Chloro-3-(2-isopropoxyphenoxy)-4-pyridazinol (Compound No. 387) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.28-7.10 (3H, m), 6.97 (1H, td, J=7.3, 2.3 Hz), 6.83 (1H, brs), 4.52 (1H, septet, J=6.2 Hz), 1.07 (6H, d, J=6.2 Hz). Melting point (° C.): 178-1.79. EXAMPLE 124 6-Chloro-3-[2-(difluoromethoxy)phenoxy]-4-pyridazinol (Compound No. 390) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.40 (4H, s), 6.63 (1H, s) 6.53 (1H, t, J=73.8 Hz). Melting point (° C.): 210-212. EXAMPLE 125 6-Chloro-3-[2-(trifluoromethoxy)phenoxy]-4-pyridazinol (Compound No. 391) 1H-NMR (200 MHz, CDCl3+CD3OD) δ ppm: 7.38-7.20 (4H, m), 6.60 (1H, s). Melting point (° C.): 215. EXAMPLE 126 6-Chloro-3-[2-(2-methoxyethoxy)phenoxy]-4-pyridazinol (Compound No. 396) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.26-6.93 (4H, m), 6.62 (1H, s), 4.78-4.03 (2H, m), 3.55-3.50 (2H, m), 3.24 (3H, s). Appareance: paste state. EXAMPLE 127 6-Chloro-3-[2-(2-hydroxyphenoxy)phenoxy]-4-pyridazinol (Compound No. 399) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.27-6.75 (8H, m), 6.61 (1H, s). Appareance: amorphous. EXAMPLE 128 6-Chloro-3-{2-{2-[(6-chloro-4-ethoxy-3-pyridazinyl)-oxy]phenoxy}phenoxy}-4-pyridazinol (Compound No. 400) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65-6.70 (8H, m), 6.63-6.59 (2H, m), 4.19 (2H, q, J=7.0 Hz), 1.50 (3H, t, J=7.0 Hz). Appareance: amorphous. EXAMPLE 129 6-Chloro-3-[2-(methylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 401) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.43-7.11 (4H, m), 6.71 (1H, s), 2.40 (3H, s). Melting point (° C.): 174-175. EXAMPLE 130 6-Chloro-3-[2-(isopropylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 403) Melting point (° C.): 176-177. EXAMPLE 131 6-Chloro-3-(2-cyanophenoxy)-4-pyridazinol (Compound No. 330) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.82-7.68 (2H, m), 7.46-7.34 (2H, m), 6.79 (1H, s) Appareance: amorphous. EXAMPLE 132 1-{2-[6-Chloro-4-hydroxy-3-pyridazinyl]oxy}phenyl}-ethanone(Compound No. 336) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.88-7.85 (1H, m), 7.65-7.57 (1H, m), 7.43-7.26 (2H, m), 6.73 (1H, s), 2.50 (3H, br.s). Melting point (° C.): 186-189. EXAMPLE 133 6-Chloro-3-(3-chlorophenoxy)-4-pyridazinol (Compound No. 410) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.45-7.10 (5H, m), 6.72 (1H, s). Melting point (° C.): 217. EXAMPLE 134 6-Chloro-3-(3-iodophenoxy)-4-pyridazinol (Compound No. 412) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.64-7.53 (2H, m), 7.28-6.70 (3H, m). Melting point (° C.): 202-203. EXAMPLE 135 6-Chloro-3-(3-methylphenoxy)-4-pyridazinol (Compound No. 413) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.35-6.80 (4H, m), 6.95 (1H, s), 2.35 (3H, s). Melting point (° C.): 205-208. EXAMPLE 136 6-Chloro-3-(3-isopropylphenoxy)-4-pyridazinol (Compound No. 415) Melting point (° C.): 176-177. EXAMPLE 137 3-(3-tert-Butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 416) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.40-6.65 (4H, m), 6.67 (1H, s), 1.27 (9H, s). Melting point (° C.): 203-207. EXAMPLE 138 6-Chloro-3-(3-cyclopropylphenoxy)-4-pyridazinol (Compound No. 417) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35-7.20 (1H, m), 6.98-6.85 (3H, m), 6.78 (1H, brs), 2.00-1.88 (1H, m), 0.98-0.87 (2H, m), 0.70-0.60 (2H, m). Melting point (° C.): 179-181. EXAMPLE 139 6-Chloro-3-[3-(trifluoromethyl)phenoxy]-4-pyridazinol (Compound No. 418) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.70-7.40 (4H, m), 6.95 (1H, s). Melting point (° C.): 213-216. EXAMPLE 140 6-Chloro-3-[3-(2-furyl)phenoxy]-4-pyridazinol (Compound No. 419) 1H-NMR (200 MHz, CDCl3+CD3OD) δ ppm: 7.55-7.35 (4H, m), 7.08-7.02 (1H, m), 6.67 (1H, d, J=3.3 Hz), 6.59 (1H, brs), 6.48 (1H, dd, J=3.3, 1.8 Hz). Melting point (° C.): 200-202. EXAMPLE 141 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]benzonitrile (Compound No. 420) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.70-7.40 (4H, m), 6.75 (1H, s). Melting point (° C.): 226-229. EXAMPLE 142 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]benzaldehyde (Compound No. 421) 1H-NMR (200 MHz, CD3OD) δ ppm: 9.96 (1H, s), 7.72-7.53 (3H, m), 7.46-7.41 (1H, m), 6.54 (1H, s). Melting point (° C.): 188-192. EXAMPLE 143 1-{3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}-ethanone(Compound No. 422) Melting point (° C.): 195-198. EXAMPLE 144 Methyl 3-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-benzoate (Compound No. 423) 1H-NMR (90 MHz, CD3OD) δ ppm: 8.00-7.70 (2H, m), 7.70-7.30 (2H, m), 6.75 (1H, s), 3.30 (3H, s). Melting point (° C.): 207. EXAMPLE 145 6-Chloro-3-(3-nitrophenoxy)-4-pyridazinol (Compound No. 424) 1H-NMR (60 MHz, DMF-d7) δ ppm: 8.30-7.90 (2H, m), 7.90-7.70 (2H, m), 6.50 (1H, s), 5.80-5.15 (1H, brs). Melting point (° C.): 217-219. EXAMPLE 146 6-Chloro-3-(3-methoxyphenoxy)-4-pyridazinol (Compound No. 425) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 7.50-7.10 (1H, m), 6.90-6.60 (3H, m), 6.70 (1H, s), 5.88 (1H, brs), 3.77 Melting point (° C.): 199-203. EXAMPLE 147 6-Chloro-3-(4-chlorophenoxy)-4-pyridazinol (Compound No. 427). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.45-7.38 (2H, m), 7.23-7.15 (2H, m), 6.70 (1H, s). Melting point (° C.): 226-231. EXAMPLE 148 6-Chloro-3-(4-methylphenoxy)-4-pyridazinol (Compound No. 430) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.25-6.83 (4H, m), 6.68 (1H, s), 2.25. (3H, s). Melting point (° C.): 261-263. EXAMPLE 149 6-Chloro-3-(4-isopropylphenoxy)-4-pyridazinol (Compound No. 432) Melting point (° C.): 233-235. EXAMPLE 150 3-(4-tert-Butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 433) Melting point (° C.): 224-225. EXAMPLE 151 6-Chloro-3-(4-cyclopropylphenoxy)-4-pyridazinol (Compound No. 434) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.15-7.02 (4H, m), 6.82 (1H, brs), 2.01-1.90 (1H, m), 0.99-0.90 (2H, m), 0.70-0.62 (2H, m) Melting point (° C.): 221-227. EXAMPLE 152 6-Chloro-3-(4-methoxyphenoxy)-4-pyridazinol (Compound No. 435) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.26-6.85 (4H, m), 6.80 (1H, brs), 3.81 (3H, s). Melting point (° C.): 260-263.5. EXAMPLE 153 6-Chloro-3-[4-(trimethylsilyl)phenoxy]-4-pyridazinol (Compound No. 436) Melting point (° C.): 197-199. EXAMPLE 154 6-Chloro-3-(2,3-difluorophenoxy)-4-pyridazinol (Compound No. 437) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.24-7.05 (3H, m), 6.73 (1H, s). Melting point. (C): 188-193. EXAMPLE 155 6-Chloro-3-(3-chloro-2-fluorophenoxy)-4-pyridazinol (Compound No. 438) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.43-7.21 (3H, m), 6.75 (1H, s). Melting point (° C.): 187-195. EXAMPLE 156 6-Chloro-3-[2-fluoro-3-(trifluoromethyl)phenoxy]-4-pyridazinol (Compound No. 441) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.78-7.66 (2H, m), 7.48 (1H, t, J=8.1 Hz), 6.83 (1H, s). Melting point (° C.): 185-189. EXAMPLE 157 6-Chloro-3-(2,3-dichlorophenoxy)-4-pyridazinol (Compound No. 443) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.62-7.57 (1H, m), 7.50-7.37 (2H, m), 6.89 (1H, s). Melting point (° C.): 233-238. EXAMPLE 158 6-Chloro-3-[2-chloro-3-(trifluoromethyl)phenoxy]-4-pyridazinol (Compound No. 446) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.74-7.55 (3H, m), 6.76 (1H, s). Melting point (° C.): 170-200. EXAMPLE 159 3-(2-Bromo-3-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 450) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35 (1H, t, J=7.5 Hz), 7.27 (1H, dd, J=7.5, 2.2 Hz), 7.16 (1H, dd, J=7.5, 2.2 Hz), 6.87 (1H, brs), 2.41 (3H, s). Melting point (° C.): 140-141. EXAMPLE 160 6-Chloro-3-(3-fluoro-2-methylphenoxy)-4-pyridazinol (Compound No. 453) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.30-7.15 (1H, m), 7.08-6.85 (2H, m), 6.73 (1H, s), 2.09 (3H, d, J=1.8 Hz). Melting point (° C.): 242-244. EXAMPLE 161 6-Chloro-3-(3-chloro-2-methylphenoxy)-4-pyridazinol (Compound No. 454) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.39-7.12 (4H, m), 2.14 (3H, s). Melting point (° C.): 250-252. EXAMPLE 162 6-Chloro-3-(2,3-dimethylphenoxy)-4-pyridazinol (Compound No. 456) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.22-6.98 (3H, m), 6.77 (1H, s), 2.30 (3H, s), 2.02 (3H, s). Melting point (° C.): 240-241. EXAMPLE 163 6-Chloro-3-(2-methyl-3-nitrophenoxy)-4-pyridazinol (Compound No. 458) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.89-7.84 (1H, m), 7.58-7.47 (2H, m), 6.90 (1H, brs), 2.25 (3H, s). Melting point (° C.): 241-244. EXAMPLE 164 6-Chloro-3-(3-methoxy-2-methylphenoxy)-4-pyridazinol (Compound No. 459) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.14 (1H, t, J=8.4 Hz), 6.78 (1H, d, J=8.4 Hz), 6.63 (1H, d, J=8.4 Hz), 6.55 (1H, s), 3.83 (3H, s), 2.00 (3H, s). Melting point (° C.): 224-237. EXAMPLE 165 6-Chloro-3-{3-[(6-chloro-4-hydroxy-3-pyridazinyl)-oxy]-2-methylphenoxy}-4-pyridazinol (Compound No. 460) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.16 (1H, t, J=8.4 Hz), 6.85 (2H, d, J=8.4 Hz), 6.48 (2H, s), 2.15 (3H, s). Melting point (° C.): >290. EXAMPLE 166 6-Chloro-3-(2-cyclopropyl-3-methylphenoxy)-4-pyridazinol (Compound No. 472) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.18 (1H, t, J=7.7 Hz), 7.07 -(1H, br.d, J=7.7 Hz), 6.91 (1H, br.d, J=7.7 Hz), 6.82 (1H, brs), 2.40 (3H, s), 1.43-1.28 (1H, m), 0.79-0.68 (2H, m), 0.59-0.48 (2H, m). Melting point (° C.): 197-198. EXAMPLE 167 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl tetrahydro-2H-pyran-4-carboxylate (Compound No. 3856) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.15-7.04 (2H, m), 6.90-6.78 (1H, m), 4.10-3.95 (2H, m), 3.60-3.43 (2H, m), 3.03-2.86 (1H, m), 2.11 (3H, s), 2.06-1.90 (4H, m), 1.80-1.60 (1H, m), 0.80-0.50 (4H, m). Appareance: caramel-like. EXAMPLE 168 Methyl 2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-6-fluorobenzoate (Compound No. 491) 1H-NMR (270 MHz, CDCl3) δ ppm: 7.62 (1H, td, J=8.4, 5.6 Hz), 7.23 (1H, t, J=8.4 Hz), 7.02 (1H, d, J=8.4 Hz), 3.83 (3H, s). Appareance: amorphous. EXAMPLE 169 6-Chloro-3-(3-methyl-2-nitrophenoxy)-4-pyridazinol (Compound No. 498) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.48 (1H, t, J=8.1 Hz), 7.26 (1H, d, J=8.1 Hz), 7.19 (1H, d, J=8.1 Hz), 6.66 (1H, s), 2.37 (3H, s). Melting point (° C.): 191-200. EXAMPLE 170 6-Chloro-3-(2,3-dimethoxyphenoxy)-4-pyridazinol (Compound No. 503) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.14-6.78 (4H, m), 3.84 (3H, s), 3.61 (3H, s). Melting point (° C.): 199-201. EXAMPLE 171 6-Chloro-3-(2,3-dihydro-1H-inden-4-yloxy)-4-pyridazinol (Compound No. 506) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.20 (1H, t, J=7.3 Hz), 7.14 (1H, d, J=7.3 Hz), 6.92 (1H, d, J=7.3 Hz), 6.83 (1H, brs), 2.92 (1H, t, J=7.3 Hz), 2.64 (1H, t, J=7.3 Hz), 2.00 (1H, quintet, J=7.3 Hz). Melting point (° C.): 230-232. EXAMPLE 172 6-Chloro-3-[(3-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 507) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.17 (1H, t, J=7.7 Hz), 7.08 (1H, d, J=7.7 Hz), 6.88 (1H, d, J=7.7 Hz), 6.69 (1H, s), 3.35-3.15 (1H, m), 3.10-2.70 (2H, m), 2.40-2.15 (1H, m), 1.80-1.55 (1H, m), 1.15 (3H, d, J=7.0 Hz). Melting point (° C.): 232. EXAMPLE 173 6-Chloro-3-[(1-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 510) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.21 (1H, dd, J=8.1, 7.3 Hz) 7.09 (1H, d, J=7.3 Hz), 6.91 (1H, d, J=8.1 Hz), 6.70 (1H, s), 3.30-3.05 (1H, m), 2.85-2.50 (2H, m), 2.40-2.20 (1H, m), 1.70-1.45 (1H, m), 1.29 (3H, d, J=7.0 Hz). Melting point (° C.): 228-230. EXAMPLE 174 6-Chloro-3-[(2,2-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 513) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.17 (1H, t, J=7.7 Hz), 7.05 (1H, d, J=7.7 Hz), 6.89 (1H, d, J=7.7 Hz), 6.69 (1H, s), 2.76 (2H, s), 2.53 (2H, s), 1.13 (6H, s). Melting point (° C.): 220-223. EXAMPLE 175 6-Chloro-3-{spiro[cyclopropane-1,3′-(2′,3′-dihydro-1′H-inden)]-4′-yloxy}-4-pyridazinol (Compound No. 514) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.15-6.95 (2H, m), 6.75 (1H, dd, J=6.6, 2.6 Hz), 6.66 (1H, s), 3.02 (2H, dd, J=7.7, 7.3 Hz), 2.15-1.95 (2H, m), 1.28-1.15 (2H, m), 0.80-0.70 (2H, m) Appareance: amorphous. EXAMPLE 176 6-Chloro-3-(4-fluorophenoxy)-4-pyridazinol (Compound No. 426) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.26-7.05 (4H, m), 6.70 (1H, s). Melting point (° C.): 241-248. EXAMPLE 177 3-(Bicyclo[4.2.0]octa-1,3,5-trien-2-yloxy)-6-chloro-4-pyridazinol (Compound No. 505) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.22 (1H, dd, J=8.2, 7.3 Hz), 6.96 (1H, d, J=8.2 Hz), 6.91 (1H, d, J=7.3 Hz), 6.69 (1H, s), 3.19-3.11 (2H, m), 3.10-3.00 (2H, m). Melting point (° C.): 145-155. EXAMPLE 178 7-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-2,3-dihydro-1H-inden-1-one 0-methyloxime (Compound No. 520) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.50-7.15 (2H, m), 7.07 (1H, dd, J=8.1, 7.3 Hz), 6.55 (0.4H, s), 5.77 (0.6H, s), 3.73 (1.8H, s), 3.67 (1.2H, s), 3.15-3.00 (2H, m), 2.90-2.73 (2H, m). Melting point (° C.): >250. EXAMPLE 179 6-Chloro-3-(5,6,7,8-tetrahydro-1-naphthalenyloxy)-4-pyridazinol (Compound No. 521) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.14 (1H, t, J=7.7 Hz), 6.98 (1H, d, J=7.7 Hz), 6.89 (1H, d, J=7.7 Hz), 6.82 (1H, brs), 2.80-2.70 (2H, m), 2.50-2.40 (2H, m), 1.85-1.70 (4H, m). Melting point. (C): 232-237. EXAMPLE 180 6-Chloro-3-(1-naphthyloxy)-4-pyridazinol (Compound No. 527) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 8.10-7.20 (7H, m), 6.85 (1H, s), 6.20 (1H, brs). Melting point (° C.): 243-245. EXAMPLE 181 6-Chloro-3-(2,3-dihydro-1-benzofuran-4-yloxy)-4-pyridazinol (Compound No. 528) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.11 (1H, t, J=8.1 Hz), 6.65 (1H, s), 6.60 (1H, d, J=8.1 Hz), 6.56 (1H d, J=8.1 Hz), 4.53 (2H, t, J=8.5 Hz), 2.97 (2H , t, J=8.5 Hz). Melting point (° C.): 219-221. EXAMPLE 182 6-Chloro-3-[(3-methyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 529) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.15 (1H, t, J=8.1 Hz), 6.85 (1H, brs), 6.67 (1H, d, J=8.1 Hz), 6.62 (1H, d, J=8.1 Hz), 4.65 (1H, t, J=8.8 Hz), 4.12-4.04 (1H, m), 3.50-3.39 (1H, m), 1.14 (3H, d, J=7.0 Hz). Melting point (° C.): 238-245. EXAMPLE 183 3-(1-benzofuran-4-yloxy)-6-chloro-4-pyridazinol (Compound No. 531) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.99 (1H, d, J=2.0 Hz), 7.52 20 (1H, d, J=7.8 Hz), 7.35 (1H, t, J=7.8 Hz), 7.06 (1H, d, J=7.8 Hz), 6.87 (1H, s), 6.81 (1H, d, J=2.0 Hz). Melting point (° C.): 220-225. EXAMPLE 184 6-Chloro-3-[(3-methyl-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 532) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.44 (1H, d, J=1.5 Hz), 7.33-7.20 (2H, m), 6.91 (1H, dd, J=7.0, 1.5 Hz), 6.61 (1H, s), 2.01 (3H, s). Melting point (° C.): 218-225. EXAMPLE 185 3-(1-Benzothien-4-yloxy)-6-chloro-4-pyridazinol (Compound No. 534) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.75 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=5.5 Hz), 7.35 (1H, dd, J=8.1, 7.7 Hz), 7.28 (1H, 35 dd, J=5.5, 0.7 Hz), 7.10 (1H, dd, J=7.7, 0.7 Hz), 6.64 (1H, s). Melting point (° C.): 181-183. EXAMPLE 186 6-Chloro-3-(8-quinolynyloxy)-4-pyridazinol (Compound No. 535) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 8.80 (1H, dd, J=4.0, 1.5 Hz), 8.46 (1H, dd, J=8.4, 1.5 Hz), 7.93-7.87 (1H, m), 7.70-7.63 (2H, m), 7.57 (1H, dd, J=8.4, 4.0 Hz), 6.82 (1H, s). Melting point (° C.): >200 (dec.). EXAMPLE 187 6-Chloro-3-(8-quinolynyloxy)-4-pyridazinol (Compound No. 536) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 8.81 (1H, dd, J=4.0, 1.5 Hz), 8.41 (1H, dd, J=8.4, 1.5 Hz), 7.81 (1H, d, J=7.0 Hz), 7.62-7.52 (2H, m), 7.41 (1H, d, J=7.7 Hz), 6.43 (1H, s). Melting point (° C.): >180 (dec.). EXAMPLE 188 6-Chloro-3-[(2-methyl-1,3-benzoxazol-4-yl)oxy]-4-pyridazinol (Compound No. 538) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55-7.32 (2H, m), 7.22-7.10 (1H, m), 6.73 (1H, s), 2.59 (3H, s). Melting point (° C.): 221-222. EXAMPLE 189 6-Chloro-3-(2,3-dihydro-1-benzofuran-7-yloxy)-4-pyridazinol (Compound No. 539) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.13-7.08 (1H, m), 6.95 (1H, d, J=7.3 Hz), 6.85 (1H, dd, J=8.1, 7.3 Hz), 6.67 (1H, s), 4.54 (2H, t, J=8.4 Hz), 3.30-3.20 (2H, m). Appareance: amorphous. EXAMPLE 190 6-Chloro-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-4-pyridazinol (Compound No. 540) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.08 (1H, d, J=7.3 Hz), 6.96 (1H, d, J=8.1 Hz), 6.87-6.79 (2H, m), 3.06 (2H, s), 1.37 (6H, s). Melting point (° C.): 228-229.5. EXAMPLE 191 3-(1-Benzofuran-7-yloxy)-6-chloro-4-pyridazinol (Compound No. 541) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.73 (1H, d, J=2.2 Hz), 7.53 (1H, dd, J=7.7, 1.4 Hz), 7.26 (1H, t, J=7.7 Hz), 7.15 (1H, dd, J=7.7, 1.4 Hz), 6.90 (1H, d, J=2.2 Hz), 6.76 (1H, s). Melting point (° C.): 201-202. EXAMPLE 192 3-(1,3-Benzodioxol-4-yloxy)-6-chloro-4-pyridazinol (Compound No. 544) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 6.94-6.75 (4H, m), 6.01 (2H, s). Melting point (° C.): 206-211. EXAMPLE 193 6-Chloro-3-(2,3-dihydro-1,4-benzodioxyn-5-yloxy)-4-pyridazinol (Compound No. 547) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 6.90-6.72 (4H, m), 4.27-4.15 (4H, m). Melting point (° C.): 218-223.5. EXAMPLE 194 6-Chloro-3-[(2-methyl-1,3-benzoxazol-7-yl)oxy]-4-pyridazinol (Compound No. 549) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.52 (1H, dd, J=8.1, 1.1 Hz) 7.37 (1H, t, J=8.1 Hz), 7.21 (1H, dd, J=8.1, 1.1 Hz), 6.76 (1H, s), 2.65 (3H, s). Melting point (° C.): 197-202. EXAMPLE 195 6-Chloro-3-(2,4-dichlorophenoxy)-4-pyridazinol (Compound No. 552) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.55 (1H, t, J=1.8 Hz), 7.35 (2H, d, J=1.8 Hz), 6.88 (1H, s). Melting point (° C.): 233-237. EXAMPLE 196 3-(2-Bromo-4-tert-butylphenoxy)-6-chloro-4-pyridazinol (Compound No. 556) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.61 (1H, d, J=2.0 Hz), 7.43 (1H, dd, J=8.4, 2.0 Hz), 7.17 (1H, d, J=8.4 Hz), 6.73 (1H, s), 1.32 (9H, s). Melting point (° C.): >202 (dec.). EXAMPLE 197 6-Chloro-3-(4-chloro-2-methylphenoxy)-4-pyridazinol (Compound No. 558) 1H-NMR (60 MHz, DMSO-d6+CDCl3) δ ppm: 7.40-7.10 (3H, m), 6.65 (1H, s), 2.18 (3H, s). Melting point (° C.): 235-235.5. EXAMPLE 198 6-Chloro-3-(2,4-dimethylphenoxy)-4-pyridazinol (Compound No. 559) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.17-6.98 (3H, m), 6.85 (1H, s), 2.29 (3H, s), 2.07 (3H, s). Melting point (° C.): 217.5. EXAMPLE 199 6-Chloro-3-(2-ethyl-4-iodophenoxy)-4-pyridazinol (Compound No. 562) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.59 (1H, d, J=2.2 Hz), 7.49 (1H, dd, J=8.4, 2.2 Hz), 6.75 (1H, d, J=8.4 Hz), 6.48 (1H, s), 2.65-1.95 (2H, m), 1.16 (3H, t, J=7.7 Hz). Melting point (° C.): 199-201. EXAMPLE 200 3-(4-Bromo-2-isopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 566) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.44 (1H, brs), 7.37 (1H, dd, J=8.0, 2.2 Hz), 7.00 (1H, d, J=8.0 Hz), 6.73 (1H, s), 3.01 (1H, septet, J=6.8 Hz), 1.15 (6H, d, J=6.8 Hz). Melting point (° C.): 215-225. EXAMPLE 201 3-(2-tert-Butyl-4-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 567) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.25 (1H, d, J=2.0 Hz), 7.05 (1H, dd, J=8.0, 2.0 Hz), 6.85 (1H, d, J=8.0 Hz), 6.70 (1H, s), 2.30 (3H, s), 1.35 (9H, s). Melting point (° C.): 230-236. EXAMPLE 202 6-Chloro-3-(2-cyclopropyl-4-methylphenoxy)-4-pyridazinol (Compound No. 571) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.05-6.95 (1H, m), 6.96 (1H, s), 6.81 (1H, s), 6.68 (1H, m), 2.30 (3H, s), 1.90-1.75 (1H, m), 0.90-0.70 (2H, m), 0.70-0.50 (2H, m). Melting point (IC): 239. EXAMPLE 203 6-Chloro-3-(2-chloro-5-methylphenoxy)-4-pyridazinol (Compound No. 614) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.40 (1H, d, J=8.5 Hz), 7.15 (1H, s), 7.10 (1H, d, J=8.5 Hz), 6.70 (1H, s), 2.35 (3H, s). Melting point (° C.): 170. EXAMPLE 204 6-Chloro-3-(5-chloro-2-methylphenoxy)-4-pyridazinol (Compound No. 618) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.28 (1H, d, J=8.8 Hz), 7.21-7.15 (1H, m), 7.16 (1H, s), 6.72 (1H, s), 2.15 (3H, Melting point (° C.): 174-180. EXAMPLE 205 6-Chloro-3-(2,5-dimethylphenoxy)-4-pyridazinol (Compound No. 621) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.16 (1H, d, J=9.0 Hz), 7.08 (1H, d, J=9.0 Hz), 6.90 (1H, s), 6.70 (1H, s), 2.30 (3H, s) 2.10 (3H, s). Melting point (° C.): 80-83. EXAMPLE 206 6-Chloro-3-(5-isopropyl-2-methylphenoxy)-4-pyridazinol (Compound No. 623) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.20 (1H, d, J=7.5 Hz), 7.15-6.98 (1H, m), 6.95 (1H, s), 6.70 (1H, s), 2.88 (1H, s J=7.5 Hz), 2.10 (3H, s), 1.23 (6H, d, J=7.5 Hz). Melting point (° C.): 168-169. EXAMPLE 207 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-4-methylbenzoic acid (Compound No. 626) Melting point (° C.): 238-240. EXAMPLE 208 3-(5-Amino-2-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 627) Melting point (° C.): >310. EXAMPLE 209 6-Chloro-3-[5-(dimethylamino)-2-methylphenoxy]-4-pyridazinol (Compound No. 628) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08 (1H, d, J=8.4 Hz), 6.68 (1H, s), 6.61 (1H, dd, J=8.4, 2.6 Hz), 6.50 (1H, d, J=2.6 Hz), 2.88 (6H, s), 2.02 (3H, s). Melting point (° C.): 181-182. EXAMPLE 210 6-Chloro-3-(5-methoxy-2-methylphenoxy)-4-pyridazinol (Compound No. 629) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.16 (1H, d, J=8.4 Hz), 6.78-6.67 (3H, m), 3.75 (3H, s), 2.07 (3H, s). Melting point (° C.): 170-172. EXAMPLE 211 6-Chloro-3-(2-ethyl-5-methoxyphenoxy)-4-pyridazinol (Compound No. 635) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.15 (1H, br.d, J=8.0 Hz), 6.74 (1H, brs), 6.73 (1H, br.d, J=8.0 Hz), 6.63 (1H, s), 3.73 (3H, s), 2.46 (2H, q, J=7.0 Hz), 1.10 (3H, t, J=7.0 Hz). Melting point (° C.): 124-126. EXAMPLE 212 6-Chloro-3-(2-isopropyl-5-methylphenoxy)-4-pyridazinol (Compound No. 640) 1H-NMR (60 MHz, CDCl3+DMF-d7) δ ppm: 7.50-6.70 (3H, m), 6.58 (1H, s), 3.30-2.60 (1H, m), 2.26 (3H, s), 1.13 (6H, d, J=6.60 Hz). Melting point (° C.): 193-195. EXAMPLE 213 6-Chloro-3-(3,5-diisopropylphenoxy)-4-pyridazinol (Compound No. 642) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 7.25 (1H, d, J=8.0 Hz), 7.11 (1H, d, J=1.8 Hz), 6.92 (1H, dd, J=8.0, 1.8 Hz), 6.73 (1H, s), 2.84 (2H, septet, J=7.0 Hz), 1.18 (6H, d, J=7.0 Hz), 1.12 (6H, d, J=7.0 Hz). Melting point (° C.): 231-235. EXAMPLE 214 3-(2-tert-Butyl-5-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 650) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.35 (1H, d, J=8.0 Hz), 6.95 (1H, dd, J=8.0, 1.5 Hz), 6.80 (1H, s), 6.70 (1H, s), 2.27 (3H, s), 1.35 (9H, s). Melting point (° C.): 226. EXAMPLE 215 6-Chloro-3-(2,5-di-tert-butylphenoxy)-4-pyridazinol (Compound No. 653) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.50-7.10 (3H, m), 6.94 (1H, s), 4.98 (1H brs), 1.37 (9H, s), 1.28 (9H, s). Melting point (° C.): 249-258. EXAMPLE 216 6-Chloro-3-(2-cyclopropyl-5-fluorophenoxy)-4-pyridazinol (Compound No. 658) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.10-6.85 (3H, m), 6.72 (1H, s), 1.92-1.75 (1H, m), 0.85-0.70 (2H, m), 0.70-0.54 (2H, m). Melting point (° C.): 227-228. EXAMPLE 217 6-Chloro-3-(5-chloro-2-cyclopropylphenoxy)-4-pyridazinol (Compound No. 659) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.19 (1H, d, J=7.7 Hz), 7.16 (1H, s), 7.01 (1H, d, J=7.7 Hz), 6.72 (1H, s), 1.94-1.79 (1H, m), 0.90-0.75 (2H, m), 0.75-0.58 (2H, m). Melting point (° C.): 194-195. EXAMPLE 218 6-Chloro-3-(2-cyclopropyl-5-methylphenoxy)-4-pyridazinol (Compound No. 662) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.96 (1H, d, J=7.7 Hz), 6.89 (1H, s), 6.87 (1H, d, J=7.7 Hz), 6.68 (1H, s), 2.28 (3H, s), 1.87-1.73 (1H, m), 0.80-0.51 (4H, m) Melting point (° C.): 150-159. EXAMPLE 219 6-Chloro-3-(2-cyclopropyl-5-ethylphenoxy)-4-pyridazinol (Compound No. 663) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.01 (1H, d, J=8.0 Hz), 6.92 (1H, s), 6.92 (1H, d, J=8.0 Hz), 6.69 (1H, s), 2.61 (2H, t, J=7.7 Hz), 1.88-1.72 (1H, m), 1.20 (3H, q, J=7.7 Hz), 0.82-0.66 (2H, m), 0.65-0.52 (2H, m). Appareance: amorphous. EXAMPLE 220 6-Chloro-3-(2-cyclopropyl-5-isopropylphenoxy)-4-pyridazinol (Compound No. 664) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.05 (1H, dd, J=7.7, 1.8 Hz), 7.00 (1H, brs), 6.93 (1H, d, J=7.7 Hz), 6.70 (1H, s), 2.87 (1H, septet, J=7.0 Hz), 1.90-1.72 (1H, m), 1.22 (6H, d, J=7.0 Hz), 0.85-0.68 (2H, m), 0.68-0.52 (2H, m). Melting point (° C.): 211-212. EXAMPLE 221 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-4-cyclopropylbenzonitrile (Compound No. 667) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.58-7.48 (2H, m), 7.15 (1H, d, J=8.8 Hz), 6.74 (1H, s), 2.10-1.90 (1H, m), 1.05-0.93 (2H, m), 0.83-0.70 (2H, m). Melting point (° C.): 211-212. EXAMPLE 222 6-Chloro-3-[5-fluoro-2-(1-propenyl)phenoxy]-4-pyridazinol (Compound No. 679) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.61-7.53 (1H, m), 7.03-6.90 (2H, m), 6.72 (1H, s), 6.44-6.19 (2H, m), 1.80 (3H, d, J=5.5 Hz). Melting point (° C.): 210-217. EXAMPLE 223 6-Chloro-3-[5-chloro-2-(1-propenyl)phenoxy]-4-pyridazinol (Compound No. 680) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55 (1H, d, J=8.4 Hz), 7.24-7.17 (2H, m), 6.72 (1H, s), 6.46-6.30 (2H, m), 1.81 (3H, d, J=5.1 Hz). Melting point (° C.): 221-224. EXAMPLE 224 2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-4-(dimethylamino)benzaldehyde (Compound No. 692) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 9.78 (1H, s), 7.69 (1H, d, J=6.0 Hz), 6.81 (1H, s), 6.78-6.46 (2H, m), 3.05 (6H, s). Melting point (° C.): 124-127. EXAMPLE 225 3-(5-Chloro-2-methoxyphenoxy)-6-chloro-4-pyridazinol (Compound No. 701) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.23-7.18 (2H, m), 7.05 (1H, d, J=8.8 Hz), 6.66 (1H, s), 3.73 (3H, s). Melting point (° C.): 143-155. EXAMPLE 226 3-(5-Bromo-2-methoxyphenoxy)-6-chloro-4-pyridazinol (Compound No. 702) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.39-7.31 (2H, m), 7.02 (1H, d, J=8.4 Hz), 6.67 (1H, s), 3.74 (3H, s). Melting point (° C.): 135-137. EXAMPLE 227 6-Chloro-3-(4-fluoro-2-methylphenoxy)-4-pyridazinol (Compound No. 557) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.14-6.88 (3H, m), 6.71 (1H, s), 2.16 (3H, s). Melting point (° C.): 249-250. EXAMPLE 228 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-4-methoxybenzonitrile (Compound No. 707) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.66 (1H, dd, J=8.4, 2.2 Hz), 7.58 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=8.4 Hz), 6.71 (1H, s), 3.85 (3H, s). Melting point (° C.): 187-192. EXAMPLE 229 6-Chloro-3-(2-methoxy-5-nitrophenoxy)-4-pyridazinol (Compound No. 708) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.18 (1H, dd, J=9.2, 2.6 Hz) 8.04 (1H, d, J=2.6 Hz), 7.27 (1H, d, J=9.2 Hz), 6.59 (1H, s), 3.89 (3H, s). Appareance: amorphous. EXAMPLE 230 6-Chloro-3-(2,5-dimethoxyphenoxy)-4-pyridazinol (Compound No. 709) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.04-6.99 (1H, m), 6.81-6.78 (2H, m), 6.68 (1H, s), 3.76 (3H, s), 3.70 (3H, s). Melting point (° C.): 150-152. EXAMPLE 231 6-Chloro-3-(2,6-difluorophenoxy)-4-pyridazinol (Compound No. 710) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.54-7.20 (3H, m), 6.88 (1H, s). Melting point (° C.): 209-213. EXAMPLE 232 6-Chloro-3-(2-chloro-6-fluorophenoxy)-4-pyridazinol (Compound No. 711) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.35-7.13 (3H, m), 6.61 (1H, s). Melting point (° C.): 235. EXAMPLE 233 3-(2-Bromo-6-fluorophenoxy)-6-chloro-4-pyridazinol (Compound No. 712) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.31-7.15 (3H, m), 6.65 (1H, s). Appareance: amorphous. EXAMPLE 234 6-Chloro-3-(2-fluoro-6-propylphenoxy)-4-pyridazinol (Compound No. 716) Melting point (° C.): 134-137. EXAMPLE 235 6-Chloro-3-(2-fluoro-6-isopropylphenoxy)-4-pyridazinol (Compound No. 717) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.35-7.15 (3H, m), 6.89 (1H, brs), 3.02 (1H, septet, J=7.0 Hz), 1.14 (6H, J=7.0 Hz). Melting point (° C.): 215-220. EXAMPLE 236 6-Chloro-3-(2-cyclopropyl-6-fluorophenoxy)-4-pyridazinol (Compound No. 719) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.22-6.96 (2H, m), 6.81-6.71 (1H, m), 6.72 (1H, s), 2.03-1.89 (1H, m), 0.93-0.80 (2H, m), 0.69-0.62 (2H, m). Melting point (° C.): 200-203. EXAMPLE 237 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-6-fluorophenoxy}-4-pyridazinol (Compound No. 728) 1H-NMR (200 MHz, CD3OD) δ ppm : 7.42 (1H, d, J=8.1 Hz), 7.26-7.15 (1H, m), 7.07-6.97 (1H, m), 6.46 (1H, s), 4.33 (1H, q, J=7.0 Hz), 2.42-2.20 (2H, m), 1.43 (3H, d, J=7.0 Hz), 1.02 (3H, t, J=7. 0 Hz) Physical property: amorphous. EXAMPLE 238 6-Chloro-3-(2-fluoro-6-nitrophenoxy)-4-pyridazinol (Compound No. 731) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.03-7.99 (1H, m), 7.78-7.53 (2H, m), 6.89 (1H, s) Melting point (° C.): 210 (sublimation). EXAMPLE 239 6-Chloro-3-(2-fluoro-6-methoxyphenoxy)-4-pyridazinol (Compound No. 732) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.26 (1H, dd, J=15.0, 8.1 Hz), 7.02-6.91 (2H, m), 6.84 (1H, s), 3.75 (3H, s). Melting point (° C.): 190-194 (sublimation). EXAMPLE 240 6-Chloro-3-(2 ,6-dichlorophenoxy)-4-pyridazinol (Compound No. 733) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 7.70-7.10 (3H, m), 6.80 (1H, s). Melting point (° C.): 265. EXAMPLE 241 6-Chloro-3-(2-chloro-6-iodophenoxy)-4-pyridazinol (Compound No. 735) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.90 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=8.1 Hz), 7.12 (1H, t, J=8.1 Hz), 7.02-6.80 (1H, br.m). Melting point (° C.): 262-264. EXAMPLE 242 6-Chloro-3-(2-chloro-6-methylphenoxy)-4-pyridazinol (Compound No. 736) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.50-7.00 (3H, m), 6.75 (1H, s), 2.22 (3H, s). Melting point (° C.): 235. EXAMPLE 243 6-Chloro-3-(2-chloro-6-ethylphenoxy)-4-pyridazinol (Compound No. 737) Melting point (° C.): 194-195. EXAMPLE 244 6-Chloro-3-(5-fluoro-2-methoxyphenoxy)-4-pyridazinol (Compound No. 700) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.13-6.94 (3H, m), 6.71 (1H,s), 3.74 (1H,s). Melting point (° C.): 187-191. EXAMPLE 245 6-Chloro-3-(2-chloro-6-cyclopropylphenoxy)-4-pyridazinol (Compound No. 740) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.30 (1H, dd, J=8.1, 1.5 Hz), 7.17 (1H, dd, J=8.1, 7.7 Hz), 6.96 (1H, dd, J=7.7, 1.5 Hz), 6.76 (1H, s), 2.00-1.84 (1H, m), 0.95-0.80 (2H, m), 0.70-0.60 (2H, m). Melting point (° C.): 224-225. EXAMPLE 246 6-Chloro-3-[2-chloro-6-(2-methyl-2-propenyl)phenoxy]-4-pyridazinol (Compound No. 746) Melting point (° C.): 198-200. EXAMPLE 247 6-Chloro-3-(2-chloro-6-nitrophenoxy)-4-pyridazinol (Compound No. 754) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.12 (1H, dd, J=8.1, 1.5 Hz), 7.95 (1H, dd, J=8.1, 1.5 Hz), 7.59 (1H, t, J=8.1 Hz), 6.76 (1H, s). Appareance: amorphous. EXAMPLE 248 6-Chloro-3-(2,6-dibromophenoxy)-4-pyridazinol (Compound No. 756) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.65 (2H, d, J=8.1 Hz), 7.11 (1H, t, J=8.1 Hz), 6.74 (1H, brs). Melting point (° C.): 274-278. EXAMPLE 249 3-(2-Bromo-6-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 758) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.56 (1H, br.d, J=7.7 Hz) 7.36 (1H, br.d, J=7.7 Hz), 7.16 (1H, t, J=7.7 Hz), 6.92 (1H, brs), 2.14 (3H, s). Melting point (° C.): 242-243. EXAMPLE 250 3-(2-Bromo-6-ethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 759) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.49 (1H, dd, J=7.9, 1.6 Hz), 7.32 (1H, dd, J=7.9, 1.6 Hz), 7.14 (1H, t, J=7.9 Hz), 6.75 (1H, s), 2.58 (2H, q, J=7.5 Hz), 1.18 (3H, t, J=7.5 Hz). Melting point (° C.): 215-217. EXAMPLE 251 3-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-4-methoxybenzonitrile (Compound No. 707) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.66 (1H, dd, J=8.4, 2.2 Hz), 7.58 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=8.4 Hz), 6.71 (1H, s), 3.85 (3H, s). Melting point (° C.): 187-192. EXAMPLE 252 3-(2-Bromo-6-chlorophenoxy)-6-chloro-4-pyridazinol (Compound No. 734) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.64 (1H, dd, J=1.5 Hz, 8.1 Hz), 7.52 (1H, dd, J=1.5 Hz, 8.0 Hz), 7.21 (1H, t, J=8.1 Hz), 6.76 (1H, s). Melting point (° C.): 266-274. EXAMPLE 253 3-(2-Bromo-6-cyclopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 762) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.51 (1H, d, J=7.8 Hz), 7.14 (1H, t, J=7.8 Hz), 7.02 (1H, d, J=7.8 Hz), 6.89 (1H, s), 1.89-1.75 (1H, m), 0.88-0.75 (2H, m), 0.75-0.58 (2H, m). Melting point (° C.): 230-232. EXAMPLE 254 3-Bromo-2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-benzonitrile (Compound No. 775) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.00 (1H, dd, J=8.1, 1.5 Hz), 7.82 (1H, dd, J=8.1, 1.5 Hz), 7.37 (1H, t, J=8.1 Hz), 6.75 (1H, s). Melting point (° C.): 188 (dec.). EXAMPLE 255 3-(2-Bromo-6-methoxyphenoxy)-6-chloro-4-pyridazinol (Compound No. 778) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.26-7.05 (3H, m), 6.70 (1H, s), 3.78 (3H, s). Melting point (° C.): 220-221. EXAMPLE 256 6-Chloro-3-(2-iodo-6-methylphenoxy)-4-pyridazinol (Compound No. 780) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.70 (1H, d, J=7.7 Hz), 7.29 (1H, d, J=8.1 Hz), 6.95 (1H, t, J=7.7 Hz), 6.76 (1H, s), 2.20 (3H, s). Melting point (° C.): 250-252. EXAMPLE 257 6-Chloro-3-(2-ethyl-6-iodophenoxy)-4-pyridazinol (Compound No. 781) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.72 (1H, dd, J=7.7, 1.5 Hz), 7.33 (1H, dd, J=7.7, 1.5 Hz), 7.00 (1H, t, J=7.7 Hz), 6.76 (1H, s), 2.57 (2H, q, J=7.7 Hz), 1.17 (3H, t, J=7.7 Hz). Melting point (° C.): 242-244. EXAMPLE 258 6-Chloro-3-(2-iodo-6-isopropylphenoxy)-4-pyridazinol (Compound No. 782) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.70 (1H, dd, J=8.0, 1.5 Hz) 7.40 (1H, dd, J=8.0, 1.5 Hz), 7.03 (1H, t, J=8.0 Hz), 6.76 (1H, s), 3.01 (1H, septet, J=7.0 Hz), 1.18 (6H, d, J=7.0 Hz). Melting point (° C.): 250-255. EXAMPLE 259 3-Bromo-2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-benzonitrile (Compound No. 775) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.00 (1H, dd, J=8.1, 1.5 Hz), 7.82 (1H, dd, J=8.1, 1.5 Hz), 7.37 (1H, t, J=8.1 Hz), 6.75 (1H, s). Melting point (° C.): 188 (dec.). EXAMPLE 260 6-Chloro-3-(2-ethyl-6-methylphenoxy)-4-pyridazinol (Compound No. 802) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.12-6.97 (3H, m), 6.52 (1H, s), 2.37 (2H, q, J=7.6 Hz), 1.95 (3H, s), 1.04 (3H, t, J=7.6 Hz). Appearance: amorphous. EXAMPLE 261 6-Chloro-3-(2-isopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 803) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.23-7.06 (3H, m), 6.72 (1H, s), 2.96 (1H, septet, J=7.0 Hz), 2.10 (3H, s), 1.16 (6H, d, J=7.0 Hz). Melting point (° C.): 215-220. EXAMPLE 262 3-(2-s-Butyl-6-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 804) Melting point (° C.): 187-189. EXAMPLE 263 6-Chloro-3-[2-(2,2-dichlorocyclopropyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 827) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.25 (1H, br.d, J=6.2 Hz), 7.16 (1H, dd, J=7.7, 7.3 Hz), 6.98 (1H, br.d, J=7.7 Hz), 6.72 (1H, s), 2.85 (1H, dd, J=11.0, 10.6 Hz), 2.22 (3H, s). Melting point (° C.): 213-215. EXAMPLE 264 6-Chloro-3-(2-methyl-6-vinylphenoxy)-4-pyridazinol (Compound No. 834) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.46 (1H, dd, J=6.6, 2.6 Hz), 7.25-7.05 (2H, m), 6.71 (1H, dd, J=17.6, 11.4 Hz), 6.70 (1H, s), 5.74 (1H, dd, J=17.6, 1.5 Hz), 5.21 (1H, dd, J=11.4, 1.5 Hz), 2.11 (3H, s). Appearance: amorphous. EXAMPLE 265 6-Chloro-3-(6-cyclopropyl-3-fluoro-2-methylphenoxy)-4-pyridazinol (Compound No. 1052) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.92-6.70 (3H, m), 2.06 (3H, d, J=2.2 Hz), 1.85-1.70 (1H, m), 0.79-0.45 (4H, m). Melting point (° C.): 230-231. EXAMPLE 266 6-Chloro-3-(2-methyl-6-nitrophenoxy)-4-pyridazinol (Compound No. 844) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.95 (1H, d, J=8.1 Hz), 7.76 (1H, d, J=7.7 Hz), 7.45 (1H, dd, J=8.1, 7.7 Hz), 6.80 (1H, s), 2.20 (3H, s). Appearance: paste state. EXAMPLE 267 6-Chloro-3-(2-methoxy-6-methylphenoxy)-4-pyridazinol (Compound No. 845) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.10-7.01 (1H, m), 6.79-6.72 (2H, m), 6.55 (1H, s), 3.64 (3H, s), 2.08 (3H, s). Appearance: amorphous. EXAMPLE 268 6-Chloro-3-(2,6-diethylphenoxy)-4-pyridazinol (Compound No. 846) 1H-NMR (60 MHz, CDCl3) δ ppm: 10.21 (1H, brs), 7.02 (3H, brs), 6.47 (1H, s), 2.27 (4H, q, J=7.6 Hz), 0.98 (6H, t, J=7.6 Hz). Melting point (° C.): 181-185. EXAMPLE 269 6-Chloro-3-(2-cyclopropyl-6-ethylphenoxy)-4-pyridazinol (Compound No. 850) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.11 (2H, d, J=4.8 Hz), 6.85 (1H, t, J=4.8 Hz), 6.71 (1H, s), 2.52 (2H, q, J=7.5 Hz), 1.87-1.72 (1H, m), 1.16 (3H, t, J=7.5 Hz), 0.80-0.65 (2H, m), 0.65-0.50 (2H, m). Appearance: amorphous. EXAMPLE 270 6-Chloro-3-(2,6-dipropylphenoxy)-4-pyridazinol (Compound No. 890) Melting point (° C.): 191-193. EXAMPLE 271 6-Chloro-3-(2,6-diisopropylphenoxy)-4-pyridazinol (Compound No. 894) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 7.28 (3H, s), 6.80 (1H, s), 2.88 (2H, septet, J=7.0 Hz), 1.15 (12H, d, J=7.0 Hz). Melting point (° C.): >285. EXAMPLE 272 6-Chloro-3-(2-cyclopropyl-6-isopropylphenoxy)-4-pyridazinol (Compound No. 896) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.22-7.12 (2H, m), 6.83 (1H, brs), 6.82 (1H, dd, J=6.6, 2.2 Hz), 2.91 (1H, septet, J=7.0 Hz), 1.74-1.63 (1H, m), 1.11 (6H, d, J=7.0 Hz), 0.75-0.71 (2H, m), 0.58-0.50 (2H, m). Melting point (° C.): 242-245. EXAMPLE 273 6-Chloro-3-(2-isopropyl-6-nitrophenoxy)-4-pyridazinol (Compound No. 911) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 8.00 (1H, d, J=7.7 Hz), 7.88 (1H, d, J=7.7 Hz), 7.54 (1H, t, J=7.7 Hz), 6.96 (1H, brs), 3.07 (1H, septet, J=7.0 Hz), 1.16 (6H, d, J=7.0 Hz). Melting point (° C.): 205-209. EXAMPLE 274 3-(2-tert-Butyl-6-cyclopropylphenoxy)-6-chloro-4-pyridazinol (Compound No. 914) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.28 (1H, br.d, J=8.1 Hz), 7.10 (1H, dd, J=8.1 and 7.7 Hz), 6.90 (1H, d, J=7.7 Hz), 6.70 (1H, s), 1.80-1.55 (1H, m), 1.34 (9H, s), 0.85-0.60 (2H, m), 0.50-0.20 (2H, m) Melting point (° C.): 230-231. EXAMPLE 275 6-Chloro-3-(2,6-dicyclopropylphenoxy)-4-pyridazinol (Compound No. 931) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08 (1H, t, J=7.7 Hz), 6.81 (2H, d, J=7.7 Hz), 6.71 (1H, s), 1.95-1.75 (2H, m), 0.85-0.70 (4H, m), 0.70-0.50 (4H, m). Melting point (° C.): 232-234. EXAMPLE 276 6-Chloro-3-(2-cyclopropyl-6-methoxyphenoxy)-4-pyridazinol (Compound No. 964) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.13 (1H, t, J=8.1 Hz), 6.92 (1H, d, J=8.1 Hz), 6.81 (1H, brs), 6.54 (1H, d, J=8.1 Hz), 3.68 (3H, s), 1.87-1.78 (1H, m), 0.87-0.78 (2H, m), 0.64-0.56 (2H, m). Melting point (° C.): 194-199. EXAMPLE 277 6-Chloro-3-(2-cyclopropyl-6-ethoxyphenoxy)-4-pyridazinol (Compound No. 965) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.07 (1H, t, J=8.1 Hz), 6.84 (1H, dd, J=8.4, 1.5 Hz), 6.71 (1H, s), 6.54 (1H, dd, J=8.4, 1.5 Hz), 3.97 (2H, q, J=7.0 Hz), 2.04-1.91 (1H, m), 1.18 (3H, t, J=7.0 Hz), 0.89-0.79 (2H, m), 0.66-0.60 (2H, m). Melting point (° C.): 174-179. EXAMPLE 278 6-Chloro-3-{2,6-di[(1E)-1-propenyl]phenoxy}-4-pyridazinol (Compound No. 979) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40 (2H, d, J=7.8 Hz), 7.15 (1H, t, J=7.8 Hz), 6.72 (1H, s), 6.34 (2H, d, J=16.4 Hz), 6.27 (2H, dd, J=16.4, 4.9 Hz), 1.79 (6H, d, J=4.9 Hz) Melting point (° C.): 163-164. EXAMPLE 279 6-Chloro-3-(2,6-diallylphenoxy)-4-pyridazinol (Compound No. 982) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.20-7.15 (3H, m), 6.70 (1H, s), 5.95-5.75 (2H, m), 5.02-4.87 (4H, m), 3.26 (4H, d, J=6.8 Hz). Melting point (° C.): 131-135. EXAMPLE 280 6-Chloro-3-(2,6-dimethoxyphenoxy)-4-pyridazinol (Compound No. 987) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.19 (1H t, J=8.3 Hz), 6.79-6.75 (3H m), 3.71 (6H, s). Melting point (° C.): 199-201. EXAMPLE 281 6-Chloro-3-(3,5-dimethylphenoxy)-4-pyridazinol (Compound No. 998) 1H-NMR (60 MHz, DMSO-d6) δ ppm: 6.90-6.65 (4H, m), 2.27 (6H, s). Melting point (° C.): 178-182. EXAMPLE 282 6-Chloro-3-(3-isopropyl-5-methylphenoxy)-4-pyridazinol (Compound No. 1000) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.94 (1H, s), 6.84 (1H, s) 6.81 (1H, s), 6.69 (1H, s), 2.87 (1H, septet, J=7.0 Hz), 2.32 (3H, s), 1.23 (6H, d, J=7.0 Hz). Melting point (° C.): 204-206. EXAMPLE 283 6-Chloro-3-(3,5-diisopropylphenoxy)-4-pyridazinol (Compound No. 1007) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.98 (1H, s), 6.87 (1H, s) 6.86 (1H, s), 6.68 (1H, s), 2.90 (2H, septet, J=7.0 Hz), 1.24 (12H, d, J=7.0 Hz). Melting point (° C.): 249-253. EXAMPLE 284 3-[3,5-Bis(trifluoromethyl)phenoxy]-6-chloro-4-pyridazinol (Compound No. 1009) 1H-NMR (200 MHz, DMF-d7) δ ppm: 8.20-7.80 (3H, m), 6.94 (1H, s), 5.50-4.50 (1H, brs). Melting point (° C.): 237-242. EXAMPLE 285 3-(2-Bromo-3,5-dimethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1013) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.11 (1H, s), 7.00 (1H, s), 6.86 (1H, brs), 2.37 (3H, s), 2.27 (3H, s). Melting point (° C.): 240-244. EXAMPLE 286 6-Chloro-3-(2,3,5-trimethylphenoxy)-4-pyridazinol (Compound No. 1016) 1H-NMR (90 MHz, CD3OD) δ ppm: 6.90 (1H, s), 6.75 (1H, s) 6.70 (1H, s), 2.30 (6H, s), 2.02 (3H, s). Melting point (° C.): 223-224. EXAMPLE 287 6-Chloro-3-(3,5-dimethyl-2-propylphenoxy)-4-pyridazinol (Compound No. 1020) 1H-NMR (90 MHz, DMSO-d6) δ ppm: 6.90 (1H, s), 6.81 (1H, s), 6.77 (1H, s), 2.29 (3H, s), 2.21 (3H, s), 2.53-2.19 (2H, m), 1.57-1.29 (2H, m), 0.86 (3H, t, J=6.6 Hz). Melting point (° C.): 154.5. EXAMPLE 288 6-Chloro-3-(2-cyclopropyl-3,5-dimethylphenoxy)-4-pyridazinol (Compound No. 1023) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.89 (1H, s), 6.73 (1H, s) 6.69 (1H, s), 2.39 (3H, s), 2.26 (3H, s), 1.45-1.28 (1H, m), 0.78-0.67 (2H, m), 0.65-0.51 (2H, m). Melting point (° C.): 200-203. EXAMPLE 289 6-Chloro-3-[3,5-dimethyl-2-(methylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 1027) Melting point (° C.): 213-214. EXAMPLE 290 3-(2-Bromo-3,6-dimethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1040) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.16 (1H, d, J=7.9 Hz), 7.10 (1H, d, J=7.9 Hz), 6.72 (1H, s), 2.38 (3H, s), 2.16 (3H, s). Melting point (° C.): 255-257. EXAMPLE 291 3-(6-Bromo-3-fluoro-2-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1050) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.51 (1H, dd, J=8.8, 5.9 Hz), 7.00 (1H, t, J=8.8 Hz), 6.96 (1H, s), 2.13 (3H, d, J=2.2 Hz). Appearance: amorphous. EXAMPLE 292 3-(6-Bromo-3-chloro-2-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1053) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.47 (1H, d, J=8.1 Hz), 7.23 (1H, d, J=8.1 Hz), 6.64 (1H, s), 2.24 (3H, s). Melting point (° C.): 254-260. EXAMPLE 293 6-Chloro-3-(3-chloro-6-cyclopropyl-2-methylphenoxy)-4-pyridazinol (Compound No. 1055) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.18 (1H, d, J=8.4 Hz), 6.81 (1H, d, J=8.4 Hz), 6.64 (1H, s), 2.17 (3H, s), 1.89-1.76 (1H, m), 0.80-0.71 (2H, m), 0.68-0.51 (2H, m). Melting point (° C.): 233. EXAMPLE 294 3-(6-Bromo-2,3-dimethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1058) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.34 (1H, d, J=8.1 Hz), 6.99 (1H, d, J=8.1 Hz), 6.71 (1H, s), 2.28 (3H, s), 2.12 (3H, s). Melting point (° C.): 263-268. EXAMPLE 295 6-Chloro-3-(2,3,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1060) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.0 (2H, s), 6.73 (1H, s), 2.27 (3H, s), 2.07 (3H, s), 2.03 (3H, s). Melting point (° C.): 228. EXAMPLE 296 6-Chloro-3-(6-cyclopropyl-2,3-dimethylphenoxy)-4-pyridazinol (Compound No. 1061) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.96 (1H, d, J=8.1 Hz), 6.72 (1H, d, J=8.1 Hz), 6.69 (1H, s), 2.24 (3H, s), 2.04 (3H, s), 1.85-1.70 (1H, m), 0.75-0.46 (4H, m). Melting point (° C.): 229-234. EXAMPLE 297 2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-3,4-dimethylbenzaldehyde 0-methyloxime (Compound No. 1063) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.98 (1H, s), 7.50 (1H, d, J=8.1 Hz), 7.11 (1H, d, J=8.1 Hz), 6.69 (1H, s), 3.81 (3H, s), 2.32 (3H, s), 2.06 (3H, s). Appearance: amorphous. EXAMPLE 298 6-Chloro-3-(6-methoxy-2,3-dimethylphenoxy)-4-pyridazinol (Compound No. 1064) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.00 (1H, d, J=8.4 Hz), 6.78 (1H, d, J=8.4 Hz), 6.66 (1H, s), 3.69 (3H, s), 2.23 (3H, s), 2.08 (3H, s). Appearance: amorphous. EXAMPLE 299 3-(6-Bromo-3-methoxy-2-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1066) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.42 (1H, d, J=9.2 Hz), 6.82 (1H, d, J=9.2 Hz), 6.69 (1H, s), 3.86 (3H, s), 2.05 (3H, s). Melting point (° C.): 246-253. EXAMPLE 300 6-Chloro-3-(6-cyclopropyl-3-methoxy-2-methylphenoxy)-4-pyridazinol (Compound No. 1069) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.83 (1H, d, J=8.8 Hz), 6.75 (1H, d, J=8.8 Hz), 6.66 (1H, s), 3.81 (3H, s), 1.99 (3H, s), 1.78-1.70 (1H, m), 0.69-0.63 (2H, m), 0.52-0.47 (2H, m). Melting point (° C.): 250-253. EXAMPLE 301 6-Chloro-3-(2-cyclopropyl-3,6-dimethylphenoxy)-4-pyridazinol (Compound No. 1073) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.20 (1H, d, J=7.6 Hz), 6.95 (1H, d, J=7.6 Hz), 6.68 (1H, s), 2.39 (3H, s), 2.10 (3H, s), 1.50-1.25 (1H, m), 0.90-0.70 (2H, m), 0.70-0.50 (2H, m). Melting point (° C.): 171-175. EXAMPLE 302 3-(2-Allyl-6-ethyl-3-methoxyphenoxy)-6-chloro-4-pyridazinol (Compound No. 1080) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.11 (1H, d, J=8.4 Hz), 6.85 (1H, s), 6.83 (1H, d, J=8.4 Hz), 6.10-5.30 (1H, m), 5.00-4.60 (2H, m), 3.83 (3H, s), 3.30-3.10 (2H, m), 2.40 (2H, q, J=7.6 Hz), 1.10 (3H, t, J=7.6 Hz). Melting point (° C.): 183-186. EXAMPLE 303 6-Chloro-3-{3,6-dimethyl-2-[(methylsulfanyl)methyl]-phenoxy}-4-pyridazinol (Compound No. 1083) 1H-NMR (90 MHz, CD3OD) δ ppm: 7.21-6.90 (2H, m), 6.71 (1H, s), 3.68 (2H, s), 2.38 (3H, s), 2.09 (3H, s), 2.00 (3H, s). Appearance: amorphous. EXAMPLE 304 3-[(5-Bromo-2,3-dihydro-1H-inden-4-yl)oxy]-6-chloro-4-pyridazinol (Compound No. 1086) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.39 (1H, d, J=8.1 Hz), 7.05 (1H, d, J=8.1 Hz), 6.71 (1H, s), 2.94 (2H, t, J=7.3 Hz), 2.79 (2H, t, J=7.3 Hz), 2.10-2.00 (2H, m). Appearance: amorphous. EXAMPLE 305 6-Chloro-3-[(5-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 1088) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.11-7.01 (2H, m), 6.83 (1H, brs), 2.88 (3H, t, J=7.3 Hz), 2.59 (3H, t, J=7.3 Hz), 2.06 (3H, s), 2.06-1.91 (2H, m). Melting point (° C.): 222-225. EXAMPLE 306 6-Chloro-3-[(5-ethyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 1089) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.06 (2H, s), 6.71 (1H, S) 2.91 (2H, t, J=7.3 Hz), 2.67 (2H, t, J=7.3 Hz), 2.51 (2H, q, J=7.7 Hz), 2.04 (2H, quintet, J=7.3 Hz), 1.13 (3H, t, J=7.7 Hz). Melting point (° C.): 193-196. EXAMPLE 307 6-Chloro-3-[(5-cyclopropyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 1091) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.02 (1H, d, J=7.7 Hz), 6.79 (1H, d, J=7.7 Hz), 6.71 (1H, s), 2.90 (2H, t, J=7.3 Hz), 2.72 (2H, t, J=7.3 Hz), 2.18-1.98 (2H, m), 1.92-1.75 (1H, m), 0.82-0.70 (2H, m), 0.60-0.47 (2H, m). Melting point (° C.): 218-220. EXAMPLE 308 6-Chloro-3-[(6-methyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-4-pyridazinol (Compound No. 1096) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.99 (1H, d, J=7.7 Hz), 6.72 (1H, d, J=7.7 Hz), 6.70 (1H, s), 4.53 (2H, t, J=8.8 Hz), 3.20 (2H, br.t, J=8.8 Hz), 2.15 (3H, s). Melting point (° C.): 217-219. EXAMPLE 309 3-[(6-Bromo-1-benzofuran-7-yl)oxy]-6-chloro-4-pyridazinol (Compound No. 1099) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.75 (1H, d, J=2.2 Hz), 7.48 (1H, d, J=8.4 Hz), 7.47 (1H, d, J=8.4 Hz), 6.92 (1H, d, J=2.2 Hz), 6.78 (1H, s) Appearance: amorphous. EXAMPLE 310 6-Chloro-3-[(6-methyl-1-benzofuran-7-yl)oxy]-4-pyridazinol (Compound No. 1100) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.65 (1H, d, J=2.2 Hz), 7.40 (1H, d, J=8.1 Hz), 7.14 (1H, d, J=8.1 Hz), 6.82 (1H, d, J=2.2 Hz), 6.75 (1H, s), 2.31 (3H, s). Appearance: oily product. EXAMPLE 311 6-Chloro-3-[(6-cyclopropyl-1-benzofuran-7-yl)oxy]-4-pyridazol (Compound No. 1102) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.65 (1H, d, J=2.2 Hz), 7.40 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 6.81 (1H, d, J=2.2 Hz), 6.75 (1H, s), 2.10-1.98 (1H, m), 0.98-0.80 (2H, m), 0.80-0.64 (2H, m) Melting point (° C.): 175-180. EXAMPLE 312 6-Chloro-3-[(5-methyl-1-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 1109) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.65 (1H, d, J=2.2 Hz), 7.32 (1H, d, J=8.4 Hz), 7.18 (1H, d, J=8.4 Hz), 6.73 (1H, s), 6.60 (1H, d, J=2.2 Hz), 2.23 (3H, s). Melting point (° C.): 222-225. EXAMPLE 313 6-Chloro-3-(2,4-dicyclopropyl-6-fluorophenoxy)-4-pyridazinol (Compound No. 1115) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.71-6.65 (2H, m), 6.54 (1H, s), 2.02-1.81 (2H, m), 1.01-0.72 (4H, m), 0.68-0.60 (4H, m). Appearance: amorphous. EXAMPLE 314 6-Chloro-3-(2,4-dibromo-3,6-dimethylphenoxy)-4-pyridazinol (Compound No. 1118) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.54 (1H, s), 6.71 (1H, s), 2.56 (3H, s), 2.16 (3H, s). Melting point (° C.): 241-248. EXAMPLE 315 3-(2-Bromo-4,6-dimethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1119) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.31 (1H, brs), 7.10 (1H, brs), 6.74 (1H, s), 2.31 (3H, s), 2.17 (3H, s). Melting point (° C.): 254-256. EXAMPLE 316 6-Chloro-3-(2-ethyl-4,6-diiodophenoxy)-4-pyridazinol (Compound No. 1120) 1H-NMR (200 MHz, CD3OD) δ ppm: 8.03 (1H, d, J=2.2 Hz), 7.66 (1H, d, J=2.2 Hz), 6.74 (1H, s), 2.52 (2H, q, J=7.7 Hz), 1.17 (3H, t, J=7.7 Hz). Melting point (° C.): 142-144. EXAMPLE 317 6-Chloro-3-(2,4,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1122) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.90 (2H, s), 6.71 (1H, s), 2.27 (3H, s), 2.07 (6H, s). Melting point (° C.): 235-239. EXAMPLE 318 6-Chloro-3-(2-cyclopropyl-4,6-dimethylphenoxy)-4-pyridazinol (Compound No. 1123) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.88 (1H, brs), 6.69 (1H, s), 6.63 (1H, brs), 2.26 (3H, s), 2.09 (3H, s), 1.85-1.70 (1H, m), 0.80-0.65 (2H, m), 0.65-0.50 (2H, m). Melting point (° C.): 215-217. EXAMPLE 319 3-(2-Bromo-3,5,6-trimethylphenoxy)-6-chloro-4-pyridazinol (Compound No. 1124) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.13 (1H, s), 6.88 (1H, brs), 2.32 (3H, s), 2.23 (3H, s), 2.01 (3H, s). Melting point (° C.): 280-290. EXAMPLE 320 6-Chloro-3-(2,3,5,6-tetramethylphenoxy)-4-pyridazinol (Compound No. 1125) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.88 (1H, s), 6.69 (1H, s), 2.22 (6H, s), 1.98 (6H, s). Melting point (° C.): 278-283. EXAMPLE 321 6-Chloro-3-[(5,6-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy]-4-pyridazinol (Compound No. 1129) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.72 (1H, s), 6.68 (1H, s), 2.88 (2H, t, J=7.4 Hz), 2.70 (2H, t, J=7.4 Hz), 2.24 (3H, s), 2.17 (3H, s), 2.05 (2H, quintet, J=7.4 Hz). Melting point (° C.): 210-213. EXAMPLE 322 6-Chloro-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yloxy)-4-pyridazinol (Compound No. 1133) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.95 (1H, s), 6.65 (1H, s), 2.88 (4H, t, J=7.3 Hz), 2.68 (4H, t, J=7.3 Hz), 2.20-1.90 (4H, m). Appearance: amorphous. EXAMPLE 323 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl acetate (Compound No. 1140) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.40 (1H, s), 7.26-6.98 (4H, m), 2.40 (3H, s), 1.93-1.76 (1H, m), 0.85-0.59 (4H, m). Appearance: amorphous. EXAMPLE 324 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl acetate (Compound No. 1151) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.39 (1H, s), 7.15-7.00 (2H, m), 6.90-6.75 (1H, m), 2.42 (3H, s), 2.12 (3H, s), 1.90-1.67 (1H, m), 0.85-0.50 (4H, m). Melting point (° C.): 98-101. EXAMPLE 325 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl pivalate (Compound No. 1207) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.15-7.05 (2H, m), 6.90-6.84 (1H, m), 2.13 (3H, s), 1.81-1.65 (1H, m), 1.41 (9H, s), 0.90-0.50 (4H, m). Melting point (° C.): 84-87. EXAMPLE 326 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl decanoate (Compound No. 1251) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.15-7.05 (2H, m), 6.93-6.80 (1H, m), 2.67 (2H, t, J=7.3 Hz), 2.12 (3H, s), 1.85-1.65 (3H, m), 1.55-1.10 (12H, m), 0.95-0.80 (3H, m), 0.80-0.65 (2H, m), 0.65-0.52 (2H, m). Appearance: oily product. EXAMPLE 327 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl cyclopropanecarboxylate (Compound No. 1266) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.43 (1H, s), 7.22-6.98 (4H, m), 2.00-1.75 (2H, m), 1.30-1.08 (4H, m), 0.86-0.51 (4H, m). Melting point (° C.): 122-125. EXAMPLE 328 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl benzoate (Compound No. 1387) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.23-8.18 (2H, m), 7.75-7.50 (3H, m), 7.60 (1H, s) 7.30-7.08 (4H, m), 2.18 (3H, s). Appearance: oily product. EXAMPLE 329 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl benzoate (Compound No. 1391) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20 (2H, d, J=7.3 Hz), 7.74-7.50 (4H, m), 7.26-7.01 (3H, m), 6.98-6.97 (1H, m), 1.91-1.80 (1H, m), 0.83-0.57 (4H, m). Appearance: amorphous. EXAMPLE 330 6-Chloro-3-[4-(trimethylsilyl)phenoxy]-4-pyridazinyl benzoate (Compound No. 1396) Melting point (° C.): 100-102. EXAMPLE 331 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl benzoate (Compound No. 1417) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.24-8.20 (2H, m), 7.75-7.68 (2H, m), 7.67-7.52 (3H, m), 7.09-7.07 (2H, m), 6.87-6.82 (1H, m), 2.16 (3H, s), 1.82-1.71 (1H, m), 0.75-0.71 (2H, m), 0.62-0.53 (2H, m) Appearance: amorphous. EXAMPLE 332 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1446) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.35-8.08 (2H, m), 7.59 (1H, s), 7.68-7.00 (6H, m), 2.70 (3H, s), 2.21 (3H, s). Melting point (° C.): 91-93. EXAMPLE 333 6-Chloro-3-(2-isopropylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1448) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.15-8.00 (2H, m), 7.58 (1H, s), 7.75-6.90 (6H, m), 3.40-2.85 (1H, m), 2.69 (3H, s), 1.15 (6H, d, J=7.0 Hz). Refractive index: nD22 1.5709. EXAMPLE 334 3-(2-s-Butylphenoxy)-6-chloro-4-pyridazinyl 2-methylbenzoate (Compound No. 1450) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.28-8.05 (1H, m), 7.60-7.05 (7H, m), 7.52 (1H, s), 3.05-2.60 (1H, m), 2.65 (3H, s), 1.70-1.00 (2H, m), 1.10 (3H, d, J=7.0 Hz), 0.90-0.50 (3H, m). Appearance: paste state. EXAMPLE 335 6-Chloro-3-(2-cyclohexylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1455) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.30-7.00 (8H, m), 7.54 (1H, s), 2.68 (1H, brs), 2.67 (3H, s), 2.00-1.00 (10H, m). Melting point (° C.): 89-91. EXAMPLE 336 3-([1,1′-Biphenyl]-2-yloxy)-6-chloro-4-pyridazinyl 2-methylbenzoate (Compound No. 1456) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.20-7.90 (1H, m), 7.60-7.10 (13H, m), 2.58 (3H, s). Refractive index: nD28 1.6055. EXAMPLE 337 3-(3-tert-Butylphenoxy)-6-chloro-4-pyridazinyl 2-methylbenzoate (Compound No. 1457) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.28-8.02 (1H, m), 7.55 (1H, s), 7.65-6.85 (7H, m), 2.64 (3H, s), 1.28 (9H, s). Melting point (° C.): 63-64. EXAMPLE 338 6-Chloro-3-(3-methoxyphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1458) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.30-8.00 (1H, m), 7.70-7.10 (4H, m), 7.55 (1H, s), 6.90-6.60 (3H, m), 3.74 (3H, s), 2.64 (3H, s). Melting point (° C.): 66-67. EXAMPLE 339 6-Chloro-3-(2-isopropyl-5-methylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1459) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.30-8.00 (1H, m), 7.54 (1H, s), 7.50-6.80 (6H, m), 3.30-2.75 (1H, m), 2.65 (3H, s), 2.28 (3H, s), 1.15 (6H, d, J=7.00 Hz). Melting point (° C.): 95-97. EXAMPLE 340 6-Chloro-3-(1-naphthyloxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1461) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.20-7.00 (12H, m), 2.65 (3H, s) Melting point (° C.): 133-134. EXAMPLE 341 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 2-methoxybenzoate (Compound No. 1509) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.11-7.89 (2H, m), 7.70-6.80 (6H, m), 7.50 (1H, s), 3.84 (3H, s), 2.10 (3H, s). Melting point (° C.): 114-116. EXAMPLE 342 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-methylbenzoate (Compound No. 1553) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.07 (2H, d, J=8.0 Hz), 7.58 (1H, s), 7.40-7.03 (4H, m), 7.36 (2H, d, J=8.0 Hz), 2.51 (3H, s), 2.23 (3H, s). Melting point (° C.): 105-108. EXAMPLE 343 6-Chloro-3-(2-isopropylphenoxy)-4-pyridazinyl 4-methylbenzoate (Compound No. 1554) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.28-7.82 (2H, m), 7.61 (1H, s), 7.51-6.90 (6H, m), 3.30-2.80 (1H, m), 2.46 (3H, s), 1.19 (6H, d, J=7.0 Hz). Refractive index: nD22 1.5731. EXAMPLE 344 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 2,4-dichlorobenzoate (Compound No. 1603) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.04 (1H, d, J=8.4 Hz), 7.58 (1H, s), 7.58-6.92 (6H, m), 2.20 (3H, s). Melting point (° C.): 81-82.5. EXAMPLE 345 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl methyl carbonate (Compound No. 1658) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.51 (1H, s), 7.23-6.98 (4H, m), 3.99 (3H, s), 1.91-1.82 (1H, m), 0.84-0.61 (4H, m). Appearance: amorphous. EXAMPLE 346 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl ethyl carbonate (Compound No. 1706) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.51 (1H, s), 7.38-7.00 (4H, m), 4.40 (2H, q, J=7.0 Hz), 2.20 (3H, s), 1.40 (3H, t, J=7.0 Hz). Melting point (° C.): 73-74. EXAMPLE 347 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl ethyl carbonate (Compound No. 1710) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.51 (1H s), 7.26-6.98 (4H, m), 4.40 (2H, q, J=7.0 Hz), 1.90-1.80 (1H, m), 1.41 (3H, t, J=7.0 Hz), 0.84-0.60 (4H, m). Appearance: amorphous. EXAMPLE 348 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl isobutyl carbonate (Compound No. 1757) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.45 (1H, s), 7.30-7.00 (4H, m), 4.08 (2H, d, J=5.8 Hz), 2.16 (3H, s), 2.20-1.70 (1H, m), 0.96 (6H, d, J=5.8 Hz). Melting point (° C.): 46-47. EXAMPLE 349 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 2,2,2-trichloroethyl carbonate (Compound No. 1789) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.52 (1H, s), 7.28-7.03 (4H, m), 4.94 (2H, s), 2.18 (3H, s). Appearance: amorphous. EXAMPLE 350 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl phenyl carbonate (Compound No. 1840) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.50-7.20 (5H, m), 7.20-7.05 (2H, m), 6.92-6.82 (1H, m), 2.16 (3H, s), 1.88-1.72 (1H, m), 0.80-0.55 (4H, m). Appearance: oily product. EXAMPLE 351 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl dimethylcarbamate (Compound No. 1877) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.40-6.92 (4H, m), 3.10 (3H, s), 3.01 (3H, s), 2.19 (3H, s). Melting point (° C.): 107-109. EXAMPLE 352 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl dimethylcarbamate (Compound No. 1879) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.22-6.98 (4H, m), 3.13 (3H, s), 3.04 (3H, s), 1.97-1.80 (1H, m), 0.85-0.63 (4H, m). Melting point (° C.): 137-138. EXAMPLE 353 6-Chloro-3-[3-(trifluoromethyl)phenoxy]-4-pyridazinyl dimethylcarbamate (Compound No. 1881) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.60 (1H, s), 7.65-7.22 (4H, m), 3.11 (3H s), 3.05 (3H s). Melting point (° C.): 92-93. EXAMPLE 354 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl diethylcarbamate (Compound No. 1898) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.40-6.92 (4H, m), 3.41 (4H, q, J=6.2 Hz), 2.20 (3H, s), 1.27 (6H, t, J=6.2 Hz). Melting point (° C.): 74-75.5. EXAMPLE 355 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 1-pyrrolidinecarboxylate (Compound No. 1924) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.42-7.02 (4H, m), 3.67-3.37 (4H, m), 2.19 (3H, s), 2.07-1.72 (4H, m). Melting point (° C.): 126-127. EXAMPLE 356 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl methanesulfonate (Compound NO. 1981) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.33-7.06 (4H, m), 3.43 (3H, s), 2.20 (3H, s) Appearance: oily product. EXAMPLE 357 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl methanesulfonate (Compound No. 1985) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.26-7.23 (2H, m), 7.21-7.02 (2H, m), 3.44 (3H, s), 1.89-1.80 (1H, m), 0.86-0.61 (4H, m) Melting point (° C.): 162-172. EXAMPLE 358 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methanesulfonate (Compound No. 2010) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s), 7.18-7.09 (2H, m), 6.91-6.86 (1H, m), 3.47 (3H, s), 2.16 (3H, s), 1.82-1.68 (1H, m), 0.75-0.69 (2H, m), 0.67-0.55 (2H, m). Appearance: amorphous. EXAMPLE 359 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 1-propanesulfonate (Compound No. 2038) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.34-7.05 (4H, m), 3.48 (2H, t, J=7.7 Hz), 2.20 (3H, s), 2.10 (2H, sixtet, J=7.7 Hz), 1.14 (3H, t, J=7.7 Hz). Melting point (° C.): 72-73. EXAMPLE 360 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl 1-propanesulfonate (Compound No. 2040) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.28-7.15 (2H, m), 7.12-6.99 (2H, m), 3.52-3.45 (2H, m), 2.17-1.98 (2H, m), 1.92-1.78 (1H, m), 1.11 (3H, t, J=7.3 Hz), 0.85-0.73 (2H, m), 0.69-0.60 (2H, m). Appearance: paste state. EXAMPLE 361 6-Chloro-3-(2,3-dihydro-1H-inden-4-yloxy)-4-pyridazinyl 1-propanesulfonate (Compound No. 2042) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s), 7.26-7.14 (2H, m), 6.94 (1H, dd, J=7.0, 1.8 Hz), 3.50-3.42 (2H, m), 2.98 (2H, t, J=7.3 Hz), 2.74 (2H, t, J=7.3 Hz), 2.17-1.98 (4H, m), 1.12 (3H, t, J=7.3 Hz). Appearance: paste state. EXAMPLE 362 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-5-iodo-4-pyridazinol (Compound No. 3849) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08-7.05 (2H, m), 6.84-6.80 (1H, m), 2.14 (3H, s), 1.86-1.75 (1H, m), 0.81-0.65 (2H, m), 0.60-0.52 (2H, m) Appearance: amorphous. EXAMPLE 363 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl trifluoromethanesulfonate (Compound No. 2106) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.52 (1H, s), 7.19-7.09 (2H, m), 6.96-6.89 (1H, m), 2.15 (3H, s), 1.81-1.67 (1H, m), 0.73-0.58 (4H, m) Melting point (° C.): 64-67. EXAMPLE 364 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl benzenesulfonate (Compound No. 2147) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.10-7.83 (2H, m), 7.80-7.40 (3H, m), 7.59 (1H, s), 7.30-7.00 (3H, m), 6.90-6.60 (1H, m). Melting point (° C.): 91.5-92. EXAMPLE 365 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl benzenesulfonate (Compound No. 2151) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.02-7.98 (2H, m), 7.78-7.70 (1H, m), 7.62-7.54 (2H, m), 7.58 (1H, s), 7.26-7.09 (2H, m), 6.98-6.93 (1H, m), 6.78-6.69 (1H, m), 1.68-1.54 (1H, m), 0.74-0.52 (4H, m). Appearance: oily product. EXAMPLE 366 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl benzenesulfonate (Compound No. 2176) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07-8.01 (2H, m), 7.80-7.71 (1H, m), 7.65-7.56 (2H, m), 7.60 (1H, s), 7.11-6.99 (2H, m), 6.80 (1H, dd, J=4.4, 2.4 Hz), 1.93 (3H, s), 1.61-1.45 (1H, m), 0.65-0.45 (4H, m). Melting point (° C.): 105-106. EXAMPLE 367 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-chlorobenzenesulfonate (Compound No. 2198) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.94 (2H, d, J=8.4 Hz), 7.60 (1H, s), 7.59 (2H, d, J=8.4 Hz), 7.23-7.09 (3H, m), 6.90-6.60 (1H, m), 2.93 (3H, s). Melting point (° C.): 93-94. EXAMPLE 368 3-(2-Isopropylphenoxy)-4-pyridazinyl 4-chlorobenzenesulfonate (Compound No. 2199) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.91 (2H, d, J=8.4 Hz), 7.62 (1H, s), 7.55 (2H, d, J=8.4 Hz), 7.50-7.00 (3H, m), 6.80-6.60 (1H, m), 3.20-2.50 (1H, m), 1.14 (6H, d, J=7.0 Hz). Refractive index: nD22 1.5315. EXAMPLE 369 3-(2-tert-Butylphenoxy)-6-chloro-4-pyridazinyl 4-chlorobenzenesulfonate (Compound No. 2200) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.05-7.05 (8H, m), 6.70-6.40 (1H, m), 1.26. (9H, s) Melting point (° C.): 83.5-84.5. EXAMPLE 370 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2220) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.83 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.32-6.95 (4H, m), 6.85-6.55 (1H, m), 2.43 (3H, s), 1.98 (3H, s). Melting point (° C.): 102-104. EXAMPLE 371 6-Chloro-3-(2-ethylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2221) Refractive index: nD28 1.5847. EXAMPLE 372 6-Chloro-3-(2-isopropylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2222) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.00-6.50 (8H, m), 7.55 (1H, s), 2.85 (1H, septet, J=7.0 Hz), 2.42 (3H, s), 1.11 (6H, d, J=7.0 Hz). Melting point (° C.): 99-100. EXAMPLE 373 3-(2-s-Butylphenoxy)-6-chloro-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2223) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.98-6.50 (8H, m), 7.52 (1H, s), 2.99-2.31 (1H, m), 2.41 (3H, s), 1.82-0.95 (2H, m), 1.08 (3H, d, J=7.0 Hz), 0.90-0.35 (3H, m). Melting point (° C.): 65-66. EXAMPLE 374 3-(2-tert-Butylphenoxy)-6-chloro-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2224) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.98-7.00 (7H, m), 7.61 (1H s), 6.78-6.45 (1H, m), 2.40 (3H, s), 1.29 (9H, s). Melting point (° C.): 98-99. EXAMPLE 375 5,6-Dichloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3837) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08-7.06 (2H, m), 6.85-6.80 (1H, m), 2,14 (3H, s), 1.87-1.78 (1H, m), 0.81-0.72 (2H, m), 0.64-0.52 (2H, m) Appearance: amorphous. EXAMPLE 376 6-Chloro-3-(2-cyclohexylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2230) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.00-6.50 (8H, m), 7.50 (1H, s), 2.50 (1H, brs), 2.40 (3H, s), 2.00-0.90 (1OH, m). Melting point (° C.): 120-121. EXAMPLE 377 3-([1,1′-Biphenyl]-2-yloxy)-6-chloro-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2231) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.80-6.60 (14H, m), 2.42 (3H, s). Melting point (° C.): 106-108. EXAMPLE 378 6-Chloro-3-(2-methoxyphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2232) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.00-6.70 (8H, m), 7.56 (1H, s), 3.62 (3H, s), 2.44 (3H, s). Melting point (° C.): 153-157. EXAMPLE 379 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl propionate (Compound No. 1160) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.39 (1H, s), 7.14-7.05 (2H, m), 6.89-6.82 (1H, m), 2.72 (2H, q, J=7.6 Hz), 2.12 (3H, s), 1.82-1.68 (1H, m), 1.31 (3H, t, J=7.6 Hz), 0.77-0.53 (4H, m). Melting point (° C.): 75-77. EXAMPLE 380 6-Chloro-3-(3-chlorophenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2234) Refractive index: nD28 1.5970. EXAMPLE 381 3-(3-tert-Butylphenoxy)-6-chloro-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2235) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.73 (2H, d, J=8.2 Hz), 7.49 (1H, s), 7.23 (2H, d, J=8.2 Hz), 7.14 (1H, d, J=4.0 Hz), 6.90-6.45 (3H, m), 2.38 (3H, s), 1.26 (9H, s). Melting point (° C.): 56-57. EXAMPLE 382 6-Chloro-3-[3-(trifluoromethyl)phenoxy]-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2236) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.95-6.93 (9H, m), 2.40 (3H, s). Refractive index: nD25.5 1.5556. EXAMPLE 383 6-Chloro-3-(3-cyanophenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2237) 1H-NMR (90 MHz, CDCl3) δ ppm: 7.85 (2H, d, J=8.0 Hz), 7.70-7.00 (7H, m), 2.49 (3H, s). Appearance: paste state. EXAMPLE 384 6-Chloro-3-(3-methoxyphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2238) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.90-6.30 (8H, m), 7.47 (1H, s), 3.71 (3H, s), 2.40 (3H, s). Melting point (° C.): 89-90. EXAMPLE 385 6-Chloro-3-(1-naphthyloxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2240) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.90-6.80 (12H, m), 2.38 (3H, s). Melting point (° C.): 92-94. EXAMPLE 386 3-(2-Bromo-4-tert-butylphenoxy)-6-chloro-6-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2245) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.89 (2H, d, J=8.4 Hz), 7.63 (1H, s), 7.62-7.18 (3H, m), 6.84 (2H, d, J=8.4 Hz), 2.43 (3H, s), 1.29 (9H, s) Melting point (° C.): 110-112. EXAMPLE 387 6-Chloro-3-(4-chloro-2-methylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2246) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.95-7.75 (2H, m), 7.60-7.00 (5H, m), 6.80-6.60 (1H, m), 2.46 (3H, s), 2.00 (3H, s). Melting point (° C.): 115-116. EXAMPLE 388 6-Chloro-3-(2,4-dimethylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2247) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.94-7.78 (2H, m), 7.54 (1H, s), 7.41-7.23 (2H, m), 7.02-6.53 (3H, m), 2.46 (3H, s), 2.30 (3H, s), 1.96 (3H, s). Melting point (° C.): 80-81. EXAMPLE 389 3-(4-Bromo-2-isopropylphenoxy)-6-chloro-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2248) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.80 (2H, d, J=8.4 Hz), 7.51 (1H, s), 7.45-7.10 (3H, m), 6.56 (2H, d, J=8.4 Hz), 2.85 (1H, septet, J=6.8 Hz), 2.43 (3H, s), 1.10 (6H, d, J=6.8 Hz). Melting point (° C.): 119-122. EXAMPLE 390 6-Chloro-3-(2-isopropyl-5-methylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2249) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.00-6.80 (6H, m), 7.56 (1H, s), 6.46 (1H, brs), 2.95-2.50 (1H, m), 2.44 (3H, s), 2.25 (3H, s), 1.09. (6H, d, J=7.0 Hz). Melting point (° C.): 90-92. EXAMPLE 391 6-Chloro-3-(2,6-dimethylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2263) Melting point (° C.): 89-90. EXAMPLE 392 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methylbenzenesulfonate (Compound No. 2265) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.90 (2H, d, J=8.1 Hz), 7.60 (1H, s), 7.38 (2H, d, J=8.1 Hz), 7.11-7.01 (2H, m), 6.80 (1H, dd, J=6.6, 2.6 Hz), 2.47 (3H, s), 1.93 (3H, s), 1.59-1.46 (1H, m), 0.64-0.45 (4H, m). Melting point (° C.): 85-87. EXAMPLE 393 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-nitrobenzenesulfonate (Compound No. 2287) 1H-NMR (60 MHz, CDCl3) δ ppm: 8.41 (2H, d, J=8.4 Hz), 8.33 (2H, d, J=8.4 Hz), 7.61 (1H, s), 7.30-7.02 (3H, m), 6.95-6.63 (1H, m), 2.03 (3H, s). Melting point (° C.): 166-169. EXAMPLE 394 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl 4-nitrobenzenesulfonate (Compound No. 2289) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.39 (2H, d, J=8.8 Hz), 8.23 (2H, d, J=8.8 Hz), 7.59 (1H, s), 7.20-7.09 (2H, m), 6.97-6.92 (1H, m), 6.77-6.73 (1H, m), 1.67-1.59 (1H, m), 0.78-0.54 (4H, m). Melting point (° C.): 158. EXAMPLE 395 6-Chloro-3-(2-cyclopropylphenoxy)-4-pyridazinyl dimethylsulfamate (Compound No. 2351) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.60 (1H, s), 7.26-7.01 (4H, m), 3.09 (6H, s), 1.95-1.78 (1H, m), 0.85-0.63 (4H, m). Appearance: oily product. EXAMPLE 396 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylpropanoate (Compound No. 1172) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.14-7.05 (2H, m), 6.90-6.83 (1H, m), 2.93 (1H, septet, J=7.0 Hz), 2.13 (3H, s), 1.80-1.66 (1H, m), 1.36 (6H, d, J=7.0 Hz), 0.78-0.56 (4H, m). Melting point (° C.): 38-39. EXAMPLE 397 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl pentanoate (Compound No. 1178) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.13-7.00 (2H, m), 6.90-6.77 (1H, m), 2.68 (2H, t, J=7.3 Hz), 2.12 (3H, s), 1.88-1.65 (3H, m), 1.60-1.35 (2H, m)., 0.95 (3H, t, J=7.3 Hz), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 398 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methylbutanoate (Compound No. 1184) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.14-7.07 (2H, m), 6.89-6.82 (1H, m), 2.55 (2H, d, J=7.0 Hz), 2.27 (1H, br.septet, J=6.8 Hz), 2.12 (3H, s), 1.80-1.67 (1H, m), 1.07 (6H, d, J=6.6 Hz), 0.77-0.55 (4H, m). Melting point (° C.): 71-74. EXAMPLE 399 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl pentadecanoate (Compound No. 1260) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.10-7.00 (2H, m), 6.87-6.77 (1H, m), 2.66 (2H, t, J=6.4 Hz), 2.12 (3H, s), 1.85-1.65 (3H, m), 1.35-1.18 (22H, m), 0.95-0.82 (3H, m), 0.80-0.50 (4H, m). Melting point (° C.): 35-37. EXAMPLE 400 6-Chloro-3-phenoxy-5-(trimethylsilyl)-4-pyridazinol (Compound No. 2402) 1H-NMR (90 MHz, CDCl3) δ ppm: 12.0 (1H, brs), 7.30-6.81 (5H, m), 0.28 (9H, s). Melting point (° C.): 119-120. EXAMPLE 401 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl cyclobutanecarboxylate (Compound No. 1286) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.38 (1H, s), 7.14-7.05 (2H, m), 6.89-6.79 (1H, m), 3.58-3.40 (1H, m), 2.60-1.85 (6H, m), 2.13 (3H, s), 1.82-1.67 (1H, m), 0.80-0.67 (2H, m), 0.64-0.53 (2H, m). Appearance: paste state. EXAMPLE 402 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl cyclohexanecarboxylate (Compound No. 1298) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.15-7.05 (2H, m), 6.90-6.80 (1H, m), 2.78-2.60 (1H, m), 2.12 (3H, s), 1.90-1.20 (1OH, m), 0.80-0.50 (4H, m). Melting point (° C.): oily product. EXAMPLE 403 3-(2-Isopropylphenoxy)-6-methyl-4-pyridazinol (Compound No. 2418) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.35 (1H, m), 7.25-7.16 (2H, m), 7.04-6.98 (1H, m), 6.43 (1H, s), 3.06 (1H, septet, J=7.0 Hz), 2.36 (3H, s), 1.18 (6H, d, J=7.0 Hz). Melting point (° C.): 259-260. EXAMPLE 404 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-bromobutanoate (Compound No. 1334) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.44 (1H, s), 7.14-7.05 (2H, m), 6.90-6.83 (1H, m), 4.45 (1H, t, J=7.6 Hz), 2.22 (1H, dq, J=7.3, 7.6 Hz), 2.13 (3H, s), 1.81-1.69 (1H, m), 1.17 (3H, t, J=7.3 Hz), 0.74-0.69 (2H, m), 0.58-0.56 (2H, m). Appearance: paste state. EXAMPLE 405 3-(2-Isopropylphenoxy)-6-(trifluoromethyl)-4-pyridazinol (Compound No. 2431) 1H-NMR (60 MHz, CDCl3) δ ppm: 7.60-6.70 (4H, m), 6.87 (1H, s), 2.97 (1H, septet, J=7.0 Hz), 1.10 (6H, d, J=7.0 Hz). Melting point (° C.): 126.5. EXAMPLE 406 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chlorobutanoate (Compound No. 1340) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.40 (1H, s), 7.14-7.05 (2H, m), 6.89-6.82 (1H, m), 3.68 (2H, t, J=6.2 Hz), 2.91 (2H, t, J=7.0 Hz), 2.31-2.18 (2H, m), 2.11 (3H, s), 1.79-1.65 (1H, m), 0.80-0.67 (2H, m), 0.63-0.53 (2H, m). Appearance: paste state. EXAMPLE 407 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methyl-2-butenoate (Compound No. 1358) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.44 (1H, s), 7.12-7.05 (2H, m), 6.88-6.80 (1H, m), 5.99-5.97 (1H, m), 2.26 (3H, d, J=1.1 Hz), 2.13 (3H, s) 2.04 (3H, d, J=1.1 Hz), 1.83-1.70 (1H, m), 0.77-0.64 (2H, m), 0.60-0.53 (2H, m). Appearance: paste state. EXAMPLE 408 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl (2E)-3-phenyl-2-propenoate (Compound No. 1364) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.96 (1H, d, J=16.0 Hz), 7.63-7.59 (2H, m), 7.53 (1H, s), 7.48-7.43 (3H, m), 7.09-7.05 (2H, m), 6.86-6.81 (1H, m), 6.66 (1H, d, J=16.0 Hz), 2.16 (3H, s), 1.83-1.75 (1H, m), 0.79-0.54 (4H, m). Appearance: amorphous. EXAMPLE 409 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methyl succinate (Compound No. 1382) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.44 (1H, s), 7.08-7.02 (2H, m), 6.88-6.74 (1H, m), 3.69 (3H, s), 3.01 (2H, t, J=7.3 Hz), 2.78 (2H, t, J=7.3 Hz), 2.11 (3H, s), 1.85-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: oily product. EXAMPLE 410 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chlorobenzoate (Compound No. 1441) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.14 (1H, d, J=8.8 Hz), 7.58 (1H, s), 7.59-7.39 (3H, m), 7.10-7.05 (2H, m), 6.88-6.80 (1H, m), 2.16 (3H, s), 1.90-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: oily product. EXAMPLE 411 3-(2-Methylphenoxy)-6-(2-thienyl)-4-pyridazinol (Compound No. 2478) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56-7.48 (2H, m), 7.21-7.00 (4H, m), 6.97-6.90 (1H, m), 6.69 (1H, s), 2.11 (3H, s). Melting point (° C.): 86-87. EXAMPLE 412 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylbenzoate (Compound No. 1481) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20 (1H, d, J=7.0 Hz), 7.56 (1H, s), 7.52 (1H, d, J=7.7 Hz), 7.40-7.28 (2H, m), 7.10-7.00 (2H, m), 6.90-6.88 (1H, m), 2.69 (3H, s), 2.16 (3H, s), 1.90-1.70 (1H, m), 0.82-0.65 (2H, m), 0.65-0.50 (2H, m). Appearance: oily product. EXAMPLE 413 3,6-Bis(2-methylphenoxy)-4-pyridazinol (Compound No. 2492) 1H-NMR (60 MHz, DMF-d7) δ ppm: 7.40-6.90 (8H, m), 5.79 (1H, s), 2.19 (6H, brs) Melting point (° C.): 247-250. EXAMPLE 414 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methoxybenzoate (Compound No. 1522) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.09 (1H, dd, J=7.9, 2.0 Hz) 7.68-7.57 (1H, m), 7.59 (1H, s), 7.15-7.03 (4H, m), 6.90-6.82 (1H, m), 3.96 (3H, s), 2.17 (3H, s), 1.96-1.72 (1H, m), 0.78-0.65 (2H, m), 0.65-0.51 (2H, m). Appearance: gum state. EXAMPLE 415 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methylbenzoate (Compound No. 1531) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.05-8.00 (2H, m), 7.58 (1H, s), 7.55-7.38 (2H, m), 7.10-7.05 (2H, m), 6.88-6.80 (1H, m), 2.46 (3H, s), 2.16 (3H, s), 1.90-1.68 (1H, m), 0.80-0.50 (4H, m). Appearance: oily product. EXAMPLE 416 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chlorobenzoate (Compound No. 1537) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.16 (2H, d, J=8.8 Hz), 7.59 (1H, s), 7.54 (2H, d, J=8.8 Hz), 7.14-7.07 (2H, m), 6.88-6.83 (1H, m), 2.15 (3H, s), 1.84-1.69 (1H, m), 0.80-0.70 (2H, m), 0.62-0.55 (2H, m). Appearance: amorphous. EXAMPLE 417 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-bromobenzoate (Compound No. 1543) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07 (2H, d, J=8.6 Hz), 7.70 (2H, d, J=8.6 Hz), 7.59 (1H, s), 7.12-7.03 (2H, m), 6.89-6.82 (1H, m), 2.15 (3H, s), 1.83-1.67 (1H, m), 0.78-0.50 (4H, m). Appearance: amorphous. EXAMPLE 418 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-iodobenzoate (Compound No. 1549) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.94 (2H, s), 7.93 (1H, m) 7.62 (1H, s), 7.29 (1H, s), 7.12-7.09 (2H, m), 6.89-6.87 (1H, m), 2.17 (3H, s), 1.84-1.73 (1H, m), 0.79-0.70 (2H, m), 0.62-0.55 (2H, m). Appearance: paste state. EXAMPLE 419 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methylbenzoate (Compound No. 1566) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.10 (2H, d, J=8.1 Hz), 7.60 (1H, s), 7.34 (2H, d, J=8.1 Hz), 7.12-7.03 (2H, m), 6.88-6.81 (1H, m), 2.46 (3H, s), 2.15 (3H, s), 1.85-1.71 (1H, m), 0.78-0.65 (2H, m), 0.62-0.52 (2H, m). Melting point (° C.): 77.5-78. EXAMPLE 420 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-tert-butylbenzoate (Compound No. 1575) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.15 (2H, d, J=8.8 Hz), 7.59 (1H, s), 7.56 (2H, d, J=8.8 Hz), 7.09-7.06 (2H, m), 6.86-6.82 (1H, m), 2.15 (3H, s), 1.37 (9H, s), 1.82-1.73 (1H, m), 0.76-0.69 (2H, m), 0.60-0.56 (2H, m). Melting point (° C.): 139-142. EXAMPLE 421 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-nitrobenzoate (Compound No. 1593) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.41 (4H, s), 7.61 (1H, s) 7.14-7.08 (2H, m), 6.89-6.83 (1H, m), 2.17 (3H, s), 1.81-1.70 (1H, m), 0.80-0.71 (2H, m), 0.62-0.54 (2H, m). Appearance: amorphous. EXAMPLE 422 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methoxybenzoate (Compound No. 1599) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.17 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.12-7.04 (2H, m), 7.01 (2H, d, J=8.8 Hz), 6.88-6.82 (1H, m), 3.90 (1H, s), 2.16 (3H, s), 1.85-1.71 (1H, m), 0.78-0.69 (2H, m), 0.60-0.52 (2H, m). Appearance: amorphous. EXAMPLE 423 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4-dichlorobenzoate (Compound No. 1616) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.11 (1H, d, J=8.4 Hz), 7.60-7.57 (2H, m), 7.42 (1H, dd, J=8.4, 2.2 Hz), 7.14-7.08 (2H, m), 6.89-6.83 (1H, m), 2.15 (3H, s), 1.85-1.72 (1H, m), 0.78-0.67 (2H, m), 0.63-0.54 (2H, m). Appearance: amorphous. EXAMPLE 424 6-Chloro-3-(2-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1620) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.98-7.94 (1H, m), 7.88-7.84 (1H, m), 7.81-7.71 (2H, m), 7.57 (1H, s), 7.28-7.17 (6H, m), 7.08-7.03 (1H, m), 3.70 (3H, s), 2.26 (3H, s), 2.15 (3H, s). Appearance: amorphous. EXAMPLE 425 Potassium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinoate (Compound No. 3811) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.05-6.95 (2H, m), 6.83-6.72 (1H, m), 6.47 (1H, s), 2.00-1.83 (1H, m), 0.80-0.64 (2H, m), 0.64-0.48 (2H, m). Melting point (° C.): 187-189. EXAMPLE 426 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H -pyrazol-5-yl isophthalate (Compound No. 1631) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.61 (1H, t, J=1.5 Hz), 8.54-8.47 (1H, m), 8.22-8.16 (1H, m), 7.71 (1H, t, J=8.1 Hz), 7.61 (1H, s), 7.15-6.96 (4H, m), 6.89-6.82 (1H, m), 3.67 (3H, s), 2.44 (3H, s), 2.17 (3H, s), 1.88-1.72 (1H, m), 0.83-0.71 (2H, m), 0.64-0.53 (2H, m). Appearance: amorphous. EXAMPLE 427 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-furoate (Compound No. 1643) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.74-7.73 (1H, m), 7.56 (1H, s), 7.50 (1H, dd, J=3.7, 0.7 Hz), 7.13-7.04 (2H, m), 6.88-6.81 (1H, m), 6.65-6.63 (1H, m), 2.15 (3H, s), 1.85-1.71 (1H, m), 0.78-0.69 (2H, m), 0.62-0.52 (2H, m). Appearance: paste state. EXAMPLE 428 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-thiophenecarboxylate (Compound No. 1649) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07-8.05 (1H, m), 7.78-7.75 (1H, m), 7,58 (1H, s), 7.24-7.20 (1H, m), 7.13-7.06 (2H, m), 6.89-6.83 (1H, m), 2.16 (3H, s), 1.83-1.71 (1H, m), 0.80-0.70 (2H, m), 0.65-0.55 (2H, m). Appearance: amorphous. EXAMPLE 429 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl isobutyl carbonate (Compound No. 1770) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.49 (1H, s), 7.15-7.05 (2H, m), 6.89-6.82 (1H, m), 4.13 (2H, d, J=6.6 Hz), 2.14 (3H, s), 2.09 (1H, br.septet, J=7.0 Hz), 1.88-1.68 (1H, m), 1.01 (6H, d, J=7.0 Hz), 0.78-0.52 (4H, m). Melting point (° C.): 72-74. EXAMPLE 430 Allyl 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl carbonate (Compound No. 1811) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.50 (1H, s), 7.15-7.06 (2H, m), 6.89-6.82 (1H, m), 6.10-5.90 (1H, m), 5.51-5.35 (2H, m), 4.84-4.80 (2H, m), 2.14 (3H, s), 1.85-1.70 (1H, m), 0.78-0.53 (4H, m). Appearance: oily product. EXAMPLE 431 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl dimethylcarbamate (Compound No. 1891) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H s), 7.13-7.05 (2H, m), 6.89-6.82 (1H, m), 3.16 (3H, s), 3.05 (3H, s), 2.15 (3H, s), 1.85-1.71 (1H, m), 0.78-0.54 (4H, m). Melting point (° C.): 136-138. EXAMPLE 432 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl diethylcarbamate (Compound No. 1911) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.10-7.07 (2H, m), 6.87-6.83 (1H, m), 3.48 (2H, q, J=7.3 Hz), 3.41 (2H, q, J=7.0 Hz), 2.15 (3H, s), 1.82-1.72 (1H, m), 1.29 (3H, t, J=7.3 Hz), 1.23 (3H, t, J=7.0 Hz), 0.74-0.57 (4H, m). Melting point (° C.): 119-121. EXAMPLE 433 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl diisopropylcarbamate (Compound No. 1920) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.61 (1H, s), 7.10-7.00 (2H, m), 6.90-6.85 (1H, m), 4.20-3.90 (2H, m), 2.14 (3H, s), 1.87-1.67 (1H, m), 1.45-1.20 (12H, m), 0.80-0.50 (4H, m). Melting point (° C.): 103-105. EXAMPLE 434 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-thiophenesulfonate (Compound No. 3792) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.89-7.82 (2H, m), 7.58 (1H, s), 7.22-7.13 (1H, m), 7.13-7.02 (2H, m), 6.84-6.79 (1H, m), 1.99 (3H, s), 1.69-1.53 (1H, m), 0.70-0.48 (4H, m). Appearance: amorphous. EXAMPLE 435 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methyl(phenyl)carbamate (Compound No. 1946) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.40-7.25 (6H, m), 7.11-7.08 (2H, m), 6.87-6.82 (1H, m), 3.42 (3H, br.s), 2.15 (3H, br.s), 1.82-1.68 (1H, m), 0.71-0.56 (4H, m). Appearance: amorphous. EXAMPLE 436 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl diphenylcarbamate (Compound No. 1952) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.45-7.28 (11H, m), 7.16-7.09 (2H, m), 6.87-6.82 (1H, m), 2.11 (3H, s), 1.79-1.66 (1H, m), 0.69-0.56 (4H, m). Appearance: amorphous. EXAMPLE 437 O-[6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] S-methyl thiocarbonate (Compound No. 1958) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.47 (1H, s), 7.13-7.06 (2H, m), 6.89-6.83 (1H, m), 2.49 (3H, s), 2.14 (3H, s), 1.83-1.69 (1H, m), 0.78-0.65 (2H, m), 0.63-0.55 (2H, m). Appearance: paste state. EXAMPLE 438 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl ethanesulfonate (Compound No. 2034) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.15-7.05 (2H, m), 6.92-6.82 (1H, m), 3.58 (2H, q, J=7.4 Hz), 2.15 (3H, s), 1.82-1.68 (1H, m), 1.64 (3H, t, J=7.4 Hz), 0.78-0.52 (4H, m). Melting point (° C.): 96-97. EXAMPLE 439 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-propanesulfonate (Compound No. 2051) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.18-7.05 (2H, m), 6.94-6.83 (1H, m), 3.53 (2H, t, J=7.7 Hz), 2.20-2.00 (2H, m), 2.15 (3H, s), 1.82-1.67 (1H, m), 1.15 (3H, t, J=7.7 Hz), 0.80-0.50 (4H, m). Melting point (° C.): 70.5-71.5. EXAMPLE 440 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-propanesulfonate (Compound No. 2060) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.18-7.07 (2H, m), 6.93-6.82 (1H, m), 3.75 (1H, septet, 7.0 Hz), 2.15 (3H, S), 1.85-1.65 (1H, m), 1.65 (6H, d, J=7.0 Hz), 0.78-0.50 (4H, m). Appearance: oily product. EXAMPLE 441 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-octanesulfonate (Compound No. 2066) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.15-7.07 (2H, m), 6.89-6.85 (1H, s), 3.60-3.50 (2H, m), 2.15 (3H, s), 2.15-1.98 (2H, m), 1.83-1.67 (1H, m), 1.58-1.15 (1OH, m), 0.95-0.83 (3H, m), 0.80-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 442 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl chloromethanesulfonate (Compound No. 2072) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.18-7.09 (2H, m), 6.92-6.85 (1H, m), 5.02 (2H, s), 2.16 (3H, s), 1.83-1.68 (1H, m), 0.80-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 443 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,2,2-trifluoroethanesulfonate (Compound No. 2136) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.19-7.05 (2H, m), 6.90 (1H, dd, J=6.6, 2.9 Hz), 4.39 (2H, q, J=8.2 Hz), 2.15 (3H, s), 1.80-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: amorphous. EXAMPLE 444 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chlorobenzenesulfonate (Compound No. 2212) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.01-7.92 (2H, m), 7.62-7.53 (3H, m), 7.13-7.00 (2H, m), 6.85-6.77 (1H, m), 2.04 (3H, s), 1.58-1.45 (1H, m), 0.70-0.45 (4H, m). Appearance: gum state. EXAMPLE 445 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-nitrobenzenesulfonate (Compound No. 2300) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.50-8.39 (2H, m), 8.33-8.20 (2H, m), 7.59 (1H, s), 7.15-7.00 (2H, m), 6.85-6.75 (1H, m), 1.94 (3H, s), 1.65-1.45 (1H, m), 0.75-0.45 (4H, m). Appearance: gum state. EXAMPLE 446 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methoxybenzenesulfonate (Compound No. 2309) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.99-7.91 (2H, m), 7.61 (1H, s), 7.11-6.98 (4H, m), 6.80 (1H, dd, J=2.6 Hz, 6.6 Hz), 3.90 (3H, s), 1.95 (3H, s), 1.60-1.45 (1H, m), 0.70-0.45 (4H, m). Appearance: caramel-like. EXAMPLE 447 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4,6-trimethylbenzenesulfonate (Compound No. 2315) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.13-6.98 (4H, m), 6.85-6.75 (1H, m), 2.70 (6H, s), 2.32 (3H, s), 2.04 (3H, s), 1.65-1.45 (1H, m), 0.78-0.44 (4H, m). Appearance: amorphous. EXAMPLE 448 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4,6-triisopropylbenzenesulfonate (Compound No. 2321) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.52 (1H, s), 7.28-7.20 (2H, m), 7.10-6.98 (2H, m), 6.85-6.75 (1H, m), 4.16 (2H, septet, J=6.6 Hz), 2.93 (1H, septet, J=6.6 Hz), 1.93 (3H, s), 1.75-1.50 (1H, m), 1.35-1.20 (18H, m), 0.75-0.45 (4H, m). Appearance: amorphous. EXAMPLE 449 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H -pyrazol-5-yl 1,2-benzenedisulfonate (Compound No. 2327) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.52-8.40 (1H, m), 8.15-8.07 (1H, m), 8.00-7.82 (2H, m), 7.63 (1H, s), 7.18 (2H, s), 7.15-6.97 (3H, m), 6.79 (1H, dd, J=7.0, 2.6 Hz), 3.84 (3H, s), 2.11 (3H, s), 1.99 (3H, s), 1.75-1.57 (1H, m), 0.74-0.45 (4H, m). Appearance: caramel-like. EXAMPLE 450 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chloro-3-nitrobenzenesulfonate (Compound No. 3786) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.55 (1H, d, J=2.2 Hz), 8.18 (1H, dd, J=8.8, 2.2 Hz), 7.81 (1H, d, J=8.8 Hz), 7.59 (1H, s), 7.13-7.06 (2H, m), 6.84-6.79 (1H, m), 1.98 (3H, s), 1.61-1.48 (1H, m), 0.68-0.52 (4H, m). Appearance: amorphous. EXAMPLE 451 6-Chloro-3-[2-(2-chloro-2-fluorocyclopropyl)phenoxy]-4-pyridazinol (Compound No. 2519) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.42-7.15 (4H, m), 6.70 (1H, s), 2.80-2.62 (1H, m), 2.18-1.65 (2H, m). Melting point (° C.): 175-177. EXAMPLE 452 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dichlorobenzenesulfonate (Compound No. 3780) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.09-8.08 (1H, m), 7.61-7.52 (3H, m), 7.12-7.01 (2H, m), 6.81-6.76 (1H, m), 1.98 (3H, s), 1.67-1.49 (1H, m), 0.82-0.60 (2H, m), 0.58-0.48 (2H, m). Appearance: amorphous. EXAMPLE 453 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 10H-phenothiazine-10-carboxylate (Compound No. 3720) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.76-7.67 (3H, m), 7.49-7.40 (3H, m), 7.40-7.23 (3H, m), 7.20-7.10 (2H, m), 6.95-6.83 (1H, m), 2.19 (3H, s), 1.88-1.70 (1H, m), 0.85-0.57 (4H, m). Appearance: amorphous. EXAMPLE 454 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 9H-carbazole-9-carboxylate (Compound No. 3714) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.40 (2H, d, J=7.4 Hz), 8.02 (2H, d, J=7.0 Hz), 7.99 (1H, s), 7.60-7.35 (4H, m), 7.13-7.03 (2H, m), 6.92-6.80 (1H, m), 2.19 (3H, s), 1.90-1.73 (1H, m), 0.84-0.50 (4H, m). Melting point (° C.): 157-159. EXAMPLE 455 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,4-dihydro-2(1H)-isoquinolinecarboxylate (Compound No. 3708) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.32-7.02 (6H, m), 6.90-6.78 (1H, m), 4.86 (1H, s), 4.72 (1H, s), 3.92 (1H, t, J=5.9 Hz), 3.81 (1H, t, J=5.9 Hz), 3.05-2.95 (2H, m), 2.14 (3H, s), 1.86-1.67 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 456 3-[3-(Benzyloxy)phenoxy]-6-chloro-4-pyridazinol (Compound No. 2547) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.48-7.25 (6H, m), 6.94-6.66 (4H, m), 5.07 (2H, s). Melting point (° C.): 184-185. EXAMPLE 457 3-[4-(Benzyloxy)phenoxy]-6-chloro-4-pyridazinol (Compound No. 2548) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.48-7.28 (5H, m), 7.12-6.96 (4H, m), 6.58 (1H, s), 5.07 (2H, s). Melting point (° C.): 170-180. EXAMPLE 458 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-thiomorpholinecarboxylate (Compound No. 3702) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.15-7.04 (2H, m), 6.92-6.80 (1H, m), 4.05-3.78 (4H, m), 2.75-2.64 (4H, m), 2.13 (3H, s), 1.85-1.65 (1H, m), 0.80-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 459 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-dimethyl-4-morpholinecarboxylate (Compound No. 3696) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.54 (1H, s), 7.18-7.05 (2H, m), 6.94-6.80 (1H, m), 4.17-3.97 (2H, m), 3.78-3.55 (2H, m), 2.95-2.60 (2H, m), 2.14 (3H, s), 1.85-1.67 (1H, m), 1.35-1.15 (6H, m), 0.80-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 460 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-morpholinecarboxylate (Compound No. 3690) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.13-7.06 (2H, m), 6.90-6.83 (1H, m), 3.70-3.55 (8H, m), 2.14 (3H, s), 1.83-1.68 (1H, m), 0.80-0.65 (2H, m), 0.65-0.53 (2H, m). Melting point (° C.): 102.5-103.5. EXAMPLE 461 6-Chloro-3-[(1-methyl-1H-indol-4-yl)oxy]-4-pyridazinol (Compound No. 2565) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.29 (1H, d, J=8.4 Hz), 7.17 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=2.9 Hz), 6.85 (1H, d, J=7.7 Hz), 6.72 (1H, s), 6.23 (1H, d, J=2.9 Hz), 4.87 (3H, s). Melting point (° C.): 203-206. EXAMPLE 462 6-Chloro-3-[(1-methyl-1H-indol-7-yl)oxy]-4-pyridazinol (Compound No. 2568) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.42 (1H, d, J=7.0 Hz), 7.07 (1H, d, J=2.9 Hz), 6.99 (1H, t, J=7.7 Hz), 6.86 (1H, d, J=6,6 Hz), 6.74 (1H, s), 6.44 (1H, d, J=2.9 Hz), 3.80 (3H, s). Melting point (° C.): 219-221. EXAMPLE 463 1-{4-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-3-methylphenyl}ethanone (Compound No. 2570) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.94-7.86 (2H, m), 7.21-7.16 (1H, m), 6.75 (1H, s), 2.60 (3H, s), 2.25 (3H, s). Melting point (° C.): 182-184. EXAMPLE 464 1-{4-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-3-methylphenyl}ethanone O-methyloxime (Compound No. 2571) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.59-7.51 (2H, m), 7.11-7.06 (1H, m), 6.71 (1H, s), 3.95 (3H, s), 2.20 (3H, s). Melting point (° C.): 189-192. EXAMPLE 465 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-phenyl-1-piperazinecarboxylate (Compound No. 3684) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.60 (1H, s), 7.35-7.23 (2H, m), 7.13-7.04 (2H, m), 7.00-6.80 (4H, m), 3.95-3.84 (2H, m), 3.84-3.72 (2H, m), 3.31-3.18 (4H, m), 2.15 (3H, s), 1.86-1.66 (1H, m), 0.80-0.53 (4H, m). Appearance: caramel-like. EXAMPLE 466 4-{[4-(Benzoyloxy)-6-chloro-3-pyridazinyl]oxy}-3-methylphenyl benzoate (Compound No. 3850) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.21-8.17 (4H, m), 7.72-7.48 (7H, m), 7.22-7.07 (3H, m), 2.21 (3H, s). Melting point (° C.): 118-120. EXAMPLE 467 Methyl 3-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-4-methoxybenzoate (Compound No. 2574) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.95 (1H,dd J=8.6, 2.2 Hz), 7.78 (1H, d, J=1.8 Hz), 7.19 (1H, d, J=8.8 Hz), 6.71 (1H, s), 3.87 (3H,s), 3.84 (3H, s). Melting point (° C.): 115-123. EXAMPLE 468 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methyl-1-piperazinecarboxylate (Compound No. 3678) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.15-7.04 (2H, m), 6.90-6.80 (1H, m), 3.80-3.55 (4H, m), 2.54-2.40 (4H, m), 2.32 (3H, s), 2.14 (3H, s), 1.85-1.67 (1H, m), 0.80-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 469 6-Chloro-3-(2-isopropenyl-6-methylphenoxy)-4-pyridazinol (Compound No. 2577) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.20-7.10 (3H, m), 6.66 (1H, s), 5.01 (1H, m), 4.95 (1H, m), 2.15 (3H, s), 1.99 (3H, s). Melting point (° C.): 183-186. EXAMPLE 470 6-Chloro-3-[(1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)oxy-4-pyridazinol (Compound No. 2585) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.15 (1H, d, J=8.1 Hz), 6.95 (2H, br.d, J=8.1 Hz), 6.68 (1H, s), 2.89 (2H, t, J=7.3 Hz), 1.96 (2H, t, J=7.3 Hz), 1.27 (6H, s). Melting point (° C.): 209-212. EXAMPLE 471 3-(3-Bromo-6-cyclopropyl-2-methylphenoxy)-6-chloro-4-pyridazinol (Compound No. 2587) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.38 (1H, d, J=8.4 Hz), 6.78 (1H, d, J=8.4 Hz), 6.72 (1H, s), 2.22 (3H, s), 1.85-1.72 (1H, m), 0.85-0.72 (2H, m), 0.65-0.50 (2H, m). Melting point (° C.): 234-235. EXAMPLE 472 6-Chloro-3-(6-cyclopropyl-2-methyl-3-nitrophenoxy)-4-pyridazinol (Compound No. 2589) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.80 (1H, d, J=8.4 Hz), 7.02 (1H, d, J=8.4 Hz), 6.77 (1H, s), 2.32 (3H, s), 1.99-1.88 (1H, m), 0.95-0.88 (2H, m), 0.74-0.70 (2H, m). Melting point (° C.): 140-143. EXAMPLE 473 6-Chloro-3-[(5-methyl-1,3-dihydro-2-benzofuran-4-yl)oxy]-4-pyridazinol (Compound No. 2592) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.20 (1H, d, J=7.7 Hz), 7.08 (1H, d, J=7.7 Hz), 5.06 (2H, br.s), 4.88 (2H, br.s), 2.16 (3H, s). Melting point (° C.): 188-200. EXAMPLE 474 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,2,6,6-tetramethyl-1-piperidinecarboxylate (Compound No. 3672) 1H-NMR (200 MHz, CDCl3) δ ppm: 7,53 (1H, s), 7.14-7.03 (2H, m), 6.90-6.78 (1H, m), 2.13 (3H, s), 1.90-1.62 (7H, m), 1.55 (12H, s), 0.80-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 475 6-Chloro-3-(2-fluoro-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2597) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.92 (1H, d, J=7.0 Hz), 6.73 (1H, s), 2.24 (3H, s), 2.21 (3H, s), 2.06 (3H, s). Melting point (° C.): 258-260. EXAMPLE 476 6-Chloro-3-(2-chloro-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2599) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 7.11 (1H, s), 6.86 (1H, br.s), 2.29 (3H,s), 2.24 (3H, s), 1.99 (3H, s). Melting point (° C.): 298-300. EXAMPLE 477 6-Chloro-3-(2-iodo-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2600) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.06 (1H, s), 6.75 (1H, s) 2.40 (3H, s), 2.26 (3H, s), 2.09 (3H, s). Melting point (° C.): 235 (decomposed). EXAMPLE 478 6-Chloro-3-(2-ethyl-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2601) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 6.95 (1H, s), 6.81 (1H, br.s), 2.32 (2H, q, J=7.5 Hz), 2.24 (3H, s), 2.12 (3H, s), 1.94 (3H, s), 1.04 (3H, t, J=7.5 Hz). Melting point (° C.): 188-195. EXAMPLE 479 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1,4-dioxa-8-azaspiro[4.5]decan-8-carboxylate (Compound No. 3666) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.15-7.04 (2H, m), 6.92-6.80 (1H, m), 3.99 (4H, s), 3.85-3.62 (4H, m), 2.14 (3H, s), 1.85-1.65 (5H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 480 6-Chloro-3-(2-isopropenyl-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2605) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.91 (1H, s), 6.58 (1H, s), 5.00-4.90 (2H, bm), 2.27 (3H, s), 2.20 (3H, s), 2.07 (3H, s), 1.96 (3H, s). Appearance: amorphous. EXAMPLE 481 1-[6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 4-ethyl 1,4-piperidinedicarboxylate (Compound No. 3660) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s) 7.13-7.04 (2H, m), 6.90-6.80 (1H, m), 4.30-4.00 (2H, m), 3.35-3.02 (2H, m), 2.65-2.45 (1H, m), 2.14 (3H, s), 2.10-1.93 (3H, m), 1.93-1.65 (4H, m), 1.25 (3H, t, J=7.0 Hz), 0.80-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 482 1-{2-[(6-Chloro-4-hydroxy3-pyridazinyl)oxy]-3,4,6-trimethylphenyl}ethanone (Compound No. 2607) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55 (1H, s), 6.72 (1H, s) 2.45 (3H, s), 2.36 (3H, s), 2.29 (3H, s), 2.11 (3H, s). Appearance: amorphous. EXAMPLE 483 6-Chloro-3-(2,3,5-trimethyl-6-nitrophenoxy)-4-pyridazinol (Compound No. 2608) 1H-NMR (200 MHz, CD3OD) δ ppm: 7.11 (1H, s), 6.65 (1H, s), 2.33 (3H, s), 2.28 (3H, s), 2.05 (3H, s). Melting point (° C.): 172-174. EXAMPLE 484 6-Chloro-3-(2,4-dichloro-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 2609) 1H-NMR (200 MHz, DMSO-d6) δ ppm: 6.91 (1H, s), 2.46 (3H, s), 2.36 (3H, s), 2.10 (3H, s). EXAMPLE 485 6-Chloro-3-(2,3,4,5,6-pentamethylphenoxy)-4-pyridazinol (Compound No. 2614) 1H-NMR (200 MHz, CD3OD) δ ppm: 6.69 (1H, s), 2.23 (3H, s), 2.21 (6H, s), 2.02 (6H, s). Melting point (° C.): 238-240 (decomposed). EXAMPLE 486 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,3-dimethylbutanoate (Compound No. 2662) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.13-7.05 (2H, s), 6.88-6.82 (1H, s), 2.55 (2H, s), 2.12 (3H, s), 1.82-1.67 (1H, m), 1.15 (9H, s), 0.80-0.65 (2H, m), 0.63-0.52 (2H, m). Melting point (° C.): 91-92. EXAMPLE 487 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-adamantanecarboxylate (Compound No. 2671) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.12-7.05 (2H, m), 6.92-6.80 (1H, m), 2.13 (3H, s), 2.08 (9H, s), 1.76 (7H, br.s), 0.85-0.45 (4H, m). Appearance: oily product. EXAMPLE 488 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylacrylate (Compound No. 2677) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.48 (1H, s), 7.14-7.05 (2H, m), 6.89-6.83 (1H, m), 6.46 (1H, br.s), 5.91 (1H, br.s), 2.13 (3H, s), 2.09 (3H, s), 1.81-1.68 (1H, m), 0.78-0.53 (4H, m). Melting point (° C.): 98-100. EXAMPLE 489 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-bromo-2-methylpropanoate (Compound No. 2697) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.47 (1H, s), 7.11-7.08 (2H, m), 6.89-6.85 (1H, m), 2.13 (3H, s), 2.10 (6H, s), 1.77-1.69 (1H, m), 0.74-0.58 (4H, m). Melting point (° C.): 69-71. EXAMPLE 490 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-chloro-2,2-dimethylpropanoate (Compound No. 2703) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.43 (1H, s), 7.13-7.05 (2H, m), 6.90-6.84 (1H, m), 3.76 (2H, s), 2.13 (3H, s), 1.83-1.65 (1H, m), 1.50 (6H, s), 0.85-0.45 (4H, br.s). Melting point (° C.): 112-115. EXAMPLE 491 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-bromopentanoate (Compound No. 2709) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.83 (1H, s), 7.11-7.05 (2H, m), 6.86-6.82 (1H, m), 3.43 (2H, d, J=6.2 Hz), 2.73 (2H, d, J=7.0 Hz), 2.12 (3H, s), 2.04-1.93 (4H, m), 1.77-1.69 (1H, m), 0.74-0.56 (4H, m). Appearance: caramel-like. EXAMPLE 492 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl hydratropate (Compound No. 2715) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.42-7.20 (5H, m), 7.32 (1H, s), 7.15-7.02 (2H, m), 6.86-6.75 (1H, m), 4.20-4.00 (1H, m), 2.04 (3H, s), 1.66 (3H, d, J=7.0 Hz), 1.70-1.50 (1H, m), 0.70-0.42 (4H, m). Appearance: oily product. EXAMPLE 493 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl (4-methoxyphenyl)acetate (Compound No. 2721) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.37 (1H, s), 7.27 (2H, d, J=8.2 Hz), 7.13-7.05 (2H, m), 6.89-6.80 (3H, m), 3.91 (2H, s), 3.76 (3H, s), 2.07 (3H, s), 1.73-1.60 (1H, m), 0.75-0.50 (4H, m). Appearance: paste state. EXAMPLE 494 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl ethyl succinate (Compound No. 2727) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.08-6.92 (2H, m), 6.85-6.68 (1H, m), 6.55 (1H, s), 4.14 (2H, br.q, J=7.1 Hz), 3.00 (1H, t, J=7.0 Hz), 2.76 (1H, t, J=7.0 Hz), 2.61 (2H, br.s), 1.98 (3H, s), 1.78-1.60 (1H, m), 1.25 (3H, t, J=7.1 Hz), 0.75-0.40 (4H, m). Appearance: amorphous. EXAMPLE 495 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methyl-1-piperidinecarboxylate (Compound No. 3654) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s), 7.14-7.04 (2H, m), 6.90-6.80 (1H, m), 4.35-4.10 (2H, m), 3.15-2.80 (2H, m), 2.14 (3H, s), 1.85-1.50 (4H, m), 1.35-1.06 (2H, m), 0.96 (3H, d, J=6.2 Hz), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 496 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-bromo-1-piperidinecarboxylate (Compound No. 3648) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.15-7.04 (2H, m), 6.90-6.80 (1H, m), 4.54-4.38 (1H, m), 4.00-3.53 (4H, m), 2.30-1.90 (7H, m), 1.85-1.67 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 497 Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] succinate (Compound No. 2733) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.32 (2H, s), 7.14-7.03 (4H, m), 6.88-6.81 (2H, m), 3.17 (4H, s), 2.10 (6H, s), 1.80-1.65 (2H, m), 0.78-0.53 (8H, m). Appearance: caramel-like. EXAMPLE 498 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxyacetate (Compound No. 2752) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.43 (1H, s), 7.15-7.04 (2H, m), 6.90-6.82 (1H, m), 4.41 (2H, s), 3.55 (3H, s), 2.12 (3H, s), 1.82-1.67 (1H, m), 0.80-0.67 (2H, m), 0.64-0.55 (2H, m). Appearance: paste state. EXAMPLE 499 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl phenoxyacetate (Compound No. 2758) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.42 (1H, s), 7.29-7.25 (2H, m), 7.23-6.96 (5H, m), 6.89-6.83 (1H, m), 5.00 (2H, s), 2.08 (3H, s), 1.73-1.64 (1H, m), 0.71-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 500 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-phenoxypropanoate (Compound No. 2764) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.33 (1H, s), 7.25-7.19 (2H, m), 7.17-7.04 (2H, m), 7.00-6.91 (3H, m), 6.86-6.82 (1H, m), 5.09 (1H, q, J=6.6 Hz), 2.05 (3H, s), 1.84 (3H, d, J=6.6 Hz), 1.64-1.58 (1H, m), 0.68-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 501 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxy(phenyl)acetate (Compound No. 2770) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56-7.51 (2H, m), 7.40-7.30 (4H, m), 7.12-7.02 (2H, m), 6.83-6.78 (1H, m), 5.10 (1H, s), 3.52 (3H, s), 2.01 (3H, s), 1.67-1.50 (1H, m), 0.70-0.43 (4H, m). Appearance: paste state. EXAMPLE 502 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-(methylsulfanyl)propanoate (Compound No. 2776) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.42 (1H, s), 7.10-7.00 (2H, m), 6.90-6.77 (1H, m), 3.07-2.83 (4H, m), 2.17 (3H, s), 2.12 (3H, s), 1.85-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 503 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl oxo(2-thienyl)acetate (Compound No. 2782) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07 (1H, dd, J=1.5 Hz, 4.1 Hz), 7.77 (1H, dd, J=1.5 Hz, 4.1 Hz), 7.58 (1H, s), 7.22 (1H, t, J=4.0 Hz), 7.10-7.02 (2H, m), 6.90-6.77 (1H, m), 2.15 (3H, s), 1.90-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 504 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-fluorobenzoate (Compound No. 2788) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.17-8.09 (1H, m), 7.73-7.62 (1H, m), 7.57 (1H, s), 7.36-7.20 (2H, m), 7.09-7.07 (2H, m), 6.87-6.82 (1H, m), 2.16 (3H, s), 1.85-1.72 (1H, m), 0.76-0.56 (4H, m). Appearance: amorphous. EXAMPLE 505 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-bromobenzoate (Compound No. 2805) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20-8.05 (1H, m), 7.85-7.70 (1H, m), 7.59 (1H, s), 7.55-7.38 (2H, m), 7.15-7.00 (2H, m), 6.90-6.80 (1H, m), 2.17 (3H, s), 1.88-1.70 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 506 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-iodobenzoate (Compound No. 2814) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20-8.05 (2H, m), 7.60-7.44 (2H, m), 7.35-7.20 (1H, m), 7.13-7.00 (2H, m), 6.90-6.78 (1H, m), 2.17 (3H, s), 1.90-1.72 (1H, m), 0.85-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 507 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-(trifluoromethyl)benzoate (Compound No. 2820) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.13-8.09 (1H, m), 7.91-7.86 (1H, m), 7.76-7.72 (2H, m), 7.55 (1H, s), 7.11-7.06 (2H, m), 6.88-6.83 (1H, m), 2.16 (3H, s), 1.86-1.71 (1H, m), 0.75-0.56 (4H, m). Appearance: caramel-like. EXAMPLE 508 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-benzylbenzoate (Compound No. 2826) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.22-8.18 (1H, d, J=7.2 Hz) 7.62-7.54 (1H, t, J=7.6 Hz), 7.44-7.06 (1OH, m), 6.85-6.81 (1H, m), 4.46 (1H, s), 2.11 (3H, s), 1.80-1.67 (1H, m), 0.75-0.64 (2H, m), 0.60-0.52 (2H, m). Appearance: paste state. EXAMPLE 509 Bis[6-chloro-3-(2-methylphenoxy)-4-pyridazinyl] phthalate (Compound No. 2827) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.06 (2H, dd, J=6.0, 3.4 Hz) 7.57 (2H, s), 7.25-7.15 (8H, m), 7.05-7.01 (2H, m), 2.14 (6H, s). Melting point (° C.): 157-158. EXAMPLE 510 1-[6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 2-methyl 1,2-piperidinedicarboxylate (Compound No. 3642) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.60 (0.5H, s), 7.59 (0.5H, s), 7.14-7.03 (2H, m), 6.92-6.80 (1H, m), 5.10-4.90 (1H, m), 4.32-4.06 (1H, m), 3.73 (1.5H, s), 3.71 (1.5H, s), 3.40-3.05 (1H, m), 2.43-2.20 (1H, m), 2.15 (1.5H, s), 2.13 (1.5H, s), 2.00-1.20 (6H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 511 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-nitrobenzoate (Compound No. 2850) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.15-8.05 (1H, m), 7.95-7.72 (3H, m), 7.65 (1H, s), 7.14-7.05 (2H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.85-1.70 (1H, m), 0.78-0.65 (2H, m), 0.65-0.50 (2H, m). Appearance: oily product. EXAMPLE 512 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-phenoxybenzoate (Compound No. 2856) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.35 (1H, dd, J=8.2, 1.8 Hz), 8.15 (1H, dd, J=8.0, 1.8 Hz), 7.74 (1H, dt, J=7.0, 1.4 Hz), 7.61-7.21 (5H, m), 7.15-6.98 (4H, m), 6.84-6.79 (1H, m), 2.09 (3H, s), 1.80-1.68 (1H, m), 0.70-0.71 (2H, m), 0.59-0.51 (2H, m). Appearance: paste state. EXAMPLE 513 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-chlorobenzoate (Compound No. 2868) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.18 (1H, d, J=1.8 Hz), 8.10 (1H, d, J=8.1 Hz), 7.68 (1H, br.d, J=9.2 Hz), 7.57 (1H, s), 7.50 (1H, t, J=8.1 Hz), 7.08 (1H, d, J=5.8 Hz), 7.07 (1H, d, J=3.7 Hz), 6.85 (1H, dd, J=5.8, 3.7 Hz), 2.15 (3H, s), 1.85-1.66 (1H, m), 0.80-0.50 (4H, m). Appearance: amorphous. EXAMPLE 514 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-fluorobenzoate (Compound No. 2862) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.02 (1H, dd, J=6.2, 1.5 Hz), 7.89 (1H, br.d, J=8.8 Hz), 7.60-7.34 (2H, m), 7.59 (1H, s), 7.13-7.04 (2H, m), 6.90-6.78 (1H, m), 2.15 (3H, s), 1.83-1.68 (1H, m), 0.80-0.50 (4H, m). Appearance: oily product. EXAMPLE 515 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-bromobenzoate (Compound No. 2874) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.33 (1H, s), 8.14 (1H, d, J=8.0 Hz), 7.82 (1H, d, J=8.0 Hz), 7.56 (1H, s), 7.43 (1H, t, J=8.0 Hz), 7.13-7.03 (2H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.85-1.68 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 516 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-iodobenzoate (Compound No. 2880) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.54 (1H, d, J=1.8 Hz), 8.20-8.15 (1H, m), 8.03 (1H, d, J=8.1 Hz), 7.56 (1H, s), 7.34-7.26 (1H, m), 7.13-7.05 (2H, m), 6.89-6.82 (1H, m), 2.15 (3H, s), 1.83-1.71 (1H, m), 0.80-0.68 (2H, m), 0.65-0.52 (2H, m). Appearance: amorphous. EXAMPLE 517 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-(trifluoromethyl)benzoate (Compound No. 2900) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.47 (1H, s), 8.41 (1H, d, J=7.7 Hz), 7.96 (1H, d, J=7.3 Hz), 7.75-7.67 (1H, m), 7.58 (1H, s), 7.12-7.06 (2H, m), 6.89-6.82 (1H, m), 2.16 (3H, s), 1.84-1.71 (1H, m), 0.80-0.53 (4H, m). Appearance: caramel-like. EXAMPLE 518 Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] isophthalate (Compound No. 2906) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.02 (1H, s), 8.53 (2H, d, J=8.2 Hz), 7.78 (1H, t, J=7.8 Hz), 7.58 (2H, s), 7.08-7.06 (4H, m), 6.86-6.82 (2H, m), 2.14 (6H, s), 1.83-1.68 (2H, m), 0.78-0.69 (4H, m), 0.60-0.53 (4H, m). Appearance: paste state. EXAMPLE 519 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-nitrobenzoate (Compound No. 2918) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.05-9.04 (1H, m), 8.59-8.52 (2H, m), 7.79 (1H, t, J=7.7 Hz), 7.59 (1H, s), 7.13-7.07 (2H, m), 6.89-6.82 (1H, m), 2.15 (3H, s), 1.83-1.72 (1H, m), 0.80-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 520 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-phenoxybenzoate (Compound No. 2924) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.95-7.90 (1H, m), 7.80-7.78 (1H, m), 7.57 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.40-7.30 (3H, m), 7.17-7.10 (1H, m), 7.09-7.03 (3H, m), 7.07 (1H, s), 6.87-6.82 (1H, m), 2.13 (3H, s), 1.81-1.67 (1H, m), 0.78-0.66 (2H, m). 0.59-0.54 (2H, m). Appearance: paste state. EXAMPLE 521 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-fluorobenzoate (Compound No. 2930) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.30-8.18 (2H, m), 7.59 (1H, s), 7.30-7.15 (2H, m), 7.15-7.02 (2H, m), 6.90-6.78 (1H, m), 2.15 (3H, s), 1.85-1.70 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 522 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-ethylbenzoate (Compound No. 2961) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.13 (2H, d, J=8.5 Hz), 7.60 (1H, s), 7.36 (2H, d, J=8.5 Hz), 7.12-7.04 (2H, m), 6.88-6.81 (1H, m), 2.75 (2H, q, J=7.6 Hz), 2.04 (3H, s), 1.85-1.71 (1H, m), 1.28 (3H, t, J=7.6 Hz), 0.79-0.65 (2H, m), 0.61-0.52 (2H, m) Appearance: paste state. EXAMPLE 523 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-propylbenzoate (Compound No. 2970) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.12 (2H, d, J=8.4 Hz), 7.59 (1H, s), 7.34 (2H, d, J=8.4 Hz), 7.12-7.05 (2H, m), 6.88-6.81 (1H, m), 2.69 (2H, t, J=7.3 Hz), 2.16 (3H, s), 1.85-1.60 (3H, m), 0.96 (3H, t, J=7.3 Hz), 0.80-0.68 (2H, m), 0.63-0.52 (2H, m). Appearance: paste state. EXAMPLE 524 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-isopropylbenzoate (Compound No. 2976) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.14 (2H, d, J=8.4 Hz), 7.59 (1H, s), 7.40 (2H, d, J=8.4 Hz), 7.12-7.05 (2H, m), 6.90-6.82 (1H, m), 3.01 (1H, septet, J=7.0 Hz), 2.15 (3H, s), 1.85-1.70 (1H, m), 1.29 (6H, d, J=7.0 Hz), 0.80-0.65 (2H, m), 0.63-0.52 (2H, m). Appearance: paste state. EXAMPLE 525 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-butylbenzoate (Compound No. 2982) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.12 (2H, d, J=8.1 Hz), 7.59 (1H, s), 7.35 (2H, d, J=8.1 Hz), 7.12-7.03 (2H, m), 6.89-6.81 (1H, m), 2.72 (2H, t, J=7.3 Hz), 2.16 (3H, s), 1.85-1.57 (3H, m), 1.47-1.22 (2H, m), 0.94 (3H, t, J=7.3 Hz), 0.80-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 526 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(trifluoromethyl)benzoate (Compound No. 2988) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.34 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.14-7.07 (2H, m), 6.89-6.83 (1H, m), 2.15 (3H, s), 1.83-1.72 (1H, m), 0.79-0.71 (2H, m), 0.63-0.54 (2H, m). Melting point (° C.): 127-128. EXAMPLE 527 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-cyanobenzoate (Compound No. 2994) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.33 (2H, d, J=8.8 Hz), 7.86 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.14-7.07 (2H, m), 6.89-6.83 (1H, m), 2.14. (3H, s), 1.82-1.68 (1H, m), 0.79-0.53 (4H, m). Appearance: caramel-like. EXAMPLE 528 Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] terephthalate (Compound No. 3001) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.39 (4H, s), 7.62 (2H, s) 7.10-7.07 (4H, m), 6.87-6.83 (2H, m), 2.15 (6H, s), 1.81-1.68 (2H, m), 0.78-0.70 (4H, m), 0.61-0.53 (4H, m). Melting point (° C.): 247-249. EXAMPLE 529 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl [1,1′-biphenyl]-4-carboxylate (Compound No. 3016) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.31-8.23 (2H, m), 7.79-7.74 (2H, m), 7.67-7.62 (3H, m), 7.54-7.42 (3H, m), 7.09-7.06 (2H, m), 6.87-6.82 (1H, m), 2.17 (3H, s), 1.84-1.75 (1H, m), 0.77-0.56 (4H, m). Melting point (° C.): 135-137. EXAMPLE 530 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(trifluoromethoxy)benzoate (Compound No. 3022) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.28 (2H, d, J=9.2 Hz), 7.59 (1H, s), 7.38 (2H, d, J=9.2 Hz), 7.14-7.04 (2H, m), 6.89-6.82 (1H, m), 2.15 (3H, s), 1.83-1.69 (1H, m), 0.78-0.65 (2H, m), 0.62-0.53 (2H, m) Appearance: paste state. EXAMPLE 531 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(benzyloxy)benzoate (Compound No. 3028) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.16 (2H, d, J=9.2 Hz), 7.60 (1H, s), 7.50-7.30 (5H, m), 7.10-7.03 (4H, m), 6.89-6.82 (1H, m), 5.17 (2H, s), 2.15 (3H, s), 1.85-1.72 (1H, m), 0.80-0.68 (2H, m), 0.65-0.53 (2H, m). Appearance: paste state. EXAMPLE 532 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,3-difluorobenzoate (Compound No. 3034) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.93-7.85 (1H, m), 7.57 (1H, s), 7.57-7.44 (1H, m), 7.32-7.21 (1H, m), 7.10-7.05 (2H, m), 6.87-6.82 (1H, m), 2.15 (3H, s), 1.81-1.73 (1H, m), 0.76-0.72 (2H, m), 0.60-0.56 (2H, m). Appearance: paste state. EXAMPLE 533 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-fluoro-3-(trifluoromethyl)benzoate (Compound No. 3040) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.36-8.28 (1H, m), 7.99-7.92 (1H, m), 7.56 (1H, s), 7.49-7.41 (1H, m), 7.13-7.05 (2H, m), 6.89-6.83 (1H, m), 2.15 (3H, s), 1.84-1.72 (1H, m), 0.80-0.54 (4H, m). Appearance: amorphous. EXAMPLE 534 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,3-dimethylbenzoate (Compound No. 3046) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.00-7.96 (1H, m), 7.54 (1H, s), 7.45-7.41 (1H, m), 7.27-7.20 (1H, m), 7.14-7.05 (2H, m), 6.89-6.82 (1H, m), 2.57 (3H, s), 2.37 (3H, s), 2.16 (3H, s), 1.86-1.72 (1H, m), 0.79-0.69 (2H, m), 0.61-0.53 (2H, m). Appearance: paste state. EXAMPLE 535 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-chloro-2-methylbenzoate (Compound No. 3052) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.04 (1H, d, J=8.1 Hz), 7.65 (1H, d, J=8.1 Hz), 7.54 (1H, s), 7.33-7.25 (1H, m), 7.13-7.06 (2H, m), 6.89-6.83 (1H, m), 2.73 (3H, s), 2.15 (3H, s)., 1.83-1.71 (1H, m), 0.79-0.68 (2H, m), 0.65-0.53 (2H, m). Appearance: amorphous. EXAMPLE 536 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4-difluorobenzoate (Compound No. 3058) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.23-8.12 (1H, m), 7.56 (1H, s), 7.10-6.94 (4H, m), 6.87-6.82 (1H, m), 2.15 (3H, s), 1.81-1.73 (1H, m), 0.75-0.56 (4H, m). Appearance: amorphous. EXAMPLE 537 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chloro-2-fluorobenzoate (Compound No. 3064) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07 (1H, dd, J=7.4 Hz, 8.5 Hz), 7.55 (1H, s), 7.38-7.22 (2H, m), 7.14-7.03 (2H, m), 6.90-6.78 (1H, m), 2.15 (3H, s), 1.85-1.68 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 538 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-fluoro-4-(trifluoromethyl)benzoate (Compound No. 3070) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.30-8.22 (1H, m), 7.61-7.52 (2H, m), 7.57 (1H, s), 7.14-7.05 (2H, m), 6.87-6.82 (1H, m), 2.15 (3H, m), 1.83-1.69 (1H, m), 0.78-0.70 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 539 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chloro-4-fluorobenzoate (Compound No. 3076) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.25-8.18 (1H, m), 7.57 (1H, s), 7.34-7.29 (1H, m), 7.19-7.05 (3H, m), 6.89-6.82 (1H, m), 2.15 (3H, m), 1.84-1.70 (1H, m), 0.79-0.68 (2H, m), 0.64-0.53 (2H, m). Appearance: paste state. EXAMPLE 540 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-bromo-2-chlorobenzoate (Compound No. 3082) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.01 (1H, d, J=8.4 Hz), 7.76 (1H, d, J=1.8 Hz), 7.60-7.55 (2H, m), 7.10-7.07 (2H, m), 6.87-6.83 (1H, m), 2.15 (3H, s), 1.83-1.71 (1H, m), 0.77-0.71 (2H, m), 0.62-0.56 (2H, m). Appearance: paste state. EXAMPLE 541 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-bromo-2-methylbenzoate (Compound No. 3088) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.05 (1H, d, J=8.4 Hz), 7.56-7.48 (3H, m), 7.09-7.07 (2H, m), 6.86-6.82 (1H, m), 2.14 (3H, s), 2.04 (3H, s), 1.85-1.72 (1H, m), 0.79-0.71 (2H, m), 0.64-0.55 (2H, m). Appearance: paste state. EXAMPLE 542 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4-dimethylbenzoate (Compound No. 3094) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.11 (1H, d, J=8.9 Hz), 7.57 (1H, s), 7.16-7.13 (2H, m), 7.09-7.05 (2H, m), 6.88-6.81 (1H, m), 2.65 (3H, s), 2.41 (3H, s), 2.15 (3H, s), 1.85-1.71 (1H, m), 0.80-0.68 (2H, m), 0.67-0.55 (2H, m). Appearance: paste state. EXAMPLE 543 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dichlorobenzoate (Compound No. 3100) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.10 (1H, d, J=2.2 Hz), 7.60-7.45 (3H, m), 7.15-7.04 (2H, m), 6.90-6.78 (1H, m), 2.15 (3H, s), 1.85-1.70 (1H, m), 0.80-0.50 (4H, m). Melting point (° C.): 128-130. EXAMPLE 544 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-bromo-2-chlorobenzoate (Compound No. 3106) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20 (1H, d, J=2.2 Hz), 7.68 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.54 (1H, s), 7.43 (1H, d, J=8.4 Hz), 7.14-7.03 (2H, m), 6.92-6.80 (1H, m), 2.15 (3H, s), 1.87-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 545 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-bromo-5-methoxybenzoate (Compound No. 3112) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.67-7.57 (3H, m), 7.12-7.00 (3H, m), 6.87-6.82 (1H, m), 3.85 (3H, s), 2.16 (3H, s), 1.87-1.75 (1H, m), 0.80-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 546 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dimethylbenzoate (Compound No. 3129) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.99 (1H, s), 7.54 (1H, s) 7.37-7.30 (1H, m), 7.25-7.21 (1H, m), 7.13-7.05 (2H, m), 6.89-6.82 (1H, m), 2.63 (3H, s), 2.40 (3H, s), 2.16 (3H, s), 1.86-1.72 (1H, m), 0.80-0.70 (2H, m), 0.62-0.54 (2H, m). Appearance: oily product. EXAMPLE 547 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-difluorobenzoate (Compound No. 3138) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.68-7.50 (2H, m), 7.15-7.00 (4H, m), 6.90-6.77 (1H, m), 2.15 (3H, s), 1.90-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 548 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chloro-6-fluorobenzoate (Compound No. 3144) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.57-7.00 (5H, m), 6.90-6.78 (1H, m), 2.16 (3H, s), 1.90-1.75 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 549 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-dichlorobenzoate (Compound No. 3150) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.43-7.41 (3H, m), 7.11-7.08 (2H, m), 6.88-6.83 (1H, m), 2.17 (3H, s), 1.85-1.77 (1H, m), 0.74-0.56 (4H, m). Appearance: amorphous. EXAMPLE 550 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-dimethylbenzoate (Compound No. 3156) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.48 (1H, s), 7.32 (1H, dd, J=8.4, 7.0 Hz), 7.15-7.07 (3H, m), 6.87-6.83 (1H, m), 2.53 (6H, s), 2.16 (3H, s), 1.84-1.76 (1H, m), 0.75-0.69 (2H, m), 0.62-0.57 (2H, m). Appearance: paste state. EXAMPLE 551 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-dimethoxybenzoate (Compound No. 3162) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.39 (1H, t, J=8.8 Hz), 7.09-7.07 (2H, m), 6.85-6.81 (1H, m), 6.62 (2H, d, J=6.6 Hz), 3.84 (6H, s), 2.17 (3H, s), 1.96-1.81 (1H, m), 0.74-0.55 (4H, m). Melting point (° C.): 127-128. EXAMPLE 552 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,4-difluorobenzoate (Compound No. 3168) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.10-7.99 (2H, m), 7.58 (1H, s), 7.43-7.25 (1H, m), 7.15-7.02 (2H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.83-1.67 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 553 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-fluoro-4-methylbenzoate (Compound No. 3185) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.90 (1H, d, J=8.1 Hz), 7.83 (1H, d, J=9.9 Hz), 7.59 (1H, s), 7.37 (1H, dd, J=7.3 Hz, 7.7 Hz), 7.15-7.00 (2H, m), 6.90-6.78 (1H, m), 2.39 (3H, d, 1.5 Hz), 2.15 (3H, s), 1.85-1.67 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 554 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,4-dichlorobenzoate (Compound No. 3194) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.29 (1H, d, J=1.8 Hz), 8.03 (1H, dd, J=8.4, 2.2 Hz), 7.65 (1H, d, J=8.4 Hz), 7.57 (1H, s), 7.15-7.02 (2H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.82-1.68 (1H, m), 0.78-0.47 (4H, m). Appearance: amorphous. EXAMPLE 555 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-chloro-3-nitrobenzoate (Compound No. 3200) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.69 (1H, d, J=1.8 Hz), 8.33 (1H, dd, J=8.4, 1.8 Hz)., 7.78 (1H, d, J=8.4 Hz), 7.57 (1H, s), 7.10-7.05 (2H, m), 6.87-6.82 (1H, m), 2.14 (3H, s), 1.77-1.69 (1H, m), 0.75-0.56 (4H, m). Appearance: amorphous. EXAMPLE 556 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-difluorobenzoate (Compound No. 3217) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.80-7.65 (2H, m), 7.58 (1H, s), 7.32-7.00 (3H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.85-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: amorphous. EXAMPLE 557 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-dichlorobenzoate (Compound No. 3226) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.07 (2H, d, J=2.0 Hz), 7.69 (1H, t, J=2.0 Hz), 7.55 (1H, s), 7.13-7.00 (2H, m), 6.89-6.82 (1H, m), 2.15 (3H, s), 1.83-1.60 (1H, m), 0.80-0.70 (2H, m), 0.63-0.55 (2H, m). Melting point (° C.): 168-174. EXAMPLE 558 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-dimethylbenzoate (Compound No. 3243) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.82 (2H, s), 7.56 (1H, s) 7.32 (1H, s,), 7.13-7.04 (2H, m), 6.89-6.82 (1H, m), 2.41 (6H, s), 2.16 (3H, s), 1.85-1.72 (1H, m), 0.80-0.70 (2H, m), 0.63-0.53 (2H, m). Melting point (° C.): 117-119. EXAMPLE 559 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,5-dimethoxybenzoate (Compound No. 3252) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.34 (1H, s) 7.33 (1H, s), 7.08-7.06 (2H, m), 6.87-6.82 (1H, m), 6.78-6.75 (1H, m), 3.86 (6H, s), 2.16 (3H, s), 1.86-1.72 (1H, m), 0.80-0.72 (2H, m), 0.63-0.54 (2H, m). Appearance: paste state. EXAMPLE 560 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,4,6-trichlorobenzoate (Compound No. 3258) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.55 (1H, s), 7.46 (2H, s) 7.15-7.05 (2H, m), 6.90-6.82 (1H, m), 2.16 (3H, s), 1.86-1.72 (1H, m), 0.78-0.67 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 561 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3,4,5-trimethoxybenzoate (Compound No. 3264) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.45 (2H, s), 7.14-7.04 (2H, m), 6.89-6.83 (1H, m), 3.96 (3H, s), 3.94 (6H, s), 2.16 (3H, s), 1.85-1.72 (1H, m), 0.80-0.67 (2H, m), 0.63-0.54 (2H, m). Appearance: amorphous. EXAMPLE 562 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-naphthoate (Compound No. 3270) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.02 (1H, d, J=8.4 Hz), 8.55 (1H, d, J=7.3 Hz), 8.17 (1H, d, J=8.0 Hz), 7.95 (1H, d, J=8.0 Hz), 7.75-7.54 (4H, m), 7.13-7.00 (2H, m), 6.90-6.80 (1H, m), 2.18 (3H, s), 1.93-1.75 (1H, m), 0.83-0.52 (4H, m). Appearance: amorphous. EXAMPLE 563 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-naphthoate (Compound No. 3276) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.81 (1H, s), 8.18 (1H, dd, J=1.5 Hz, 8.5 Hz), 8.05-7.87 (3H, m), 7.70-7.52 (3H, m), 7.10-7.00 (2H, m), 6.90-6.77 (1H, m), 2.18 (3H, s), 1.90-1.73 (1H, m), 0.83-0.53 (4H, m). Appearance: amorphous. EXAMPLE 564 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-methyl-1H-pyrrole-2-carboxylate (Compound No. 3282) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.25 (1H, s), 7.08-7.06 (2H, m), 6.96 (1H, s), 6.86-6.81 (1H, m), 6.24-6.21 (1H, m), 3.97 (3H, s), 2.15 (3H, s), 1.87-1.72 (1H, m), 0.80-0.70 (2H, m), 0.63-0.52 (2H, m). Melting point (° C.): 143-144. EXAMPLE 565 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-bromo-2-furoate (Compound No. 3288) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.43 (1H, d, J=3.7 Hz), 7.15-7.03 (2H, m), 6.90-6.78 (1H, m), 6.59 (1H, d, J=3.7 Hz), 2.15 (3H, s), 1.83-1.70 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 566 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-furoate (Compound No. 3294) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.30 (1H, t, J=0.7 Hz), 7.57-7.53 (1H, m), 7.55 (1H, s), 7.13-7.04 (2H, m), 6.92-6.81 (2H, m), 2.15 (3H, s), 1.83-1.69 (1H, s), 0.80-0.53 (4H, m). Appearance: paste state. EXAMPLE 567 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-tert-butyl-2-methyl-3-furoate (Compound No. 3300) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.09-7.07 (2H, m), 6.87-6.83 (1H, m), 6.33 (1H, s), 2.64 (3H, s), 2.15 (3H, s), 1.78-1.73 (1H, m), 1.29 (9H, s), 0.75-0.57 (4H, m). Appearance: caramel-like. EXAMPLE 568 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-methyl-2-(trifluoromethyl)-3-furoate (Compound No. 3306) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.13-7.04 (2H, m), 6.89-6.82 (1H, m), 6.64 (1H, s), 2.42 (3H, s), 2.13 (3H, s), 1.81-1.67 (1H, m), 0.78-0.68 (2H, m), 0.65-0.53 (2H, m). Appearance: paste state. EXAMPLE 569 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furoate (Compound No. 3312) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.70-7.66 (2H, m), 7.56 (1H, s), 7.47-7.42 (2H, .m), 7.19 (1H, s), 7.14-7.05 (2H, m), 6.90-6.82 (1H, m), 2.14 (3H, s), 1.83-1.69 (1H, m), 0.80-0.68 (2H, m), 0.65-0.53 (2H, m). Appearance: paste state. EXAMPLE 570 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-chloro-2-thiophenecarboxylate (Compound No. 3318) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.68 (1H, d, J=5.5 Hz), 7.58 (1H, s), 7.14 (1H, d, J=5.5 Hz), 7.11-7.03 (2H,m), 6.90-6.80 (1H, m), 2.16 (3H, s), 1.85-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 571 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-methyl-2-thiophenecarboxylate (Compound No. 3324) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65-7.55 (2H, m), 7.13-6.95 (3H, m), 6.90-6.80 (1H, m), 2.63 (3H, s), 2.16 (3H, s), 1.90-1.70 (1H, m), 0.85-0.50 (4H, m). Appearance: amorphous. EXAMPLE 572 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-ethoxy-2-thiophenecarboxylate (Compound No. 3330) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.62 (1H, s), 7.59 (1H, d, J=5.5 Hz), 7.08-7.06 (2H, m), 6.90 (1H, d, J=5.5 Hz), 6.86-6.81 (1H, m), 4.26 (2H, q, J=7.0 Hz), 2.17 (3H, s), 1.86-1.75 (1H, m), 1.46 (3H, t, J=7.0 Hz), 0.75-0.55 (4H, m). Appearance: caramel-like. EXAMPLE 573 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-chloro-2-thiophenecarboxylate (Compound No. 3336) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.86 (1H, d, J=4.0 Hz), 7.57 (1H, s), 7.14-7.03 (3H, m), 6.90-6.83 (1H, m), 2.15 (3H, m), 1.83-1.68 (1H, m), 0.80-0.68 (2H, m), 0.65-0.53 (2H, m). Appearance: paste state. EXAMPLE 574 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-bromo-2-thiophenecarboxylate (Compound No. 3342) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.80 (1H, d, J=4.0 Hz), 7.57 (1H, s), 7.19 (1H, d, J=4.0 Hz), 7.10-7.00 (2H, m), 6.90-6.80 (1H, m), 2.15 (3H, s), 1.85-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 575 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-methyl-2-thiophenecarboxylate (Compound No. 3348) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.87 (1H, d, J=3.7 Hz), 7.57 (1H, s), 7.12-7.00 (2H, m), 6.93-6.87 (2H, m), 2.58 (3H, s), 2.15 (3H, s), 1.85-1.70 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 576 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-acetyl-2-thiophenecarboxylate (Compound No. 3354) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.02 (1H, d, J=4.0 Hz), 7.72 (1H, d, J=4.0 Hz), 7.58 (1H, s), 7.10-7.07 (2H, m), 6.87-6.83 (1H, m), 2.63 (3H, s), 2.15 (3H, s), 1.79-1.71 (1H, m), 0.75-0.56 (4H, m). Appearance: amorphous. EXAMPLE 577 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-nitro-3-thiophenecarboxylate (Compound No. 3360) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.52 (1H, d, J=1.8 Hz), 8.43 (1H, d, J=1.8 Hz), 7.56 (1H, s), 7.13-7.05 (2H, m), 6.90-6.80 (1H, m), 2.14 (3H, s), 1.85-1.65 (1H, m), 0.85-0.50 (4H, m). Appearance: amorphous. EXAMPLE 578 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4,5-dibromo-2-thiophenecarboxylate (Compound No. 3366) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.84 (1H, s), 7.56 (1H, s) 7.14-7.05 (2H, m), 6.90-6.83 (1H, m), 2.14 (3H, s), 1.83-1.69 (1H, m), 0.79-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: amorphous. EXAMPLE 579 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-thiophenecarboxylate (Compound No. 3372) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.42-8.40 (1H, m), 7.70-7.66 (1H, m), 7.58 (1H, s), 7.47-7.41 (1H, m), 7.13-7.05 (2H, m), 6.88-6.82 (1H, m), 2.15 (3H, s), 1.84-1.70 (1H, m), 0.80-0.68 (2H, m), 0.64-0.55 (2H, m). Appearance: paste state. EXAMPLE 580 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methoxy-3-thiophenecarboxylate (Compound No. 3378) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.33 (1H, d, J=3.5 Hz), 7.59 (1H, s), 7.09-7.06 (2H, m), 6.87-6.82 (1H, m), 6.38 (1H, d, J=3.5 Hz), 3.93 (3H, s), 2.16 (3H, s), 1.82-1.74 (1H, m), 0.75-0.56 (4H, m). Melting point (° C.): 146-149. EXAMPLE 581 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-benzyl-3-tert-butyl-1H-pyrazole-5-carboxylate (Compound No. 3384) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.44 (1H, s), 7.21 (5H, s), 7.09-7.06 (2H, m), 6.98 (1H, s), 6.85-6.80 (1H, m), 5.72 (2H, s), 2.08 (3H, s), 1.76-1.64 (1H, m), 1.36 (9H, s), 0.75-0.64 (2H, m), 0.59-0.50 (2H, m). Appearance: paste state. EXAMPLE 582 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylate (Compound No. 3390) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.62 (1H, s), 7.09-7.07 (2H, m), 6.87-6.82 (1H, m), 3.86 (3H, s), 2.52 (3H, s), 2.14 (3H, s), 1.84-1.77 (1H, m), 0.75-0.67 (2H, m), 0.60-0.53 (2H, m). Appearance: paste state. EXAMPLE 583 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarboxylate (Compound No. 3396) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.48-7.42 (2H, m), 7.41-7.30 (2H, m), 7.08-7.06 (2H, m), 6.83-6.78 (1H, m), 2.89 (3H, s), 2.02 (3H, s), 1.67-1.53 (1H, m), 0.68-0.50 (4H, m). Appearance: amorphous. EXAMPLE 584 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-methyl-1,2,3-thiadizaole-5-carboxylate (Compound No. 3402) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.15-7.05 (2H, m), 6.91-6.84 (1H, m), 3.08 (3H, s), 2.14 (3H, s), 1.80-1.65 (1H, m), 0.80-0.72 (2H, m), 0.64-0.53 (2H, m). Appearance: paste state. EXAMPLE 585 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 6-methyl-2-pyridinecarboxylate (Compound No. 3408) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.12 (1H, d, J=7.7 Hz), 7.82 (1H, t, J=7.7 Hz), 7.55 (1H, s), 7.46 (1H, d, J=7.7 Hz), 7.12-7.02 (2H, m), 6.85-6.76 (1H, m), 2.71 (3H, s), 2.15 (3H, s), 1.87-1.74 (1H, m), 0.82-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 586 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5-butyl-2-pyridinecarboxylate (Compound No. 3414) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.67 (1H, br.s), 8.22 (1H, d, J=7.7 Hz), 7.74 (1H, br.d, J=7.7 Hz), 7.53 (1H, s), 7.08-7.05 (2H, m), 6.83-6.78 (1H, m), 2.75 (2H, t, J=7.7 Hz), 2.15 (3H, s), 1.84-1.59 (3H, m), 1.48-1.32 (2H, m), 0.95 (3H, t, J=7.0 Hz), 0.75-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 587 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl nicotinate (Compound No. 3420) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.42-9.41 (1H, m), 8.91 (1H, dd, J=4.8, 0.8 Hz), 8.50-8.44 (1H, m), 7.60 (1H, s), 7.56-7.49 (1H, m), 7.13-7.04 (2H, m), 6.88-6.78 (1H, m), 2.15 (3H, s), 1.90-1.70 (1H, m), 0.81-0.70 (2H, m), 0.63-0.55 (2H, m). Appearance: paste state. EXAMPLE 588 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chloronicotinate (Compound No. 3426) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.66 (1H, dd, J=4.8, 2.0 Hz), 8.45 (1H, dd, J=7.7, 2.0 Hz), 7.59 (1H, s), 7.45 (1H, dd, J=7.7, 4.8 Hz), 7.14-7.06 (2H, m), 6.89-6.83 (1H, m), 2.15 (3H, s), 1.84-1.70 (1H, m), 0.80-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 589 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-methylnicotinate (Compound No. 3432) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.74 (1H, dd, J=4.8, 1.5 Hz), 8,46 (1H, dd, J=7.7, 1.5 Hz), 7.58 (1H, s), 7.34 (1H, dd, J=7.7, 4.8 Hz), 7.13-7.05 (2H, m), 6.89-6.83 (1H, m), 2.93 (3H, s), 2.15 (3H, s), 1.83-1.67 (1H, m), 0.80-0.68 (2H, m), 0.65-0.55 (2H, m). Appearance: paste state. EXAMPLE 590 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-phenoxynicotinate (Compound No. 3438) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.50 (1H, dd, J=7.8, 2.2 Hz), 8.39 (1H, dd, J=4.8, 2.2 Hz), 7.61 (1H, s), 7.46-7.38 (2H, m), 7.29-7.20 (1H, m), 7.19-7.04 (5H, m), 6.86-6.81 (1H, m), 2.14 (3H, s), 1.85-1.72 (1H, m), 1.36 (9H, s), 0.75-0.65 (2H, m), 0.58-0.52 (2H, m). Appearance: paste state. EXAMPLE 591 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-(methylsulfanyl)nicotinate (Compound No. 3444) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.70 (1H, dd, J=4.9, 1.8 Hz), 8.47 (1H, dd, J=7.7, 1.8 Hz), 7.63 (1H, s), 7.16 (1H, dd, J=7.7, 4.8 Hz) 7.12-7.05 (2H, m), 6.89-6.82 (1H, m), 2.59 (3H, s), 2.16 (3H, s), 1.84-1.71 (1H, m), 0.80-0.70 (2H, m), 0.65-0.53 (2H, m). Appearance: paste state. EXAMPLE 592 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-(allylsulfanyl)nicotinate (Compound No. 3450) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.67 (1H, dd, J=4.8, 1.8 Hz), 8.46 (1H, dd, J=8.2, 1.8 Hz), 7.62 (1H, s), 7.16 (1H, dd, J=8.2, 4.8 Hz), 7.09-7.04 (2H, m), 6.89-6.82 (1H, m), 6.10-5.90 (1H, m), 5.33 (1H, dd, J=16.8, 1.6 Hz), 5.12 (1H, dd, J=11.0, 1.2 Hz), 3.91 (1H, dd, J=6.8, 1.2 Hz), 2.15 (3H, s), 1.85-1.70 (1H, m), 0.78-0.71 (2H, m), 0.60-0.51 (2H, m). Appearance: paste state. EXAMPLE 593 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-(phenylsulfanyl)nicotinate (Compound No. 3456) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.50 (1H, s), 8.47 (1H, d, J=2.6 Hz), 7.65 (1H, s), 7.59-7.51 (2H, m), 7.48-7.41 (3H, m), 7.17-7.05 (3H, m), 6.90-6.82 (1H, m), 2.18 (3H, s), 1.89-1.74 (1H, m), 0.82-0.70 (2H, m), 0.65-0.54 (2H, m). Appearance: paste state. EXAMPLE 594 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(trifluoromethyl)nicotinate (Compound No. 3462) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.42 (1H, s), 9.08 (1H, d, J=5.1 Hz), 7.79 (1H, d, J=5.1 Hz), 7.57 (1H, s), 7.14-7.06 (2H, m), 6.90-6.84 (1H, m), 2.16 (3H, s), 1.84-1.72 (1H, m), 0.79-0.71 (2H, m), 0.63-0.55 (2H, m). Melting point (° C.): 92-93. EXAMPLE 595 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 6-chloronicotinate (Compound No. 3468) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.19 (1H, d, J=2.0), 8.40 (1H, dd, J=8.4, 2.6), 7.59 (1H, s), 7.54 (1H, d, J=8.4 Hz), 7.10-7.08 (1H, m), 7.07 (1H, s), 6.87-6.82 (1H, m), 2.14 (3H, s), 1.79-1.65 (1H, m), 0.79-0.70 (2H, m), 0.62-0.53 (2H, m). Appearance: paste state. EXAMPLE 596 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,6-dichloronicotinate (Compound No. 3474) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.46 (1H, d, J=8.1 Hz), 7.67 (1H, s), 7.52 (1H, d, J=8.1 Hz), 7.13-7.02 (2H, m), 6.90-6.75 (1H, m), 2.14 (3H, s), 1.85-1.68 (1H, m), 0.85-0.48 (4H, m). Appearance: amorphous. EXAMPLE 597 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chloro-6-methylnicotinate (Compound No. 3480) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.37 (1H, d, J=7.7 Hz), 7.58 (1H, s), 7.27 (1H, d, J=7.7 Hz), 7.14-7.08 (2H, m), 6.89-6.80 (1H, m), 2.65 (3H, s), 2.15 (3H, s), 1.83-1.69 (1H, m), 0.80-0.70 (2H, m), 0.68-0.55 (2H, m). Appearance: paste state. EXAMPLE 598 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 5,6-dichloronicotinate (Compound No. 3486) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.07 (1H, d, J=2.2 Hz), 8.50 (1H, d, J=2.2 Hz), 7.57 (1H, s), 7.10-7.07 (2H, m), 6.87-6.82 (1H, m), 2.13 (3H, s), 1.80-1.65 (1H, m), 0.75-0.70 (2H, m), 0.58-0.55 (2H, m). Appearance: paste state. EXAMPLE 599 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2-chloroisonicotinate (Compound No. 3492) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.68 (1H, d, J=5.0 Hz), 8.05 (1H, s), 7.95-7.92 (1H, m), 7.57 (1H, s), 7.10-7.07 (2H, m), 6.87-6.83 (1H, m), 2.14 (3H, s), 1.77-1.68 (1H, m), 0.75-0.71 (2H, m), 0.58-0.56 (2H, m). Appearance: paste state. EXAMPLE 600 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-benzofuran-2-carboxylate (Compound No. 3498). 1H-NMR (200 MHz, CDCl3) δ ppm: 7.86-7.75 (2H, m), 7.68-7.51 (3H, m), 7.38 (1H, dd, J=7.7, 7.0 Hz), 7.12-7.05 (2H, m), 6.89-6.80 (1H, m), 2.17 (3H, s), 1.86-1.73 (1H, m), 0.80-0.68 (2H, m), 0.64-0.55 (2H, m). Appearance: amorphous. EXAMPLE 601 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-benzothiophene-2-carboxylate (Compound No. 3504) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.34 (1H, s), 7.94 (2H, m), 7.64 (1H, s), 7.59-7.42 (2H, m), 7.09-7.07 (2H, m), 6.87-6.83 (1H, m), 2.18 (3H, s), 1.88-1.72 (1H, m), 0.77-0.71 (2H, m), 0.61-0.53 (2H, m). Melting point (° C.): 105-107. EXAMPLE 602 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1,3-benzothiazole-6-carboxylate (Compound No. 3510) 1H-NMR (200 MHz, CDCl3) δ ppm: 9.24 (1H, s), 8.89 (1H, d, J=1.4 Hz), 8.36 (1H, dd, J=8.4, 1.4 Hz), 8.28 (1H, d, J=8.4 Hz), 7.65 (1H, s), 7.09-7.06 (2H, m), 6.87-6.82 (1H, m), 2.17 (3H, s), 1.86-1.73 (1H, m), 0.78-0.72 (2H, m), 0.63-0.55 (2H, m). Appearance: amorphous. EXAMPLE 603 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1,3-benzodioxole-5-carboxylate (Compound No. 3516) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.85 (1H, dd, J=8.4, 1.8 Hz), 7.60-7.59 (2H, m), 7.09-7.06 (2H, m), 6.93 (1H, d, J=8.0 Hz), 6.86-6.82 (1H, m), 6.10 (2H, s), 2.15 (3H, s), 1.86-1.74 (1H, m), 0.79-0.70 (2H, m), 0.62-0.53 (2H, m). Appearance: paste state. EXAMPLE 604 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-isoquinolinecarboxylate (Compound No. 3522) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.45 (1H, d, J=8.1 Hz), 7.78-7.70 (2H, m), 7.61-7.53 (2H, m), 7.16 (1H, d, J=7.7 Hz), 7.12-7.05 (2H, m), 6.90-6.83 (1H, m), 6.66 (1H, d, J=7.3 Hz), 2.15 (3H, s), 1.81-1.66 (1H, m), 0.79-0.67 (2H, m), 0.63-0.53 (2H, m). Appearance: amorphous. EXAMPLE 605 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl tert-butyl(methyl)carbamate (Compound No. 3528) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.51 (1H, s), 7.15-7.03 (2H, m), 6.90-6.80 (1H, m), 3.11 (3H, s), 2.14 (3H, s), 1.85-1.70 (1H, m), 1.47 (9H, S), 0.80-0.50 (4H, m) Melting point (° C.): 113-115. EXAMPLE 606 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl dibutylcarbamate (Compound No. 3534) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.15-7.03 (2H, m), 6.90-6.78 (1H, m), 3.50-3.26 (4H, m), 2.13 (3H, s), 1.87-1.50 (5H, m), 1.50-1.15 (4H, m), 1.10-0.85 (6H, m), 0.80-0.54 (4H, m). Appearance: caramel-like. EXAMPLE 607 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl benzyl(methyl)carbamate (Compound No. 3540) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (0.5H, s), 7.57 (0.5H, s), 7.40-7.20 (5H, m), 7.15-7.03 (2H, m), 6.92-6.80 (1H, m), 4.68 (1H, s), 4.57 (1H, s), 3.08 (1.5H, s), 3.02 (1.5H, s), 2.15 (1.5H, s), 2.13 (1.5H, s), 1.85-1.65 (1H, m), 0.80-0.45 (4H, m). Appearance: caramel-like. EXAMPLE 608 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl cyanomethyl(methyl)carbamate (Compound No. 3546) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (0.4H, s), 7.56 (0.6H, s), 7.15-7.04 (2H, m), 6.90-6.80 (1H, m), 4.42 (0.8H, s), 4.36 (1.2H, s), 3.30 (1.8H, s), 3.19 (1.2H, s), 2.14 (3H, s), 1.85-1.62 (1H, m), 0.80-0.53 (4H, m). Appearance: caramel-like. EXAMPLE 609 Ethyl N-({[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl]oxy}carbonyl)-N-methylglycinate (Compound No. 3552) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.61 (0.5H, s), 7.60 (0.5H, s), 7.15-7.02 (2H, m), 6.90-6.80 (1H, m), 4.28-4.11 (4H, m), 3.23 (1.5H, s), 3.13 (1.5H, s), 2.15 (1.5H, s), 2.13 (1.5H, s), 1.85-1.65 (1H, m), 1.31-1.18 (3H, m), 0.80-0.50 (4H, m) Appearance: caramel-like. EXAMPLE 610 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methyl(2-pyridinyl)carbamate (Compound No. 3558) 1H-NMR (200 MHz, CDCl3) δ ppm: 8.35-8.25 (1H, m), 7.70-7.55 (1H, m), 7.05-6.90 (5H, m), 6.85-6.74 (1H, m), 3.56 (3H, s), 2.03 (3H, s), 1.72-1.55 (1H, m), 0.75-0.45 (4H, m). Melting point (° C.): 140-147. EXAMPLE 611 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-piperidinecarboxylate (Compound No. 3636) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s), 7.15-7.03 (2H, m), 6.90-6.80 (1H, m), 3.70-3.60 (2H, m), 3.60-3.45 (2H, m), 2.15 (3H, s), 1.86-1.70 (1H, m), 1.70-1.50 (6H, m), 0.80-0.53 (4H, m). Appearance: caramel-like. Example 612 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(2-chloroethyl)carbamate (Compound No. 3570) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.58 (1H, s), 7.15-7.05 (2H, m), 6.92-6.82 (1H, m), 3.98-3.70 (8H, m), 2.13 (3H, s), 1.82-1.65 (1H, m), 0.80-0.50 (4H, m). Melting point (° C.): 166-167. EXAMPLE 613 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl diallylcarbamate (Compound No. 3576) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.56 (1H, s), 7.12-7.04 (2H, m), 6.88-6.80 (1H, m), 6.00-5.70 (2H, m), 5.30-5.15 (4H, m), 4.10-3.93 (4H, m), 2.13 (3H, s), 1.85-1.68 (1H, m), 0.80-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 614 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(cyanomethyl)carbamate (Compound No. 3582) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.18-7.05 (2H, m), 6.90-6.80 (1H, m), 4.54 (2H, s), 4.48 (2H, s), 2.13 (3H, s), 1.80-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 615 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(2-cyanoethyl)carbamate (Compound No. 3588) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.61 (1H, s), 7.18-7.05 (2H, m), 6.92-6.82 (1H, m), 3.91 (2H, t, J=6.6 Hz), 3.77 (2H, t, J=6.2 Hz), 2.85 (2H, t, J=6.6 Hz), 2.78 (2H, t, J=6.2 Hz), 2.13 (3H, s), 1.80-1.63 (1H, m), 0.82-0.53 (4H, m). Melting point (° C.): 159-161. EXAMPLE 616 Ethyl N-({[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl]oxy}carbonyl)-N-(2-ethoxy-2-oxoethyl)glycinate (Compound No. 3594) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65 (1H, s), 7.13-7.03 (2H, m), 6.90-6.80 (1H, m), 4.33-4.05 (8H, m), 2.12 (3H, s), 1.83-1.65 (1H, m), 1.28 (3H, t, J=7.3 Hz), 1.19 (3H, t, J=7.3 Hz), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 617 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(2-methoxyethyl)carbamate (Compound No. 3600) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.15-7.05 (2H, m), 6.90-6.80 (1H, m), 3.80-3.50 (8H, m), 3.32 (6H, s), 2.15 (3H, s), 1.86-1.69 (1H, m), 0.80-0.52 (4H, m). Appearance: caramel-like. EXAMPLE 618 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl bis(2-ethoxyethyl)carbamate (Compound No. 3606) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.57 (1H, s), 7.15-7.03 (2H, m), 6.90-6.80 (1H, m), 3.78-3.55 (8H, m), 3.46 (4H, q, J=6.9 Hz), 2.14 (3H, s), 1.87-1.65 (1H, m), 1.15 (3H, t, J=6.9 Hz), 1.14 (3H, t, J=6.9 Hz), 0.80-0.53 (4H, m). Appearance: caramel-like. EXAMPLE 619 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-azetizinecarboxylate (Compound No. 3612) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.13-7.02 (2H, m), 6.90-6.78 (1H, m), 4.38-4.05 (4H, m), 2.45-2.29 (2H, m), 2.15 (3H, s), 1.85-1.67 (1H, m), 0.80-0.50 (4H, m). Melting point (° C.): 134-136. EXAMPLE 620 1-[6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 2-methyl 1,2-pyrrolidinedicarboxylate (Compound No. 3618) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.65 (0.5H, s), 7.62 (0.5H, s), 7.15-7.02 (2H, m), 6.90-6.78 (1H, m), 4.63-4.57 (0.5H, m), 4.51-4.44 (0.5H, m), 3.91-3.55 (2H, m), 3.75 (1.5H, s), 3.65 (1.5H, s), 2.50-1.90 (4H, m), 2.15 (1.5H, s), 2.13 (1.5H, s), 1.90-1.69 (1H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 621 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 3-hydroxy-1-pyrrolidinecarboxylate (Compound No. 3624) 1H-NMR (200 MHz, CDCl3) δ ppm: 7.60 (1H, s), 7.13-7.03 (2H, m), 6.90-6.80 (1H, m), 4.65-4.52 (1H, m), 3.85-3.55 (4H, m), 2.14 (3H, s), 2.13-2.00 (2H, m), 1.87-1.70 (2H, m), 0.80-0.50 (4H, m). Appearance: caramel-like. EXAMPLE 622 6-Chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1126) (1) 2,3,5-Trimethylphenyl acetate In dichloromethane (150 mL) was dissolved 15.09 g (0.1108 mol) of 2,3,5-trimethylphenol, and 17.82 mL (0.2204 mol) of pyridine, then 20.78 mL (0.2202 mol) of acetic anhydride were added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with dichloro-methane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 20.08 g (0.1127 mol, Yield: quantitative) of 2,3,5-trimethylphenyl acetate. (2) 1-(2-Hydroxy-3,4,6-trimethylphenyl)ethanone To 13.83 g (77.60 mmol) of 2,3,5-trimethylphenyl acetate obtained in (1) was added 20.69 g (155.2 mmol) of aluminum chloride little by little in an ice bath with stirring. The mixture was stirred while heating to 100° C. overnight. After cooling, the reaction mixture was added to ice water little by little. The mixture was extracted with dichloromethane, the organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 12.75 g (71.55 mmol, Yield: 92.20%) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone. (3) 1-(2-Methoxy-3,4,6-trimethylphenyl)ethanone In acetone (100 mL) was dissolved 8.00 g (44.9 mmol) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone obtained in (2), to the mixture were added 18.6 g (135 mmol) of potassium carbonate, and then, 8.40 mL (135 mmol) of methyl iodide, and the resulting mixture was refluxed for 27 hours and 30 minutes. Moreover, 18.6 g (135 mmol) of potassium carbonate, and 8.40 mL (135 mmol) of methyl iodide were additionally added to the mixture, and the resulting mixture was refluxed for 6 hours. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate, gradient) to obtain 8.04 g (41.9 mmol, Yield: 93.3%) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone. (4) 1-(2-Methoxy-3,4,6-trimethylphenyl)ethanol In methanol (100 mL) was dissolved 5.01 g (26.1 mmol) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone obtained in (3), and in an ice bath, 1.00 g (26.5 mmol) of sodium borohydride was added to the solution and the mixture was stirred in an ice bath for 2 hours and 30 minutes. The reaction mixture was poured into 400 mL of ice water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 4.35g (22.4 mmol, Yield: 85.8%) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanol. (5) 2-(1-Chloroethyl)-3-methoxy-1,4,5-trimethylbenzene To 0.652 g (3.36 mmol) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanol obtained in (4) was added dropwise with stirring 0.150 mL (1.72 mmol) of oxalyl chloride, and the mixture was stirred at 100° C. for 2 hours. Then, dichloromethane (1 mL) and triethylamine (3 mL) were added to the reaction mixture, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into 60 ml of ice water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 0.620 g (2.91 mmol, Yield: 86.6%) of 2-(1-chloroethyl)-3-methoxy-1,4,5-trimethylbenzene. (6) 3-Methoxy-1,2,5-trimethyl-4-vinylbenzene In N,N-dimethylformamide (DMF, 6 mL) was dissolved 0.620 g (2.91 mmol) of 2-(1-chloroethyl)-3-methoxy-1,4,5-trimethylbenzene obtained in (5), and 1.20 g (8.70 mmol) of potassium carbonate was added to the solution and the resulting mixture was refluxed for 9 hours. The reaction mixture was poured into 50 ml of ice water, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate, gradient) to obtain 0.360 g (2.05 mmol, Yield: 70.4%) of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene. (7) 2-Cyclopropyl-3-methoxy-1,4,5-trimethylbenzene To dry dichloromethane (5 mL) was added 3.07 mL (3.04 mmol) of diethyl zinc (0.99 mol/L hexane solution), a dichloromethane (2.5 mL) solution containing 0.23 mL (3.0 mmol) of trifluoroacetic acid was gradually added dropwise with stirring in an ice bath. After completion of the dropwise addition, the mixture was stirred in an ice bath for 30 minutes, and 0.24 mL (3.0 mmol) of diiodomethane was added dropwise to the mixture. Then, a dichloromethane (3 mL) solution containing 0.268 g (1.52 mmol) of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene obtained in (6) was added dropwise, and the mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, made acidic with diluted hydrochloric acid, and then, extracted with dichloromethane. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 2 plates were used, developed by hexane:ethyl acetate=25:1) to obtain 0.212 g (1.12 mmol, Yield: 73.7%) of 2-cyclopropyl-3-methoxy-1,4,5-trimethylbenzene. (8) 2-Cyclopropyl-3,5,6-trimethylphenol Under nitrogen atmosphere, in dry N,N-dimethylformamide (5 mL) was suspended 134 mg (3.35 mmol) of 60% sodium hydride, and 0.26 mL (3.5 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 30 minutes, a dry N,N-dimethylformamide (5 mL) solution containing 0.212 g (1.12 mmol) of 2-cyclopropyl-3-methoxy-1,4,5-trimethylbenzene obtained in (7) was added dropwise to the mixture, and the resulting mixture was stirred at 160° C. for 5 hours. After allowing to stand for cooling, the reaction mixture was poured into water, made acidic by adding diluted hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=25:1) to obtain 179 mg (1.02 mmol, Yield: 91.1%) of 2-cyclopropyl-3,5,6-trimethylphenol. (9) Mixture of 6-chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide (Step B-2) 179 mg (1.02 mmol) of 2-cyclopropyl-3,5,6-trimethylphenol, 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) were mixed, 125 mg (1.12 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred for 10 minutes. To the mixture was added 167 mg (1.01 mmol) of 3,6-dichloropyridazine 1-oxide, and the mixture was allowed to stand at room temperature for 3 days. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 263 mg of a mixture of 6-chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide. (10) 4,6-Dichloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine (Step B-3) 263 mg of a mixture of 6-chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide obtained in (9) and 3.0 mL (32 mmol) of phosphorus oxychloride were mixed, and the mixture was stirred at room temperature overnight. Dichloromethane and water were added to the reaction mixture, and after stirring, the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 198 mg (0.613 mmol, Yield from 3,6-dichloropyridazine 1-oxide: 60.7%) of 4,6-dichloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine. Also, 43.8 mg (0.144 mmol, Yield from 3,6-dichloropyridazine 1-oxide: 14.2%) of 3-chloro-6-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine 1-oxide was obtained. (11) 6-Chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1126, Step A-3 and A-4) In dimethylsulfoxide (10 mL) was dissolved 198 mg (0.613 mmol) of 4,6-dichloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)pyridazine obtained in (10), 251 mg (3.06 mmol) of sodium acetate was added to the solution and the mixture was stirred at 120° C. for 4 hours. The reaction mixture was cooled, poured into water, and made acidic with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05717, 2 plates were used, developed by hexane:ethyl acetate=1:2) to obtain 116 mg (0.380 mmol, Yield: 62.0%) of 6-chloro-3-(2-cyclopropyl-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1126). 1H-NMR (200 MHz, CD3OD) δ ppm: 6.67 (1H, s), 6.62 (1H, s), 2.22 (3H, s), 2.16 (3H, s), 2.05 (3H, s), 1.85-1.65 (1H, m), 0.75-0.62 (2H, m), 0.60-0.45 (2H, m). Melting point (° C.): 212-219. EXAMPLE 623 6-Chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1128) (1) 1-[2-(Benzyloxy)-3,4,6-trimethylphenyl]ethanone In N,N-dimethylformamide (8 mL) was dissolved 2.00 g (11.2 mmol) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone obtained in Example 622 (2). To the solution was added in an ice bath 0.488 g (11.2 mmol) of 60% sodium hydride, and after stirring in an ice bath for 10 minutes, 1.92 g (11.2 mmol) of benzyl bromide was gradually added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 2.36 g (8.81 mmol, Yield: 78.7%) of 1-[2-(benzyloxy)-3,4,6-trimethylphenyl]ethanone. (2) 2-(Benzyloxy)-3,4,6-trimethylphenyl acetate In dichloromethane (3 mL) was dissolved 500 mg (1.87 mmol) of 1-[2-(benzyloxy)-3,4,6-trimethylphenyl]ethanone obtained in (1), a dichloromethane (6 mL) solution containing 921 mg (purity 70-75%, 3.73-3.99 mmol) of m-chloroper-benzoic acid was added to the solution, and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was poured into a saturated aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed to obtain 560 mg of 2-(benzyloxy)-3,4,6-trimethylphenyl acetate. (3) 2-(Benzyloxy)-3,4,6-trimethylphenol In ethanol (15 mL) was dissolved 560 mg of 2-(benzyloxy)-3,4,6-trimethylphenyl acetate obtained in (2), 2N aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature overnight and at 60° C. for 4 hours. The reaction mixture was cooled up to room temperature, and poured into water. To the mixture was added 1N hydrochloric acid to make the mixture acidic, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 290 mg (1.20 mmol, Yield from 1-[2-(benzyloxy)-3,4,6-trimethylphenyl]ethanone: 64.2%) of 2-(benzyloxy)-3,4,6-trimethylphenol. (4) 3-(Benzyloxy)-2-methoxy-1,4,5-trimethylbenzene In acetone (3 mL) was dissolved 290 mg (1.20 mmol) of 2-(benzyloxy)-3,4,6-trimethylphenol obtained in (3), 350 mg (2.54 mmol) of potassium carbonate was added to the solution, and the mixture was stirred at room temperature for 15 minutes. Then, 0.180 mL (2.89 mmol) of methyl iodide was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by ethyl acetate:hexane=10:1) to obtain 196 mg (0.766 mmol, Yield: 63.8%) of 3-(benzyloxy)-2-methoxy-1,4,5-trimethylbenzene. (5) 2-Methoxy-3,5,6-trimethylphenol In methanol (3 mL) was dissolved 180 mg (0.703 mmol) of 3-(benzyloxy)-2-methoxy-1,4,5-trimethylbenzene obtained in (4), 0.10 g of 5% palladium-carbon was added to the solution, and the mixture was stirred under hydrogen atmosphere (1 atm) for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. 90.7 mg (0.546 mmol, Yield: 77.7%) of 2-methoxy-3,5,6-trimethylphenol was obtained. (6) Mixture of 6-chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide (Step B-2) 90.0 mg (0.542 mmol) of 2-methoxy-3,5,6-trimethylphenol obtained in (5), 1,4-dioxane (1.5 mL) and dimethylsulfoxide (1.5 mL) were mixed, 73.5 mg (0.656 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 15 minutes. To the mixture was added 93.2 mg (0.565 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 140 mg of a mixture of 6-chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide. (7) 4,6-Dichloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine (Step B-3) 140 mg of a mixture of 6-chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide obtained in (6) and 0.25 mL (2.7 mmol) of phosphorus oxychloride were mixed, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 111 mg (0.355 mmol, Yield from 3,6-dichioropyridazine 1-oxide: 62.8%) of 4,6-dichloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine. Also, 38.3 mg (0.130 mmol, Yield from 3,6-dichloropyridazine 1-oxide: 23.0%) of 3-chloro-6-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine 1-oxide was obtained. (8) 6-Chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1128, Step B-4) To a dimethylsulfoxide (10 mL) solution containing 111 mg (0.355 mmol) of 4,6-dichloro-3-(2-methoxy-3,5,6-trimethylphenoxy)pyridazine obtained in (7) was added 0.3 mL (0.6 mmol) of 2 mol/L aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 2 hours and 30 minutes. The reaction mixture was poured into ice-cooled 1 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The aqueous layer was separated, made acidic by adding conc. hydrochloric acid in an ice bath, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over magnesium sulfate. The solvent was removed, and the obtained residue was washed with ether to obtain 38.9 mg (0.132 mmol, Yield: 37.2%) of 6-chloro-3-(2-methoxy-3,5,6-trimethylphenoxy)-4-pyridazinol (Compound No. 1128). 1H-NMR (200 MHz, CD3OD) δ ppm: 6.73 (1H, s), 6.67 (1H, s), 3.69 (3H, s), 2.29 (3H, s), 2.15 (3H, s),-2.09 (3H, s). Melting point (° C.): 209-210. EXAMPLE 624 6-Chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol (Compound No. 2529) and 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2542) (1) 1-[2-(Methoxymethoxy)phenyl]ethanone In N,N-dimethylformamide (25 mL) was dissolved 3.39 g (24.9 mmol) of commercially available 1-(2-hydroxyphenyl)-ethanone, 1.52 g (38.0 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise 3.00 mL (39.5 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.33 g (24.1 mmol, Yield: 96.8%) of 1-[2-(methoxymethoxy)phenyl]ethanone. (2) 2-[2-(Methoxymethoxy)phenyl]-3-methyl-2-butanol In dry tetrahydrofuran (3 mL) was dissolved 1.00 g (5.56 mmol) of 1-[2-(methoxymethoxy)phenyl]ethanone obtained in (1), and under nitrogen atmosphere and ice-cooling, 2.8 mL (5.6 mmol) of a tetrahydrofuran solution containing 2 mol/L isopropylmagnesium bromide was added dropwise. After completion of dropwise addition, the reaction mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into water, made acidic with diluted hydrochloric acid, and then, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 0.522 g (2.33 mmol, Yield: 41.9%) of 2-[2-(methoxymethoxy)phenyl]-3-methyl-2-butanol. (3) Mixture containing 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine 1-oxide and 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine 1-oxide, etc. In dichloromethane (3 mL) was dissolved 0.522 g (2.33 mmol) of 2-[2-(methoxymethoxy)phenyl]-3-methyl-2-butanol obtained in (2), and in an ice bath, 0.50 mL (3.6 mmol) of triethylamine, then, 0.25 mL (3.2 mmol) of methanesulfonyl chloride were added to the solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 186 mg of a crude product containing 2-(1,2-dimethyl-1-propenyl)phenol, etc. 132 mg of the crude product was mixed with 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL), and 100 mg (0.893 mmol) of potassium tert-butoxide was added to the mixture. Then, to the mixture was added 119 mg (0.721 mmol) of 3,6-dichloropyridazine 1-oxide, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 220 mg of a mixture containing 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine 1-oxide and 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine 1-oxide, etc. (4) 4,6-Dichloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine and 4,6-dichloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-pyridazine (Step B-3) In chloroform (0.4 mL) was dissolved 200 mg of a mixture containing 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine 1-oxide and 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine 1-oxide, etc. obtained in (3), 0.40 mL (4.3 mmol) of phosphorus oxychloride was mixed with the mixture and the resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:acetone =20:1 three times) to obtain 23 mg of 4,6-dichloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine (purity 86%, containing 14% of 4,6-dichloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine), and 50 mg of 4,6-dichloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine (purity 81%, containing 19% of 4,6-dichloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine). (5) 6-Chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol (Compound No. 2529, Step A-3 and A-4) In dimethylsulfoxide (1 mL) was dissolved 23 mg of 4,6-dichloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine (purity 86%, containing 14% of 4,6-dichloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]pyridazine) obtained in (4), 80 mg (0.98 mmol) of sodium acetate was added to the solution and the mixture was stirred at 60° C. for 9 hours. The reaction mixture was cooled, poured into water, and made acidic with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=1:1) to obtain 4.5 mg of 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol (Compound No. 2529, purity 91%, containing 9% 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol). Also, 11.0 mg of 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol (containing 23% 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol) with a purity of 77% was obtained. 1H-NMR (200 MHz, CD3OD) δ ppm: 7.40-7.05 (4H, m), 6.59 (1H, s), 5.90 (1H, s), 5.04 (1H, s), 2.71 (1H, septet, J=6.9 Hz), 0.98 (6H, d, J=6.9 Hz). Appearance: amorphous. (6) 6-Chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2542, Step A-3 and A-4) In dimethylsulfoxide (2 mL) was dissolved 50 mg of 4,6-dichloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-pyridazine (purity 81%, containing 19% of 4,6-dichloro-3-[2-(1-isopropylvinyl)phenoxy]pyridazine) obtained in (4), 68 mg (0.83 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 50° C. for 11 hours. The reaction mixture was cooled, poured into water, and made acidic with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 40.2 mg of 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2542, purity 86%, containing 14% of 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol). Also, 3.7 mg of 6-chloro-3-[2-(1,2-dimethyl-1-propenyl)phenoxy]-4-pyridazinol (containing 27% of 6-chloro-3-[2-(1-isopropylvinyl)phenoxy]-4-pyridazinol) with a purity of 73% was obtained. 1H-NMR (200 MHz, CD3OD) δ ppm: 7.38-7.05 (4H, m), 6.59 (1H, s), 1.78 (3H,s), 1.62 (3H, s), 1.46 (3H, s). Appearance: amorphous. EXAMPLE 625 6-Chloro-3-[2-(2-methyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2540) (1) 1-(2-Methoxyphenyl)-2-methyl-1-propanol Dry tetrahydrofuran (3 mL) was added to 1.01 g (7.43 mmol) of commercially available 2-methoxybenzaldehyde under nitrogen atmosphere, and the mixture was ice-cooled. To the mixture was added dropwise a 3.8 mL (7.6 mmol) of tetrahydrofuran solution containing 2 mol/L isopropyl-magnesium bromide. After completion of dropwise addition, the reaction mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water, made acidic with diluted hydrochloric acid, and then, extracted with ether. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 1.00 g (5.56 mmol, Yield: 74.8%) of 1-(2-methoxyphenyl)-2-methyl-1-propanol. (2) 1-(l-Chloro-2-methylpropyl)-2-methoxybenzene In dichloromethane (3 mL) was dissolved 630 mg (3.50 mmol) of 1-(2-methoxyphenyl)-2-methyl-1-propanol obtained in (1), and then, 0.70 mL (5.0 mmol) of triethylamine, then 0.35 mL (4.5 mmol) of methanesulfonyl chloride were added to the solution, and the resulting mixture was stirred for 1 hour. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 720 mg of 1-(1-chloro-2-methylpropyl)-2-methoxybenzene. (3) 1-Methoxy-2-(2-methyl-1-propenyl)benzene In dry N,N-dimethylformamide (8 mL) was dissolved 410 mg of 1-(1-chloro-2-methylpropyl)-2-methoxybenzene obtained in (2), and to the solution was added 395 mg (3.52 mmol) of potassium tert-butoxide in an ice bath. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, and poured into water. The mixture was extracted with hexane, the obtained organic layers were combined, washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed to obtain 460 mg of 1-methoxy-2-(2-methyl-1-propenyl)benzene. (4) 2-(2-Methyl-1-propenyl)phenol Under nitrogen atmosphere, in dry N,N-dimethylformamide (3 mL) was suspended 60.0 mg (1.50 mmol) of 60% sodium hydride, and to the suspension was gradually added dropwise 0.11 mL (1.5 mmol) of ethanethiol in an ice bath. After stirring for 10 minutes, a dry N,N-dimethylformamide (0.5 mL) solution containing 200 mg of 1-methoxy-2-(2-methyl-1-propenyl)benzene obtained in (3) was added dropwise to the mixture, and the resulting mixture was refluxed for 2 hours and 30 minutes. After allowing to stand for cooling, the reaction mixture was poured into water, made acidic by adding diluted hydrochloric acid, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 220 mg of 2-(2-methyl-1-propenyl)phenol. (5) Mixture of 6-chloro-3-[2-(2-methyl-1-propenyl)phenoxy]-pyridazine 1-oxide and 3-chloro-6-[2-(2-methyl-1-propenyl)phenoxy]pyridazine 1-oxide (Step B-2) 200 mg of 2-(2-methyl-1-propenyl)phenol obtained in (4), 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) were mixed, 151 mg (1.35 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 15 minutes. To the mixture was added 207 mg (1.25 mmol) of 3,6-dichloropyridazine 1-oxide, and the mixture was stirred in an ice bath for 15 minutes, and then, at room temperature for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 90.0 mg (0.325 mmol, Yield from 1-(2-methoxyphenyl)-2-methyl-1-propanol: 41.2%) of a mixture of 6-chloro-3-[2-(2-methyl-1-propenyl)phenoxy]pyridazine 1-oxide and 3-chloro-6-[2-(2-methyl-1-propenyl)phenoxy]-pyridazine 1-oxide. (6) 4,6-Dichloro-3-[2-(2-methyl-1-propenyl)phenoxy]-pyridazine (Step B-3) In chloroform (0.2 mL) was dissolved 90.0 mg (0.325 mmol) of a mixture of 6-chloro-3-[2-(2-methyl-1-propenyl)phenoxy]pyridazine 1-oxide and 3-chloro-6-[2-(2-methyl-1-propenyl)phenoxy]pyridazine 1-oxide obtained in (5), 0.20 mL (2.2 mmol) of phosphorus oxychloride was mixed with the above mixture, and the resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into water, extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=9:1) to obtain 85.0 mg (0.288 mmol, Yield: 88.6%) of 4,6-dichloro-3-[2-(2-methyl-1-propenyl)phenoxy]pyridazine. (7) 6-Chloro-3-[2-(2-methyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2540, Step A-3 and A-4) In dimethylsulfoxide (3 mL) was dissolved 85.0 mg (0.288 mmol) of 4,6-dichloro-3-[2-(2-methyl-1-propenyl)phenoxy]pyridazine obtained in (6), 122 mg (1.49 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled up to room temperature, poured into water, and made acidic with diluted hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by ethyl acetate) to obtain 39.6 mg (0.143 mmol, Yield: 49.7%) of 6-chloro-3-[2-(2-methyl-1-propenyl)phenoxy]-4-pyridazinol (Compound No. 2540). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.35-7.15 (3H, m), 7.15-7.05 (1H, m), 6.65 (1H, s), 6.05 (1H, s), 1.76 (3H, s), 1.70 (3H, s). Melting point (° C.): 149-152. EXAMPLE 626 6-Chloro-3-(3-hydroxyphenoxy)-4-pyridazinol (Compound No. 2544) (1) Mixture of 1-{3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-phenyl}ethanone and 1-{3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl}ethanone 306 mg (2.25 mmol) of 1-(3-hydroxyphenyl)ethanone, 1,4-dioxane (6 mL) and dimethylsulfoxide (6 mL) were mixed, 297 mg (2.65 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 15 minutes. To the mixture was added 342 mg (2.07 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 400 mg (1.51 mmol, Yield: 72.9%) of a mixture of 1-{3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]phenyl}ethanone and 1-{3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl}ethanone. (2) Mixture of 3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-phenyl acetate and 3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl acetate In 3 mL of dichloromethane was dissolved was dissolved 400 mg (1.51 mmol) of a mixture of 1-{3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]phenyl}ethanone and 1-{3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl}ethanone obtained in (1), a dichloromethane (3 mL) solution containing 1.1 g (purity 70-75%, 4.5-4.8 mmol) of m-chloroperbenzoic acid was added to the solution, and the resulting mixture was stirred at room temperature for 4 days. To the reaction mixture was added a saturated aqueous sodium sulfite solution, and after stirring, the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 330 mg of a mixture of the starting material, 3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]phenyl acetate, and 3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl acetate. In dichloromethane (3 mL) was dissolved 280 mg of the mixture, 1.1 g (purity 70-75%, 4.5-4.8 mmol) of m-chloroperbenzoic acid was added to the solution, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with dichloromethane. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was washed with hexane to obtain 310 mg of a mixture of 3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]phenyl acetate and 3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl acetate. (3) 3-[(4,6-Dichloro-3-pyridazinyl)oxy]phenyl acetate (Step B-3) With chloroform (0.4 mL) was mixed 310 mg of a mixture of 3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]phenyl acetate and 3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl acetate obtained in (2), 0.40 mL (4.3 mmol) of phosphorus oxychloride was mixed with the above mixture, and the resulting mixture was stirred at 70° C. for 3 hours. The reaction mixture was poured into water and after stirring, the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 46.0 mg (0.154 mmol, Yield from a mixture of 1-{3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-phenyl}ethanone and 1-{3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]phenyl}ethanone: 9.6%) of 3-[(4,6-dichloro-3-pyridazinyl)oxy]phenyl acetate. (4) 6-Chloro-3-(3-hydroxyphenoxy)-4-pyridazinol (Compound No. 2544, Step A-3 and A-4) In dimethylsulfoxide (1 mL) was dissolved 40.0 mg (0.134 mmol) of 3-[(4,6-dichloro-3-pyridazinyl)oxy]phenyl acetate obtained in (3), 56.0 mg (0.683 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 1 hour. After cooling up to room temperature, the reaction mixture was poured into 0.5 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was made acidic with 4 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed to obtain 30 mg (0.126 mmol, Yield: 94.0%) of 6-chloro-3-(3-hydroxyphenoxy)-4-pyridazinol (Compound No. 2544). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.25-7.10 (1H, m), 6.70-6.57 (4H, m). Melting point (° C.): 248-251. EXAMPLE 627 6-Chloro-3-(2-iodo-3-methoxyphenoxy)-4-pyridazinol (Compound No. 2551) (1) 1-Methoxy-3-(methoxymethoxy)benzene In N,N-dimethylformamide(50 mL) was dissolved 3.68 g (29.7 mmol) of commercially available 3-methoxyphenol, 1.81 g (45.4 mmol) of 60% sodium hydride was added to the solution in an ice bath, and the resulting mixture was stirred in an ice bath for 20 minutes. To the mixture was gradually added dropwise in an ice bath 4.05 mL (53.3 mmol) of chloro(methoxy)methane, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.81 g (28.6 mmol, Yield: 96.3%) of 1-methoxy-3-(methoxymethoxy)benzene. (2) 2-Iodo-1-methoxy-3-(methoxymethoxy)benzene In dry ether (50 mL) was dissolved 3.70 g (22.0 mmol) of 1-methoxy-3-(methoxymethoxy)benzene obtained in (1), the solution was cooled to −78° C. under nitrogem atmosphere, and 5.60 mL (37.2 mmol) of tetramethylethylenediamine, then, 22.0 mL (35.2 mmol) of n-butyl lithium-hexane solution (1.60 M) were added to the solution. The resulting mixture was stirred at −78° C. for 30 minutes, then at 0C for 30 minutes, and cooled to −78° C., 9.80 g (38.6 mmol) of iodine was added to the mixture. The mixture was stirred at −78° C. for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium thiosulfate solution, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 6.59 g of 2-iodo-1-methoxy-3-(methoxymethoxy)benzene. (3) 2-Iodo-3-methoxyphenol In methanol (70 mL) was dissolved 6.59 g of 2-iodo-1-methoxy-3-(methoxymethoxy)benzene obtained in (2), conc. hydrochloric acid (0.18 mL) was added dropwise to the solution, and the resulting mixture was stirred at 65° C. for 1 hour and 15 minutes. Moreover, conc. hydrochloric acid (0.20 mL) was additionally added thereto, and the resulting mixture was stirred at 65° C. for 2 hours and 40 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 4.61 g (18.4 mmol, Yield from 1-methoxy-3-(methoxymethoxy)benzene: 83.6%) of 2-iodo-3-methoxyphenol. (4) Mixture of 6-chloro-3-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide (Step B-2) 298 mg (1.19 mmol) of 2-iodo-3-methoxyphenol obtained in (3), 1,4-dioxane (2.5 mL) and dimethylsulfoxide (2.5 mL) were mixed, 215 mg (1.92 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 10 minutes. To the mixture was added 196 mg (1.19 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the resulting mixture was stirred at at room temperature for 3 days. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=3:1, then, hexane:ethyl acetate=1:1) to obtain 324 mg (0.855 mmol, Yield: 71.8%) of a mixture of 6-chloro-3-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide. (5) 4,6-Dichloro-3-(2-iodo-3-methoxyphenoxy)pyridazine (Step B-3) 1.0 mL (1.1 mmol) of phosphorus oxychloride was added to 324 mg (0.855 mmol) of a mixture of 6-chloro-3-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide and 3-chloro-6-(2-iodo-3-methoxyphenoxy)pyridazine 1-oxide obtained in (4), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=5:1) to obtain 225 mg (0.567 mmol, Yield: 66.3%) of 4,6-dichloro-3-(2-iodo-3-methoxyphenoxy)pyridazine. (6) 6-Chloro-3-(2-iodo-3-methoxyphenoxy)-4-pyridazinol (Compound No. 2551, Step A-3 and A-4) In dimethylsulfoxide (2 mL) was dissolved 105 mg (0.264 mmol) of 4,6-dichloro-3-(2-iodo-3-methoxyphenoxy)-pyridazine obtained in (5), 118 mg (1.44 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 1 hour and 30 minutes. After cooling the mixture up to room temperature, 4 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was removed, and the obtained residue was washed with isopropyl ether to obtain 51.2 mg (0.135 mmol, Yield: 51.1%) of 6-chloro-3-(2-iodo-3-methoxyphenoxy)-4-pyridazinol (Compound No. 2551). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.39 (1H, t, J=8.4 Hz), 6.84 (2H, br.t, J=8.4 Hz), 6.73 (1H, s), 3.90 (3H, s). Melting point (° C.): 231-234. EXAMPLE 628 6-Chloro-3-{[7-(3-hydroxypropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}-4-pyridazinol (Compound No. 2555) (1) 2-Iodo-3-methoxyphenyl trifluoromethanesulfonate In dry dichloromethane was dissolved 3.75 g (15.0 mmol) of 2-iodo-3-methoxyphenol obtained in Example 627(3), and 7.28 mL (90.0 mmol) of pyridine was added to the solution. The mixture was cooled to −20° C., 5.40 mL (32.2 mmol) of trifluoromethanesulfonic anhydride was added thereto, and the resulting mixture was stirred for 3 hours and 50 minutes. The reaction mixture was poured into water, and extracted with dichloromethane, then with ethyl acetate. The organic layers were combined, washed successively with 4 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=10:1) to obtain 5.52 g (14.5 mmol, Yield: 96.7%) of 2-iodo-3-methoxyphenyl trifluoromethanesulfonate. (2) tert-Butyl[(8-methoxy-2,3,4,4a-tetrahydro-8bH-benzo-[3,4]cyclobuta[1,2-b]pyran-8b-yl)oxy]dimethylsilane In dry tetrahydrofuran (15 mL) was dissolved 1.10 g (2.88 mmol) of 2-iodo-3-methoxyphenyl trifluoromethanesulfonate obtained in (1), and 1.00 mL (4.37 mmol) of commercially available tert-butyl(3,4-dihydro-2H-pyran-6-yloxy)dimethylsilane was added to the solution under nitrogen atmosphere. The mixture was cooled to −78° C., 4.50 mL (7.20 mmol) of n-butyl lithium-hexane solution (1.60 M) was added to the mixture and the resulting mixture was stirred for 20 minutes. The reaction mixture was poured into a buffer (prepared by dissolving 9.1 g of KH2PO4 and 4.3 g of Na2HPO4 in 1 L of water) with a pH of 7, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=50:1) to obtain 0.897 g (2.79 mmol, Yield: 96.9%) of tert-butyl[(8-methoxy-2,3,4,4a-tetrahydro-8bH -benzo[3,4]cyclobuta[1,2-b]pyran-8b-yl)oxy]dimethylsilane. (3) 8-(3-Hydroxypropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one In acetonitrile (12 mL) was dissolved 897 mg (2.79 mmol) of tert-butyl[(8-methoxy-2,3,4,4a-tetrahydro-8bH -benzo[3,4]cyclobuta[1,2-b]pyran-8b-yl)oxy]dimethylsilane obtained in (2), 0.30 mL (7.96-8.30 mmol) of 46-47% hydrofluoric acid aqueous solution was added to the solution in an ice bath, and the resulting mixture was stirred for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=7:3) to obtain 446 mg (2.17 mmol, Yield: 77.8%) of 8-(3-hydroxypropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one. (4) 8-(3-Chloropropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one In dichloromethane (22 mL) was dissolved 474 mg (2.30 mmol) of 8-(3-hydroxypropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one obtained in (3), 467 mg (3.49 mmol) of N-chlorosuccinimide and 917 mg (3.5 mmol) of triphenylphosphine were added to the solution, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, a saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=20:1) to obtain 409 mg (1.82 mmol, Yield: 79.1%) of 8-(3-chloropropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one. (5) 7-(3-Chloropropyl)-2-methoxybicyclo[4.2.0]octa-1,3,5-triene Water (6 mL) was added to 111 mg (0.408 mmol) of mercury chloride (HgCl2) to dissolve therein, 4.00 g (6.12 mmol) of zinc powder was added to the solution and the resulting mixture was stirred at room temperature for 50 minutes. After removing the supernatant, the remained solid was washed once with water. To the material were gradually added water (6.0 mL), and then, conc. hydrochloric acid (5.0 mL), and further added acetic acid (2.4 mL), and finally 409 mg (1.82 mmol) of 8-(3-chloropropyl)-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one obtained in (4) dissolved in toluene (2 mL) and ethanol (2 mL). The mixture was stirred at 115° C. overnight, and cooled up to room temperature. Toluene (20 mL) was added to the mixture and the resulting mixture was stirred at 30 minutes, and the organic layer was separated. The obtained organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=20:1) to obtain 304 mg (1.44 mmol, Yield: 79.1%) of 7-(3-chloropropyl)-2-methoxybicyclo[4.2.0]octa-1,3,5-triene. (6) 7-(3-Chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-ol In dichloromethane(2.0 mL) was dissolved 304 mg (1.44 mmol) of 7-(3-chloropropyl)-2-methoxybicyclo[4.2.0]octa-1,3,5-triene obtained in (5), 0.50 mL (5.32 mmol) of boron tribromide was added to the solution in an ice bath with stirring, and the resulting mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=4:1) to obtain 303 mg (1.54 mmol, Yield: quantitative) of 7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-ol. (7) Mixture of 6-chloro-3-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide and 3-chloro-6-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide (Step B-2) 303 mg (1.54 mmol) of 7-(3-chloropropyl)bicycle[4.2.0]octa-1,3,5-trien-2-ol obtained in (6), 1,4-dioxane (2.0 mL) and dimethylsulfoxide (2.0 mL) were mixed, 275 mg (2.46 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 10 minutes. To the mixture was added 254 mg (1.54 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=3:1) to obtain 364 mg (1.12 mmol, Yield: 72.7%) of a mixture of 6-chloro-3-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide and 3-chloro-6-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide. (8) 4,6-Dichloro-3-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine (Step B-3) 1.0 mL (11 mmol) of phosphorus oxychloride was added to 364 mg (1.12 mmol) of a mixture of 6-chloro-3-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide and 3-chloro-6-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine 1-oxide obtained in (7), and the resulting mixture was stirred at room temperature for 7 hours and 15 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=2:1) to obtain 253 mg (0.735 mmol, Yield: 65.6%) of 4,6-dichloro-3-{[7-(3-chloropropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine. (9) 6-Chloro-3-{[7-(3-hydroxypropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}-4-pyridazinol (Compound No. 2555, Step A-3 and A-4) In dimethylsulfoxide (5.0 mL) was dissolved 253 mg (0.735 mmol) of 4,6-dichloro-3-{[7-(3-chloropropyl)bicycle[4.2.0]octa-1,3,5-trien-2-yl]oxy}pyridazine obtained in (8), 250 mg (3.05 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. After cooling up to room temperature, 4 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, and washed with brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=2:1) to obtain 48.5 mg (0.158 mmol, Yield: 21.5%) of 6-chloro-3-{[7-(3-hydroxypropyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl]oxy}-4-pyridazinol (Compound No. 2555). Also, 28.2 mg of a mixture of 6-chloro-3-{[7-(3-chloropropyl)bicycle[4.2.0]octa-1,3,5-trien-2-yl]oxy}-4-pyridazinol and 3-{2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl}propyl acetate was obtained. 1H-NMR (200 MHz, CD3OD) δ ppm: 7.22-7.18 (1H, m), 6.98-6.94 (2H, m), 6.70 (1H, s), 3.62-3.56 (2H, m), 3.46 (1H, br.s), 3.34 (1H, br.s), 3.18 (1H, dd, J=13.9, 5.5 Hz), 2.62 (1H, dd, J=13.9, 2.2 Hz), 1.81-1.62 (4H, m). Appearance: oily product. EXAMPLE 629 6-Chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-4-pyridazinol (Compound No. 2556) (1) 5-Methoxy-8,8-dimethylbicyclo[4.2.0]octa-1,3,5-trien-7-one In dry tetrahydrofuran(10 mL) was dissolved 723 mg (1.89 mmol) of 2-iodo-3-methoxyphenyl trifluoromethanesulfonate obtainable by the method of Example 628(1), and 0.50 mL (2.47 mmol) of commercially available [(1-methoxy-2-methyl-1-propynyl)oxy](trimethyl)silane was added to the solution under nitrogen atmosphere. The mixture was cooled to −78° C., 2.70 mL (4.32 mmol) of n-butyl lithium-hexane solution (1.60M) was added thereto and the resulting mixture was stirred for 20 minutes. The reaction mixture was poured into a buffer (prepared by dissolving 9.1 g of KH2PO4 and 4.3 g of Na2HPO4 in 1 L of water) with a pH of 7, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and to the residue were added tetrahydrofuran (2.0 mL), water (0.2 mL) and acetic acid (2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. Ether was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=2:1) to obtain 182 mg (1.03 mmol, Yield: 54.5%) of 5-methoxy-8,8-dimethylbicyclo[4.2.0]octa-1,3,5-trien-7-one. (2) 2-Methoxy-7,7-dimethylbicyclo[4.2.0]octa-1,3,5-triene Water (6 mL) was added to 109 mg (0.401 mmol) of mercury chloride (HgCl2) to dissolve therein, 3.98 g (6.09 mmol) of zinc powder was added thereto and the resulting mixture was stirred at room temperature for 1 hour. The supernatant was removed, and the remained solid was washed once with water. To the material were gradually added water (6.0 mL), then conc. hydrochloric acid (5.0 mL), and further acetic acid(2.4 mL), and finally 182 mg (1.03 mmol) of 5-methoxy-8,8-dimethylbicyclo[4.2.0]octa-1,3,5-trien-7-one obtained in (1) dissolved in toluene (2 mL) and ethanol (2 mL). The resulting mixture was stirred at 115° C. over-night, and cooled up to room temperature. Toluene (20 mL) was added to the mixture and the mixture was stirred for 20 minutes, and the organic layer was separated. The obtained organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=25:1) to obtain 85.1 mg (0.525 mmol, Yield: 51.0%) of 2-methoxy-7,7-dimethylbicyclo[4.2.0]octa-1,3,5-triene. (3) 7,7-Dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-ol In dichloromethane(5.0 mL) was dissolved 85.1 mg (0.525 mmol) of 2-methoxy-7,7-dimethylbicyclo[4.2.0]octa-1,3,5-triene obtained in (2), 0.20 mL (2.12 mmol) of boron tribromide was added to the solution in an ice bath with stirring, and the resulting mixture was stirred in an ice bath for 2 hours and 10 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 97.6 mg of 7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-ol. (4) 6-Chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine 1-oxide and 3-chloro-6-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine 1-oxide (Step B-2) 97.6 mg of 7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-ol obtained in (3), 1,4-dioxane (1.5 mL) and dimethylsulfoxide (1.5 mL) were mixed, 97.8 mg (0.873 mmol) of potassium tert-butoxide was added to the solution, and the resulting mixture was stirred in an ice bath for 10 minutes. To the mixture was added 90.2 mg (0.547 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=3:1 two times) to obtain 61.7 mg (0.223 mmol, Yield from 2-methoxy-7,7-dimethylbicyclo[4.2.0]octa-1,3,5-triene: 42.5%) of a mixture of 6-chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine 1-oxide and 3-chloro-6-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-pyridazine 1-oxide. (5) 4,6-Dichloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine(Step B-3) 0.50 mL (5.4 mmol) of phosphorus oxychloride was added to 61.7 mg (0.223 mmol) of a mixture of 6-chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-pyridazine 1-oxide and 3-chloro-6-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine 1-oxide obtained in (4), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=5:1) to obtain 43.7 mg (0.148 mmol, Yield: 66.4%) of 4,6-dichloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine. (6) 6-Chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-4-pyridazinol (Compound No. 2556, Step A-3 and Step A-4) In dimethylsulfoxide(2.0 mL) was dissolved 43.7 mg (0.148 mmol) of 4,6-dichloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]pyridazine obtained in (5), 63.1 mg (0.770 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. After cooling up to room temperature, 4 mol/L hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed, and the obtained residue was washed with isopropyl ether to obtain 31.6 mg (0.114 mmol, Yield: 77.0%) of 6-chloro-3-[(7,7-dimethylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)oxy]-4-pyridazinol (Compound No. 2556). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.26-7.19 (1H, m), 6.97-6.89 (2H, m), 6.71 (1H, s), 2.81 (2H, s), 1.41 (6H, s). Melting point (° C.): 197-199. EXAMPLE 630 4-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-3-methylphenyl acetate (Compound No. 2572) (1) Mixture of 1-{4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone and 1-{4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone (Step B-2) 784 mg (5.23 mmol) of commercially available 1-(4-hydroxy-3-methylphenyl)ethanone, 1,4-dioxane (5 mL) and dimethylsulfoxide (5 mL) were mixed, 938 mg (8.38 mmol) of potassium tert-butoxide was added to the mixture and the resulting mixture was stirred in an ice bath for 10 minutes. To the mixture was added 861 mg (5.22 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=5:1) to obtain 758 mg (2.74 mmol, Yield: 52.5%) of a mixture of 1-{4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone and 1-{4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone. (2) Mixture of 4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate and 4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate In 1,2-dichloroethane (13 mL) was dissolved 758 mg (2.74 mmol) of a mixture of 1-{4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone and 1-{4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl}ethanone obtained in (1), a dichloromethane (3 mL) solution containing 1.1 g (purity 70-75%, 4.5-4.8 mmol) of m-chloroperbenzoic acid was added to the solution, and the resulting mixture was stirred at room temperature for 4 hours and 45 minutes. Moreover, 1.20 g (purity 70-75%, 4.86-5.20 mmol) of m-chloroperbenzoic acid was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=5:1) to obtain the starting material and 330 mg of a mixture of 3-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-phenyl acetate and 3-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-phenyl acetate. In dichloromethane (3 mL) was dissolved 280 mg of the mixture, 2.62 g (purity 70-75%, 10.6-11.4 mmol) of m-chloroperbenzoic acid was added to the solution, and the resulting mixture was stirred at room temperature for 4 hours and 45 minutes. Moreover, 1.20 g (purity 70-75%, 4.86-5.20 mmol) of m-chloroperbenzoic acid was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate=5:1) to obtain the starting material and 622 mg of a mixture of 4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate and 4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate. 0.5 mL (4.85 mmol) of 30% hydrogen peroxide aqueous solution was mixed with 1,2-dichloroethane (2.2 mL), 3.2 mL (22.7 mmol) of trifluoroacetic anhydride was added dropwise thereto in an ice bath, and the resulting mixture was stirred at room temperature. In an ice bath, this mixture was added to the mixture of the starting material, 4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate, and 4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate, which was previously obtained and dissolved in 1,2-dichloroethane (2.2 mL), and the resulting mixture was stirred in an ice bath for 1 hour, and at room temperature overnight. The reaction mixture was poured into 10% aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium carbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate gradient) to obtain 413 mg (1.40 mmol, Yield: 51.1%) of a mixture of 4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate and 4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate. (3) 4-[(4,6-Dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate (Step B-3) In chloroform(2 mL) was dissolved 413 mg (1.40 mmol) of a mixture of 4-[(6-chloro-1-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate and 4-[(6-chloro-2-oxide-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in (2), 2.0 mL (22 mmol) of phosphorus oxychloride was mixed with the solution, and the resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with dichloromethane, and then, poured into water. The mixture was extracted with dichloromethane, and then, with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, hexane-ethyl acetate=6:1) to obtain 336 mg (1.07 mmol, Yield: 76.4%) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate. (4) 4-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]-3-methylphenyl acetate (Compound No. 2572, Step A-3 and Step A-4) In dimethylsulfoxide (1.5 mL) was dissolved 160 mg (0.511 mmol) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in (3), 136 mg (1.66 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. After cooling up to room temperature, 4 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed, and the obtained residue was washed with isopropyl ether to obtain 37.3 mg (0.126 mmol, Yield: 24.7%) of 4-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]-3-methylphenyl acetate (Compound No. 2572). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.13-6.94 (3H, m), 6.70 (1H, s), 2.27 (3H, s), 2.17 (3H, s). Melting point (° C.): 255 (dec.). EXAMPLE 631 6-Chloro-3-[2-(difluoromethyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 2576) (1) 2-(methoxymethoxy)-3-methylbenzaldehyde In N,N-dimethylformamide(50 mL) was dissolved 4.96 g (36.5 mmol) of 2-hydroxy-3-methylbenzaldehyde, 2.19 g (54.6 mmol) of 60% sodium hydride was added to the solution in an ice bath and the resulting mixture was stirred for 10 minutes. To the mixture was added 3.59 mL (47.3 mmol) of chloro(methoxy)methane in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate=50:1) to obtain 6.60 g (36.6 mmol, Yield: 100%) of 2-(methoxymethoxy)-3-methylbenzaldehyde. (2) 1-(Difluoromethyl)-2-(methoxymethoxy)-3-methylbenzene In dichloromethane(10 mL) was dissolved 589 mg (3.27 mmol) of 2-(methoxymethoxy)-3-methylbenzaldehyde obtained in (1), 0.863 mL (6.52 mmol) of (diethylamino)sulfur trifluoride (DAST) was added to the solution under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. After allowing to stand at room temperature overnight, the reaction mixture was poured into water, and extracted with dichloromethane. The organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate=10:1) to obtain 229 mg (1.13 mmol, Yield: 34.6%) of 1-(difluoromethyl)-2-(methoxymethoxy)-3-methylbenzene. (3) 2-(Difluoromethyl)-6-methylphenol In methanol (5 mL) was dissolved 229 mg (1.13 mmol) of 1-(difluoromethyl)-2-(methoxymethoxy)-3-methylbenzene obtained in (2), two drops of conc. hydrochloric acid was added to the solution at room temperature and the resulting mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with brineand dried over anhydrous sodium sulfate. The solvent was removed to obtain 135 mg (0.854 mmol, Yield: 75.6%) of 2-(difluoromethyl)-6-methylphenol. (4) 6-Chloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide and 3-chloro-6-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide (Step B-1) In 1,4-dioxane (1.5 mL) and dimethylsulfoxide (1.5 mL) was dissolved 135 mg (0.854 mmol) of 2-(difluoromethyl)-6-methylphenol obtained in (3), 115 mg (1.03 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 5 minutes. To the mixture was added 141 mg (0.855 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (eluted by hexane:ethyl acetate=2:1) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 28.6 mg (0.0997 mmol, Yield: 11.7%) of a mixture of 6-chloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide and 3-chloro-6-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide. (5) 4,6-Dichloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine(Step B-3) In chloroform(0.5 mL) was dissolved 28.6 mg (0.0997 mmol) of a mixture of 6-chloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide and 3-chloro-6-[2-(difluoromethyl)-6-methylphenoxy]pyridazine 1-oxide obtained in (4), 76.5 mg (0.50 mmol) of phosphorus oxychloride was added to the solution and the resulting mixture was refluxed for 8 hours. After allowing to stand at room temperature overnight, water and dichloromethane were added to the reaction mixture, and the resulting mixture was stirred for 30 minutes. The mixture was extracted with dichloromethane, the organic layers were combined, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, developed by hexane:ethyl acetate=4:1) to obtain 19.1 mg (0.0626 mmol, Yield: 62.8%) of 4,6-dichloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine. (6) 6-Chloro-3-[2-(difluoromethyl)-6-methylphenoxy]-4-pyridazinol (Compound No. 2576) In dimethylsulfoxide(0.5 mL) was dissolved 19.1 mg (0.0626 mmol) of 4,6-dichloro-3-[2-(difluoromethyl)-6-methylphenoxy]pyridazine obtained in (5), 25.7 mg (0.313 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. After cooling up to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, developed by ethyl acetate) to obtain 17.8 mg (0.0620 mmol, Yield: 99.0%) of 6-chloro-3-[2-(difluoromethyl)-6-methylphenoxy-4-pyridazinol (Compound No. 2576). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.55-7.25 (3H, m), 6.83 (1H, t, J=55.1 Hz). 2.15 (3H, s). Melting point (° C.): 204-205. EXAMPLE 632 6-Chloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 2596) (1) 4,6-Dichloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]pyridazine 2.05 g (8.84 mmol) of commercially available 1-bromo-2-methoxy-4-nitrobenzene and water (200 mL) were mixed, and 11.4 g (213 mmol) of ammonium chloride, then 4.78 g (73.2 mmol) of zinc powder were added to the mixture. After stirring at room temperature for 5 hours, the mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 1.78 g of the residue. The residue was mixed with water (9 mL) and 47% hydrobromic acid aqueous solution (3 mL), an aqueous solution (3.6 mL of water) containing 655 mg (9.49 mmol) of sodium nitrite was added dropwise to the mixture in an ice bath with stirring. After completion of the dropwise addition, the mixture was stirred for 10 minutes, and 973 mg (6.80 mmol) of cuprous bromide dissolved in 47% hydrobromic acid aqueous solution (3.6 mL) was added dropwise to the mixture. The reaction mixture was stirred at 110° C. for 2 hours and 30 minutes, then cooled up to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane: ethyl acetate=10:1) and by preparative thin-layer chromatography (available from MERCK CO., 1.05717, developed multiply by hexane:ethyl acetate=4:1) to obtain 751 mg of a crude product. Under nitrogen atmosphere, in dry N,N-dimethylformamide (5 mL) was suspended 339 mg (8.46 mmol) of 60% sodium hydride, and 0.65 mL (8.78 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 30 minutes, 751 mg of the previously obtained crude product dissolved in N,N-dimethylformamide (8 mL) was added to the mixture, and the resulting mixture was stirred at 160° C. for 5 hours. After the reaction mixture was allowed to stand at room temperature overnight, it was poured into water, made acidic by adding diluted hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed multiply by hexane:ethyl acetate=4:1) to obtain 109 mg of a phenolic crude product. 109 mg of the obtained phenolic crude product was mixed with 1,4-dioxane (3 mL) and dimethylsulfoxide (3 mL), 53.5 mg (0.478 mmol) of potassium tert-butoxide was added to the mixture, and the resulting mixture was stirred in an ice bath for 15 minutes. To the mixture was added 71.2 mg (0.432 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 3 plates were used, developed multiply by hexane:ethyl acetate=2:1) to obtain 71.5 mg of an etheric crude product. In phosphorus oxychloride (3 mL) was dissolved 44.8 mg of the etheric crude product, and the resulting mixture was stirred at 60° C. for 21 hours. Water and dichloromethane were added to the reaction mixture and after stirring, the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 14.4 mg (0.0314 mmol, Yield: 0.567%) of 4,6-dichloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]pyridazine. (2) 6-Chloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 2596, Step A-3 and A-4) In dimethylsulfoxide (3 mL) was dissolved 33.4 mg (0.0728 mmol) of 4,6-dichloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]pyridazine obtained in (1), 29.8 mg (0.363 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 4 hours and 30 minutes. After allowing to stand at room temperature overnight, water was added to the reaction mixture, the mixture was made acidic by adding diluted hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK Co., 1.05744, developed multiply by ethyl acetate) to obtain 13.1 mg (0.0297 mmol, Yield: 40.8%) of 6-chloro-3-[2,4-dibromo-5-(ethylsulfanyl)phenoxy]-4-pyridazinol (Compound No. 2596). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.84 (1H, s), 7.21 (1H, s) 6.72 (1H, s), 2.97 (2H, q, J=7.3 Hz), 1.33 (3H, t, J=7.3 Hz). Melting point (° C.): 225-228. EXAMPLE 633 6-Chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)-4-pyridazinol (Compound No. 2603) (1) 1-(2-Methoxy-3,4,6-trimethylphenyl)ethanone In acetone (30 mL) was dissolved 2.00 g (11.2 mmol) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone which can be produced by the method disclosed in Chemical Research in Toxicology, 1997, vol. 10, No. 3, pp. 335-343, 3.10 g (22.4 mmol) of potassium carbonate, then 1.40 mL (22.5 mmol) of methyl iodide were added to the solution, and the resulting mixture was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate gradient) to obtain 1.90 g (9.90 mmol, Yield: 88.4%) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone. (2) 1-(2-Methoxy-3,4,6-trimethylphenyl)ethanol In methanol (8 mL) was dissolved 1.00 g (5.21 mmol) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone obtained in (1), and 170 mg (4.50 mmol) of sodium borohydride was added to the solution little by little with stirring. After confirmation of disappearance of the starting materials by thin layer chromatography (TLC) for analysis, the reaction mixture was poured into water, and made acidic by adding hydrochloric acid. The mixture was extracted with hexane, the organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 1.0 g of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanol. (3) 2-(l-Chloroethyl)-3-methoxy-1,4,5-trimethylbenzene In dichloromethane(10 mL) was dissolved 1.0 g of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanol obtained in (2), and 1.10 mL (7.91 mmol) of triethylamine, then, 0.56 mL (7.21 mmol) of methanesulfonyl chloride were added to the solution in an ice bath with stirring. The reaction mixture was stirred at room temperature for 20 minutes, poured into water, and extracted with dichloromethane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 1.2 g of 2-(1-chloroethyl)-3-methoxy-1,4,5-trimethylbenzene. (4) 3-Methoxy-1,2,5-trimethyl-4-vinylbenzene In dry N,N-dimethylformamide (12 mL) was dissolved 1.2 g of 2-(1-chloroethyl)-3-methoxy-1,4,5-trimethylbenzene obtained in (3), and 1.14 g (10.2 mmol) of potassium tertbutoxide was added to the solution in an ice bath with stirring. The reaction mixture was stirred at room temperature for 30 minutes, then, under reflux for 30 minutes. After cooling to room temperature, the mixture was poured into water, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 870 mg of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene. (5) 2,3,5-Trimethyl-6-vinylphenol and 2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenol Under nitrogen atmosphere, in dry N,N-dimethylformamide (8 mL) was suspended 270 mg (6.75 mmol) of 60% sodium hydride, and 0.60 mL (8.10 mmol) of ethanethiol was gradually added dropwise to the suspension. After stirring for 15 minutes, 400 mg (2.27 mmol) of 3-methoxy-1,2,5-trimethyl-4-vinylbenzene obtained in (4) and dissolved in dry N,N-dimethylformamide (1.5 mL) was added to the mixture, and the resulting mixture was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into water, made acidic by adding hydrochloric acid, and extracted with hexane. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate=20:1) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, developed by hexane:ethyl acetate=8:1) to obtain 63.0 mg (0.389 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 16.2%) of 2,3,5-trimethyl-6-vinylphenol and 330 mg (1.47 mmol, Yield from 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone: 61.4%) of 2-[1-(ethylsulfanylethyl]-3,5,6-trimethylphenol. (6) Mixture of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide (Step B-2) In 1,4-dioxane (0.4 mL) and dimethylsulfoxide (0.4 mL) was dissolved 43.0 mg (0.265 mmol) of 2,3,5-trimethyl-6-vinylphenol obtained in (5), 36.0 mg (0.321 mmol) of potassium tert-butoxide was added to the mixture in an ice bath, and the resulting mixture was stirred for 10 minutes. To the mixture was added 47.6 mg (0.288 mmol) of 3,6-dichloropyridazine 1-oxide in an ice bath, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 27.6 mg (0.0949 mmol, Yield: 35.8%) of a mixture of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide. (7) 4,6-Dichloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine (Step B-3) 0.02 mL (0.22 mmol) of phosphorus oxychloride was added to 27.6 mg (0.0949 mmol) of a mixture of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide and 3-chloro-6-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine 1-oxide obtained in (6), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 0.4 mL of chloroform, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 0.2 mL (2.2 mmol) of phosphorus oxychloride was added to the residue and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by hexane:ethyl acetate=5:1) to obtain 5.0 mg (0.016 mmol, Yield: 17%) of 4,6-dichloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine. (8) 6-Chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)-4-pyridazinol (Compound No. 2603, Step A-3 and Step A-4) In dimethylsulfoxide(1 mL) was dissolved 5.0 mg (0.016 mmol) of 4,6-dichloro-3-(2,3,5-trimethyl-6-vinylphenoxy)pyridazine obtained in (7), 10.3 mg (0.126 mmol) of sodium acetate was added to the solution and the resulting mixture was stirred at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water, made acidic by adding hydrochloric acid, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 1 plate was used, developed by ethyl acetate) to obtain 1.5 mg (0.0052 mmol, Yield: 33%) of 6-chloro-3-(2,3,5-trimethyl-6-vinylphenoxy)-4-pyridazinol (Compound No. 2603). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.25 (1H, s), 6.67 (1H, dd, J=11.0 Hz, 17.6 Hz), 6.56 (1H, s), 5.66 (1H, dd, J=1.5 Hz, 17.6 Hz), 5.10 (1H, dd, J=1.5 Hz, 11.0 Hz), 2.29 (3H, s), 2.20 (3H, s), 2.04 (3H, s). Appearance: amorphous. EXAMPLE 634 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-pyridazinol (Compound No. 2606) (1) 6-Chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine(Step D-1) In a mixed solvent of 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) was dissolved 150 mg (0.670 mmol) of 2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenol obtained in Example 633(5), 93 mg (0.83 mmol) of potassium tert-butoxide was added to the solution in an ice bath, and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was again cooled in an ice bath, 120 mg (0.670 mmol) of 3,6-dichloro-4-methoxypyridazine was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 26.7 mg (0.0728 mmol, Yield: 10.9%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine. Also, 60.0 mg (0.163 mmol, Yield: 24.3%) of 3-chloro-6-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine was obtained. (2) 6-Chloro-3-{2-[l-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-pyridazinol (Compound No. 2606, Step D-2) In dimethylsulfoxide (1 mL) was dissolved 34.0 mg (0.358 mmol) of 2-hydroxypyridine, 41.0 mg (0.366 mmol) of potassium tert-butoxide was added to the solution at room temperature, and the resulting mixture was stirred at room temperature for 20 minutes. To the mixture was added a dimethylsulfoxide (1 mL) solution containing 26.7 mg (0.0728 mmol) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine obtained in (1), and the resulting mixture was stirred at 60° C. After completion of the reaction, the reaction mixture was allowed to stand for cooling, and poured into water. After making the mixture acidic by adding hydrochloric acid to the mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, developed by ethyl acetate) to obtain 6.6 mg (0.019 mmol, Yield: 26%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-pyridazinol (Compound No. 2606). 1H-NMR (200 MHz, CD3OD) 8 ppm: 7.20 (2H, s), 6.64 (1H, s), 2.40-2.15 (8H, m), 2.03 (3H, s), 1.40 (3H, d, J=7.0 Hz), 1.24 (1H, m), 1.03 (3H, t, J=7.3 Hz). Appearance: amorphous. EXAMPLE 635 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1625) and bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] phthalate (Compound No. 2838, Step I) In acetonitrile (3 mL) was suspended 207 mg (0.726 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 81.6 mg (0.729 mmol) of 1,4-diazabicyclo[2.2.2]octane was added to the suspension and the resulting mixture was stirred. To the mixture was added 105 iL (0.729 mmol) of phthaloyl dichloride, and after stirring at room temperature for 1 hour, 200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was further added, and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Daisogel 1001W, hexane:ethyl acetate, gradient) to obtain 28.0 mg (0.0405 mmol, Yield: 5.61%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1625) and 163 mg (0.238 mmol, Yield: 33.0%) of bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] phthalate (Compound No. 2838). 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl phthalate (Compound No. 1625): 1H-NMR (200 MHz, CDCl3) 8 ppm: 8.01-7.96 (1H, m), 7.89-7.68 (3H, m), 7.57 (1H, s), 7.29-7.06 (5H, m), 6.90-6.83 (1H, m), 3.71 (3H, s), 2.27 (3H, s), 2.13 (3H, s), 1.82-1.68 (1H, m), 0.77-0.53 (4H, m). Appearance: amorphous. Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] phthalate (Compound No. 2838): 1H-NMR (200 MHz, CDCl3) 8 ppm: 8.13-8.06 (2H, m), 7.84-7.78 (2H, m), 7.58 (2H, s), 7.15-7.06 (4H, m), 6.90-6.83 (2H, m), 2.13 (6H, s), 1.82-1.68 (2H, m), 0.73-0.52 (8H, m). Appearance: amorphous. EXAMPLE 636 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl 1,3-benzenedisulfonate (Compound No. 2333) and bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 1,3-benzenedisulfonate (Compound No. 3755, Step I) In acetonitrile (4 mL) was suspended 122 mg (0.428 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 72.0 mg (0.643 mmol) of 1,4-diazabicyclo[2.2.2]octane, then 117 mg (0.425 mmol) of 1,3-benzenedisulfonyl dichloride were added to the suspension in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, and further 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 135 mg (0.177 mmol, Yield: 49.0%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl 1,3-benzenedisulfonate (Compound No. 2333) and 38.0 mg (0.0503 mmol, Yield: 13.9%) of bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 1,3-benzenedisulfonate (Compound No. 3755). 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl 1,3-benzenedisulfonate (Compound No. 2333): H-NMR (200 MHz, CDCl3) δ ppm: 8.67 (1H, t, J=1.9 Hz), 8.40-8.34 (1H, m), 8.31-8.24 (1H, m), 7.86 (1H, t, J=8.0 Hz), 7.56 (1H, s), 7.37 (1H, d, J=1.9 Hz), 7.29-7.23 (1H, m), 7.15-7.00 (3H, m), 6.85-6.78 (1H, m), 3.81 (3H, s), 2.00 (3H, s), 1.94 (3H, s), 1.70-1.52 (1H, m), 0.73-0.45 (4H, m). Appearance: amorphous. Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 1,3-benzenedisulfonate (Compound No. 3755): 1H-NMR (200 MHz, CDCl3) δ ppm: 8.77 (1H, dd, J=1.8 Hz, 1.8 Hz), 8.41 (2H, dd, J=7.7 Hz, 1.8 Hz), 7.88 (1H, t, J=8.0 Hz), 7.48 (2H, s), 7.15-6.95 (4H, m), 6.90-6.75 (2H, m), 1.97 (6H, s), 1.67-1.46 (2H, m), 0.75-0.44 (8H, m). Appearance: amorphous. EXAMPLE 637 Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] pentanedioate (Compound No. 2746) and 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl pentanedioate (Compound No. 2739) In acetonitrile (8 mL) was suspended 241 mg (0.870 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, in an ice bath 139 mg (1.23 mmol) of 1,4-diazabicyclo[2.2.2]octane, then 146 mg (0.864 mmol) of pentanedioyl dichloride, and further 244 mg (0.856 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone were added to the suspension, and the resulting mixture was stirred at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane: ethyl acetate, gradient) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1 or 1:1) to obtain 42.0 mg (0.0646 mmol, Yield: 7.48%) of bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] pentanedioate (Compound No. 2746) and 35.0 mg (0.0532 mmol, Yield: 6.21%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl pentanedioate (Compound No. 2739). Bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] pentanedioate (Compound No. 2746): 1H-NMR (200 MHz, CDCl3) δ ppm: 7.23 (2H, s), 7.14-7.02 (4H, m), 6.83 (2H, dd, J=6.6, 2.9 Hz), 2.89 (4H, t, J=7.0 Hz), 2.25 (2H, quintet, J=7.0 Hz), 2.10 (6H, s), 1.80-1.65 (2H, m), 0.78-0.52 (8H, m). Appearance: caramel-like. 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl pentanedioate (Compound No. 2739): 1H-NMR (200 MHz, CDCl3) δ ppm: 7.45-7.17 (4H, m), 7.14-7.00 (2H, m), 6.90-6.75 (1H, m), 3.53 (3H, s), 2.83 (2H, t, J=7.0 Hz), 2.57 (2H, t, J=7.0 Hz), 2.20-2.00 (2H, m), 2.11 (3H, s), 2.10 (3H, s), 1.80-1.65 (1H, m), 0.80-0.50 (4H, m). Appearance: amorphous. EXAMPLE 638 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-pyrrolidinecarboxylate (Compound No. 1937) 200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was mixed with toluene (3 mL) and the mixture was ice-cooled. To the mixture were added 60 iL (0.742 mmol) of pyridine, then 0.67 mL (0.724 mmol) of 1.08 mol/L phosgene-toluene solution under nitrogen atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, 60 iL (0.722 mmol) of pyridine, then 60 iL (0.719 mmol) of pyrrolidine were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 4 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 190 mg (0.508 mmol, Yield: 70.7%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 1-pyrrolidinecarboxylate (Compound No. 1937). 1H-NMR (200 MHz, CDCl3) δ ppm: 7.59 (1H, s), 7.15-7.03 (2H, m), 6.90-6.80 (1H, m), 3.62 (2H, dd, J=6.6 Hz, 6.9 Hz), 3.51 (2H, dd, J=6.9 Hz, 6.6 Hz), 2.15 (3H, s), 2.05-1.90 (4H, m), 1.88-1.68 (1H, m), 0.80-0.50 (4H, m). Melting point (° C.): 115-118. EXAMPLE 639 6-Chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxy(methyl)carbamate (Compound No. 3564) 200 mg (0.722 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was mixed with toluene (3 mL) and the mixture was ice-cooled. To the mixture were added 60 iL (0.742 mmol) of pyridine, then 0.67 mL (0.724 mmol) of 1.08 mol/L phosgene-toluene solution under nitrogen atmosphere with stirring, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was ice-cooled, 120 iL (1.48 mmol) of pyridine, then 70.4 mg (0.722 mmol) of N,O-dimethylhydroxylamine hydrochloride were added to the mixture, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane: ethyl acetate, gradient) to obtain 100 mg (0.275 mmol, Yield: 38.1%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl methoxy(methyl)carbamate (Compound No. 3564). 1H-NMR (200 MHz, CDCl3) δ ppm: 7.53 (1H, s), 7.15-7.03 (2H, m), 6.90-6.82 (1H, m), 3.84 (3H, s), 3.35 (3H, s), 2.15 (3H, s), 1.87-1.67 (1H, m), 0.80-0.52 (4H, m). Melting point (° C.): 63-64.5. EXAMPLE 640 6-Chloro-3-(2-cyclopropyl-6-methylphen6xy)-4-pyridazinyl 2,5-dimethyl-1H-pyrrole-1-carboxylate (Compound No. 3630) 37.4 mg (0.393 mmol) of 2,5-dimethyl-1H-pyrrole was mixed with toluene (1 mL), 40.0 iL (0.407 mmol) of pyridine, then 0.34 mL (0.367 mmol) of 1.08 mol/L phosgene-toluene solution were added to the mixture in an ice bath with stirring, and the resulting mixture was stirred for 1 hour. To the mixture were added 40.0 iL (0.407 mmol) of pyridine, then 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 24.0 mg (0.0603 mmol, Yield: 16.7%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 2,5-dimethyl-1H-pyrrole-1-carboxylate (Compound No. 3630). 1H-NMR (200 MHz, CDCl3) δ ppm: 8.20-8.03 (1H, m), 7.63 (1H, s), 7.13-7.00 (2H, m), 6.90-6.80 (1H, m), 6.36 (1H, d, J=2.9 Hz), 2.55 (3H, s), 2.22 (3H, s), 2.15 (3H, s), 1.90-1.70 (1H, m), 0.80-0.50 (4H, m). Melting point (° C.): 208-210. EXAMPLE 641 4-{[4-(benzoyloxy)-6-chloro-3-pyridazinyl]oxy}-3-methylphenyl benzoate (Compound No. 3850) (1) 6-Chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol In 1,4-dioxane(1.4 mL) was dissolved 173 mg (0.553 mmol) of 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate obtained in Example 630(3), 0.7 mL (2.1 mmol) of 3 mol/L sodium hydroxide solution and dimethylsulfoxide (2.8 mL) were added to the solution and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added 4 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (developed by dichloromethane:methanol=36:1) to obtain 66.8 mg of 6-chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol. (2) 4-{[4-(Benzoyloxy)-6-chloro-3-pyridazinyl]oxy}-3-methylphenyl benzoate (Compound No. 3850) In acetonitrile (1.0 mL) was dissolved 66.8 mg of 6-chloro-3-(4-hydroxy-2-methylphenoxy)-4-pyridazinol obtained in (1), 60.0 mg (0.536 mmol) of 1,4-diazabicyclo[2.2.2]-octane., then, 61 iL (0.523 mmol) of benzoyl chloride were added to the solution and the resulting mixture was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed. The obtained residue was purified by preparative thin-layer chromatography (developed by hexane:ethyl acetate=5:1) to obtain 36.9 mg (0.0800 mmol, Yield from 4-[(4,6-dichloro-3-pyridazinyl)oxy]-3-methylphenyl acetate: 14.5%) of 4-{[4-(benzoyloxy)-6-chloro-3-pyridazinyl]oxy}-3-methylphenyl benzoate (Compound No. 3850). 1H-NMR (200 MHz, CDCl3) δ ppm: 8.21-8.17 (4H, m), 7.72-7.48 (7H, m), 7.22-7.07 (3H, m), 2.21 (3H, s). Melting point (° C.): 118-120. EXAMPLE 642 3-(2-Aminophenoxy)-3-chloro-4-pyridazinol (Compound No. 377) (1) 2-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]aniline(Step D-1) In a mixed solvent of 1,4-dioxane (7 mL) and dimethylsulfoxide (7 mL) was dissolved 670 mg (6.15 mmol) of 2-aminophenol, 690 mg (6.16 mmol) of potassium tertbutoxide was added to the solution in an ice bath and the resulting mixture was stirred for 10 minutes. To the mixture was added 1000 mg (5.59 mmol) of 3,6-dichloro-4-methoxypyridazine, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, and after adding brine, the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) to obtain 328 mg (1.30 mmol, Yield: 23.3%) of 2-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]aniline and 100 mg of a mixture of 2-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]aniline and 2-[(6-chloro-5-methoxy-3-pyridazinyl)oxy]aniline. (2) 3-(2-Aminophenoxy)-3-chloro-4-pyridazinol (Compound No. 377, Step D-2) In dimethylsulfoxide (0.4 mL) was dissolved 50.0 mg (0.198 mmol) of 2-[(6-chloro-4-methoxy-3-pyridazinyl)oxy]aniline obtained in (1), (0.2 mL, 0.4 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into brine, and extracted with tetrahydrofuran. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by dichloromethane:methanol=10:1) to obtain 17.0 mg (0.0714 mmol, Yield: 36.1%) of 3-(2-aminophenoxy)-3-chloro-4-pyridazinol (Compound No. 377). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.50-6.94 (2H, m), 6.90-6.82 (1H, m), 6.85-6.63 (2H, m). Melting point (° C.): 249-250. EXAMPLE 643 N-{2-[(6-Chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}acetamide (Compound No. 380) 18.0 mg (0.0756 mmol) of 3-(2-aminophenoxy)-3-chloro-4-pyridazinol obtained in Example 641 was mixed with dichloromethane (0.8 mL), 0.050 mL (0.36 mmol) of triethylamine, then 0.010 mL (0.14 mmol) of acetyl chloride were added to the mixture in an ice bath with stirring, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into brine, and extracted with tetrahydrofuran. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05715, developed by dichloromethane:methanol=10:1) to obtain 3.6 mg (0.0129 mmol, Yield: 17.1%) of N-{2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}acetamide (Compound No. 380). 1H-NMR (200 MHz, CD3OD) δ ppm: 8.10-8.00 (1H, m), 7.25-7.08 (3H, m), 6.60 (1H, s), 2.12 (3H, s). Melting point (° C.): 135. EXAMPLE 644 N,N,N-Tributyl-1-butanaminium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate(Compound No. 3798) To an ethanol (2 mL) solution containing 105 mg (0.379 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 0.19 mL (0.38 mmol) of 2 mol/L aqueous sodium hydroxide solution, then, 106 mg (0.381 mmol) of tetrabutylammonium chloride, and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was allowed to stand at room temperature overnight, and the solid was removed by filtration. The filtrate was concentrated to obtain N,N,N-tributyl-1-butanaminium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate (Compound No. 3798). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.05-6.95 (2H, m), 6.80-6.73 (1H, m), 6.43 (1H, s), 3.30-3.15 (8H, m), 2.14 (3H, s), 2.00-1.85 (1H, m), 1.76-1.53 (8H, m), 1.50-1.30 (8H, m), 1.02 (9H, t, J=7.1 Hz), 0.78-0.63 (2H, m), 0.63-0.48 (2H, m). Melting point (° C.): 113-114. EXAMPLE 645 Sodium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate (Compound No. 3805) 0.18 mL (0.36 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to an ethanol (2 mL) solution containing 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred at 50° C. for 4 hours. The reaction mixture was concentrated to obtain 108 mg (0.361 mmol, Yield: 100%) of sodium 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinolate (Compound No. 3805). 1H-NMR (200 MHz, CD3OD) 8 ppm: 7.05-6.95 (2H, m), 6.77 (1H, dd,J=6.4, 3.1 Hz), 6.43 (1H, s), 2.14 (3H, s), 2.00-1.82 (1H, m), 0.78-0.63 (2H, m), 0.63-0.48 (2H, m). Melting point (° C.): >260. EXAMPLE 646 5-Bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843) 108 mg (0.607 mmol) of N-bromosuccinimide was added to a N,N-dimethylformamide (2 mL) solution containing 157 mg (0.567 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol, and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Water, and then, 4 mol/L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO. 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 123 mg (0.346 mmol, Yield: 61.0%) of 5-bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843). 1H-NMR (200 MHz, CD3OD) δ ppm: 7.08-7.05 (2H, m), 6.85-6.80 (1H, m), 2.14 (3H, s), 1.88-1.76 (1H, m), 0.82-0.72 (2H, m), 0.60-0.56 (2H, m). Appearance: amorphous. Compounds of Compounds Nos. 1 and 6 can be produced in accordance with the method of Example 2. Compounds of Compounds Nos. 123-127, 130-138, 144, 145, 151, 163, 173, 184, 202, 217, 226, 249, 264, 265, 266, 267, 269-275, 279, 280, 284, 287, 288, 292, 293, 300, 304, 305, 306, 307, 308, 309, 311, 315, 324, 325, 329, 330, 334, 336, 339, 344, 348, 349, 355, 356, 359, 361, 362, 364-370, 375, 376, 379, 383, 385-387, 390, 391, 396, 399-401, 403, 410, 412, 413, 415-425, 426, 427, 430, 432-438, 441, 443, 446, 450, 453, 454, 456, 458-460, 472, 491, 498, 503, 505, 506, 507, 510, 513, 514, 520, 521, 527-529, 531, 532, 534-536, 538-541, 544, 547, 549, 552, 556, 557, 558, 559, 562, 566, 567, 571, 614, 618, 621, 623, 626-629, 635, 640, 642, 650, 653, 658, 659, 662-664, 667, 679, 680, 692, 700, 701, 702, 707-712, 716, 71.7, 719, 731-733, 734, 735-737, 740, 746, 754, 756, 758, 759, 762, 775, 778, 780-782, 802-804, 834, 844-846, 850, 890, 894, 896, 911, 914, 931, 964, 965, 979, 982, 987, 998, 1000, 1007, 1009, 1013, 1016, 1020, 1023, 1027, 1040, 1050, 1052, 1053, 1055, 1058, 1060, 1061, 1063, 1064, 1066, 1069, 1073, 1080, 1083, 1086, 1088, 1089, 1091, 1096, 1099, 1100, 1102, 1115, 1118-1120, 1122-1125, 1129, 1133, 2519, 2547, 2548, 2565, 2568, 2570, 2571, 2574, 2577, 2585, 2587, 2589, 2592, 2597, 2599, 2600, 2601, 2605, 2607, 2608, 2609 and 2614 can be produced in accordance with the method of Example 1, Example 6, Example 13, Example 16, Example 21, Example 22 or Example 23. Compounds of Compound No. 1140, 1151, 1160, 1172, 1178, 1184, 1207, 1251, 1260, 1266, 1286, 1298, 1334, 1340, 1358, 1364, 1382, 1387, 1391, 1396, 1417, 1441, 1446, 1448, 1450, 1455-1459, 1461, 1481, 1509, 1522, 1531, 1537, 1543, 1549, 1553, 1554, 1566, 1575, 1593, 1599, 1603, 1616, 1643, 1649, 1658, 1706, 1710, 1757, 1770, 1789, 1811, 1840, 1877, 1879, 1881, 1898, 1924, 1981, 1985, 2010, 2034, 2038, 2040, 2042, 2051, 2060, 2066, 2072, 2106, 2136, 2147, 2151, 2176, 2198-2200, 2212, 2220-2224, 2230-2232, 2234-2238, 2240, 2245-2249, 2263, 2265, 2287, 2289, 2300, 2309, 2315, 2321, 2351, 2662, 2671, 2677, 2697, 2703, 2709, 2715, 2721, 2727, 2752, 2758, 2764, 2770, 2776, 2782, 2788, 2805, 2814, 2820, 2826, 2850, 2856, 2862, 2868, 2874, 2880, 2900, 2906, 2918, 2924, 2930, 2961, 2970, 2976, 2982, 2988, 2994, 3016, 3022, 3028, 3034, 3040, 3046, 3052, 3058, 3064, 3070, 3076, 3082, 3088, 3094, 3100, 3106, 3112, 3129, 3138, 3144, 3150, 3156, 3162, 3168, 3185, 3194, 3200, 3217, 3226, 3243, 3252, 3258, 3264, 3270, 3276, 3282, 3288, 3294, 3300, 3306, 3312, 3318, 3324, 3330, 3336, 3342, 3348, 3354, 3360, 3366, 3372, 3378, 3384, 3390, 3396, 3402, 3408, 3414, 3420, 3426, 3432, 3438, 3444, 3450, 3456, 3462, 3468, 3474, 3480, 3486, 3492, 3498, 3504, 3510, 3516, 3780, 3786, 3792 and 3856 can be produced in accordance with the method of Example 26, Example 27 or Example 28. A compound of Compound No. 2402 can be produced in accordance with the method of Example 33. Compounds of Compound No. 2418 and 2431 can be produced in accordance with the method of Example 1, Example 6 or Example 22. A compound of Compound No. 2478 can be produced in accordance with the method of Example 35, Example 36, Example 37, Example 39 or Example 40. A compound of Compound No. 2492 can be produced in accordance with the method of Example 41. Compounds of Compound No. 1620, 1631, 2827 and 3001 can be produced in accordance with the method of Example 635. Compounds of Compound No. 1891, 1911, 1920, 1946, 1952, 1958, 3522, 3528, 3534, 3540, 3546, 35.52, 3558, 3570, 3576, 3582, 3588, 3594, 3600, 3606, 3612, 3618, 3624, 3636, 3642, 3648, 3654, 3660, 3666, 3672, 3678, 3684, 3690, 3696, 3702, 3708, 3714 and 3720 can be produced in accordance with the method of Example 26, Example 27, Example 28, Example 638, Example 639 or Example 640. A compound of Compound No. 2327 can be produced in accordance with the method of Example 636. A compound of Compound No. 2733 can be produced in accordance with the method of Example 637. A compound of Compound No. 3811 can be produced in accordance with the method of Example 645. Compounds of Compound No. 3837 and 3849 can be produced in accordance with the method of Example 646. In the following Preparation example, all “%” mean % by weight. PREPARATION EXAMPLE 1 Wettable Powder A compound (10 parts by weight) of Example 1 (Compound No. 128), Carplex #80D (available from Shionogi & Co. Ltd., 10 parts by weight), GOHSENOL GLO5 (available from The Nippon Synthetic Chemical Industry Co.,Ltd., 2 parts by weight), Newcol 291PG (dioctylsulfosuccinate sodium salt, available from Nippon Nyukazai Co.,Ltd., 0.5 part by weight), Neogen Powder (available from DAI-ICHI KOGYO SEIYAKU CO., LTD., 5 parts by weight), Radiolite #200 (available from SHOWA CHEMICAL CO., LTD., 10 parts by weight) and H Bifun (fine cray, available from Keiwa Rozai Co.,Ltd, 62.5 parts by weight) were sufficiently mixed, and pulverized by Ecksample Mill Type KII-1 (available from Fuji Paudal Co.,Ltd.) to obtain wettable powder. PREPARATION EXAMPLE 2 Granule A compound (5 parts by weight) of Example 61 (Compound No. 136), sodium tripolyphosphate (available from Mitsui Chemicals, Inc., 2 parts by weight), Amycol No.1 (dextrin, available from NIPPON STARCH CHEMICAL CO., LTD., 1.5 parts by weight), bentonite (available from Hojun Co.,Ltd., 25 parts by weight) and Calfin 600 (calcium carbonate, available from Ashidachi Sekkai K.K., 66.5 parts by weight) were mixed in a kneader (available from Fujisangyo Co.,Ltd., Type FM-NW-5), and water (13 parts by weight) was added to the mixture to carry out further mixing, and subjected to extrusion granulation by using Dom Gran (available from Fuji Paudal Co.,Ltd., screen 1.0 mmo). The obtained granules were dried by using a tray type dryer (available from Tabai K.K., PERFECT OVEN Type PS-222, 60° C.), and sieved to 600 to 1190 mm to obtain granules. PREPARATION EXAMPLE 3 Water Dispersible Granules A compound (80 parts by weight) of Example 7 (Compound No. 140), Geropon SC/213 (polycarboxylic acid type surfactant, available from Rohdia K.K., 7 parts by weight), Neopelex No.6F Powder (dodecylbenzene sulfonate, KAO CORPORATION, 3 parts by weight), Amycol No.1 (5 parts by weight) and titanium oxide (SAKAI CHEMICAL INDUSTRY CO., LTD., 5 parts by weight) are mixed, pulverized by air mill (SK-JET 0 MIZER model 0101, available from SEISHIN ENTERPRISE CO., LTD.,), then added to a rotary mixer, and granulated by spraying water. When almost all the part become a size of 1.00 mm to 0.15 mm, then the granules are taken out, and after drying in a tray type dryer, they are sieved to obtain a granular wettable powder with a size of 1.00 mm to 0.15 mm. PREPARATION EXAMPLE 4 Suspension Consentrato A compound (10 parts by weight) of Example 171 (Compound No. 506), Newcol 291PG (1 parts by weight), Pearlrex CP (lignin sulfonic acid calcium salt, available from NIPPON PAPER INDUSTRIES CO., LTD., 10 parts by weight), propylene glycol (available from Nippon Nyukazai Co.,Ltd., 10 parts by weight) and water (69 parts by weight) were together mixed and pulverized in an attritor (MISUI MINING CO., LTD.) until the diameter of solid particles became 5 im or less. To the pulverized slurry (90 parts by weight) was added 0.05% (W/W) xanthane gum aqueous solution (10 parts by weight) and mixed to obtain an aqueous suspension. PREPARATION EXAMPLE 5 Wettable Powder A compound (10 parts by weight) of Example 6 (Compound No. 139), Compound A (10 parts by weight), Carplex #80D (available from Shionogi & Co. Ltd., 10 parts by weight), GOHSENOL GLO5-S (available from The Nippon Synthetic Chemical Industry Co.,Ltd., 2 parts by weight), Newcol 291PG (dioctylsulfosuccinate sodium salt, available from Nippon Nyukazai Co.,Ltd., 0.5 parts by weight), Neogen Powder (available from DAI-ICHI KOGYO SEIYAKU CO., LTD., 5 parts by weight), Radiolite #200 (available from SHOWA CHEMICAL CO., LTD., 10 parts by weight) and H Bifun (fine cray, available from Keiwa Rozai Co.,Ltd, 52.5 parts by weight) were sufficiently mixed. The mixture was pulverized by air mill (SK-JET 0 MIZER Model 0101, available from SEISHIN ENTERPRISE CO., LTD.,) to obtain mixed wettable powder of the compound (10%) of Example 6 and compound A (10%). PREPARATION EXAMPLE 6 Wettable Powder A compound (10 parts by weight) of Example 23 (Compound No. 806), Compound B (10 parts by weight), Carplex #80D (available from Shionogi & Co. Ltd., 10 parts by weight), GOHSENOL GLO5-S (available from The Nippon Synthetic Chemical Industry Co.,Ltd., 2 parts by weight), Newcol 291PG (dioctylsulfosuccinate sodium salt, available from Nippon Nyukazai Co.,Ltd., 0.5 parts by weight), Neogen Powder (available from DAI-ICHI KOGYO SEIYAKU CO., LTD., 5 parts by weight), Radiolite #200 (available from SHOWA CHEMICAL CO., LTD., 10 parts by weight) and H Bifun (fine cray, available from Keiwa Rozai Co.,Ltd, 52.5 parts by weight) were sufficiently mixed. The mixture was pulverized by air mill (SK-JET 0 MIZER Model 0101, available from SEISHIN ENTERPRISE CO., LTD.,) to obtain a mixed wettable powder of the compound (10%) of Example 23 and Compound B (10%). PREPARATION EXAMPLE 7 Granules Compound A (61.22 parts by weight), Newcol 291PG (0.85 parts by weight) and water (37.93 parts by weight) were mixed, and pulverized by using an attritor (available from MISUI MINING CO., LTD.) until the average particle size became about 2 im to obtain a slurry. To the slurry (98 parts by weight) was added Toxanone (available from Sanyo Chemical Industries, Ltd., 2 parts by weight) and then mixed to obtain Slurry 2. A compound (5 parts by weight) of Example 171 (Compound No. 506), sodium tripolyphosphate (available from Mitsui Chemicals, Inc., 2 parts by weight), Amycol No.1 (dextrin, available from NIPPON STARCH CHEMICAL CO., LTD., 1.5 parts by weight), bentonite (available from Hojun Co.,Ltd., 25 parts by weight) and Calfin 600 (calcium carbonate, available from Ashidachi Sekkai K.K., 61.27 parts by weight) were mixed in a kneader (available from Fujisangyo Co.,Ltd., Type FM-NW-5), and further Slurry 2 (8.33 parts by weight) were added and mixed. The kneading material was subjected to extrusion granulation by using Dom Gran (available from Fuji Paudal Co.,Ltd., screen 1.0 mmö), and the obtained granules were dried by using a tray type dryer (available from Tabai K.K., PERFECT OVEN Type PS-222, 60° C.), then sieved to a size of 600 to 1190 mm to obtain granules of the compound. (5%) of Example 171 and Ccompound A (5%). PREPARATION EXAMPLE 8 Suspension Concentrato A compound (11.11 parts by weight) of Example 1 (Compound No. 128), Compound C (11.11 parts by weight), Newcol 291PG (1 parts by weight), ligninsulfonic acid calcium salt (Pearlrex CP, available from NIPPON PAPER INDUSTRIES CO., LTD., 10 parts by weight), propylene glycol (available from Nippon Nyukazai Co.,Ltd., 10 parts by weight) and water (56.78 parts by weight) were mixed and pulverized in an attritor (MISUI MINING CO., LTD.) until a diameter of solid particles became 5 im or less to obtain a slurry. To the slurry (90 parts) was added 0.05% xanthane gum aqueous solution (10 parts by weight) and mixed to obtain a mixed aqueous suspension of the compound (10%) of Example 1 and Compound C (10%). PREPARATION EXAMPLE 9 Wettable Powder A compound (10 parts by weight) of Example 23 (Compound No. 806), Compound D (2 parts by weight), Carplex #80D (available from Shionogi & Co. Ltd., 10 parts by weight), GOHSENOL GLO5-S (available from The Nippon Synthetic Chemical Industry Co.,Ltd., 2 parts by weight), Newcol 291PG (dioctylsulfosuccinate sodium salt, available from Nippon Nyukazai Co.,Ltd., 0.5 parts by weight), Neogen Powder (available from DAI-ICHI KOGYO SEIYAKU CO., LTD., 5 parts by weight), Radiolite #200 (available from SHOWA CHEMICAL CO., LTD., 10 parts by weight) and H Bifun (fine cray, available from Keiwa Rozai Co.,Ltd, 60.5 parts by weight) were sufficiently mixed. The mixture was pulverized by air mill (SK-JET 0 MIZER Model 0101, available from SEISHIN ENTERPRISE CO., LTD.,) to obtain a mixed wettable powder of the compound (10%) of Example 23 and Compound D (2%). PREPARATION EXAMPLE 10 Wettable Powder A compound (10 parts by weight) of Example 23 (Compound No. 806), Compound E (8 parts by weight), Carplex #80D (available from Shionogi & Co. Ltd., 10 parts by weight), GOHSENOL GLO5-S (available from The Nippon Synthetic Chemical Industry Co.,Ltd., 2 parts by weight), Newcol 291PG (dioctylsulfosuccinate sodium salt, available from Nippon Nyukazai Co.,Ltd., 0.5 parts by weight), Neogen Powder (available from DAI-ICHI KOGYO SEIYAKU CO., LTD., 5 parts by weight), Radiolite #200 (available from SHOWA CHEMICAL CO., LTD., 10 parts by weight) and H Bifun (fine cray, available from Keiwa Rozai Co.,Ltd, 54.5 parts by weight) were sufficiently mixed. The mixture was pulverized by air mill (SK-JET 0 MIZER Model 0101, available from SEISHIN ENTERPRISE CO., LTD.,) to obtain a mixed wettable powder of the compound (10%) of Example 23 and Compound E (8%). PREPARATION EXAMPLE 11 Wettable Powder In the same manner as in Preparation example 10 except for using Compound F in place of Compound E, a mixed wettable powder of the compound (10%) of Example 23 and Compound F (8%) was obtained. TEST EXAMPLE 1 Tests of Herbicidal Effects and Crop Injury Against Paddy-Field Rice A paddy soil was filled in 1/10,000 are pot, and seeds of barnyardgrass (Echinochloa oryzicola Vasing.), Scirpus joncoides and annual broad-leaved weeds (Lindernia spp., Rotala indica) which are awaken from dormancy were mixed at the surface layer of 1 cm. Also, tuber of Cyperus serotinus which is germinated was planted, and further seedlings of paddy-field rice at 2.2-leaf stage were transplanted, and they were grown under the flooded condition in a greenhouse. After 3 days from transplanting, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 1 was diluted in water, and the solution was applied to the pot and herbicidal effects and crop injury against transplanted paddy-field rice were judged after 25 days from the treatment. Also, 3-(2-allylphenoxy)-6-chloro-4-methoxypyridazine described in Chemical Pharmaceutical Bulletin, 1972, vol. 20, No. 10, pp. 2191-2203 was used as Comparative compound. The results are shown in Table 2. Incidentally, herbicidal effects and crop injury against transplanted paddy-field rice were judged by the following judgment standard, and “-” in the table means no test was carried out. Judgment standard 0: Growth inhibition rate; 0 to 10% 1: Growth inhibition rate; 11 to 30% 2: Growth inhibition rate; 31 to 50% 3: Growth inhibition rate; 51 to 70% 5 4: Growth inhibition rate; 71 to 90% 5: Growth inhibition rate; 91 to 100%. TABLE 2 Crop injury against Chemical Herbicidal effects trans- dosage Barnyard Broad Scirpus Cyperus planted Test compound (g/a) grass leaf joncoides serotinus rice Compound of Example 1 25 5 5 5 5 0 (Compound No. 128) Compound of Example 1 12.5 4 5 5 5 0 (Compound No. 128) Compound of Example 6 20 3 5 5 5 0 (Compound No. 139) Compound of Example 6 10 2 5 5 5 0 (Compound No. 139) Compound of Example 14 10 0 5 4 5 0 (Compound No. 515) Compound of Example 15 10 1 5 — 5 0 (Compound No. 516) Compound of Example 16 20 1 5 5 5 0 (Compound No. 704) Compound of Example 16 10 0 5 5 5 0 (Compound No. 704) Compound of Example 18 25 1 5 4 5 2 (Compound No. 738) Compound of Example 18 12.5 0 5 3 5 1 (Compound No. 738) Compound of Example 19 25 1 5 4 5 1 (Compound No. 760) Compound of Example 19 12.5 0 5 4 5 1 (Compound No. 760) Compound of Example 21 10 2 5 5 5 0 (Compound No. 801) Compound of Example 22 25 2 5 4 4 2 (Compound No. 805) Compound of Example 22 12.5 1 5 2 3 1 (Compound No. 805) Compound of Example 23 20 4 5 5 5 2 (Compound No. 806) Compound of Example 23 10 3 5 5 5 0 (Compound No. 806) Compound of Example 26 20 4 5 5 5 0 (Compound No. 2081) Compound of Example 26 10 4 5 5 5 0 (Compound No. 2081) Compound of Example 27 20 4 5 5 5 0 (Compound No. 2225) Compound of Example 27 10 2 5 4 5 0 (Compound No. 2225) Compound of Example 34 20 2 4 4 5 0 (Compound No. 2411) Compound of Example 34 10 1 2 2 5 0 (Compound No. 2411) Compound of Example 49 25 2 5 4 5 0 (Compound No. 124) Compound of Example 49 12.5 1 3 3 5 0 (Compound No. 124) Compound of Example 50 25 3 5 4 5 0 (Compound No. 125) Compound of Example 50 12.5 2 5 3 5 0 (Compound No. 125) Compound of Example 51 25 2 5 5 5 0 (Compound No. 126) Compound of Example 51 12.5 2 4 3 5 0 (Compound No. 126) Compound of Example 52 20 4 5 5 5 0 (Compound No. 127) Compound of Example 52 10 3 5 5 5 0 (Compound No. 127) Compound of Example 55 25 2 5 4 5 0 (Compound No. 130) Compound of Example 55 12.5 2 5 3 5 0 (Compound No. 130) Compound of Example 56 25 0 5 3 4 0 (Compound No. 131) Compound of Example 56 12.5 0 4 2 4 0 (Compound No. 131) Compound of Example 57 25 2 5 4 5 0 (Compound No. 132) Compound of Example 57 12.5 2 5 3 5 0 (Compound No. 132) Compound of Example 61 25 2 5 5 5 0 (Compound No. 136) Compound of Example 61 12.5 1 5 5 5 0 (Compound No. 136) Compound of Example 72 20 3 5 5 5 0 (Compound No. 217) Compound of Example 72 10 3 5 5 4 0 (Compound No. 217) Compound of Example 85 10 2 4 3 5 0 (Compound No. 284) Compound of Example 88 25 0 5 5 5 0 (Compound No. 292) Compound of Example 88 12.5 0 4 4 5 0 (Compound No. 292) Compound of Example 121 25 3 5 4 5 0 (Compound No. 385) Compound of Example 121 12.5 2 5 3 5 0 (Compound No. 385) Compound of Example 122 20 0 5 5 5 0 (Compound No. 386) Compound of Example 122 10 0 5 4 5 0 (Compound No. 386) Compound of Example 123 20 1 5 4 5 0 (Compound No. 387) Compound of Example 123 10 0 5 3 4 0 (Compound No. 387) Compound of Example 125 20 2 5 4 5 0 (Compound No. 391) Compound of Example 125 10 1 5 3 4 0 (Compound No. 391) Compound of Example 129 25 2 5 4 5 0 (Compound No. 401) Compound of Example 129 12.5 1 5 3 4 0 (Compound No. 401) Compound of Example 154 20 2 5 5 5 0 (Compound No. 437) Compound of Example 154 10 1 5 3 5 0 (Compound No. 437) Compound of Example 166 20 1 5 5 5 0 (Compound No. 472) Compound of Example 166 10 0 5 5 5 0 (Compound No. 472) Compound of Example 171 20 4 5 5 5 0 (Compound No. 506) Compound of Example 171 10 3 5 5 5 0 (Compound No. 506) Compound of Example 172 20 5 5 5 5 0 (Compound No. 507) Compound of Example 172 10 5 5 5 4 0 (Compound No. 507) Compound of Example 179 20 1 4 4 5 0 (Compound No. 521) Compound of Example 179 10 0 4 3 5 0 (Compound No. 521) Compound of Example 180 25 0 5 3 5 0 (Compound No. 527) Compound of Example 180 12.5 0 5 2 5 0 (Compound No. 527) Compound of Example 181 20 2 5 4 5 0 (Compound No. 528) Compound of Example 181 10 1 5 3 4 0 (Compound No. 528) Compound of Example 182 20 2 5 4 5 0 (Compound No. 529) Compound of Example 183 20 2 5 5 5 0 (Compound No. 531) Compound of Example 183 10 1 5 5 5 0 (Compound No. 531) Compound of Example 184 20 0 5 4 5 0 (Compound No. 532) Compound of Example 185 5 1 3 2 3 0 (Compound No. 534) Compound of Example 189 10 3 5 5 5 3 (Compound No. 539) Compound of Example 189 5 2 5 4 5 0 (Compound No. 539) Compound of Example 191 20 5 5 5 5 5 (Compound No. 541) Compound of Example 191 10 4 5 5 5 2 (Compound No. 541) Compound of Example 192 20 5 3 5 5 1 (Compound No. 544) Compound of Example 192 10 2 2 5 5 0 (Compound No. 544) Compound of Example 202 10 2 5 — 4 0 (Compound No. 571) Compound of Example 203 25 2 5 5 5 0 (Compound No. 614) Compound of Example 203 12.5 1 5 5 5 0 (Compound No. 614) Compound of Example 204 25 2 5 5 5 0 (Compound No. 618) Compound of Example 204 12.5 2 5 5 5 0 (Compound No. 618) Compound of Example 205 25 1 5 5 5 0 (Compound No. 621) Compound of Example 205 12.5 0 5 5 5 0 (Compound No. 621) Compound of Example 212 25 2 5 5 5 0 (Compound No. 640) Compound of Example 212 12.5 1 5 5 5 0 (Compound No. 640) Compound of Example 216 20 4 5 5 5 2 (Compound No. 658) Compound of Example 216 10 4 5 5 5 0 (Compound No. 658) Compound of Example 217 20 4 5 5 5 0 (Compound No. 659) Compound of Example 217 10 2 5 5 5 0 (Compound No. 659) Compound of Example 218 20 1 5 5 5 0 (Compound No. 662) Compound of Example 218 10 0 5 5 5 0 (Compound No. 662) Compound of Example 219 20 4 5 5 — 0 (Compound No. 663) Compound of Example 219 10 3 5 5 — 0 (Compound No. 663) Compound of Example 232 20 4 5 4 5 0 (Compound No. 711) Compound of Example 232 10 4 5 3 4 0 (Compound No. 711) Compound of Example 233 20 4 5 5 5 0 (Compound No. 712) Compound of Example 233 10 3 4 3 4 0 (Compound No. 712) Compound of Example 234 25 0 5 4 5 0 (Compound No. 716) Compound of Example 234 12.5 0 5 3 5 0 (Compound No. 716) Compound of Example 235 20 3 5 5 5 0 (Compound No. 717) Compound of Example 235 10 3 5 5 5 0 (Compound No. 717) Compound of Example 236 20 4 5 5 5 0 (Compound No. 719) Compound of Example 236 10 3 5 5 5 0 (Compound No. 719) Compound of Example 239 20 0 5 5 4 0 (Compound No. 732) Compound of Example 240 25 3 5 4 5 0 (Compound No. 733) Compound of Example 240 12.5 2 5 3 5 0 (Compound No. 733) Compound of Example 241 20 3 5 4 5 0 (Compound No. 735) Compound of Example 241 10 1 5 3 5 0 (Compound No. 735) Compound of Example 242 25 4 5 4 5 0 (Compound No. 736) Compound of Example 242 12.5 3 5 3 5 0 (Compound No. 736) Compound of Example 243 25 2 5 4 5 0 (Compound No. 737) Compound of Example 243 12.5 1 5 4 5 0 (Compound No. 737) Compound of Example 245 20 4 5 5 5 0 (Compound No. 740) Compound of Example 245 10 4 5 5 5 0 (Compound No. 740) Compound of Example 248 10 3 5 — 5 0 (Compound No. 756) Compound of Example 248 5 1 5 — 5 0 (Compound No. 756) Compound of Example 249 20 3 5 5 5 3 (Compound No. 758) Compound of Example 249 10 2 5 5 5 0 (Compound No. 758) Compound of Example 250 20 4 5 5 5 0 (Compound No. 759) Compound of Example 250 10 3 5 5 5 0 (Compound No. 759) Compound of Example 253 20 4 5 5 5 5 (Compound No. 762) Compound of Example 253 10 3 5 5 5 5 (Compound No. 762) Compound of Example 255 20 5 5 4 5 2 (Compound No. 778) Compound of Example 255 10 5 5 4 5 0 (Compound No. 778) Compound of Example 256 20 4 5 5 5 3 (Compound No. 780) Compound of Example 256 10 3 5 5 5 2 (Compound No. 780) Compound of Example 258 10 3 5 — — 0 (Compound No. 782) Compound of Example 260 20 3 5 5 5 0 (Compound No. 802) Compound of Example 260 10 2 5 5 5 0 (Compound No. 802) Compound of Example 261 20 2 5 5 5 0 (Compound No. 803) Compound of Example 261 10 2 5 4 5 0 (Compound No. 803) Compound of Example 267 20 2 5 5 5 0 (Compound No. 845) Compound of Example 267 10 1 5 4 5 0 (Compound No. 845) Compound of Example 268 25 1 5 5 5 1 (Compound No. 846) Compound of Example 268 12.5 0 5 5 5 1 (Compound No. 846) Compound of Example 269 20 3 5 5 5 5 (Compound No. 850) Compound of Example 269 10 2 5 5 5 3 (Compound No. 850) Compound of Example 271 25 2 5 4 4 1 (Compound No. 894) Compound of Example 271 12.5 1 5 2 3 0 (Compound No. 894) Compound of Example 272 20 0 5 5 4 0 (Compound No. 896) Compound of Example 272 10 0 5 4 4 0 (Compound No. 896) Compound of Example 274 20 3 5 4 4 0 (Compound No. 914) Compound of Example 274 10 3 5 3 4 0 (Compound No. 914) Compound of Example 275 20 4 5 5 5 3 (Compound No. 931) Compound of Example 275 10 4 5 5 5 1 (Compound No. 931) Compound of Example 276 20 4 5 4 5 0 (Compound No. 964) Compound of Example 276 10 3 5 3 5 0 (Compound No. 964) Compound of Example 277 20 1 5 5 5 0 (Compound No. 965) Compound of Example 277 10 0 5 — 5 0 (Compound No. 965) Compound of Example 281 25 0 5 3 5 0 (Compound No. 998) Compound of Example 281 12.5 0 5 2 5 0 (Compound No. 998) Compound of Example 282 25 0 5 4 5 0 (Compound No. 1000) Compound of Example 282 12.5 0 5 3 4 0 (Compound No. 1000) Compound of Example 285 20 0 5 5 3 0 (Compound No. 1013) Compound of Example 285 10 0 5 4 2 0 (Compound No. 1013) Compound of Example 286 25 0 5 5 5 0 (Compound No. 1016) Compound of Example 286 12.5 0 5 5 5 0 (Compound No. 1016) Compound of Example 287 25 0 5 5 3 0 (Compound No. 1020) Compound of Example 287 12.5 0 5 5 1 0 (Compound No. 1020) Compound of Example 288 20 1 5 5 5 0 (Compound No. 1023) Compound of Example 288 10 0 5 5 5 0 (Compound No. 1023) Compound of Example 289 25 0 5 5 5 0 (Compound No. 1027) Compound of Example 289 12.5 0 4 4 4 0 (Compound No. 1027) Compound of Example 290 10 0 5 4 5 0 (Compound No. 1040) Compound of Example 294 20 2 5 5 5 0 (Compound No. 1058) Compound of Example 294 10 1 5 5 5 0 (Compound No. 1058) Compound of Example 295 25 1 5 5 5 0 (Compound No. 1060) Compound of Example 295 12.5 0 5 5 5 0 (Compound No. 1060) Compound of Example 296 20 2 5 5 5 0 (Compound No. 1061) Compound of Example 296 10 1 5 5 5 0 (Compound No. 1061) Compound of Example 303 25 1 4 4 5 0 (Compound No. 1083) Compound of Example 303 12.5 0 3 3 5 0 (Compound No. 1083) Compound of Example 304 20 4 5 5 5 0 (Compound No. 1086) Compound of Example 304 10 4 5 4 4 0 (Compound No. 1086) Compound of Example 305 10 1 5 5 5 0 (Compound No. 1088) Compound of Example 306 10 1 5 5 5 0 (Compound No. 1089) Compound of Example 307 20 4 5 5 5 0 (Compound No. 1091) Compound of Example 307 10 3 5 5 5 0 (Compound No. 1091) Compound of Example 308 20 4 5 5 5 0 (Compound No. 1096) Compound of Example 308 10 2 5 4 5 0 (Compound No. 1096) Compound of Example 309 20 5 5 5 5 5 (Compound No. 1099) Compound of Example 309 10 4 5 5 5 2 (Compound No. 1099) Compound of Example 310 20 5 5 5 5 0 (Compound No. 1100) Compound of Example 310 10 4 5 5 5 0 (Compound No. 1100) Compound of Example 311 20 3 5 5 5 0 (Compound No. 1102) Compound of Example 311 10 1 5 4 4 0 (Compound No. 1102) Compound of Example 313 20 1 5 — — 0 (Compound No. 1115) Compound of Example 315 20 4 5 — 5 0 (Compound No. 1119) Compound of Example 316 20 3 5 — — 0 (Compound No. 1120) Compound of Example 316 10 2 5 — — 0 (Compound No. 1120) Compound of Example 317 25 0 5 3 5 1 (Compound No. 1122) Compound of Example 317 12.5 0 4 2 5 0 (Compound No. 1122) Compound of Example 318 20 1 5 5 5 0 (Compound No. 1123) Compound of Example 318 10 0 5 5 5 0 (Compound No. 1123) Compound of Example 319 20 3 5 5 5 0 (Compound No. 1124) Compound of Example 319 10 2 5 5 5 0 (Compound No. 1124) Compound of Example 320 25 2 5 5 5 0 (Compound No. 1125) Compound of Example 320 12.5 1 5 5 5 0 (Compound No. 1125) Compound of Example 323 20 4 5 5 5 0 (Compound No. 1140) Compound of Example 323 10 3 5 5 5 0 (Compound No. 1140) Compound of Example 327 20 4 5 5 5 0 (Compound No. 1266) Compound of Example 327 10 4 5 5 5 0 (Compound No. 1266) Compound of Example 328 20 4 5 5 5 0 (Compound No. 1387) Compound of Example 328 10 3 3 3 5 0 (Compound No. 1387) Compound of Example 329 20 4 5 5 5 0 (Compound No. 1391) Compound of Example 329 10 2 5 5 5 0 (Compound No. 1391) Compound of Example 345 20 4 5 5 5 0 (Compound No. 1658) Compound of Example 345 10 3 5 5 5 0 (Compound No. 1658) Compound of Example 347 20 4 5 5 5 0 (Compound No. 1710) Compound of Example 347 10 3 5 5 5 0 (Compound No. 1710) Compound of Example 349 20 4 5 5 5 0 (Compound No. 1789) Compound of Example 349 10 3 4 4 5 0 (Compound No. 1789) Compound of Example 352 20 4 5 5 — 0 (Compound No. 1879) Compound of Example 356 20 3 5 5 5 0 (Compound No. 1981) Compound of Example 356 10 2 4 3 5 0 (Compound No. 1981) Compound of Example 357 20 3 5 5 5 0 (Compound No. 1985) Compound of Example 357 10 2 5 5 5 0 (Compound No. 1985) Compound of Example 359 20 5 5 4 5 0 (Compound No. 2038) Compound of Example 359 10 4 3 3 5 0 (Compound No. 2038) Compound of Example 360 20 4 5 5 5 0 (Compound No. 2040) Compound of Example 360 10 3 5 5 5 0 (Compound No. 2040) Compound of Example 361 20 3 5 5 5 0 (Compound No. 2042) Compound of Example 361 10 2 5 5 4 0 (Compound No. 2042) Compound of Example 365 20 3 5 5 5 0 (Compound No. 2151) Compound of Example 365 10 2 5 4 5 0 (Compound No. 2151) Compound of Example 394 20 3 5 5 5 0 (Compound No. 2289) Compound of Example 394 10 2 5 4 5 0 (Compound No. 2289) Comparative compound 25 0 1 0 0 0 TEST EXAMPLE 2 Tests of Herbicidal Effects (Soil Treatment) Upland soll was filled in 150 cm2 pot, and seeds of barnyardgrass and indian mustard (Brassica juncea (L.) Czern. et Coss) were sowed, and grown in a greenhouse. At the next day of seeding, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 1 was diluted in water and applied to soil surface. After 21 days from the treatment, herbicidal effects were judged in accordance with the judgment standard of Test example 1, and the results were shown in Table 3. TABLE 3 Test of herbicidal effects Herbicidal effects Dosage Barnyard- indian Test compound (kg/a) grass mustard Example 23 2 4 5 (Compound No. 806) Example 171 5 5 5 (Compound No. 506) Example 236 5 3 5 (Compound No. 719) Example 245 5 3 5 (Compound No. 740) Example 249 5 4 5 (Compound No. 758) Example 256 5 3 5 (Compound No. 780) Example 309 5 5 5 (Compound No. 1099) Example 310 5 5 5 (Compound No. 1100) TEST EXAMPLE 3 Test of Herbicidal Effects (Foliar Treatment) Upland soil was filled in 150 cm2 pot, and seeds of velvetleaf, tall morningglory, indian mustard, black nightshade redroot pigweed were sowed, and grown in a greenhouse. After the weeds were grown with 10 to 15 cm or so, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 1 was diluted with water containing 0.05% of GRAMIN-S and applied as a foliar treatment. After 14 days from the treatment, herbicidal effects were judged in accordance with the judgment standard of Test example 1, and the results were shown in Table 4. Incidentally, in the table means no test was carried out. TABLE 4 Test of herbicidal effects Herbicidal effects Chemical Tall dosage Velvet- Morning Indian Black Redroot Test compound (kg/a) leaf glory mustard Nightshade pigweed Example 23 2 4 5 5 5 4 (Compound No. 806) Example 236 0.5 — 4 3 — 3 (Compound No. 719) TEST EXAMPLE 4 Tests of Herbicidal Effects and Crop Injury Against Transplanted Paddy-Field Rice Paddy filed soil was filled in 1/5000 are Wagner pot, seeds of barnyardgrass (Echinochloa oryzicola Vasing.), Scirpus joncoides and annual broad-leaved weeds (Lindernia spp. and Rotala indica) which are awaken from dormancy were mixed at the surface layer of 1 cm. Also, tubers of Cyperus serotinus, Sagittaria pygmaea and Eleocharis kuroguwai which are awaken from dormancy were planted, and further seedlings of paddy-field ric at 2.2-leaf stage were transplantedand they were grown under the flooded condition in a greenhouse. After 3 days from the transplanting, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 5 was diluted with water, and applied to the pot. After 25 days, herbicidal effects and crop injury against transplanted paddy-field rice were judged according to the following judgment standard, and the results were shown in Table 5. Incidentally, “-” in the table means a composition containing no effective ingredient. Judgment standard 0: Growth inhibition rate; 0 to 15% 1: Growth inhibition rate; 16 to 35% 2: Growth inhibition rate; 36 to 55% 3: Growth inhibition rate; 56 to 75% 4: Growth inhibition rate; 76 to 95% 5: Growth inhibition rate; 96 to 100%. TABLE 5 Tests of herbicidal effects and crop injury against transplanted paddy-field rice Second herbi- cidally 3-phenoxy-4- active Crop injury pyridazinol com- Herbicidal effects against Test derivatives pound Barnyard Broad Scirpus Sagittaria Cyperus Eleocharis transplanted No. (g/a) (g/a) grass leaf joncoides pygmaea serotinus kuroguwai rice 1 Example 1 (10) A(5) 5 5 5 5 5 5 0 2 Example 1 (5) A(5) 5 5 5 5 5 4 0 3 Example 1 (10) B(5) 5 5 5 5 5 4 0 4 Example 1 (5) B(5) 5 5 5 5 5 4 0 5 Example 1 (10) C(5) 5 5 5 5 5 4 0 6 Example 1 (5) C(5) 5 5 5 5 5 4 0 7 Example 1 (10) — 4 4 4 4 5 0 0 8 Example 1 (5) — 2 3 2 4 4 0 0 9 Example 6 (10) A(5) 5 5 5 5 5 5 0 10 Example 6 (5) A(5) 5 5 5 5 5 5 0 11 Example 6 (10) C(5) 5 5 5 5 5 5 0 12 Example 6 (5) C(5) 5 5 5 5 5 5 0 13 Example 6 (10) — 2 5 5 5 5 3 0 14 Example 6 (5) — 1 5 5 5 5 2 0 15 Example 16 A(5) 5 5 5 5 5 2 0 (10) 16 Example 16 (5) A(5) 5 5 5 5 5 2 0 17 Example 16 B(5) 5 5 5 5 5 3 0 (10) 18 Example 16 (5) B(5) 5 5 5 5 5 2 0 19 Example 16 — 0 5 5 4 5 1 0 (10) 20 Example 16 (5) — 0 5 3 3 4 0 0 21 Example 23 A(5) 5 5 5 5 5 5 0 (10) 22 Example 23 (5) A(5) 5 5 5 5 5 3 0 23 Example 23 B(5) 5 5 5 5 5 5 0 (10) 24 Example 23 (5) B(5) 5 5 5 5 5 3 0 25 Example 23 C(5) 5 5 5 5 5 5 0 (10) 26 Example 23 (5) C(5) 5 5 5 5 5 2 0 27 Example 23 — 3 5 5 5 5 3 0 (10) 28 Example 23 (5) — 2 5 5 5 5 2 0 29 Example 47 A(5) 5 5 5 5 5 5 0 (10) 30 Example 47 (5) A(5) 5 5 5 5 5 5 0 31 Example 47 — 3 5 5 5 5 2 0 (10) 32 Example 47 (5) — 3 5 4 5 5 1 0 33 Example 171 A(5) 5 5 5 5 5 4 0 (10) 34 Example 171 A(5) 5 5 5 5 5 4 0 (5) 35 Example 171 B(5) 5 5 5 5 5 4 0 (10) 36 Example 171 B(5) 5 5 5 5 5 4 0 (5) 37 Example 171 C(5) 5 5 5 5 5 4 0 (10) 38 Example 171 C(5) 5 5 5 5 5 3 0 (5) 39 Example 171 — 3 5 5 5 5 3 0 (10) 40 Example 171 — 2 5 5 5 5 2 0 (5) 41 Example 191 A(5) 5 5 5 5 5 3 0 (2.5) 42 Example 191 B(5) 5 5 5 5 5 3 0 (2.5) 43 Example 191 C(5) 5 5 5 5 5 3 0 (2.5) 44 Example 191 — 1 3 3 2 5 1 0 (2.5) 45 Example 245 A(5) 5 5 5 5 5 3 0 (10) 46 Example 245 A(5) 5 5 5 5 5 2 0 (5) 47 Example 245 C(5) 5 5 5 5 5 3 0 (10) 48 Example 245 C(5) 5 5 5 5 5 2 0 (5) 49 Example 245 — 4 5 5 5 5 1 0 (10) 50 Example 245 — 3 5 5 4 4 0 0 (5) 51 Example 249 A(5) 5 5 5 5 5 3 0 (10) 52 Example 249 A(5) 5 5 5 5 5 3 0 (5) 53 Example 249 — 2 5 5 5 5 2 0 (10) 54 Example 249 — 1 5 3 5 5 1 0 (5) 55 Example 288 A(5) 5 5 5 5 5 5 0 (10) 56 Example 288 A(5) 5 5 5 5 5 5 0 (5) 57 Example 288 — 0 5 5 5 5 3 0 (10) 58 Example 288 — 0 5 5 5 4 2 0 (5) 59 — A 5 5 4 5 4 2 0 (30) 60 — A(5) 3 4 3 4 2 0 0 61 — B 5 5 4 5 4 2 0 (30) 62 — B(5) 3 4 3 4 2 0 0 63 — C 5 5 4 5 4 2 0 (30) 64 — C(5) 3 5 2 4 1 0 0 TEST EXAMPLE 5 Tests of Herbicidal Effects and Crop Injury Against Upland Crops (Soil Treatment) Upland soil was filled in 150 cm2 pot, and seeds of barnyardgrass, Cyperus esculentus L., velvetleaf, black nightshade, tall morningglory and corn were sowed, and grown in a greenhouse. At the next day of seeding, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 5 was diluted with water and applied to soil surface. After 21 days from the treatment, herbicidal effects and crop injury against corn were judged according to the following judgment standard, and the results were shown in Tables 6 to 8. Incidentally, “-” in the table means that the composition does not contain the effective ingredient. Judgment standard 0: Growth inhibition rate; 0 to 9% 1: Growth inhibition rate; 10 to 19% 2: Growth inhibition rate; 20 to 29% 3: Growth inhibition rate; 30 to 39% 4: Growth inhibition rate; 40 to 49% 5: Growth inhibition rate; 50 to 59% 6: Growth inhibition rate; 60 to 69% 7: Growth inhibition rate; 70 to 79% 8: Growth inhibition rate; 80 to 89% 9: Growth inhibition rate; 90 to 98% 10: Growth inhibition rate; 99 to 100%. TABLE 6 Tests of herbicidal effects and crop injury against corn (Example 23 + compound D) Second 3-phenoxy- herbicidally Crop 4-pyridazinol active Herbicidal effects injury Test derivatives compound Barnyard- Tall Black against No. (g/ha) (g/ha) grass Velvetleaf Morningglory Nightshade corn 1 Example 23 D(25) 10 10 9 10 0 (250) 2 Example 23 D(25) 10 10 7 10 0 (125) 3 Example 23 D(25) 10 10 8 10 0 (63) 4 — D(25) 10 9 5 9 0 5 Example 23 D(12.5) 10 10 9 10 0 (250) 6 Example 23 D(12.5) 10 10 5 9 0 (125) 7 Example 23 D(12.5) 10 9 3 9 0 (63) 8 — D(12.5) 10 7 0 9 0 9 Example 23 D(6.3) 10 10 6 9 0 (250) 10 Example 23 D(6.3) 9 10 5 10 0 (125) 11 Example 23 D(6.3) 5 9 1 9 0 (63) 12 — D(6.3) 3 6 2 5 0 TABLE 7 Test of herbicidal effects and chemical damage against corn (Example 23 + compound E) 3-phenoxy- Second 4-pyrida- herbi- zinol cidally crop deriva- active Herbicidal effects injury Test tives compound Barnyard- Cyperus Velvet- TallMorning Black against No. (g/ha) (g/ha) grass esculentus leaf glory Nightshade corn 1 Example 23 E(200) 10 9 10 10 10 0 (125) 2 Example 23 E(200) 10 9 10 10 10 0 (63) 3 — E(200) 10 8 10 10 9 0 4 Example 23 E(100) 10 9 10 10 10 0 (125) 5 Example 23 E(100) 10 8 10 10 9 0 (63) 6 — E(100) 9 8 7 7 6 0 7 Example 23 E(50) 9 8 10 8 10 0 (125) 8 Example 23 E(50) 10 9 9 7 9 0 (63) 9 — E(50) 7 8 7 6 7 0 TABLE 8 Test of herbicidal effects and chemical damage against corn (Example 23 + compound F) 3- phenoxy- 4- Second pyrida- herbi- zinol cidally Crop deriva- active Herbicidal effects injury Test tives compound Barnyard- Cyperus Tall Black against No. (g/ha) (g/ha) grass esculentus Velvetleaf Morningglory Nightshade corn 1 Example F(100) 10 9 10 9 10 0 23 (125) 2 Example F(100) 10 9 10 9 10 0 23 (63) 3 — F(100) 9 9 10 8 8 0 4 Example F(50) 10 9 10 7 10 0 23 (125) 5 Example F(50) 9 9 10 7 10 0 23 (63) 6 — F(50) 8 9 10 5 3 0 7 Example F(25) 9 9 10 7 9 0 23 (125) 8 Example F(25) 7 8 9 5 10 0 23 (63) 9 — F(25) 4 8 9 2 6 0 TEST EXAMPLE 6 Tests of Herbicidal Effects and Crop Injury Against Upland crops (foliar treatment) Upland soil was filled in 150 cm2 pot, and seeds of barnyardgrass, Cyperus esculentus L., velvetleaf, black nightshade, tall morningglory and corn were sowed, and grown in a greenhouse. After the weeds were grown with 10 to 15 cm or so, a predetermined chemical dosage of the wettable powder prepared in accordance with Preparation example 5 was diluted with water containing 0.05% of GRAMIN S and applied as a foliar treatment. After 14 days from the treatment, herbicidal effects and crop injury were judged in accordance with the judgment standard of Test example 5, and the results were shown in Tables 9 and 10. Incedentally, “-” in the table means no effective ingredient was contained. TABLE 9 Test of herbicidal effects and crop injury against corn (Example 23 + compound E) 3-phenoxy- Second 4-pyrida- herbi- zinol cidally crop deriva- active Herbicidal effects injury Test tives compound Barnyard Cyperus Velvet- TallMorning Black against No. (g/ha) (g/ha) grass esculentus leaf glory Nightshade corn 1 Example 23 E(200) 9 8 10 9 10 0 (250) 2 Example 23 E(200) 9 9 10 9 10 0 (125) 3 Example 23 E(200) 9 9 10 8 10 0 (63) 4 — E(200) 7 8 10 9 10 0 5 Example 23 E(100) 9 9 10 9 10 0 (250) 6 Example 23 E(100) 9 8 10 9 10 0 (125) 7 Example 23 E(100) 8 9 10 8 9 0 (63) 8 — E(100) 2 7 10 7 10 0 9 Example 23 E(50) 8 9 10 7 10 0 (250) 10 Example 23 E(50) 5 8 10 9 10 0 (125) 11 Example 23 E(50) 2 8 10 8 10 0 (63) 12 — E(50) 1 6 9 6 9 0 TABLE 10 Test of herbicidal effects and crop injury against corn (Example 23 + compound F) Second herbi- 3-phenoxy-4- cidally Crop pyridazinol active Herbicidal effects injury Test derivatives compound Barnyard- Cyperus Velvet- TallMorning Black against No. (g/ha) (g/ha) grass esculentus leaf glory Nightshade corn 1 Example 23 F(100) 8 7 10 9 10 0 (250) 2 Example 23 F(100) 6 7 9 9 10 0 (125) 3 — F(100) 2 6 10 9 9 0 4 Example 23 F(50) 4 7 10 9 10 0 (250) 5 Example 23 F(50) 2 7 10 9 10 0 (125) 6 — F(50) 0 5 10 5 10 0 7 Example 23 F(25) 1 7 10 6 10 0 (250) 8 Example 23 F(25) 1 6 10 5 10 0 (125) 9 — F(25) 0 4 9 2 7 0 Utilizability in Industry The compounds of the present invention have herbicidal activities, and can be used as a herbicidal composition for a paddy field, upland field, orchard, pasture, turf, forest or non-crop land. The compounds of the present invention show herbicidal activities against various weeds which cause problems in a paddy field, for example, annual broad-leaved weeds such as Lindernia spp., Vandellia angustifolia Benth., Rotala indica, Elatine triandra, Monochoria vaginaris, Murdannia keisak, Dopatirum junceum (Roxb.) Hamilt, Ammannia multiflora, etc.; perennial arrowhead weeds such as Sagittaria pygmaea Miq., arrowhead (Sagittaria trifolia L.), Alisma canaliculatum, etc.; annual Cyperaceous weeds such as flatsedge, smallflower umbrellasedge, etc.; perennial Cyperaceous weeds such as needle spikerush, Scirpus joncoides, Cyperus serotinus, Scrips Nipponicus Makino, etc.; or annual perennial Graminaceous weeds such as barnyardgrass, Leersia oryzoides (L.) Swartz., and the like, and show no crop injury against rice which causes any problem. Also, the compounds of the present invention show herbicidal activities both by foliar application and soil application agaist valious kinds of weeds, which are troublesome in upland fields. Moreover, they can be used not only in a paddy field and an upland filed, but also in an orchard, a mulberry field and a non-crop land. Also, weeding spectrum of the herbicidal composition of the present invention can be enlarged by using 3-phenoxy-4-pyridazinol derivatives and a second herbicidally active compound in admixture which are effective ingredients than its range to be applied which had been obtained with a single agent use. The weeding spectrum of the composition according to the present invention covers Graminaceous weeds, annual broad-leaved weeds and whole perennial weeds such as Arrowhead, Cyperaceous weeds, etc. Moreover, the composition of the present invention has high safety to paddy-field rice or upland crops, and has a wide application window. Also, the composition of the present invention shows synergistic effects in the herbicidal effects, and shows sufficient effects with a mixture of compounds with a markedly lower chemical dosage than the chemical dosage is used as a single agent in the case where each. As a result, the composition of the present invention is hightened in herbicidal activity so that it is sufficient with a one time treatment agent, and its effects are continued for a long period of time. Also, the composition of the present invention shows no crop injury against paddy-field rice, and it can be applied both of before transplanting and immediately after transplanting.

<SOH> BACKGROUND ART <EOH>In Chemical Pharmaceutical Bulletin, 1972, vol. 20, No. 10, pp. 2191-2203, 3-(2-allylphenoxy)-6-chloro-4-methoxypyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed, and there is no description about a herbicide. In Journal of the Chemical Society: Perkin Transaction I, 1975, No. 6, pp. 534-538, 3-(2-hydroxyphenoxy)-4-methoxypyridazine and 6-chloro-3-(2-hydroxyphenoxy)-4-methoxypyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed, and there is no description about a herbicide. In U.S. Pat. No. 5,559,080, a 3-(phenoxy which may be substituted)pyridazine compound having a haloalkylphenoxy group at the 4-position of the pyridazine has been disclosed but a 3-phenoxy-4-pyridazinol compound having a hydroxyl group at the 4-position of the pyridazine has not been disclosed. Also, in the 3-(phenoxy which may be substituted)pyridazine compound having a haloalkylphenoxy group at the 4-position of the pyridazine, an oxygen atom bonded to the 4-position of the pyridazine is bonded by a benzene ring, and its herbicidal activity was insufficient. Also, at present, a number of herbicides have been practically used as a herbicide for a paddy field, and widely been used for general purpose as a single agent and a mixed agent. However, there are many kinds of paddy field weeds, and germination and growth period of the respective weeds are not uniform, in particular, occurrence of perennial weeds ranges for a long period of time. Thus, it is extremely difficult to prevent from and kill all weeds with one time spread of a herbicide. Accordingly, as a herbicide, an appearance of a chemical which can kill many kinds of weeds including annual weeds and perennial weeds, that is, which has a wide weed-killing spectrum, is effective for already grown weeds, preventing and killing effects of weeds of which can be maintained for a certain period of time, and has high safety to paddy rice has earnestly been desired. Also, as upland herbicides, a number of herbicides have now been commercially available and practically used, but there are many kinds of weeds to be prevented, and occurrence thereof ranges for a long period of time, so that a herbicide which has higher herbicidal effects, has broad weed-killing spectrum, and causes no chemical damage to crops has been desired. One of the effective ingredient of the herbicidal composition of the present invention (hereinafter referred to as a second herbicidally active compound), 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-pyrazolyl-p-toluenesulfonate [hereinafter referred to as Compound A. General name: Pyrazolate], 2-[4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazol-5-yloxy]acetophenone [hereinafter referred to as Compound B. General name: Pyrazoxyfen], 2-[4-(2,4-dichloro-m-toluoyl)-1,3-dimethylpyrazol-5-yloxy]-4′-methylacetophenone (hereinafter referred to as Compound C. General name: Benzofenap], 5-cyclopropyl-1,2-oxazol-4-yl α,α,α-trifluoro-2-mesyl-p-tolyl ketone [hereinafter referred to as Compound D. General name: Isoxaflutole], 2-(2-chloro-4-mesylbenzoyl)cyclohexan-1,3-dione [hereinafter referred to as Compound E. General name: sulcotrione], 2-(4-mesyl-2-nitrobenzoyl)cyclohexan-1,3-dione [hereinafter referred to as Compound F. General name: mesotrion] and 4-chloro-2-(methylsulfonyl)phenyl 5-cyclopropyl-4-isoxazolyl ketone [hereinafter referred to as Compound G. General name: Isoxachlortole] are each conventionally known herbicidal compound, and each described in The Pesticide Manual 11th Edition, pp. 1049 to 1050, Ibid. pp. 1054 to 1055, Ibid. pp. 111 to 112, The Pesticide Manual, 12th Edition p. 563, Ibid. p. 848, Ibid. p. 602 and EP 470 856(1990). These compounds have high effects against annual broad-leaved weeds and a part of perennial weeds, but their effects against rice plant weeds or a part of perennial weeds are not necessarily sufficient.

20040227

20091027

20050217

90995.0

VAJDA, KRISTIN ANN

3-PHENOXY-4-PYRIDAZINOL DERIVATIVES AND HERBICIDE COMPOSITION CONTAINING THE SAME

UNDISCOUNTED

ACCEPTED

ACCEPTED

Button lock

There is provided a button-operated lock device capable of increasing a setting amount of information in response to operation of a control button, obtaining a large setting amount and a wide-range of selection thereof, enhancing safety performance, simplifying the structure and achieving a small size and a light-weight, thereby achieving a low manufacturing cost, executing such various operations as setting or inputting information and altering thereof correctly, safely, easily and rationally, and preventing decoding or perceiving of preset or inputted information so that any third party is prevented from making a falsification and/or conversion of this device. The button-operated lock comprises a plurality of control buttons (10) axially displacedly arranged and capable of setting or inputting a predetermined information; a control plate (128) for allowing an unlocking procedure at the time of setting or imputing the predetermined information; a driving cam (16) linked to the control plate (128) and capable of being operatively connected to a pair of door handles (4, 5); and a lock element linked to the driving cam (16), wherein a plurality of same or different information can be set or inputted to each of the control buttons (10) and the plurality of same or different information can be set or inputted every time the control button (10) is operated.

1. A button-operated lock comprising a plurality of control buttons (10) axially displacedly and capable of setting or inputting a predetermined information; a control plate (128) for allowing an unlocking procedure at the time of setting or imputing the predetermined information; a driving cam (16) linked to said control plate (128) and capable of being operatively connected to a pair of door handles (4, 5); and a lock element linked to said driving cam (16), wherein a plurality of same or different information can be set or inputted to each of said control buttons (10) and said plurality of same or different information can be set or inputted every time said control button (10) is operated. 2. A button-operated lock according to claim 1, wherein said setting or inputting information can be controlled in association with the number of times of operation of said control buttons (10). 3. A button-operated lock according to claim 2, wherein a part (34) of control means for said setting or inputting information is built in said control button (10). 4. A button-operated lock according to claim 2, wherein said control means includes a gear button (34) which can be intermittently turned every time said control button (10) is axially displaced. 5. A button-operated lock according to claim 4, wherein said plurality of information can be set or inputted during one turn of said control button (10). 6. A button-operated lock according to claim 1, wherein a lock plate (140) is interposed between said control plate (128) and said driving cam (16), one end of said lock plate (140) is swingably connected to said control plate (128), and the other end of said lock plate (140) is arranged to be engageable with or disengageable from said driving cam (16). 7. A button-operated lock according to claim 2, wherein a terminal gear (66) is arranged to be engageable with said button gear (34), a reset gear (43) is arranged to be engageable with said terminal gear (66), and said reset gear (43) is biased in such a manner as to be able to rotationally return in accordance with a rotation angle displacement thereof. 8. A button-operated lock according to claim 7, wherein said button gear (34) and said terminal gear (66) can be disengaged from each other, and said terminal gear (66) and said reset gear (43) can be normally engaged with each other. 9. A button-operated lock according to claim 7, wherein said reset gear (43) is provided with a stopper (83) which is unable to engage said terminal gear (66). 10. A button-operated lock according to claim 7, wherein said terminal gear (66) is provided with a square hole (76), a clutch shaft (67) capable of rotationally support said terminal gear (67), said clutch shaft (67) being provided with a square shaft (79) which is engageable with and disengageable from said square hole (76), and said square shaft (79) being biased for engagement with said square hole (76). 11. A button-operated lock according to claim 10, wherein a plurality of engagement parts engageable with said square shaft (79) are formed at said square hole (79), and the number of said engagement parts is set to be equal to an amount of information which can be set or inputted by only one control button (10). 12. A button-operated lock according to claim 10, wherein a plurality of control holes are formed in a surface of a case (14) which is exposed to the outside, so that a control tool (154) can be inserted in said control holes, and one end part of said clutch shaft (67) is faced with an inner side opening part of said control hole (12). 13. A button-operated lock according to claim 12, wherein said clutch shaft (67) is axially displaceable through said control tool (154), so that the engagement between said square shaft (79) and said square hole (76) can be released, and said terminal gear (66) is rotatably supported by said clutch shaft (67). 14. A button-operated lock according to claim 12, wherein a cam shaft (80) is projected from the other end of said clutch shaft (67), a control cam (65) is attached to said cam shaft (80) such that said control cam (65) is simultaneously movable with said cam shaft (80), an engagement claw (129) of said control plate (128) is removably received in a cutout groove (72) formed in said control cam (128), and said engagement claw (129) is biased such that said engagement claw (129) is engageable with and disengageable from said cutout groove (72). 15. A button-operated lock according to claim 14, wherein a plurality of passage holes (24) are formed in a back plate (13), which is attached to a back part of said case (14), in such a manner as to face with an end part of said cam shaft (80), and a plurality of check marks (170) are arranged on the outside of said passage holes (24) in isometric positions. 16. A button-operated lock according to claim 12, wherein at the time of setting or inputting information through said control buttons (10), said cutout grooves (72) are directed toward said engagement claw (129) side and positioned in the same phase as said engagement claw (129), and said engagement claws (129) are brought into engagement with said cutout grooves (72), respectively, so that said control plate (128) can allow an unlocking procedure. 17. A button-operated lock according to claim 12, wherein at the time of setting or inputting information through said control buttons (10), said engagement claws (129) are brought into engagement with said control cam (65) and prohibited from being engaged with said cutout grooves (72), so that said control plate (128) is unable to allow an unlocking procedure. 18. A button-operated lock according to claim 12, wherein a block main body (46) on which said terminal gear (66) and said reset gear (43) can be mounted is provided, a memory releasing link (113) is engaged with said block main body (46), said block main body (46) is biased in such a manner as to be able to move toward said control button (10) side, so that said terminal gear (66) and said button gear (34) can be engaged with each other, one end part of said memory releasing link (113) is engaged with said driving cam (16), so that said block main body (46) is brought away from said control button (10) side through the turning motion of said driving cam (16), thereby allowing said terminal gear (66) and said button gear (34) to be disengaged from each other. 19. A button-operated lock according to claim 18, wherein said block main body (46) is provided with a guide groove (59), said memory releasing link (113) is provided with a pin (115) projecting therefrom and engageable with said guide groove (59), said pin (115) is positioned such that it can normally engage one side edge of said guide groove (59), said guide groove (59) is provided at the other end edge thereof with a locking projection (164) engageable with said pin (115), and at the time of engagement between said pin (115) and said locking projection (164), operation of said memory releasing link (113) is prohibited and engagement between said terminal gear (66) and said button gear (34) is prohibited from releasing. 20. A-button-operated lock according to claim 18, wherein said memory releasing link (113) is turnably provided at the other end side thereof with a changeover shaft (123) which is linked to a changeover knob (6) on the indoor side, said changeover shaft (123) is provided with two cams (124), (125) which are different in length, and said two cams (124), (125) is selectively engageable with the other end part of said memory releasing link (113). 21. A button-operated lock according to claim 20, wherein the separation distance between said block main body (46) and said control button (10) is made different in accordance with the lengths of said two cams (124), (125), said two cams are each capable of releasing engagement between said terminal gear (66) and said button gear (34), at the time of engagement with said long side cam (125), engagement between said engagement claw (129) and said cutout groove (72) of said control plate (128) can be maintained, and at the time of engagement with said short side cam (124), engagement between said engagement claw (129) and said cutout groove (72) can be maintained. 22. A button-operated lock according to claim 12 or 18, wherein said case (14) is provided at an inner side surface side thereof with a protection plate (146) such that said protection plate (146) can move along said control holes (12), and a plurality of through-holes (147), which can communicate with said control holes (12), are formed in said protection plate (146), such that one end of said protection plate (146) can engage said driving cam (16). 23. A button-operated lock according to claim 20, wherein engagement between said terminal gear (66) and said button gear (34) is released through turning operation of said door handles (4), (5) or said changeover shaft (123), and said terminal gear (66) is turned by elastic force of a set spring (86) which is formed after said information is set or imputed, so that said control cam (65) or its cutout groove (72) can be returned to its original position. 24. A button-operated lock according to claim 23, wherein after said control cam (65) or its cutout groove (72) is returned to its original position, current information of said control button (10) is set or imputed to turn said button gear (34) by an amount of the set or inputted information, said terminal gear (66) and said reset gear (43) are moved in operative connection to the turning motion of said button gear (66), said terminal gear (66) is biased to return to its original position by an amount of the set or inputted information, the engagement between said terminal gear (66) and said button gear (34) is released through the turning operation of said door handles (4), (5), said terminal gear (66) is reversely turned for offset by an amount of the set or inputted information, thereby releasing the set or inputted current information so that said lock can be unlocked. 25. A button-operated lock according to claim 23, wherein after said control cam (65) or its cutout groove (72) is returned to its original position, said terminal gear (66) is rotatably supported on said clutch shaft (67) through said control tool (154), and the engagement between said square shaft (79) and said square hole (76) is released, so that the original position of said control cam (65) or its cutout groove (72) can be maintained. 26. A button-operated lock according to claim 23, wherein after the original position of said control cam (65) or its cutout groove (72) is maintained through said control tool (154), at the time for altering information where said button gear (34) is turned in the same direction as at the setting or inputting time of information, said control button (10) is operated by an amount equal to the difference between the turning angles of said button gear (34) before and after the alternation of information, then said terminal gear (66) and said reset gear (43) are operatively connected thereto, said terminal gear (66) is biased such that it can turningly return by an amount equal to the difference between said turning angles, said square shaft (79) and said square hole (76) are engaged with each other after said button gear (34) is turned, and the original position of said control cam (65) or its cutout groove (72) is linked to said terminal gear (66), the engagement between said terminal gear (66) and said button gear (34) is released through turning operation of said door handles (4), (5), said terminal gear (66) is turned by an amount equal to the elasticity of said reset spring (86) formed after the alternation of information, and an amount equal to the turning angle of said terminal gear (66) is added to the position of said control cam (65) or its cutout groove (72), so that the setting or inputting information can be altered. 27. A button-operated lock according to claim 26, wherein the number of times of operation of said control button (10) is a quotient obtained by dividing the difference of turning angles of said button gear (34) before and after the alternation of information by a unit operation turning angle of said turning button (10). 28. A button-operated lock according to claim 23, wherein at the time for altering information where said button gear (34) is turned in a reverse direction to the direction at the time of setting or inputting information, said changeover shaft (123) is turned to bring said cam (124) on its short side into engagement with an end part of said memory releasing link (113) and to release the engagement between said terminal gear (66) and said button gear (34), the engagement between said cutout groove (72) and said engagement claw (129) is maintained to maintain the original position of said control cam (65) or its cutout groove (72), said terminal gear (66) is turnably supported on said clutch shaft (67) through said control tool (154), said terminal gear (66) is turningly returned by an amount of elasticity of said reset spring (86) equal to the amount of elasticity necessary for forming the original position, after the original position of said control cam (65) or its cutout groove (72) is released, said changeover shaft (123) is turningly returned to the original position to bring said terminal gear (66) into engagement with said button gear (34), said button gear (34) is turned by an amount equal to the amount of angle of the alternation of information by operating said control button (10) through said control tool (154), then said terminal gear (66) and said reset gear (43) are operatively connected thereto, so that said terminal gear (66) is biased such that it can turningly return by an amount equal to the difference between said turning angles, said square shaft (79) and said square hole (76) are engaged with each other after said button gear (34) is turned, said clutch shaft (67) is linked to said terminal gear (66) to release the engagement between said terminal gear (66) and said button gear (34) through turning operation of said door handles (4), (5), said terminal gear (66) is turned by an amount equal to elasticity of said reset spring (86) formed after the alternation of information, the position of said control cam (65) or its cutout groove (72) is reset by an amount equal to the turning angle of said terminal gear (66), so that the setting or inputting information can be altered. 29. A button-operated lock according to claim 1, wherein a ball retainer (159) for disengageably receiving therein a ball (158) biased toward the inner side of said door handles (4), (5) and adapted to normally turn said door handles (4), (5) and said driving cam (16) but idly turn said door handle (4) and prohibit the turning of said driving cam (16) when excessively large torque acts on said door handle (4), is formed in the shape of a plate, and said ball retainer (159) is mounted on a surface part of said case (14). 30. A button-operated lock according to claim 1, wherein the arrangement of said door handles (4), (5) and said control buttons (10) can be selectively or symmetrically altered together with their inside mechanisms.

TECHNICAL FIELD This invention relates to a button-operated lock device capable of increasing a setting amount of information in response to operation of a control button, obtaining a large setting amount and a wide-range of selection thereof, enhancing safety performance, simplifying the structure and achieving a small size and a light-weight, thereby achieving a low manufacturing cost, executing such various operations as setting or inputting information and altering thereof correctly, safely, easily and rationally, and preventing decoding or perceiving of preset or inputted information so that any third party is prevented from making a falsification and/or conversion of this device. BACKGROUND ART Recently, a keyless lock of the type requiring the use of no key has been popularized as a door lock to be used for individual dwelling houses, companies, shops, hospitals and the like. As a keyless lock of the type mentioned above, there are a so-called mechanical lock in which the locking and unlocking procedure is made by a structural means and an electric or electronic lock in which the locking and unlocking procedure is made by an electrical means. Of these two types of keyless locks, the mechanical lock, when compared with the electronic or electric lock, has such advantages that there is no worry about power failure or battery exhaustion because no wiring work is required, the user of such a lock is free from electrical trouble such as malfunction, and in addition, the mechanical strength is large. The mechanical lock, in general, includes a plurality of control buttons. Memory information corresponding to the control buttons is stored in association with a cam or link mechanism or a gear train, the memory information of the respective control buttons is combined by the same number as the number of the control buttons, and a password number consisting of the number of digits of the control buttons is set or inputted. At the time of unlocking, the control buttons corresponding to the password number are operated so that the lock can be unlocked. For example, in the invention disclosed in Japanese Patent Publication No. S62-54951 the present applicant previously filed, the respective control buttons are inserted in the slits formed in a case frame in their erected or inverted states, and the numbers of the respective control buttons are set to 1 or 0, i.e., two modes of either “set” or “unset”. Then, it is selectively decided whether the number setting for the respective control buttons is necessary or not so that the password number can be set or inputted by a combination of the corresponding numbers. At the time of unlocking, the control buttons for which the number setting has been made are depressed to engage the slits formed in those buttons with the keyplate. On the other hand, the control buttons for which the number setting has not been made are not depressed to maintain the engagement relation between the slits and the keyplate. Owing to this arrangement, the cam pin can be turned to allow the handle to turn, so that the lock can be unlocked. However, in this conventional device, since only two modes, i.e., number setting and number unsetting, can be obtained for each control button and the setting amount of information for each control button is limited, the number of the password number depends on the number of the control buttons and thus, a sufficient setting amount of information is unobtainable. Since the range of selection thereof is limited, a large enough safety performance is unobtainable. In order to solve those problems, if the number of the control buttons should be increased, the number of the component parts would be increased to that extent. Thus, the construction and the locking and unlocking procedure becomes complicated, and the case frame and the packing plate become large in size, thus resulting in large size and heavy weight of the entire button-operated lock. Moreover, the outer appearance of the door is degraded. Those problems are also common in U.S. Pat. No. 3,115,765. That is, the lock disclosed in the above U.S. patent includes a generally elongate box-like casing. This casing is retractably provided at a face plate thereof with a plurality of key systems which are linked to the control buttons. A plurality of shafts are turnably suspended in the longitudinal direction of the casing. The respective gears are engageably arranged in such a manner as to face with the key system positions of those shafts. The gears are intermittently turned through the pressing operation of those key systems. A control shaft, which is linked to a door handle is disposed at one end of the casing. A slide plate is provided in such a manner as to be engageable with a cam disposed at the control shaft. A plurality of engagement elements disposed at the slide plate are engageable with and disengageable from the respective gears which are fixed to the above-mentioned shaft. The memory system by the key system can be stored in the gear train or reset. However, the lock taught by the above U.S. patent has the following problems. Since each control button can set only a single memory information, a combination of memory information achievable through each control button is limited, and selection of password numbers and safety performance are limited. Moreover, since the number setting of the control buttons is linked to the number setting of the adjacent control buttons and the password number is stored in order of the setting input, the number setting lacks in versatility and the smooth execution of the locking and unlocking procedure is jeopardized. Moreover, since the turning force of the door handle acts on the slide plate, it can easily be perceived whether or not memory setting has been made through the respective control buttons. This, together with the above-mentioned disadvantage in limitation of the memory capacity, tends to create such a fear that repeated evil attempt should be made on the control buttons, the lock could be unlocked comparatively easily. On the other hand, a long time use of a same password number leads gives a chance to a third party to perceive and decode the number. This is not desirable in view of protection of the password number. Therefore, it is desirable that the password number is altered frequently. However, since the alternation mechanism and operation thereof requires a time-consuming troublesome work in view of its structure, the simplification and easiness are demanded. For example, the lock proposed by the present applicant in Japanese Patent Publication No. S62-54951 is designed such that at the time for altering the password number, a case frame and a packing plate, which are arranged at the inside and the outside of the door, is removed therefrom, the corresponding control buttons are pulled out in their exposed states, and inserted into a slit in their erected or inverted states and then reassembled. However, this method has such problems that since the case frame and the backing plate are required to be detached from the door and the buttons are required to be detached or replaced, complicated and time-consuming work is required. In the lock of the above-mentioned U.S. Pat. No. 3,115,765, at the time for altering the password, the control buttons are operated to set or input the current password number and thereafter, the slide plate is moved to release the engagement between the engagement element and the groove. After the current password number is canceled, the control buttons are operated to set or input a new password number. This method, when compared with the above-mentioned method, has such advantages that the troublesome work for removing the related parts from the door is no more required and thus, this operation can be made in a simple and convenient manner. However, it has such a problem that since the password number can be altered from the outside of the door, the third party can make a falsification relatively easily. Therefore, uneasiness in relation to protection and security occurs. It is, therefore, a main object of the present invention, to provide a button-operated lock which is capable of solving the above-mentioned problems and in which the amount of information to be set to the control buttons is increased, a large setting amount of information and its wide selection can be obtained, and safety performance can be enhanced. Another object of the present invention is to provide a button-operated lock, in which the structure can be simplified and made compact and light-weight, and the manufacturing cost can be reduced. A further object of the present invention is to provide a button-operated lock, in which the setting or inputting of information to the control buttons, as well as an altering operation thereof, can be made correctly, safely, easily and rationally. A still further object of the present invention is to provided a button-operated lock, in which decoding or perceiving of information, which would otherwise be made by the third party relatively easily, is prohibited so that the third party is prevented from making a falsification and/or conversion of such information. A yet further object of the present invention is to provide a button-operated lock, in which a criminal unlocking procedure, which would otherwise be made by the third party comparatively easily through a control hole formed in a case, can be prevented from occurring. DISCLOSURE OF THE INVENTION A button-operated lock according to the present invention comprises a plurality of control buttons axially displacedly arranged and capable of setting or inputting a predetermined information; a control plate for allowing an unlocking procedure at the time of setting or imputing the predetermined information; a driving cam linked to the control plate and capable of being operatively connected to a pair of door handles; and a lock element linked to the driving cam, wherein a plurality of same or different information can be set or inputted to each of the control buttons and the plurality of same or different information can be set or inputted every time the control button is operated. Accordingly, a large number of combination of password numbers can be obtained compared with the conventional technique in which only one memory information is set or inputted to a plurality of control buttons and plural sorts of password numbers are obtained by changing the combinations of the control buttons. Since the range of selection can be widened, the safety performance can be enhanced and the number of the control buttons can be reduced to that extent. Moreover, no reset button is required contrary to the conventional technique. Thus, the number of component parts can be reduced and the structure can be simplified. In addition, the device according to the present invention can be manufactured easily and economically. Accordingly, the case, etc. can be made short and small, and reduced in width by an amount equal to the reduction of the number of control buttons. Thus, the invented device can be made compact and light weight, and the appearances of the button-operated lock and the door can be improved. Moreover, the backset dimensions from the side end face of the door to the center of the lock can be made compact and thus, this lock can be suited to be used for a kitchen door. Moreover, in the button-operated lock, plural sorts of memory information can be set or inputted in accordance with the number of times of depressing operation of the control buttons. Accordingly, there is no worry for being perceived the memory information from the finger prints printed on the surfaces of the control buttons and the wearing condition of the surfaces of the control buttons when compared with the conventional technique in which only one memory information is set or inputted to a plurality of control buttons. Thus, the safety performance can be enhanced. Moreover, in the button-operated lock according to the present invention, the setting or inputting information can be controlled in association with the number of times of operation of the control buttons. Accordingly, the setting or inputting operation of information can be made correctly by sorting, counting and recognizing the information. Moreover, in the button-operated lock according to the present invention, a part of the control means of the information to be set or inputted is built in the control button. Accordingly, the device can be made small in size and light in weight. Moreover, in the button-operated lock according to the present invention, the control means includes a gear button which can be intermittently turned every time the control button is axially displaced. Accordingly, the displacement of the control button can be transmitted correctly and in a stable manner. Moreover, in the button-operated lock according to the present invention, the plurality of information can be set or inputted during one turn of the control button. Accordingly, malfunction occurrable when the control button is turned by plural turns can be prevented, and correctness and safety of the locking/unlocking operation can be obtained. Moreover, in the button-operated lock according to the present invention, a lock plate is interposed between the control plate and the driving cam, one end of the lock plate is swingably connected to the control plate, and the other end of the lock plate is arranged to be engageable with or disengageable from the driving cam. Accordingly, there is no worry that the password number is perceived by turning operation of the door handle as in the conventional technique in which the control plate and the driving cam are directly associated. Thus, the safety performance can be enhanced. In the button-operated lock according to the present invention, a terminal gear is arranged to be engageable with the button gear, a reset gear is arranged to be engageable with the terminal gear, and the reset gear is biased in such a manner as to be able to rotationally return in accordance with a rotation angle displacement thereof. Accordingly, a plurality of information can be inputted correctly through a plurality of control buttons, and a correct and stable operation of the terminal gear can be obtained. Moreover, in the button-operated lock according to the present invention, wherein the button gear and the terminal gear can be disengaged from each other, and the terminal gear and the reset gear can be normally engaged with each other. Accordingly, the setting or inputting of information through the control buttons and alternation thereof can be realized in a reliable manner. Moreover, in the button-operated lock according to the present invention, the reset gear is provided with a stopper which is unable to engage the terminal gear. Accordingly, information can reliably be set or inputted in a range of one turn of the control button. Moreover, malfunction, which would otherwise be occurrable by more than one turn of the control button, can be prevented from occurring. In addition, by restricting the amount of information which can be set or inputted by only one control button, malfunction can be prevented from occurring. In the button-operated lock according to the present invention, the terminal gear is provided with a square hole, a clutch shaft capable of rotationally support the terminal gear, the clutch shaft being provided with a square shaft which is engageable with and disengageable from the square hole, and the square shaft being biased for engagement with the square hole. Accordingly, the operation of the button gear and the reset gear can be transmitted to the control cam correctly and in a stable manner through the terminal gear and the clutch shaft. Moreover, in the button-operated lock according to the present invention, a plurality of engagement parts engageable with the square shaft are formed at the square hole, and the number of the engagement parts is set to be equal to an amount of information which can be set or inputted by only one control button. Accordingly, information can be set or inputted reliably through the control button. Moreover, in the button-operated lock according to the present invention, a plurality of control holes are formed in a surface of a case which is exposed to the outside, so that a control tool can be inserted in the control holes, and one end part of the clutch shaft is faced with an inner side opening part of the control hole. Accordingly, information can be altered from the outdoor side through the control buttons by realizing a clutching operation of the clutch shaft by using the control tool. In the button-operated lock according to the present invention, the clutch shaft is axially displaceable through the control tool, so that the engagement between the square shaft and the square hole can be released, and the terminal gear is rotatably supported by the clutch shaft. Accordingly, the setting or inputting of information and alternation thereof can be realized smoothly through the control buttons by realizing a clutching operation of the clutch shaft by suing the control tool. Moreover, in the button-operated lock according to the present invention, a cam shaft is projected from the other end of the clutch shaft, a control cam is attached to the cam shaft such that the control cam is simultaneously movable with the cam shaft, an engagement claw of the control plate is removably received in a cutout groove formed in the control cam, and the engagement claw is biased such that the engagement claw is engageable with and disengageable from the cutout groove. Accordingly the engagement claw is brought into engagement with and disengagement from the cutout groove depending on where the cutout groove is located. By doing so, the operation of the control plate is controlled to realize the locking/unlocking operation. Moreover, in the button-operated lock according to the present invention, a plurality of passage holes are formed in a back plate, which is attached to a back part of the case, in such a manner as to face with an end part of the cam shaft, and a plurality of check marks are arranged on the outside of the passage holes in isometric positions. Accordingly, the memory number of the control cam or the input information of the control button can correctly and easily be confirmed by referring the position of the end part of the cam shaft to the check mark. In this way, the inputting of information and alternation thereof can correctly be made. In the button-operated lock according to the present invention, at the time of setting or inputting information through the control buttons, the cutout grooves are directed toward the engagement claw side and positioned in the same phase as the engagement claw, and the engagement claws are brought into engagement with the cutout grooves, respectively, so that the control plate can allow an unlocking procedure. Accordingly, the lock can be unlocked only when the set information is available. By doing so, safety at actual use can be ensured. Moreover, in the button-operated lock according to the present invention, at the time of setting or inputting information through the control buttons, the engagement claws are brought into engagement with the control cam and prohibited from being engaged with the cutout grooves, so that the control plate is unable to allow an unlocking procedure. Accordingly, the lock can be prohibited from being unlocked by false operation and safety at actual use can be ensured. Moreover, in the button-operated lock according to the present invention, a block main body on which the terminal gear and the reset gear can be mounted is provided, a memory releasing link is engaged with the block main body, the block main body is biased in such a manner as to be able to move toward the control button side, so that the terminal gear and the button gear can be engaged with each other, one end part of the memory releasing link is engaged with the driving cam, so that the block main body is brought away from the control button side through the turning motion of the driving cam, thereby allowing the terminal gear and the button gear to be disengaged from each other. Accordingly, any falsification and erroneous operation which could otherwise be achieved by operating the driving cam or door handle, namely, by resetting operation after setting information by the control buttons, can be obviated, and the state at the time of setting the information can be recovered easily. By doing so, any malfunction can be prevented from occurring thereafter, and a smooth and reliable locking/unlocking operation can be realized. On the other hand, by realizing the resetting operation through the door handle, the conventional reset button can be eliminated. Thus, the lock of this type can be simplified and made small in size and light in weight. Moreover, in the button-operated lock according to the present invention, the block main body is provided with a guide groove, the memory releasing link is provided with a pin projecting therefrom and engageable with the guide groove, the pin is positioned such that it can normally engage one side edge of the guide groove, the guide groove is provided at the other end edge thereof with a locking projection engageable with the pin, and at the time of engagement between the pin and the locking projection, operation of the memory releasing link is prohibited and engagement between the terminal gear and the button gear is prohibited from releasing. Accordingly, any false unlocking operation using, for example, the control hole can be prohibited, and safety at actual use and security can be ensured. Moreover, in the button-operated lock according to the present invention, the memory releasing link is turnably provided at the other end side thereof with a changeover shaft which is linked to a changeover knob on the indoor side, the changeover shaft is provided with two cams which are different in length, and the two cams is selectively engageable with the other end part of the memory releasing link. Accordingly, the use of so-called empty lock for this type of a lock and the use at the time of alternation of information can be met by only one changeover shaft. Moreover, in the button-operated lock according to the present invention, the separation distance between the block main body and the control button is made different in accordance with the lengths of the two cams, the two cams are each capable of releasing engagement between the terminal gear and the button gear, at the time of engagement with the long side cam, engagement between the engagement claw and the control cam cutout groove can be maintained, and at the time of engagement with the short side cam, engagement between the engagement claw and the cutout groove can be maintained. Accordingly, at the time of the engagement of the elongate side cam, the use of so-called empty lock of this type of a lock can be obtained, and at the time of the engagement of the short side cam, the reasonable use at the time of alternation of information can be obtained. In the button-operated lock according to the present invention, the case is provided at an inner side surface side thereof with a protection plate such that the protection plate can move along the control holes, and a plurality of through-holes, which can communicate with the control holes, are formed in the protection plate, such that one end of the protection plate can engage the driving cam. Accordingly, a false unlocking operation through the control hole can be prevented from occurring. Moreover, in the button-operated lock according to the present invention, engagement between the terminal gear and the button gear is released through turning operation of the door handles or the changeover shaft, and the terminal gear is turned by elastic force of a set spring which is formed after the information is set or imputed, so that the control cam or its cutout groove can be returned to its original position. Accordingly, the resetting operation can be realized through the door handle or changeover shaft. Thus, the current information can easily be reproduced, and the setting of information or alternation thereof can rapidly be attained. Moreover, in the button-operated lock according to the present invention, after the control cam or its cutout groove is returned to its original position, current information of the control button is set or imputed to turn the button gear by an amount of the set or inputted information, the terminal gear and the reset gear are moved in operative connection to the turning motion of the button gear, the terminal gear is biased to return to its original position by an amount of the set or inputted information, the engagement between the terminal gear and the button gear is released through the turning operation of the door handles, the terminal gear is reversely turned for offset by an amount of the set or inputted information, thereby releasing the set or inputted current information so that the lock can be unlocked. Accordingly, a reliable unlocking operation can be obtained. In the button-operated lock according to the present invention, after the control cam or its cutout groove is returned to its original position, the terminal gear is rotatably supported on the clutch shaft through the control tool, and the engagement between the square shaft and the square hole is released, so that the original position of the control cam or its cutout groove can be maintained. Accordingly, it can eliminate such elaboration that at the time of altering information, the information which has been set or inputted by operating the control buttons is once deleted and the information which has been set or inputted is inputted once again by operating the control buttons. Moreover, in the button-operated lock according to the present invention, after the original position of the control cam or its cutout groove is maintained through the control tool, at the time for altering information where the button gear is turned in the same direction as at the setting or inputting time of information, the control button is operated by an amount equal to the difference between the turning angles of the button gear before and after the alternation of information, then the terminal gear and the reset gear are operatively connected thereto, the terminal gear is biased such that it can turningly return by an amount equal to the difference between the turning angles, the square shaft and the square hole are engaged with each other after the button gear is turned, and the original position of the control cam or its cutout groove is linked to the terminal gear, the engagement between the terminal gear and the button gear is released through turning operation of the door handles, the terminal gear is turned by an amount equal to elasticity of the reset spring formed after the alternation of information, and an amount equal to the turning angle of the terminal gear is added to the position of the control cam or its cutout groove, so that the setting or inputting information can be altered. Accordingly, the information altering operation achieved by turning the button gear in the same direction as at the time of setting or inputting the information can be made from the outer side of the door safely, reasonably and rapidly. Moreover, in the button-operated lock according to the present invention, the number of times of operation of the control button is a quotient obtained by dividing the difference of turning angles of the button gear before and after the alternation of information by a unit operation turning angle of the turning button. Accordingly, the above-mentioned information altering operation can be made reasonably and easily. In the button-operated lock according to the present invention, at the time for altering information where the button gear is turned in a reverse direction to the direction at the time of setting or inputting information, the changeover shaft is turned to bring the cam on its short side into engagement with an end part of the memory releasing link and to release the engagement between the terminal gear and the button gear, the engagement between the cutout groove and the engagement claw is maintained to maintain the original position of the control cam or its cutout groove, the terminal gear is turnably supported on the clutch shaft through the control tool, the terminal gear is turningly returned by an amount of elasticity of the reset spring equal to the amount of elasticity necessary for forming the original position, after the original position of the control cam or its cutout groove is released, the changeover shaft is turningly returned to the original position to bring the terminal gear into engagement with the button gear, the button gear is turned by an amount equal to the amount of angle of the alternation of information by operating the control button through the control tool, then the terminal gear and the reset gear are operatively connected thereto, so that the terminal gear is biased such that it can turningly return by an amount equal to the difference between the turning angles, the square shaft and the square hole are engaged with each other after the button gear is turned, the clutch shaft is linked to the terminal gear to release the engagement between the terminal gear and the button gear through turning operation of the door handles, the terminal gear is turned by an amount equal to elasticity of the reset spring formed after the alternation of information, the position of the control cam or its cutout groove is reset by an amount equal to the turning angle of the terminal gear, so that the setting or inputting information can be altered. Accordingly, the information altering operation achieved by turning the button gear in the reverse direction to that at the time of setting or inputting the information can be realized. In addition, by making it necessary to turn the changeover shaft, it becomes indispensable that the information changing operation is made from the indoor side and it becomes impossible to make such information changing operation from the outdoor side. Thus, this type of operation can be made safely. Moreover, in the button-operated lock according to the present invention, a ball retainer for disengageably receiving therein a ball biased toward the inner side of the door handles and adapted to normally turn the door handles and the driving cam but idly turn the door handle and prohibit the turning of the driving cam when excessively large torque acts on the door handle, is formed in the shape of a plate, and the ball retainer is mounted on a surface part of the case. Accordingly, the ball retainer or button-operated lock can be made small in size and light in weight. Moreover, in the button-operated lock according to the present invention, the arrangement of the door handles and the control buttons can be selectively or symmetrically altered together with their inside mechanisms. Accordingly, the outer appearance or design of the lock can easily be changed in accordance with the circumstance under which the lock is used and the condition under which the lock is attached to the door. The above-mentioned objects, features and advantages of the present invention will become more manifest from the following detailed description with reference to the attached drawings. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a perspective view showing one embodiment of the present invention, in which a button-operated lock according to the present invention is mounted on an entrance door. FIG. 2 is a front view showing the button-operated lock according to the present invention, in which the lock is mounted on the entrance door. FIG. 3 is a left side view of FIG. 2. FIG. 4 is a perspective view showing an essential part of the present invention in an exploded manner. FIG. 5 is a front view showing a case and a protection plate to which the present invention is applied. FIG. 6 is a sectional view taken on line A-A of FIG. 5. FIG. 7 is a sectional view taken on line B-B of FIG. 5. FIG. 8 is a sectional view taken on line C-C of FIG. 5, additionally showing an attaching state of a control button to the button-operated lock. FIG. 9 is a sectional view taken on line D-D of FIG. 5. FIG. 10 is a perspective view showing a control button to which the present invention is applied, in an exploded manner. FIG. 11 is a perspective view showing an assembling state of a block assembly to which the present invention is applied, in which a case is omitted. FIG. 12 is a sectional view taken on line E-E of FIG. 11, in which a part of a back plate is omitted. FIG. 13 is a sectional view taken on line F-F of FIG. 11, in which a part of the back plate is omitted. FIG. 14 is a sectional view taken on line G-G of FIG. 11, in which a part of the back plate is omitted. FIG. 15 is an enlarged sectional view taken on line H-H of FIG. 11. FIG. 16 is an enlarged sectional view taken on line I-I of FIG. 11. FIG. 17 is a front view showing an assembling state of the present invention, in a simplified manner. FIG. 18 is an enlarged sectional view taken on line J-J of FIG. 17, showing a state in which a control tool is not yet inserted. FIG. 19 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 18 and in which the control buttons are not yet depressed. FIG. 20 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 19 and in which the control buttons are already depressed. FIG. 21 is a perspective view showing the block assembly to which the present invention is applied, in an exploded manner. FIG. 22 is a sectional view taken on line K-K of FIG. 21. FIG. 23 is an enlarged sectional view taken on line L-L of FIG. 21. FIG. 24 is a front view showing a terminal gear to which the present invention is applied. FIG. 25 is a sectional view taken on line M-M of FIG. 24. FIG. 26 is an explanatory view showing a relation between a control cam to which the present invention is applied and a cutout groove thereof, and a cam shaft and memory information in sequential order. FIG. 27 is a perspective view showing a state of a driving cam to which the present invention is applied. FIG. 28 is a perspective view showing a state of the driving cam to which the present invention is applied, but when view from the opposite side of FIG. 27. FIG. 29 is a sectional view taken on line N-N of FIG. 27, showing an assembling state of the driving cam to which the present invention is applied and a door handle on the outdoor side. FIG. 30 is a sectional view taken on line O-O of FIG. 27. FIG. 31 is a perspective view showing a memory releasing link to which the present invention is applied. FIG. 32 is a perspective view showing a changeover shaft to which the present invention is applied. FIG. 33 is a front view showing an assembling state of the memory releasing line to which the present invention is applied and a control plate. FIG. 34 is a perspective view showing a control plate to which the present invention is applied and a lock plate, in which an assembling state thereof is shown. FIG. 35 is an enlarged sectional view taken on line P-P of FIG. 34. FIG. 36 is a front view showing an assembling state of the control plate to which the present invention is applied and a block main body. FIG. 37 is a perspective view showing a button-operated lock according to the second embodiment of the present invention, in which the button-operated lock is mounted on the entrance door. FIG. 38 is a perspective view showing an essential part of the button-operated lock according to the second embodiment in an exploded manner, in which a back plate is omitted. FIG. 39 is a perspective view showing the button-operated lock according to the second embodiment in an exploded manner, in which a case is omitted. FIG. 40 is a perspective view showing, in an exploded manner, a block assembly which is applied to the button-operated lock according to the second embodiment. FIG. 41 is a sectional view showing an essential part of a safety mechanism of a door handle which is applied to the button-operated lock according to the second embodiment. FIG. 42 is a sectional view showing an essential part of a ball retainer which is applied to the safety mechanism of the door handle according to the second embodiment. FIG. 43 is a front view showing an essential part of the safety mechanism which is applied to a block main body according to the second embodiment, in which a guide groove and a pin are in engagement relation. FIG. 44 is a front view showing an essential part of FIG. 43 on an enlarged basis. FIG. 45 is a sectional view showing an assembling state of an information altering unit which is applied to the second embodiment. FIG. 46 is a sectional view taken on line Q-Q of FIG. 45. FIG. 47 is a perspective view showing a control cam which is applied to the second embodiment. FIG. 48 is a sectional view of a terminal gear which is applied to the second embodiment. FIG. 49 is a front view showing a crutch shaft which is applied to the second embodiment. FIG. 50 is a plan view of FIG. 49. FIG. 51 is a perspective view showing a button-operated lock according to the third embodiment of the present invention, in which the button-operated lock is attached to a kitchen door. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described hereinafter in the form of one preferred embodiment with reference to the accompanying drawings. In FIGS. 1 through 36, reference numeral 1 denotes a left suspension type door, which one end part on the suspending base side is turnably attached to a framework (both of them are not shown) through a hinge, and a main lock (not shown) of the present invention is embedded in the other side end part. A vertically elongated oval-shaped button-operated lock 2 is disposed at the other side end part of the outdoor of the door 1. A seat plate 3 having a generally same configuration as the button-operated lock 2 and having a small thickness is disposed at the indoor side of the door 1. The button-operated lock 2 and the seat plate 3 are provided at lower end parts thereof with door handles 4, 5, respectively, such that the door handles 4, 5 can turn independently. A changeover knob 6 such as a thumb turn knob is attached to an upper end part of the seat plate 3 such that the knob 6 can turn by a predetermined angle. The changeover knob 6 and the door handle 5 are turnably attached to the seat plate 3 through a stop ring (not shown) and engaged in and attached to a changeover shaft and a connection bar as later described. In the Figures, reference numeral 7 denotes a front plate attached to the other side end face of the door 1. A dead bolt 8 and a latch trigger 9, which are operatively connected to the main lock, are retractably disposed at an intermediate part of the front plate 7. The latch trigger 9, when retracting, causes the dead bolt 8 to project in association with a cam mechanism of the main lock, so that the lock can be locked automatically. The button-operated lock 2 uses numerical figures as set or inputted information, and it includes a plurality of control buttons 10 (five control buttons in this embodiment) through which the password number can be set or inputted. Those control buttons 10 are one-sidedly and vertically arranged in a row. Each control button 10 is provided at one side thereof with an indication part 11 for specifying this particular control button 10. In this embodiment, numerical FIGS. 1 through 5 are assigned as the indication parts 11 to the respective control buttons 10 in this order from the top. Basically, the button-operated lock 2 is designed such that a certain password number consisting of numerical figures of the number of digits (five digits in this embodiment) corresponding to the number of the control buttons 10 can be set or inputted. In this embodiment, the password number “12345” are set or inputted from the top. In the Figures, reference numeral 12 denotes control holes which are arranged between the control buttons 10 and the button indication parts 11, respectively. In this embodiment, a plurality of through-holes are formed, as the control holes 12, at locations where they can face with the information altering elements as later described. The button-operated lock 2 includes a back plate 13 and a case 14 which are made of diecast zinc alloy and which form an outer jacket of the lock 2. A block assembly 15 and a driving cam 16 are received in the case 14. The back plate 13 is formed in a shape of an elongated thin oval. A recess 17 capable of supporting a pivot part of the driving cam 16 is formed in the inner side surface of the back plate 13. A through-hole 18 is formed in the center of the recess 17. A barrel part (not shown) projects from the outer side edge part of this hole 18. Referring back to the Figures, reference numeral 19 denotes a pair of left and right screw holes formed at opposite end parts of the back plate 13; 20, pipe shaft insertion holes formed at generally end parts of the back plate 13; and 21, 22, control windows for adjusting a suspending base position of a door 1 which is installed at a proximal position to the recess 17 and allowing a tool such as a screw driver to be inserted therein, respectively. A plurality of elliptical recess grooves 23 are formed in a central part of the inner side surface of the back plate 13 along the longitudinal direction of the back plate 13. A control cam, as later described, is received in each recess groove 23 such that the control cam can slide in a direction orthogonal to the longitudinal direction of the back plate 13. Each recess groove 23 has an elongate hole 24 as a passage hole which is formed therein in such a manner as to be offset to one side of the recess groove 23. One end of a crutch shaft, as later described, can be received in the elongate hole 24. A bottomed cylindrical button retainer 25 projects from a proximal position to each recess groove 23. A guide shaft (not shown) of the control button 10 and its biasing spring can be received in the button retainer 25. In the Figures, reference numeral 26 denotes a bead-like hooking projection projects from one side end part of the inner side surface of the back plate 13, and a pair of long grooves 27 are formed at the other side surface. An engagement pin of a memory releasing link as later described can be received in each long groove 27. Reference numeral 28 denotes a passage hole formed in the opposite side end part to the passage hole 20 of the back plate 13, and a changeover shaft as later described can be received in the passage hole 28. Reference numeral 29 denotes a hooking projection arranged proximate to button retainer 25 at the lowest position. On the other hand, the case 14 is formed in a generally elongate oval box-like configuration from a diecast zinc alloy of the same quality as the button-operated lock 2. A plurality of button insertion holes 30 are one-sidedly arranged in a row on the surface of the case 14. The control buttons 10 are axially displaceably inserted in the button insertion holes 30 (in this embodiment, the control buttons 10 are inserted in the holes 30 such that they are displaceable when pressed). Each control button 10 can set or input 8 sorts of memory information from “0” to “7” through a predetermined depressing operation. The memory information is defined by the number of times of a depressing operation. That is, when the control button 10 is depressed once, a memory information of “1” is set or inputted, when the button 10 is depressed twice, a memory of “2” is set or inputted, and when the button 10 is depressed three times, a memory information of “3” is set or inputted. When a zero-times operation is made, i.e., when no depressing operation is made, a memory information of “0” is set or inputted. Accordingly, the password number of “12345” in this embodiment can be set or inputted by depressing the control buttons 10 once, twice, three times, four times and five times in this order from the top down. By means of combination of the memory information of those control buttons 10, the password number is set. A combination of the password number obtained by depressing the five control buttons as in the embodiment, is the fifth power of 8. In other words, 32768 sorts can be set or inputted. In this case, of the password number of 5 digits, the digit of 10000-places is set or inputted with the memory information of the uppermost place, i.e., through the control button 10 which is indicated by the indication number “1” in the button indication part, the digit of 1000-places is set or inputted with the memory information through the control button 10 which is indicated by the indication number “2” in the button indication part, the digit of 100-places is set or inputted with the memory information through the control button 10 which is indicated by the indication number “3” in the button indication part, the digit of 10-places is set or inputted with the memory information through the control button 10 which is indicated by the indication number “4” in the button indication part, and the digit of 1-place is set or inputted with the memory information through the control button 10 which is indicated by the indication number “5” in the button indication part. A short tubular guide ring 31 is press-fitted in or integrally formed with the inner side of an opening edge part of each button insertion hole 30. A plurality (eight in this embodiment) of guide ribs 32 project in the axial direction of the tubular guide ring 31. A button case 33, which is made of diecast zinc alloy and which forms the control button 10, and a button gear 34 which forms control means which is composed of a gear train mechanism as later described, are engageably fitted to the guide rib 32 The button case 33 is formed in a bottomed cylindrical shape. A plurality (eight in this embodiment) of hook elements 35 project from the peripheral surface of the lower end part of the button case 33. Each of the eight guide ribs 32 is engageably interposed between every adjacent hook elements 35 such that the up and down movement the button case 33 can be enhanced. The upper ends of the hook elements 35 are engageable with the inner side opening edge part of the button insertion hole 30 for the purpose of prevention of coming-off. A plurality (eight in this embodiment) of serrated dogs 36 project from the peripheral edge of the lower end part of the button case 33. The corresponding number of dogs 37 of the button gear 34 are removably engaged with those dogs 36. The button gear 34 is provided with 16 teeth and slide shaft parts 38, 39, which are different in diameter, project from opposite sides in the direction of the width of the tooth of the button gear 34. The upper side slide shaft part 38, which is large in diameter, is slideably inserted in the button case 33. The corresponding number of serrated dogs 37 engageable with the dogs 36 project from the peripheral surface of the slide shaft part 38. A plurality (four in this embodiment) of tapered cams 39 project from the outer peripheral surfaces of the dogs 37. The length in the peripheral direction of each cam 39 is set to a pitch which is generally equal to two teeth of the button gear 34. The cams 39 are arranged such that the cam faces are engageable with the end parts of the guide ribs 32. When the cam faces of the cams 39 are in engagement with the end parts of the guide ribs 32, the button gear 34 can intermittently turn by one pitch portion, i.e., 45 degrees which correspond to the distance between the adjacent guide ribs 32, 32, in one direction. The lower side slide shaft part 39, which is small in diameter, is formed in a hollow cylindrical shape and slideably inserted in the button retainer 25. Through the elasticity of a set spring 40 received in the button retainer 25, the button case 33 and the button gear 34 are biased upward and the button case 33 is projected forward of the case 14. A long elliptical guide groove 41 is formed adjacent to each button insertion hole 30 in the left and right direction. A generally oval slide groove 42 is formed in the groove 41 on the side of the button insertion hole 30. A barrel part 44 of a reset gear 43 and an information altering element 45, which form the block assembly 15, are slideably received in the guide groove 41 and the slide groove 42. The block assembly 15 is composed of a diecast zinc alloy-made block main body 46 received in the button-operated lock 2 such that it can move leftward and rightward, a cover plate 47 attached to the upper surface of the main body 46 by screw fixing or the like, the same number of information altering units 48 and reset gears 43 as the control buttons 10 which are mounted over the block main body 46 and the cover plate 47. The block main body 46 is composed of an elongate rectangular plate upper and lower surfaces of which are flat and smooth, and thin. As shown in FIGS. 21 and 22, the same number of bottomed first gear insertion holes 49 as the control buttons 10 are formed at one side of the upper surface of the block main body 46, and the same number of bottomed second gear insertion holes 50 as the first gear insertion holes 49 are formed at the other side. The first and second gear insertion holes 49, 50 are communicated at an intermediate part of the block main body 46 with each other, and parts of the outer peripheral surfaces of those holes 49, 50 are open to the opposite side surfaces of the block main body 46. A bottomed cutout hole 51 is formed in one side end part of the block main body 46 at an area slightly offset from the first gear insertion hole 49, and a part of the button gear 34 can be received in the cutout groove 51, so that the button gear 34 and a terminal gear as later described can be engaged with each other. A cam hole 52 having the same diameter as the insertion hole 49 is formed at one side end part of the block main body 46 immediately under the first gear insertion hole 49. The cam hole 52 and the first gear insertion hole 49 are communicated with each other through a passage hole 53. Moreover, a cutout groove 73 communicated with the passage hole 53 of each cam hole 52 is formed at one side end part of the block main body 46, such that an engagement claw of a control plate, as later described, can be inserted therein. In the Figures, reference numeral 54 denotes a shaft-like spring hook projecting from a bottom part of the second gear insertion hole 50. The spring hook 54 is provided at its center with a slitting 55 in which a reset spring, as later described, can hook. Reference numeral 56 denotes a hook part disposed at one end of the block main body 46. This hook part 56 is engageable with an expanded part 57 of the case 14. Reference numeral 59 denotes diagonal guide grooves disposed at opposite end parts of the block main body 46. Reference numeral 60 denotes a recessed spring retainer disposed at the other side end part of the block main body 46. A shift spring 153 is interposed between the spring retainer 60 and the inner surface of the side wall of the case 14. The block assembly 15 is biased toward the control button 10 side through the elasticity of the spring 153, so that the terminal gear 66 is engageable with the button gear 34. The cover plate 47 is formed in a generally same shape as the planar shape of the block main body 46. A plurality of arcuate cutouts 61 are formed at one side end part of the cover plate 47. Those cutouts 61 are arranged immediately above the cutout hole 51. In the Figures, reference numeral 62 denotes an attachment hole for the information altering unit 48; 63, a screw hole; and 64, an insertion hole for allowing a boss 44 of the recess gear 43 to be inserted therein, formed in the cover plate 47, respectively. The information altering unit 48 is, as shown in FIG. 21, composed of an information altering cam 65 received in the cam hole 52, a terminal gear 66 receiving in the first gear insertion hole 49, a clutch shaft 67 opposite shaft end parts of which are inserted in the information altering cam 65 and the terminal gear 66, a washer 68 disposed on an opening edge part of the attachment hole 62, a set spring 69, and an information altering element 70 linked to the clutch shaft 67. Of those components, the information altering cam 65 is formed in a generally truncated cone shape from a synthetic resin which is excellent in wear-resisting property. A generally half moon-like shaft hole 71 is formed in the center of the information altering cam 65. A bottomed cutout groove 72 is formed in the side surface of the information altering cam 65 and directed toward the shaft hole 71, so that an engagement claw of a control plate, as later described, is removably engageable with the groove 72. The information altering cam 65 is turnably received in the cam hole 52 with the cutout groove 72 facing upward. The flat undersurface of the information altering cam 25 is received on the recessed groove 23 of the back plate 13 and a lower part of the clutch shaft 67 is inserted in the shaft hole 71 of the information altering cam 25 so that the position of the cutout groove 72 is regulated. That is, the position of the cutout groove 72 is changed in operative connection to the turning motion of the clutch shaft 67. Before the password number is set, the cutout groove 72 is open directing toward the position of the password number zero (0), i.e., toward the cutout part 73. The terminal gear 66 is engageable with the button gear 34 and the set gear 43, and the diameter of its pitch circle is same as the diameter of the button gear 34 and as the same number of teeth as the button gear 34. The terminal gear 66 is slightly smaller in diameter than the set gear 43 and has a boss 74 projecting from its upper surface. A stepped hole 75 is formed from the inside of the boss 74 to the inside of the terminal gear 66. A square hole 76 having a plurality of engagement parts, for example, polygonal (octagonal in this embodiment) is formed on an enlarged diameter part at the lower step of the stepped hole 75. In the Figures, reference numeral 77 denotes an assembling counter mark which is formed on the upper surface of the boss 74. The clutch shaft 67 is obtained by machining a brass rod and has a circular hook plate 78 formed at an intermediate part thereof. A regular octagonal cylindrical square shaft 79, which is removably engageable with the square hole 76 is projected from the upper surface of the hook plate 78. The square shaft 79 allows the clutch shaft 67 to intermittently turn by an equal angle at a time which is equal to an amount of a turning angle, i.e., 45 degrees, of the button gear 34 and the terminal gear 66 and also allows a cam shaft 80 having a generally half moon like shape in section and projecting from the undersurface of the hook plate 78 to move together with the clutch shaft 67. In the Figures, reference numeral 81 denotes a threaded hole which is formed at the inside of the clutch shaft 67. A machine screw serving as the information altering element 70 is screwed into this threaded hole. The information altering element 70 is provided at one end thereof with a wide input retainer 82 which is engageable with a rod-like control tool as later described. The input retainer 82 is faced with the rear part of the control hole 12. In this embodiment, a commercially available machine screw is used as the information altering element 70, and the head part of this machine screw is used as the input retainer 82. By screwing its threaded shaft, the information altering element 70 is connected to the clutch shaft 67. At the time for rational assembly, in the information altering unit 48, the terminal gear 66 is retained with its boss 74 facing upward, and the clutch shaft 67 is inserted into the stepped hole 75 from below. Then, the square shaft 79 is fitted to the square hole 76 and the altering shaft 67 is inserted in the cover plate 47 from below. Then, the washer 68 and the set spring 69 is inserted to the clutch shaft 67 projecting from the cover plate 47 and the threaded shaft of the information altering element 70 is screwed in the threaded hole 81 of the clutch shaft 67. By doing so, a set of information altering unit 48 only excluding the control cam 65 is attached to the cover plate 47. All the other information altering units 48 are attached to the cover plate 47 in the same manner, and the respective terminal gears 66 in their assembled states are received in the first insertion holes 49 and the cover plate 47 is fixed to the block main body 46 by machine screws. Thereafter, the block main body 46 is counter-rotated and the shaft holes 71 of the control cams 65 are inserted to the cam shafts 80 projecting into the respective cam holes 52. Then, the whole block main body 46 is received in the back plate 13 and the lower end parts of the cam shafts 80 are received in the passage holes 24. In the information altering unit 48 thus assembled, the clutch shaft 67 and the information altering element 70 are biased forward, i.e., toward the case 14 side by the elasticity of the set spring 69, and the square shaft 79 is engaged with the square hole 76 so that the terminal gear 66 and the clutch shaft 67, and the cam shaft 80 and the control cam 65 can be moved altogether. On the other hand, the clutch shaft 67 is displaceable in the axial direction against the elasticity of the set spring 69 by the depressing operation of the information altering element 70. At the time of displacement of the clutch shaft 67, the engagement between the square shaft 79 and the square hole 76 is released, so that power transmission from the terminal gear 66 to the clutch shaft 67 can be cut off. Then, at the time of setting or inputting the password number of the information altering unit 48, the cam shaft 80 and the control cam 65 mounted on the cam shaft 80 are turned by an amount equal to the turning angle of the control button 10 by setting or inputting of the respective control buttons 10 and the position of the cutout groove 72 is made correspondence thereto, so that a state is created whether the engagement between the cutout groove 72 and the engagement claw of the control plate can be engaged with each other as later described. That is, the clutch shaft 67 or cam shaft 80 of each information altering unit 48 is turned by an amount equal to the turning angle of the corresponding control button 10 to determine the position of the cutout groove 72. The relation between the memory information and the control cam at that time is as shown in FIG. 26. For example, at the time of setting or inputting the memory information “1” obtained by depressing the control button 10 only once, as shown in FIG. 26(b), the button gear 34 is turned by an amount equal to the controlling operation made only once, i.e., 45 degrees, thereby turning the cutout groove 72 by the same angle. In that case, the cutout groove 72 is in a position unable to engage the engagement claw of the control plate as later described, and the engagement claw is, as shown in FIG. 15, located generally vertically between the hook plate 78 and the control cam 65. At the time of setting or inputting the memory information “2” obtained by depressing the control button 10 twice, as shown in FIG. 26(c), the button gear 34 is turned by an amount equal to the controlling operation made twice, i.e., 90 degrees, and at the time of setting or inputting the memory information “3” obtained by depressing the control button 10 three times, as shown in FIG. 26(d), the button gear 34 is turned by an amount equal to the controlling operation made three times, i.e., 135 degrees, thereby turning the cutout groove 72 by the same angles, respectively. In those cases, the cutout groove 72 is in a position unable to engage the engagement claw, and the engagement claw is, as in the above-mentioned case, is located generally vertically between the hook plate 78 and the control cam 65. Similarly, the cutout groove 72 is turned by an amount equal to a turning angle obtained by multiplying 45 degrees to the number of times of depressing operation of the control button 10. Also in this case, the cutout groove 72 is in a position unable to engage the engagement claw, and the engagement claw is, as in the above-mentioned case, is located generally vertically between the hook plate 78 and the control cam 65. On the other hand, at the time of setting or inputting the memory information “0” obtained by not depressing the control button 10, the button gear 34 is not turned, and as shown in FIG. 26(a), the cutout groove 72 is correctly faced with the engagement claw and in a position engageable with the engagement claw. At that time, only when the cutout grooves 72 of all the control cams 65 are correctly faced with the respectively engagement claws and in positions engageable with the engagement claws, they can be engaged with each other and the control plate can be swung. On the other hand, the set gear 43 is formed of a same material as the terminal gear 66 such that the diameter of the set gear 43 is slightly larger than the diameter of a pitch circle of the terminal gear 66 and the set gear 43 has an increased number of teeth by two (2) than the terminal gear 66. A wide stopper 83, which is synthesized of two teeth, is formed on a part of the set gear 43. This stopper 83 is unable to engage the terminal gear 66. Moreover, owing to this stopper 83, an amount of information which can be set or inputted by only one control button 10 is restricted. Accordingly, the set gear 43 substantially has the same number of teeth as the terminal gear 66 and therefore, the set gear 43 is engageable with the terminal gear 66. The barrel part 44 is integrally formed with the set gear 43, and a recessed hole 84 is formed therein. A pin 85 eccentrically projects from an inner part of the recessed hole 84. A set spring 86, that is a torsion spring, is received in the recessed hole 84. One end of the set spring 86 is hooked to the slitting 54 and a hook part 87 at the other end of the set spring 86 is hooked to the pin 85. And the elasticity of the set spring 86 is accumulated in accordance with the turning angle of the set gear 43, and the set gear 43 is rotationally biased in the counter-rotating direction by its elasticity so that this rotational motion may act on the terminal gear 66. In the Figures, reference numeral 88 denotes an assembling counter mark which is formed on the surface of the barrel part 44. The driving cam 16 is turnably received in a cam hole 101 which has a large diameter and which is formed on the inner surface of the case 14. The driving cam 16 is normally biased by a cam spring (not shown) so that it can turnably return to the original position. The driving cam 16 is formed in a thin generally disc-like shape from a diecast zinc alloy. The driving cam 16 has turnable shafts 89, 90 projecting from its front and rear surfaces, respectively. Those shafts 89, 90 are turnably supported in the passage hole 18 of the back plate 13 and the passage hole 102 of the case 14. Of them, the turnable shaft 89 on the rear side is turnably inserted in the recessed hole 17 of the back plate 13. A connection bar 91 associating with the main lock and its inner side handle door 5 is turnably inserted in the turnable shaft 89 and its turning angle is restricted by a pair of projections 92. One end of the connection bar 91 is disposed between the projections 92, 92 with a tolerance such that the above-mentioned one end of the connection bar 91 is substantially unable to engage the projection 92, thus making it unable to turn the driving cam 16 through turning operation of the inner side door handle 5. The driving cam 16 is provided at its rear end part with a generally half moon-like slide surface 93. The slide surface 93 is slideably received in the periphery of an inner side opening part of the recessed hole 17, and tapered engagement parts 94, 94 engageable with a lock plate as later described are formed on its opposite sides. A block cam 95 projects from a skirt part of the engagement part 94. The block cam 95 has a flat cam end 66 engageable with a memory releasing link as later described. Cam edges 97, 97 project from the opposite sides of the cam end 96. One of the cam edges 97 is engageable with the memory releasing link at the time of turning operation of the block cam 95. In the Figures, reference numeral 98 denotes a pair of left and right threaded holes formed at the opposite sides of the block cam 95. A door suspending base setting thread (not shown) can be crewed in one of the threaded holes 98. Reference numeral 99 denotes a connection bolt received in an inner part of the turnable shaft 89, and a threaded shaft of the connection bolt 99 can be screwed in a threaded hole 100 of the door handle 4. The turnable shaft 90 is turnably inserted in the passage hole 102, and it has a pair of dogs 103 projecting from its one end face. This pair of dogs 103 can be fitted between a pair of dogs 105 projecting from one end part of the handle shaft 104 of the door handle 4. In the Figures, reference numeral 106 denotes a slide surface formed on a front end face of the driving cam 16. This slide surface 106 is slideably received in the bottom surface of the cam hole 101. Reference numeral 107 denotes a recessed hole which is formed at a lower part of the outer surface of the case 14. A seal rib 108 of the door handle 4 can be inserted in the recessed hole 107. Reference numerals 109, 110 denote threaded holes adapted to connect a pipe shaft which projects from the inner side of the case 14. Reference numeral 111 denotes a pair of right and left threaded holes disposed at upper and lower positions of the cam hole 101, and 112, a pair of left and right cutout grooves which are open to the peripheral surface of the lower part of the cam hole 101, respectively. Opposite ends of the cam spring can be hooked to the cutout grooves 112. The memory releasing link 113 is formed in a generally horizontal “U” shape from diecast zinc alloy, and it has, as shown in FIG. 31, an inner side surface which is engageable with the stepped part of the block main body 46. The memory releasing link 113 is provided with two kinds of pins 114, 115 projecting from opposite side surfaces of its opposite end parts. Of those two kinds of pins 114, 115, the pin 114 is engageably inserted in the long groove 27 of the back plate 13, and the other pin 115 is engageably inserted in the guide groove 59 of the block main body 46. Engagement arms 116, 117 project from the opposite end parts of the memory releasing link 113. Of those engagement arms 116, 117, the engagement arm 116 is arranged such that its outer peripheral part is engageable with the cam end 96 of the driving cam 16. In the Figures, reference numeral 116a denotes an engagement stepped part disposed at a distal end part of the engagement art 116 and engageable with a lock plate as later described. The engagement arm 116 is operatively connected to the turning motion of the driving cam 16 to thereby move the memory releasing link upward and move the block main body 46 or block assembly 15 outward, so that the engagement between the button gear 34 and the terminal gear 66 can be released. On the other hand, the engagement arm 117 is slideably received in a guide groove 118 which is formed at an upper part within the case 14, and it has an engagement projection 119 projecting from the inner side of its forward end part. The engagement projection 119 can be engaged with a changeover shaft as later described. In the Figures, reference numeral 120 denotes a set spring interposed between the engagement arm 117 and the inner side surface of the case 14 The memory releasing link 113 is biased downward through the elasticity of the set spring 120. Reference numeral 121 denotes a partition wall formed proximal to the guide groove 118. The partition wall 121 is engageable with the outer surface of the hook part 56 of the block main body 46. A shaft hole 122 is formed in a basal part of the partition wall 121. A front end part of the changeover shaft 123 is turnably supported by the shaft hole 122. The changeover shaft 123 is shaped in a rod-like shape from diecast zinc alloy. The changeover shaft 123 has two small and large cams 124, 125 which are slightly axially spaced apart and mutually diametrically projecting from its front end part. Those cams 124, 125 are placed in their horizontal postures when in locked, and released their engagement with the inner surface of the engagement arm 117. By the normal/counter-rotational turning operation of the changeover shaft 123, the changeover shaft 123 can be engaged with the inner surface of the engagement arm 117 of the memory releasing link 113. And at the time of engagement, the block main body 46 is separated outward to release the engagement between the terminal gear 66 and the button gear 34. At that time, an amount of separation displacement of the block main body 46 is set to an amount equal to the lengths of the cams 124, 125, so that empty lock can be used or the password number can be altered. That is, at the time of using of the empty lock, the changeover shaft 123 is counter-rotated through the changeover knob 6 to thereby bring the long side cam 125 into engagement with the inner surface of the arm 117 and bringing the block main body 46 sufficiently outward, so that the engagement between the terminal gear 66 and the button gear 34 can be released. Moreover, the engagement between the cutout groove 72 of the control cam 65 and the engagement claw of the control plate is released so that the door handles 4, 5 can be turned. On the other hand, at the time of altering the password number, the changeover shaft 123 is turned normally through the changeover knob 6 to bring the short cam 124 on the front end part side into engagement with the inner surface of the engagement arm 117, so that the block main body 46 is separated by an amount slightly smaller than at the time of using empty lock. Then, only the engagement between the terminal gear 66 and the button gear 34 is released, and the engagement between the cutout groove 72 of the control cam 65 and the engagement claw of the control plate is maintained to maintain the current memory information, so that alternation of the password number can be made. In the Figures, reference numeral 126 denotes a square shaft part which is formed on a front end part of the changeover shaft 123. The plate spring 127 is elastically pressurizeably disposed at the square shaft part 126, so that the turning angle of the changeover shaft 126 can be detected. The control plate 128 is swingable toward the door 1 side at the time of unlocking of the button-operated lock 2 where an engagement claw 129 of a control plate 128 is inserted between the hook plate 78 within the block main body 46 and the control cam 65 through the cutout groove 73, and the opening directions of the cutout grooves 72 of the respective control cams 65 are aligned. That is, the control plate 128 is, as shown in FIGS. 33 through 35, formed in a generally elongated rectangular plate shape by pressing a steel plate The control plate 128 has the same number of circular or semi-circular cutouts 130 as the number of the control buttons 10 which are formed at its lengthwise one side. The button retainer 25 can be received in the inner side of each cutout groove 130. An engagement claw 129 projects from an opening edge part of each cutout groove 130. The engagement claw 129 is removably inserted between the hook plate 78 within the block main body 46 and the control cam 65 through the cutout groove 73 A forward end part of the engagement claw 129 is acutely bent in the direction of the thickness of the control plate 128 and its bending end part can be engaged with the hook plate 78. In the Figures, reference numerals 131, 132 denote pivot parts projecting from one side end parts of the control plate 128. The pivot parts 131, 132 are pivotably received in an engagement groove 133 which is provided at an inner side end part of the case 14. A hooking wall 134 projects from the inner side end part of the back plate 13 in such a manner as to face with the opening edge part of the engagement groove 133 and pivotably supported by one side edge part of the control plate 128. That is, the control plate 128 is attached to the side parts within the back plate 13 and the case 14 such that it can swung in the back and forth direction about the hooking wall 134. A set spring 137 is interposed between a spring retainer 135 projecting from the surface of the control plate 128 and a spring retainer 136 formed on the case 14. The control plate 128 is backwardly swingably biased through the elasticity of the set spring 137. The engagement claw 129 is engageable with the control cam 65. A spring hanger 138 is diagonally bent to one end part in the longitudinal direction of the control plate 128, and one end of a lock spring 139 is hooked to the spring hanger 138 and the other end of the lock spring 139 is hooked to a lock plate 140. The lock plate 140 is shaped into a generally laterally long rectangular shape by pressing a steel plate. The longitudinal sectional configuration of the lock plate 140 is formed in a generally letter “Z” shape. A spring hanger 141 is upwardly press-worked in a generally ring-like shape at an intermediate part of the lock plate 140. The lock plate 140 has recessed engagement parts 142, 144, 145 formed at its forward end part. Of those engagement parts 142, 144 145, the engagement part 142 is engageable with the engagement stepped part 116a of the memory releasing link 113, and the remaining engagement parts 144, 145 are engageable with the head parts of left and right suspending base position setting machine screws 143. One end of the lock plate 140 is placed behind a lower end part of the control plate 128 and the other end is placed on the engagement stepped part 116a of the engagement arm 116. The engagement part 142 is engageable with the engagement stepped part 116a. Normally, the lock plate 140 is engageably biased to the control plate 128 through the elasticity of the lock spring 139. In the Figures, reference numeral 146 denotes an elongate rectangular protection plate which is made of a steel plate and which constitutes a first safety mechanism of the button-operated lock 2. The protection plate 146 is faced with the control hole 12 and vertically movably attached to the inner surface of the case 14. A plurality of through-holes 147 each having a same diameter as the control holes 12 are formed at one side end part of the protection plate 146 in such a manner as to correspond to the control holes 12, and elongate machine screw holes 148 are formed proximate thereto. The protection plate 148 is movably attached to the case 14 through machine screws and horizontal U-shaped metal pieces or washers (not shown), or the like. A spring retainer 149 whose end edge is bent at right angles is formed at the upper end part of the protection plate 146. A push spring 150 is interposed between the spring retainer 149 and the partition wall 121. The protection wall 146 is biased toward the driving cam 16 side through the elasticity of the push spring 150. An engagement piece 151 having a letter L-shape in section is formed at a lower end part of the protection plate 146. The end edge of the engagement piece 151 is engageable with the engagement stepped part 106a of FIG. 28 formed at a slide surface of the driving cam 16. Owing to this arrangement, the protection plate 146 can be moved up and down through the turning motion of the driving cam 16. That is, any evil attempt should be made to insert a control tool as later described into the control hole 12 and to turn the door handle 4 for unlocking by means of falsification or the like while in the locked position, such an unlocking operation would be prohibited by preventing the turning of the driving cam 16 due to engagement between the engagement piece 151 and the engagement stepped part 106a. In FIGS. 5 through 9, the protection plate 146 is attached to the guide groove 41 and the slide groove 42. It is also accepted that those grooves 41, 42, for example, are eliminated and those areas are flattened so that the protection plate 146 is slideably attached thereto and in addition, the protection plate 146 is attached as tightly as possible to the inner sides of the control holes 12. Thus, insertion of the control tool becomes impossible to thereby effectively prevent any attempt for picking. It is also an interesting alternative that as shown in FIG. 29, the engagement element 151 is interposed between the driving cam 16 and the case 16, and the engagement piece 151 is engaged with the engagement stepped part 106a. Accordingly, even if the driving cam 16 should be subjected to an enormous turning force given by a thief, the engagement piece 151 would not be bent and prohibit the driving cam 16 from turning. Thus, the picking prevention effect is more enhanced. In the Figures, reference numeral 152 denotes a recessed control mark and reference numeral 154 denotes a rod-like control tool which is used at the time of setting or inputting the password number and altering the same. The control tool 154 can be inserted in the control holes and through-holes 147. In the button-operated lock 2 thus constructed, a plurality of information can be set or inputted to each of the plurality of control buttons 10. Accordingly, a large number of password numbers can be obtained compared with the conventional technique in which only one memory information is set or inputted to a plurality of control buttons 10 and plural sorts of password numbers are obtained by changing the combinations of the control buttons 10. Since the range of selection can be widened, the safety performance can be enhanced and the number of the control buttons 10 can be reduced to that extent. Moreover, no reset button as later described is required contrary to the conventional technique. Thus, the number of component parts can be reduced and the structure can be simplified. In addition, the device according to the present invention can be manufactured easily and economically. Accordingly, the back plate 13 and the case 14 can be made short and small, and reduced in width. Thus, the invented device can be made compact and light weight, and the appearances of the button-operated lock 2 and the door 1 can be improved. Moreover, the backset dimensions LBS from the side end face of the door 1 to the center of the lock (not shown) can be made compact and thus, this lock can be suited to be used for a kitchen door. Moreover, in the button-operated lock 2, plural sorts of memory information can be set or inputted in accordance with the number of times of depressing operation of the control buttons 10. Accordingly, there is no worry, when compared with the conventional technique, for being perceived the memory information from the finger prints printed on the surfaces of the control buttons 10 and the wearing condition of the surfaces of the control buttons 10. Thus, the safety performance can be enhanced. Moreover, in the button-operated lock 2, the turning force of the door handles 4, 5 is transmitted to the memory releasing line 113 to move the block assembly 15 so that the engagement between the terminal gear 66 and the button gear 34 is maintained/cut off. Since the direct association of the door handles 4, 5 and the respective gears 34, 43, 66 is avoided, there is no worry that the password number is perceived by turning operation of the door handle 4. Thus, the safety performance can be enhanced in this respect, too. Furthermore, the protection plate 146 is attached to the back of the case 14 so that entry of a picking tool to the driving cam 16 through the control hole 12 can be prevented. Moreover, since the driving cam 16 cannot be turned by up and down motion of the protection plate 146 attempted from the outside, even if it is attempted, for example, to insert a picking wire through the control hole 12 to turn the driving cam 16, false unlocking operation can be prevented because the engagement piece 151 is engaged with the engagement stepped part 106a to prohibit the turning motion of the driving cam 16. Next, the procedure for making the button-operated lock 2 will be described. For example, the door handles 4, 5, the back plate 13, the case 14, the driving cam 16, the button case 33 and the button gear 34, the block main body 46, the memory releasing link 113, the changeover knob 123, etc. are shaped from diecast zinc alloy. The terminal gear 66, the set gear 43 and the control cam are molded from synthetic resin, the seat plate 3, the cover plate 47, the control plate 128, the lock plate 140, the protection plate 146, etc. are press-molded from a sheet metal, and the clutch shaft 67 is machined. At that time, the guide ring 31 is integrally molded with or press-fitted to the opening edge part of the button insertion hole 30 which is formed in the case 14. The procedure for reasonably assembling the component parts thus obtained will now be described. The block assembly 15 is preliminarily assembled. In that event, the same number, i.e., five (5), of the information altering units 48 as the control buttons 10 are assembled, and then the cover plate 47 is attached to the main body 46. The procedure for assembling each information altering unit 48 is made in the manner as shown in FIG. 21. Firstly, the first and second gear insertion holes 49, 50 are placed in such a manner as to face upward and the block main body 46 is set to an assembling jig (not shown). Next, the boss 74 is placed in such a manner as to face upward and the terminal gear 66 is retained by the boss 74. The clutch shaft 67 is inserted from below the stepped hole 75, the square shaft 79 is fitted to the square hole 76, and the upper part of the clutch shaft 67 is inserted in the machine screw hole 63 from below the cover plate 47. Then, the washer 68 and the set spring 69 are inserted in the clutch shaft 67 projecting from the cover plate 47, the threaded shaft of the information altering element 70 is screwed in the threaded hole 81 of the clutch shaft 67, and one set of the information altering units 48 only excluding the control cam 65 is attached to the cover plate 47. Similarly, other information altering units 48 are attached to the cover plate 47. Subsequently, the set spring 86 is inserted in the second gear insertion hole 50 of the block main body 46, one end of the set spring 86 is hooked to the spring retainer 54, the reset gear 43 is inserted in the spring 86 from above, and the inside pin 85 is inserted in the hook part 87 of the set spring 86. Then, the cover plate 47 with the information altering unit 48 assembled thereto is retained, the terminal gear 43 and the hook plate 78 of each information altering unit 48 are received in the first gear insertion hole 49 and the passage hole 53, the terminal gear 43 and its adjacent reset gear 43 are engaged with each other. The insertion hole 64 of the cover plate 47 is inserted in the boss 44 of the terminal gear 43, and the cover plate 47 is fixed to the block main body 46 by machine screws and then, the procedure is held in a standby state for assembling the same to the back plate 13 and the case 14. Next, the guide groove 41 and the slide groove 42 are placed in such a manner as to face upward, the case 14 is set to an assembling jig (not shown), and the seal rib 108 of the door handle 4 is inserted in the recessed hole 107. Then, the driving cam 16 with a cam spring mounted on the turnable shaft 90 is received in the cam hole 102 from the upper side of the case 14, and the turnable shaft 90 is inserted in the passage hole 102 and fitted with the dogs 103, 105. Then, the connection bolt 99 is screwed in the threaded hole 100 of the door handle 4, and the door handle 4 and the driving cam 16 are connected such that they can turn in synchronism. Thereafter, the suspending base position setting machine screw 143 is screwed in one of the threaded holes 98, 98 of the driving cam 16 depending on the suspending base position of the door 1. Then, the button case 33 is inserted in each guide ring 31 attached to the case 14 from the inner side, and the hooking element 35 is hooked to the opening edge part of the button insertion hole 30. This state is as shown in FIG. 10. The button gear 34 and the set spring 40 are inserted in the button case 33 in order and their dogs 36, 37 are engaged with each other. Furthermore, the protection plate 146 is attached to each guide groove 41 over the entire length of each guide groove 41 such that the protection plate 146 can slide in the longitudinal direction of the case 14. The push spring 150 is interposed between one of the spring retainers 149 and the partition wall 121, and the other engagement element 151 is brought into engagement with the cam end 96 of the driving cam 16. Then, the block assembly 15 is received onto the protection plate 146 with the cam groove 52 facing upward, and the shift spring 153 is interposed between the spring retainer 60 at the side end part of the block main body 46 and a side wall of the case 14. The front end part of the changeover shaft 123 is inserted in the shaft hole 122 of the case 14, and the plate spring 127 is engageably disposed proximate to the square shaft part 126. Then, the memory releasing link 113 is received onto the block main body 46, one of its pins 115, 115 is inserted in the guide grooves 59, 59 of the block main body 46, the engagement arm 117 is hooked to the changeover shaft 123, and a reset spring 120 is interposed between the engagement arm 117 and the inner side surface of the case 14. Thereafter, the set spring 137 is received in the spring retainer 136 of the case 14, the pin 135 is inserted in the set spring 137 to retain the control plate 128, its respective engagement claws 129 are inserted in the cutout parts 73 of the block main body 46, and its respective forward end parts are inserted in the passage hole 53 and the cam hole 52. Then, the control cam 65 is received in the cam hole 52 with the cutout groove 72 facing downward, the cam shaft 80 is inserted in its shaft hole 71, and the engagement claw 129 is received between the control cam 65 and the hook plate 78. The control plate 128 is preliminarily connected with the lock plate 140 through the spring retainers 134, 141 and the lock spring 138. One end part of the lock plate 140 is superimposed on the control plate 128, the engagement part 142 of the other end part is engagingly arranged at the engagement stepped part 116a, and the remaining engagement part 142 is engagingly arranged at the suspending base position setting machine screw 143. Thereafter, the threaded shaft of the pipe shaft is screwed in the threaded holes 109, 110 of the case 14, and one end of the connection bar 91 is engaged in the shaft part 92 of the driving cam 16. Subsequently, the back plate 13 is attached to the case 14 and the machine screws are screwed in the machine screw holes 19, 111 so that the back plate 13 and the case 14 are connected to each other. The button-operated lock 2 thus constructed has the plurality of control buttons 10 which are vertically one-sidedly arranged in one row one its surface, and the outer side door handle 4 are located at its lower end part. A vertically pair of pipe shafts project from its rear surface, the changeover shaft 123 projects from immediately above the pipe shaft on its upper side, and the connection bar 91 projects from immediately above the pipe shaft on its lower side. Of the passage holes 21, 22 opening to the back sheet 13, the head part of the door suspending base position setting machine screw 143 is located. The procedure for attaching the button-operated lock 2 thus constructed to the door 1 will now be described. An attachment hole, a vertically pair of pipe shaft insertion holes and an insertion hole for the changeover shaft 123 are formed in a side end part of the door 1, and the main lock is embedded in the attachment hole. Then, the button-operated lock 2 is placed at a predetermined position on the outer side of the door 1. The connection bar 91 is inserted in the square hole of the main lock and the pipe shaft is inserted in the pipe shaft insertion hole (not shown) so as to allow them to project inward of the door 1. On the other hand, the seat plate 3 is placed in a predetermined position on the inner side of the door 1 and a machine screw is screwed in the pipe shaft from the outer side of the seat plate 3 to attach the seat plate 3 to the door 1. The changeover knob 6 and a door handle 5 are preliminarily, tumably attached to the seat plate 3 through a stop ring or the like. The changeover knob 6 is engaged in the projected-part of the changeover shaft 123, and the forward end part of the connection bar 91 is engaged in the door handle 5. The button-operated lock 2 thus attached to the door 1 is as shown in FIGS. 1 through 3. The plurality of control buttons 10 are vertically arranged in one row on one side of the outer surface of the case 14. The plurality of through-holes 12 serving as the control holes are vertically arranged in one row at a generally central area of the outer surface of the case 14. The outer side door handle 4 is located at the lower end part of the outer surface of the case 14. The button-operated lock 2 is less in number of the control buttons 10 as previously mentioned. The reset button, which was conventionally needed, can be eliminated and therefore, the structure can be simplified. Since the entire device is compact, the appearance of the door 1 becomes good. In this case, there are two types In the first type of the button-operated lock 2, the password numbers are preliminarily set on the maker's side at random and then such a button-operated lock 2 is supplied to the client. In the second type of the button-operated lock 2, no password numbers are preliminarily set or inputted on the maker's side and such a button-operated lock 2 is supplied to the client. However, there are no substantial difference in those two types. Therefore, in order to avoid duplicated explanation, only the second type will be described hereinafter in which the password numbers are set or inputted on the client's side. Thus, the procedure for setting or inputting the password numbers on the maker's side is also executed substantially in the same manner as the manner described hereinafter. In the button-operated lock 2, each control button 10 is biased forward by the elasticity of the set spring 40, and the button case 33 is projected from the case 14 only excluding the hook element 35. In the button case 33, the hook element 35 is engaged with the inner side opening edge part of the button insertion hole 30, the guide rib 32 of the guide ring 31 is engaged between the hook elements 35, 35, the dog 36 is engaged with the dog 37 on the button gear 34 side received in the button case 33, the button gear 34 is engaged with the terminal gear 66 of the block assembly 15. This state is as shown in FIG. 18. The block assembly 15 is biased toward the button gear 34 side by the elasticity of the shift spring 153 to facilitate the engagement between the afore-mentioned gears 34, 66. The hook part 56 of the block main body 46 is engaged with the expanded part 57 of the case 14. The memory releasing link 11 is engaged with the block main body 46, the pin 115 of the link 113 is engaged with the guide groove 59 of the block main body 46, and the pin 114 is engaged with the long groove 27. The memory releasing link 113 is normally biased downward, i.e., toward the driving cam 16 side by the elasticity of the set spring 123, the lower side engagement arm 116 is engaged with the cam end 96 of the driving cam 16, and the upper side engagement arm 117 is in a position engageable with the changeover shaft 123. In the changeover shaft 123, the plate spring 127 is engaged and elastically contacted with the square shaft part 126, and the cams 124, 125 are normally in horizontal neutral positions. In each information altering unit 48 mounted on the block assembly 15, the clutch shaft 67 and the information altering element 70 are biased forward by the elasticity of the set spring 69, and the information altering element 70 is located behind the inner side opening edge part of the through-hole 12. The control cam 65 of the information altering unit 48 is located at the cam hole 52, and the engagement claw 129 of the control plate 128 is engaged between the control cam 65 and the hook plate 78. The control plate 128 is located sideways of the block assembly 15 on the opposite side to the memory releasing link 113 and behind the button gear 34. The control plate 128 is normally biased toward the back plate 13 side, i.e., toward the door 1 side by the elasticity of the set spring 137. Before the password numbers are set, as shown in FIG. 33, the cutout groove 72 of the control cam 65 is open in the same direction on the control plate 128 side, and the engagement claw 129 is engaged in the cutout groove 72 so that the control plate 128 is pushed and fallen backward. The lock plate 140 connected to the control plate 128 is pushed and fallen together with the control plate 128 against the elasticity of the set spring 137, and the engagement part 144 is disengaged from the suspending base position setting machine screw 143 to form a small gap therebetween. The driving cam 16, as shown in FIG. 17, is assembled to the case 14 with the cam end 96 facing upward, such that the driving cam 16 can turn by 90 degrees leftward and rightward. The inner and outer door handles 4, 5 can make the same movement as the driving cam 16. And those component parts are biased by the elasticity of the cam spring (not shown) so as to be turningly returned to their original positions. The protection plate 146, which constitutes the first safety mechanism of the button-operated lock 2, is slideably attached to the inner surface of the case 14. The engagement element 151 disposed at the lower end part is, as shown in FIG. 29, inserted between the case 14 and the driving cam 16, and then caused to engage the engagement stepped part 106a by the elasticity of the push spring 150. The respective through-holes 147 are located at the same positions as the corresponding control holes 12. In case predetermined password numbers, five (5) digit password numbers “12345” in this embodiment, are to be set or inputted to the button-operated lock 2 in the above-mentioned condition, no memory information is inputted to the respective control buttons yet, in other words, the memory information of the respective control buttons are all “0”. Since the numerical figures at the respective digits of the password numbers are larger than “0”, the password numbers can be set or inputted from the outer side of the door 1 which is in a closed position. The setting or inputting operation of the password numbers is executed in the following manner. The control tool 154 is inserted in the adjacent through-hole 12 which corresponds to each control button 10, the clutch shaft 67 is pushed down to release the engagement between square shaft 79 and the square hole 76, and the corresponding control button 10 is depressed while maintaining the above-mentioned state. In this case, since an independent unlocking operation is attained for every control button 10 by means of one set of the control button 10 and the terminal gear 66 and the reset gear 43 corresponding to the control button 10, the operation of the control button 10 can be made at random irrespective of the depressing order of the control buttons 10 and the clutch shaft 67. However, the operation of one set of the clutch shaft and the control button 10 must be made in an associated manner, and the control button 10 must be operated only after the clutch shaft 67 is depressed. Although the protection plate 146 is attached to the inner surface of the case 14, insertion of the control tool 154 is not interfered by the protection plate 146 because each through hole 147 is located at the same position as the control hole 12. That is, the control tool 154 is inserted in an optional through-hole 12. The control tool 154 is pushed in the through-hole 12 against the elasticity of the set spring 67, and the clutch shaft 67 is pushed down to push the square shaft 79 out of the square hole 76 so that their engagement is released. Thus, the terminal gear 66 is turnably supported by the clutch shaft 67, and the current turning angle, i.e., memory information, of the cam shaft 80 and the control cam 65 is maintained and the engaging relation among the terminal gear 6, the button gear 34 and the reset gear 43 is maintained. This state is as shown in FIG. 19. Under the above-mentioned condition, the control button 10 corresponding to the through-hole 12 is depressed. This depressing operation is made as follows. Since the password numbers are “12345” of five digits in this embodiment, when the control tool 154 is inserted in the through-hole 12 in the highest position, the highest control button 10 indicated by “1” in the button indication part 11 is depressed only once, so that the numerical FIG. 1 of the digit of 10000-places is set or inputted. When the control tool 154 is inserted in the second highest through-hole 12, the control button 10 indicated by “1” in the indication part 11 is depressed twice so that the numerical FIG. 2 of the digit of 1000-places is set or inputted. Similarly, when the control tool 154 is inserted in the third highest through-hole 12, the control button 10 indicated by “3” in the indication part 11 is depressed three times so that the numerical FIG. 3 of the digit of 100-places is set or inputted, when the control tool 154 is inserted in the fourth highest through-hole 12, the control button 10 indicated by “4” in the indication part 11 is depressed four times so that the numerical FIG. 4 of the digit of 10-places is set or inputted, and when the control tool 154 is inserted in the through-hole 12 in the lowest position, the control button 10 indicated by “5” in the indication part 11 is depressed five times so that the numerical FIG. 5 of the digit of 1-place is set or inputted. When, for example, the control button 10 in the highest position is depressed once, the button case 33 is pushed down along the guide rib 32 against the elasticity of the set spring 40 and the button gear 34 makes the same movement. This state is as shown in FIG. 20. When the hand is released from the control button 10, the button gear 34 is pushed forward by the elasticity of the set spring 40, and the cam 34 projecting from the gear 34 is engaged with the inner side end part of the adjacent guide rib 32 and makes a helical turn. Thus, the cam 39 is turned by an amount equal to one pitch of the guide rib 32, i.e., 45 degrees equal to two teeth of the button gear 34 and transmits its torque to the terminal gear 66 which is engaged with the button gear 34. On the other hand, the button gear 34 is further pushed out, and the guide rib 32 is engaged between the hook elements 35, 35 to stop the turning motion of the button gear 34, so that the turning angle of the button gear 34 is maintained. The hook element 35 comes into engagement with the opening edge part of button the insertion hole 30, and the button case 33 is returned to its original position. When the torque of the button gear 34 is transmitted to the terminal gear 66 as mentioned above, the terminal gear 66 is turned by 45 degrees, which are equal to two teeth, about the shaft of the clutch shaft 67 and transmits its torque to the reset gear 43 which is engaged with the terminal gear 66. Thus, the reset gear 43 is turned by an amount equal to two teeth and the boss 44 integral with the gear 43 moves together with the reset gear 43, so that the reset spring 86 hooked to its inside is twisted therein. Then, the elasticity of the reset spring 86 is acted on the terminal gear 66 through the reset gear 43 and biases the gear 66 so that the gear 66 can return to its original position. When the memory information “1” is set or inputted to the control button 10 in the highest position in the manner as mentioned above, the control tool 154 is pulled out of the through-hole 12 and the clutch shaft 67 is allowed to project forward to bring the square shaft 79 into engagement with the square shaft 76, so that the original state of the information altering unit 43 can be recovered. Thereafter, for example, at the time of setting or inputting the memory information “2” to the second highest control button 10, the control button 10 is depressed twice, the button gear 34 is turned by 90 degrees equal to four teeth of the button gear 34 to turn the terminal gear 66 and the reset gear 43, which are linked to the gear 34, by the above-mentioned angle portion, so that the reset spring 86 is twisted therein. Then, an amount of elasticity equal to the turning motion of 90 degrees of the reset gear 43 is accumulated in the reset spring 86, and the control tool 154 is pulled out of the through-hole 12. Similarly, the third highest control button 10 is depressed three times, the button gear 34 is turned by 135 degrees equal to six teeth portion of the button gear 34, so that an amount of elasticity equal to the turning motion of 135 degrees of the reset gear 43 is accumulated in the reset gear 86, and the control tool 154 is pulled out of the through-hole 12. Similarly, the fourth highest control button 10 is depressed four times, the button gear 34 is turned by 180 degrees equal to eight teeth portion of the button gear 34, so that an amount of elasticity equal to the turning motion of 180 degrees of the reset gear 43 is accumulated in the reset gear 86, and the control tool 154 is pulled out of the through-hole 12. Similarly, the control button 10 in the lowest position is depressed five times, the button gear 34 is turned by 225 degrees equal to ten teeth portion of the button gear 34, so that an amount of elasticity equal to the turning motion of 225 degrees of the reset gear 43 is accumulated in the reset gear 86, and the control tool 154 is pulled out of the through-hole 12. When all memory information has been set or inputted through the control button 10, the outer side door handle 4 is reset and the handle 4 is turned clockwise by approximately 90 degrees. By doing so, the driving cam 16, which moves together with the door handle 4, is turned clockwise in FIG. 17, the cam end 96 is brought into engagement with the engagement arm 116 of the memory releasing link 113, and the link 113 is pushed up against the elasticity of the set spring 120. The memory releasing link 113 pulls back the block main body 46 or block assembly 15 which forms the guide groove 59 which is in engagement with the pin 115 at the time of upward movement of the memory releasing link 113 leftward in FIG. 17 against the elasticity of the shift spring 153. Owing to this arrangement, the assembly 15 is brought away from the button gear 34, the engagement between the button gear 34 and the terminal gear 66 is released, and the engagement claws 129 of the control plate 128 are pulled away from the respective cutout grooves 73 of the block main body 46. By doing so, the terminal gear 66 and the reset gear 43 become ready to turn, the reset gear 43 is turnably returned by the elasticity of the set spring 86, that is, the reset gear 43 is turned in a direction reverse to that at the time of depressing operation of the control button 10, and the terminal gear 66 which is in engagement with the gear 43 is turned. The turning direction of the terminal gear 66 is the same direction as the turning direction at the time of the pressing operation of the button gear 34, its turning angle is in proportion to the amount of elasticity accumulated in the reset spring 86, and its angle displacement is transmitted to the cam shaft 80 through the square shaft 79 which is fitted to the square hole 76 formed in the gear 66. Owing to this arrangement, the cam shaft 80 is turned by an approximately same angle as the terminal gear 66, the control cam 65 which is fitted to the shaft 80 moves together with the cam shaft 80 to position the cutout groove formed in the cam 65. That is, the positions of the respective cutout grooves 72 are established in accordance with the elasticity of the reset spring 76 or each memory information. This state is as shown in FIG. 26 (b) through (f). As apparent from this illustration, the positions of the respective cutout grooves 72 are shifted from the position of FIG. 26(a), i.e., position of the memory information “0”, where the cutout groove 72 is engageable with the engagement claw of the control plate 128. Owing to this arrangement, the engagement claws 129 which are engaged in the respective cutout grooves 72 are contacted with the control cams 65, and the engagement claws 125 are sprung out from the cutout grooves 72 against the elasticity of the set spring 103 and held in their generally vertical postures between the control cams 65 and the hook plates 78, i.e., on a plane parallel to the door 1. Accordingly, one end of the lock plate 140 is pulled in the direction of the thickness of the control plate 128 by the elasticity of the lock spring 139 and superimposed on the control plate 128. The one end part of the lock plate 10 is engaged with the side wall of the case 14 and the engagement part 144 at the other end part becomes ready to engage the hanging base position setting machine screw 143. And the movement of the lock plate 140 is restrained. Consequently, the door handle 4 or driving cam 16 becomes unable to turn, and the button-operated lock 2 is locked. The procedure for unlocking the button-operated lock 2 will now be described. The outer side door handle 4 is reset to turn the handle 4 clockwise by approximately 90 degrees. By doing so, as mentioned previously, the driving cam 16 which moves together with the door handle 4 is turned counterclockwise in FIG. 17, and the cam end 96 is brought into engagement with the engagement arm 116 of the memory releasing link 113 to push up the link 113 against the elasticity of the set spring 120. The memory releasing link 113 pulls the block main body 46 or block assembly 15 having the guide groove 59 formed therein which guide groove 59 is in engagement with the pin 115, leftward in FIG. 17 during its upward movement, the assembly 15 is brought away from the button gear 34, the engagement between the button gear 34 and the terminal gear 66 is released, and the engagement claws 129 of the control plate 128 are pulled away from the respective cutout parts 73 of the block main body 46. By doing so, the terminal gear 66 and the reset gear 43 are ready to turn, the reset gear 43 turningly returned by the elasticity of the reset spring 86, the terminal gear 66 which is in engagement with the gear 43 is turned to cancel the state created by falsification and erroneous depression of the control buttons 10 at the time of unlocking operation conducted by a third party after the password numbers are set or inputted, and the state of the terminal gear 66 or cam shaft 80 at the time of setting or inputting the password numbers is recovered. That is, for example, when the control buttons 10 are depressed by falsification and erroneous operation made by a third party at the time of unlocking operation after the password numbers are set or inputted, the button gear 34 is turned by the number of times of depressing operation as mentioned above, and then the terminal gear 66 and the reset gear 43 are also turned so that the original password numbers are converted, thus making it unable to unlock the lock by unlocking operation using the regular password numbers. So, as mentioned above, resetting operation is conducted before unlocking operation is made. The reset gear 43 and the terminal gear 66 are turned by the elasticity of the reset spring 86 accumulated after the password numbers are set or inputted, so that the elasticity is consumed and a state at the time of setting or inputting the password numbers is recovered. The resetting operation is instantaneously made at the time of movement of the memory assembly 48. After the resetting operation is made, the memory assembly 48 is returned to the original position, the terminal gear 66 is engaged with the button gear 34, and the engagement claws 129 are engaged in the respective cutout parts 73. Since the turning angle between the reset gear and the terminal gear 66 at the time of resetting is established based on the elasticity of the reset spring 86 accumulated after the password numbers are set or inputted, the gears 43, 66 will never turn more than or less than the consumption of the elasticity. Thus, the password numbers established at the time of setting or inputting originally will not be altered. After the resetting operation is made, the password numbers “12345” are inputted from the outer side of the door 1 through the control buttons 10. That is, the control button 10 in the highest position is depressed once, the second highest control button 10 is depressed twice, the third highest control button 10 is depressed three times, the fourth highest control button 10 is depressed four times, and the control button in the lowermost position is depressed five times. In this case, since an independent unlocking operation is attained for every control button 10 by means of one set of the control button 10 and the terminal gear 66 and the reset gear 43 corresponding to the control button 10, the operation of the control button 10 can be made at random irrespective of the depressing order of the control buttons 10 for respective digits. By doing so, the button gears 34 corresponding to the respective buttons 10 are turned by 45 degrees, 90 degrees, 135 degrees, 180 degrees and 225 degrees, respectively, and the respective terminal gears 66 engaged with those button gears 34 are turned by the same angle but in the direction opposite to that of the button gears 34. In this case, since the turning direction of the terminal gears 66 is opposite to the turning direction at the time of resetting operation at the time of setting or inputting the password numbers and the turning angle is all same, the respective terminal gears 66 are turned in the opposite direction to the direction at the time of setting or inputting the password numbers and the turning angle at the time of setting or inputting the password numbers is offset so that the memory information is canceled. That is, the terminal gears 66 are all “zero” in turning angle, the respective control cams 65 or cutout grooves 73 are in the state as shown in FIG. 26(a), and the respective cutout grooves 73 become ready to engage the engagement claws 129 of the control plate 128. Owing to this arrangement, the forward end parts of the respective engagement claws 129 are engaged in the respective cutout grooves 173 by the elasticity of the set spring 137, the control plate 128 is pushed and fallen backward and slantwise as indicated by imaginary lines of FIG. 15, the lock plate 140 follows the control plate 128, and the engagement part 144 of the lock plate 140 is brought away from the door suspending base position setting machine screw 143. Thereafter, the door handle 4 is turned in the opening direction, that is, turned in the direction opposite to the resetting direction, the main lock is actuated to cause the deadbolt 8 backward through the connection bar 91 which moves together with the door handle 4. Thus, the door 1 is ready to open. In this case, the driving cam 16 is turned by turning the door handle 4 in the opening direction, the cam end 96 is brought into engagement with the engagement arm 116 to push up the memory releasing link 113, the memory assembly 15 is pulled toward the link 113, the engagement between the terminal gear 66 and the button gear 34 is released, the engagement claw 129 is pulled out of the cutout groove part 73, and then, the same operation as the resetting operation as mentioned above is performed. However, even if the gears 66, 34 are separated from each other, it is only small elasticity which is remained in the reset spring 86. This remaining small elasticity is not enough to turn the reset gear 43 and the terminal gear 66. Thus, the gears 43, 66 cannot be turned, and the same state as that at the time of resetting, i.e., the password numbers as set originally are maintained, and the smooth opening operation of the door 1 or smooth unlocking operation is not jeopardized. On the other hand, in case the door 1 is to be closed, the door handle 4 is turned in the closing direction, i.e., turned in the same direction as that at the time of resetting operation. At the time of closing the door 1, the latch trigger 9 is retracted to actuate the main lock, so that the deadbolt 8 is projected to lock. Here again, although the same operation as the afore-mentioned resetting operation is made by the turning the door handle 4 in the closing direction, the gears 43, 66 cannot be turned by the same reason as mentioned above. Thus, the same state as that at the time of resetting, i.e., the password numbers as originally set or inputted are maintained, and the smooth opening operation of the door 1 or smooth unlocking operation is not jeopardized. In case the door 1 is to be opened from the inner side, the door handle 5 may simply be turned in the opening direction. That is, when the door handle 5 is turned in the opening direction, its inside connection bar 91 is moved together with the door handle 5 and the main lock is actuated by the bar 91 to cause the deadbolt 8 to move backward. Thus, the door 1 is ready to open. In this case, since the other end of the connection bar 91 is non-engageable with the driving cam 16, the driving cam 16 is not turned by turning operation of the door handle 5 in the opening direction, and no resetting operation is made. The same is truth when the door 1 is to be closed from the inner side. That is, the main lock is actuated to project the deadbolt 8, thus making the door 1 ready to be closed. Next, in case the button-operated lock 2 is used as the so-called empty lock, that is, in case the door 1 is to be opened/closed by turning operation of the door handle 4, 5 without the need of operating the buttons for unlocking, the changeover knob 6 is turned and the changeover shaft 123 which is directly linked to the changeover knob 6 is moved together with the changeover knob 6, the cam 125 on the long side is engaged with the inner surface of the engagement arm 117 to push up the memory releasing link 113 against the elasticity of the set spring 120, and this state is maintained. By doing so, the memory releasing link 113 pulls the block main body 46 or block assembly 15 which forms the guide groove 59 which is in engagement with the pin 115, leftward in FIG. 17 against the elasticity of the shift spring 153 during the upward movement of the memory releasing link 113, the assembly 15 is separated from the button gear 34, the engagement between the button gear 34 and the terminal gear 66 is released, and the engagement claws 129 of the control plate 128 are pulled away from the respective cutout parts 73 of the block main body 46. That is, the same operating state as the resetting operation is realized through the operation of the changeover knob 6 while maintaining the password numbers. By doing so, the control plate 128 is biased backward by the reset spring 137 in a state parallel to the plane of the door 1, the lock plate 140 is moved together with the control plate 124, the engagement part 144 and door suspending base position setting machine screw 144 become ready to engage each other, and the other end part becomes ready to engage the side wall of the case 14, so that the turning direction of the door handle 4 is restricted to one direction. Accordingly, when the door handle 4 is turned in a predetermined direction, the main lock is actuated, and the deadbolt 8 is projected/retracted so that the door 1 becomes ready to open/close. The same is true with the inner side door handle 5. In case the password numbers for the button-operated lock 2 in use are to be altered for the sake of security, alternation can be made safely, rationally and rapidly only if the password numbers before alternation are known. For example, in case the password numbers “12345” of this embodiment are to be altered to “33357”, in other words, in case the numerical figures at the respective digits of the passwords number after alternation are all larger than those of the password numbers before alternation (including a case wherein the difference between the numerical figures at some same digits is zero (0)), alternation can be made from the outer side of the door 1 easily and rapidly while holding the door 1 in a closed position. That is, in this case, first, the door handle 4 is turned to make a resetting operation, so that any falsification applied to the button-operated door 2, erroneous depression of the control buttons 10, etc. are deleted and the password numbers before alternation are recovered. After resetting, the block assembly 15 is returned to its original position and the respective terminal gears 66 and the button gears 34 are engaged with each other so that the original state can be recovered. Then, the password numbers before alternation are inputted to the respective control buttons 10, and the corresponding control buttons 10 are depressed by the number of the password numbers before alternation. By doing so, the respective control buttons 10 are turned by an angle obtained by multiplying 45 degrees to the number of times of depression, and the terminal gears 66 engaged with the respective control buttons 10 are turned by the same angle in the opposite direction, so that the turning angle at the time of setting or inputting the password numbers can be offset and the original memory information can be deleted. That is, the terminal gears 66 are all placed in a state in which the turning angle of the terminal gears 66 is zero (0), the respective control cams 65 or cutout grooves 73 are held in the state as shown in FIG. 26(a). In that state, the respective cutout grooves 73 become ready to engage the engagement claws 129 of the control plate 128. Under the above circumstance, the control buttons 10 corresponding to the altered digits of all the password numbers after alternation, and the through-holes 12 are operated. That is, the control tool 154 is inserted into the corresponding through-holes 12 from the outer side of the door 1 and pushed therein against the elasticity of the set spring 67 so that the clutch shaft 67 is pushed down and the square shaft 79 is pushed out of the square hole 76 for releasing their engagement. By doing so, the terminal gears 66 are turnably supported on the clutch shafts 67, the current turning angle of the cam shafts 80 and the control cams 65, i.e., memory information can be maintained, and the engagement relation among the terminal gears 66, the button gears 34 and the reset gears 43 can be maintained. In this case, since each clutch shaft 67 is merely pushed down and not turned, the position of the cutout groove 72 of the cam shaft 80 or control cam 65 is held in the same position as that before the clutch shaft 67 is pushed down and the turning angle corresponding to the memory information before alternation is maintained. And while maintaining the pushing state of the control tool 154, the corresponding control buttons 10 are depressed by the difference between before and after alternation of the numerical figures at respective digits of the password numbers. For example, in case the password numbers “12345” before alternation of this embodiment is to be altered to “33357”, the control button 10 of the digit of 10000-places, in other words, the control button 10 in the highest position is depressed twice which is equal to the difference between the numerical figures “1” and “3” before and after alternation. By doing so, the button gear 34 corresponding to the control button 10 is turned by 90 degrees which correspond to 4-teeth, and then, the terminal gear 66 which is engaged with the button gear 34 and the reset gear 43 which is engaged with the gear 66 are turned, so that elasticity equal to the turning amount of the reset gear 43 is accumulated in the reset spring 86. After the memory information of the control button 10 in the highest position is altered in the manner as just mentioned, the control tool 154 is pulled out of the through-hole 12, the clutch shaft 67 is projected forward, and the square shaft 79 is engaged with the square hole 76. In this way, the original state of this specific information altering unit 48 is recovered. Then, for example, the control button 10 of the digit of 1000-places, in other words, the control button 10 in the second highest position is depressed once which is equal to the difference between the numerical figures “2” and “3” before and after alternation. By doing so, the button gear 34 corresponding to the control button 10 is turned by 45 degrees which correspond to 2-teeth, and then, the terminal gear 66 which is engaged with the button gear 34 and the reset gear 43 which is engaged with the gear 66 are turned, so that elasticity equal to the turning amount of the reset gear 43 is accumulated in the reset spring 86. After the memory information of the control button 10 in the second highest position is altered in the manner as just mentioned, the control tool 154 is pulled out of the through-hole 12, the clutch shaft 67 is projected forward, and the square shaft 79 is brought into engagement with the square hole 76. In this way, the original state of this specific information altering unit 48 is recovered. Similarly, the control button 10 of the digit of 10-places, in other words, the control button 10 in the fourth highest position is depressed once which is equal to the difference between the numerical figures “4” and “5” before and after alternation, and the control button 10 in the digit of 1-place, in other words, the control button 10 in the lowest position 10 is depressed twice which is equal to the difference between the numerical figures “5” and “7” before and after alternation. By doing so the respective button gears 34 are turned by 45 degrees and 90 degrees. Since the numerical FIG. 3 of the digit of 100-places is not altered, the corresponding control button 10 is not required to depress. After the memory information of all the corresponding control buttons 10 is altered, the outer side door handle 4 is reset, the handle 4 is turned clockwise by approximately 90 degrees so that the driving cam 16 is turned together with the handle 4. Thus, the cam end 96 is brought into engagement with the engagement arm 116 of the memory releasing link 113 to push up the link 113 against the elasticity of the set spring 120. The memory releasing link 113 pulls the block main body 46 or block assembly 15 leftward in FIG. 17 through the guide groove 59 which is in engagement with the pin 115 against the elasticity of the shift spring 153 during the upward movement of the memory releasing link 113, the assembly 15 is separated from the button gear 34, the engagement between the button gear 34 and the terminal gear 66 is released, and the engagement claws 129 of the control plate 128 are pulled away from the respective cutout parts 73 of the block main body 46. By doing so, the terminal gear 66 and the reset gear 43 become ready to turn, the reset gear 43 is turningly returned by the elasticity of the reset spring 86, in other words, the reset gear 43 is turned in the opposite direction to that at the time of depressing the control button 10, and the terminal gear 66 which is in engagement with the gear 43 is turned. The turning direction of the terminal gear 66 is the same direction as the turning direction at the time of the pressing operation of the button gear 34, its turning angle is in proportion to the amount of elasticity accumulated in the reset spring 86, and its angle displacement is transmitted to the cam shaft 80 through the square shaft 79 which is fitted to the square hole 76 formed in the gear 66. Thus, the cam shaft 80 is turned by approximately same angle as the terminal gear 66, and the control cam 55 fitted to the shaft 80 is moved together with the shaft 80, so that the cutout groove 72 formed in the cam 65 can be established. That is, the cutout groove 72 or cam shaft 80 after alternation of the memory information is set to the position obtained by adding the turning angle caused by the memory information altering operation to the turning angle before alternation of the memory information. As apparent from the above, at the time of alternation of the password numbers in which the memory information at the respective digits are increased, in other words, at the time of alternation of information in which the button gear 34 is turned in the same direction as that at the time of setting or inputting the information, the respective control buttons 10 are depressed by the number of times which is equal to the difference of the numerical figures before and after alternation of the respective digits from the outer side of the door 1 while closing the door 1. That is, since alternation is made on the basis of the password numbers before alternation, the person who can perform the alternation operation is limited to the particular person(s) who know the password numbers. Thus, safety is ensured. Moreover, the number of times of depressing the control buttons 10 is decreased compared with the conventional technique in which the password numbers before alternation are once canceled and then the password numbers after alternation are newly set or inputted once again. Thus, the troublesome work is much lessened, and the alternation operation of the password numbers can be made simply and rapidly. On the other hand, in case the password numbers “12345” are to be altered to “54321”, in other words, in case a part of all of the numerical figures at the respective digits of the password numbers after alternation are smaller than those before alternation, that is, at the time of altering the information in which the button gear 34 is turned in the opposite direction to that at the time of setting or inputting the information, the password numbers can be altered safely and rapidly while opening the door 1. In this case, in the same manner as in the above-mentioned operation for altering the numbers, first, the door handle 4 is turned to make a resetting operation, so that any falsification applied to the button-operated door 2, erroneous depression of the control buttons 10, etc. are deleted and the password numbers before alternation are recovered. After resetting, the block assembly 15 is returned to its original position and the respective terminal gears 66 and the button gears 34 are engaged with each other so that the original state can be recovered. Then, the password numbers before alternation are inputted to the respective control buttons 10, and the corresponding control buttons 10 are depressed by the number of the password numbers before alternation. By doing so, the respective control buttons 10 are turned by an angle obtained by multiplying 45 degrees to the number of times of depression, and the terminal gears 66 engaged with the respective control buttons 10 are turned by the same angle in the opposite direction, so that the turning angle at the time of setting or inputting the password numbers can be offset and the original memory information can be deleted. Under the above circumstance, the control buttons 10 corresponding to the altered digits of all the password numbers after alternation, and the through-holes 12 are operated. Of all the password numbers after alternation, the numerical figures “5” and “4” of the digits of 10000-places and 1000-places larger than those before alternation. Thus, as previously mentioned, the corresponding control buttons 10 are depressed by the number of times equal to the difference between the numerical figures at the digits before and after alternation, so that the elasticity is accumulated in the corresponding reset springs 86. Since the numerical figure “3” at the digit of 100-places is unchanged before and after alternation, no altering operation is required. Next, since the numerical figures “2” and “1” of the digits of 10-places and 1-place are smaller than those before alternation, a different operation from that just mentioned is required. That is, the changeover knob 6 is turned from the inner side of the door 1 to turn the changeover shaft 123 linked to the changeover knob 6, the cam 124 on the short side is brought into engagement with the inner surface of the engagement arm 117 to push up the memory releasing link 113, the block assembly 15 linked to the memory releasing link 113 is pulled toward the outer side, and the terminal gear 66 is pulled away from the button gear 34 to release the engagement therebetween. In this case, since the push-up displacement of the memory releasing link 113 is smaller by the short portion compared with the cam 215, the movement displacement of the block assembly 15 is also small. Therefore, only the engagement between the terminal gear 66 and the button gear 34 is released but the engagement between the cutout groove 72 and the engagement claw 129 is maintained so that the memory information before alternation is maintained. Under the above circumstance, the control tool 154 is inserted into the through-holes 12 corresponding to the digit of 10-places, i.e., the through-hole 12 in the fourth highest position and pushed therein against the elasticity of the set spring 67 so that the clutch shaft 67 is pushed down and the square shaft 79 is pushed out of the square hole 76 for releasing their engagement. By doing so, since the terminal gears 66 are turnably supported on the clutch shafts 67, the reset gear 43 is turning returned by the elasticity accumulated in the reset spring 86 which elasticity corresponds to the memory information before alternation and the terminal gear 66 is turned following the motion of the reset gear 43, so that the accumulated elasticity is consumed. Thereafter, the changeover knob 6 is reversely turned to reversely turn the changeover shaft 123 which is associated therewith, the memory releasing link 113 is pushed back by the elasticity of the set spring 120, the block assembly 15 is returned to the original position, the terminal gear 66 and the button gear 34 are engaged with each other, and the engagement claw 129 is engaged with the cutout groove 72. After the memory information resetting operation is made with respect to the control button 10 corresponding to the digit of 10-places, the control tool 154 is inserted in the through-hole 12 and pushed further therein against the elasticity of the set spring 67, the clutch shaft 67 is pushed down to push the square shaft 79 out of the square hole 76, so that their engagement is released, and the terminal gear 66 is rotatably set to the clutch shaft 67. And while maintaining the engagement released relation between the square shaft 79 and the square hole 76, the control button 10 in the fourth highest position corresponding to the digit of 10-places is depressed twice which corresponds to the memory information “2” after alternation, its button gear 34 is turned 90 degrees, and the terminal gear 66 and the reset gear 43 are operatively connected thereto, so that the corresponding amount of elasticity is accumulated in the reset spring 86. Thereafter, the control tool 154 is pulled out of the through-hole 12, the square shaft 79 is fitted to the square hole 76 to integrally connect the clutch shaft 67 and the terminal gear 66 together. By doing so, the substantial memory information altering operation is finished with respect to the digit of 10-places. Next, the memory information altering operation corresponding to the digit of 1-place is substantially same as the altering operation with respect to the digit of 10-places only except that the number of times of depressing the control button 10 is 1. After the operation for altering the memory information of the respective digits is finished in the manner as mentioned above, the door handle 4 is turned for resetting operation to release the engagement between the button gears 34 and the terminal gears 66 once, the reset gears 43 are turningly returned by the elasticity accumulated in the respective reset springs 86, the terminal gears 66 are operatively connected thereto, so that the position of the clutch shaft 67 or control cam 65 is set to the memory information position after alternation. By doing so, a series of altering operation is completed. As apparent, since the operation for altering the memory information requires to make operation of the changeover knob 6 or changeover shaft 123 from the indoor side, falsification, which would otherwise be possible as in the conventional technique in which the altering operation can be made from the outdoor side, can be prevented from occurring. In the above-mentioned embodiment, 8 sorts of memory information 0 through 7 can be set or inputted to the control buttons 10, and in correspondence to this, square holes 76 and square shafts 79 each having an octagonal shape are formed at the terminal gear 66 and the clutch shaft 67. However, 10 sorts of memory information 0 through 10 or even larger sorts of memory information may be inputted by freely using setting information other than numerical figure, for example, alphabetical letters. In that case, the square hole 76 and the square shaft 79 may be formed in a polygonal shape having a larger number of sides and angles. FIGS. 37 through 51 show other embodiments of the present invention. Corresponding component parts to those of the above-mentioned embodiment are denoted by same reference numeral. Of those Figures, FIGS. 37 through 50 show the second embodiment of the present invention which includes an improvement in design of the above-mentioned embodiment and some other improvements. That is, the door handles 4, 5 are formed in a generally circular cylindrical shape or generally disc-like shape. Its mode of use is changed from a grip type to a handle type for the sake of easy turning operation. Moreover, the number of the control buttons 10 is changed from 5 to 4, and the button-operated lock 2 is made small in size and light in weight. Of the two door handles 4, 5, the outer side door handle 4 is provided with a second safety mechanism for the button-operated lock 2, so that the door handle 4 and the inside mechanism of the lock linked to the handle 4 is protected from a thief trying to apply excessively large torque to the handle 4. In addition, the button-operated lock 2 is made small in size and light in weight and the structure is simplified. That is, the door handle 4 includes thick grip parts 4a, 5a radially projecting from the outer surface of a disc-like handle main body, and a recessed hole 155 formed in its inner end face. A pair of spring receiving holes 155 are formed in the bottom surface of the recessed hole 155. Set springs 157 are received in the spring receiving holes 156. The balls 158 are biased inward by the elasticity of the set springs 157 so that the balls 158 sit on a ball retainer 159. The connection bolts 99 are biased outward by the elasticity of the set spring 157, and the head part 99a of the connection bolt 99 is engaged with the stepped part of the recessed hole 160. The driving cam 16 is capable of moving together with the door handle 4 by the engaging force, i.e., contact surface pressure between the connection bolt 99 and the recessed hole 160. The recessed hole 160 is circular, and the circular cylindrical head part 99a is turnably received in the recessed hole 160. The ball retainer 159 is interposed between the recessed hole 155 and the recessed hole 107 of the case 14. The ball retainer 159 is formed in a thick generally disc-like shape from diecast zinc alloy. The ball retainer 159 has a passage hole 161 formed in its central area. This passage hole 161 is adapted to allow the connection bolt 99 to insert therein. A pair of engagement holes 162 are formed in the outer side of the passage hole 161. Each engagement hole 162 is tapered such that the hole 162 is gradually enlarged in diameter toward the outer side. The ball 158 is engageably received in the tapered surface of the hole 162. The balls 158, 158 are larger in pitch than the conventional comparable balls and they are engaged with the engagement holes 162 with larger parts thereof projected from the holes 172, so that the balls 158 are readily escaped from the engagement holes 162 when excessively large torque of the door handle 4 acts thereon. In the Figures, reference numeral 163 denotes a pair of locking projections arranged in their opposing relation and faced with the inner side opening edge of the passage hole 160, and the dog 103 is engaged therebetween so that the driving cam 16 and the ball retainer 159 can move together. The two balls 158 are pressed against the engagement hole 162 of the ball retainer 159 by the set springs 157. The head part 99a of the connection bolt 99 is engaged with the stepped part of the recessed hole 160 by the elasticity of the set springs 157, and the driving cam 16 is made movable together with the door handle 4 by their engaging force. Accordingly, when the button-operated lock 2 is in the unlocked position where the engagement between the engagement part 144 of the lock plate 140 and the suspending base position setting machine screw 143 is released and the driving cam 16 is turnable, the door handle 4 and the driving cam 16 are synchronously turned. At that time, the ball retainer 159 is also synchronously turned through the locking projection 163 which is engaged with the dog 103 of the driving cam 16. On the other hand, when the button-operated lock 2 is in the locked position where the engagement part 144 of the lock plate 140 and the suspending base position setting machine screw 143 are engaged with each other and the driving cam 16 is non-turnable, if the door handle 4 is turned with excessively large torque by, for example, a thief, connection bolt 99 is turned with its head part 99a engaged with the stepped part of the recessed hole 160, and the door handle 4 is turned idly. At that time, the ball 158 is engaged with the engagement hole 162 to enhance the idling turning of the door handle 4 while the spring receiving hole 156 and the engagement hole 162 are in opposing relation. When the spring receiving hole 156 is moved from the engagement hole 162, the ball 158 comes into engagement with the opening edge part of the spring receiving hole 156 and raked into the spring receiving hole 156 from the engagement hole 162. When the spring receiving hole 156 and the engagement hole 162 are not aligned, the ball 158 in the spring receiving hole 156 is rollingly moved on the ball retainer 159 to enhance the idling turning of the door handle 4. Thus, even in case the door handle 4 is subjected to excessively large torque, breakage of the door handle 4 and breakage of the inside mechanism of the button-operated lock 2 linked to the door handle 4 can be prevented from occurring, and safety thereof can be maintained. Moreover, since the ball retainer 159 as an important member of the second safety mechanism is formed in a plate-like shape and compact compared with the conventional barrel shaped-one, a mechanism or button-operated lock 2 of this type can be made thin and compact. The number of the balls 158 and the set springs 157 is reduced. Since the number of the component parts are reduced, the construction can be simplified. Moreover, the pitch of the balls 158 can be enlarged compared with the conventional ones, the door handle 4 can be increased in torque and made large in size, and its operability is enhanced. Next, the guide grooves 59, 59 formed at the block main body 46 include generally chevron-like locking projections 164, 164 formed in same phase on one end part side thereof. At the time of locking of the button-operated lock 2, the projections 164, 164 are engageable with the pins 115, 115 projecting from the memory releasing link 113. The above arrangement constitutes the third safety mechanism for the button-operated lock 2. That is, the locking projection 164, as shown in FIG. 44, is formed on one end part side, i.e., on the driving cam 16 side, of the guide groove 59. When the button-operated lock 2 is in the locked position, this projection 164 is engageable with the pin 115 located at one end part of the guide groove 59 and adapted to prohibit the pin 115 from moving upward. The locking projection 164 allows the pin 115 to move between its forward end part and the other side edge of the guide groove 59 Also, the locking projection 164 makes it possible to unlock the button-operated lock 2. The third safety mechanism is functioned, for example, when a thief tries to make an abnormal unlocking operation without making a resetting operation, when the button-operated lock 2 is in the locked position where the pin 115 is positioned on one end part side of the guide groove 59 and engageable with the locking projection 164 and the pin 115 is prohibited from moving upward. That is, when the button-operated lock 2 is in the locked position, if an attempt is made such that, for example, the control tool 154 or similar false tool is pushed in the through-hole 12 and further pushed in the input receiving part 82 of the information altering element 70 and swung leftward and rightward about the through-hole 12, so that the block assembly 15 or block main body 46 with the information altering element 70 built therein is separated from the button gear 34 against the elasticity of the shift spring 153, and in that condition, the control buttons 10 are properly depressed, there is a fear that the lock 2 is accidentally unlocked. In that case, the block assembly 115 or block main body 46 is moved in the direction as indicated by an arrow of FIG. 44, the right side opening edge part of the guide groove 59 is engaged with the pin 115, and the pin 115 is engaged with the locking projection 164 so that the pin 115 or memory releasing link 113 is prohibited from moving upward. Accordingly, the block assembly 15 or block main body 46 and the button gear 34 are prohibited from being separated from each other, thereby prohibiting the button-operated lock 2 from being unlocked. Moreover, as mentioned above, since the engagement element 151 at one end of the protection plate 146 is brought into engagement with the engagement stepped part 106a of the driving cam 46 to prohibit the driving cam 46 or door handle 4 from turning, the false unlocking operation can positively be prevented with the help of the above-mentioned arrangement. Thus, safety and security of the button-operated lock 2 is ensured for actual use. On the other hand, when the button lock 2 is in the locked position, the block main body 46 is biased upward and rightward in FIG. 44, i.e., toward the control 128 side by the elasticity of the shift spring 153, and the left side opening edge part of the guide groove 59 is engaged with the pin 115 or becomes ready to engage the pin 115. Thus, thereafter, when the resetting operation is made to turn the door handle 4 in the manner as already mentioned to normally unlock the button-operated lock 2, the pin 115 is moved upward as indicated by the imaginary lines in FIG. 44. The pin 115 passes through the side of the locking projection 164 and moves upward along the left side opening edge part of the guide groove 59. That is, the memory releasing link 113 is moved upward without allowing the pin 115 to engage the locking projection 164, so that the block main body 46 is pulled leftward in FIG. 17 and the block main body 46 is separated from the button gear 34 to realize the previously-mentioned unlocked-state. Accordingly, the resetting operation is not interfered by the locking projection 164. In this embodiment, a part of the construction of the preceding embodiment is improved. That is, the shape of the shaft hole 71 in plan view of the information altering cam 65 which constitutes the information altering unit 48 is formed into an elongate rectangular shape from the generally half-moon shape, and the sectional shape of the cam shaft 80 of the clutch shaft 67 inserted in the shaft hole 71 is formed in the same shape as the shaft hole 71. The square shaft 79 projecting from the hook plate 78 of the clutch shaft 67 is formed into a generally diamond shape from the regular octagonal shape, an arcuate guide surface 79a is formed at each of the opposite end parts on the enlarged-diameter side of the square shaft 79 so as to facilitate the smooth engagement with the square hole 76 of the terminal gear 66, and the square hole 76 is formed into a generally gear-like shape having eight teeth from the regular octagonal shape. In this case, although the opposite end parts on the enlarged-diameter side of the square shaft 79 is engaged with the square hole 76, only one end part of the enlarged-diameter side of the square shaft 79 may be engaged therewith. The operation of the terminal gear 66, the clutch shaft 67 and the information altering cam 65 of this embodiment is substantially same as that of the preceding embodiment. In this embodiment, a plurality of bending elements 165 are formed on one side of the protection plate 146, and machine screws 166 are screwed into the case 14 in the vicinity of the moving area of the bending elements 165 such that the side surfaces of the head parts 166a are ready to engage the bending elements 165. Owing to this arrangement, the protection plate 146 is restricted its swinging motion and the movement of the projection plate 146 can be made in a stable manner. In the illustration, reference numeral 167 denotes the afore-mentioned cam spring; and 168 denotes setscrews which can be screwed into the threaded holes 109, 110. A hexagonal hole is formed at one end of each setscrew 168. One end of a pipe shaft 169 is screwed into the setscrew 168, and a fixing machine screw (not shown) for the use of connection is screwed into the other end of the setscrew 168. Reference numeral 170 denotes a check mark shaped in a recessed-shape at the opening part of the elongate hole 24. Four check marks 170 are arranged at equal angular positions (90 degrees), so that the position (angle) of the clutch shaft 80 exposed to the outside of the elongate hole 24 can reliably and easily be confirmed. In this way, since the memory numbers or memory information of the control buttons 10 can be known correctly, information can be set or altered reliably and easily. Moreover, since the sectional shape of the clutch shaft 80 is formed in an elongate rectangular shape in this embodiment, the position of the shaft 80 can be confirmed correctly. FIG. 51 is the third embodiment of the present invention, showing another mode of use in which the button-operated lock 2 according to the second embodiment is modified so as to be suited to apply to the kitchen door instead of the entrance door 1. This embodiment is obtained by symmetrically constructing the button-operated lock 2 according to the second embodiment by 180 degrees. Specifically, the inner and outer door handles 4, 5 are arranged at the upper side of the case 14 or seat plate 3, the control buttons 10 are arranged at the right side of the case 14 when viewed in the direction of the front surface of the case 14, the button indication part 11 is arranged at the left side, and the respective control holes 12 are arranged slantwise upward of the corresponding control buttons 10. In this embodiment, the various component parts are substantially same as the second embodiment and they can be commonly used. The manner for assembling and attaching them is also substantially same as in the second embodiment. However, in case a main lock (not shown) to be attached to the kitchen door is different from the main lock for use of the entrance door 1, the attaching manner is, as a matter of course, different, depending on the type of the main lock. As apparent from the above, the button-operated lock 2 according to this embodiment can be obtained by symmetrically constructing the lock 2 of the second embodiment by 180 degrees while commonly using the component parts. Moreover, its design or outer appearance can selectively and easily be changed in accordance with the conditions of attaching the lock 2 and the circumstance under which the lock 2 is used. Industrial Applicability A button-operated lock according to the present invention is capable of increasing a setting amount of information in response to operation of a control button, obtaining a large setting amount and a wide-range of selection thereof, enhancing safety performance, simplifying the structure and achieving a small size and a light-weight, thereby achieving a low manufacturing cost, executing such various operations as setting or inputting information and altering thereof correctly, safely, easily and rationally, and preventing decoding or perceiving of preset or inputted information so that any third party is prevented from making a falsification and/or conversion of this device.

<SOH> BACKGROUND ART <EOH>Recently, a keyless lock of the type requiring the use of no key has been popularized as a door lock to be used for individual dwelling houses, companies, shops, hospitals and the like. As a keyless lock of the type mentioned above, there are a so-called mechanical lock in which the locking and unlocking procedure is made by a structural means and an electric or electronic lock in which the locking and unlocking procedure is made by an electrical means. Of these two types of keyless locks, the mechanical lock, when compared with the electronic or electric lock, has such advantages that there is no worry about power failure or battery exhaustion because no wiring work is required, the user of such a lock is free from electrical trouble such as malfunction, and in addition, the mechanical strength is large. The mechanical lock, in general, includes a plurality of control buttons. Memory information corresponding to the control buttons is stored in association with a cam or link mechanism or a gear train, the memory information of the respective control buttons is combined by the same number as the number of the control buttons, and a password number consisting of the number of digits of the control buttons is set or inputted. At the time of unlocking, the control buttons corresponding to the password number are operated so that the lock can be unlocked. For example, in the invention disclosed in Japanese Patent Publication No. S62-54951 the present applicant previously filed, the respective control buttons are inserted in the slits formed in a case frame in their erected or inverted states, and the numbers of the respective control buttons are set to 1 or 0, i.e., two modes of either “set” or “unset”. Then, it is selectively decided whether the number setting for the respective control buttons is necessary or not so that the password number can be set or inputted by a combination of the corresponding numbers. At the time of unlocking, the control buttons for which the number setting has been made are depressed to engage the slits formed in those buttons with the keyplate. On the other hand, the control buttons for which the number setting has not been made are not depressed to maintain the engagement relation between the slits and the keyplate. Owing to this arrangement, the cam pin can be turned to allow the handle to turn, so that the lock can be unlocked. However, in this conventional device, since only two modes, i.e., number setting and number unsetting, can be obtained for each control button and the setting amount of information for each control button is limited, the number of the password number depends on the number of the control buttons and thus, a sufficient setting amount of information is unobtainable. Since the range of selection thereof is limited, a large enough safety performance is unobtainable. In order to solve those problems, if the number of the control buttons should be increased, the number of the component parts would be increased to that extent. Thus, the construction and the locking and unlocking procedure becomes complicated, and the case frame and the packing plate become large in size, thus resulting in large size and heavy weight of the entire button-operated lock. Moreover, the outer appearance of the door is degraded. Those problems are also common in U.S. Pat. No. 3,115,765. That is, the lock disclosed in the above U.S. patent includes a generally elongate box-like casing. This casing is retractably provided at a face plate thereof with a plurality of key systems which are linked to the control buttons. A plurality of shafts are turnably suspended in the longitudinal direction of the casing. The respective gears are engageably arranged in such a manner as to face with the key system positions of those shafts. The gears are intermittently turned through the pressing operation of those key systems. A control shaft, which is linked to a door handle is disposed at one end of the casing. A slide plate is provided in such a manner as to be engageable with a cam disposed at the control shaft. A plurality of engagement elements disposed at the slide plate are engageable with and disengageable from the respective gears which are fixed to the above-mentioned shaft. The memory system by the key system can be stored in the gear train or reset. However, the lock taught by the above U.S. patent has the following problems. Since each control button can set only a single memory information, a combination of memory information achievable through each control button is limited, and selection of password numbers and safety performance are limited. Moreover, since the number setting of the control buttons is linked to the number setting of the adjacent control buttons and the password number is stored in order of the setting input, the number setting lacks in versatility and the smooth execution of the locking and unlocking procedure is jeopardized. Moreover, since the turning force of the door handle acts on the slide plate, it can easily be perceived whether or not memory setting has been made through the respective control buttons. This, together with the above-mentioned disadvantage in limitation of the memory capacity, tends to create such a fear that repeated evil attempt should be made on the control buttons, the lock could be unlocked comparatively easily. On the other hand, a long time use of a same password number leads gives a chance to a third party to perceive and decode the number. This is not desirable in view of protection of the password number. Therefore, it is desirable that the password number is altered frequently. However, since the alternation mechanism and operation thereof requires a time-consuming troublesome work in view of its structure, the simplification and easiness are demanded. For example, the lock proposed by the present applicant in Japanese Patent Publication No. S62-54951 is designed such that at the time for altering the password number, a case frame and a packing plate, which are arranged at the inside and the outside of the door, is removed therefrom, the corresponding control buttons are pulled out in their exposed states, and inserted into a slit in their erected or inverted states and then reassembled. However, this method has such problems that since the case frame and the backing plate are required to be detached from the door and the buttons are required to be detached or replaced, complicated and time-consuming work is required. In the lock of the above-mentioned U.S. Pat. No. 3,115,765, at the time for altering the password, the control buttons are operated to set or input the current password number and thereafter, the slide plate is moved to release the engagement between the engagement element and the groove. After the current password number is canceled, the control buttons are operated to set or input a new password number. This method, when compared with the above-mentioned method, has such advantages that the troublesome work for removing the related parts from the door is no more required and thus, this operation can be made in a simple and convenient manner. However, it has such a problem that since the password number can be altered from the outside of the door, the third party can make a falsification relatively easily. Therefore, uneasiness in relation to protection and security occurs. It is, therefore, a main object of the present invention, to provide a button-operated lock which is capable of solving the above-mentioned problems and in which the amount of information to be set to the control buttons is increased, a large setting amount of information and its wide selection can be obtained, and safety performance can be enhanced. Another object of the present invention is to provide a button-operated lock, in which the structure can be simplified and made compact and light-weight, and the manufacturing cost can be reduced. A further object of the present invention is to provide a button-operated lock, in which the setting or inputting of information to the control buttons, as well as an altering operation thereof, can be made correctly, safely, easily and rationally. A still further object of the present invention is to provided a button-operated lock, in which decoding or perceiving of information, which would otherwise be made by the third party relatively easily, is prohibited so that the third party is prevented from making a falsification and/or conversion of such information. A yet further object of the present invention is to provide a button-operated lock, in which a criminal unlocking procedure, which would otherwise be made by the third party comparatively easily through a control hole formed in a case, can be prevented from occurring.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a perspective view showing one embodiment of the present invention, in which a button-operated lock according to the present invention is mounted on an entrance door. FIG. 2 is a front view showing the button-operated lock according to the present invention, in which the lock is mounted on the entrance door. FIG. 3 is a left side view of FIG. 2 . FIG. 4 is a perspective view showing an essential part of the present invention in an exploded manner. FIG. 5 is a front view showing a case and a protection plate to which the present invention is applied. FIG. 6 is a sectional view taken on line A-A of FIG. 5 . FIG. 7 is a sectional view taken on line B-B of FIG. 5 . FIG. 8 is a sectional view taken on line C-C of FIG. 5 , additionally showing an attaching state of a control button to the button-operated lock. FIG. 9 is a sectional view taken on line D-D of FIG. 5 . FIG. 10 is a perspective view showing a control button to which the present invention is applied, in an exploded manner. FIG. 11 is a perspective view showing an assembling state of a block assembly to which the present invention is applied, in which a case is omitted. FIG. 12 is a sectional view taken on line E-E of FIG. 11 , in which a part of a back plate is omitted. FIG. 13 is a sectional view taken on line F-F of FIG. 11 , in which a part of the back plate is omitted. FIG. 14 is a sectional view taken on line G-G of FIG. 11 , in which a part of the back plate is omitted. FIG. 15 is an enlarged sectional view taken on line H-H of FIG. 11 . FIG. 16 is an enlarged sectional view taken on line I-I of FIG. 11 . FIG. 17 is a front view showing an assembling state of the present invention, in a simplified manner. FIG. 18 is an enlarged sectional view taken on line J-J of FIG. 17 , showing a state in which a control tool is not yet inserted. FIG. 19 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 18 and in which the control buttons are not yet depressed. FIG. 20 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 19 and in which the control buttons are already depressed. FIG. 21 is a perspective view showing the block assembly to which the present invention is applied, in an exploded manner. FIG. 22 is a sectional view taken on line K-K of FIG. 21 . FIG. 23 is an enlarged sectional view taken on line L-L of FIG. 21 . FIG. 24 is a front view showing a terminal gear to which the present invention is applied. FIG. 25 is a sectional view taken on line M-M of FIG. 24 . FIG. 26 is an explanatory view showing a relation between a control cam to which the present invention is applied and a cutout groove thereof, and a cam shaft and memory information in sequential order. FIG. 27 is a perspective view showing a state of a driving cam to which the present invention is applied. FIG. 28 is a perspective view showing a state of the driving cam to which the present invention is applied, but when view from the opposite side of FIG. 27 . FIG. 29 is a sectional view taken on line N-N of FIG. 27 , showing an assembling state of the driving cam to which the present invention is applied and a door handle on the outdoor side. FIG. 30 is a sectional view taken on line O-O of FIG. 27 . FIG. 31 is a perspective view showing a memory releasing link to which the present invention is applied. FIG. 32 is a perspective view showing a changeover shaft to which the present invention is applied. FIG. 33 is a front view showing an assembling state of the memory releasing line to which the present invention is applied and a control plate. FIG. 34 is a perspective view showing a control plate to which the present invention is applied and a lock plate, in which an assembling state thereof is shown. FIG. 35 is an enlarged sectional view taken on line P-P of FIG. 34 . FIG. 36 is a front view showing an assembling state of the control plate to which the present invention is applied and a block main body. FIG. 37 is a perspective view showing a button-operated lock according to the second embodiment of the present invention, in which the button-operated lock is mounted on the entrance door. FIG. 38 is a perspective view showing an essential part of the button-operated lock according to the second embodiment in an exploded manner, in which a back plate is omitted. FIG. 39 is a perspective view showing the button-operated lock according to the second embodiment in an exploded manner, in which a case is omitted. FIG. 40 is a perspective view showing, in an exploded manner, a block assembly which is applied to the button-operated lock according to the second embodiment. FIG. 41 is a sectional view showing an essential part of a safety mechanism of a door handle which is applied to the button-operated lock according to the second embodiment. FIG. 42 is a sectional view showing an essential part of a ball retainer which is applied to the safety mechanism of the door handle according to the second embodiment. FIG. 43 is a front view showing an essential part of the safety mechanism which is applied to a block main body according to the second embodiment, in which a guide groove and a pin are in engagement relation. FIG. 44 is a front view showing an essential part of FIG. 43 on an enlarged basis. FIG. 45 is a sectional view showing an assembling state of an information altering unit which is applied to the second embodiment. FIG. 46 is a sectional view taken on line Q-Q of FIG. 45 . FIG. 47 is a perspective view showing a control cam which is applied to the second embodiment. FIG. 48 is a sectional view of a terminal gear which is applied to the second embodiment. FIG. 49 is a front view showing a crutch shaft which is applied to the second embodiment. FIG. 50 is a plan view of FIG. 49 . FIG. 51 is a perspective view showing a button-operated lock according to the third embodiment of the present invention, in which the button-operated lock is attached to a kitchen door. detailed-description description="Detailed Description" end="lead"?

20040218

20080108

20050428

75267.0

BOSWELL, CHRISTOPHER J

BUTTON LOCK

SMALL

ACCEPTED

ACCEPTED

Use of lh in controlled ovarian hyperstimulation

The invention provides a new use for LH, and analogues having LH-activity for aiding folliculogenesis in controlled ovarian hyperstimulation (COH), in which the LH or an analogue thereof is administered during a priming period lasting from day 1 to about day 4 of the stimulatory phase in COH.

1. A method of inducing multiple folliculogenesis in a human patient, comprising administering luteinising hormone (LH) or an analogue thereof during a priming period lasting from day 1 to about day 4 of the stimulatory phase in COH. 2. The method according to claim 1, wherein the medicament is administered in the absence of administration of exogenous FSH in the priming period. 3. The method according to claim 1, wherein the medicament is administered at a dosage of about 20-400 IU LH/day, about 100-200 IU LH/day or about 150 IU LH/day. 4. The method according to claim 1, wherein the priming period lasts from day 1 to day 3 of the stimulatory phase. 5. The method according to claim 1, wherein the priming period lasts from day 1 to day 2 of the stimulatory phase. 6. The method according to claim 1, wherein the medication is to be administered as a single dose on day 1 of the stimulatory phase. 7. (Cancelled) 8. The method according to claim 1, wherein the LH is rhLH. 9. A method for inducing multiple folliculogenesis in a human patient, comprising administering human chorionic gonadotropin (hCG) or an analogue thereof, during a priming period lasting from day 1 to about day 4 of the stimulatory phase of COH. 10. The method according to claim 9, wherein the hCG or an analogue thereof is administered in the absence of administration of exogenous FSH in the priming period. 11. A pharmaceutical composition for enhancing folliculogenesis comprising LH or an analogue thereof, at a daily dose of 20-400 IU LH, to be administered from day 1 to about day 4 of the stimulatory phase in COH. 12. A method for determining the response of a patient to FSH in COH, the method comprising the steps of: (A) measuring androgen concentration in the patient to yield a basal value A1; (B) administering LH at about 20 to about 400 IU to the patient; (C) measuring androgen concentration in the patient at least once after administering LH, about 6 or more hours after administering LH, to yield a value A2; (D) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in androgen levels. 13. The method according to claim 12, wherein the amount of LH that is administered in step (B) is about 150 IU. 14. The method according to claim 12, wherein in step (C) the androgen concentration is measured several times over a period of 24 hours. 15. The method according to claim 12, wherein the androgen that is measured is androstenedione. 16. The method according to claim 15, wherein a good responder is a patient showing an increase in serum androstenedione levels after 24 hours of about 2 nmol/L or more. 17. A method for determining the response of a patient to FSH in COH, the method comprising the steps of: (A) measuring estrogen concentration in the patient to yield a basal value E1; (B) administering LH at about 20 to about 400 IU to the patient; (C) administering FSH at about 5 to about 300 IU to the patient, at least about 6 hours after administering LH; (D) measuring estrogen concentration in the patient, at least about 12 hours after administering FSH, to yield the value E2; (E) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in estrogen levels (E2-E1). 18. The method of claim 17, wherein the amount of LH that is administered in step (B) is about 150 IU. 19. The method of claim 17, wherein the amount of FSH that is administered in step (C) is about 150 IU. 20. The method of claim 17, wherein the estrogen concentration is measured several times over a period of 24 hours. 21. The method of claim 17, wherein the estrogen that is measured is estradiol. 22. The method of claim 21, wherein a good responder is a patient showing an increase in serum estradiol levels after 24 hours of about 5 pmol/L or more. 23. A kit for the induction of folliculogenesis in a human patient, the kit comprising one to five daily doses of 20-400 IU of LH, or an equivalent dose of an analogue thereof, and about six or more daily doses of FSH, or an analogue thereof.

FIELD OF INVENTION The invention relates to the field of in vivo and in vitro assisted reproduction technologies (ART), specifically controlled ovarian hyperstimulation (COH) using gonadotropins. BACKGROUND OF THE INVENTION Numerous infertile patients undergo ovulation induction procedures every year. Up until two decades ago ovulation induction was used solely for the treatment of anovulatory infertility; however, the introduction of assisted reproduction technology (ART) has expanded the use of these procedures to eumenorrheic women, with the goal of achieving multiple folliculogenesis. For assisted reproduction techniques (ART), such as in vitro fertilisation (IVF) or IVF in conjunction with intracytoplasmic sperm injection (IVF/ICSI) and embryo transfer (ET), oocytes are collected from a female patient immediately prior to ovulation. The oocytes are fertilised in vitro, the resulting embryos are evaluated, and selected for implantation. Fertilisation will not occur for every oocyte, and not every fertilised oocyte will develop into a viable embryo. Furthermore, implantation may fail to occur. Because of the many possibilities for an unsuccessful outcome, and the relatively invasive nature of oocyte collection, it is desirable to maximise the number of oocytes collected. For this reason, ART is typically carried out using controlled ovarian hyperstimulation (COH) to increase the number of oocytes1. Standard regimens2 for COH include a down-regulation phase in which endogenous luteinising hormone (LH) is down-regulated by administration of a gonadotropin releasing hormone (GnRH) agonist followed by a stimulatory phase in which follicular development (folliculogenesis) is induced by daily administration of follicle stimulating hormone (FSH), usually at about 150-225 IU/day. Other molecules having FSH activity may also be used. Alternatively stimulation is started with FSH after spontaneous or induced menstruation, followed by administration of a GnRH-antagonist (typically starting around day six of the stimulatory phase). When there are at least 3 follicles>16 mm (one of 18 mm), a single bolus of hCG (5-10,000 IU) is given to mimic the natural LH surge and trigger ovulation. Oocyte recovery is timed for 36-38 hours after the hCG injection. The rationale for the use of GnRH analogues, e.g. agonists or antagonists, in this context is the prevention of an untimely LH surge which can cause premature ovulation and follicle luteinisation3. It has consistently been found that long GnRH agonist regimens (i.e., those started in the midluteal phase of the cycle preceding ovulation induction, or before) are associated with easier patient scheduling, greater follicle yield, and overall better clinical results.4 The use of antagonists is relatively new to the clinic, but it is expected to yield similar benefits, with the advantage of a shorter dosing period. The prolonged administration of GnRH agonists or the administration of GnRH antagonists results in profound suppression of endogenous LH throughout the cycle, in the case of an agonist, or late in the stimulatory phase, with an antagonist. This situation, while not incompatible with follicle development, does not mimic the natural cycle. In the natural cycle, LH levels show a gradual increase several days before the large peak at midcycle. Many groups have investigated the importance of LH during the stimulatory phase of COH and ovulation induction regimens. As is well known and recognised in the art, techniques or methods of ovulation induction (01) are distinct from methods of COH, although both may involve the administration of FSH. Filicori et al. has investigated the role of low doses of hCG, as a surrogate for LH, in folliculogenesis and ovulation induction5. hCG was given (50 IU hCG/day), starting synchronously with FSH administration. This regimen was continued on a daily basis until ovulation was triggered with a bolus of hCG. The numbers of small (<10 mm), medium (10-14 mm) and large (>14 mm) follicles were comparable between a group receiving hCG and a control group receiving FSH alone, however, the cumulative dose of FSH and the duration of FSH stimulation were reduced in the hCG treated group. WO 00/67778 (Applied Research Systems) proposes the use of LH during the stimulatory phase. In one study, patients were administered FSH and LH in the early stimulatory phase, and then either both FSH and LH or just LH during the late stimulatory phase. In another study, patients were administered FSH alone in the early stimulatory phase and then LH in the late stimulatory phase. It was suggested that LH in the late stimulatory phase is responsible for atresia of non-dominant follicles. The regimen is proposed to encourage the development of a single dominant follicle. The administration of rhLH (75 and 225 IU/day) for supporting rhFSH-induced follicular development in hypogonadotrophic hypogonadal women is reported by the European Recombinant Human LH Study Group to promote estradiol secretion, enhance the effect of FSH on follicular growth, and permit the successful luteinisation of follicles when exposed to hCG, as compared to a regimen of FSH alone6. The LH was administered starting on the same day as FSH stimulation, and was continued until hCG administration to trigger ovulation. Sullivan et al. report that LH late in the stimulatory phase sustains follicular estradiol production when FSH is withdrawn7. Sills et al. report a study in which patients suffering from infertility of various types were treated with either FSH or FSH and 75 IU rhLH throughout the stimulatory phase. The authors conclude that the addition of exogenous LH throughout ovulation induction does not materially alter cycle performances. Ben-Amor et al.9 and Werlin et al.10 have examined the effect of administering rhLH during the second half of the follicular phase in normally ovulatory patients with a long down regulation regimen, and Williams et al.11 have studied the effect of administering different doses of r-hLH during the whole FSH stimulation. No substantial clinical benefits were reported in these patient groups. In COH regimens using FSH, some patients (“poor responders”) fail to respond to the initial doses of FSH, and the treatment cycle may be abandoned, and a new cycle started with a higher initial dose of FSH. Other groups of patients require repeated cycles because they fail to become pregnant even though oocyte recovery is successful. If repeat cycles are necessary, there may be adverse physical and emotional effects on the patient. Each repeat cycle entails a tremendous disruption in the life of the infertile couple. It would be desirable to have a method that would permit the same or improved follicular response to COH using decreased FSH doses or decreased dosing periods. It would also be desirable to have a diagnostic test which could determine which patients may be poor or sub-optimal responders, and which patients may respond on a decreased FSH dose. SUMMARY OF THE INVENTION It is an object of the invention to provide an improved regimen for COH. It is a further object of the invention to provide a method for providing multiple follicles for multiple oocyte recovery for ART. It is a further object of the invention to provide a method for determining which patients may show a good, poor or sub-optimal response to FSH in COH. In a first aspect, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for the manufacture of a medicament for inducing multiple folliculogenesis in a human patient, wherein the medicament is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Viewed alternatively, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for the manufacture of a medicament for inducing multiple folliculogenesis in a human patient, wherein the medicament is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. In a second aspect, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for inducing multiple folliculogenesis in a human patient, wherein the LH is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Viewed alternatively, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for inducing multiple folliculogenesis in a human patient, wherein the LH is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase of COH. In a third aspect, the invention provides a pharmaceutical composition comprising LH or an analogue thereof, at a daily dose of 20-400 IU LH, to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Preferably the medicament or pharmaceutical composition (comprising LH or an analogue thereof) is to be administered from day 1 to day 4, preferably from day 1 to day 3 or most preferably from day 1 to day 2 of the stimulatory phase. Single daily doses of medicament or pharmaceutical compositions may be administered. Alternatively the medicament or pharmaceutical composition may be administered as a single dose on day 1 of the stimulatory phase. Preferably the pharmaceutical compositions of the invention are designed for use in the methods and uses of the invention. In a fourth aspect, the invention provides a kit for the induction of folliculogenesis in a human patient, the kit comprising one to five daily doses of 20-400 IU of LH, or an equivalent dose of an analogue thereof, and at or about six or more daily doses of FSH, or an analogue thereof. Thus, the kits of the invention may comprise or consist of one, two, three, four or five daily doses of LH, or an analogue thereof, and at or about six or more daily doses of FSH, or an analogue thereof. Appropriate daily doses of LH and FSH are described elsewhere herein. Preferred kits may comprise two, three or four daily doses of at or about 150 IU of LH or 225 IU of LH and eight to twelve daily doses of at or about 150 IU FSH. Preferably the kits of the invention are designed for use in the methods and uses of the invention. In a fifth aspect, the invention provides a method for determining the response of a patient to FSH in COH, the method comprising the steps: (A) measuring androgen concentration in the patient to yield a basal value A1; (B) administering LH at about 20 to about 400 IU to the patient; (C) measuring androgen concentration in the patient at least once after administering LH, at or about 6 or more hours, or preferably at or about 12 or more hours, after administering LH, to yield a value A2; (D) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in androgen levels. Alternatively, as will be described in more detail below, in step (C) of the above method androgen levels/concentrations may be monitored/measured at least once over a period of time after the LH administration, and one or more of these measurements of androgen levels may be taken within the first six hours after the administration of LH, e.g. after 1 hour, and then subsequent measurements may be taken at one or more later time points, to yield a value A2. Generally the measurements are taken over a period of 24 hours after LH administration. In a sixth aspect, the invention provides a method for determining the response of a patient to FSH in COH, the method comprising the steps: (A) measuring oestrogen concentration in the patient to yield a basal value E1; (B) administering LH at about 20 to about 400 IU, to the patient; (C) administering FSH at about 5 to about 300 IU to the patient, at or about 6 or more hours, or preferably at or about 12 or more hours, more preferably at or about 24 or more hours after administering LH; (D) measuring oestrogen concentration in the patient, at or about 12 or more hours after administering FSH, to yield the value E2; (E) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in oestrogen levels (E2-E1). Alternatively as will be described in more detail below, in step (D) of the above method oestrogen levels/concentrations may be monitored/measured at least one over a period of time after the FSH administration, and one or more of these measurements of oestrogen levels may be taken within the first twelve hours after the administration of FSH, e.g. after 6 hours, and then subsequent measurements may be taken at one or more later time points, to yield a value E2. In all the above described methods for determination, the measurements of oestrogen and androgen levels are preferably carried out in vitro on a sample taken from an appropriate patient. A further aspect of the invention provides LH or an analogue thereof for inducing multiple folliculogenesis in a human patient, wherein the LH, or an analogue thereof is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. A further aspect of the invention provides LH or an analogue thereof for inducing multiple folliculogenesis in a human patient, wherein the LH, or an analogue thereof, is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. In a yet further aspect, the present invention provides a method of inducing multiple folliculogenesis in a patient, which method comprises the administration of LH or an analogue thereof to the patient, wherein said administration is carried out from day 1 to at or about day 4 of the stimulatory phase in COH. In a further aspect, the present invention provides a method of inducing multiple folliculogenesis in a patient, which method comprises the administration of LH or an analogue thereof to the patient, wherein said administration is carried out during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the administration of LH (or an analogue thereof in order to induce multiple folliculogenesis or otherwise improve COH regimens in a human patient, in terms of for example increasing the number of retrieved embryos which show early cleavage and thereby have a higher chance of implantation and pregnancy, an increase in the number of follicles of over 15 mm on the day of ovulation triggering, a higher ratio of large follicles to small follicles on the day of ovulation triggering and a greater number of oocytes. Thus, the invention can also be viewed as providing improved COH regimens which result in increased or improved implantation and/or pregnancy rates in a human patient, for example compared to a patient or group of patients undergoing conventional COH regimens. It has surprisingly been found that the administration of a comparatively short regimen of LH starting at the beginning of the stimulatory phase, and followed by FSH administration in a COH treatment has the effect of enhancing multiple folliculogenesis and generally improving the COH regimen in terms of for example increasing the number of retrieved embryos which show early cleavage and thereby have a higher chance of implantation and pregnancy, an increase in the number of follicles of over 15 mm on the day of ovulation triggering, a higher ratio of large follicles to small follicles on the day of ovulation triggering and a greater number of oocytes. Moreover, it is possible to decrease the dose of FSH that is required to achieve multiple follicular development in a patient. The technique has been called “LH priming”. The period in which LH is administered is termed the priming period. For the purposes of this description, the beginning of the priming period defines the beginning of the stimulatory phase. It is believed that LH interacts with receptors on theca cells of the developing follicle, stimulating the production of androgens. Oestrogen synthesis requires the availability of androgens as aromatase substrates. It is believed that the increased local concentration of androgens induced by LH enhances the action of FSH on the growing follicle. Where LH is used or administered in the aspects of the invention described herein the dosage may be in the range of from at or about 20 to at or about 400 IU, preferably from at or about 5 to at or about 300 IU or from at or about 75 IU to at or about 225 IU, more preferably from at or about 100 IU to at about 200 IU or from at or about 75 IU to at or about 150 IU LH, most preferably at or about 150 IU. Alternative dosages may be from at or about 150 IU to at or about 300 IU LH, preferably at or about 225 IU LH. Preferably these doses are daily doses. If an LH analogue is used, the equivalent to these LH doses can be calculated and administered. Where FSH is used or administered in the aspects of the invention described herein the dosage may be in the range of from at or about 5 to at or about 300 IU, preferably from at or about 100 to at or about 250 IU, most preferably at or about 150 IU. Alternative doses of FSH may be at or about 75-600 IU, 75-450 IU, preferably at or about 150-375 IU, more preferably at or about 300 IU. Preferably these doses are daily doses. If an FSH analogue is used, the equivalent to these doses can be calculated and administered. In a preferred protocol, a GnRH agonist is administered to the patient, in a dosage sufficient to attain suppression of ovarian function. Appropriate methods to obtain such suppression are well known and documented in the art and any of these can be used, for example, a single injection of 3.75 mg of depot Triptorelin, or daily doses of Buserelin or leuprolide acetate can be used. Suppression of ovarian function may be monitored by monitoring LH or estradiol levels (LH<5 IU/L, E2<50 pg/ml generally indicate quiescence). The stimulatory phase can be started with daily injections of LH (for example at the doses described above, e.g. about 20-400 IU, and preferably at 150 IU or 225 IU). After about 3 to 4 days, for example after 2.5 days, 3 days, 3.5 days, 4 days or 4.5 days, LH administration is ceased and FSH is given (for example at the doses described above, usually about 50-300 IU/day). FSH administration is generally continued until ultrasound imaging reveals at least 3 follicles>16 mm (one of 17 mm or 18 mm or more). Ovulation is triggered with a bolus of hCG (5'000-10'000 IU). In an alternative preferred protocol FSH and LH administration can overlap by one day, i.e. FSH can be administered on the last day of LH administration. A single administration of LH or an analogue thereof may suffice, and FSH administration may be commenced simultaneously, or preferably, the following day. When a single dose of LH is administered, it should preferably be about 20-400 IU LH. Alternatively, LH may be administered for up to a total of four days, e.g. the LH (or analogue) may be administered from day 1 up to at or about day 4 or from day 1 up to at or about day 3 or from day 1 up to at or about day 2. In such cases preferably the LH is administered on a daily or semi-daily basis, for example at the doses described above. FSH administration may be started simultaneously with LH administration, or may overlap for three, two or one day, but preferably begins after LH administration has ceased or with only one day of overlap. In other words, in preferred embodiments LH is administered in the absence of administration of exogenous FSH in the priming period. Preferred doses of FSH and LH in this regard are again described above. The daily doses need not be equal. For example, in a preferred regimen, on day 1 a dose of 150-300, preferably 225 IU LH may be given, on day 2, a dose of 75-225, preferably 150 IU LH may be given, and on days 3 and 4, doses of 75-225, preferably 75-150 IU LH may be given. Alternatively, the daily doses may be equal and in an alternative preferred regimen daily doses of 225 IU LH may be given. The preferred routes for gonadotropin administration are well known and documented in the art and are by subcutaneous, intramuscular or intravenous injection. Analogues may be administered by subcutaneous, intramuscular or intravenous injection, or orally, transdermally, rectally or intranasally as appropriate for the analogue in question. An LH priming regimen may also be used in conjunction with treatment with a GnRH antagonist rather than a GnRH agonist. The stimulatory phase is started by administration of LH (as described above) in the late luteal phase of the previous cycle (preferably days 23-26, or about three days prior to the anticipated start of menses). Then FSH is given, as above, starting on day 1-3 of menstruation (without previous administration of a GnRH agonist). Then, on about FSH stimulation day 6, a GnRH antagonist is administered, for example Antide, Azaline B, Cetrorelix, Ganirelix or Antarelix. Ovulation is triggered with a bolus of hCG. Usually the antagonist is administered until the day of hCG administration. Preferably LH and FSH administration do not substantially overlap, for example it is preferred that they overlap for not more than three days, more preferably not more than two days and most preferably not more than one day. More preferably FSH administration begins after LH administration has ceased, i.e. there is no overlap. In order to better predict the start of menses, it may be desirable to administer a contraceptive pill to the patient for about one month, prior to starting the LH priming regimen. Withdrawal of the contraceptive is usually followed by menses about two or three days later. If a contraceptive pill is used, LH priming may be started on the day that the pill is withdrawn. Ultrasound imaging may be used throughout the stimulatory phase to monitor the development of follicles. The use of LH in the early stimulatory phase of a COH regimen can permit the reduction of total FSH dose that is used, as compared to a COH regimen without LH. For example, the usual dose of FSH that is used without previous LH administration, is in the range of 100-250 IU/day, usually about 150 IU/day. With LH priming, if follicular response is judged sufficient, the FSH dose may be reduced to for example a dose of less than 150 IU/day, or less than 100 IU/day, for example a dose of 50-140 IU/day or 50-90 IU/day. Alternatively the same or lower daily dose may be used, and ovulation triggered earlier than is the case without LH priming, meaning that the cumulative FSH dose is less. The invention has been described with respect to luteinising hormone (LH), however, one skilled in the art will understand that compounds having LH activity i.e. LH analogues which exert the same physiological, biochemical or biological effects as LH may also be used. For example, it is well known that chorionic gonadotropin (CG) can serve as a surrogate for LH. As a general rule 1 IU of hCG is equivalent to 5-7 IU of LH in the pharmacopoeia Van Hell bioassay12 and thus equivalent doses of hCG can be calculated by a person skilled in the art. Other examples of analogues of LH are as disclosed, for example in European patent no. EP 0 322 226 (Applied Research Systems), WO 99/25849, WO 90/06844, WO 93/06844 and WO 96/05224 (all to Washington University), and WO 00/61586 (Akzo Nobel). The invention has been discussed in the context of FSH as the major follicular stimulating agent. It will be understood by one of skill in the art that FSH may be substituted by a biologically active analogue, or by a compound that stimulates endogenous FSH secretion. In this latter class are included aromatase inhibitors, and anti-oestrogens such as tamoxifen and clomiphene citrate (CC). These compounds stimulate endogenous FSH secretion by removing the negative feedback exerted by oestrogen on the hypothalamus (either by antagonising oestrogen receptors, as is the case with CC and tamoxifen, or by greatly decreasing oestrogen concentrations, as is the case with aromatase inhibitors). FSH may also be used in conjunction with these agents during the stimulatory phase. A particularly preferred form of FSH for use in conjunction with the use of LH according to the invention is known as FSH-CTP. This long-acting human FSH is described in WO 93/06844, and has a wild type FSH α-subunit and a β-subunit that consists of the wild type FSH β-subunit fused at its carboxyl terminal to the carboxy terminal peptide (CTP) of the β-subunit of hCG (residues 112-118 to position 145 of the native hCGβ sequence). Other types of FSH analogues include, for example single chain FSH analogues in which the β-subunit is fused to the CTP of hCG, which in turn is fused to FSH α-subunit, as described in WO 96/05224 (single chain FSH-CTP). FSH may also be used in conjunction with these agents during the stimulatory phase. Administration of LH preferably begins on day 1 of the stimulatory phase, and does not continue beyond day 4. If a patient is judged to be a good responder, daily doses of about 20-400 IU of LH on days 1 and 2 may suffice. If a patient is judged to be a poor or sub-optimal responder, daily doses of 20-400 IU LH may be continued and stopped on any one of days 3 or 4. The determination of whether a patient is a good, sub-optimal or poor responder may be based on results in previous ART cycles, or on the results of a diagnostic test, as described below. As mentioned previously, hCG exerts many of the same biological effects as LH. hCG has a considerably longer half-life than LH, so if hCG is used instead of LH, a single administration of hCG (about 3-100 IU hCG) on day 1 may suffice. As mentioned above, in a further aspect, the invention provides a method for determining the response of a patient to FSH in COH. This allows the tailoring of the COH regimen to the patient, avoiding excessive doses of FSH in good responders and increasing the chances of success for sub-optimal and poor responders. The method uses a single administration, e.g. injection of LH (for example at the doses described above, e.g. about 50-300 IU, preferably 100-200 IU, more preferably about 150 IU) at the beginning of the stimulatory phase of a COH regimen, as a “challenge” in order to stimulate androgen synthesis by theca cells. The LH injection is made on day 1 of the stimulatory phase. Serum androgen levels are then measured at least once, at least at or about 6 hours after LH administration, preferably at least at or about 12 hours after LH administration. Before 6 hours, the response to the LH challenge will not be significant. More preferably, androgen levels are monitored, over a period of time, for example, at 0, 1, 6, 12 and 24 hours after the LH injection, giving a picture of the increase in androgen concentrations in response to the LH injection. Androgen levels after the LH challenge are compared with levels prior to the challenge. For example, if the androgen level prior to the LH injection is A1 and the androgen level post injection is A2, the difference between these two values, ΔA, is calculated (i.e. ΔA=A2-A1). The value ΔA is intended to represent a general parameter representing a change in androgen serum levels. It is not limited to a simple difference calculated from two values, but can also be a composite result from a number of points. If a single measurement of androgen levels is made, it should not be made before about 6 hours, as androgen levels will not have time to respond to the LH challenge. If a single measurement is made, it is preferably made after 12 hours, more preferably at or about 18 to at or about 24 hours. The LH challenge method is preferably used in patients undergoing a pituitary down-regulation regimen, involving a treatment of at least about 3 days, preferably about 7 days, with a GnRH agonist before LH administration. Patients showing a good androgen response may continue the COH regimen with FSH alone. Patients showing a poor or sub-optimal response may receive LH injections (e.g. at the dosages described above, e.g. 50-300 IU, preferably 75-225 IU, more preferably about 150 IU/day) for up to about three days more, for example the patient would receive injections for 1, 2 or 3 days more, for example until a good androgen response is seen. Then FSH is administered daily, at about 75-600 or 75-450 IU/day, preferably about 150-375 IU/day, more preferably at about 300 IU/day. The androgens which are preferably monitored are androstenedione and testosterone, more preferably androstenedione. In addition, precursors to these may be measured, for example 17-α-hydoxyprogesterone (17αOHP). Good responders are those patients showing an increase in serum androstenedione concentration (ΔA) after 24 hours of at or about 2 nmol/L or more. Poor and sub-optimal responders show an increase less than at or about 2 nmol/L. If testosterone concentrations are measured, a good responder will show an increase in testosterone serum levels after 24 hours of at or about 0.25 to 0.75 nmol/L or more, whereas poor and sub-optimal responders show an increase of less than 0.25 nmol/L. Patients which show a good, poor or sub-optimal androgen response, respectively, leads to the patients in turn being determined as likely to show a good, poor or sub-optimal response, respectively, to FSH in COH. Thus, for example a patient which shows a good androgen response leads to the patient being determined as likely to show a good response to FSH in COH in the methods of the invention described herein. To increase the sensitivity of the method, background levels of androgen may be essentially eliminated by administering to the patient an inhibitor of adrenal androgen secretion, for example dexamethasone, prior to the LH challenge. In a variation of the above LH challenge, serum oestrogen levels are monitored rather than androgen levels. LH stimulates production of androgens by theca cells, and androgens are then converted to oestrogens by aromatase. Because conversion of androgens to estrogens is enhanced by FSH, in a further variation of the LH challenge method, the LH challenge may be followed by an FSH injection, and oestrogen levels may then be measured. Again, a single injection of LH (e.g. at the dosages described above, e.g. about 50-300 IU, preferably 75-225 IU, more preferably about 150 IU) is given on day 1 of the stimulatory phase of a COH regimen, as a “challenge” in order to stimulate androgen synthesis by theca cells. Following the LH injection, an FSH injection is given (about 50-300 IU, preferably about 150 IU). The FSH injection is given not before at or about 6 hours, preferably at or about 12 hours, more preferably at or about 24 hours after the LH challenge. FSH stimulates aromatase production, thus the increase of androgen that is caused by LH stimulation of theca cells, will be converted by aromatase into oestrogens. Oestrogen levels are then measured at least once, preferably not before at or about 12 hours after FSH administration. The 12-hour interval allows aromatase upregulation to occur in response to FSH. More preferably, oestrogen levels are monitored, over a period of time, for example, at 0, 6, 12 and 24 hours after the FSH injection. Oestrogen levels after the LH challenge are compared with levels prior to the challenge. For example, if the oestrogen level prior to the LH injection is E1 and the oestrogen level post injection is E2, the difference between these two values, ΔE, is calculated (i.e. ΔE=E2-E1). The value ΔE is intended to represent a general parameter representing a change in oestrogen serum levels. It is not limited to a simple difference calculated from two values, but can also be a composite result from a number of points. If a single measurement of oestrogen levels is made, it should not be made before about 12 hours after the FSH challenge injection, as oestrogen levels will not have time to respond to the LH/FSH challenge. If a single measurement is made, it is preferably made after 18 hours, more preferably at or about 24 hours. The LH+FSH challenge method is preferably used in patients undergoing a pituitary down-regulation regimen, involving a treatment of at least about 3 days, preferably about 7 days, with a GnRH agonist before LH administration. Patients showing a good oestrogen response may continue the COH regimen with FSH alone (about 100-225 FSH IU/day, preferably about 150 IU FSH/day). Patients showing a poor or sub-optimal response may continue LH injections (e.g. at the doses described above, e.g. 50-300 IU, preferably 75-225 IU, more preferably about 150 IU/day) for up to about three days more, for example the patient would receive injections for 1, 2 or 3 days more, for example until a good oestrogen response is seen, then FSH doses are started (e.g. at the doses described above or e.g. about 75-450 IU FSH/day, preferably about 150-375 IU/day, more preferably about 300 IU/day). The oestrogen that is preferably monitored is estradiol (E2). Good responders are those patients showing an increase of oestradiol serum levels after 24 hours of at or about 5 pmol/L or more. Poor and sub-optimal responders show a response less than this. Patients which show a good, poor or sub-optimal oestrogen response, respectively, leads to the patients in turn being determined as likely to show a good, poor or sub-optimal response, respectively, to FSH in COH. Thus, for example a patient which shows a good oestrogen response leads to the patient being determined as likely to show a good response to FSH in COH in the methods of the invention described herein. To increase the sensitivity of the method, background levels of androgen may be essentially eliminated by administering to the patient an inhibitor of adrenal androgen secretion, for example dexamethasone, prior to the LH challenge. Any of the above challenges may be repeated, during the course of the stimulatory phase. In any of the above challenges, both androgens and oestrogens are preferably monitored. Methods of monitoring androgens and oestrogens are well known and documented in the art and any of these may be used. Testosterone levels may be measured, using for example, a solid-phase coated-tube radioimmunoassay (Coat-A-Count™, Diagnostic Products Corporation, Los Angeles, USA). Androstenedione levels may be measured, for example using radioimmunoassay (Diagnostic Laboratories Inc., Webster, USA). 17β-estradiol may be measured, for example, by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, USA). The gonadotropins that are used in the methods and uses of the invention should preferably be human gonadotropins and may be from any source, provided they are not contaminated with any materials (particularly other gonadotropins) which will substantially affect their action. Urinary gonadotropins may be used, although it is preferred to use recombinant FSH and LH (rhFSH and rhLH), because of their high purity. It is particularly preferred to use rhLH. The pharmaco-kinetics of rhLH are very similar to those of pituitary LH. Following a rapid distribution phase with an initial t1/2 of 1 h, rhLH is eliminated with a terminal t1/2 of approximately 10 h. Total body clearance is 2 L/h, with less than 5% of the dose being excreted renally. The steady state volume is 8 L. These PK characteristics contrast with urine-derived hCG PK characteristics. The latter have been shown to have a terminal tyexceeding 30 hours. hCG is expected to remain in circulation 2 to 3 times longer than LH. Pharmaceutical compositions comprising LH or an analogue thereof and a pharmaceutically acceptable diluent, carrier or excipient, for use in the method of the invention, e.g. for inducing or enhancing folliculogenesis are also within the scope of the present invention. A person skilled in the art is aware of a whole variety of such diluents or excipients suitable to formulate a pharmaceutical composition. Preferably said pharmaceutical compositions comprise a daily dose of LH (e.g. a dose of 20-400 IU, preferably 50-300 IU, more preferably 75-225 IU or 100-200 IU or most preferably 150 IU of LH) to be administered from day 1 to about day 4, preferably from day 1 to day 4, more preferably from day 1 to day 3, most preferably from day 1 to day 2 or only on day 1 of the stimulatory phase in COH. Other appropriate doses of LH are described elsewhere herein. LH is typically formulated as a unit dosage in the form of a solid ready for dissolution to form a sterile injectable solution for intramuscular or subcutaneous use. The solid usually results from lyophilisation. Typical excipients and carriers include sucrose, lactose, sodium chloride, buffering agents like sodium phosphate monobasic and sodium phosphate dibasic. The solution may be prepared by diluting with water for injection immediately prior to use. LH may also be formulated as a solution for injection, comprising any of the excipients and buffers listed above, and others known to one skilled in the art. Small molecule LH agonists, such as those reported in WO 00/61586 (Akzo Nobel) may be given orally, in the form of a syrup, tablet or capsule, after admixing with a suitable excipient. Alternatively, they may be given intranasally, in the form of a solution or fine powder suitable for spraying. The invention will now be described in more detail in the following non-limiting Example. EXAMPLE Patients are selected as follows: Inclusion criteria Type of infertility: Tubal IVF and unexplained infertility. (n=120 in total) Normal menstrual rhythm Aged <37 years Body mass index (BMI) <30 No recent hormone administration 2 functional ovaries Exclusion Criteria Ultrasound determination of PCO BMI >30 Single functional ovary Other compromising disease Protocol Patients are down-regulated (starting on day 18-23 of a menstrual cycle) with injections of Lupron®, Synarel® or Zoladex® for 14-18 days prior to start. The start point for the priming period (day L1) requires oestradiol (E2) serum levels of <150 pmol/L (50 pg/ml) and no more than one ovarian cyst with diameter <30 mm. On days L1-L4 (the priming period), the patients receive placebo, or 225 IU rhLH daily. Starting on the last day of the priming period, the patients receive 150 IU FSH daily (LH administration ceases after L4), for 7 days (S1 to S7). Doses may be reduced at S7 or later, if there is risk of over-stimulation. At S7, doses are increased to 300 IU FSH/day if the circulating concentration of E2 is less than 450 pmol /L, and/or there are <6 follicles with diameter >8 mm. FSH administration is continued until the largest follicle has reached a mean diameter of at least 17 mm, and there are two other follicles with a mean diameter of >16 mm, at which point an ovulation triggering dose of hCG (5'000-10'000 IU hCG) is administered. Oocyte retrieval is timed for approximately 36 hours after the hCG injection. Oocytes are fertilised in vitro. Embryos that show early cleavage (by 25 hours after insemination) are considered to have considerably higher chances of implantation and pregnancy. The early cleavage (EC) check is carried out at 25 h after insemination, and the number of cleaved embryos, syngamy (merging of the sperm and the ova) and non-cleaved embryos recorded. Also recorded are: Number and diameter of follicles on day of hCG, and in particular the number of follicles over 15 mm in diameter; oocyte yield; ampoules of rFSH used; ampoules of rFSH used per oocyte; circulating concentration of oestradiol on S7; reduction in the incidence of ‘poor responses’ to standard dose therapy (150 IU FSH/d) in a clinic population; Ratio of large follicles to small follicles at the time of hCG administration; the number of follicles with mean diameter >10 mm at S7; circulating inhibin-B concentrations at S7. References: 1 Healy et al.; Lancet 343 1994; 1539-1544 2 for example, a conventional technique is described in EP 0 170 502 (Serono Laboratories, Inc.) 3 Filicori, M.; J. Clin. Endocrinol. Metab. 81 1996; 24136 4 Filicori, M. et al.; Fertil. Steril. 65 1996; 387-93 5 Filicori et al.; J. Clin. Endocrnol. Metab. 84 1999; 2659-2663 6The European Recombinant Human LH Study Group; J. Clin. Endocrinol. Metab. 83 1998; 1507-1514 7 Sullivan, M. W. et al.; J. Clin. Endocrinol. Metab. 84 1999; 228-232 8 Sills et al.; Human Reproduction 14 1999; 2230-2235 9 Ben-Amor A-F, on behalf of the Study Group (Tarlatzis B, Tavmergen E, Shoham Z, Szamatowicz M, Barash A, Amit A, Levitas I, and Geva E). The effect of luteinizing hormone administered during late follicular phase in normo-ovulatory women undergoing in vitro fertilization. Hum Reprod 2000;15 (Abstract book 1):46 (Abstract no. 0-116). 10 Werlin L., Kelly, E, Weathersbee P., Nebiolo L., Ferrande L. A multi-center, randomized, comparative, open-trial to assess the safety and efficacy of Gonal-F (r-hFSH) versus Gonal-F and recombinant human luteinizing hormone (r-hLH) in patients undergoing ICSI: Preliminary data. . Fertil. Steril. 1999 72;3 (Suppl 1)(Abstract no. 0-032). 11 Williams R. S., A multi-center study comparing the efficacy of recombinant human FSH (Gonal-F) versus r-hFSH plus recombinant human LH in patients undergoing Controlled Ovarian Hyperstimulation for Assisted Reproductive Technology. Fertil. Steril. 2000, 74;3 (Suppl 1)(Abstract no. P-428) 12 Van Hell et al.; Acta Endocrin, 47 1964; 409-418

<SOH> BACKGROUND OF THE INVENTION <EOH>Numerous infertile patients undergo ovulation induction procedures every year. Up until two decades ago ovulation induction was used solely for the treatment of anovulatory infertility; however, the introduction of assisted reproduction technology (ART) has expanded the use of these procedures to eumenorrheic women, with the goal of achieving multiple folliculogenesis. For assisted reproduction techniques (ART), such as in vitro fertilisation (IVF) or IVF in conjunction with intracytoplasmic sperm injection (IVF/ICSI) and embryo transfer (ET), oocytes are collected from a female patient immediately prior to ovulation. The oocytes are fertilised in vitro, the resulting embryos are evaluated, and selected for implantation. Fertilisation will not occur for every oocyte, and not every fertilised oocyte will develop into a viable embryo. Furthermore, implantation may fail to occur. Because of the many possibilities for an unsuccessful outcome, and the relatively invasive nature of oocyte collection, it is desirable to maximise the number of oocytes collected. For this reason, ART is typically carried out using controlled ovarian hyperstimulation (COH) to increase the number of oocytes 1 . Standard regimens 2 for COH include a down-regulation phase in which endogenous luteinising hormone (LH) is down-regulated by administration of a gonadotropin releasing hormone (GnRH) agonist followed by a stimulatory phase in which follicular development (folliculogenesis) is induced by daily administration of follicle stimulating hormone (FSH), usually at about 150-225 IU/day. Other molecules having FSH activity may also be used. Alternatively stimulation is started with FSH after spontaneous or induced menstruation, followed by administration of a GnRH-antagonist (typically starting around day six of the stimulatory phase). When there are at least 3 follicles>16 mm (one of 18 mm), a single bolus of hCG (5-10,000 IU) is given to mimic the natural LH surge and trigger ovulation. Oocyte recovery is timed for 36-38 hours after the hCG injection. The rationale for the use of GnRH analogues, e.g. agonists or antagonists, in this context is the prevention of an untimely LH surge which can cause premature ovulation and follicle luteinisation 3 . It has consistently been found that long GnRH agonist regimens (i.e., those started in the midluteal phase of the cycle preceding ovulation induction, or before) are associated with easier patient scheduling, greater follicle yield, and overall better clinical results. 4 The use of antagonists is relatively new to the clinic, but it is expected to yield similar benefits, with the advantage of a shorter dosing period. The prolonged administration of GnRH agonists or the administration of GnRH antagonists results in profound suppression of endogenous LH throughout the cycle, in the case of an agonist, or late in the stimulatory phase, with an antagonist. This situation, while not incompatible with follicle development, does not mimic the natural cycle. In the natural cycle, LH levels show a gradual increase several days before the large peak at midcycle. Many groups have investigated the importance of LH during the stimulatory phase of COH and ovulation induction regimens. As is well known and recognised in the art, techniques or methods of ovulation induction ( 01 ) are distinct from methods of COH, although both may involve the administration of FSH. Filicori et al. has investigated the role of low doses of hCG, as a surrogate for LH, in folliculogenesis and ovulation induction 5 . hCG was given (50 IU hCG/day), starting synchronously with FSH administration. This regimen was continued on a daily basis until ovulation was triggered with a bolus of hCG. The numbers of small (<10 mm), medium (10-14 mm) and large (>14 mm) follicles were comparable between a group receiving hCG and a control group receiving FSH alone, however, the cumulative dose of FSH and the duration of FSH stimulation were reduced in the hCG treated group. WO 00/67778 (Applied Research Systems) proposes the use of LH during the stimulatory phase. In one study, patients were administered FSH and LH in the early stimulatory phase, and then either both FSH and LH or just LH during the late stimulatory phase. In another study, patients were administered FSH alone in the early stimulatory phase and then LH in the late stimulatory phase. It was suggested that LH in the late stimulatory phase is responsible for atresia of non-dominant follicles. The regimen is proposed to encourage the development of a single dominant follicle. The administration of rhLH (75 and 225 IU/day) for supporting rhFSH-induced follicular development in hypogonadotrophic hypogonadal women is reported by the European Recombinant Human LH Study Group to promote estradiol secretion, enhance the effect of FSH on follicular growth, and permit the successful luteinisation of follicles when exposed to hCG, as compared to a regimen of FSH alone 6 . The LH was administered starting on the same day as FSH stimulation, and was continued until hCG administration to trigger ovulation. Sullivan et al. report that LH late in the stimulatory phase sustains follicular estradiol production when FSH is withdrawn 7 . Sills et al. report a study in which patients suffering from infertility of various types were treated with either FSH or FSH and 75 IU rhLH throughout the stimulatory phase. The authors conclude that the addition of exogenous LH throughout ovulation induction does not materially alter cycle performances. Ben-Amor et al. 9 and Werlin et al. 10 have examined the effect of administering rhLH during the second half of the follicular phase in normally ovulatory patients with a long down regulation regimen, and Williams et al. 11 have studied the effect of administering different doses of r-hLH during the whole FSH stimulation. No substantial clinical benefits were reported in these patient groups. In COH regimens using FSH, some patients (“poor responders”) fail to respond to the initial doses of FSH, and the treatment cycle may be abandoned, and a new cycle started with a higher initial dose of FSH. Other groups of patients require repeated cycles because they fail to become pregnant even though oocyte recovery is successful. If repeat cycles are necessary, there may be adverse physical and emotional effects on the patient. Each repeat cycle entails a tremendous disruption in the life of the infertile couple. It would be desirable to have a method that would permit the same or improved follicular response to COH using decreased FSH doses or decreased dosing periods. It would also be desirable to have a diagnostic test which could determine which patients may be poor or sub-optimal responders, and which patients may respond on a decreased FSH dose.

<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the invention to provide an improved regimen for COH. It is a further object of the invention to provide a method for providing multiple follicles for multiple oocyte recovery for ART. It is a further object of the invention to provide a method for determining which patients may show a good, poor or sub-optimal response to FSH in COH. In a first aspect, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for the manufacture of a medicament for inducing multiple folliculogenesis in a human patient, wherein the medicament is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Viewed alternatively, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for the manufacture of a medicament for inducing multiple folliculogenesis in a human patient, wherein the medicament is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. In a second aspect, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for inducing multiple folliculogenesis in a human patient, wherein the LH is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Viewed alternatively, the invention provides the use of luteinising hormone (LH) or an analogue thereof, for inducing multiple folliculogenesis in a human patient, wherein the LH is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase of COH. In a third aspect, the invention provides a pharmaceutical composition comprising LH or an analogue thereof, at a daily dose of 20-400 IU LH, to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. Preferably the medicament or pharmaceutical composition (comprising LH or an analogue thereof) is to be administered from day 1 to day 4, preferably from day 1 to day 3 or most preferably from day 1 to day 2 of the stimulatory phase. Single daily doses of medicament or pharmaceutical compositions may be administered. Alternatively the medicament or pharmaceutical composition may be administered as a single dose on day 1 of the stimulatory phase. Preferably the pharmaceutical compositions of the invention are designed for use in the methods and uses of the invention. In a fourth aspect, the invention provides a kit for the induction of folliculogenesis in a human patient, the kit comprising one to five daily doses of 20-400 IU of LH, or an equivalent dose of an analogue thereof, and at or about six or more daily doses of FSH, or an analogue thereof. Thus, the kits of the invention may comprise or consist of one, two, three, four or five daily doses of LH, or an analogue thereof, and at or about six or more daily doses of FSH, or an analogue thereof. Appropriate daily doses of LH and FSH are described elsewhere herein. Preferred kits may comprise two, three or four daily doses of at or about 150 IU of LH or 225 IU of LH and eight to twelve daily doses of at or about 150 IU FSH. Preferably the kits of the invention are designed for use in the methods and uses of the invention. In a fifth aspect, the invention provides a method for determining the response of a patient to FSH in COH, the method comprising the steps: (A) measuring androgen concentration in the patient to yield a basal value A 1 ; (B) administering LH at about 20 to about 400 IU to the patient; (C) measuring androgen concentration in the patient at least once after administering LH, at or about 6 or more hours, or preferably at or about 12 or more hours, after administering LH, to yield a value A 2 ; (D) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in androgen levels. Alternatively, as will be described in more detail below, in step (C) of the above method androgen levels/concentrations may be monitored/measured at least once over a period of time after the LH administration, and one or more of these measurements of androgen levels may be taken within the first six hours after the administration of LH, e.g. after 1 hour, and then subsequent measurements may be taken at one or more later time points, to yield a value A 2 . Generally the measurements are taken over a period of 24 hours after LH administration. In a sixth aspect, the invention provides a method for determining the response of a patient to FSH in COH, the method comprising the steps: (A) measuring oestrogen concentration in the patient to yield a basal value E 1 ; (B) administering LH at about 20 to about 400 IU, to the patient; (C) administering FSH at about 5 to about 300 IU to the patient, at or about 6 or more hours, or preferably at or about 12 or more hours, more preferably at or about 24 or more hours after administering LH; (D) measuring oestrogen concentration in the patient, at or about 12 or more hours after administering FSH, to yield the value E 2 ; (E) classifying the patient as a poor, sub-optimal or good responder on the basis of the change in oestrogen levels (E 2 -E 1 ). Alternatively as will be described in more detail below, in step (D) of the above method oestrogen levels/concentrations may be monitored/measured at least one over a period of time after the FSH administration, and one or more of these measurements of oestrogen levels may be taken within the first twelve hours after the administration of FSH, e.g. after 6 hours, and then subsequent measurements may be taken at one or more later time points, to yield a value E 2 . In all the above described methods for determination, the measurements of oestrogen and androgen levels are preferably carried out in vitro on a sample taken from an appropriate patient. A further aspect of the invention provides LH or an analogue thereof for inducing multiple folliculogenesis in a human patient, wherein the LH, or an analogue thereof is to be administered from day 1 to at or about day 4 of the stimulatory phase in COH. A further aspect of the invention provides LH or an analogue thereof for inducing multiple folliculogenesis in a human patient, wherein the LH, or an analogue thereof, is to be administered during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. In a yet further aspect, the present invention provides a method of inducing multiple folliculogenesis in a patient, which method comprises the administration of LH or an analogue thereof to the patient, wherein said administration is carried out from day 1 to at or about day 4 of the stimulatory phase in COH. In a further aspect, the present invention provides a method of inducing multiple folliculogenesis in a patient, which method comprises the administration of LH or an analogue thereof to the patient, wherein said administration is carried out during a priming period lasting from day 1 to at or about day 4 of the stimulatory phase in COH. detailed-description description="Detailed Description" end="lead"?

20040914

20080311

20050303

99844.0

HARLE, JENNIFER I

USE OF LH IN CONTROLLED OVARIAN HYPERSTIMULATION

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for processing a continuously cast metal slab or strip, and plate or strip produced in this way

The invention relates to a method for processing a continuously cast metal slab or strip, in which the slab or strip is passed between a set of rotating rolls of a rolling mill stand in order to roll the slab or strip. According to the invention, the rolls of the rolling mill stand have different peripheral velocities, and the difference in peripheral velocity is at least 5% and at most 100%, and the thickness of the slab or strip is reduced by at most 15% for each pass. The invention also relates to metal plate or strip produced using this method.

1. A method for processing a continuously cast slab or strip, comprising passing the slab or strip between a set of rotating rolls of a rolling mill stand to roll the slab or strip, wherein the rolls of the rolling mill stand have different peripheral velocities, and the difference in peripheral velocity is at least 5% and at most 100%, and the thickness of the slab or strip is reduced by at most 15% for each pass. 2. The method as claimed in claim 1, wherein the thickness of the slab or strip is reduced by at most 8% each pass. 3. The method as claimed in claim 1, wherein the difference in peripheral velocity is at least 20%. 4. The method as claimed in in claim 1, wherein the rolling mill rolls have different diameters. 5. The method as claimed in claim 1, wherein the rolls have different rotational speeds. 6. The method as claimed in claim 1, wherein the rolling is carried out at an elevated temperature. 7. The method as claimed in claim 1, wherein the slab is introduced between the rolls at an angle of between 5 and 45° with respect to the perpendicular to the plane through the center axes of the rolls. 8. The method as claimed in claim 1, wherein the slab or strip has a thickness of at most 70 mm at the start of said passing step. 9. The method as claimed in claim 1, wherein the processing operation is repeated one or more times after the rolling has been carried out for the first time. 10. The method as claimed in claim 9, wherein the slab, plate or strip is passed through the rolling mill stand in opposite directions for each pass. 11. The method as claimed in claim 9, wherein the slab, plate or strip is successively passed through two or more rolling mill stands. 12. The method as claimed in claim 1, wherein the processing operation is preceded or followed by a rolling operation carried out using a rolling mill in which the rolls have substantially identical peripheral velocities. 13. Method according to claim 1, wherein the metal slab is formed by two or more layers of metal. 14. Metal plate or strip produced using the method as claimed in claim 1, wherein the metal is selected from the group consisting of aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy thereof. 15. The metal plate as claimed in claim 14, wherein the plate has a thickness of between 5 and 60 mm. 16. The metal plate as claimed in claim 15, wherein the plate consists of an aluminum alloy selected from the group consisting of AA 1xxx or AA 3xxx series. 17. The metal strip as claimed in claim 14, wherein the strip has a thickness of at most 7 mm. 18. The metal strip as claimed in claim 17, wherein the strip consists of an aluminum alloy from the AA 5xxx series. 19. A method of use of aluminum strip as claimed in claim 18 comprising forming the strip into a part for a vehicle. 20. A metal plate or strip produced by continuous casting, wherein the pores in the core of the plate or strip have a maximum dimension of less than 20 μm. 21. A metal plate or strip produced by continuous casting, wherein the unrecrystallized metal plate or strip, in the core of the plate or billet, has a deformed grain structure, the grain having a mean length which is 2 to 20 times greater than their thickness. 22. A metal plate or strip produced by continuous casting, wherein the metal plate or strip, after recrystallization, has a substantially homogenous degree of recrystallization over its entire thickness. 23. The metal plate or strip as claimed in claim 20, in which the metal is selected from the group consisting of aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy thereof. 24. The method as claimed in claim 1, wherein the thickness of the slab or strip is reduced by at most 5% each pass. 25. The method as claimed in claim 1, wherein the difference in peripheral velocity is at least 50%. 26. The method as claimed in claim 1, wherein slab or strip comprises aluminum and the rolling is carried out at a temperature between 300 and 550° C. 27. The method as claimed in claim 1, wherein slab or strip comprises aluminum and the rolling is carried out at a temperature between 425 and 475° C. 28. The method as in claim 1, wherein the slab is introduced between the rolls at an angle of between 15 and 25° with respect to the perpendicular to the plane through the center axes of the rolls. 29. The method as in claim 1, wherein the slab or strip has a thickness of at most 25 mm at the start of said passing step. 30. Method according to claim 1, wherein the metal slab is formed by two or more layers consisting of different alloys of a metal or different metals. 31. The metal plate as claimed in claim 14, wherein the plate has a thickness of between 5 and 20 mm. 32. The metal plate as claimed in claim 15, wherein the plate consists of an aluminum alloy selected from the group consisting of AA 1050 or AA 1200, or AA 3103. 33. The metal strip as claimed in claim 14, wherein the strip has a thickness of at most 2 mm. 34. The metal strip as claimed in claim 17, wherein the strip consists of AA 5182 aluminum alloy. 35. A method of use of aluminum strip as claimed in claim 18, comprising forming the strip into a structural part for the interior of a vehicle. 36. A metal plate or strip of claim 20 produced by continuous casting, wherein the pores in the core of the plate or strip have a maximum dimension of less than 10 μm. 37. A metal plate or strip produced by continuous casting, according to the method of claim 1, wherein the pores in the core of the plate or strip have a maximum dimension of less than 20 μm. 38. A metal plate or strip produced by continuous casting, according to the method of claim 1, wherein the pores in the core of the plate or strip have a maximum dimension of less than 10 μm. 39. A metal plate or strip of claim 21 produced by continuous casting, wherein the unrecrystallized metal plate or strip, in the core of the plate or billet, has a deformed grain structure, the grain having a mean length 5 to 20 times greater than their thickness. 40. A metal plate or strip produced by continuous casting, and the method of claim 1, wherein the unrecrystallized metal plate or strip, in the core of the plate or billet, has a deformed grain structure, the grain having a mean length 2 to 20 times greater than their thickness. 41. A metal plate or strip produced by continuous casting, and the method of claim 1, wherein the unrecrystallized metal plate or strip, in the core of the plate or billet, has a deformed grain structure, the grain having a mean length 5 to 20 times greater than their thickness. 42. A metal plate or strip produced by continuous casting and the method as claimed in claim 1, wherein the metal plate or strip, after recrystallization, has a substantially homogenous degree of recrystallization over its entire thickness. 43. The metal plate or strip as claimed in claim 21, wherein the metal is selected from the group consisting of aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy thereof. 44. The metal plate or strip as claimed in claim 22, wherein the metal is selected from the group consisting of aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy thereof.

The invention relates to a method for processing a continuously cast slab or strip, in which the slab or strip is passed between a set of rotating rolls of a rolling mill stand in order to roll the slab or strip. Rolling is a very standard processing operation for imparting desired dimensions and properties to metals. For example, rolling results in an improvement to the microstructure as a result of grain refinement taking place under the influence of the rolling. If thin plate or strip is to be produced from a thick slab of, for example, 30 cm or more, the production of thin plate or strip is a very laborious process, since rolling has to be repeated a very large number of times. Therefore, other casting techniques have been developed in order to obtain a thin slab or a strip directly. In order still to produce sufficient material, these processes are carried out continuously. For the continuous casting of aluminum, in principle three methods can be distinguished which are currently in use. The first method uses one cooled roll on which a thin layer of molten aluminum is cooled until it solidifies. The strip obtained in this way has a thickness of approximately 1 mm. For technical reasons, this thickness cannot be much greater. The second method uses two cooled rolls between which molten aluminum is passed in order to solidify into a strip. The improved cooling means that this method usually produce a thickness of between 6 and 10 mm; the minimum thickness which can currently be achieved is approximately 1 mm. Depending, inter alia, on the thickness, the strip which is formed will be cut into slabs or coiled. In the third method, the molten aluminum is guided onto a conveyer belt, on which it solidifies, or passed between two conveyer belts in order to solidify. On account of the longer solidification path, more heat can be dissipated and it is possible to produce a thicker solidified strip. The thickness is usually approximately 20 mm. The thick strip formed in this way can then be cut in slabs or coiled. In all three methods, it is also possible for the strip to be rolled in one or more rolling mill stands immediately after the continuous casting and then to be coiled. The above three methods or also other methods can be used for the continuous casting of other metals, and if appropriate it is also possible to produce a thicker strip. These methods and methods derived from them are in the present context jointly referred to as “continuous casting”, and the product obtained thereby is referred to as “continuously cast slab or strip”. One drawback of these products is that the end product still largely has the cast microstructure, since the slabs and the strip have scarcely been rolled. Consequently, the mechanical properties of the end products are relatively poor, and consequently the use of the end products is relatively limited, for example as a foil and a starting material for fins of heat exchangers and the like. It is an object of the invention to provide a method for processing a continuously cast metal slab or strip which allows the properties of the product produced thereby to be improved. It is another object of the invention to provide a method for processing a continuously cast metal slab or strip with which it is possible to close up pores in the cast material. Yet another object of the invention is to provide a method for processing a continuously cast metal slab or strip which results in grain refinement in the product which is thereby produced. Yet another object of the invention is to provide a method for processing continuously cast metal by means of which the surface of the slab or strip is improved. It is also an object of the invention to provide a metal plate or strip with improved mechanical properties which is preferably produced with the aid of this method. According to a first aspect of the invention, one or more of these objects are achieved by a method for processing a continuously cast slab or strip, in which the slab or strip is passed between a set of rotating rolls of a rolling mill stand in order to roll the slab or strip, in which method the rolls of the rolling mill stand have different peripheral velocities, and the difference in peripheral velocity is at least 5% and at most 100%, and in which method the thickness of the slab or strip is reduced by at most 15% for each pass. As a result of the rolls being provided with a different peripheral velocity, shearing occurs in the slab or strip and has been found to occur throughout the entire thickness of the slab or strip. It has been found that this requires a velocity difference of at least 5%. The shearing leads to pores in the continuously cast material being closed up to a considerable extent. This does not require a major change in thickness, but rather a change in thickness of at most 15% can suffice. This is advantageous in a continuously cast metal slab or strip, which in many cases is cast with a low thickness, because the thickness is then substantially retained. In addition, it is important that the rolling according to the invention can result in a grain refinement which occurs throughout the entire thickness of the rolled material, which is advantageous for the mechanical properties of the slab or strip. Inter alia, the strength of the material increases. The shearing also breaks up the eutectic particles, which results in an improved toughness. In addition, it is expected that the material will have an improved fatigue crack growth rate, since the grains will have a more or less knurled shape as a result of the shearing. This results in an improved toughness and a reduced susceptibility to damage. It is also expected that the processing according to the invention will result in a rolled sheet with less spread. It is also expected that the processing according to the invention will cause the surface layer of the material to be different than is the case with conventional rolling of the material. Ordinary rolling results in the formation of a layer comprising very fine-grained material. This layer is much thinner in the processing according to the invention. The expectation is that this will improve the corrosion resistance of the material. This may be favorable for the use of continuously cast aluminum plates and strip material for applications other than the current ones. The thickness of the slab or strip is preferably reduced by at most 8% for each pass, and preferably by at most 5%. Since the shearing and therefore the grain refinement are brought about by the difference in peripheral velocity between the rolls, the reduction in thickness of the material is not necessary in order to obtain grain refinement. The reduction in thickness is required primarily in order to enable the rolls to grip the material. This only requires a slight change in thickness, which is advantageous in the case of thin continuously cast aluminum slabs and strip material. The smaller the reduction, the thicker the slab or strip remains after each pass. The possible applications of continuously cast aluminum slabs and strip material increase as a result. The difference in peripheral velocity is preferably at least 20%, more preferably at least 50%. As the difference in peripheral velocity of the rolls is larger, the shearing will be higher. As a result, the grain refinement becomes stronger and the mechanical properties increase. According to an advantageous embodiment, the rolling mill is designed in such a manner that the rolls have different diameters. This makes it possible to obtain the desired difference in peripheral velocity. According to another advantageous embodiment, the rolls have a different rotational speed. This too makes it possible to obtain the desired difference in rotational speed. It is also possible for these latter two measures to be combined in order to obtain the desired difference in rotational speed. The rolling is preferably carried out at an elevated temperature. This makes the rolling run more smoothly. The rolling is preferably carried out at a temperature between 300 and 550° C., since in this temperature range good deformation on the continuously cast aluminum slabs and strip is possible. More preferably, the rolling is carried out at a temperature between 425 and 475° C. The deformation of aluminum is easiest at approximately 450° C. According to an advantageous embodiment of the method, the slab is introduced between the rolls at an angle of between 5 and 45° with respect to the perpendicular to the plane through the center axes of the rolls. Introducing the slab between the rolls at an angle makes it easier for the rolls to grip the slab, with the result that the change in thickness can be kept as low as possible. The slab is preferably fed in at an angle of between 15 and 25°, since the grip of the rolls is best in that case. The starting point is preferably a slab or strip with a thickness of at most 70 mm, more preferably at most 25 mm. Standard rolling involves rolling to a thickness of approximately one millimeter or thinner in order to obtain better mechanical properties. With the aid of the method according to the invention, better mechanical properties can be imparted to the slab or strip, with the result that thinner material can be used for same application. Since the method according to the invention can be used to impart better properties to the relatively thin continuously cast metal, it is to be expected that thicker continuously cast plate and strip material, now with better mechanical properties, will also find industrial applications. For this purpose, after the rolling has been carried out for the first time, the processing operating is preferably repeated one or more times. For example, sufficiently good grain refinement is obtained by carrying out the processing operating according to the invention three times. However, the number of times that the processing operation has to be carried out depends on the thickness of the continuously cast material, the difference in peripheral velocity of the rolls and the desired grain refinement. By carrying out the processing operation according to the invention a large number of times and subjecting the material to an annealing treatment in between these operations if necessary, it is possible to obtain an ultrafine grain structure. The processing operation can be repeated sufficiently often for the material to become superplastic. Superplastic material has extremely small grains and as a result under certain conditions can stretch almost infinitely without cracking. This is a highly advantageous property for the deformation of metal, for example deep-drawing of a blank. Obviously, when the processing operation according to the invention is repeated a number of times, the material does become thinner, and it is therefore desirable to start from a continuously cast metal, such as aluminum, with the maximum possible thickness. If the processing operation according to the invention is repeated a number of times, according to an advantageous embodiment the slab, plate or strip can be passed through the rolling mill stand in opposite directions for each pass. The slab, plate or strip then changes direction after each rolling operation and is always passed through the same rolling mill stand. In this case, the rolls have to rotate in opposite directions for each pass. According to another advantageous embodiment, the slab, plate or strip is successively passed through two or more rolling mill stands. This method is suitable primarily for strip material, which in this way can undergo the desired processing operation very quickly. It is possible for the method according to the invention to be preceded or followed by a rolling operation which is carried out using a rolling mill in which the rolls have substantially identical peripheral velocities. In this way, by way of example, an accurately desired thickness or smoothness can be imparted to the product. According to an advantageous embodiment, the metal slab is formed by two or more layers of metal, preferably two or more layers consisting of different alloys of a metal or different metals. In this way it is possible, for example, to produce laminated material, such as what is known as clad material for, for example, aluminum brazing sheet. Another aspect of the invention provides a metal plate or strip produced using the above method, in which the metal is aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy of one of these metals. These metals and their alloys are particularly suitable for production with the aid of the method according to the invention, since they are metals which are in widespread use in industry and for which it is very desirable to obtain better mechanical properties if they are produced by continuous casting. A continuously cast metal plate preferably has a thickness of between 5 and 60 mm, more preferably between 5 and 20 mm. This thickness is obviously dependent on the thickness with which the metal can be continuously cast. Therefore, the processing operation according to the invention makes it possible to produce relatively thick plates with good mechanical properties even from relatively thin continuously cast material. The plate preferably consists of an aluminum alloy from the AA 1xxx or the AA 3xxx series, preferably AA 1050 or AA 1200, or AA 3103. A continuously cast metal strip preferably has a thickness of at most 7 mm, more preferably at most 2 mm. By means of the processing operation according to the invention, it is possible to obtain relatively thick strip material with good mechanical properties, although it is also possible, of course, to provide the strip with a standard thickness or even to make it thinner, since the mechanical properties are improved. The metal strip is, for example, a strip consisting of an aluminum alloy from the AA 5xxx series, preferably AA 5182. This material can be used as auto body sheet as a result of the processing operation according to the invention. The invention also relates to an improved metal plate or strip which has been produced by continuous casting, preferably with the aid of the method according to the first aspect of the invention, in which the pores in the core of the plate or strip have a maximum dimension of less than 20 μm, preferably less than 10 μm. As a result of the continuous casting, continuously cast plate and strip material always has pores which are significantly larger than 20 μm. The standard rolling operations can only close up these pores in the core to a slight extent or cannot do so at all. The rolling operation according to the invention makes it possible to provide continuously cast plate and strip material having pores which are much smaller. The invention also relates to an improved metal plate or strip which is produced by continuous casting, preferably with the aid of the method according to the first aspect of the invention, in which the unrecrystallized metal plate or strip, in the core of the plate or billet, has a deformed grain structure, the grain having a mean length which is 2 to 20 times greater than their thickness, preferably a length which is 5 to 20 times greater than their thickness. Since with conventional rolling continuously cast metal is only subject to slight deformation in the core, the metal grains in the core are scarcely deformed. The rolling treatment according to the invention makes it possible to provide continuously cast plate and strip material with highly deformed grains. As a result, a very fine grain structure will be formed during recrystallization. The invention also relates to an improved metal plate or strip which is produced by continuous casting, preferably with the aid of the method according to the first aspect of the invention, in which the metal plate or strip, after recrystallization, has a substantially homogenous degree of recrystallization over its entire thickness. The fact that the grains have all been subjected to shearing as a result of the rolling operation according to the invention, including those in the core, means that the continuously cast plate and strip material will recrystallize over the entire thickness. The metal plate or strip with this size of pores, deformed grain structure or this level of recrystallization is preferably made from aluminum, steel, stainless steel, copper, magnesium or titanium or an alloy thereof, since these metals are readily capable of industrial application.

20040823

20080311

20050106

99485.0

KERNS, KEVIN P

METHOD FOR PROCESSING A CONTINUOUSLY CAST METAL SLAB OR STRIP, AND PLATE OR STRIP PRODUCED IN THIS WAY

UNDISCOUNTED

ACCEPTED

ACCEPTED

Vacuum cleaner and device having ion generator

When the electrically driven fan (14) of a vacuum cleaner is driven, air containing dust is drawn into the cleaner main body (1) through a hose (7) connected to a hose socket (8) and is exhausted into the outside of the cleaner main body (1) through an exhaust port (1b) via first and second suction passageways (10, 13). Disposed outside the first suction passageway (10) is an ion generator (23), it being arranged that plus and minus ions generated in the ion generator (23) are fed to the air stream flowing in the first suction passageway (10). Since the plus and minus ions kill floating germs in the air stream, the exhaust can be purified.

1. An electric vacuum cleaner that, while driving an electric blower, sucks in air containing dust, then passes the airthrough a suction air passage, and then discharges the air out of the electric vacuum cleaner, comprising: an ion generator for generating H+(H2O)n as positive ions and O2−(H2O)m as negative ions, wherein airborne germs present in air are killed by the positive and negative ions. 2. The electric vacuum cleaner according to claim 1, wherein ions generated by the ion generator are fed into the suction air passage. 3. (Canceled) 4. The electric vacuum cleaner according to claim 2, wherein the ion generator is disposed away from a heat source inside a body of the electric vacuum cleaner. 5. An electric vacuum cleaner that, while driving an electric blower, sucks in air and then discharges the air out of the electric vacuum cleaner, comprising: an ion generator for generating H+(H2O)n as positive ions and O2−(H2O)m as negative ions, wherein the air is discharged out of the electric vacuum cleaner after being mixed with the positive and negative ions so that airborne germs present in air are killed by the positive and negative ions. 6. The electric vacuum cleaner according to claim 5, wherein the air sucked into the electric vacuum cleaner is discharged out of the electric vacuum cleaner after being passed through a purification filter, and the air is mixed with the ions after being passed through the purification filter. 7-12. (Canceled) 13. The device according to claim 6, wherein, when air is fed to an ion generating part of the ion generator at a rate of 50 cm/s or more, concentrations of the positive and negative ions are each 10,000 ions/cm3 or more at a position 10 cm away from the ion generating part. 14. An electric vacuum cleaner that has casters arranged on both side faces of a body having an electric blower housed therein and that exhausts the electric blower of air through ventilation openings formed in the casters, comprising: an ion generator that generates H+(H2O)n as positive ions and O2−(H2O)m as negative ions into a mixing chamber formed by the casters wherein airborne germs present in air are killed by the positive and negative ions generated by the ion generator. 15. An electric vacuum cleaner that has an electric blower and an ion generator housed in a body, the body comprising: a drive switch for driving the ion generator, the drive switch being provided independently of a control panel for controlling the electric vacuum cleaner, wherein airborne germs present in air are killed by the ion generator. 16. The electric vacuum cleaner according to claim 15, further comprising: timer means for driving the electric blower and the ion generator for a predetermined length of time after the drive switch is operated. 17. The electric vacuum cleaner according to claim 1, wherein quantities of ions generated by the ion generator is controlled according to a power with which the electric blower is driven. 18. The electric vacuum cleaner according to claim 1, wherein the ion generator is driven for a predetermined length of time according to a storage state of the electric vacuum cleaner. 19. The electric vacuum cleaner according to claim 1, wherein the ion generator has two ion generating electrodes so that the positive and negative ions are generated from the two separate electrodes. 20. The electric vacuum cleaner according to claim 1, wherein the ion generator can variably control a proportion between quantities of positive and negative ions generated.

TECHNICAL FIELD The present invention relates to an electric vacuum cleaner, and more particularly to an electric vacuum cleaner provided with a sterilizing function. BACKGROUND ART As a conventional electric vacuum cleaner provided with an ozone generating function, the one disclosed in Japanese Patent Application Laid-Open No. H1-238815 will be described below with reference to FIG. 30. In this conventional electric vacuum cleaner, inside a body 101 thereof is formed a suction air passage 104 that runs from a hose socket 102 formed in the front wall of the body 101 to an exhaust opening 103 formed in the rear wall of the body 101, and in this suction air passage 104 are arranged a dust collection bag 105, a dust filter 106, and an electric blower 107 in this order. The dust collection bag 105 permits air to pass therethrough. The electric blower 107 communicates with the exhaust opening 103. When the electric blower 107 is driven, air containing dust is sucked in through a suction hose 108 fitted into the hose socket 102, is then passed through the dust collection bag 105, dust filter 106, and electric blower 107, and is then discharged out of the body 101 through the exhaust opening 103. Meanwhile, the dust collection bag 105 removes the dust contained in the air. On the other hand, inside the body 101 of this electric vacuum cleaner, outside and above the suction air passage 104 is formed an ozone reservoir 109, in which an ozone generator 110 is provided. While the electric blower 107 is operating, ozone generated by the ozone generator 110 is reserved in the ozone reservoir 109, and, when the electric blower 107 is de-energized, valves 111 and 112 are opened so that the reserved ozone is fed into the suction air passage 104 so as to kill germs present in the suction air passage 104. In this conventional electric vacuum cleaner, the ozone fed into the suction air passage 104 acts on the stream of air that has been cleaned by the dust collection bag 105, but does not sufficiently act on the dust and germs collected in the dust collection bag 105. This makes it impossible for ozone to exert a satisfactory antibacterial effect. Moreover, since ozone is reserved in the ozone reservoir 109 during operation, the body 101, which is formed of synthetic resin, is exposed to the reserved ozone for a long time. This causes the body 101 to deteriorate, making it prone to cracks and breakage in the relevant part thereof In particular, in a vacuum-type cleaner, cracks are likely to develop in a part thereof where the pressure is low during operation, lowering the suction performance and leading ultimately to a burst. DISCLOSURE OF THE INVENTION The present invention has been devised to address the aforementioned problems with conventional electric vacuum cleaners. Specifically, according to the present invention, an electric vacuum cleaner that, while driving an electric blower, sucks in air containing dust such as dirt, particulate dust, and water, then passes the air through a suction air passage, and then discharges the air out of itself is provided with an ion generator. The ion generator generates H+(H2O)n as positive ions and O2−(H2O)m as negative ions, which are fed into the suction air passage. In this construction, the positive and negative ions generated by the ion generator are discharged into the suction air passage so as to sterilize the stream of air, exerting a satisfactory antibacterial effect. The ion generator may be disposed outside the suction air passage, with the ions fed into the suction air passage. The positive and negative ions generated by the ion generator may be fed into the air on the downstream side of the electric blower where the air is about to be discharged. Incidentally, as the ion generator generates positive and negative ions, it also generates ozone as a byproduct. Accordingly, by treating the part of the suction air passage around the needle-shaped electrode with anti-ozone treatment, it is possible to prevent its deterioration caused by ozone. As is well known, as temperature rises, ozone exerts increasingly high oxidizing power, prompting the deterioration of the components arranged nearby, especially those formed of resin materials. For this reason, to reduce the oxidizing power of the ozone present around the electrode, i.e., the source at which ozone is generated, it is ideal to place the ion generator away from a heat source such as the electric blower. By passing the air sucked into the electric vacuum cleaner through an purification filter before discharging it out of the electric vacuum cleaner, and by mixing the air that has been passed through the purification filter with the positive and negative ions, it is possible to kill germs that have passed through the purification filter without being caught by it. Alternatively, according to the present invention, an electric vacuum cleaner that has casters arranged on both side faces of a body having an electric blower housed therein and that exhausts the electric blower of air through ventilation openings formed in the casters is provided with an ion generator that generates H+(H2O)n as positive ions and O2−(H2O)m as negative ions into a mixing chamber formed by the casters. In this construction, positive and negative ions are generated by the ion generator inside the mixing chamber formed by the casters, and the positive and negative ions are then discharged, by being carried by the stream of air passing through the electric vacuum cleaner, through the ventilation openings formed in the casters to sterilize the interior of the room. This is expected to produce a satisfactory antibacterial effect. Alternatively, an electric vacuum cleaner has an electric blower and an ion generator housed in a body, and the body is provided with, independently of a control panel for controlling the electric vacuum cleaner, a drive switch for driving the ion generator. With this construction, for example, when only the body of the electric vacuum cleaner, i.e., with its hose removed, is placed inside a closet or the like, and the drive switch is turned on to suck in and discharge the air inside the space such as a closet, it is possible to discharge the generated positive and negative ions into the space and thereby achieve purification in the space. In this case, it is preferable to provide timer means for driving the electric blower and the ion generator for a predetermined length of time after the drive switch is operated. The quantities of ions generated by the ion generator may be controlled according to the power with which the electric blower is driven. This prevents unnecessary operation of the ion generator, and thus helps extend its life. Moreover, it is possible to prevent unnecessary discharge of ions. The ion generator may be driven for a predetermined length of time according to the storage state of the electric vacuum cleaner. This permits purification to be performed automatically for a predetermined length of time inside a comparatively airtight space such as the storage space during storage. If both positive and negative ions are generated with a single ion generating electrode, part of them cancel each other, resulting in lower effective quantities of ions generated at the initial stage of generation. To avoid this, it is preferable to provide two electrodes so that positive and negative ions are generated from separate electrodes. This makes it possible to variably control the proportion between the quantities of positive and negative ions generated. Incidentally, the aforementioned ion generator is of the type that generates both positive and negative ions or negative ions alone. It is believed that positive and negative ions exert an effect of killing germs floating in the air, and that negative ions exert an effect of relaxing the feelings of humans. It is particularly preferable to design and operate the ion generator in such a way that, when air is fed to the ion generating part thereof at the rate of 50 cm/s or more, the concentrations of positive and negative ions are each 10,000 ions/cm3 or more at a position 10 cm away from the ion generating part. This helps obtain a high sterilizing effect. Here, only such examples are dealt with in which an electric vacuum cleaner is provided with an ion generator. It is, however, also possible to provide an ion generator for generating ions in any device that is furnished with an air blowing means and a moving means, such as wheels, so that it can be moved around while in use, for example a mobile cleaning robot. This permits the ion generator to be moved around while in operation, and thus makes it possible to purify air efficiently and unattendedly over a wide area or behind an obstacle where a stationary ion generator cannot reach. Thus, it is possible to purify air wherever such a device can be brought into without performing cleaning by suction. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an external side view showing the electric vacuum cleaner of a first embodiment of the invention. FIG. 2 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 3 is an enlarged side sectional view showing the internal construction of the ion generator used in the electric vacuum cleaner. FIG. 4 is an enlarged view of another example of the needle-shaped electrode of the ion generator. FIG. 5 is an enlarged view of still another example of the needle-shaped electrode of the ion generator. FIG. 6 is a sie sectional view showing the internal construction of the electric vacuum cleaner of a second embodiment of the invention. FIG. 7 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a third embodiment of the invention. FIG. 8 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fourth embodiment of the invention. FIG. 9 is an external perspective view of the ion generator used in the electric vacuum cleaner, as seen from the ion generating element side. FIG. 10 is an external perspective view of the ion generator, as seen from the side opposite to the ion generating element. FIG. 11 is an exploded perspective view of the ion generator. FIG. 12A is an outline perspective view showing the ion generating element of the ion generator. FIG. 12B is a sectional view showing the ion generating element of the ion generator. FIG. 13 is an enlarged side sectional view sowing another example of the infernal construction of the ion generator. FIG. 14 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 15 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fifth embodiment of the invention. FIG. 16 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 17 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 18 is a vertical sectional view showing the internal construction of the body, in its rear part, of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 19 is a sectional view taken along line A-A shown in FIG. 18. FIG. 20A is a side view showing the posture of the body of the electric vacuum cleaner during cleaning operation. FIG. 20B is a side view showing the posture of the body of the electric vacuum cleaner during storage. FIG. 21 is a sectional view taken along line A-A shown in FIG. 18, showing another example of the electric vacuum cleaner. FIG. 22 is a vertical sectional view showing the internal construction of the body, in its rear part, of still another example of the electric vacuum cleaner. FIG. 23 is an external perspective view showing the electric vacuum cleaner of an eighth embodiment of the invention. FIG. 24 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 25 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a ninth embodiment of the invention. FIG. 26 is a diagram showing the measurements of the concentrations of ions generated by the electric vacuum cleaner. FIG. 27 is a diagram showing the effect of eliminating ammonia achieved by the operation of the electric vacuum cleaner. FIG. 28 is a side sectional view showing the internal construction of the body of an example of an exhaust-recycling-type electric vacuum cleaner provided with an ion generator. FIG. 29A is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit that drives the electric blower and ion generator simultaneously. FIG. 29B is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit used when the ion generator shown in FIG. 13 is provided in the body. FIG. 30 is an external side sectional view of a conventional electric vacuum cleaner. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. The examples described hereinafter all deal with a so-called cyclone-type electric vacuum cleaner, in which air containing dust and the like is sucked into a cylindrical dust collection case and is passed through a circular suction air passage in such a way that the air swirls around inside the cylinder of the dust collection case so that, by the action of centrifugal force, the dust and the like contained in the air is separated therefrom and collected. A first embodiment of the invention will be described below with reference to the drawings. FIG. 1 is an external view showing the outward appearance of the cyclone-type electric vacuum cleaner of a first embodiment of the invention, and FIG. 2 is a side sectional view of its body. As will be clear from these figures, the electric vacuum cleaner is roughly divided into the following parts: an electric vacuum cleaner body (hereinafter, simply the “body”) 1; a dust collector 2 that is removably attached to the body 1; a connection pipe 3 that has a control panel 4 and a handle 5 provided at the upper end thereof and that has a nozzle unit 6 removably attached to the lower end thereof; and a connection hose 7 of which one end is removably connected to the connection pipe 3 and of which the other end is removably fitted into a hose socket 8 formed as an air intake opening in the body 1. As shown in FIG. 2, the body 1 is built as a casing of which the contour as seen from the side is substantially L-shaped so as to form, in a central part in the top face thereof, a housing 9 for removably supporting the dust collector 2. Inside the body 1 are provided the following parts: a first suction air passage 10 that starts from the hose socket 8, which is formed in the front wall of the body 1, then extends horizontally inside the body 1, then bends upward, and then connects to a first coupling member 11 provided on a horizontal wall surface 9a of the housing 9; a second suction air passage 13 that is, at one end thereof, connected to a second coupling member 12 provided on the horizontal wall surface 9a at a level higher than the first coupling member 11 and that then bends downward so that the other end thereof extends toward an exhaust opening 1b formed in the rear wall of the body 1; an electric blower 14 that is connected to the other end of the second suction air passage 13; and a deodorizing filter 15 that is disposed between the electric blower 14 and the exhaust opening 1b. As shown in FIG. 2, the dust collector 2 is composed of the following parts: a dust cup 16 built as a cylindrical container that is open at the top and that has an inflow pipe 20 fitted into the side wall thereof; a lid 17 that is fitted on the dust cup 16 so as to close the top opening thereof; an exhaust cylinder 18 that is fitted in a central part of a separator plate 17a provided in the lid 17 so as to suspend therefrom into the dust cup 16; and an exhaust pipe 19 that is housed inside the lid 17 and that is connected, at one end thereof, to an exhaust port 18a of the exhaust cylinder 18 and, at the other end thereof, to an outflow pipe 21 fitted into the side wall of the lid 17. A filter 18b is arranged in the outer circumferential wall of the exhaust cylinder 18. The dust collector 2 is removably housed in the housing 9 of the body 1, and, when it is housed in position, the inflow pipe 20 and outflow pipe 21 communicate with the first coupling member 11 and second coupling member 12, respectively. Here, the first coupling member 11 and second coupling member 12 are both formed of elastic material such as rubber so that, in particular by flange-like parts formed at one end thereof, their communication with the inflow pipe 20 and outflow pipe 21 is kept air-tight when the dust collector 2 is housed in the housing 9. A handle 22 is fitted on the top surface of the lid 17 of the dust collector 2. An ion generator 23 is disposed near the hose socket 8, on the inner surface side of the top wall of the body 1. The ion generator 23 discharges ions from an electrode by applying a voltage to the electrode. Here, by switching the type (negative or positive) of the voltage with which the electrode is loaded, it is possible to switch the generated and thus discharged ions between positive and negative ions. By providing a selecting means for switching, continuously or at predetermined time intervals, the type of the voltage with which the electrode is loaded, it is possible to easily choose between positive and negative ions. Negative ions exert a healing effect, and discharging positive and negative ions simultaneously produces a sterilizing effect. The ion generator 23 may be configured in any manner, so long as it is designed as a device provided with a means for generating ions. In the following descriptions, the healing, sterilizing, and other effects brought about by ions are collectively referred to as “purification.” Now, the ion generator 23 will be described, assuming that it has a needle-shaped electrode. A practical example of the details of the ion generator 23 is shown in FIG. 3. As shown in this figure, the ion generator 23 has a body casing 24, which has an ion outflow port 25 formed in the bottom face thereof and of which the interior is divided into a front chamber 27, a rear chamber 28, and an upper chamber 29. The front chamber 27 is located in front of the rear chamber 28, with the two chambers separated from each other by a separation wall 26. The upper chamber 29 is located above the front and rear chamber 27 and 28, and communicates only with the rear chamber 28 through a communication port 26a. In the front chamber 27 is arranged an ion generating circuit 30. On the other hand, in the rear chamber 28, which serves as an ion generation chamber, is arranged a needle-shaped electrode 31, which has its tip end shaped into a needle pointing toward the ion outflow port 25 and which serves as an ion generating element. A conductor lead 32, which is formed of a single wire, runs from the ion generating circuit 30, then penetrates the separation wall 26, and then further runs inside the rear chamber 28, where the conductor lead 32 is supported by a supporting member 33 formed of insulating material such as synthetic resin and provided on the wall. Below the supporting member 33, the conductor lead 32 connects, both electrically and mechanically, to the needle-shaped electrode 31, with the needle-shaped end thereof pointing downward. Thus, supported by the supporting member 33 at its top, the needle-shaped electrode 31 is stably kept in position. In a case where the conductor lead 32 is formed of twisted wires, the needle-shaped electrode 31 may be supported directly by the supporting member 33. A filter 34 is arranged in the upper chamber 29. The ion generator 23 configured as described above is disposed near the hose socket 8, on the inner surface side of the top wall of the body 1, with the ion outflow port 25 connected to a connection port 10a formed in the middle of the first suction air passage 10. The filter 34 arranged inside the upper chamber 29 faces a number of air intake holes 36 formed in the top wall of the body 1. More precisely, these air intake holes 36 are formed all over a reversed-dish-shaped cover 35 that closes an opening la formed in the top wall of the body 1 and thereby covers the filter 34 arranged in the upper chamber 29. In FIG. 2, the deodorizing filter 15 located on the downwind side of the needle-shaped electrode 31 is composed of a corrugated-honeycomb-shaped member coated with a low-temperature deodorant catalyst and an absorbent. This deodorizing filter 15 is removably disposed between the electric blower 14 and the exhaust opening 1b so that it can be replaced and cleaned to keep the interior of the electric vacuum cleaner clean. The deodorizing filter 15 may be composed of a filter or a piece of unwoven fabric impregnated with a low-temperature deodorant catalyst and an absorbent, but a honeycomb-shaped structure is preferable because it minimizes the pressure loss. The deodorizing filter 15 may be treated with antibacterial treatment. The low-temperature deodorant catalyst is a copper-manganese-based oxide that oxidizes and thereby decomposes order-producing substances such as amine- and thiol-based volatlie substances and hydrogen sulfide. A copper-manganese-based oxide also funstions as an ozone-decomposing catalyst, and thus helps decompose ozone. This eliminats the need to separately provide an ozone eliminating device, and thus helps minimize the increse in the manufacturing costs of the electric vacuum cleaner. Moreover, it is possible to reduce the ozone concentration to so low a level as to be negligible in terms of the deteriorztion of resin-molded components. Thus, the ozone contained in the air sucked in is decomposed by the deodorizing filter 15 provided in the body 1, and is therefore not discharged out of the body 1. The deodorizing filter 15 may be impregnated with a dedicated ozone-decomposing catalyst that effectively decomposes ozone. Examples of such ozone-decomposing catalysts include, to name a few, manganese dioxide, platinum powder, lead dioxide, copper oxide II, and nickel. The deodorizing filter 15 may be provided with a HEPA filter or a sterilizing filter impregnated with a germicide. This helps further enhance the sterilizing, antibacterial, and dust-removing effects. The deodorizing filter 15 may be impregnated with an absorbent. This absorbent is for absorbing odor-producing substances, ozone, and airborne germs. Examples of such absorbents include, to name a few, silica gel, activated charcoal, zeolite, and sepiolite. The deodorizing filter 15 may be separately provided with a granulate or particulate absorbent. The electric vacuum cleaner according to the invention is constructed as described above, and operates as described below. When the control panel 4 is so operated as to start operation, the electric blower 14 and the ion generating circuit 30 are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 and the ion generating circuit 30 starts to operate to apply a high voltage to the needle-shaped electrode 31. As a result, first, as the electric blower 14 is driven, as indicated by broken-line arrows in FIG. 1, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the connection pipe 3, connection hose 7, and hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as indicated by broken-line arrows in FIG. 1, the stream of air passing through the first suction air passage 10 produces a negative pressure near the connection port 10a and the ion outflow port 25, and thus the air in the rear chamber 28, which serves as the ion generation chamber of the ion generator 23, is sucked into the first suction air passage 10. As a result, air is sucked in through the air intake holes 36 from outside, is then passed through the filter 34, and is then, along with the ions generated in the rear chamber 28, sucked into the first suction air passage 10. A blower (for example, like the blower 23a shown in FIG. 13) may be additionally provided to blow out the generated ions through the ion outflow port 25 of the ion generator 23. This permits ions to be fed effectively into the first suction air passage 10. Moreover, ions can then be discharged irrespective of whether the electric blower 14 is being driven or not. This makes it possible to discharge ions to purify air even when the electric blower 14 is not operating. This air containing ions is, along with the stream of air sucked through the hose socket 8 into the first suction air passage 10, sucked through the first coupling member 11 and the inflow pipe 20 into the dust cup 16 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. On the other hand, the air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. Meanwhile, various germs present in the stream of air are killed by the ions generated by the needle-shaped electrode 31, with the result that the air is purified. The present invention works as described above, and the ion generator 23 mentioned above works as described below. When a high voltage is applied from the ion generating circuit 30 by way of the conductor lead 32 to the needle-shaped electrode 31, an electric field concentrates on the point of the needle-shaped electrode 31. Thus, when the air taken in through the air intake holes 36 reaches around the needle-shaped electrode 31, insulation in the air is destroyed locally at the point of the needle-shaped electrode 31, causing corona discharge. The corona discharge here produces positive and negative ions, which flock together and surround airborne germs floating in the air and kill them by the action of active species such as hydroxyl radical —OH and hydrogen peroxide H2O2. Thereafter, the deodorizing filter 15 absorbs and thereby eliminates the odor-producing substances originating from the dust and the like collected in the dust cup 16 and elsewhere and the minute quantity of ozone produced by the corona discharge. When the motor 54 of the electric blower 14 is not operating, positive and negative ions may be fed directly to the dust cup 16 to fill it with the ions so as to enhance the sterilizing effect inside the dust cup 16. In this embodiment, the conductor lead 32 is given a length of 200 mm or less to reduce the lowering of discharge efficiency and to permit easy wiring. Preferably, the conductor lead 32 is given a length of 100 mm or less to further reduce the lowering of discharge efficiency; more preferably, it is given a length of 50 mm or less to permit connection of the needle-shaped electrode 31 with almost no lowering of discharge efficiency. As the result of the corona discharge at the needle-shaped electrode 31, when the voltage applied thereto is positive, positive ions, mainly H+(H2O)n, are generated; when the voltage is negative, negative ions, mainly O2−(H2O)m, are generated. These positive and negative ions, namely H+(H2O)n and O2−(H2O)m, flock together on the surface of microorganisms, and surround airborne germs such as microorganisms present in the air. Then, as expressed by the formulae noted below, they collide together to produce active species, namely hydroxyl radical —OH and hydrogen peroxide H2O2, on the surface of microorganisms and the like and thereby kill airborne germs. In this way, in this embodiment, airborne germs present in the air are killed by the action of positive and negative ions. This makes it possible to obtain a more efficient sterilizing effect than with conventional methods of sterilization exploiting the action of ozone. H+(H2O)n+O2−(H2O)m→—OH+1/2O2+(n+m)H2O (1) Moreover, there is provided no opposing electrode opposite the needle-shaped electrode 31, or no collecting electrode for collecting positive ions. Thus, no ions are absorbed by such electrodes due to a voltage difference. This permits ions to be spread widely inside the rear chamber 28, i.e., the ion generation chamber, even without a strong blow of air. Accordingly, the ions spread in the rear chamber 28 are then efficiently sucked through the connection port 10a and the ion outflow port 25 into the first suction air passage 10. This helps enhance the sterilizing power. Moreover, both a positive and a negative voltage are applied to the needle-shaped electrode 31, and therefore the ion generating circuit 30 never remains charged even without being grounded. This eliminates the need to secure a ground to the earth, and thus permits the electric vacuum cleaner to be moved freely around. According to formulae (1) to (3) noted above, to produce the active species, the quantity of negative ions generated needs to be equal to or larger than the quantity of positive ions generated. In this embodiment, the quantity of positive ions generated is made smaller than that of negative ions. This permits positive and negative ions to flock together on the surface of microorganism and produce active species to kill airborne germs, and simultaneously permits the extra negative ions to suppress the proliferation of airborne germs. Here, if the quantity of positive ions generated is less than 3% of the quantity of negative ions generated, —OH is produced in too small a quantity to obtain satisfactory sterilizing power. For this reason, in this embodiment, where sterilization is aimed at, the quantity of positive ions generated is made 3% or more of the quantity of negative ions generated. Moreover, by making the quantity of positive ions generated equal to or more than 5,000 ions (preferably, 10,000 ions) per 1 cm3, it is possible to obtain sufficient sterilizing power. Moreover, by providing control that permits the proportions of positive and negative ions generated to be varied, it is possible to generate appropriate quantities of positive and negative ions according to whether the desired effect is a sterilizing, healing, or other effect. Two ways of controlling the quantities of ions generated are: (1) to vary the durations for which a positive and a negative voltage are applied respectively; and (2) to control the duty of voltage application, i.e., the durations for which a voltage is and is not applied. Moreover, the voltage applied to the needle-shaped electrode 31 is made so low as to minimize the quantity of ozone produced by corona discharge. In addition, when the duty is controlled, it is preferable to turn on and off the applied voltage repeatedly at short time intervals, because this helps reduce the generation of ozone. As temperature rises, ozone exerts increasingly high oxidizing power, prompting the deterioration of the components arranged nearby, especially those formed of resin materials. To cope with this problem, in this embodiment, the needle-shaped electrode 31 is disposed in an upstream part of the stream of air so as not to be affected by the heat generated by the electric blower 14, i.e., inside the rear chamber 28, which is located away from a heat source such as the electric blower 14. As a result, even when ozone is generated, its oxidizing power around the needle-shaped electrode 31, i.e., the source at which it is generated, is minimized. As shown in FIG. 4, the needle-shaped electrode 31 may be composed of a plurality of needle-shaped conductors 31a that are kept at an equal potential and that are supported by a common supporting member 33 via conductor leads 32a. Alternatively, as shown in FIG. 5, a plurality of needle-shaped parts 31b, for example three of them, may be formed at the lower end of a single needle-shaped electrode 31. In this case, ions are discharged from the ends of the needle-shaped parts 31b into a range of angles covering about 45°. In this way, by arranging a plurality of needle-shaped parts 31b so that they point in different directions, it is possible to discharge ions into a wide range and thereby obtain enhanced purifying power. The direction in which the needle-shaped electrode 31 causes discharge is set to be along the direction of the stream of air. This permits ions to be discharged over a wider area in the direction of the stream of air. This also makes dust less likely to settle on the needle-shaped electrode 31, permitting easy maintenance. Part of the wall of the suction air passage, especially the part thereof located on the downstream side of the ion generator 23, may be treated with anti-ozone treatment as by being coated with a metal, or being coated with an ozone-resistant substance, or being covered with a metal sheet. This helps confine most of the generated ozone inside the wall of the suction air passage, and thus helps alleviate the deterioration of the components arranged nearby other than the wall of the suction air passage. If the distance (L in FIG. 3) between the supporting member 33 and the needle-shaped electrode 31 is too short, when the humidity in the room where cleaning is performed is high, a high voltage may be applied to the supporting member 33. To avoid this, the distance L is set to be 3.5 mm or more, for example 5 mm, so that the supporting member 33 is located away from the needle-shaped electrode 31 and is thereby surely insulated therefrom. This permits the high voltage to be stably applied to the needle-shaped electrode 31, permits corona discharge to take place surely, and thus permits ions to be discharged stably. When both positive and negative ions are generated with a single needle-shaped electrode 31, part of them cancel each other, resulting in lower effective quantities of ions generated at the initial stage of generation. This problem can be overcome by providing two electrodes so that positive and negative ions are generated separately. This helps increase the effective quantities of ions generated. Moreover, this construction permits the two electrodes to be controlled independently, and thus permits easy and separate adjustment of the quantities of positive and negative ions. Needles to say, even when two electrodes are provided in this way, it is possible to drive only one of them to generate ions of one type alone. As the circuit configuration, applied voltage, electrode shape, electrode material, and other factors are varied, the two electrodes, for example a plurality of electrodes consisting of two types of electrodes, permit easy adjustment of the balance with which ions are generated. Moreover, by arranging the two electrodes 10 mm or more, for example 30 mm, apart from each other, it is possible to use the generated ions effectively for sterilization with almost no cancellation between positive and negative ions. The two electrodes may be given any other shape than a needle-like one. For example, ions may be generated with a voltage applied between electrodes that are arranged so as to face each other with an insulator sandwiched in between. By arranging a plurality of electrodes at predetermined intervals (for example, 10 mm) in a direction approximately perpendicular to the direction of the stream of air, and arranging the electrodes, especially when there are provided three or more of them, in such a way that they are inclined alternately in opposite directions, and arranging every two adjacent electrodes, which are inclined in opposite directions, at predetermined angles such that their points tend to overlap, i.e., make contact with, each other in the direction of the stream of air (for example, at angles of about 30° in such directions in which they come closer together toward the stream of air). This permits ions to be generated and distributed more evenly over a wider area, and thus helps further enhance the sterilizing power. In this case also, as described above, by generating positive and negative ions alternately, or by generating positive and negative ions with separate electrodes, it is possible to efficiently and evenly generate and distribute ions over a wide area, and thereby further enhance the sterilizing power. The ion generator 23 is driven with one of the following patterns of timing: (1) The ion generator 23 is turned on and off completely in synchronism with the timing with which the power switch of the electric blower 14 is turned on and off. This permits the ion generator 23 to be turned on and off as the user wishes it to be, and thus contributes to safety. (2) The ion generator 23 is turned off with a delay after the power switch of the electric blower 14 is turned off. This permits sterilization of the air that has just been exhausted and is still floating around. (3) The ion generator 23 is turned on and off independently of the turning on and off of the power switch of the electric blower 14. This permits the ion generator 23 to be turned on to purify air even during storage, and thus makes it possible to purify the air inside the storage space, for example a closet, during storage. (4) The quantities of ions generated are controlled in a manner interlocked with the control of the power with which the electric blower 14 is driven. This prevents unnecessary operation of the ion generator 23, and thus helps extend its life. Moreover, it is possible to prevent unnecessary discharge of ions. A second embodiment of the invention will be described below with reference to the drawings. FIG. 6 is a diagram showing the second embodiment of the invention. In this embodiment, an ion generator 23 is coupled to the inner wall surface of the ceiling of the lid of the dust collector 2. The ion outflow port 25 formed in the bottom face of the body casing 24 communicates with an opening 17b formed in the separator plate 17 of the lid 17, and outside air is taken in through air intake holes 36 formed in the ceiling wall of the lid 17. In this construction, when the control panel 4 is so operated as to start operation, the electric blower 14 and the ion generating circuit 30 are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 and the ion generating circuit 30 starts to operate to apply a high voltage to the needle-shaped electrode 31. As a result, first, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as indicated by broken-line arrows in FIG. 6, the air sucked into the suction air passage 10 is sucked through the inflow pipe 20 into the dust cup 16 of the dust collector 2 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. On the other hand, as indicated by broken-like arrows in FIG. 6, the air swirling around inside the dust cup 16 produces a negative pressure near the ion outflow port 25, and thus the air in the rear chamber 28 is sucked into the dust cup 16. As a result, the air sucked in through the air intake holes 36 from outside is passed through the filter 34, is then, along with the ions generated in the rear chamber 28, sucked into the dust cup 16, is then, along with the stream of air swirling inside the dust cup 16, into the second suction air passage 13, and is then passed through the electric blower 14 and the deodorizing filter 15 so as to be discharged out of the body 1 through the dust cup 16. Meanwhile, various germs present in the stream of air are killed by the ions generated by the needle-shaped electrode 31, with the result that the air is purified. In this embodiment, as described above, the ion generator 23 is disposed inside the dust collector 2 and outside the suction air passage, and the ions generated by the ion generator 23 are discharged evenly over the entire upper region of the interior of the dust cup 16. This permits effective killing of airborne germs captured inside the dust cup 16 over the entire region thereof. A third embodiment of the invention will be described below with reference to the drawings. FIG. 7 is a diagram showing the third embodiment of the invention. In this embodiment, an ion generator 23 is disposed along the second suction air passage 13. Specifically, the body casing 24 of the ion generator 23 is disposed along the second suction air passage 13. The ion outflow port 25 formed in the bottom face of the body casing 24 communicates with the second suction air passage 13, and outside air is taken in through air intake holes 36 formed in an upper part of the side wall of the body 1. In this construction, when the control panel 4 is so operated as to start operation, the electric blower 14 and the ion generating circuit 30 are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 and the ion generating circuit 30 starts to operate to apply a high voltage to the needle-shaped electrode 31. As a result, first, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as shown in FIG. 7, the air sucked into the first suction air passage 10 is sucked through the inflow pipe 20 into the dust cup 16 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. On the other hand, the stream of air passing through the second suction air passage 13 produces a negative pressure near the ion outflow port 25, and thus the air in the rear chamber 28 is sucked into the second suction air passage 13. As a result, air is sucked in through the air intake holes 36 from outside, is then passed through the filter 34, and is then, along with the ions generated in the rear chamber 28, passed through the second suction air passage 13 to the electric blower 14. Thereafter, the air is passed through the deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. Meanwhile, various germs present in the stream of air are killed by the ions generated by the needle-shaped electrode 31, with the result that the air is purified. The present invention is applicable not only to cyclone-type electric vacuum cleaners but also to electric vacuum cleaners of any other types. A fourth embodiment of the invention will be described below with reference to the drawings. The first to third embodiments described above deal with an ion generator 231 having a needle-shaped electrode. The ion generator 231 is simply for discharging ions from an electrode as a result of application of a voltage thereto, and thus can be constructed in various manners. The fourth to seventh embodiments described below deal with a grid-shaped ion generator 231 that is constructed differently from the ion generator 23 having a needle-shaped electrode as shown in FIG. 3. First, the construction of the ion generator 231 will be described. FIG. 9 is an external perspective view of the ion generator 231 as seen from the ion generating element 210 side thereof, and FIG. 10 is an external perspective view of the ion generator 231 as seen from the opposite side. FIG. 11 is an exploded perspective view of the ion generator 231, FIG. 12A is an external perspective view of the ion generating element 210, and FIG. 12B is a sectional view of the generating element 210. The ion generating element 210 includes: a surface electrode 213 laid on the surface of a flat-plate-shaped dielectric 211; a surface electrode contact 215 formed on the surface of the dielectric 211 to permit electric power to be fed to the surface electrode 213; an inner electrode 212 buried inside the dielectric 211 and laid parallel to the surface electrode 213; and an inner electrode contact 214 formed on the surface of the dielectric 211 to permit electric power to be fed to the inner electrode 212. The dielectric 211 is composed of a top plate 211a, a bottom plate 211b, and a surface protection plate 211c. The ion generator 231, which incorporates the ion generating element 210 structured as described above, is provided with a voltage step-up coil 251, a circuit board 252, a common case 253, and a lid plate 254. The voltage step-up coil 251 has a pair of high-voltage terminals and a pair of input terminals provided on one side of a resin case. A circuit for generating a waveform for driving the ion generating element 210 is formed on one surface (the lower surface in FIG. 11) of the circuit board 252, and thus on this surface of the circuit board 252 are mounted various circuit components, such as capacitors and semiconductor devices. The circuit board 252 has four connection pins for external connection provided so as to protrude from the one surface. The common case 253 is box-shaped. The common case 253 has a rectangular opening formed all over one side thereof to permit the circuit board 252 to be inserted therein. On the opposite side thereof, the common case 253 has a bottom part having a semicircular sectional shape. This bottom part is divided into a coil housing 253b and a circuit component housing 253c by a partition wall 253a, which is formed substantially perpendicularly to the length direction and has a predetermined height. All around the inside of the common case 253, at the same height as the upper edge of the partition wall 253a, a support frame for supporting the circuit board 252 is formed so as to protrude inward. At the rim of the open side of the common case 253, at two separate places on each of the opposite longer sides, depressions are formed with which the lid plate 254 engages. The lid plate 254 is a flat plate formed of a resin material. In one side of the lid plate 254 along its length, a rectangular depression is formed that corresponds to the ion generating element 210. In this depression is formed a hole 254a, which has an elliptic window hole and a resistive element cavity integrally formed to penetrate the lid plate 254 in positions corresponding to the surface electrode contact 214 and the inner electrode contact 215 of the ion generating element 210. When the ion generating element 210 is fitted into the aforementioned depression of the lid plate 254 structured as described above, the lid plate 254 integrally holds the ion generating element 210. To build the ion generator 231, the voltage step-up coil 251, circuit board 252, common case 253, and the lid plate 254 having the ion generating element 210 secured thereto, of which each is structured as described above, are assembled together in the following manner. First, the voltage step-up coil 251 is inserted, with the aforementioned high-voltage, ground, and input terminals protruding upward, into the coil housing 253b formed in the bottom part of the common case 253. Then, the coil housing 253b is filled with a filling material 255 under a vacuum in such a manner as to prevent entry of bubbles. Thus, a molding for insulation is formed. Thereafter, after the filling material 255 is dried and cured, the circuit board 252 is inserted into the common case 253 through its top opening. The insertion here is performed in the following manner. First, the component-mounted side of the circuit board 252 is kept down, and the connection holes for connection to the voltage step-up coil 251 are positioned right above the voltage step-up coil 251 secured in the coil housing 253b. Then, the circuit board 252 is inserted until the bottom surface thereof strikes the partition wall 253c and the support frame. After the insertion, the aforementioned high-voltage, ground, and input terminals are, at their one end, welded to their respective positions on the top surface of the circuit board 252. As a result of this welding, the circuit board 252 is supported from below by the support frame and the top edge of the partition wall 253a, and is fixed in position, with the high-voltage, ground, and input terminals serving as the support legs of the circuit board 252, by the voltage step-up coil 251, which in turn is fixed in position by the filling material 255. After the circuit board 252 is fitted in this way, the lid plate 254, with the ion generating element 210 held therein as described above, is fitted. Here, the fitting is performed in the following manner. The hole 254a formed in one side of the lid plate 254 along its length is positioned right above the window hole formed in the circuit board 252 previously fixed in the common case 253, and then, while the surface of the lid plate 254 on which the ion generating element 210 is held is kept up, the lid plate 254 is fitted into the top opening of the common case 253. Here, the engagement claws formed on opposite edges of the lid plate 254 deform and then retrieve their original shapes to thereby engage with the corresponding depressions formed at the rim of the opening of the common case 253. Thus, the lid plate 254 is fitted at an appropriate distance from the top surface of the circuit board 252 in such a way as to close the opening of the common case 253. After the fitting, the filling material 255 is introduced through a window hole 254b formed in the lid plate 254 so that the filling material 255 fills the space between the lid plate 254 and the circuit board 252. In this way, the space between the circuit board 252 and the ion generating element 210 is filled with a molding for insulation. When the filling material 255 is dried and cured, the assembly of the ion generator 231 is complete. The purpose of using a grid-shaped electrode as the surface electrode 213 as shown in FIGS. 12A and 12B is to maximize the quantities of ions generated when a drive voltage is applied thereto. On the other hand, the inner electrode 212 is formed as a strip-shaped electrode of which the center coincides with the center of the surface electrode 213 and which is smaller than the surface electrode 213 in both length and width. This shape also contributes to maximizing the quantities of ions generated. For example, a top plate 211a and a bottom plate 211b, each about 0.45 mm thick, are laid together to form a dielectric 211 measuring about 15 mm×37 mm×0.9 mm. On the surface of this dielectric 211, conductors, each 0.25 mm wide, are arranged vertically and horizontally with a pitch of 0.8 mm to form a grid-shaped surface electrode 213 measuring about 10.4 mm×28 mm. Moreover, between the top plate 211a and the bottom plate 211b, a sheet-shaped inner electrode 212 measuring about 6 mm×24 mm is formed. When, as a drive voltage, a high-voltage current having a voltage of about 4.6 kV (peak) and a frequency of 22 kHz was applied between those electrodes, it was confirmed that the plasma discharge that occurred between the electrodes 212 and 213 generated over 200,000 ions/cc of positive ions and over 200,000 ions/cc of negative ions at a position 25 cm away from the ion generating element 210. These quantities of ions generated are sufficient for air purification in a typically-sized room in a household. The quantities of ions generated by the ion generator 231 can be increased by making the ion generating element 210 larger, or by making the drive voltage higher. However, when the drive voltage is increased, the quantity of ozone generated increases accordingly. Thus, it is not preferable to excessively increase the drive voltage, and it is preferable, for example, to intermittently apply the drive voltage so as to reduce the quantity of ozone generated and simultaneously save energy. In a case where the ion generator 231 constructed as described above is used in one of the electric vacuum cleaners of the embodiments that have already been described and those which will be described later, it is preferable that the ion generator 231 be disposed near the stream of air produced when the electric blower 14 is driven, and that the ion generator 231 be fitted in such a way that the surface thereof on which the ion generating element 210 is fitted faces the stream of air. In this case, as opposed to in the ion generator 23 shown in FIG. 3, the ion generating element 210 is exposed, and thus can be fitted in a position where it easily faces the stream of air. After the fitting, connection terminals 257 and 258 (see FIG. 10) on the outside of the common case 253 are connected to an unillustrated external power supply and to the control circuit of the electric vacuum cleaner, so that the ion generator 231 generates ions and discharges them in a form mixed with the stream of air produced inside and outside the electric vacuum cleaner. Here, the positive ions mentioned above are cluster ions each having a plurality of water molecules attached around a hydrogen ion (H+), and are expressed as H+(H2O)m (where m is a natural number). On the other hand, the negative ions are cluster ions each having a plurality of water molecules attached around an oxygen ion (O2−), and are expressed as O2−(H2O)n (where n is a natural number). After being discharged in a form mixed with the air produced inside and outside the electric vacuum cleaner, those positive and negative ions, as described earlier, flock together around airborne objects (particles, bacteria) present in the air inside the space into which they have been discharged, and chemically react with each other to produce, as an active substance, hydrogen peroxide H2O2 or hydroxyl radical —OH. Thus, through an oxidation reaction, the ions deactivate airborne particles and kill airborne bacteria. As a result, it is possible to purify the air inside the suction air passage running through the electric vacuum cleaner described below and the air present in the living room where the electric vacuum cleaner is used. As shown in FIG. 13, the ion generator 231 may be provided with an ion discharge fan 23a so that ions are discharged by a stream of air produced as the ion discharge fan 23a rotates. Specifically, the ion generator 231 and the ion discharge fan 23a may be housed in a casing 23b and then, along with an ion generating circuit and a power supplying means, built into an ion generator 230, which is then fitted to an electric vacuum cleaner. This makes it easy to additionally incorporate an ozone-separating or -absorbing function into the casing 23b, and thus makes its manufacture easy. As a power supplying means, it is possible to use dry cells, rechargeable cells, or the like. This makes it possible to generate and discharge ions independently. In this way, incorporating the ion discharge fan 23a for discharging ions makes it possible to supply ions irrespective of whether the electric blower 14 is being driven or not. Thus, with the electric vacuum cleaner placed in a place where air needs to be purified, the ion generator 231 and the ion discharge fan 23a can be driven to purify the air in that space. Moreover, by disposing the ion generator 231 and the ion discharge fan 23a in the suction air passage by way of which dust is sucked in through the nozzle unit 6 and air is discharged out of the body 1, it is possible to supply ions more effectively. FIG. 8 is a diagram showing a fourth embodiment of the invention. In this embodiment, the ion generator 231 is disposed on the inside of the rear wall of the body 1 so that ions are discharged into the air that is discharged through the exhaust opening 1b, and are thus discharged into the room by that stream of air. Specifically, near the exhaust opening 1b (for example, closely above the exhaust opening 1b), an ion discharge port 37 is formed to penetrate the rear wall of the body 1, and the ion generator 231 is disposed in close contact with the ion discharge port 37. In this construction, when the control panel 4 (see FIG. 1) is so operated as to start operation, the electric blower 14 and the ion generating circuit (not illustrated) are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 (see FIG. 1) and the ion generating circuit (not illustrated) starts to operate to apply a high voltage to the electrode of the ion generator. First, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as shown in FIG. 8, the air sucked into the first suction air passage 10 is sucked, through the inflow pipe 20, into the dust cup 16 of the dust collector 2 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. The positive and negative ions generated by the ion generator 231 are discharged out of the body 1 through the ion discharge port 37 so as to be mixed with the air near the exhaust opening 1b. As a result, ions are carried by the stream of air discharged through the exhaust opening 1b so as to reach all corners of the room, achieving air purification inside the stream of air and inside the room. As shown in FIG. 14, the electric blower 14 and the deodorizing filter 15 may be disposed at a distance from each other so as to leave a space 40 between the discharge side of the electric blower 14 and the deodorizing filter 15 of the body 1, with the ion generator 231 disposed to point toward the space 40. This permits ions to reach the deodorizing filter 15, and thus makes it possible to kill bacteria settled on the deodorizing filter 15. A fifth embodiment of the invention will be described below with reference to the drawings. FIG. 15 is a diagram showing the fifth embodiment of the invention. In this embodiment, the ion generator 231 is disposed on the outside of the rear wall of the body 1, and ions are generated toward the stream of air discharged through the exhaust opening 1b so that ions are discharged into the room by that stream of air. Specifically, in a rear part of the body 1, a projecting part 39 is formed so as to overhang the exhaust opening 1b, and, below this projecting part 39, an ion generation chamber 38 is formed. The ion generator 231 is deposed inside this ion generation chamber 38. The ion generation chamber 18 is located closely above the exhaust opening 1b, and has an ion discharge port 37 located near the exhaust opening 1b. In this construction, when the control panel 4 (see FIG. 1) is so operated as to start operation, the electric blower 14 and the ion generating circuit (not illustrated) are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 (see FIG. 1) and the ion generating circuit (not illustrated) starts to operate to apply a high voltage to the electrode of the ion generator. As a result, first, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as indicated by broken-line arrows in FIG. 15, the air sucked into the first suction air passage 10 is sucked, through the inflow pipe 20, into the dust cup 16 of the dust collector 2 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged out of the body 1 through the exhaust opening 1b. The ions generated by the ion generator 231 are discharged out of the ion generation chamber 38 through the ion discharge port 37 so as to be mixed with the air near the exhaust opening 1b. As a result, ions are carried by the stream of air discharged through the exhaust opening 1b so as to reach all corners of the room, achieving air purification inside the stream of air and inside the room. As shown in FIG. 16, the ion generation chamber 38 may be so disposed as to discharge ions toward the exhaust opening 1b, with the bottom face of the ion generation chamber 38 made open to form an exhaust opening 41, with the ion generator 231 disposed on the inside of the rear wall thereof, and with an exhaust opening 42 formed near the ion generator 231. This permits ions to be discharged toward the air discharged through the exhaust opening 1b of the body 1, and thus makes it possible to purify the discharged air in a centralized manner so that ions are distributed to all corners of the room through the exhaust openings 41 and 42 by a stream of clean air. A sixth embodiment of the invention will be described below. FIG. 17 is a diagram showing the sixth embodiment of the invention. In this embodiment, ions are mixed with the air that is discharged through the exhaust opening 1b so as to be discharged into the room by that stream of air. Specifically, the exhaust opening 1b is fitted with a cover 43 so as to form a separate mixing chamber 44 below an ion generation chamber 38 provided in a rear part of the body 1, and an exhaust opening 45 is formed in the rear wall of this cover 43. The ion generation chamber 38 is located closely above the exhaust opening 1b, and has an ion discharge port 37 facing the interior of the mixing chamber 44. In this construction, when the control panel 4 (see FIG. 1) is so operated as to start operation, the electric blower 14 and the ion generating circuit (not illustrated) are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 (see FIG. 1) and the ion generating circuit (not illustrated) starts to operate to apply a high voltage to the electrode of the ion generator 231. As a result, first, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the hose socket 8, into the body 1. As air is sucked in in this way, inside the body 1, as shown in FIG. 17, the air sucked into the first suction air passage 10 is sucked, through the inflow pipe 20, into the dust cup 16 of the dust collector 2 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is sucked through the filter 18b into the exhaust cylinder 18, is then passed through the exhaust pipe 19, outflow pipe 21, and second coupling member 12 into the second suction air passage 13, and is then passed through the electric blower 14 and deodorizing filter 15 so as to be discharged through the exhaust opening 1b into the mixing chamber 44. The air remains in the mixing chamber 44 for a while, and is then discharged through the exhaust opening 45 into the room. The ions generated by the ion generator 231 are drawn into the mixing chamber 44 by the stream of air passing therethrough so as to be mixed with the air inside the mixing chamber 44. As a result, inside the mixing chamber 44, the ions are mixed evenly with the air discharged through the exhaust opening 1b. This makes it possible to purify the discharged air in a centralized manner so that ions are distributed to all corners of the room through the exhaust opening 45 by a stream of clean air. FIG. 18 is an external view of the electric vacuum cleaner of a seventh embodiment of the invention, showing its state during storage. FIG. 19 is a sectional view of the body shown in FIG. 18, taken along line A-A. The body 1A of the electric vacuum cleaner of this embodiment incorporates an electric blower 14, is provided with casters 46 on both sides, has a mixing chamber 44 formed by the casters 46, and incorporates an ion generator 231. The body 1A is freely movable in all directions. Moreover, a dust collector 2A is disposed between the body 1A and a nozzle unit 6. To the nozzle unit 6 is connected a suction pipe 301, which is sealed with seals 311a and 311b and is slidably provided relative to the dust collector 2A. Alternatively, as shown in FIG. 21, the casters 46 may be provided only around the periphery, with caster covers 601 provided inside them so as to form an ion mixing chamber 44. This permits the ion generator 231 to be maintained easily with only the covers 601 removed. The stream of air sucked in through the nozzle unit 6 is passed through a hose socket 8, the electric blower 14, a filter 15, and a cord reel 51 so as to be discharged through a ventilation openings 46b formed in the casters 46. The filter 15 is so arranged as to enclose the electric blower 14. This helps reduce the noise produced by the electric blower 14, and makes it possible to adopt a filter with a large area, contributing to good ventilation efficiency. Thus, it is possible to arrange a HEPA filter with extra fine ventilation pores such as to catch dust as small as 1 μm or less. The outer circumference of the filter 15 may be covered with a soundproof material such as urethane to achieve securer soundproofing. The electric blower 14 is held on the body 1A by way of damping members 503 and 504 formed of rubber or the like. During storage, the electric vacuum cleaner is leaned on stands 501. As shown in FIG. 18, the stands 501 are provided in pairs; specifically, for each of the casters 46, two stands 501a and 501b are provided on either side of its rolling direction so as to be rotatable about rotation shafts 511a and 511b, respectively. Moreover, the stands 501a and 501b are coupled together by couplers 505 (see FIGS. 20A and 20B), and are loaded by springs 506 with a force that tends to cause them to pop outside the casters. The body 1A of this type is freely movable in all directions, and is therefore, during storage, prevented from rolling by the stands 501. FIG. 20A is a side view of the body IA, showing its posture during cleaning operation. In this state, the stands 501 are kept away from the floor to permit the casters 46 to roll and thereby permit the body 1A to freely move. Thus, the stands 501 do not hamper cleaning. When the body 1A is rotated in the direction indicated by the arrow, the stands 501a make contact with the floor, then rotate about the rotation shafts 511a, and thus retract into the body 1A. As the stands 501a rotate about the rotation shafts 511a, the stands 501b, which are coupled thereto by the rods 506, also rotate about the rotation shafts 511b in their retracting direction. When the body 1A is rotated further, as shown in FIG. 20B, all the stands 501 are retracted. When the stands 501 are located right below, all the stands 501 and 501b are, at their ends, in contact with the floor. Even when the body 1A is rotated further in the direction indicated by the arrow until the stands 501a come off the floor, the stands 501b remain in contact with the floor, and thus none of the stands 501 prop outside the body 1A. This permits smooth rotation of the body 1A. The stands 501 are fitted, at their ends, with damping members 512 formed of a damping material such as rubber or urethane to prevent impact and damage resulting from collision with the floor. In an upper part of the body 1A, opposite to the stands 501, is provided a handle 502 that permits the electric vacuum cleaner to be carried around. As described above, even in the state shown in FIG. 20B, the stands 501 are in contact with the floor, and therefore, for storage, the body 1A needs to be lifted upward so that the ends of the stands 501 come off the floor to permit the stands 501 to return to their original position under the force exerted by the springs 506. That is, by lifting up the handle 502 to permit the body 1A to come off the floor, it is possible to return the stands 501 to their original position. The handle 502 is rotatable about a rotation shaft 502a. To return the stands 501 to their original position outside the casters 46 for storage, the handle 502 is rotated to the position indicated by broken lines in FIG. 30B and is then lifted up. A locking means is provide to prevent the handle 502 from rotating beyond a predetermined position. A projection 502b is formed on the handle 502, and a recess 502c that engages therewith is formed in the body 1A. Thus, when the handle 502 is lifted up, the projection 502b makes contact with the recess 502c so that the handle 502 is held in the position indicated by the broken lines in FIG. 20B. This prevents instability of the body 1A when it is lifted up. Moreover, then, the ends of the stands 501 remain substantially parallel to the floor, permitting secure storage on the floor. When the handle 502 is let go, it returns, with the help of a spring (not illustrate) or the like, to the position indicated by the solid lines. Here, the electric vacuum cleaner may be so configured as to recognize the storage state to drive the ion generator 231 independently for a predetermined length of time. This permits purification to be performed automatically for a predetermined length of time inside a comparatively airtight space such as the storage space. Alternatively, as shown in FIG. 22, the body 1A may be provided with, independently of the control panel 4 for the electric vacuum cleaner, a drive switch 400 for driving the electric blower 14 and the ion generator 231. With this construction, even in a space other than the aforementioned storage space, for example in a closet, the body 1A can be placed with the connection hose 7 removed, and the drive switch can be turned on so that the air inside this space is sucked in and discharged and meanwhile the generated positive and negative ions are discharged into the space in order to achieve purification in the space. In this case, it is preferable that, after the drive switch 400 is so operated as to turn the power on, the electric blower 14 and the ion generator 231 be driven for a predetermined length of time (for example, 30 minutes). Thus, it is preferable to provide a time control circuit (not illustrated) to permit the setting of the driving time. The drive switch 400 may be provided directly on the body 1A, or may be provided in the form of a remote control system for remotely controlling the body 1A, with a receiver 402 provided on the body 1A and a transmitter 401 provided as a separate unit. With such a remote control system, even when the body 1A is placed in a narrow space as in a closet, the user can drive the electric blower 14 and the ion generator 231 by operating the remote control unit. This helps further enhance the usability. FIGS. 29A and 29B show examples of the control circuit for controlling the electric blower and the ion generator. FIG. 29A shows an example of the control circuit for simultaneously driving the electric blower 14 and the ion generator 231 housed in the body 1A described above. On the control panel 4 (see FIG. 22) is provided a switch 41a that is connected in series with both the electric blower 14 and the ion generator 231. Likewise, as the drive switch 400 (see FIG. 22) is provided a switch 41b that is connected in series with both the electric blower 14 and the ion generator 231. Moreover, the remote control system, composed of the transmitter 401 and the receiver 402 (see FIG. 22), includes a switch 41c that is connected in series with both the electric blower 14 and the ion generator 231. It is preferable that the switches 41a and 41b be so structured that their contact is closed or opened as a turning-on or -off operation is performed on the control panel 4 or the drive switch 400. On the other hand, it is preferable that the switch 42c be built as an electronic circuit switch that is controlled according to a signal fed from the receiver 402 as a turning-on or -off operation is performed on the remote control unit. Through the operation of the control circuit described above, when the control panel 4, the drive switch 400, or the remote control unit is so operated as to turn the power on, the corresponding switch 41a, 41b, or 41c is closed. As a result, electric power starts to be supplied from a power supply D to the electric blower 14 and the ion generator 231, so that the electric blower 14 and the ion generator 231 start to be driven. On the other hand, when the control panel 4, the drive switch 400, or the remote control unit is so operated as to turn the power off, the corresponding switch 41a, 41b, or 41c is opened. As a result, electric power stops being supplied from the power supply D to the electric blower 14 and the ion generator 231, so that the electric blower 14 and the ion generator 231 stop being driven. Thus, for example, in a case where air is purified while the interior of the room is cleaned, or in a case where the air in a space such as a closet is sucked in and discharged so as to be purified, whichever of the switches suits the purpose can be operated to drive the electric blower 14 and the ion generator 231. FIG. 29B shows an example of the control circuit used when, in place of the ion generator 231, the ion generator 230 shown in FIG. 13 is provided in the body 1A. On the control panel 4 are provided a switch 41a that is connected in series with the electric blower 14 and a switch 42a that is connected in series with the ion generator 231 of the ion generator 230 and with the motor 23c of the ion discharge fan 23a. As the drive switch 400 is provided a switch 41b that is connected in series with the ion generator 231 of the ion generator 230 and with the motor 23c of the ion discharge fan 23a. Likewise, the remote control system, composed of the transmitter 401 and the receiver 402 (see FIG. 22), includes a switch 41c that is connected in series with the ion generator 231 of the ion generator 230 and with the motor 23c of the ion discharge fan 23a. It is preferable that the switches 41a and 42a be so structured that their contact is closed or opened as a turning-on or -off operation is performed on the control panel 4. In this case, in response to a turning-on or -off operation performed on the control panel 4, the switches 41a and 42a may be closed or opened simultaneously. Alternatively, the switches 41a and 42a may be so controlled that, in response to a turning-on operation performed on the control panel 4, the switch 42a is closed first and then the switch 41a is closed and, in response to a turning-off operation performed on the control panel 4, the switch 41a is opened first and then the switch 42a is opened. Alternatively, an unillustrated timer control circuit may be provided that so controls that, when a turning-off operation is performed on the control panel 4, the switch 41a is opened first and then, a predetermined length of time thereafter, the switch 42a is opened. The control panel 4 may be so configured that the switches 41a and 42a can be operated individually. With the configuration described above, flexible control is possible, for example, by first stopping the driving of the electric blower 14 and then, with a delay, stopping the driving of the ion generator. This makes it possible to further purify the air floating around after being discharged by the electric blower 14. It is preferable that the switch 41b be so structured that its contact is closed or opened as a turning-on or off operation is performed on the drive switch 400. The switch 41b may be so structured that, when closed, it is opened a predetermined length of time thereafter by an unillustrated time control circuit. It is preferable that the switch 41c be built as an electronic circuit switch that is controlled according to a signal fed from the receiver 402 as a turning-on or -off operation is performed on the remote control unit. The switch 41c may be so structured that, when closed, it is opened a predetermined length of time thereafter by an unillustrated time control circuit. When the control panel 4 is so operated that the switches 41a and 42a are closed simultaneously, electric power starts to be supplied from the power supply D to the electric blower 14, to the ion generator 231 of the ion generator 230, and to the motor 23c of the ion discharge fan 23a, so that these start to be driven. When the drive switch 400 or the remote control unit is so operated that the corresponding switch 41b or 41c is closed, electric power start to be supplied to the ion generator 231 of the ion generator 230 and to the motor 23c of the ion discharge fan 23a, so that these start to be driven. Accordingly, for the purpose of cleaning a room and purifying air, the control panel 4 can be operated so that the electric blower and the ion generator 230 are driven simultaneously. On the other hand, since the ion generator 230 is so configured as to be able to discharge ions on its own, for the purpose of discharging ions into a room without cleaning it, the drive switch 400 or the remote control unit can be operated so that the ion generator 230 alone is driven. In this construction, when the control panel is so operated as to start operation, the electric blower 14 and the ion generating circuit (not illustrated) are energized, so that the electric blower 14 starts to be driven to suck air in through the nozzle unit 6 (see FIG. 1) and the ion generating circuit (not illustrated) starts to operate to apply a high voltage to the electrode of the ion generator 231. As a result, first, as the electric blower 14 is driven, the air, containing dust, sucked in through the nozzle unit 6 is introduced, through the suction pipe 301, into a dust cup 16 while swirling around. Thus, the stream of air swirls around inside the dust cup 16, with the result that, by the action of centrifugal force, the dust contained in the stream of air is separated from the air and is collected inside the dust cup 16. The air having dust removed therefrom and thus purified is passed through the hose socket 8 into the body 1A, and is then introduced, through the electric blower 14, deodorizing filter 15, and ventilation opening 48a, into a cord housing 50, where the air cools the cord reel 51. This air is discharged through the exhaust opening 1b into the mixing chamber 44, where the air remains for a while. The air is then discharged out of the body 1 through the exhaust opening 46b. In the cord housing 50 and the mixing chamber 44 may be arranged, other than the cord reel 51, any component, such as a circuit (not illustrated), that generates heat. This permits such a heat-generating component to be cooled with the stream of air. The ions generated by the ion generator 231 are discharged into the mixing chamber 44 so as to be mixed with the air inside it. As a result, inside the mixing chamber 44, the ions are mixed evenly with the air discharged through the exhaust opening 1b. This makes it possible to purify the discharged air in a centralized manner so that ions are distributed to all corners of the room through the exhaust opening 45 by a stream of clean air. Furthermore, in this embodiment, the mixing chamber 44 can be formed inside the casters 46 pivoted on the side walls of the body 1. This permits the use of existing components without changing the design of conventional electric vacuum cleaners. This helps keep the product prices low. The descriptions given thus far deal only with constructions including a cyclone-type dust collecting device and an ion generator. It is, however, also possible to obtain similar effects, as will be described below, with the type of electric vacuum cleaner that collects dust by passing air through (i.e., by filtering it with) a dust collection bag 2A formed of cloth or paper. An eighth embodiment of the invention will be described below with reference to the drawings. FIG. 23 is an overall perspective view of the electric vacuum cleaner of the eighth embodiment of the invention. As shown in FIG. 23, the electric vacuum cleaner has a body 1, casters 46, a hose 7, a handle 5, and a nozzle unit 6. FIG. 24 is a sectional view of the body of the electric vacuum cleaner. The body 1 shown in FIG. 24 is provided with a first suction passage 10A, an electric blower 14 that drives a motor 54 to rotate a fan 55 and thereby produces a suction stream of air, and a dust collection bag 2A that collects dust that has been sucked in. The electric blower 14 is fixed inside the body 1 by the use of a support member 56 having a circular opening formed at the center. Moreover, an ion generator 23 (231) that generates ions is disposed in the first suction passage 10A, which runs from a hose socket 8 to the dust collector 2A. When a carpet or the like is cleaned with the electric vacuum cleaner having its body 1 constructed as described above, dust, such as animal hair, house mites, mold, and pollen, is sucked in and is collected in the dust collection bag 2A. When the air containing such dust passes through the first suction passage 10A, by the action of the positive and negative ions discharged from the ion generator 23, the odor-producing substances and allergenic chemical substances contained in the air are decomposed. As a result, the exhaust air discharged out of the electric vacuum cleaner returns to the room as air that is free from not only dust but also odor-producing substances. FIG. 25 is a sectional view of the body of the electric vacuum cleaner of a ninth embodiment of the invention. The body shown in FIG. 25 incorporates a first suction passage 10A, an electric blower 14 that drives a motor 54 to rotate a fan 55 and thereby produces a suction stream of air, and a dust collection bag 2A that collects dust that has been sucked in. Moreover, an ion generator 23 is disposed between the dust collection bag 2A and an exhaust opening 1b. When a carpet or the like is cleaned with the electric vacuum cleaner having its body 1 constructed as described above, dust, such as animal hair, house mites, mold, and pollen, is sucked in and collected in the dust collection bag 2A, and the chemical substances such as odor-producing substances contained in the air having dust removed therefrom are decomposed by the action of the positive and negative ions discharged from the ion generator 23. Furthermore, ions are discharged into the room by the stream of exhausted air so as to eliminate chemical substances remaining in the room. FIG. 26 shows the result of measurements of the concentrations of ions generated by the electric vacuum cleaner shown in FIG. 25. The concentrations of ions were measured with an ion counter manufactured by Dan Kagaku Co., Ltd., Japan, with the ion sensor portion thereof placed at a distance of 10 cm from the exhaust opening. As shown in FIG. 26, it was found that, the faster the wind speed of the exhaust air discharged along with ions through the exhaust opening 1b, the higher the ion concentrations, and thus the larger the quantities of ions discharged. Next, it was evaluated how effective the ions discharged from the electric vacuum cleaner were on odor-producing substances. As an odor-producing substance, ammonia was fed into a box of acrylic resin having a volume of 1 m3 in such a way that the initial concentration of ammonia was 10 ppm. Then, the electric vacuum cleaner shown in FIG. 24 was placed inside the box, and the box was then sealed so as to be air-tight. Then, ions were discharged through the exhaust opening at an appropriate wind speed, and, 30 minutes later, the reduced amount of ammonia was measured. Then, on the basis of the initial concentration and the reduced amount of ammonia, the elimination rate was calculated as 100×(reduced amount)/(initial concentration). FIG. 27 shows the result. As shown in FIG. 27, it was found that, the faster the wind speed, and thus the larger the quantities of ions discharged, the more ammonia was eliminated. It was also found that an ammonia elimination rate of about 50% was achieved when the wind speed of the ion wind blown out through the exhaust opening was 50cm/s. On the basis of these facts, it was found that, to satisfactorily eliminate odor-producing substances, the wind speed from the exhaust opening needed to be at least 50 cm/s, which resulted in ion concentrations of about 10,000 ions/cm3. The electric vacuum cleaner of this embodiment can be realized very simply by externally adding a single device for air purification. This construction can be applied not only to electric vacuum cleaners of the type described above as an example but also to electric vacuum cleaners adopting any other dust collection method. It is to be understood that the embodiments described above are merely examples of constructions according to the present invention. That is, the present invention can be implemented in any other manners than specifically described above, and many modifications and variations are possible within the scope of the subject matter of the present invention. For example, one of the first, second, third, and eighth embodiments may be combined with one of the fourth, fifth, sixth, seventh, and ninth embodiments. Specifically, the suction air passage by way of which air is sucked in and discharged may be divided into an upstream part and a downstream part with respect to the electric blower, with an ion generator provided in each of the upstream and downstream parts thereof This permits not only the interior of the electric vacuum cleaner to be purified, but also permits ions to be mixed with the air discharged out of the electric vacuum cleaner so that purification is performed both inside and outside the electric vacuum cleaner. The configurations shown in FIGS. 8 to 14, 24, and 25 can be realized very simply by externally adding a device for air purification. The configurations shown in FIGS. 15 to 17, where the ion generator is arranged on the outside, permit easy addition of a separately built ion generator to an existing electric vacuum cleaner. As shown in FIG. 13, a blower 23a may be additionally provided to discharge ions through the ion discharge port of the ion generator 231. This permits ions to be supplied irrespective of whether the electric blower 14 is being driven or not. Thus, with the electric vacuum cleaner placed in a space, such as a closet, where purification is needed, the ion generator 231 and the blower 231a can be driven to obtain a sterilizing, healing, or other effect that suits the intended purpose. The ion generator 231 shown in FIGS. 18 to 21 or the ion generator 230 shown in FIG. 13 may be provided in a device of the type that is moved around inside a room as it is used by the user or that has the function of moving around on its own. This makes it possible, as achieved with an electric vacuum cleaner according to the invention, to perform sterilization inside a room to which such a device is carried. Examples of such devices include, to name a few, hair dryers, telephone handsets, intelligent robots, and self-moving cleaners provided with wheels. Similar effects can be obtained even in a electric vacuum cleaner of the so-called exhaust-recycling type wherein the exhaust is recycled, i.e., the stream of air sucked in is returned from the exhaust side of the electric blower 14 to the nozzle unit 6. FIG. 28 is a sectional view of the body 1B of an exhaust-recycling type electric vacuum cleaner. To the hose socket 8 are connected a first suction air passage 10 that communicates with the dust collecting device and a return stream tube 10b that communicates with the downstream side of the electric blower 14. Correspondingly, though not illustrated, through a connection pipe and a connection hose are formed a suction air passage 7a and a return stream passage 7b that communicate with the first suction air passage 10 and the return stream pipe 10b, respectively. The connection hose is removably fitted into the hose socket 8. Thus, the suction air passage 7a and the return stream passage 7b communicate with the interior of an unillustrated nozzle unit through the connection hose and the connection pipe. The stream of air sucked in through the nozzle unit 6 is then sucked, through the suction air passage 7a, first suction air passage 10, dust collection device 2, and second suction air passage 13, into the electric blower 14, and is then recycled by being returned through the deodorizing filter 15, return stream pipe 10b, and return stream passage 7b to the interior of the nozzle unit 6. In this construction, by discharging ions from the ion generator 23 into the suction air passage by way of which air is sucked in through the nozzle unit 6 and fed to the electric blower 14, or into the return stream passage by way of which air is recycled by being returned from the electric blower 14 to the nozzle unit 6, it is possible to purify the suction stream of air or the recycled return stream of air. Industrial Applicability As described above, according to the present invention, by discharging both negative and positive ions, or negative ions alone, generated by an ion generator, and by discharging those ions into the air sucked in or into the air discharged out of an electric vacuum cleaner as an electric blower is driven, it is possible to eliminate unpleasant odors produced when the electric vacuum cleaner is used and to kill bacteria such as microorganisms all over a wide area. In particular, in a case where the ion generator is disposed near an exhaust opening, it is possible to discharge ions into a room. This makes it possible to deliver ions to all corners of the room and purify the air inside the room. Moreover, by driving the ion generator along with a blowing means for blowing ions, it is possible to purify the air in the room even while the electric vacuum cleaner is stored. Moreover, the ion generator uses a needle-shaped electrode. This permits an electric field to concentrate, and thus permits discharge to take place more easily, resulting in efficient discharge of ions into the sucked air. In addition, this needle-shaped electrode is arranged along the stream of air. This makes the electrode almost free from dust electrostatically settling thereon, and thus makes its maintenance easy. Moreover, the present invention can be applied to electric vacuum cleaners adopting any dust collection method, such as those employing a cyclone-type dust collecting device or a dust collection bag. Thus, simply by adding an ion generator as a device for air purification, it is possible to purify air that tends to be polluted during cleaning.

<SOH> BACKGROUND ART <EOH>As a conventional electric vacuum cleaner provided with an ozone generating function, the one disclosed in Japanese Patent Application Laid-Open No. H1-238815 will be described below with reference to FIG. 30 . In this conventional electric vacuum cleaner, inside a body 101 thereof is formed a suction air passage 104 that runs from a hose socket 102 formed in the front wall of the body 101 to an exhaust opening 103 formed in the rear wall of the body 101 , and in this suction air passage 104 are arranged a dust collection bag 105 , a dust filter 106 , and an electric blower 107 in this order. The dust collection bag 105 permits air to pass therethrough. The electric blower 107 communicates with the exhaust opening 103 . When the electric blower 107 is driven, air containing dust is sucked in through a suction hose 108 fitted into the hose socket 102 , is then passed through the dust collection bag 105 , dust filter 106 , and electric blower 107 , and is then discharged out of the body 101 through the exhaust opening 103 . Meanwhile, the dust collection bag 105 removes the dust contained in the air. On the other hand, inside the body 101 of this electric vacuum cleaner, outside and above the suction air passage 104 is formed an ozone reservoir 109 , in which an ozone generator 110 is provided. While the electric blower 107 is operating, ozone generated by the ozone generator 110 is reserved in the ozone reservoir 109 , and, when the electric blower 107 is de-energized, valves 111 and 112 are opened so that the reserved ozone is fed into the suction air passage 104 so as to kill germs present in the suction air passage 104 . In this conventional electric vacuum cleaner, the ozone fed into the suction air passage 104 acts on the stream of air that has been cleaned by the dust collection bag 105 , but does not sufficiently act on the dust and germs collected in the dust collection bag 105 . This makes it impossible for ozone to exert a satisfactory antibacterial effect. Moreover, since ozone is reserved in the ozone reservoir 109 during operation, the body 101 , which is formed of synthetic resin, is exposed to the reserved ozone for a long time. This causes the body 101 to deteriorate, making it prone to cracks and breakage in the relevant part thereof In particular, in a vacuum-type cleaner, cracks are likely to develop in a part thereof where the pressure is low during operation, lowering the suction performance and leading ultimately to a burst.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is an external side view showing the electric vacuum cleaner of a first embodiment of the invention. FIG. 2 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 3 is an enlarged side sectional view showing the internal construction of the ion generator used in the electric vacuum cleaner. FIG. 4 is an enlarged view of another example of the needle-shaped electrode of the ion generator. FIG. 5 is an enlarged view of still another example of the needle-shaped electrode of the ion generator. FIG. 6 is a sie sectional view showing the internal construction of the electric vacuum cleaner of a second embodiment of the invention. FIG. 7 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a third embodiment of the invention. FIG. 8 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fourth embodiment of the invention. FIG. 9 is an external perspective view of the ion generator used in the electric vacuum cleaner, as seen from the ion generating element side. FIG. 10 is an external perspective view of the ion generator, as seen from the side opposite to the ion generating element. FIG. 11 is an exploded perspective view of the ion generator. FIG. 12A is an outline perspective view showing the ion generating element of the ion generator. FIG. 12B is a sectional view showing the ion generating element of the ion generator. FIG. 13 is an enlarged side sectional view sowing another example of the infernal construction of the ion generator. FIG. 14 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 15 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fifth embodiment of the invention. FIG. 16 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 17 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 18 is a vertical sectional view showing the internal construction of the body, in its rear part, of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 19 is a sectional view taken along line A-A shown in FIG. 18 . FIG. 20A is a side view showing the posture of the body of the electric vacuum cleaner during cleaning operation. FIG. 20B is a side view showing the posture of the body of the electric vacuum cleaner during storage. FIG. 21 is a sectional view taken along line A-A shown in FIG. 18 , showing another example of the electric vacuum cleaner. FIG. 22 is a vertical sectional view showing the internal construction of the body, in its rear part, of still another example of the electric vacuum cleaner. FIG. 23 is an external perspective view showing the electric vacuum cleaner of an eighth embodiment of the invention. FIG. 24 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 25 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a ninth embodiment of the invention. FIG. 26 is a diagram showing the measurements of the concentrations of ions generated by the electric vacuum cleaner. FIG. 27 is a diagram showing the effect of eliminating ammonia achieved by the operation of the electric vacuum cleaner. FIG. 28 is a side sectional view showing the internal construction of the body of an example of an exhaust-recycling-type electric vacuum cleaner provided with an ion generator. FIG. 29A is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit that drives the electric blower and ion generator simultaneously. FIG. 29B is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit used when the ion generator shown in FIG. 13 is provided in the body. FIG. 30 is an external side sectional view of a conventional electric vacuum cleaner. detailed-description description="Detailed Description" end="lead"?

20040819

20090922

20050106

63405.0

WILSON, LEE D

VACUUM CLEANER AND DEVICE HAVING ION GENERATOR

UNDISCOUNTED

ACCEPTED

ACCEPTED

Optical processing

To operate an optical device comprising an SLM with a two-dimensional array of controllable phase-modulating elements groups of individual phase-modulating elements are delineated, and control data selected from a store for each delineated group of phase-modulating elements. The selected control data are used to generate holograms at each group and one or both of the delineation of the groups and the selection of control data is/are varied. In this way upon illumination of the groups by light beams, light beams emergent from the groups are controllable independently of each other.

1. a method of operating an optical device comprising an SLM having a two-dimensional array of controllable phase-modulating elements, the method comprising delineating groups of individual phase-modulating elements; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other: 2. A method of operating an optical device according to clam 1, wherein control of said light beams is selected from the group comprising: control of direction, control of power, focussing, aberration compensation, sampling and beam shaping. 3. A method of operating an optical device according to claim 1, wherein each phase modulating element is responsive to a respective applied voltage to provide a corresponding phase shift to emergent light, the method further comprising controlling said phase-modulating elements of the spatial light modulator to provide respective actual holograms derived from the respective generated holograms, wherein the controlling step comprises: resolving the respective generated holograms modulo 2pi. 4. A method of operating an optical device according to claim 1, comprising: providing a discrete number of voltages available for application to each phase modulating element; on the basis of the respective generated holograms, determining the desired level of phase modulation at a predetermined point on each phase modulating element and choosing for each phase modulating element the available voltage which corresponds most closely to the desired level. 5. A method of operating an optical device according to claim 1, comprising: providing a discrete number of voltages available for application to each phase modulating element; determining a subset of the available voltages which provides the best fit to the generated hologram. 6. A method of operating an optical device according to claim 1, further comprising the step of storing said control data wherein the step of storing said control data comprises calculating an initial hologram using a desired direction change of a beam of light, applying said initial hologram to a group of phase modulating elements, and correcting the initial hologram to obtain an improved result. 7. A method of operating an optical device according to claim 1, further comprising the step of providing sensors for detecting temperature change, and performing said varying step in response to the outputs of those sensors. 8. A method of operating an optical device according to claim 1, in which the SLM is integrated on a substrate and has an integrated quarter-wave plate whereby it is substantially polarisation insensitive. 9. A method of operating an optical device according to claim 1, wherein the phase-modulating elements are substantially reflective, whereby emergent beams are deflected from the specular reflection direction. 10. A method of operating an optical device according to claim 3 comprising, for at least one said group of phase-modulating elements, providing control data indicative of two holograms to be displayed by said group and generating a combined hologram before said resolving step. 11. An optical device comprising an SLM and a control circuit, the SLM having a two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged to vary the delineation of the groups and/or the selection of control data, whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. 12. An optical device according to claim 11, having sensor devices arranged to detect light emergent from the SLM, the control circuit being responsive to signals from the sensors to vary said delineation and/or said selection. 13. An optical device according to claim 11, having temperature responsive devices constructed and arranged to feed signals indicative of device temperature to said control circuit, whereby said delineation and/or selection is varied. 14. An optical routing device having at least first and second SLMs and a control circuit, the first SLM being disposed to receive respective light beams from an input fibre array, and the second SLM being disposed to receive emergent light from the first SLM and to provide light to an output fibre array, the first and second SLMs each having a respective two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged, to vary the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. 15. A device for shaping one or more light beams in which the or each light beam is incident upon a respective group of pixels of a two-dimensional SLM, and the pixels of the or each respective group are controlled so that the corresponding beams emerging from the SLM are shaped as required. 16. An optical device comprising one or more optical inputs at respective locations, a diffraction grating constructed and arranged to receive light from the or each optical input, a focussing device and a continuous array of phase modulating elements, the diffraction grating and the array of phase modulating elements being disposed in the focal plane of the focussing device whereby diverging light from a single point on the diffraction grating passes via the focussing device to form beams at the array of phase modulating elements, the device further comprising one or more optical output at respective locations spatially separate location from the or each optical input, whereby the diffraction grating is constructed and arranged to output light to the or each optical output. 17. A method of filtering light comprising applying a beam of said light to a diffraction grating whereby emerging light from the grating is angularly dispersed by wavelength, forming respective parallel beams from said emerging light by passing the emerging light to a focussing device having the grating at its focal plane, passing the respective parallel beams to an SLM at the focal plane of the focussing device, the SLM having a two-dimensional array of controllable phase-modulating elements, selectively reflecting light from different locations of said SLM and passing said reflected light to said focussing device and then to said grating. 18. A method according to claim 17 comprising delineating groups of individual phase-modulating elements to receive beams of light of differing wavelength; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data. 19. An optical add/drop multiplexer having a reflective SLM having a two-dimensional array of controllable phase-modulating elements, a diffraction device and a focussing device wherein light beams from a common point on the diffraction device are mutually parallel when incident upon the SLM, and wherein the SLM displays respective holograms at locations of incidence of light to provide emergent beams whose direction deviates from the direction of specular reflection. 20. A test or monitoring device comprising an SLM having a two-dimensional array of pixels, and operable to cause incident light to emerge in a direction deviating from the specular direction, the device having light sensors at predetermined locations arranged to provide signals indicative of said emerging light. 21. A test or monitoring device according to claim 20, further comprising further sensors arranged to provide signals indicative of light emerging in the specular directions. 22. A power control device for one or more beams of light in which the or each beam is incident on respective groups of pixels of a two-dimensional SLM, and power-control holograms are applied to the respective groups so that the emergent beams have power reduced by comparison to the respective incident beams. 23. An optical routing module having at least one input and at least two outputs and operable to select between the outputs, the module comprising a two dimensional SLM having an array of pixels, with circuitry constructed and arranged to display holograms on the pixels to route beams of different frequency to respective outputs. 24. A routing device having an input and plural outputs, the input constructed and arranged to receive a light beam having plural wavelengths, the device comprising an optical device for selecting the wavelengths of the input beam to appear in the outputs, wherein each output may contain any desired set of the plural wavelengths. 25. A routing device according to claim 24, wherein the members of the desired set may be varied in use. 26. A routing device according to claim 24, wherein at least two of the outputs contain at least one common wavelength. 27. A routing device having plural input signals and an output, the output constructed and arranged to deliver a signal having plural wavelengths, the device comprising a device for combining the wavelengths from the input signals to appear in the output, wherein each input signal may contain any desired set of the plural wavelengths of the output. 28. A method of filtering light comprising spatially distributing the light by wavelength across an array of phase-modulating elements to form plural beams, delineating a group of said phase-modulating elements to be aligned with the centre frequency of a desired channel whereby the group truncates the beams according to wavelength, controlling the group to provide images of the truncated light beams incident on the group at a selected output waveguide wherein the original centres of the truncated light beams are substantially coincident with the centre of the output waveguide.

FIELD OF THE INVENTION The present invention relates to an optical device and to a method of controlling an optical device. More particularly but not exclusively the invention relates to the general field of controlling one or more light beams by the use of electronically controlled devices. The field of application is mainly envisaged as being to fields in which reconfiguration between inputs and outputs is likely, and stability of performance is a significant requirement. BACKGROUND OF THE INVENTION It has previously been proposed to use so-called spatial light modulators to control the routing of light beams within an optical system, for instance from selected ones of a number of input optical fibres to selected ones of output fibres. Optical systems are subject to performance impairments resulting from aberrations, phase distortions and component misalignment. An example is a multiway fibre connector, which although conceptually simple can often be a critical source of system failure or insertion loss due to the very tight alignment tolerances for optical fibres, especially for single-mode optical fibres. Every time a fibre connector is connected, it may provide a different alignment error. Another example is an optical switch in which aberrations, phase distortions and component misalignments result in poor optical coupling efficiency into the intended output optical fibres. This in turn may lead to high insertion loss. The aberrated propagating waves may diffract into intensity fluctuations creating significant unwanted coupling of light into other output optical fibres, leading to levels of crosstalk that impede operation. In some cases, particularly where long path lengths are involved, the component misalignment may occur due to ageing or temperature effects. Some prior systems seek to meet such problems by use of expensive components. For example in a communications context, known free-space wavelength multiplexers and demultiplexers use expensive thermally stable opto-mechanics to cope with the problems associated with long path lengths. Certain optical systems have a requirement for reconfigurability. Such reconfigurable systems include optical switches, add/drop multiplexers and other optical routing systems where the mapping of signals from input ports to output ports is dynamic. In such systems the path-dependent losses, aberrations and phase distortions encountered by optical beams may vary from beam to beam according to the route taken by the beam through the system. Therefore the path-dependent loss, aberrations and phase distortions may vary for each input beam or as a function of the required output port. The prior art does not adequately address this situation. Other optical systems are static in terms of input/output configuration. In such systems, effects such as assembly errors, manufacturing tolerances in the optics and also changes in the system behaviour due to temperature and ageing, create the desirability for dynamic direction control, aberration correction, phase distortion compensation or misalignment compensation. It should be noted that the features of dynamic direction control, phase distortion compensation and misalignment control are not restricted to systems using input beams coming from optical fibres. Such features may also be advantageous in a reconfigurable optical system. Another static system in which dynamic control of phase distortion, direction and (relative) misalignment would be advantageous is one in which the quality and/or position of the input beams is time-varying. Often the input and output beams for optical systems contain a multiplex of many optical signals at different wavelengths, and these signals may need to be separated and adaptively and individually processed inside the system. Sometimes, although the net aim of a system is not to separate optical signals according to their wavelength and then treat them separately, to do so increases the wavelength range of the system as a whole. Where this separation is effected, it is often advantageous for the device used to route each channel to have a low insertion loss and to operate quickly. It is an aim of some aspects of the present invention at least partly to mitigate difficulties of the prior art. It is desirable for certain applications that a method or device for addressing these issues should be polarisation-independent, or have low polarisation-dependence. SLMs have been proposed for use as adaptive optical components in the field of astronomical devices, for example as wavefront correctors. In this field of activity, the constraints are different to the present field—for example in communication and like devices, the need for consistent performance is paramount if data is to be passed without errors. Communication and like devices are desirably inexpensive, and desirably inhabit and successfully operate in environments that are not closely controlled. By contrast, astronomical devices may be used in conditions more akin to laboratory conditions, and cost constraints are less pressing. Astronomical devices are unlikely to need to select successive routings of light within a system, and variations in performance may be acceptable. SUMMARY OF THE INVENTION According to a first aspect of the invention, there is provided a method of operating an optical device comprising an SLM having a two-dimensional array of controllable phase-modulating elements, the method comprising delineating groups of individual phase-modulating elements; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. In some embodiments, the variation of the delineation and/or control data selection is in response to a signal or signals indicating a non-optimal performance of the device. In other embodiments, the variation is performed during a set up or training phase of the device. In yet other embodiments, the variation is in response to an operating signal, for example a signal giving the result of sensing non-performance system parameters such as temperature. An advantage of the method of this aspect of the invention is that stable operation can be achieved in the presence of effects such as ageing, temperature, component, change of path through the system and assembly tolerances. Preferably, control of said light beams is selected from the group comprising: control of direction, control of power, focussing, aberration compensation, sampling and beam shaping. Clearly in most situations more than one of these control types will be needed—for example in a routing device (such as a switch, filter or add/drop multiplexer) primary changes of direction are likely to be needed to cope with changes of routing as part of the main system but secondary correction will be needed to cope with effects such as temperature and ageing. Additionally such systems may also need to control power, and to allow sampling (both of which may in some cases be achieved by direction changes). Advantageously, each phase modulating element is responsive to a respective applied voltage to provide a corresponding phase shift to emergent light, and the method further comprises; controlling said phase-modulating elements of the spatial light modulator to provide respective actual holograms derived from the respective generated holograms, wherein the controlling step comprises; resolving the respective generated holograms modulo 2pi. The preferred SLM uses a liquid crystal material to provide phase shift and the liquid crystal material is not capable of large phase shifts beyond plus or minus 2pi. Some liquid crystal materials can only provide a smaller range of phase shifts, and if such materials are used, the resolution of the generated hologram is correspondingly smaller. Preferably the method comprises: providing a discrete number of voltages available for application to each phase modulating element; on the basis of the respective generated holograms, determining the desired level of phase modulation at a predetermined point on each phase modulating element and choosing for each phase modulating element the available voltage which corresponds most closely to the desired level. Where a digital control device is used, the resolution of the digital signal does not provide a continuous spectrum of available voltages. One way of coping with this is to determine the desired modulation for each pixel and to choose the individual voltage which will provide the closest modulation to the desired level. In another embodiment, the method comprises: providing a discrete number of voltages available for application to each phase modulating element; determining a subset of the available voltages which provides the best fit to the generated hologram. Another technique is to look at the pixels of the group as a whole and to select from the available voltages those that give rise to the nearest phase modulation across the whole group. Advantageously, the method further comprises the step of storing said control data wherein the step of storing said control data comprises calculating an initial hologram using a desired direction change of a beam of light, applying said initial hologram to a group of phase modulating elements, and correcting the initial hologram to obtain an improved result. The method may further comprise the step of providing sensors for detecting temperature change, and performing said varying step in response to the outputs of those sensors. The SLM may be integrated on a substrate and have an integral quarter-wave plate whereby it is substantially polarisation insensitive. Preferably the phase-modulating elements are substantially reflective, whereby emergent beams are deflected from the specular reflection direction. In some aspects, for at least one said group of pixels, the method comprises providing control data indicative of two holograms to be displayed by said group and generating a combined hologram before said resolving step. According to a second aspect of the invention there is provided an optical device comprising an SLM and a control circuit, the SLM having a two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged, to vary the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. An advantage of the device of this aspect of the invention is that stable operation can be achieved in the presence of effects such as ageing, temperature, component and assembly tolerances. Embodiments of the device can handle many light beams simultaneously. Embodiments can be wholly reconfigurable, for example compensating differently for a number of routing configurations. Preferably, the optical device has sensor devices arranged to detect light emergent from the SLM, the control circuit being responsive to signals from the sensors to vary said delineation and/or said selection. In some embodiments, the optical device has temperature responsive devices constructed and arranged to feed signals indicative of device temperature to said control circuit, whereby said delineation and/or selection is varied. In another aspect, the invention provides an optical routing device having at least first and second SLMs and a control circuit, the first SLM being disposed to receive respective light beams from an input fibre array, and the second SLM being disposed to receive emergent light from the first SLM and to provide light to an output fibre array, the first and second SLMs each having a respective two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged, to vary the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. In a further aspect, the invention provides a device for shaping one or more light beams in which the or each light beam is incident upon a respective group of pixels of a two-dimensional SLM, and the pixels of the or each respective group are controlled so that the corresponding beams emerging from the SLM are shaped as required. According to a further aspect of the invention there is provided an optical device comprising one or more optical inputs at respective locations, a diffraction grating constructed and arranged to receive light from the or each optical input, a focussing device and a continuous array of phase modulating elements, the diffraction grating and the array of phase modulating elements being disposed in the focal plane of the focussing device whereby diverging light from a single point on the diffraction grating passes via the focussing device to form beams at the array of phase modulating elements, the device further comprising one or more optical output at respective locations spatially separate from the or each optical input, whereby the diffraction grating is constructed and arranged to output light to the or each optical output. This device allows multiwavelength input light to be distributed in wavelength terms across different groups of phase-modulating elements. This allows different processing effects to be applied to any desired part or parts of the spectrum. According to a still further aspect of the invention there is provided a method of filtering light comprising applying a beam of said light to a diffraction grating whereby emerging light from the grating is angularly dispersed by wavelength, forming respective beams from said emerging light by passing the emerging light to a focussing device having the grating at its focal plane, passing the respective beams to an SLM at the focal plane of the focussing device, the SLM having a two-dimensional array of controllable phase-modulating elements, selectively reflecting light from different locations of said SLM and passing said reflected light to said focussing element and then to said grating. Preferably the method comprises delineating groups of individual phase-modulating elements to receive beams of light of differing wavelength; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data. According to a still further aspect of the invention there is provided an optical add/drop multiplexer having a reflective SLM having a two-dimensional array of controllable phase-modulating elements, a diffraction device and a focussing device wherein light beams from a common point on the diffraction device are mutually parallel when incident upon the SLM, and wherein the SLM displays respective holograms at locations of incidence of light to provide emergent beams whose direction deviates from the direction of specular reflection. In a yet further aspect, the invention provides a test or monitoring device comprising an SLM having a two-dimensional array of pixels, and operable to cause incident light to emerge in a direction deviating from the specular direction, the device having light sensors at predetermined locations arranged to provide signals indicative of said emerging light. The test or monitoring device may further comprise further sensors arranged to provide signals indicative of light emerging in the specular directions. Yet a further aspect of the invention relates to a power control device for one or more beams of lights in which the said beams are incident on respective groups of pixels of a two-dimensional SLM, and holograms are applied to the respective group so that the emergent beams have power reduced by comparison to the respective incident beams. The invention further relates to an optical routing module having at least one input and at least two outputs and operable to select between the outputs, the module comprising a two dimensional SLM having an array of pixels, with circuitry constructed and arranged to display holograms on the pixels to route beams of different frequency to respective outputs. According to a later aspect of the invention there is provided an optoelectronic device comprising an integrated multiple phase spatial light modulator (SLM) having a plurality of pixels, wherein each pixel can phase modulate light by a phase shift having an upper and a lower limit, and wherein each pixel has an input and is responsive to a value at said input to provide a phase modulation determined by said value, and a controller for the SLM, wherein the controller has a control input receiving data indicative of a desired phase modulation characteristic across an array of said pixels for achieving a desired control of light incident on said array, the controller has outputs to each pixel, each output being capable of assuming only a discrete number of possible values, and the controller comprises a processor constructed and arranged to derive, from said desired phase modulation characteristic, a non-monotonic phase modulation not extending outside said upper and lower limits, and a switch constructed and arranged to select between the possible values to provide a respective one value at each output whereby the SLM provides said non-monotonic phase modulation. Some or all of the circuitry may be on-chip leading to built-in intelligence. This leads to more compact and ultimately low-cost devices. In some embodiments, some or all on-chip circuitry may operate in parallel for each pixel which may provide huge time advantages; in any event the avoidance of the need to transfer data off chip and thereafter to read in to a computer allows configuration and reconfiguration to be faster. According to another aspect of the invention there is provided a method of controlling a light beam using a spatial light modulator (SLM) having an array of pixels, the method comprising: determining a desired phase modulation characteristic across a sub-array of said pixels for achieving the desired control of said beam; controlling said pixels to provide a phase modulation derived from the desired phase modulation, wherein the controlling step comprises providing a population of available phase modulation levels for each pixel, said population comprising a discrete number of said phase modulation levels; on the basis of the desired phase modulation, a level selecting step of selecting for each pixel a respective one of said phase modulation levels; and causing each said pixel to provide the respective one of said phase modulation levels. The SLM may be a multiple phase liquid crystal over silicon spatial light modulator having plural pixels, of a type having an integrated wave plate and a reflective element, such that successive passes of a beam through the liquid crystal subject each orthogonally polarised component to a substantially similar electrically-set phase change. If a non-integrated wave plate is used instead, a beam after reflection and passage through the external wave plate will not pass through the same zone of the SLM, unless it is following the input path, in which case the zero order component of said beam will re-enter the input fibre. The use of the wave plate and the successive pass architecture allows the SLM to be substantially polarisation independent. In one embodiment the desired phase modulation at least includes a linear component. Linear phase modulation, or an approximation to linear phase modulation may be used to route a beam of light, i.e. to select a new direction of propagation for the beam. In many routing applications, two SLMs are used in series, and the displayed information on the one has the inverse effect to the information displayed on the other. Since the information represents phase change data, it may be regarded as a hologram. Hence an output SLM may display a hologram that is the inverse of that displayed on the input SLM. Routing may also be “one-to-many” (i.e. multicasting) or “one-to-all” (i.e. broadcasting) rather than the more usual one-to-one in many routing devices. This may be achieved by correct selection of the relevant holograms. Preferably the linear modulation is resolved modulo 2pi to provide a periodic ramp. In another embodiment the desired phase modulation includes a non-linear component. Preferably the method further comprises selecting, from said array of pixels, a sub-array of pixels for incidence by said light beam. The size of a selected sub-array may vary from switch to switch according to the physical size of the switch and of the pixels. However, a typical routing device may have pixel arrays of between 100×100 and 200×200, and other devices such as add/drop multiplexers may have arrays of between 10×10 and 50×50. Square arrays are not essential. In one embodiment the level-selecting step comprises determining the desired level of phase modulation at a predetermined point on each pixel and choosing for each pixel, the available level which corresponds most closely to the desired level. In another embodiment, the level-selecting step comprises determining a subset of the available levels, which provides the best fit to the desired characteristic. The subset may comprise a subset of possible levels for each pixel. Alternatively the subset may comprise a set of level distributions, each having a particular level for each pixel. In one embodiment, the causing step includes providing a respective voltage to an electrode of each pixel, wherein said electrode extends across substantially the whole of the pixel. Preferably again the level selecting step comprises selecting the level by a modulo 2pi comparison with the desired phase modulation. The actual phase excursion may be from A to A+2pi where A is an arbitrary angle. Preferably the step of determining the desired phase modulation comprises calculating a direction change of a beam of light. Conveniently, after the step of calculating a direction change, the step of determining the desired phase modulation further comprises correcting the phase modulation obtained from the calculating step to obtain an improved result. Advantageously, the correction step is retroactive. In another embodiment the step of determining the desired phase modulation is retroactive, whereby parameters of the phase modulation are varied in response to a sensed error to reduce the error. A first class of embodiments relates to the simulation/synthesis of generally corrective elements. In some members of the first class, the method of the invention is performed to provide a device, referred to hereinafter as an accommodation element for altering the focus of the light beam. An example of an accommodation element is a lens. An accommodation element may also be an anti-astigmatic device, for instance comprising the superposition of two cylindrical lenses at arbitrary orientations. In other members of the first class, the method of the invention is performed to provide an aberration correction device for correcting greater than quadratic aberrations. The sub-array selecting step may assign a sub-array of pixels to a beam based on the predicted path of the beam as it approaches the SLM just prior to incidence. Advantageously, after the sub-array is assigned using the predicted path, it is determined whether the assignment is correct, and if not a different sub-array is assigned. The assignment may need to be varied in the event of temperature, ageing or other physical changes. The sub-array selection is limited in resolution only by the pixel size. By contrast other array devices such as MEMS have fixed physical edges to their beam steering elements. An element of this type may be used in a routing device to compensate for aberrations, phase distortions and component misalignment in the system. By providing sensing devices a controller may be used to retroactively control the element and the element may maintain an optimum performance of the system. In one embodiment of this first class, the method includes both causing the SLM to route a beam and causing the SLM to emulate a corrective element to correct for errors, whereby the SLM receives a discrete approximation of the combination of both a linear phase modulation applied to it to route the beam and a non-linear phase modulation for said corrections. Synthesising a lens using an SLM can be used to change the position of the beam focused spot and therefore correct for a position error or manufacturing tolerance in one or more other lenses or reflective (as opposed to transmissive) optical elements such as a curved mirror. The method of the invention may be used to correct for aberrations such as field curvature in which the output ‘plane’ of the image(s) from an optical system is curved, rather than flat. In another embodiment of the first class, intelligence may be integrated with sensors that detect the temperature changes and apply data from a look-up table to apply corrections. In yet another embodiment of this class, misalignment and focus errors are detected by measuring the power coupled into strategically placed sensing devices, such as photodiode arrays, monitor fibres or a wavefront sensor. Compensating holograms are formed as a result of the discrete approximations of the non-linear modulation. Changes or adjustments may then be made to these holograms, for example by applying a stimulus and then correcting the holograms according to the sensed response until the system alignment is measured to be optimised. In embodiments where the method provides routing functions by approximated linear modulation, adaptation of non-linear modulation due to changes in the path taken through the system desirably takes place on a timescale equivalent to that required to change the hologram routing, i.e. of the order of milliseconds. A control algorithm may use one or more of several types of compensation. In one embodiment a look-up table is used with pre-calculated ‘expected’ values of the compensation taking account of the different routes through the system. In another embodiment the system is trained before first being operated, by repeated changes of, or adjustments to, the compensating holograms to learn how the system is misaligned. A further embodiment employs intelligence attached to the monitor fibres for monitoring and calculation of how these compensating holograms should adapt with time to accommodate changes in the system alignment. This is achieved in some embodiments by integrating circuitry components into the silicon backplane of the SLM. In many optical systems there is a need to control and adapt the power or shape of an optical beam as well as its direction or route through the optical system. In communications applications, power control is required for network management reasons. In general, optical systems require the levelling out or compensation for path and wavelength-dependent losses inside the optical system. It is usually desirable that power control should not introduce or accentuate other performance impairments. Thus in a second class of embodiments, the modulation applied is modified for controlling the attenuation of an optical channel subjected to the SLM. In one particular embodiment, the ideal value of phase modulation is calculated for every pixel, and then multiplied by a coefficient having a value between 0 and 1, selected according to the desired attenuation and the result is compared to the closest available phase level to provide the value applied to the pixels. In another embodiment, the method further comprises selecting by a discrete approximation to a linear phase modulation, a routing hologram for display by the SLM whereby the beams may be correctly routed; selecting by a discrete approximation to a non-linear phase modulation, a further hologram for separating each beam into main and subsidiary beams, wherein the main beam is routed through the system and the or each subsidiary beam is diffracted out of the system; combining the routing and further holograms together to provide a resultant hologram; and causing the SLM to provide the resultant hologram. The non-linear phase modulation may be oscillatory. In yet another embodiment, the method further comprises selecting by a discrete approximation to a linear phase modulation, a routing hologram for display by the SLM whereby the beams may be correctly routed; selecting by a discrete approximation to a non-linear phase modulation, a further hologram for separating each beam into main and subsidiary beams, wherein the main beam is routed through the system and at least one subsidiary beam is incident on an output at an angle such that its contribution is insignificant; combining the routing and further holograms together to provide resultant hologram; and causing the SLM to display the resultant hologram. The non-linear phase modulation may be oscillatory. In a closely allied class of embodiments, light may be selectively routed to a sensor device for monitoring the light in the system. The technique used may be a power control technique in which light diverted from the beam transmitted through the system to reduce its magnitude is made incident on the sensor device. In another class of embodiments, a non-linear phase modulation profile is selected to provide beam shaping, for example so as to reduce cross-talk effects due to width clipping. This may use a pseudo amplitude modulation technique. In a further class of embodiments, the method uses a non-linear modulation profile chosen to provide wavelength dependent effects. The light may be at a telecommunications wavelength, for example 850 nm, 1300 nm or in the range 1530 nm to 1620 nm. BRIEF DESCRIPTION OF THE DRAWINGS Exemplary embodiments of the invention will now be described with reference to the accompanying drawings in which: FIG. 1 shows a cross-sectional view through an exemplary SLM suitable for use in the invention; FIG. 2 shows a sketch of a routing device in which a routing SLM is used additionally to provide correction for performance impairment due to misalignment; FIG. 3 shows a sketch of a routing device in which a routing SLM is used to route light beams and an additional SLM provides correction for performance impairment due to misalignment; FIG. 4 shows a block diagram of an adaptive corrective SLM; FIG. 5 shows an adaptive optical system using three SLMs; FIG. 6 shows a partial block diagram of a routing device with a dual function SLM and control arrangements; FIG. 7 shows a block diagram of an SLM for controlling the power transferred in an optical system; FIG. 8a shows a diagram of phase change distribution applied by a hologram for minimum attenuation; FIG. 8b shows a diagram of phase change distribution applied by a hologram enabling attenuation of the signal; FIG. 9 shows a power control system; FIG. 10 shows a phasor diagram showing the effect of non-linear oscillatory phase modulation applied to adjacent pixels; FIG. 11 shows a schematic diagram of a part of an optical routing system illustrating the effects of clipping and cross talk; FIG. 12 shows a partial block diagram of a system enabling beams of different wavelength from a composite input beam to be separately controlled before recombination; and FIG. 13 shows a schematic diagram of an add/drop multiplexer using an SLM. FIG. 14 is a diagram similar to FIG. 12 but showing a magnification stage for increasing the effective beam deflection angle; FIG. 15 shows a vector diagram of the operation of an add/drop multiplexer; FIG. 16 shows a block diagram showing how loop back may be effected; FIG. 17 is a vector diagram illustrating the operation of part of FIG. 16; FIG. 18 is a vector diagram of a multi-input/multi-output architecture; FIG. 19 is a graph showing the relative transmission Tlo for in-band wavelengths as a function of the ratio of the wavelength offset u to centre of the wavelength channel separation; FIG. 20 is a graph showing the relative transmission Thi inside adjacent channels; FIG. 21 shows a logical diagram of the sorting function; FIG. 22 shows a block diagram of an add/drop node using two routing modules; FIG. 23 shows a block diagram of modules used to cross-connect two rings; FIG. 24 shows a block diagram of routing modules connected to provide expansion; FIG. 25 shows a block diagram of an optical cross-connect; FIG. 26 shows a block diagram of an upgrades node having a cascaded module at an expansion output port; FIG. 27 is a graph showing the effect of finite hologram size of the field of a beam incident on a hologram; FIG. 28 shows a schematic layout of a wavelength filter device; and, FIG. 29 shows a schematic layout of an add/drop device; FIG. 30 shows a block diagram of an optical test set; FIG. 31 is a diagram showing the effect of finite hologram size on a beam at a wavelength different to the centre wavelength associated with the hologram; FIG. 32 shows the truncated beam shapes for wavelengths at various wavelength differences from the centre of the wavelength channel dropped in isolation; FIG. 33 shows the overlap integrands of the beams of FIG. 32 with the fundamental mode of the fibre; FIG. 34 shows beam output positions for different wavelengths with respect to two optical fibres; and FIG. 35 shows the overlap integrand between the beams of FIG. 34 and the fundamental mode of one of the optical fibres. DESCRIPTION OF THE PREFERRED EMBODIMENTS Many of the embodiments of the invention centre upon the realisation that the problems of the prior art can be solved by using a reflective SLM having a two-dimensional array of phase-modulating elements that is large in number, and applying a number of light beams to groups of those phase-modulating elements. A significant feature of these embodiments is the fact that the size, shape and position of those groups need not be fixed and can, if need be, be varied. The groups may display holograms which can be set up as required to deflect the light so as to provide a non-specular reflection at a controllable angle to the specular reflection direction. The holograms may additionally or alternatively provide shaping of the beam. The SLM may thus simulate a set of highly flexible mirrors, one for each beam of light. The size, shape and position of each mirror can be changed, as can the deflection and the simulated degree of curvature. Devices embodying the invention act on light beams incident on the device to provide emerging light beams which are controlled independently of one another. Possible types of control include control of direction, control of power, focussing, aberration compensation, sampling and beam shaping. The structure and arrangement of polarisation-independent multiple phase liquid crystal over silicon spatial light modulators (SLMs) for routing light beams using holograms are discussed in our co-pending patent application PCT/GB00/03796. Such devices have an insertion loss penalty due to the dead-space between the pixels. As discussed in our co-pending patent application GB0107742.9, the insertion loss may be reduced significantly by using a reflecting layer inside the substrate positioned so as to reflect the light passing between the pixels back out again. Referring to FIG. 1, an integrated SLM 200 for modulating light 201 of a selected wavelength, e.g. 1.5 μm, consists of a pixel electrode array 230 formed of reflective aluminium. The pixel electrode array 230, as will later be described acts as a mirror, and disposed on it is a quarter-wave plate 221. A liquid crystal layer 222 is disposed on the quarter-wave plate 221 via an alignment layer (not shown) as is known to those skilled in the art of liquid crystal structures. Over (as shown) the liquid crystal layer 222 are disposed in order a second alignment layer 223, a common ITO electrode layer 224 and an upper glass layer 225. The common electrode layer 224 defines an electrode plane. The pixel electrode array 230 is disposed parallel to the common electrode plane 224. It will be understood that alignment layers and other intermediate layers will be provided as usual. They are omitted in FIG. 1 for clarity. The liquid crystal layer 222 has its material aligned such that under the action of a varying voltage between a pixel electrode 230 and the common electrode 224, the uniaxial axis changes its tilt direction in a plane normal to the electrode plane 224. The quarter wave plate 221 is disposed such that light polarised in the plane of tilt of the director is reflected back by the mirror 230 through the SLM with its plane of polarisation perpendicular to the plane of tilt, and vice-versa. Circuitry, not shown, connects to the pixel electrodes 230 so that different selected voltages are applied between respective pixel electrodes 230 and the common electrode layer 224. Considering an arbitrary light beam 201 passing through a given pixel, to which a determined potential difference is applied, thus resulting in a selected phase modulation due to the liquid crystal layer over the pixel electrode 230. Consider first and second orthogonal polarisation components, of arbitrary amplitudes, having directions in the plane of tilt of the director and perpendicular to this plane, respectively. These directions bisect the angles between the fast and slow axes of the quarter-wave plate 221. The first component experiences the selected phase change on the inward pass of the beam towards the aluminium layer 230, which acts as a mirror. The second component experiences a fixed, non-voltage dependent phase change. However, the quarter-wave plate 221 in the path causes polarisation rotation of the first and second components by 90 degrees so that the second polarisation component of the light beam is presented to the liquid crystal for being subjected to the selected phase change on the outward pass of the beam away from the mirror layer 230. The first polarisation component experiences the fixed, non-voltage dependent phase change on the outward pass of the beam. Thus, both of the components experience the same overall phase change contribution after one complete pass through the device, the total contribution being the sum of the fixed, non-voltage dependent phase and the selected voltage dependent phase change. It is not intended that any particular SLM structure is essential to the invention, the above being only exemplary and illustrative. The invention may be applied to other devices, provided they are capable of multiphase operation and are at least somewhat polarisation independent at the wavelengths of concern. Other SLMs are to be found in our co-pending applications WO01/25840, EP1050775 and EP1053501 as well as elsewhere in the art. Where liquid crystal materials other than ferroelectric are used, current practice indicates that the use of an integral quarter wave plate contributes to the usability of multiphase, polarisation-independent SLMs. A particularly advantageous SLM uses a liquid crystal layer configured as a pi cell. Referring to FIG. 2, an integrated SLM 10 has processing circuitry 11 having a first control input 12 for routing first and second beams 1,2 from input fibres 3,4 to output fibres 5,6 in a routing device 15. The processing circuitry 11 includes a store holding control data which is processed to generate holograms which are applied to the SLM 10 for control of light incident upon the SLM 10. The control data are selected in dependence upon the data at the control input 12, and may be stored in a number of ways, including compressed formats. The processing circuitry 11, which may be at least in part on-chip, is also shown as having an additional input 16 for modifying the holograms. This input 16 may be a physical input, or may be a “soft” input—for example data in a particular time slot. The first beam 1 is incident on, and processed by a first array, or block 13 of pixels, and the second beam 2 is incident on and processed by a second array, or block 14 of pixels. The two blocks of pixels 13,14 are shown as contiguous. In some embodiments they might however be separated from one another by pixels that allow for misalignment. Where the SLM is used for routing the beams 1,2 of light, this is achieved by displaying a linearly changing phase ramp in at least one direction across the blocks or arrays 13,14. The processing circuitry 11 determines the parameters of the ramp depending on the required angle of deflection of the beam 1,2. Typically the processing circuitry 11 stores data in a look-up table, or has access to a store of such data, to enable the required ramp to be created in response to the input data or command at the first control input 12. The angle of deflection is probably a two dimensional angle where the plane common to the direction of the incident light and that of the reflected light is not orthogonal to the SLM. Assigning x and y co-ordinates to the elements of the SLM, the required amount of angular shift from the specular reflection direction may be resolved into the x and y directions. Then, the required phase ramp for the components is calculated using standard diffraction theory, as a “desired phase characteristic”. This process is typically carried out in a training stage, to provide the stored data in the look-up table. Having established a desired phase modulation characteristic across the array so as to achieve the desired control of said beam the processing circuitry 11 transforms this characteristic into one that can be displayed by the pixels 13,14 of the SLM 10. Firstly it should be borne in mind that the processing circuitry 11 controlling the pixels of an SLM 10 is normally digital. Thus there is only a discrete population of values of phase modulation for each pixel, depending on the number of bits used to represent those states. To allow the pixels 13,14 of the SLM 11 to display a suitable phase profile, the processing circuitry 11 carries out a level selecting operation for each pixel. As will be appreciated, the ability of the SLM to phase modulate has limits due to the liquid crystal material, and hence a phase ramp that extends beyond these limits is not possible. To allow for the physical device to provide the effects of the ideal device (having a continuously variable limitless phase modulation ability), the desired phase ramp may be transformed into a non-monotonic variation having maxima and minima within the capability limits of the SLM 10. In one example of this operation, the desired phase modulation is expressed modulo 2pi across the array extent, and the value of the desired modulo-2pi modulation is established at the centre of each pixel. Then for each pixel, the available level nearest the desired modulation is ascertained and used to provide the actual pixel voltage. This voltage is applied to the pixel electrode for the pixel of concern. For small pixels there may be edge effects due to fringing fields between the pixels and the correlations between the director directions in adjacent pixels. In such systems the available phase level nearest to the value of the desired modulo-2pi modulation at the centre of each pixel (as described above) should be used as a first approximation. A recursive algorithm is used to calculate the relevant system performance characteristic taking into account these ‘edge’ effects and to change the applied level in order to improve the system performance to the required level. “Linear” means that the value of phase across an array of pixels varies linearly with distance from an arbitrary origin, and includes limited linear changes, where upon reaching a maximum phase change at the end of a linear portion, the phase change reverts to a minimum value before again rising linearly. The additional input 16 causes the processing circuitry 11 to modify the holograms displayed by applying a discrete approximation of a non-linear phase modulation so that the SLM 10 synthesises a corrective optical element such as a lens or an aberration corrector. As will be later described, embodiments may also provide power control (attenuation), sampling and beam shaping by use of the non-linear phase modulation profile. “Non-linear” is intended to signify that the desired phase profile across an array of pixels varies with distance from an arbitrary origin in a curved and/or oscillatory or like manner that is not a linear function of distance. It is not intended that “non-linear” refer to sawtooth or like profiles formed by a succession of linear segments of the same slope mutually separated by “flyback” segments. The hologram pattern associated with any general non-linear phase modulation exp jφ(u)=exp j (φ0(u)+φ1(u)+φ3(u) . . . ) where j is the complex operator, can be considered as a product. In this product, the first hologram term in the product exp j φ0(u) implements the routing while the second hologram term exp j φ1(u) implements a corrective function providing for example lens simulation and/or aberration correction. The third hologram term exp j φ2(u) implements a signal processing function such as sampling and/or attenuation and/or beam shaping. The routing function is implemented as a linear phase modulation while the corrective function includes non-linear terms and the signal processing function includes non-linear oscillatory terms. Different methods of implementing the combination of these three terms are possible. In one embodiment the total required phase modulation φ0(u)+φ1(u)+φ2(u) including linear routing and corrective function and the signal processing function is resolved modulo 2 pi and approximated to the nearest available phase level before application by the pixels. In another embodiment the summation of the phase modulation required for the linear and corrective function φ0(u)+φ1(u) is resolved modulo 2 pi and approximated to the nearest phase level in order to calculate a first phase distribution. A second phase distribution φ2(u) is calculated to provide sampling and/or attenuation and/or beam shaping. The two phase distributions are then added, re-resolved modulo 2 pi and approximated to the nearest available phase level before application by the pixels. Other methods are also possible. Mathematically the routing phase modulation is periodic due to the resolution modulo 2pi and by nature of its linearity. Therefore the routing phase modulation results in a set of equally spaced diffraction orders. The greater the number of available phase levels the closer the actual phase modulation to the ideal value and the stronger the selected diffraction order used for routing. By contrast, the corrective effects are realised by non-linear phase changes φ1(u) that are therefore non-periodic when resolved modulo 2pi. This non-periodic phase modulation changes the distribution of the reflected beam about its centre, but not its direction. The combined effect of both linear (routing) and non-periodic phase modulation is to change both the direction and distribution of the beam, as may be shown using the convolution theorem. The signal processing effects are usually realised by a method equivalent to ‘multiplying’ the initial routing and/or corrective hologram exp j (φ0(u)+φ1(u)) by a further hologram exp j φ2(u) in which φ2(u) is non-linear and oscillatory. Therefore the set of diffraction orders associated with the further hologram creates a richer structure of subsidiary beams about the original routed beam, as may be shown using the convolution theorem. While this explanation is for a one-dimensional phase modulator array the same principle may be applied in 2-D. Hence in a reconfigurable optical system this non-linear phase modulation may be applied by the same spatial light modulator(s) that route the beam. It will be understood by those skilled in the art that the SLM may have only a single control input and the device may have processing circuitry for combining control data for routing and control data for corrective effects and signal processing effects to provide an output to control the SLM. The data may be entered into the SLM bit-wise per pixel so that for each pixel a binary representation of the desired state is applied. Alternatively, the data may be entered in the form of coefficients of a polynomial selected to represent the phase modulation distribution of the pixel array of concern in the SLM. This requires calculating ability of circuitry of the SLM, but reduces the data transfer rates into the SLM. In an intermediate design the polynomial coefficients are received by a control board that itself sends bit-wise per pixel data to the SLM. On-chip circuitry may interpret data being entered so as to decompress that data. The pixel array of concern could be all of the pixels associated with a particular beam or a subset of these pixels. The phase modulation distribution could be a combined phase modulation distribution for both routing and corrective effects or separate phase modulation distributions for each. Beam shaping, sampling and attenuation phase modulation distributions, as will be described later, can also be included. In some cases it may not be possible to represent the phase modulation distribution as a simple polynomial. This difficulty may be overcome by finding a simple polynomial giving a first approximation to the desired phase modulation distribution. The coefficients of this polynomial are sent to the SLM. A bit-wise correction is sent for each pixel requiring a correction, together with an address identifying the location of the pixel. When the applied distribution is periodic only the corrections for one period need be sent. The processing circuitry 11 may be discrete from or integral with the SLM, or partly discrete and partly integral. Referring to FIG. 3, a routing device 25 includes two SLMs 20,21 which display holograms for routing light 1,2 from an input fibre array 3,4 to an output fibre array 5,6. The two SLMs are reflective and define a zigzag path. The first SLM 20 hereinafter referred to as a “corrective SLM” not only carries out routing but also synthesises a corrective optical element. The second SLM 21 carries out only a routing function in this embodiment, although it could also carry out corrections or apply other effects if required. The second SLM 21 is hereinafter referred to as a “routing SLM”. Although the corrective SLM 20 is shown disposed upstream of the routing SLM 21, it may alternatively be disposed downstream of the routing SLM 21, between two routing SLMs, or with systems using routing devices other than the routing SLM 21. The routing SLM 21 has operating circuitry 23 receiving routing control data at a routing control input 24, and generating at the SLM 21 sets of holograms for routing the beams 1,2. The corrective SLM 20 has operating circuitry 26 receiving compensation or adaptation data at a control input 27 to cause the SLM 20 to display selected holograms. In this embodiment, the SLM 20 forms a reflective lens. Synthesising a lens at the SLM 20 can be used to change the position of the beam focused spot and therefore correct for a position error or manufacturing tolerance in one or more other lenses or reflective (as opposed to transmissive) optical elements, such as a curved mirror. The synthesised lens can be spherical or aspheric or cylindrical or a superposition of such lenses. Synthesised cylindrical lenses may have arbitrary orientation between their two long axes and the lens focal lengths can both be positive, or both be negative, or one can be positive and the other negative. To provide a desired phase modulation profile for a lens or curved mirror to compensate for an unwanted deviation from a required system characteristic, the system is modelled without the lens/mirror. Then a lens/mirror having the correction to cancel out the deviation is simulated, and the parameters of the lens/mirror are transformed so that when applied to an SLM the same effect is achieved. In one application what is required is to adjust the position and width of the beam waist, of a Gaussian-type beam at some particular point in the optical system, in order to compensate for temperature changes or changes in routing configuration. Hence two properties of the beam must be adjusted and so it is necessary to change two properties of the optical system. In a conventional static optical system both a lens focal length and the position of the lens are selected to achieve the required beam transformation. In the dynamic systems under consideration it is rarely possible deliberately to adjust the position of the optical components. A single variable focus action at a fixed position changes both the position and the width of the beam waist and only in special circumstances will both properties be adjusted to the required value. One method to overcome this problem is to apply both corrective phase and corrective ‘pseudo-amplitude’ modulation (to be described later) with a single SLM. However the amplitude modulation reduces the beam power which may be undesirable in some applications. A further and preferred method is to apply corrective phase modulation with two separate SLMs. For example consider coupling from one input fibre (or input beam) through a routing system into the selected output fibre (or output beam). Inside the routing system there are at least two SLMs carrying out a corrective function. They may also be routing and carrying out other functions (to be described in this application). In between a given pair of SLMs carrying out focus correction there is an intermediate optical system. At the first SLM carrying out a corrective function there may be calculated and/or measured the incident amplitude and phase distribution of the input beam that had propagated from the input fibre or beam. At the second SLM carrying out a corrective function there may be calculated and/or measured the ideal amplitude and phase distribution that the output beam would adopt if coupling perfectly into the output fibre or beam. This can be achieved by backlaunching from the output fibre or beam or by a simulation of a backlaunch. The required focus correction functions of these two SLMs is to transform the incident amplitude and phase distribution arriving at the first SLM to the ideal amplitude and phase distribution at the second SLM to achieve perfect (or the desired) coupling efficiency into the output fibre or output beam. The corrective phase modulation to be applied at the first SLM should be calculated, so as to achieve the ideal amplitude distribution at the second SLM as the beam arrives at the second SLM after passing from the first SLM and through the intermediate system. This calculation should take into account propagation through the intermediate system between the first and second SLMs. Hence the function of the first SLM is to correct the beam so as to achieve the ideal amplitude distribution for the output beam. The beam phase distribution should also be calculated as it arrives at the second SLM. The corrective phase distribution to be applied at the second SLM should be calculated so as to transform the phase distribution of the beam incident upon it from the intermediate system to the ideal phase distribution required for the output beam at the second SLM. Two variables available at the SLM to effect corrections from an optimal or other desired level of performance are firstly the blocks of pixels that are delineated for the incident light beam, and secondly the hologram that is displayed on the block(s) of concern. Starting with the delineation of blocks, it should be borne in mind that the point of arrival of light on the SLM can only be predicted to a certain accuracy and that the point may vary according to physical changes in the system, for example due to temperature effects or ageing. Thus, the device allows for assessment of the results achieved by the current assignment, and comparison of those results with a specified performance. In response to the comparison results, the delineation may be varied so as to improve the results. In one embodiment a training phase, uses for example a hill climbing approach to control and optimise the position of the centre of the block. Then if the “in-use” results deviate by more than a specified amount from the best value, the delineation of the block is varied. This process reassignment may step the assigned block one pixel at a time in different directions to establish whether an improved result is achieved, and if so continuing to step to endeavour to reach an optimum performance. The variation may be needed where temperature effects cause positional drift between components of the device. It is important to realise that unlike MEMS systems and the like, all the pixels are potentially available for all the beams. Also the size, shape and location of a delineated block is not fixed. Equally the size and shape of a block may be varied if required. Such changes may be necessary under a variety of situations, especially where a hologram change is needed. If for example a hologram requiring a larger number of pixels becomes necessary for one beam, the size of the block to display that hologram can be altered. Such changes must of course usually be a compromise due to the presence of other blocks (possibly contiguous with the present block) for displaying holograms for other beams of light. Monitoring techniques for determining whether the currently assigned block is appropriate include the techniques described later herein as “taking moments”. Turning to variation of the hologram that is displayed on the block of concern, one option to take into account for example physical changes in the system, such as movement out of alignment, is to change one normal linear-type routing hologram for another, or to adjust the present hologram in direct response to the sensed change. Thus if, due for example to temperature effects, a target location for a beam moves, it may be necessary to change the deflection currently being produced at a pixel block. This change or adjustment may be made in response to sensed information at the target location, and may again be carried out “on-line” by varying the hologram step by step. However, it may be possible to obtain an actual measure of the amount and direction of change needed, and in this case either a new hologram can be read in to the SLM or a suitable variation of the existing hologram carried out. As well as, or instead of, linear changes to linear routing holograms, corrective changes may be needed, for example to refocus a beam or to correct for phase distortion and non-focus aberrations. Having corrected the beam focus other aberrations may remain in the system. Such aberrations distort the phase distributions of the beams. These aberrations will also change with routing configuration as the beams are passing through different lenses and/or different positions on the same lenses. Similarly the aberrations will change with temperature. To obtain stable and acceptable performance of a reconfigurable optical system, the aberrations can be corrected dynamically. To provide a desired phase modulation profile for these aberrations the system may be modelled or measured to calculate the phase distortion across the SLM, compared to the ideal phase distribution. The ideal phase distribution may again be found by modelling the system ‘backwards’ from the desired output beam, or by backlaunching and measurement, while the actual phase distribution may be found by modelling the system forwards from the input beam or measurement. The calculations will include the effects of reflection from the SLM itself. The corrective function of the SLM is to transform between the actual and ideal phase distortion. The phase distortion is defined as the phase difference between the actual phase distribution and the ideal phase distribution. The desired corrective profile is the conjugate phase of the phase distortion. Alternatively, these corrective functions can be shared by two SLMS, which allows an extra degree of freedom in how the beam propagates inside the intermediate system between the two SLMs. Further, given a real system a sampling method (as will be described later) may be used to direct a fraction of the beam towards a wavefront sensor that may assess the beam. So far the process is deterministic. Then the changes are applied to the real system, and perturbations on the parameters are applied while monitoring the sensor and/or the input/output state, so as to determine whether an optimum configuration is achieved. If not, the parameters are changed until a best case is achieved. Any known optimising technique may be used. It is preferred to provide a reasonable starting point by deterministic means, as otherwise local non-optimum performance maxima may be used instead of the true optimum. The method or device of the invention may be used to correct for aberrations such as field curvature in which the output ‘plane’ of the image(s) from an optical system is curved, rather than flat. Equally, even if in use the SLM forms a corrective element by having non-linear phase modulation applied across it, if it is operated in separate training and use phases, it may be desirable while training for the SLM to route as well. In this case the SLM scans the processed beam over a detector or routes the beam, for example using one or more dummy holograms, into a monitor fibre. Referring now to FIG. 4, the corrective SLM 20, used purely for synthesising a corrective element, has operating circuitry 125, and further comprises processing circuitry 122 and temperature sensors 123. In this embodiment the operating circuitry, temperature sensors and processing circuitry are integrated on the same structure as the rest of the SLM, but this is not critical to the invention. Associated with the processing circuitry is a store 124 into which is programmed a lookup table. The sensors detect temperature changes in the system as a whole and in the SLM, and in response to changes access the look up table via the processing circuitry 122 to apply corrections to the operating circuitry. These corrections affect the holograms displayed on the blocks 13, 14 of pixels. The sensors may also be capable of correction for temperature gradients. This technique may also be applied to an SLM used for routing. Referring now to FIG. 5, an optical system 35 has a corrective SLM 30 with operating circuitry 31, and processing circuitry 32. The system includes further devices, here second and third SLMs 33 and 34, disposed downstream of the corrective SLM 30. The second SLM 33 is intended to route light to particular pixel groups 15, 16 of the third SLM 34. The third SLM 34 has monitor sensors 37 for sensing light at predetermined locations. In one embodiment these sensors 37 are formed by making the reflective layer partially transmissive, and creating a sensing structure underneath. In another, the pixel electrode of selected pixels is replaced by a silicon photodetector or germanium sensor structure. In either case, circuitry may be integrated into the silicon backplane to process the output of the sensors 37, for example to compare the outputs of adjacent sensors 37, or to threshold one sensor against neighbouring sensor outputs. Where possible, processing circuitry is on chip, as it is possible to reduce the time taken after light has been received to respond to it in this way. This is because there is no need to read information off-chip for processing, and also because calculations may be able to be performed in parallel. Provided the routing-together with any compensation effects from the corrective SLM 30—is true, the sensors 37 will receive only a minimal amount of light. However where misalignment or focus errors are present, the extent of such errors is detected by measuring the power coupled into the monitor sensors. To that end, the sensors 37 provide data, possibly after some on-chip processing, to the processing circuitry 32. The processing circuitry 32 contains a control algorithm to enable it to control the operating circuitry 31 to make changes of, or adjustments to, the compensating holograms displayed on the corrective SLM 30 until the system alignment is measured to be optimised. In some embodiments, changes to the sub-arrays to which beam affecting holograms are applied may be made in response to the sensor output data. In another embodiment a determined number of dummy ports are provided. For example for a connector two or more such ports are provided and for routing devices three or more dummy ports are provided. These are used for continuous misalignment monitoring and compensation, and also for system training at the start. Although some embodiments can operate on a trial and error basis, or can be adapted “on the fly”, a preferred optical system uses a training stage during which it causes to be stored in the look-up table data enabling operation under each of the conditions to be encountered in use. In one embodiment, in the training stage, a set of initial starting values is read in for application to the SLM 30 as hologram data, then light is applied at a fibre and the result of varying the hologram is noted. The variations may include both a change of pixels to which the hologram is applied, and a change of the hologram. Where more than one fibre is provided, light is applied to each other fibre in turn, and similar results obtained. Then other environmental changes are applied and their effects noted, e.g. at the sensors 37, and the correction for input data either calculated or sought by varying the presently-applied data using optimisation techniques to seek best or acceptable performance. Then, in use, the system may be operated on a deterministic basis—i.e. after ascertaining what effect is sought, for example responding to a temperature change or providing a change in routing, the change to the applied data for operating the device can be accessed without the need for experiment. A preferred embodiment operates in the deterministic way, but uses one or more reference beams of light passed through the device using the SLM 30. In that way the effect of deviations due to the device itself can be isolated. Also it can be confirmed that changes are being correctly made to take into account environmental and other variations. The device may also have further monitor sensors placed to receive the zero-order reflections from the SLM(s) to enable an assessment to be made of the input conditions. For example, where an input channel fails, this can be determined by observing the content of the specular reflection from the light beam representing that channel. Where there are two SLMs as in some routing systems, the specular reflections from each SLM may be sensed and compared. Referring now to FIG. 6, a dual-function SLM 40 provides both routing and correction. The SLM 40 has operating circuitry 41 and processing circuitry 42. The operating circuitry 41 receives routing data at a first control input 44 for causing the processing circuitry 42 to generate the holograms on the SLM 40 to achieve the desired routing. The processing circuitry 42 also receives routing data on an input 45, and controls the operating circuitry 41 using an algorithm enabling adaptation due to changes in the path taken through the system to take place on a timescale equivalent to that required to change the hologram display, i.e. of the order of milliseconds. The control algorithms for this embodiment may use one or more of several types of compensation. In one embodiment a look-up table is stored in a memory 43, the look-up table storing pre-calculated and stored values of the compensation for each different route through the system. In another embodiment the system is trained before first being operated, using changes of, or to the compensating holograms to learn how changing the compensating holograms affects the system performance, the resulting data being held in the memory 43. In a further embodiment, the processing circuitry 42 employs intelligence responsive to signals from monitor sensors 47,48 for monitoring and calculation of how these compensating holograms should adapt with time to accommodate changes in the system alignment. This is achieved in some embodiments by integrating circuitry components into the silicon backplane of the SLM, or by discrete components such as germanium detectors where the wavelengths are beyond those attainable by silicon devices. In some embodiments sensors 47 are provided for sensing light at areas of the SLM, and in others the sensors 48 may instead or also be remote from the SLM 40 to sense the effects of changes on the holograms at the SLM 40. Referring now to FIG. 7, an optical system 80 includes an SLM 81 for routing beams 1,2 of light from input fibres 3,4 to output fibres 5,6 by means of holograms displayed on pixel groups 13,14 of the SLM. The holograms are generated by processing circuitry 82 which responds to a control input 83 to apply voltages to an array of pixellated elements of the SLM, each of which is applied substantially uniformly across the pixel of concern. This result is a discrete approximation of a linear phase modulation to route the beams. The processing circuitry 82 calculates the ideal linear phase ramp to route the beams, on the basis of the routing control input 83 and resolves this phase modulo 2Pi. The processing circuitry at each of the pixels then selects the closest available phase level to the ideal value. For example if it is desired to route into the m′th diffraction order with a grating period Ω the ideal phase at position u on the SLM 81 is 2pi.mu/Ω. Therefore, approximately, the phase goes linearly from zero up to 2pi over a distance Ω/m after which it falls back to zero, see FIG. 8a. Control of the power in individual wavelength channels is a common requirement in communication systems. Typical situations are the need to avoid receiver saturation, to maintain stable performance of the optical amplifiers or to suppress non-linear effects in the transmission systems that might otherwise change the information content of the signals. Power control may be combined with sampling or monitoring channels to allow adjustment of the power levels to a common power level (channel equalisation) or to some desired wavelength characteristic. Deliberate changes to the value of Ω can be used to reduce the coupling efficiency into the output in order to provide a desired attenuation. This is suitable for applying a low attenuation. However, it is not suitable for a high attenuation as, in that event, the beam may then be deflected towards another output fibre, increasing the crosstalk. If there is only one output fibre this method may be used regardless of the level of attenuation. To provide a selected desired attenuation of the optical channel in the system, processing circuitry 85 responds to an attenuation control input 84 to modify the operation of the operating circuitry 83 whereby the operating circuitry selects a linear phase modulation such that by the end of each periodic phase ramp the phase has reached less than 2pi, see FIG. 8b. This may be achieved by calculating the ideal value of phase for every pixel, and then multiplying this ideal value by a coefficient r between 0 and 1, determined on the basis of the desired attenuation. The coefficient is applied to every pixel of the array in order to get a reduced level per pixel, and then the available phase level nearest to the reduced level is selected. The method of this embodiment reduces the power in this diffraction order by making the linear phase modulation incomplete, such that by the end of each periodic phase ramp the phase has only reached 2pi.r. It has however been found that the method of this embodiment may not provide sufficient resolution of attenuation. It also increases the strength of the unwanted diffraction orders likely to cause crosstalk. When combined with deliberate changes in the length of the ideal phase ramp the resolution of attenuation may be improved. Again if there is only a single output fibre the crosstalk is less important. Resolution may also be improved by having a more complex incomplete linear phase modulation. However, the unwanted diffraction orders may still remain too strong for use in a wavelength-routed network. Hence to control the power by adapting the routing hologram may have undesirable performance implications in many applications, as crosstalk worsens with increase of attenuation. The problem can be overcome by use of a complex iterative design. This could be used to suppress the higher orders but makes the routing control more expensive. Referring now to FIG. 9, a system 99 includes an SLM 90 controlled by applying a discrete approximation of a linear phase modulation to route beams 1,2 from input fibres 3,4 to output fibres 5,6 as previously described with respect to FIG. 7. Thus operating circuitry 91 selects a routing hologram for display by the SLM, in accordance with a routing input 92, whereby the beams may be correctly routed, using a look up table or as otherwise known. A memory holds sets of data each allowing the creation of a respective power controlling hologram. Processing circuitry 93 runs an algorithm which chooses a desired power controlling hologram corresponding to a value set at a power control input 94. The power controlling hologram is selected to separate each beam into respective main 1a, 2a and subsidiary 1b, 2b beams, such that the main beams 1a, 2a are routed through the system and the or each subsidiary beam(s) 1b, 2b is/are diffracted out of the system, for example to a non-reflective absorber 97. The processing circuitry 93 applies the power controlling hologram data to a second input 95 of the operating circuitry 91 which acts on the routing hologram data so as to combine the routing and power controlling holograms together to provide a resultant hologram. The operating circuitry then selects voltages to apply to the SLM 90 so that the SLM displays the resultant hologram. Thus power in a routing context is controlled by combining the routing hologram with another hologram that has the effect of separating the beam into a main beam and a set of one or more subsidiary beams of these the main beam is allowed to propagate through the system as required while the other(s) are diffracted out of the system. For example consider a hologram that applies phases of +φ and −φ on adjacent pixels. In terms of real and imaginary parts this hologram has the same real part, cos φ, on every pixel, see FIG. 10, while the imaginary part oscillates between ± sin φ. It can be shown using Fourier theory that the net effect is to multiply the amplitude of the original routed beam by a factor cos φ, and to divert the unwanted power into a set of weak beams at angles that are integer multiples of ±λ/2p with respect to the original routed beam, where λ is the operating wavelength and p is the pixel pitch. The system is designed from a spatial viewpoint such that light propagating at such angles falls outside the region of the output fibres 5,6 of FIG. 9. An alternative design directs the unwanted light into output fibres 5,6 at such a large angle of incidence that the coupling into the fundamental mode is very weak, and has no substantial effect. In this case the unwanted power is coupling into the higher-order modes of the fibre and so will be attenuated rapidly. A fibre spool or some other technique providing mode stripping is then used on the output fibre before the first splice to any other fibre. In either case, the effective attenuation of the beam is 10 log10 cos2φ. Hence, in this way, polarisation-independent phase modulation may be used to create an effect equivalent to polarisation-independent amplitude modulation. This is termed herein “pseudo amplitude modulation”. In this particular case the pseudo-amplitude modulation applied at every pixel is cos φ. It will be clear to those skilled in the art that use of alternate pixels as the period of alternation is not essential, and may in some cases be undesirable. This is because of edge effects in the pixels. The period and pattern of alternation can be varied so as to adjust the deflection angle of the ‘unwanted power’. This light directed away from the output fibres can be collected and used as a monitor signal. Hence the pseudo-amplitude modulation can be used to sample the beam incident on an SLM as previously discussed. This sampling hologram can be combined with a routing and/or power control and/or corrective SLM. In the latter case the sampled beam can be directed towards a wavefront sensor and then used to assess the quality of the beam correction. While the pseudo-amplitude modulation as described above is applied to the whole beam, it could be applied selectively to one or more parts of the beam. A further modification to this pseudo-amplitude modulation is to multiply it by a further phase modulating hologram such as to achieve a net effect equivalent to a complex modulation. It is often important that the sampling hologram takes a true sample of the output beam. Therefore in some cases the sampling hologram should be applied after the combination of all other desired effects including resolution modulo 2pi and approximation to the nearest available phase level. In this case the overall actual phase modulation distribution is achieved by a method equivalent to forming the product of the sampling hologram and the overall hologram calculated before sampling. Similar pseudo-amplitude modulation techniques may be extended to suppress the crosstalk created by clipping of the beam tails at the edges of each hologram and to tailor the coupling efficiency vs. transverse offset characteristic of the output fibres. Since the transverse position at the output fibre is wavelength dependent, this tailoring of the coupling efficiency vs. offset can be used to tailor the wavelength response of the system. This is important in the context of wavelength division multiplexing (WDM) systems where the system wavelength can be expected to lie anywhere in the range of the available optical amplifiers. The output angle for beam steering using an SLM and periodic linear phase modulation is proportional to the wavelength while the focal length of corrective lenses is also wavelength-dependent. Therefore a hologram configured to give the optimum coupling efficiency at one wavelength will produce an output beam with transverse and/or longitudinal offset at another wavelength. These effects result in wavelength-dependent losses in systems required to route many wavelength channels as an ensemble. Hence a method designed to flatten or compensate for such wavelength-dependent losses is useful and important. Among the envisaged applications are the flattening of the overall wavelength response and the compensation for gain ripple in optical amplifiers, especially Erbium-doped fibre optic amplifiers (EDFA). An SLM device may also be used to adapt the shape, e.g. the mode field shape, of a beam in order to suppress crosstalk. Beam shaping is a type of apodisation. It is advantageously used to reduce crosstalk created at a device by clipping of the energy tails of the light beams. Such clipping leads to ripples in the far field. These ripples cause the beam to spread over a wider region than is desired. In telecommunications routing this can lead to crosstalk. Other applications may also benefit from apodisation of a clipped laser beam, such as laser machining, for example, where it is desired to process a particular area of a material without other areas being affected and laser scalpels for use in surgery. Clipping occurs because the energy of the beam spreads over an infinite extent (although the amplitude of the beam tails tends to zero), while any device upon which the beam is incident has a finite width. Clipping manifests itself as a discontinuity in the beam amplitude at the edges of the device. Referring to FIG. 11, two SLMs 100,101 are used for beam steering or routing of beams 1,2 from input fibres 3,4 to output fibres 5,6, as described in PCT GB00/03796. Each SLM 100,101 is divided into a number of blocks of pixels 103a, 104a; 103b, 104b. Each block 103a, 104a is associated with a particular input fibre 3,4—i.e. the fibre of concern points to the subject block. Each block displays a hologram that applies routing. As previously discussed herein the holograms may also or alternatively provide focus compensation, aberration correction and/or power control and/or sampling, as required. The blocks 103a, 104a at the input SLM 100 each receive a beam from an associated input fibre 3,4 while the blocks 103b, 104b at the output SLM 101 each direct a beam towards an associated output fibre 5,6. Each block 103a, 103b has a finite width and height. As known to those skilled in the art and as previously noted, the beam width is infinite, therefore the block clips the beam from or to the associated fibre and this creates undesired ripples in the far field. The ripples due to clipping of the beam 1 are figuratively shown as including a beam 106 which, it will be seen, is incident on the wrong output hologram, displayed on block 104b at the output SLM 101. “Wrong” signifies holograms other than that to which the beam of concern is being routed, for example holograms displayed by blocks around the block to which the beam should be routed. Some of these ripples will then be coupled into “wrong” output fibres 5,6—i.e. those to which the beam is not deliberately being routed—leading to crosstalk. It will be clear to those skilled in the art that these effects will be present on blocks other than those adjacent to the “correct” blocks, as the field of beam 1 is infinite in extent. In any physical system the effect of the ripples created by clipping at the output SLM 101 depends on the optical architecture. In practice the non-ideal transfer function of the optics (due to finite lens apertures and aberrations) means that a sharp change in the amplitude spreads out and causes crosstalk in adjacent output fibres. In effect the optics applies a limit to the range of spatial frequencies that can be transmitted. This frequency limit causes crosstalk. The wider the device, compared to the beam spot size at the device, the weaker the ripples in the far field and the lower the crosstalk. In general a parameter C is defined such that the required width of SLM per beam is given by H=C.ω, where ω is the beam spot size at the SLM. The value of C depends on the beam shape, the optical architecture and the allowable crosstalk. Typically for a Gaussian beam, with no beam shaping and aiming for crosstalk levels around −40 dB, C would be selected to have a value greater than or equal to three. Looking at this system from the spatial frequency viewpoint, the field incident on the SLM contains (for perfect optics) all the spatial frequencies in the input beam. The finite device width cuts off the higher spatial frequencies, so, again, the optics applies a limit to the range of spatial frequencies that can be transmitted and this frequency limit causes crosstalk. Beam shaping can be used to decrease the crosstalk for a given value of C, and also allow the use of a lower value of C. Calculations for N×N switches have shown that decreasing the value of C leads to more compact optical switches and increases the wavelength range per port. Hence beam shaping can be employed to provide more compact optical switches and/or an increased wavelength range per port. The idea behind using beam shaping or ‘apodisation’ to reduce crosstalk is based on an analogy with digital transmission systems. In these systems a sequence of pulses is transmitted through a channel possessing a limited bandwidth. The frequency response of the channel distorts the edges of pulses being transmitted so that the edges may interfere with one another at the digital receiver leading to crosstalk. The channel frequency response can, however, be shaped so as to minimise such crosstalk effects. Filters with responses that have odd-symmetry can be used to make the edges go through a zero at the time instants when pulses are detected. Therefore beam-shaping with odd symmetry can be used to make the crosstalk go through a zero at the positions of the output fibres. Such a method is likely to be very sensitive to position tolerances. Another method used in digital systems is to shape the frequency cut-off so that it goes smoothly to zero. In the present context the ideal case of ‘smoothly’ is that the channel frequency response and all derivatives of the frequency response become zero. In practice it is not possible to make all derivatives go to zero but a system may be designed in which the amplitude and all derivatives up to and including the k′th derivative become zero at the ends of the frequency range. The higher the value of k, the quicker the tails of the pulse decay. Therefore the beam shaping should go as smoothly as possible to zero. To investigate the effects of beam shaping the amplitude modulation was treated as continuous. The system studied was a single lens 2f system where 2f is the length of the system between fibres and SLM, assuming f is the focal length with fibres in one focal plane, and an SLM in the other focal plane. The input fibre beam was treated as a Gaussian. Various amplitude modulation shapes were applied at the SLM and the coupling efficiency into the output fibre was calculated. In this architecture and from Abbe theory, the incident field at the SLM is proportional to the Fourier Transform of the field leaving the input fibre. In particular, different spatial frequencies in the fibre mode land on different parts of the SLM. Clipping removes the spatial frequencies outside the area of the hologram. Beam shaping at the SLM has the effect of modifying the relative amplitude of the remaining spatial frequencies. Residual ripples may still remain due to the discontinuity in the beam derivative but the ripples will be reduced in amplitude and decay more quickly. Further reduction in the ripple amplitude and increase in the rate of decay may be achieved by shaping the beam such that both the amplitude and the first k derivatives go to zero at the edges. Mathematical analysis of the effect has also been carried out. The results are as follows: The nth time derivative of a function can be expressed in terms of its Fourier Transform as shown in equation (1): d n ⁢ g ⁡ ( t ) d ⁢ ⁢ t n = ∫ - ∞ ∞ ⁢ ( i2π ⁢ ⁢ f ) n ⁢ G ⁡ ( f ) ⁢ exp ⁢ ⁢ i2 ⁢ ⁢ π ⁢ ⁢ f ⁢ ⁢ t ⁢ ⁢ ⅆ f ( 1 ) Hence, by inversion, the frequency dependence of the Fourier Transform (FT) may be expressed as an FT of any one of the function's derivatives as shown in equation (2): G ⁡ ( f ) = 1 ( i2π ⁢ ⁢ f ) n ⁢ ∫ - ∞ ∞ ⁢ d n ⁢ g ⁡ ( t ) d ⁢ ⁢ t n ⁢ exp ⁢ - i2 ⁢ ⁢ π ⁢ ⁢ f ⁢ ⁢ t ⁢ ⁢ ⅆ t ( 2 ) Choosing the zeroth derivative provides the expression in equation (3): G ⁡ ( f ) = ∫ - ∞ ∞ ⁢ g ⁡ ( t ) ⁢ exp - i2π ⁢ ⁢ f ⁢ ⁢ t ⁢ ⅆ t ( 3 ) To apply the analysis to free-space beam-steering: let x and y be the position co-ordinates at the fibre output from a switch, and u and v be the position co-ordinates at the SLM. Assume the SLM to be in one focal plane of a lens of focal length f, and the fibre array to be in the other focal plane: E FIB ⁡ ( x , y ) = i f ⁢ ⁢ λ ⁢ exp ⁡ ( - i ⁢ 2 ⁢ π λ ⁢ ( 2 ⁢ f + n ⁢ ⁢ t ) ) ⁢ ∫ ∫ E SLM ⁡ ( u , v ) ⁢ exp ⁢ ⁢ i ⁢ 2 ⁢ π ⁢ ⁢ f λ ⁢ ( xu + yv ) ⁢ ⅆ u ⁢ ⅆ v ( 4 ) such that the output field (see equation (4)) is a 2-D Fourier Transform of the field at the SLM, ESLM. In this result t is the lens thickness and N its refractive index, while λ is the optical wavelength. For the present purposes the 1-D equivalent is considered (relation 5): E FIB ⁡ ( x ) = i f ⁢ ⁢ λ ⁢ exp ⁡ ( - i ⁢ 2 ⁢ π λ ⁢ ( 2 ⁢ f + n ⁢ ⁢ t ) ) ⁢ ∫ E SLM ⁡ ( u ) ⁢ exp ⁢ ⁢ i ⁢ 2 ⁢ π ⁢ ⁢ f λ ⁢ ( x ⁢ ⁢ u ) ⁢ ⅆ u ( 5 ) Comparing with (3) it is clear that the position co-ordinate at the SLM (u) is equivalent to the time domain and the position co-ordinate at the output (x) is equivalent to the frequency domain. Hence from (2) the output field may be expressed in terms of a derivative of the field at the SLM, as shown in equation (6): E FIB ⁡ ( x ) = i f ⁢ ⁢ λ ⁢ exp ⁡ ( - i ⁢ 2 ⁢ π λ ⁢ ( 2 ⁢ f + n ⁢ ⁢ t ) ) ⁢ ( i 2 ⁢ π ⁢ ⁢ x ) n ⁢ ∫ d n ⁢ E SLM ⁡ ( u ) du n ⁢ exp ⁢ ⁢ i ⁢ 2 ⁢ π ⁢ ⁢ f λ ⁢ ( x ⁢ ⁢ u ) ⁢ ⅆ u ( 6 ) Let the kth derivative of ESLM(u) be non-zero and smoothly varying over the range [−H/2, H/2], but zero outside this range, such that the derivative changes discontinuously at u=±H/2, as defined in (7): d k ⁢ E SLM ⁡ ( u ) du k = 0 ⁢ ⁢ ∀ u ⁢ : ⁢ u < - H 2 ⁢ ⁢ = g H ⁢ ⁢ u = - H 2 ⁢ ⁢ = s ⁡ ( u ) + g H ⁢ - H 2 < u < H 2 ⁢ ⁢ ⁢ = g H ⁢ ⁢ u = + H 2 ⁢ ⁢ = 0 ⁢ ⁢ u > H 2 ( 7 ) This representation assumes ESLM to be even in u. Physically this situation represents a beam that is perfectly aligned with respect to the centre of a hologram of width H. This derivative may be expressed as the sum of a rect function and a smoothly varying function, s(u), that is zero at and outside |u|=H/2, as shown in equation (8): d k ⁢ E SLM ⁡ ( u ) du k ≡ g H ⁢ rect ( u H ) + s ⁡ ( u ) ⁢ ( 8 ) For example consider a clipped (and unapodised) Gaussian beam; the zeroth derivative (k=0) may be expressed as shown in equations (9) and (10): s ⁡ ( u ) = exp - ( u ω HOL ) 2 - exp - ( H 2 ⁢ ω HOL ) 2 ⁢ ⁢ ∀  u  < H 2 ⁢ ⁢ = 0 ⁢ ⁢ ∀  u  ≥ H 2 ( 9 ) g H = exp - ( H 2 ⁢ ω HOL ) 2 ( 10 ) Now returning to the general case (equation(8)) the k+1th derivative is calculated to be as shown in equation (11): d k + 1 ⁢ E SLM ⁡ ( u ) du k + 1 ≡ g H ⁢ { δ ( u + H 2 ) - δ ( u - H 2 ) } + ds ⁡ ( u ) du ( 11 ) It is now convenient to calculate the output field. Set n=k+1 in (6) to obtain equation (12): E FIB ⁡ ( x ) ∝ 1 ( j ⁢ ⁢ 2 ⁢ π ⁢ ⁢ x ) k + 1 ⁢ { g H ⁢ ∫ - ∞ ∞ ⁢ ( δ ⁡ ( u + H / 2 ) - δ ⁡ ( u - H / 2 ) ) ⁢ exp - j ⁢ ⁢ 2 ⁢ π ⁢ ⁢ x ⁢ ⁢ u ⁢ ⅆ u + ∫ - ∞ ∞ ⁢ ⅆ s ⁡ ( u ) ⅆ u ⁢ exp - j ⁢ ⁢ 2 ⁢ π ⁢ xu ⁢ ⅆ u } ( 12 ) which becomes equation (13): E FIB ⁡ ( x ) ∝ 1 ( j ⁢ ⁢ 2 ⁢ π ⁢ ⁢ x ) k + 1 ⁢ { 2 ⁢ jg H ⁢ sin ⁡ ( π ⁢ ⁢ xH ) + ∫ H 2 H 2 ⁢ ⅆ s ⁡ ( u ) ⅆ u ⁢ exp - j ⁢ ⁢ 2 ⁢ ⁢ π ⁢ ⁢ xu ⁢ ⁢ ⅆ u } ( 13 ) As the position is increased, the exponential term in the 2nd integral of (13) oscillates more and more rapidly. Eventually the spatial frequency is so high that the derivative of s(u) can be considered to be constant, or nearly constant, over the spatial period. In which case the integral is zero, or nearly zero, when evaluated over each period of the oscillation. Therefore at high frequencies the whole of the second integral must approach zero. It is assumed that the behaviour is dominated by the first integral. The first integral shows that if the amplitude changes discontinuously (k=0, i.e. an unapodised hologram), the spectrum (EFIB) decays as 1/x. Now, if the amplitude and the first derivative are continuous, it is the second derivative that changes discontinuously, and so k=2 and the spectrum (EFIB) decays as 1/x3. Numerical simulations have been carried out to confirm this behaviour. A particularly advantageous shape is one in which the shaped beam has odd symmetry about points midway between the centre and the edges such that the beam amplitude and all of its derivatives go to zero at the beam edges. The beam shaping may be effected to remove only a small amount of power from the central portion of the beam, to maintain acceptable system efficiency. A method for shaping a beam to achieve suppression of the ripples is now described. Defining the middle of the beam as f(u), then f(u) can describe the original beam in its central portion, or what is left in the original beam after it has already been partially shaped, using, for example, pseudo-amplitude. To avoid ripples in the far field the edges of the beam go to zero at u=±H/2, where H is the width of the hologram. Hence, at the right-hand edge, describe the beam as in equation (14): fR(u)=f(0)−f(u−H/2) (14) (The left-hand edge is considered later). To get matching of the amplitude half-way between the middle and the edge it is required that condition (15) s should be valid: f(H/4)=fR(H/4) (15) From which there is obtained equation (16): f(H/4)+f(−H/4)=f(0) (16) Now consider the derivatives at the joining point. The nth derivative of the right-hand edge function is given by equation (17): ⅆ n ⁢ f RH ⅆ u n ⁢ | u = U = ⅆ n ⁢ f ⅆ u n ⁢ | u = U - H / 2 ( 17 ) Hence at the joining point condition (18) is valid: ⅆ n ⁢ f RHEDGE ⅆ u n ⁢ | u = H / 4 ⁢ H / 4 = ⅆ n ⁢ f ⅆ u n ⁢ | u = - H / 4 ⁢ 44 ( 18 ) In order to avoid the creation of high frequency effects (crosstalk tails) by the joining point all derivatives are desirably continuous here. Hence it is required that condition (19) should be true: ⅆ n ⁢ f ⅆ u n ⁢ | n = H / 4 = ⅆ n ⁢ f ⅆ u n ⁢ | u = - H / 4 ( 19 ) To find out whether this is possible, expand the function f in a Taylor series about x=0 to obtain equation (20): f=f(0)+a1u+a2u2+a3u3+a4u4+a5u5+a6u6+. . . (20) The first derivative is given by equation (21): ⅆ f ⅆ u = a 1 + 2 ⁢ a 2 ⁢ u + 3 ⁢ a 3 ⁢ u 2 + 4 ⁢ a 4 ⁢ u 3 + … ( 21 ) The required condition (19) for the first derivative (n=1) can be obtained provided f is even in x, so that all the odd coefficients {a1, a3. . . } in (20) and (21) are zero. This makes the first derivative continuous at the joining point. Furthermore if f is an even function then f(H/4)=f(−H/4) in which case (16) becomes (22): f ⁡ ( H / 4 ) = 1 2 ⁢ f ⁡ ( 0 ) ( 22 ) Given that f is now an even function, the second derivative of f is given by equation (23): ⅆ 2 ⁢ f ⅆ u 2 = 2 ⁢ a 2 + 12 ⁢ a 4 ⁢ u 2 + … ( 23 ) Returning to the required condition in (19) it is clear that it cannot be satisfied for n=2. Hence the second derivative is discontinuous at the joining point u=H/4. The left-hand edge is given by equation (24) fLH(u)=f(0)−f(u+H/2) (24) Given that f is even, the overall function has odd symmetry in each half plane about x=±H/4. To work out what happens at u=±H/2, expand fRH and fLH in Taylor series, as shown in equations 25 and 26: f RH = a 2 ⁡ ( u - H 2 ) 2 + a 4 ⁡ ( u - H 2 ) 4 + a 6 ⁡ ( u - H 2 ) 2 + … ( 25 ) f LH = a 2 ⁡ ( u + H 2 ) 2 + a 4 ⁡ ( u + H 2 ) 4 + a 6 ⁡ ( u + H 2 ) 2 + … ( 26 ) The function and its first derivative are both zero at u=½H, but the second derivative has the value 2a2. Outside of the range [−½H, ½H] the beam drops to zero. Hence the second derivative is discontinuous at both u=±½H and u=±H/4, and the far field must therefore decay as the cube of the distance measured in the far field. From the analysis, the required properties of f(u) for a hologram of width H are that firstly it should be even in u, and that secondly its amplitude at the position u=H/4 should be half the amplitude at u=0. After apodisation has been applied the shape of the beam in the region between u=H/4 and u=H/2 should be given by fRH(u)=f(0)−f(u−H/2) while in the region between u=−H/2 and u=−H/4 the shape of the beam should be given by fLH(u)=f(0)−f(u+H/2). In practice the shaping may not increase the local beam amplitude. Hence the hologram width and/or the shape of the central portion may have to be adjusted to avoid the requirement for ‘amplifying’ shaping. As an example these conditions are satisfied by a Gaussian distribution given by equation 27: f ⁡ ( u ) = exp - ( u ⁢ ln ⁡ ( 2 ) H / 4 ) 2 ( 27 ) If the original beam satisfies the first two conditions it can be apodised without removing power from the central region. Otherwise shaping can be applied to the central region so that these two conditions are satisfied. In some systems there may be a requirement to adapt the width of the beam in the far field: either to narrow the beam or to broaden the beam. This may be useful for laser processing of materials as well as for routing. It is advantageous that the method to change the width does not introduce side lobes. A particular application that would benefit is laser drilling of holes. The SLM could be used to narrow the drilling beam as well as to change its focus so that the drilled hole remains of uniform diameter (or has reduced diameter variation) as the hole is progressively bored. In order to broaden the far field, the near field (at the SLM) needs to be made narrower. This may be implemented by applying shaping to the central portion of the beam so that its full width half maximum (FWHM) points become closer together and so that the beam shape has even symmetry about its centre. Preferably the amplitude at the very peak is not reduced so as not to lose too much power. The distance between the two FWHM points defines the effective half-width of the hologram. Further shaping should be applied to the left-hand and right-hand edges of this effective hologram, so that the beam shape has the required properties as described previously. Outside of the width of the effective hologram the beam shape should have zero amplitude. To narrow the far field, the near field (at the SLM) needs to be made broader. This may be implemented by applying shaping to the central portion of the beam, so that the FWHM points become further apart, and so that the beam shape has even symmetry about its centre. Typically this will require reduction of the amplitude around its peak. The extent of this reduction is governed by the need to be able to apply shaping to the right and left hand edges of the hologram with the constraint that the shaping may only decrease the amplitude (and not increase it). Amplitude-modulating SLMs can be used to implement the shaping but they are polarisation-dependent. Another pseudo-amplitude modulation can be created to implement the beam shaping by using a phase-modulating SLM, which may be made polarisation-independent. This may be achieved by recognising that a phase modulation exp j φ(u), where j is the complex operator, is equivalent to a phase modulation cos φ(u)+j sin φ(u). Now choose φ(u) such that the modulus of φ(u) is varying slowly but the sign is oscillating. Hence the real part of the modulation, cos φ(u), will be slowly varying and can act as the amplitude modulator to create the beam shape, while the imaginary part of the modulation, ± sin φ(u), will be oscillating rapidly with an equivalent period of two or more pixels. Hence the energy stripped off by the effective amplitude modulator will be diffracted into a set of beams that are beam-steered out of the system at large angles. In a preferred embodiment, the system is designed such that light travelling at such angles will either not reach the output plane or will land outside the region defined by the output ports. Therefore the beam component shaped by sin φ(u) is rejected by the optical system, while the beam component shaped by cos φ(u) is accepted by the system and couples into one or more output ports, as required. While this explanation is for a one-dimensional phase modulator array the same principle is applicable in 2-D. If φ(u) varies from 0 at the centre of the beam to π/2 at the edges then the amplitude of the beam shaped by cos φ(u) varies from 1 at the centre of the beam to 0 at the edges, thus removing the amplitude discontinuity that creates rippling tails in the far field. This can be achieved with minimal change to the insertion loss of the beam as it passes through the system. Indeed, often the insertion loss due to clipping is due to interference from the amplitude discontinuity, rather than the loss of energy from the beam tails. The beam-shaping hologram is non-periodic but oscillatory and may be applied as a combination with other routing and/or lens synthesis and/or aberration correcting and/or power control and/or sampling holograms. Further advantages of the beam shaping are that it reduces the required value of C for a given required crosstalk, allowing more compact optical switches. Another advantage is that the crosstalk decays much more rapidly with distance away from the target output fibre. Hence, essentially, the output fibres receive crosstalk only from their nearest neighbour fibres. Therefore in a large optical switch used as a shared N×N switch for a range of wavelengths, it should be possible to arrange the wavelength channel allocation such that no output fibre collects crosstalk from a channel at the same system wavelength as the channel it is supposed to be collecting. This would reduce significantly the homodyne beat noise accumulation in networks using such switches, and, conversely, allow an increase in the allowed crosstalk in each switch as heterodyne crosstalk has much less of an impact at the receiver, and can also be filtered out if necessary. The crosstalk suppression method uses beam shaping to suppress ripples in the beam tails. The same method can be adapted to change the beam shape around the beam centre. For the case when the output beam is an image of the beam at the SLM the beam shaping is working directly on an image of the output beam. The fraction of the initial beam that is shaped by the slowly varying function cos φ(u) can have the correct symmetry to couple efficiently into the fundamental mode of the output fibre. The fraction of the initial beam that is shaped by the rapidly varying function ± sin φ(u) has the wrong symmetry to couple into the fundamental mode and can be adjusted to be at least partially orthogonal to the fundamental mode. Effectively, it is the fraction of the beam shaped by cos φ(u) that dominates the coupling efficiency into the fundamental mode. Therefore the dependence of the coupling efficiency vs. transverse offset is dominated by the overlap integral between the cos φ(u) shaped beam and the fibre fundamental mode. When the incident beam is the same shape as the fundamental mode and for small transverse offsets the coupling efficiency decreases approximately parabolically with transverse offset. In many beam-steering systems using phase-modulating SLMs the transverse offset at the output fibre increases linearly with the wavelength difference from the design wavelength. Consequently the system coupling efficiency decreases approximately parabolically with wavelength difference from the design wavelength. Beam shaping can be used to adjust the shape of the incident beam and optimised to flatten the dependence on transverse offset and hence to flatten the wavelength response. Alternatively a more complex wavelength dependence could be synthesised to compensate for other wavelength-dependent effects. Beam shaping may also be used during system assembly, training or operation in order to measure mathematical moments of a light beam. A description of the method and theory will be followed by a description of some example applications. The method requires a first stage during which corrective phase modulation is applied by the SLM such that the phase profile of the beam leaving the SLM has no non-linear component. This may be confirmed with a collimeter or wavefront sensor or some other suitable device. In a first embodiment the phase profile has no linear component applied to deflect the beam such that the beam is reflected in a specular direction. An optical receiver is placed to receive the reflected beam. The power reflected exactly into the specular direction is proportional to the square of an integral A(n) given in equation (28) where f(n,u,v) is the complex amplitude of the beam leaving the SLM at co-ordinates u,v during the nth stage of the method. A(n)=∫∫f(n,u,v)du dv(28) The optical power received by the photodiode during the nth stage of the method is given by equation (29). P(n)=K(A(n))2 (29) where K is a constant of proportionality. If received by an optical fibre the received power will be modified according to the fibre misalignment and mode field distribution, leading to possible ambiguities in the method. Hence it is preferred instead to receive the beam by a photodiode. During the first stage of the method the net phase modulation applied by the SLM is such that the beam is of uniform phase. Let b(u, v) be the beam amplitude distribution. Therefore during this first stage the integral A is equal to the zeroth moment, a0, of the beam amplitude distribution, as shown in equation (30), and f(n,u,v) is equal to b(u,v). A(1)=a0=∫∫b(u,v)du dv (30) Therefore the power, P(1), measured by the photodiode during this first stage is given by equation (31). P(1)=Ka02 (31) In order to characterise a two-dimensional beam, moments of the beam distribution may be taken in two orthogonal directions, in this case the u and v directions. Consider the pixel block of concern to be broken up into a set of columns. To each column in the block a particular effective amplitude modulation may be applied using the pseudo-amplitude method or some other method. For example consider the pixel column with a centre at co-ordinate u*. By applying an alternating phase modulation of +φ(u*) and −φ(u*) to adjacent pixels in the same column the effective amplitude modulation applied to the particular column is cos(φ(u*)). In order to calculate the first moment in the u direction, during the second stage of the method the values of cos(φ(u*)) are chosen such as to approximate to a linear distribution, as described in equation (32). cos(φ(u*))≈mu*+c (32) Therefore the power P(2) measured during the second stage of the process is given by (33). P(2)≈K(m2a1U2+2mca1Ua0+c2a02) (33) where a1u is the first moment of the beam distribution in the u direction, as given by (34). ti a1u=∫∫ub(u,v)du dv (34) The ratio of the powers measured during the two stages is then given by equation (35) P ⁡ ( 2 ) P ⁡ ( 0 ) ≈ m 2 ⁡ ( a 1 ⁢ U a 0 ) 2 + 2 ⁢ mc ⁢ a 1 ⁢ U a 0 + c 2 ( 35 ) Given the measured power ratio and the values of m and c as chosen to satisfy the constraints of the method, the quadratic equation given in (35) may be solved to calculate the ratio of the first order moment in the u direction to the zeroth order moment. The constraints on m and c are such that the actual values of the alternating phase of each column need to be chosen from the available set and such that the total phase excursion across the expected area of the beam remains within the range [0,π] or [−π,0] so that the cos(φ(u*)) term may decrease (or increase) monotonically. In practise a photodiode of finite size will receive power diffracted from the SLM within an angular distribution about the specular direction. A further constraint on the gradient ‘m’ in equation (32) is such that the side lobes created by the linear amplitude modulation fall outside the area of the photodiode. Similar methods may be used to take approximate higher-order moments in the u direction, and also first and higher-order moments in the v direction. In the latter case to each row in the block a particular effective amplitude modulation is applied, e.g. by setting adjacent pixels in the row to alternating phases of +φ(v*) and −φ(v*), where v* is the position co-ordinate of the row. The second-order moments may also be calculated and used to estimate the beam spot size at the hologram. This estimate can be used as part of the control algorithm for focus adjustment. In a second embodiment a further linear phase modulation is applied to the hologram during each stage so as to deflect the beam to be measured while taking the moments towards a particular photodiode. Consider a Gaussian type beam b(u,v) centred at position co-ordinates (u0,v0). The even symmetry of the beam about axes parallel to the u and v directions and through the centre lead to the identities given by equations (36) and (37). ∫∫(u−u0)b(u,v)du dv=0 (36) ∫∫(v−v0)b(u,v)du dv=0 (37) Hence approximate values of the first order moments measured as described previously, or by some other method, may be used to deduce approximate positions for the beam centres, as shown by equations (38) and (39). u 0 ≈ a 1 ⁢ U a 0 ( 38 ) v 0 ≈ a 1 ⁢ V a 0 ( 39 ) In the next stage of the measurement the pixel block initially assigned to the beam is re-assigned such that it is centred within half a pixel in each of the u and v directions from the approximate centre of the beam, as just calculated. Let the new centre of the pixel block be at (u1,v1). A new hologram should be calculated such that the beam leaving the SLM acts as the product of a beam of uniform phase distribution and an effective amplitude distribution given by equation (40). cos(φ(u*))≈m(u*−u1) (40) The principle is that if the beam centre lies exactly at u1 the measured power exactly in the specular direction will be zero. Taking into account the finite area of the photodiode the measured power cannot be zero but will be minimised when u1 is within half a pixel pitch of the beam centre. This new hologram should be applied to the pixel block and the power measured. At this point the method can proceed in two ways. In one embodiment a further estimate of the beam centre can be calculated, as described previously, a new centre position u1 calculated, the hologram recalculated according to equation (40) and the power measured again. This process can be repeated until the value of u1 appears to have converged. In a second embodiment the centre of the pixel block, u1 can be re-assigned, the hologram recalculated according to (40) and the power measured again. At the current pixel block centre, u1, for which the beam centre is within half a pixel of u1, the measured power should be at a minimum value. A further embodiment is to use a suitable combination of these two alternative methods. The centre of the pixel block in the v direction can be measured using similar methods. The size of the pixel block used should be chosen so as to cover the expected area of the beam. Outside of this area the phase can be modulated on a checkerboard of, for example, ±pi/2, so that the effective amplitude modulation is zero and the light from these regions is diffracted far away from the photodiode. It can be shown that equations (36) and (37) are also satisfied if the beam waist is not coincident with the SLM, that is the beam is defocused. Although the method as described above will not be calculating the proper moments of the beam, it can be shown that the position of the beam centre may still be identified using the methods described. The beam shaping method may be extended to control and adapt the amplitude of the beam steered through the system. If φ(u) varies from ψ at the centre of the beam to π/2 at the edges then the real part of the pseudo-amplitude modulation can be considered as cos ψ multiplied by an ideal beam-shaping function that causes insignificant insertion loss. In which case there is an associated additional insertion loss given by approximately 10log10 (cos2 ψ). By varying the value of ψ the beam power can be varied. Therefore the same device can be used to achieve power control, otherwise known as channel equalisation, as well as changing the routing or direction of a beam. Deliberate changes in the beam shaping function can be used to increase the number of ‘grey levels’ possible for the beam attenuation, i.e. to provide an increased resolution. As for the beam shaping, the rejected power is diffracted out of the system. Therefore this attenuation method does not increase crosstalk. Another technique for controlling beam power without increasing crosstalk is to deflect the unwanted energy in a direction orthogonal to the fibres susceptible to crosstalk. This may be combined with yet another technique, namely distorting the beam phase in such a way that much of the energy couples in to the higher-order modes of the fibre, rather than the fundamental mode that carries the signal. The beam phase distortion may alternatively be used alone. In an embodiment, these methods are achieved by dividing the area of the SLM on which the beam is incident into a set of ‘power controlling’ stripes. The long side of the stripes are at least substantially in the plane in which the input and output-beam are travelling. By varying the relative phase in the stripes the coupling efficiency into the fundamental mode of the output fibre is changed, and hence the throughput efficiency of the optical system is set. This method can be applied to a pixellated device that is also routing or otherwise adapting a beam. In this case each ‘stripe’ would contain between one and many of the pixels already in use. Alternatively the long side of the power controlling stripes could be in one plane in one electrode, with the long side of the routing pixels in an orthogonal direction in the other electrode, of which either the stripe electrodes, or the pixellated electrodes, or both, are transparent. Alternatively the device acts solely as a beam power controller, or channel equaliser. In this case each stripe could be a single pixel. The set of stripes for each beam defines a block. Many blocks could be placed side by side to form a row of blocks, with each block in the row providing channel equalisation for a different beam. Many rows could also be provided so as to provide channel equalisation for signals coming in on different input fibres. If a pair of confocal focusing elements is disposed between the output fibre and SLM then the output fibre receives an image of the field at the SLM. In this case the attenuation at the output fibre is governed by the orthogonality between the image and the fundamental mode of the fibre. Assuming, and without loss of generality, that a perfect image is formed such that sharp phase discontinuities are preserved, it may be shown that the coupling efficiency into the fundamental mode is proportional to the square of a sum of weighted integrals. The weight is the modulation exp iφ applied by a stripe, and the associated integral is over the area onto which that stripe is imaged. The integrand is positive and depends on the square of the local electric field associated with the fundamental mode. Each integral is represented as a phasor, with a length depending on how much of the fundamental mode power passes through the region onto which the stripe is imaged, and a phasor angle depending on the phase modulation. The net coupling efficiency is given by the magnitude of the vector summation of the individual phasors associated with each stripe. For simple devices it may be advantageous to use as few stripes as possible as this reduces any losses due to dead space between the stripes and reduces the control complexity. With only two stripes of approximately equal area (and hence two phasors of approximately equal length) the possible vector sums lie on a semicircle and hence the number of possible grey levels is equal to the number of phase levels between 0 and pi, which may not be sufficient. Transverse offset of the output fibre with respect to the centre of the image has the effect of making the two phasors unequal and hence complete extinction is not possible. These problems may be overcome by using three or more stripes per hologram. For example with three stripes the loci of vector sums lie on circles centred about the semicircle taking just two of the stripes into consideration. Hence many more values are possible. Increasing the number of stripes increases the number of grey levels and the depth of attenuation. A fibre spool is used on the output fibre before any splices are encountered. It will clear to those skilled in the art that other mode stripping devices or techniques could be used instead. This system can also be adaptive: given knowledge of the applied phase by each stripe and enough measurements of the coupling efficiency, the lengths of the different phasors associated with each stripe can be calculated. Given these lengths the performance can be predicted for any other applied phases. Hence suitable algorithms can be included in the SLM or interface to train and adapt the device performance to cater for transverse offset of the output fibre and other misalignments. Sharp edges or phase discontinuities in this image will be eroded by the optical modulation transfer function (MTF) but, nevertheless, where a sufficient number of stripes is provided it is possible to vary the phase modulation of each and achieve a wide range of attenuation. Ultimately what limits the depth of attenuation is the residual zero-order due to, for example, an imperfect quarter-wave plate or Fresnel reflections from different surfaces inside the SLM such that the reflected light has not yet been phase-modulated. An example reflection is from the interface between the cover glass and transparent electrode. Such residual zero orders will couple into the output fibre independently of the phase modulation. In many cases the residual zero order will have a different polarisation state to the beam that has been properly processed by the phase modulation, so even adapting the phase modulation will not recover the depth of attenuation. In such cases it is advantageous to apply some routing to the output fibre, such that the zero order is offset from the output fibre and the intended output beam is steered into a diffraction order of the routing hologram. For a many-pixellated SLM this may be achieved using the standard routing algorithm described earlier. For a simple SLM with few pixels, e.g. the one with the stripes in the plane of the input and output fibres, these stripes can be subdivided in an orthogonal direction, that is to create a 2-D array of pixels. This however increases the device complexity. An alternative simple device is to combine it with a tip-tilt beam-steering element, as described in Optics Letters, Vol. 19, No 15, Aug. 1, 1994 “Liquid Crystal Prisms For Tip-Tilt Adaptive Optics” G D Love et al. In this case the top ‘common electrode’ is divided into a set of top electrodes, one for each device, where each device is assumed to receive a separate beam or set of beams. Each top electrode has different voltages applied on two opposite sides. The shape of the top electrode is such that the voltage between the electrodes varies nonlinearly in such a way as to compensate for the non-linearity of the phase vs. applied volts characteristic of the liquid crystal. Hence with all the stripe electrodes at the same voltage the device provides a linear phase ramp acting like a prism and deflecting the phase-modulated beam in a pre-defined direction, such that the residual zero order falls elsewhere, as required. Changing the stripe electrode voltage causes phase changes in the imaged beam but does not prevent the deflection. Small adjustments in the phase ramp can be used to compensate for component misalignments and/or curvature of the SLM substrate and/or wavelength difference from the design wavelength for the tip-tilt device. Such small adjustments in the phase ramp can also be used to achieve fine control over the attenuation. Hence such a device would be useful whether or not the required attenuation is sufficiently strong for the residual zero order to become a problem. Alternatively the top electrode can be divided into two or more areas, with the shape of each so as to compensate for the phase vs. volts non-linearity. Varying the voltage on the ends of each electrode can be used to offset the phase modulation of each stripe in order to create the desired attenuation. In this case the aluminium electrode would be common to the device, removing dead-space effects. In another embodiment of the tip-tilt device, the top electrode is common to all devices and a shaped transparent electrode is provided, e.g. by deposition, on top of the quarter-wave plate, with connections to the SLM circuitry to either side of the device. In this case the aluminium may act only as a mirror and not as an electrode. Again the shaped transparent electrode may be subdivided into two or more areas to provide the attenuation. This embodiment avoids dead-space effects and also a voltage drop across the quarter-wave plate. In a further embodiment, such a tip-tilt device has a shaped transparent electrode on both cover glass and quarter-wave plate. The planes of tip-tilt for the two devices may be orthogonal or parallel. With two parallel tip-tilt electrodes the device may act as a power-controlling two-way switch, and also, as will be described later, can be used in a multi-channel add/drop multiplexer. With two orthogonal tip-tilt electrodes the device can beam steer in 2-dimensions such as to correct for positional errors. Either of the two tip-tilt electrodes can be subdivided so as to provide attenuation. One advantageous SLM is that described in our co-pending patent application EP1053501. If there is a single focusing element between the output fibre and SLM then the field at the output fibre is the Fourier Transform of the field leaving the SLM. In this case three classes of phase modulation can be used to change the coupling efficiency into the output fibre. The first two classes assume a many-pixellated SLM while the third class assumes a few-pixel SLM with or without tip-tilt features as described earlier. In the third class the tip-tilt feature may be used to compensate for transverse positional errors in the input and output fibre. The different classes of phase modulation result in a variable coupling efficiency at the output fibres using the following methods: As noted above, the first class uses a many-pixellated SLM. A periodic phase modulation is applied that creates a set of closely spaced diffraction orders at the output fibre. The spacing is comparable to the fibre mode spot size such that there is significant interference between the tails of adjacent diffraction orders. The phases of these diffraction orders are chosen such that the resulting superposition is rapidly alternating in phase and therefore couples into the higher-order fibre modes. Varying the strength, phase and position of each diffraction order changes the attenuation. If the long sides of the stripes used to create this alternating output field are in the plane of the input and output fibres, then diffraction orders landing outside the target optical fibre fall along a line orthogonal to the output fibre array, and therefore do not cause crosstalk. In the second class, again using a many-pixellated SLM, a non-periodic smoothly varying non-linear phase modulation is applied at the SLM, in this case the SLM acts as a diffractive lens such that the beam is defocused and couples into higher-order modes. In the third class, which uses a simple SLM with few pixels, the pixels are used to apply phase distortion across the beam incident on the SLM. Such phase modulation can be considered to be equivalent to the first class but with a long period. The phase distortion at the SLM results in amplitude and phase distortion in the reflected beam and hence reduces the coupling efficiency into the output fibre. Again, all three methods require use of a mode stripper on the output fibre. Again suitable algorithms can be included in the SLM or interface to train the system. Another embodiment, not illustrated, uses a graded-index (GRIN) lens secured to one face of an SLM, and having input and output fibres directed on or attached to the opposite face. The SLM may provide selective attenuation, and/or may selectively route between respective input fibres and selected output fibres. A requirement for stable performance is fundamental for optical devices used in communications and like fields. One of the dominant manufacturing costs for such optical devices is device packaging. The GRIN lens architecture results in a compact packaged device resilient to vibrations. However, the architecture can have problems with spherical aberration and problems in achieving the required alignment accuracy. In particular there is often a requirement for precise transverse positioning of the fibres. Also due to manufacturing tolerances in the GRIN lens the focused spot in the reflected beam can be offset significantly in the longitudinal direction from the end face of the output fibre, resulting in an insertion loss penalty. This problem gets worse the longer the GRIN lens. Applying selected non-linear phase modulation to the SLM may compensate for problems such as focus errors, length errors, longitudinal positional errors and spherical aberration. Applying selected linear phase modulation to the SLM and/or using tip-tilt electrodes may compensate for problems such as transverse positional errors. Optical systems using SLMs may individually process the channels from an ensemble of channels on different wavelengths, entering the system as a multiplex of signals in a common beam. Given a continuous array of pixels the SLM may also process noise between the channels. Hence the optical system acts as a multiwavelength optical processor. The processing may include measurement of the characteristics of the signals and accompanying noise as well as routing, filtering and attenuation. In a first application, the SLMs carry out attenuation, known in this context as channel equalisation. A second application is a channel controller. A third application is an optical monitor. A fourth application is an optical test set. A fifth application is add/drop multiplexing. Further applications are reconfigurable wavelength demultiplexers and finally modular routing nodes. In all of these applications the SLMs may carry out routing and/or power control and/or beam shaping and/or sampling and/or corrective functions as described earlier. The system to be described is not restricted to this set of seven applications but is a general multi-wavelength system architecture for distributing the wavelength spectrum from one or more inputs across an array of devices and recombining the processed spectrum onto one or more selected outputs. The inputs and outputs may be to and from optical networking equipment such as transmission systems, transmitter line cards and receiver line cards. Alternatively the inputs may be from one or more local optical sources used as part of a test set: either via an intermediate optical fibre or emitting directly into the optical system. The outputs may be to one or more local photo detectors for use in testing and monitoring. Applications outside the field of communications are also possible such as spectroscopy. Such multi-wavelength architectures can be adaptations of optical architectures used for wavelength de-multiplexing. Wavelength demultiplexers typically have a single input port and many output ports. These can use one or more blazed diffraction gratings: either in free-space or in integrated form such as an AWG (Arrayed Waveguide Grating). These devices are reciprocal and hence work in reverse. Hence if a signal of the appropriate wavelength is injected into the output port it will emerge from the input port. The output port usually consists of an optical waveguide or fibre with an accepting end that receives a focused beam from the optical system and a delivery end providing an external connection. Now consider replacing the acceptance end of the output waveguide/fibre with a reflective SLM: all of the processed signals reflected straight back will couple into the input fibre and emerge from the input port. These signals can be separated from the input signal with a circulator. Alternatively the system is adapted so that the reflected signals emerge and are collected together into a different fibre. Free-space optical systems performing wavelength de-multiplexing can use diffraction gratings made by ruling, or from a master, or made holographically, or by etching. Usually these work in reflection but some can work in transmission. One or two gratings can be used in the system. The optics used to focus the beams can be based on refractive elements such as lenses or reflective elements such as mirrors or a combination of the two. Referring to FIG. 12, a channel equaliser 350 has a single grating 300 used with a refractive focusing element 310 and an SLM 320. To make the diagram clearer, the grating 300 is drawn as working in transmission. Other embodiments use two gratings and/or reflective focusing elements and/or gratings that work in reflection, such as blazed gratings. A first input beam 301 from an input port 304 contains an ensemble of channels at different wavelengths entering the equaliser on the same input port 304. As a result of the grating 300 the beam 301 is split into separate beams 301a, 301b, 301c for each wavelength channel, each travelling in a different direction governed by the grating equation. The grating 300 is positioned in the input focal plane of a main routing lens 310 with a reflective SLM 320 at the output focal plane of the routing lens 310. If desired, there may also be a field-flattening lens just in front of the SLM 320. If lens 310 were an ideal lens, rays passing through the same point on the focal plane of the lens, regardless of direction provided they are incident on the lens, emerge mutually parallel from the lens. As lens 310 is not a real lens, this is no longer strictly true: however well-known lens design techniques can be applied to make it true over the required spatial window. Hence, the beams 301a, 301b, 301c that were incident upon the lens 310 from the same point on the focal plane, but at different angular orientations, emerge mutually parallel from the routing lens 310, but spatially separate. Thus, the lens refracts each beam to a different transverse position 320a, 320b, 320c on the SLM 320. At each position the SLM 320 displays a pixellated hologram and/or has a tip-tilt device for processing the relevant wavelength component of the beam. In the preferred embodiment, the SIM 320 is a continuous pixel array of phase-modulating elements and is polarisation independent. The width of each hologram or tip/tilt device compared to the spot size of the incident beam incident is sufficient to avoid clipping effects. Instead, or additionally, beam shaping may be used. The device may be controlled to deflect or attenuate the beam as described earlier, and provides output processed beams 302a, 302b, 302c. Beams 302a and 302b have moderate channel equalisation applied by a power control hologram and routing towards the output port 305 applied by a routing hologram. As explained previously it is advantageous to use a routing hologram as it deflects the beams from their specular output direction and hence increases the available depth of attenuation. Beam 302c has strong attenuation applied in order to “block” the channel: this is achieved by selecting holograms that direct the light well away from the output port 305 towards, for example, an optical absorber 306. The processed beams are reflected back from the SLM 320 towards the main lens 310 and then refracted back by the main lens towards the diffraction grating 300. Assuming the SLM 320 is flat, all beams subjected to the same deflection at the SLM 320 and entering the system in the same common input beam emerge mutually parallel from the diffraction grating. Curvature of the SLM 320 is compensated by small changes in the deflection angle achieved due to the holograms displayed on the SLM 320. As the light beams 302a, 302b emerge parallel from the SLM 320 they are refracted by the lens 310 to beams 303a, 303b propagating towards a common point in the grating 300, which (having the same grating equation across the whole area of concern) diffracts the beams to provide a single output beam 302. Note that due to the action of the lens, beam 303a is parallel (but in the opposite direction) to beam 301a and beam 303b is parallel (but in the opposite direction) to beam 301b. Therefore all beams subjected to the same eventual output angle from the SLM 320 are collected into the same output port 305. Hence a system may be constructed with a single input port 304 and a single output port 305 that produces independent attenuation or level equalisation for each wavelength channel. Note that to obtain the same deflection angle for all wavelength channels, as required, the effective length of the hologram phase ramp, Ω/m, where m is the mode number of the excited diffraction order and Ω is the hologram period, should be adjusted in proportion to the channel wavelength. That is the wavelength dependence of the beam deflection should be suppressed. As described later the channel equalisation can be uniform across each channel so as to provide the required compensation as measured at the centre of each channel. Alternatively the channel equalisation can vary across each channel, so as to compensate for effects such as amplifier gain tilt that become important at higher bit rates such as 40 Gb/s. Channels may be blocked as described earlier so as to apply policing to remote transmitters that renege on their access agreements or whose lasing wavelength has drifted too far. Furthermore the noise between selected channels may be partially or completely filtered out, as described later. Hence in a second application the multiwavelength optical processor acts as a channel controller. Although such processing can be applied using conventional optics the multiwavelength optical processor has a number of advantages. Compared to a series of reconfigurable optical filters the multiwavelength processor has the advantage that the channels are processed by independent blocks of pixels. Hence reconfiguration of the processing applied to one or more selected channels does not cause transient effects on the other channels. Compared to a parallel optical architecture that separates the channels onto individual waveguides/fibres before delivery to a processing device (and hence avoids the transient effects) the multiwavelength optical processor has a number of advantages. Firstly it can process the whole spectrum entering the processor (subject to the grating spectral response). Secondly the filter passband width is reconfigurable and can be as much as the entire spectrum, reducing concatenation effects that occur when filtering apart sets of channels routed in the same direction. Thirdly the filter centre frequencies are reconfigurable. Further advantages are discussed later in this application. By having a choice of two or more deflection angles at the SLM every input channel may be routed independently to one of two or more output ports. There may also be two or more input ports. It may be shown that for one or more parallel input beams, the action of the grating and main routing lens is such that all channels at the same wavelength but from different input ports are incident at the same transverse position at the SLM. Again this is because “parallel rays converge to the same point”. Hence these channels at the same wavelength are incident on the same channel processing hologram and/or tip-tilt device. As every wavelength channel is incident on a different device, the device response may be optimised for that particular wavelength. For example if a pixellated SLM is used the deflection angle is proportional to the wavelength. Hence small adjustments in the phase ramp can be used to adjust the deflection angle to suit the wavelength to be routed. All channels incident on a particular transverse position on the SLM must be reflected from that same position. As this position is in the focal plane of the lens beams from said position will emerge parallel from the lens and travelling towards the grating. After the grating the beams will be diffracted (according to their wavelength). It may be shown that all beams entering the system in a parallel direction will emerge from the system in exactly the opposite direction. It may also be shown that all beams subject to the same output angle from the SLM will emerge coincident from the system and may therefore be collected into the same port. Analysis of the beams at the diffraction grating in this architecture shows that the spot size required for a given wavelength channel separation and beam clipping factor C at the hologram depends on the grating dispersion but does not depend on the routing lens focal length nor the number of output ports. The beam centres must be far enough apart to provide adequate crosstalk suppression. Hence the greater the number of output beams the further the beam must be steered by the SLM and lens. As an example consider just routing in 1-D, into the m′th diffraction order with a hologram period Ω and a routing lens of focal length f. The output beam at the diffraction grating will be offset from its zero order reflection by a distance given approximately by f.m.λ/Ω, where λ is the optical wavelength and Ω/m is the effective length of the phase ramp on the hologram (as explained previously). To increase this offset distance the length of the phase ramp can be reduced, which tends to require smaller pixels, or the lens focal length can be increased. In practice there is a lower limit to the pixel size set by the dead space losses and the size of the pixel drive circuits, while increasing the lens focal length makes the overall system longer. This can be a particular problem when there are many output ports, even when close-packing 2-D geometries are used for the output beams. Referring to FIG. 14, another method is to put a demagnification stage between the SLM 400 and a routing lens 404. This is positioned so that the SLM 400 is in the object plane of the demagnification stage while the image plane of the demagnification stage 402 is where the SLM would otherwise be, that is in the focal plane of the routing lens 404. What appears in this image plane is a demagnified image of the SLM 400, which therefore acts like a virtual SLM 402 with pixels smaller than those of the real SLM 400 and hence a shorter effective phase ramp length. As an example consider the two lens confocal magnification stage shown in FIG. 14. In FIG. 14 f1 is the focal length of the first lens 401 and f2 is the focal length of the second lens 403 (closer to the virtual SLM). The demagnification is f2/f1 while the beam-steering deflection angle is magnified by f1/f2. While this method for increasing the effective beam deflection angle has been described and illustrated in the context of one particular routing architecture it could also be applied to other optical architectures using SLMs to process an optical beam, for routing and other applications. The operating principle is that the virtual SLM 402 has an effective pixel size and hence an effective phase distribution that is smaller in spatial extent than that of the real SLM 400, by an amount equal to the demagnification ratio of the optics. The off-axis aberrations that occur in demagnification stages can be compensated using any of the methods described in this application or known to those skilled in the art. In an alternative embodiment the input beam or input beams contain bands of channels, each incident on their own device. In this and the previous embodiment for the channel equaliser the beam deflection or channel equalisation may vary discontinuously with wavelength. In a third embodiment the input beam could contain one or more signals spread almost continuously across the wavelength range. The light at a particular wavelength will be incident over a small transverse region of the SLM, with, typically a Gaussian type spatial distribution of energy against position. The position of the peak in the spatial distribution is wavelength dependent and may be calculated from the grating and lens properties. For such a system the beam deflection or channel equalisation varies continuously with wavelength. The pixellated SLM is divided into blocks, each characterised by a ‘central wavelength’, defined by the wavelength whose spatial peak lands in the middle of the block. A particular channel equalisation or beam deflection is applied uniformly across this block. Light of a wavelength with a spatial peak landing in between the centres of two blocks will see a system response averaged across the two blocks. As the spatial peak moves towards the centre of one block the system response will become closer to that of the central wavelength for the block. Hence a continuous wavelength response is obtained. The block size is selected with respect to the spatial width of each beam in order to optimise the system response. This method is particularly attractive for increasing the wavelength range of a 1 to N switch. To achieve this aim the multi-wavelength architecture described earlier, should be configured so as to allow reconfigurable routing from a single input port to one of a set of multiple output ports. The length of the phase ramp used to route the beam to each output port should vary slowly across the SLM such that the wavelength variation in the deflection angle is minimised, or certainly reduced considerably compared to the case for which the phase ramp length is uniform across the SLM. Hence the transverse position of each output beam will vary considerably less with wavelength, with a consequent reduction in the wavelength dependence of the coupling efficiency at the system output. Alternatively, the length of the phase ramp can be varied spatially so as to obtain some desired wavelength dependence in the coupling efficiency. The efficiency of a blazed diffraction grating is usually different for light polarised parallel or perpendicular to the grating fringes. In the multi-wavelength systems described above the effect of the quarter-wave plate inside the SLM is such that light initially polarised parallel to the grating fringes before the first reflection from the blazed grating is polarised perpendicular to the grating fringes on the second reflection from the blazed grating. Similarly the light initially polarised perpendicular to the grating fringes before the first reflection from the blazed grating is polarised parallel to the grating fringes on the second reflection from the blazed grating. Hence, in this architecture, the quarter-wave plate substantially removes the polarisation dependence of the double pass from the blazed grating, as well as that of the phase modulation. As is clear to those skilled in the art, this polarisation independence requires the fast and slow axes of the integrated quarter-wave plate to have a particular orientation with respect to the grating fringes. This required orientation is such that the integrated quarter-wave plate exchanges the polarisation components originally parallel and perpendicular to the grating fringes. Referring to FIG. 28 a wavelength routing and selection device 600 is shown. This device has a multiwavelength input 601 from an input port 611, and provides three outputs 602, 603, 604 at output ports 612-614. The device 600, similar to the device of FIG. 12, has a grating 620, a lens 621 and an SLM 622, with the disposition of the devices being such that the grating 620 and SLM 622 are in respective focal planes of the lens 621. Again the grating is shown as transmissive, although a reflective grating 620, such as a blazed grating, would be possible. Equally, the SLM 622 is shown as reflective and instead a transmissive SLM 622 could be used where appropriate. The grating 620 splits the incoming beam 601 to provide three single wavelength emergent beams 605, 606, 607 each angularly offset by a different amount, and incident on the lens 621. The lens refracts the beams so that they emerge from the lens mutually parallel as beams 615,616, 617. Each of the beams 615,616,617 is incident upon a respective group of pixels 623,624,625 on the SLM 622. The groups of pixels display respective holograms which each provide a different deviation from the specular direction to provide reflected beams 635, 636 and 637. The beams 635, 636, 637 are incident upon the lens 621 and routed back to the grating 620. In the embodiment shown, the beams 605 and 606 are finally routed together to output port 614 and the beam 607 is routed to output port 612. No light is routed to port 613. However it will be understood that by careful selection of the holograms, the light can be routed and combined as required. It would be possible to route light of a selected frequency right out of the system if needed so as to extinguish or “block” that wavelength channel. It is also envisaged that holograms be provided which provide only a reduced amount of light to a given output port, the remaining light being “grounded”, and that holograms may be provided to multicast particular frequencies into two or more output ports. Although the number of output ports shown is three, additional output ports can be included: with appropriate lens design the insertion loss varies weakly with the number of output ports. Although the output ports are shown in the same plane as the input it will be clear to those skilled in the art that a 2-D distribution of output ports is possible. Hence the device 600 provides the functions of wavelength demultiplexing, routing, multiplexing, channel equalisation and channel blocking in a single subsystem or module. These operations are carried out independently and in parallel on all channels. Reconfiguration of one channel may be performed without significant long-term or transient effects on other channels, as occurs in serial filter architectures. With most conventional optics (including parallel architectures) separate modules would be required for demultiplexing, routing, multiplexing and the power control functions. This adds the overheads of fibre interconnection between each module, separate power supplies, and a yield that decreases with the number of modules. The device 600 has no internal fibre connections, and a single active element requiring power—the SLM. Each active processing operation (routing, power control, monitoring etc) requires an associated hologram pattern to be applied by the controller but may be carried out by the same SLM, hence the yield does not decrease with increased functionality. Although integrated optical circuits can be made that combine different functions, in general they require a separate device inside the optical chip to perform each function. Again the power (dissipation) and the yield worsen with increased functionality. Further applications of the multiwavelength optical processor are as an optical performance monitor, and as a programmable multifunction optical test set. In both applications the SLM may perform two or more different but concurrent monitoring or testing functions on two or more portions of the wavelength spectrum. This may be achieved by applying routing holograms to the pixel block associated with said portions of the wavelength spectrum that connect optically a selected input fibre or input optical source to a selected output fibre or output detector. The routing hologram applied to each portion of the spectrum may be reconfigured as required in order to perform different testing or monitoring functions on said portion of the spectrum. To each output photo detector or to each input optical source is applied control circuitry for carrying out the required tests. Considering firstly the performance monitor, the method described later to measure the centre wavelength of a channel may be applied to a selected channel in order to monitor the lasing wavelength. Earlier in this application there is a description of how to measure the second order moments of a beam. Consider orthogonal axes u and v at the SLM. Choose the orientation of these axes such that all wavelength channels entering the system and incident on the grating in the defined parallel direction have the centres of their associated beams along a line of constant v. Hence the position along the u axis increases with wavelength. The second order moment in the v direction is related to the spot size of a monochromatic beam. The second order moment in the u direction is related to this spot size and also the wavelength distribution of the energy in each channel. Hence by measuring second order moments, as described previously, an estimate of the channel bandwidth may be obtained. The noise power between a selected pair of channels may be measured by routing that part of the spectrum between the channels towards a photo detector. Similarly the power of a selected channel may be measured by routing towards a photo detector. One or more photo detectors may be assigned to each type of measurement is allowing many parallel tests to proceed independently on different portions of the spectrum. Alternatively the control circuitry associated with each photo detector output may be designed to be able to perform two or more of the required monitor functions. Hence the multiwavelength optical processor acts as an optical spectrum analyser with integrated parallel data processing. Conventional methods for achieving this use either a grating that is rotated mechanically to measure different portions of the spectrum with a photo detector in a fixed position, or a fixed grating with a linear photodiode array. In both cases data acquisition hardware and software and data processing are used to extract the required information from the measured spectrum. Both systems are expensive and require stabilisation against the effects of thermal expansion. The multiwavelength optical processor has no moving parts, can use as few as a single photodiode, and can adapt the holograms to compensate for temperature changes, ageing, aberrations as described previously in this application. The multiwavelength processor also carries out the data processing to measure centre wavelength and channel bandwidth in the optical domain. When used in a communications network the optical performance monitor would pass the processed data from the measurements to a channel controller, such as the one described previously, and also to a network management system. The signal for monitoring would be tapped out from a monitor port at the channel controller or from a routing system or from elsewhere in the network. The monitor processing could be implemented with the same or a different SLM to the channel controller. Monitor processing can also be implemented with the same or different SLMs used to route beams in the add drop routers and routing modules described later in this application. The control electronics for the monitor processing can be integrated with the control electronics for the pixel array. With reference to FIG. 30, the programmable multifunction optical test set 900 has a multiwavelength optical processor 928 with one or more inputs 901, 902 from optical sources, 903, 904 each with control circuitry 905, 906 for performing one or more tests of optical performance. The channel equalisation and blocking functions described earlier may be used to adapt the spectrum of the selected source to suit a particular test. The channel filtering functions described later may be used to synthesise a comb or some other complex wavelength spectrum from a selected broadband optical source. A further input 907 from an optical source 910 may be used to exchange data and control information from control and communications software 929 with the same 900 or one or more other optical test sets, allowing remote operation over the fibre under test, or some other fibre. One or more outputs ports 911, 912 from the multiwavelength optical processor are connected to a set of optical fibre transmission systems (or other devices) 913, 914 to be tested. Routing holograms are applied to the pixels associated with the selected parts of the spectrum to direct said parts of the spectrum or said data and control information to the selected output port. A further or the same multiwavelength optical processor has input ports 917, 918 connected to the set of optical fibre transmission systems (or other devices) 915, 916 under test and output ports 919, 920 connected to a set of one or more photo detectors, 921, 922 each with associated control circuitry 925, 926 for carrying out testing functions. A further photo detector 924 connected to a further output port 923 is used to receive data and control information from one or more other test sets. Routing holograms are applied to direct the signals from the selected input port to the required photo detector. The optical monitor functions described above can be applied to the signals. The frequency shaping of the source or spectrum can take place at the transmitting test set or the receiving test set. The control electronics for the test set 927 and control and communications software 929 can be integrated with the control electronics for the pixel array. Conventionally, different optical sources would be used to perform different types of test on the wavelength and transmission properties of fibres or devices under test; a separate optical switch would be used to poll the devices under test, and an external communications link would be used for communication of data and control information with a remote test set. However, the multiwavelength optical processor may be used to provide a multifunction programmable optical test set that is capable of remote operation. The test set may include as few as a single source and a single photo detector and performs a wide range of tests on fibres or devices selected from a group of fibres or devices attached to the test ports of the multiwavelength processor. A multiwavelength system with two inputs and two outputs can work as an add/drop multiplexer. Add-drop multiplexers are usually used in ring topologies, with the ‘main’ traffic travelling between the ring nodes, and ‘local’ traffic being added and dropped at each node. Considering each node, one input (main in) is for the ensemble of channels that has travelled from the ‘previous’ routing node. The second input (add) is for the ensemble of channels to be added into the ring network at the add/drop node. One output (main out) is for the ensemble of channels travelling to the ‘next’ routing node while the second output (drop) is for the ensemble of channels to be dropped out of the ring network at the node. If a particular incoming wavelength channel is not to be ‘dropped’ at the node, then the channel-dedicated device at the SLM should be configured to route the incoming wavelength from the main input to the main output. However, if a particular incoming wavelength channel is to be dropped, then the channel-dedicated device at the SLM should be configured to route the incoming wavelength from the main input to the drop output. In this case the main output now has available capacity for an added channel at that same wavelength. Therefore the channel-dedicated device at the SLM should also be configured to route the incoming wavelength from the add input to the main output. The multiwavelength optical processor described in this application distributes wavelength channels across and collects the wavelength channels from a single SLM, allowing the SLM to provide a set of one or more processing operations to each of the channels. However, in most conventional reconfigurable add drop multiplexers, the routing has to be carried out in two successive stages. Usually a first 1×2 switching stage either drops the channel or routes the channel through, while a second 2×1 switching stage either receives the through channel from the first stage or receives an added channel. Fortunately, careful choice of the deflection angles applied by the SLM, and the sharing of the same hologram by input signals at the same wavelength, allows add drop routing to be carried out in a single stage. Hence add drop routing may be conveniently applied in an independent and reconfigurable manner to every wavelength channel in the multiwavelength optical processor. An explanatory diagram is shown in FIG. 13a. Referring now to FIG. 13a, an SLM 141, used in the context of the multi-wavelength architecture, has a pixel block 140 and/or tip-tilt device upon which a main input beam 130 is incident, at an angle m1 to the normal 142. The main beam has a zero order or specular reflection 130a. Holograms are made available that will cause deflections at +θ1 to the specular direction and −θ2 to the specular direction. Due to the display of a first hologram on the pixel block 140, the main output is deflected by +θ1 from the specular direction to a main output beam 132. An add input 131 is incident at an angle a1 on the block 140, and produces a zero order reflection 131a. The device also has a drop output beam direction 133. When the hologram applying the deflection of +θ1 is displayed, light at the relevant wavelength entering in the add direction 131 is not steered into either of the main output beam direction 132 or the drop output beam direction 133. Effectively it is ‘grounded’. This feature may be used to help to stop crosstalk passing between and around rings. When the hologram applying the alternative deflection of −θ2 is applied, the add input is routed to the main output beam direction 132 while the main input is routed to the drop output beam direction 133. In the interests of clarity, a simplified diagram may be used to explain an add-drop using 1-D routing. This is shown in FIG. 13b in which the point 134 represents the output position of the specular reflection from the add input while the point 135 represents the output position of the specular reflection from the main input. When a first routing hologram is applied the main output beam is deflected by an angle of +θ1 and therefore the output position of the main beam is deflected by an offset of f.θ1, compared to the output position 135 of its specular reflection. Here f is the focal length of the routing lens. In FIG. 13b this deflection is represented as a vector 136a and the output beam is routed to the main output 137. The beam from the add input is subject to the same angular deflection with respect to its specular reflection and is thus deflected by a vector of equal length and the same direction 136b with no output port to receive it this beam is “grounded”. When a second routing hologram is applied the main output beam is deflected in the opposite direction by a vector 138a to arrive at a drop output 139. The beam from the add input is deflected by an identical vector 138b to arrive at the main output 137. The example in FIG. 13a assumes 1-D routing due to the hologram. Given an ability to route in 2-D, either with two orthogonal tip-tilt electrodes or a 2-D pixel array (as described previously) the arrangement of the four ports can be generalised, as shown in FIG. 15. The use of 2-D routing allows closer packing of the input and output beams reducing off-axis aberrations. In FIG. 15 the output positions are shown in 2-D. The point 151 represents the output position of the zero order (specular) reflection from the add input while the point 152 represents the output position of the zero-order reflection from the main input. The hologram deflections are represented as vectors 155a, 155b, 156a and 156b. Vector 155b has the same length and direction as vector 155a and vector 156b has the same length and direction as vector 156a. When a first routing hologram is applied the add input beam is deflected from its specular output position 151 by the vector 155b to the main output 154 while the main input is deflected from its specular output position 152 by the identical vector 155a to the drop output 153. When the alternate routing hologram is applied the main input is deflected from its specular output position 152 by the vector 156a to the main output 154 while the add input is again ‘grounded’ due to deflection by the identical vector 156b. In this general configuration there are six variables. These are the output positions of the main output and drop output, the positions of the zero order reflections from the main input and add input, and the two hologram deflections. Of these six variables only three are mutually independent. For example, selection of the input position for the main input with respect to the routing lens axis defines the output position of the zero order reflection, 152. If this is followed by selection of the output positions for the main and drop outputs with respect to the routing lens axis then all three independent variables have been defined. Hence the required hologram deflections are determined as is the input position for the add input with respect to the routing lens axis (which then defines 151). FIGS. 13a, 13b and 15 show the hologram deflections required to provide add-drop routing: FIGS. 13a and 13b assume 1-D routing while FIG. 15 assumes 2-D routing. A multiwavelength add-drop architecture using such hologram deflections is shown in FIG. 29. Compared to other methods for achieving add-drop functionality, the advantages are as described previously for FIG. 28. Turning now to FIG. 29, an add/drop multiplexer device 700 has two input ports 701, 702 and two output ports 703,704. The first input port 701 is for an input beam 711 termed “add” and the second input port 702 is for a second input beam 712 termed “main in” having two frequencies in this embodiment. The first output port 703 is for a first output beam 713 termed “drop” and the second output port 704 is for a second output beam 714 termed “main out” The input beams 711, 712 are incident upon a grating 720 that deflects the beams according to wavelength to provide emergent beams 731, 732 and 733. The emergent beams 731, 732 and 733 are incident upon a lens 722 having its focal plane at the grating 720, and the beams emerge from the lens respectively as beams 741, 742, and 743 to be incident upon an SLM 722 in the other focal plane of the lens 721. As the beams 741, 742 do not originate on the grating 720 from the same location, they are not mutually parallel when emerging from the lens 721. The beam 743 is from a point on the grating 720 common to the origin on the grating 720 of beam742, and hence these beams are mutually parallel. Although the grating is drawn as transmissive and the SLM as reflective, these types are arbitrary. The first beam 731 and the third beam 733 are at the same wavelength, hence they emerge parallel from the grating 720 and are refracted by the lens 721 propagating as beams 741 and 743 respectively to a first group or block of pixels 723 on the SLM 722. This pixel block 723 applies the required hologram pattern that routes a channel entering the add port 701 to the main output 704, and also routes a channel entering the main input 702 to the drop port 703. Hence the first group of pixels 723 deflects the first beam 741 to provide first reflected beam 751, and deflects the third beam 743 to provide third reflected beam 753. The second beam 732 is at a different wavelength to the first and third beams 731 and 733 and therefore emerges at a different angle from the grating 720. This third beam is refracted by the lens 721 and propagates as beam 742 to a second group of pixels or pixel block 724 on the SLM 722. This second group of pixels applies the hologram pattern that routes a channel entering the main input port 702 to the main output port 704 and “grounds” a channel entering the add port 701. The second group of pixels 724 deflects the second beam 742 to provide the second reflected beam 752. The holograms on the first and second groups of pixels are selected, (examples were described for FIGS. 13a, 13b and 15), so that the first and second reflected beams 751,752 are mutually parallel; the third beam 753 is routed in a different direction. The consequence of this is that the first and second beams 751,752, after passing again through the lens 721 become incident at a common point 726 on the grating 720, and emerge as main out beam 714. The third beam 753 is incident upon a different point on the grating 720 and emerges into as the drop beam 713. In most cases ring networks are bi-directional, with separate add/drop nodes for each direction of travel. In some networks a loopback function is required. This allows isolation of one segment of the ring in case of link failure, for example. It also allows the transmission systems for both directions of a link between two nodes to be tested from a single node. This latter function is useful to confirm that a failed link has been repaired. Loop back requires the main input on each add/drop node to be routed to the main output on the other add/drop node, as shown in FIG. 16. The figure shows a first module 161a and a second module 161b. The first module 161a has a main input 162a, an add input 166a, a loop back input 165a, a main output 163a, a drop output 167a and a loop back output 164a. The second module 161b has a main input 162b, an add input 166b, a loop back input 165b, a main output 163b, a drop output 167b and a loop back output 164b. The node is divided into two sides: a west side 168 and an east side 169. Loop back may be required for one or for both sides of the node. Channels coming from the ring enter the first module 161a on a main input 162a and enter the second module 161b on a main input 162b. In normal operation through channels will be routed from the main input 162a to the main output 163a and from the main input 162b to the main output 163b. In loop back operation for the west side 168 the through channels entering the input 162a on the first module 161a are routed to the loop back output 164a. This output 164a is connected to the loop back input 165b of the second module 161b. In loop back operation for the west side all channels entering the input 165b are routed to the main output 163b of the second module 161b. In loop back operation for the east side 169 the through channels entering the second module 161b on the main input 162b are routed to the loop back output 164b. This output 164b is connected to the loop back input 165a of the first module 161a. In loop back operation for the east side 169 all channels entering the input 165a are routed to the main output 163a of the first module 161a. The function can be implemented in the four port add drop node (explained in FIGS. 13, 13a, 15 and 29) by selecting a further hologram deflection 179a and 179b, as shown in FIG. 17. In the four port architecture both sides of the node loop back at the same time. This is due to the sharing of the same hologram by input signals at the same wavelength. In FIG. 17 the vector 179a deflects the main input from its specular output position 172 to the loop back output 176. The identical vector 179b is applied by the shared hologram to the loop back input such that it is deflected from its specular output position 173 by the identical vector 179b to the main output 175. The other vectors 177a, 177b, 178a and 178b are used for normal add-drop operation: 174 is the drop output and 171 is the specular output position for the add input. When such a hologram is applied the main input is routed to the loopback output and the loop back input is routed to the main output. The two add/drop nodes are then connected as in FIG. 16. The loop back function can be implemented in other add drop architectures (described later) by reserving drop ports for loop back out and add ports for loop back in. In these other architectures the loop back may be applied to just one side of the node, as well as to both sides. The method used to provide loop back ports may also be applied to the multiport add drop (FIG. 18). This method may be used to provide cross connection ports to exchange channels between adjacent add drop nodes. It is also possible to devise holograms for multicast, i.e. forwarding an incident light beam to each of several outputs. Such a hologram can be applied to route the main input to two outputs, with vectors 177a and 178a (in FIG. 17). In this case the device is performing a drop and continue function. This is required to provide a duplicated path at nodes connecting two touching ring networks. Alternatively, or additionally, additional inputs and outputs can be provided so as to have a separate input for each added channel and a separate output for each dropped channel. This saves the expense and space taken up by additional filtering and/or wavelength multiplexing components that would otherwise be used to combine all added channels onto a common add port, and to separate all dropped channels to individual receivers. An example layout is shown in FIG. 18. In such an implementation care must be taken that sufficient distance is provided between the zero order reflections from each input, and the output positions for each output, so as to control the crosstalk. In FIG. 18 deflection v2 is used to deflect channels entering the main input from the specular output position m0 to the main output position m2. Deflections v4 to v7 are used to route from the four add inputs (with specular output positions a1, a2, a3 and a4) to the main output m2. Identical deflections v4 to v7 are applied by the shared holograms to deflect the main input from its specular output position m0 to the four drop outputs d1 to d4. For example if wavelength channels λ5 and λ7 enter on add input 2 which has its zero order (specular) reflection at a2, the holograms associated with these wavelength channels are configured to produce deflection v5. Hence these two channels will exit from the main output m2. Any channels entering the main input on these two wavelengths will experience the same hologram deflection, and will then exit from output d2. In one implementation of the multiwavelength architecture the optics between any input fibre and the corresponding input beam that arrives at the diffraction grating, is such that the beam spot that arrives at the SLM is an image of the beam spot that leaves the input fibre. Similarly the optics between any output beam and the corresponding output fibre is such that the beam spot that arrives at the output fibre is an image of the beam spot that leaves the SLM. An example embodiment that would achieve this behaviour is to have an individual collimating lens associated with and aligned to every optical fibre. Referring to FIG. 27, it is assumed that two adjacent channels are being routed in a different direction to the channel under consideration. Thus the beam under consideration has a first hologram 500, and the two adjacent beams have contiguous holograms 501 and 502 respectively. The beam under consideration has an intensity distribution shown as 510. Hence the energy incident from the beam under consideration on the two adjacent holograms, shown as 511 and 512, is lost. Given a perfect optical system what arrives at the selected output fibre is a demagnified image of the truncated beam. Due to the way that the optical system works, the centre line of the beam incident at the output fibre will be lined up with the centre of the output fibre (indeed the beam deflection angle at the SLM should be adjusted so this is the case). To each wavelength channel there is assigned a block of pixels applying the same routing hologram. Preferably this block of pixels should be chosen such that an input light beam exactly at the centre wavelength for the channel arrives at the SLM such that the centre of the beam is within a half pixel's width of the centre of the assigned pixel block. In the presence of thermal expansion of the optomechanical assembly the centre of said beam may arrive at a different point on the pixel block resulting in partial loss of signal as more of the beam tails are lost. This problem can be avoided either by expensive thermally stable optomechanics or by dynamic reassignment of pixels to the blocks associated with each channel. For this to be achievable the pixel array should be continuous. This continuity of the pixel array is advantageous for thermal stability whether or not the imaging criterion used to calculate the filter response is satisfied. The way that the architecture behaves is that for all parallel beams incident on the grating, the position at which the beam at a particular wavelength reaches the SLM is independent of the input port. Hence a reference signal of known wavelength will be incident at the same particular point on the SLM, whether it comes in with any of the signals to be routed, or on a separate input. The method to measure the position of the beam centre can be used on one or a pair of such reference signals. Given this information, an interpolation method can be used to measure the wavelength of some other signal entering the system on one of its input ports, given the measurement of the position of the centre of the beam associated with said other signal. This information can be used to monitor the behaviour of the original transmitter lasers, and also to inform the controller for the routing system. Furthermore, given the position of said reference beams as they reach the SLM, and also the centre wavelength(s) of (an)other signal(s) entering the system, the position of the beam(s) at said centre wavelength(s) upon the SLM may also be calculated. This information can be used to control the adjustment of the pixel blocks and/or holograms used to route and control said other signal(s). Conversely the position of said reference beams may be used to select a pixel block that provides a given required centre wavelength for a filter. Hence reconfigurable assignment of pixel blocks may be used to tune the centre wavelength of one or more filter pass bands. For the purpose of calculating the wavelength filtering response it is assumed that the centre of the beam at the centre wavelength of the channel (shown as 500 in FIG. 27) arrives exactly at the centre of the associated pixel block. With reference to FIG. 31, as the wavelength is increased above the centre wavelength of the channel the centre line 946 of the beam 940 lands at a distance 941 away from the centre 945 of the pixel block or hologram 942. As a result of the offset 941 due to wavelength difference, the beam loses more energy 943 to the adjacent hologram 944. Assuming perfect imaging, what arrives at the output fibre is a demagnified image of this truncated beam. An important difference for the multi-wavelength architecture, compared to conventional wavelength demultiplexers, is that a wavelength difference from the centre of a wavelength channel does not (to first order) result in an offset error of the beam at the output. This is because of the way the second pass from the grating ‘undoes’ the dispersion of the (fixed) diffraction grating, as was shown, for example, in FIG. 12. Hence the original centre line of the truncated beam should be aligned with the peak of the fundamental mode in the output fibre, or, equivalently, aligned with the optical axis of the output fibre. Standard methods for the calculation of coupling efficiency into single-mode fibres have been used to calculate the filter characteristics. Example results are in FIGS. 19 and 20. FIG. 19 shows the relative transmission Tlo for in-band wavelengths as a function of the ratio of the wavelength offset u to centre of the wavelength channel separation. Each curve in the Figure is for a different value of the hologram clipping factor (CR) in the range 2 to 4: this factor is defined as the ratio of the hologram width to the beam spot size at the hologram. FIG. 20 shows the relative transmission Thi inside the adjacent channel, with u=1 at the centre of the adjacent channel while u−0.5 is at the boundary with the adjacent channel. Again, each curve in the Figure is for a different value of the hologram clipping factor (CR) in the range 2 to 4. FIGS. 19 and 20 also show that a change in the width of the pixel block assigned to the filter passband (that is a change in CR) will change the passband width and extinction rate at the edges of the passband. Hence reconfigurable assignment of pixel blocks may be used to tune the shape and width of the filter pass bands. Independently of the clipping factor, the suppression at the edges of the wavelength channel is 6 dB and the full width half maximum (FWHM) filter bandwidth is approximately 80% of the channel separation. Comparison of the different curves in FIG. 19 shows that the flatter the filter passband the steeper the skirts at the edges, leading to greater extinction of the adjacent channel, as shown in FIG. 20. This behaviour is advantageous as it avoids the usual tradeoff between adjacent channel extinction and centre flatness. Good centre flatness means that the filters concatenate better, so more routing nodes using such filters can be traversed by a signal before the signal spectrum and hence fidelity starts to deteriorate. Good adjacent channel extinction is also important as it prevents excessive accumulation of crosstalk corrupting the signal. For example, in a known conventional wavelength demultiplexer the filter pass bands are Gaussian and the 1 dB and 3 dB filter bandwidths are inversely proportional to the square root of the adjacent channel extinction (in dB), such that the greater the extinction, the narrower the filter passband. For the same FWHM filter bandwidth of 80% a Gaussian filter would have an adjacent channel extinction weaker than 20 dB, leading to crosstalk problems. However for the SLM multi-wavelength architecture the adjacent channel extinction is better than 30 dB, avoiding such problems in most known networks. As is well-known to those skilled in the art, an arbitrary beam incident on an optical fibre couples partially into the fundamental mode of the fibre with the rest of the beam energy coupling into a superposition of the higher order modes of the fibre. The higher order modes may be stripped out with a fibre mode stripper. The coupling efficiency into the fundamental mode is given by the modulus squared of the ratio of an overlap integral divided by a normalisation integral. The overlap integrand is the product of the incident field and the fundamental mode. The normalisation integrand is the product of the fundamental mode with itself. FIGS. 33 and 34 are included with the aim of explaining the behaviour of the ‘imaging filter’ as described above. FIG. 32 shows the truncated incident beam profiles 960-964 as the wavelength is increased from the centre of the channel under consideration, 960, to the centre of the adjacent channel, 964. Truncated beams 961, 962 and 963 are for wavelength differences of a quarter, a half and three-quarters, respectively, of the channel separation. In the diagram the truncated beam profiles are offset vertically for clarity. The beam profiles are aligned horizontally as they would be physically at the output fibre; the original centre of each truncated beam is aligned with the centre of the fibre fundamental mode. This is because, as explained above, a wavelength difference from the centre of a wavelength channel does not (to first order) result in an offset error at the output. Beam 965 is the fundamental mode of the fibre. FIG. 33 shows the overlap integrands 970-974 of the truncated incident beams with the fundamental mode of the fibre, as the wavelength is increased from the centre of the channel under consideration, 970, to the centre of the adjacent channel, 974. The normalisation integrand, 975, is also shown. The results in the figures show that the overlap integrand 974 has almost vanished explaining why the adjacent channel extinction is very strong. Overlap integrands 971 and 972 are for wavelength differences of a quarter and a half, respectively, of the channel separation. These results explain why the overlap integrand decreases slowly with wavelength difference in this range leading to a flat passband centre. In particular for the halfway case, 972, the overlap integral is exactly half of the normalisation integral (from integrating 975). Hence the amplitude transmission coefficient at this wavelength difference is a half with a power extinction of 6 dB, as was shown in FIG. 19. Therefore two factors are responsible for the excellent filter characteristics. The first factor is that the field incident on the fibre is an image of the field reflected from the SLM. The second factor is that the second pass from the grating undoes the dispersion applied by the first pass from the grating, such that whatever the wavelength offset inside the collected channel, (to first order), the peak of the reflected truncated beam is aligned with the peak of the fundamental mode of the fibre. By way of comparison, FIGS. 34 and 35 illustrate the filtering process for a conventional wavelength demultiplexer. In FIG. 34 the centre of a first beam 984 is aligned with the optical axis 980 of the centre of a first optical fibre or optical waveguide 981. Hence the first beam 984 is at the centre wavelength of the channel collected by the first optical fibre 981. A second optical fibre 9B3, adjacent to the first fibre 981, has an optical axis 982. A second beam 988 is aligned with the optical axis 982 of this second optical fibre. Hence the second beam is at the centre wavelength of the channel collected by the second optical fibre, that is at the centre of the adjacent optical channel to that collected by the first fibre. Beams 985 to 987 are at wavelength differences from the first beam 984 of a quarter, a half, and three-quarters, respectively, of the wavelength separation between the two adjacent channels. The coupling efficiency of each of the beams 985 to 988 into the first optical fibre 981 again depends on the overlap integral of the respective beam with the fundamental mode of the fibre 981. This is mathematically identical to the overlap integral of the respective beam with the first beam 984. FIG. 35 shows the overlap integrands 994 to 998 plotted against a vertical axis 990. The spatial width and shape of each curve is identical, as may be shown analytically. Hence the overlap integrand is proportional to the amplitude of the curve, as may be read from the axis 990. Curve 994 is the overlap integrand at the centre of the channel, and is the product of the distribution 984 of FIG. 34 with itself. This curve has an amplitude of 1.0 and hence maximal coupling efficiency. Curves 995 to 997 are the overlap integrands at wavelength differences from the channel centre of a quarter, a half, and three-quarters, respectively, of the wavelength separation between the two adjacent channels. Curve 998 is the overlap integrand at the centre of the adjacent wavelength channel. The coupling efficiency is given by the square of the amplitude of the overlap integrand. The results in FIG. 35 show that the coupling efficiency for the conventional wavelength demultiplexer decreases more quickly around the centre of the filter passband than for the ‘imaging’ filter discussed in this application. The results also show that the adjacent channel extinction is weaker for the conventional demultiplexer. FIGS. 34 and 35 also explain why there is a performance tradeoff for the conventional multiplexer between filter passband flatness and adjacent channel extinction: to increase the width of the filter passband the beams 9B5-986 must be incident closer to the first optical fibre 981. Necessarily the beams 987-988 will also be closer to the first optical fibre, reducing the extinction of the adjacent channel, and requiring the second optical fibre 983 to be moved closer to the first fibre 981. FIGS. 32 and 33 explain why the imaging filter behaves in a different way, such that a broader filter passband is associated with a greater extinction of the adjacent channel. Beam 960 in FIG. 32 shows the truncated reflected beam at the centre of the filter passband. The first and second amplitude discontinuities 966a, 966b are due to the two edges of the hologram. An increase in the hologram width relative to the spot size moves these two discontinuities outwards. The significant amplitude discontinuity in the middle beam 962 is exactly at the centre of said beam, whatever the hologram width. This is because said middle beam is associated with a wavelength halfway between the centres of adjacent channels. Hence the coupling efficiency for this halfway point is 6 dB, independently of the hologram width. The significant amplitude discontinuity in the quarterway beam, 961, is exactly halfway between the first amplitude discontinuity, 966a of the centre beam 960 and the significant amplitude discontinuity in the halfway beam, 962. As the first discontinuity 966a moves outwards due to an increased hologram width (in the direction of arrow 967) the significant discontinuity in the quarterway beam must move in the same direction, increasing the overlap integral and improving the filter passband centre flatness. Similarly as the second discontinuity 966b moves outwards (in the direction of arrow 968) the significant discontinuities in the three-quarter way beam 963 and adjacent beam 964 must move in the direction of arrow 968, decreasing the overlap integral and improving the adjacent channel extinction. This explanation reinforces the argument that the two factors described above (imaging and the second ‘undoing’ pass from the grating) are responsible for the excellent filter characteristics. This explanation also explains how the selection of the width of the block of pixels assigned to a channel may control the filter passband characteristics. Analytically it can be shown that the filter response for dropping or adding an isolated channel is purely real. Hence there are no phase distortions with this type of dropping filter. This is advantageous because in many ‘flat-top’ filters the phase distortions associated with the steep skirts may distort the pulses, particularly in higher bit-rate transmission systems for which the signal bandwidth is broader. In these calculations it was assumed that the blocks of pixels assigned to each wavelength channel are contiguous. That is there are no ‘guard bands’ of pixels between each block. Further analysis showed that introducing such guard bands has the effect of decreasing the channel bandwidth for a given channel separation. Hence, preferably the pixel blocks assigned to each wavelength channel should be contiguous. Alternatively guard bands can be used to route in a third direction to deliberately narrow a channel bandwidth, if required. While the above discussion is for the case of an isolated channel, in which both adjacent channels are routed in a different direction to the channel under consideration, there are also filtering effects that can occur when one or both adjacent channels are routed in the same direction. These effects are caused by ‘stitching errors’ at the adjacent edges of a pair of holograms routing in the same direction. For example a stitching error of pi causes (in theory) complete extinction of a light beam at a wavelength exactly halfway between the centres of two adjacent channels, while for an absence of stitching error at either side of a hologram, the transmission is uniform right across the entire channel. Intermediate stitching errors cause intermediate extinction. This acts as an additional programmable filtering mechanism and can be used to advantage to partially or completely filter out amplifier noise between selected channels, if required. Alternatively when maximally flat passbands are required the stitching error should be minimised. As described previously, all channels entering the architecture at the same wavelength are incident on the same hologram. This is because the input beams are arranged to be parallel as they arrive at the diffraction grating, such that all channels at the same wavelength emerge parallel from the diffraction grating. As the diffraction grating is at the focal plane of the lens the beams therefore converge towards the same point in the other focal plane of the routing lens (or equivalent mirror) at which point the SLM is placed. Hence for the four port and multiport add/drop devices the channels entering on the main beam (from the main input fibre) share a hologram with those channels at the same wavelength entering on an add port. When configured with one particular routing hologram the channel entering the main input is routed to the (selected) drop port while the channel entering the add port is routed to the main output. Therefore any channel equalisation applied to an added channel will also be unavoidably applied to the dropped channel. Hence it is not possible to carry out independent channel equalisation on added and dropped channels. This problem does not occur, however, for the devices with a single input and/or with a single output. This is because in these devices there is no sharing of individual holograms between channels entering or leaving on different ports. Nor does the problem occur for the devices with multiple inputs and multiple outputs, for channels routed from the main input to the main output. Another configuration of the multi-wavelength architecture is to have a single input port and a separate output port for every wavelength channel and SLM devices for each channel capable of providing a set of many deflections. When configured so that a single channel leaves on each output port, the device acts as a reconfigurable demultiplexer such that the assignment of a particular wavelength to each output port can be changed dynamically. Conventional wavelength demultiplexers are not reconfigurable and are therefore less flexible as a routing component. They also have a Gaussian filtering characteristic, which is inferior to the filter characteristic of the SLM multiwavelength optical processor, as described earlier. A further advantage of the invention, compared to a conventional free-space wavelength demultiplexer, is that the channel filter bandwidth is independent of the physical separation between the output fibres and also independent of the spot size of the output fibre. In contrast, for the conventional demultiplexer, the channel bandwidth is proportional to the ratio of the output waveguide spot size to the physical separation of the output waveguides. Consequently, and in order to obtain sufficient channel bandwidth, microlens arrays are required to increase the effective spot size or waveguide concentrators are used to decrease the waveguide separation. When used in reverse the device acts as a reconfigurable multiplexer, allowing the use of, for example, tuneable lasers at each input. In contrast, for a conventional wavelength multiplexer, fixed-tuned lasers must be used at each input. A system with a single input port and many output ports can act as a module to form part of a modular routing node. If the system has M output ports and a single input port, then each routing device produces M different deflections, with small adjustments to compensate for wavelength differences and alignment tolerances. All devices (i.e. holograms) producing the same eventual deflection will cause the associated wavelength channel to be routed out of the same output port. Hence such a system can send none, one or many (up to the number of channels entering the input port) channels out from the same output port. The logical function of the module is to sort the incoming channels on the input port according to their required output port, as also illustrated in FIG. 21. Considering firstly the case of the routing architecture shown in FIG. 12. As there is a single input port, every wavelength channel has its own hologram. Hence independent channel equalisation may be applied for all the signals flowing through the module. One application of these modules is to use two of them to make an add/drop node, as shown in FIG. 22. FIG. 22 shows a first routing module 660 having one input 661 from a previous node, a through output 662 and three drop outputs 663-5, as well as two spare outputs 666,667. A second routing module 670 has a first input 671 connected to the through output 662 of the first module, three add inputs 672-4 and two spare inputs 675,676. The second module 670 has an output 677 to the next node. The second (output) module can be physically identical to the first (input) module but it is used ‘in reverse’. The first module routes all the through traffic out on a common through port 662 while providing multiple drop ports: one for each dropped channel. Any single wavelength or any set of wavelengths can be sent to any drop port. Hence each of the drop ports may connect to a local optoelectronic receiver in a local electronic switch, or to a remote customer requiring one or more channels for remote demultiplexing. The reconfigurability of the wavelength assignment means that the module acts like a wavelength demultiplexer combined with a matrix switching function, so may reduce the switching demands placed on the electronics servicing the drop ports. The ability to send a selectable set of wavelengths to the same port reduces the need for additional fibre/multiplexing components and increases flexibility. Furthermore the routing applied to each wavelength channel may be multicast, as well as unicast. Hence drop and continue operation may be provided in which the signal is routed to a drop port and also to the through port. If a transparent optical connection is required through to access and distribution networks this multicasting may also be applied to broadcast signals to a number of drop fibres. In this multicasting operation one or more of the previously described power control methods may be applied to equalise the channels on the through and drop fibres, as required for the transmission systems and receivers to function correctly. The first module provides any channel equalisation and monitoring required for the drop ports. Channel equalisation and monitoring for the through channels may take place in the first module, or the second module, or both. The second module provides multiple add ports: one for each added channel. Any single wavelength or any set of wavelengths can be received at any of the input ports. This allows each of the add inputs to be a tuneable laser, which would not be possible with a conventional non-reconfigurable wavelength multiplexer. In the conventional case there are two options for providing the added channels. A first option is to use conventional non-reconfigurable wavelength multiplexing to combine the added channels, because this is much more efficient in terms of insertion loss than a non-wavelength-specific multiplexer (such as a 1:N fibre splitter used in reverse, that is a N:1 combiner). However this requires each input port of the wavelength multiplexer to have a transmitter laser at a fixed wavelength. When a particular wavelength channel is added at the node the associated transmitter is in use. However when the network reconfigures its wavelength assignment that laser may no longer be in use. To allow complete reconfigurability a complete set of transmitter lasers must be provided, one for each system wavelength. This makes reconfigurable add drop nodes uneconomic when adding small numbers of channels, due to the large overhead of idle transmitter lasers. A second option is to use tuneable lasers, one for each added channel. With conventional optics this requires a non-wavelength-specific multiplexer, which imposes insertion loss penalties. The multi-wavelength architecture described provides a reconfigurable wavelength multiplexer with lower insertion loss than a N:1 combiner. Furthermore the routing applied to each wavelength channel can be reconfigured without transient effects on other wavelength channels, as occurs in ‘serial’ multiplexing architectures that have a reconfiguration capability. Any add port can receive a reconfigurable set of wavelength channels from a remote customer. The second module also provides any channel equalisation required for the added signals. Finally the second module routes the through channels entering on the port 671 to the output 677. The spare ports 666,667,675,676 can be used for routing selected channels to optical regenerators if the signal quality demands it; to wavelength converters to avoid wavelength blocking; to another add/drop node to allow cross-connection between rings, as shown in FIG. 23, or to further modules to allow expansion, as shown in FIG. 24. FIG. 23 shows a first to fourth routing modules 720, 730, 740 and 750. The first and fourth modules each have one input 721, 751, a through output 722, 752, a cross-connect output 723,753 and a number of drop outputs721, 754. The second and third modules 730,740 each have respective single output 731,741, a number of add inputs 732,742 a cross-connect input 733,743 and a through input 734, 744. The through output 722 of the first module 720 is connected to the through input 734 of the second module 730, and the through output 752 of the fourth module 750 is connected to the through input 744 of the third module 740. The cross-connect output 723 of the first module 720 is connected to the cross-connect input 743 of the third module 740, and the cross-connect output 753 of the fourth module 750 is connected to the cross-connect input 733 of the second module 730. The first and second modules 720, 730 are on one ring and the third and fourth 740, 750 on a second ring. This cross connection capability allows a new ring network to be overlaid on an original ring network when the original ring capacity is becoming exhausted. Channels may be exchanged between the two rings at each node as required. Hence the ring network acts like a ring with two fibres per link (in each direction around the ring). The concept may be extended to three or more overlaid rings, and hence three or more fibres per link (in each direction around the ring). As is well known from many traffic studies, increasing the number of fibres per link reduces significantly a phenomenon known as wavelength blocking, such that more efficient use is made of the capacity of each fibre. Hence cross connection between rings makes better use of the available capacity, allowing more traffic to be carried for the same investment in infrastructure. Cross connection may also be used to exchange signals between diverging rings. FIG. 24 shows expansion of a first (input) module 760 having a single input 761, and five outputs 762-6,via an optical amplifier 768 and an intermediate module 770 having four outputs 771-4. The first output 762 of the first module 760 is a through path, the third output 764 is an expansion port and provides an input to the optical amplifier 768, and the output 769 of the optical amplifier is to the intermediate module 770. The intermediate module 770 has an expansion port 771 and three new ports 772-4. Fourth and fifth outputs 765, 766 of the input module 760 form drop outputs. The same principle can also be applied to expansion of a second (output) module. The use of such modules allows extra add and drop ports to be provided without service interruption to the channels flowing through the add drop node. It also allows network operators to apply just in time provisioning, delaying investment in infrastructure until the demand is there to use it. Furthermore it is only the channels dropped or added through the expansion module(s) that are subject to an additional amplification stage. If every node in the ring were upgraded in this manner, the channels should only pass through an additional two amplification stages. This could be reduced to one additional stage by suitable assignment of the added and dropped channels to the original and expansion module. Returning to the basic routing module shown in FIG. 21. This type of connectivity would be useful in mesh networks where each node is connected by a multi-fibre link to, typically, each of between two and five nearest neighbour nodes. Each link carries traffic to and from one of the nearest neighbour nodes. Usually individual fibres in the link carry traffic in just one direction but some are bi-directional. For an example where a link has an average of six pairs of external fibres and a node has five links, then there would be thirty external incoming fibres and thirty external outgoing fibres. The function of the node is to route any wavelength channel from any incoming fibre to any outgoing fibre. Each fibre may carry many wavelength channels. Currently up to 160 channel systems are being installed although 40 or 80 channel systems are more usual. An ideal node architecture allows the network operator to start with one or more add/drop nodes connected to one or more rings and then allow the individual add/drop nodes to be connected so that the network topology can evolve towards a mesh. The node architecture should also allow extra fibres to be added to each link as required to meet the demand, with the extra parts or modules of the node being installed as and when required. Fibre management and installation between sub-components inside the routing node is also expensive. A known architecture for such a routing node uses a separate wavelength demultiplexer for every input fibre. The separated wavelength channels are then carried over optical fibres to N×N optical switches. To avoid internal wavelength blocking then all channels at a particular wavelength must be connected to the same N×N switch. Hence the switch will receive channels at the same wavelength from every single input fibre. The channels leaving the switch are carried over optical fibres to a separate wavelength multiplexer for every output fibre. Hence the switch will route channels at the same wavelength towards every single output fibre. These switches have a sufficient number of ports for added and dropped channels, and channels passing to and from wavelength conversion and optical regeneration. This sufficient number is estimated based on traffic analysis as it depends on the instantaneous mapping of channels between nodes and the wavelength and fibre allocation. Each switch may service one or more wavelength channels. In one device, the number of fibres is around b 3000 resulting in significant fibre management and installation costs. Even grouping together different fibres to or from the same link and grouping together the add fibres and regenerator fibres only reduces the number of separate entities to be managed to 560. With such a large number of fibres it is not economic to provide optical amplifiers inside the routing node to compensate for insertion losses. Another problem with this architecture is how to add in extra external fibres once the switch capacity has been exhausted with the current number of external fibres. This cannot be done without replacing every single switch. In advance it is difficult to know how large to provision the switch to avoid or delay this problem. An alternative node architecture uses one of the multi-wavelength architectures described to provide a separate module for every input fibre and a separate module for every output fibre. Consider first an input module. This should be designed so that none, one, many or all of the input channels may leave any of the output ports (as shown in FIG. 21). These output ports are used to carry channels towards output modules and towards other parts of the node providing wavelength conversion, regeneration and ports to electronic switches, for example. A connection between an input module and an output module carries every wavelength channel mapped between the corresponding input and output fibre. Hence the logical function of an input module is to sort the incoming channels according to their destination output fibre. This logical functionality was illustrated in FIG. 21. A particular input module does not have connections to every output module. It does not have connections to output modules going back to the same neighbouring node from which the input channels have travelled, except perhaps for network monitoring and management functions. It might not need to have separate connections to every output module for the output fibres to the other neighbouring nodes. It is however provided with sufficient connectivity to the output channels on every output link to avoid unacceptable levels of wavelength blocking. For example each input module could be connected to a subset of the output modules, with an overflow system used to provide a connection to the other output modules, when required. An output module is designed like an input module but works in the opposite direction. Hence the logical function of the output module is to collect the channels coming from each input module and direct them to a common output port. In this architecture, the dropped channels and channels needing wavelength conversion may exit from each module on a common port or a pair of ports. As a result of using the modules it can be shown that satisfactory performance is achieved using fewer than 1000 fibres and fewer than 50 fibre groups. Hence the total number of fibres inside the node is reduced by a factor of over 3 while the total number of fibre entities to be installed and managed is reduced by a factor of 10 or more. This represents a significant reduction in cost and complexity. An example wavelength-routing crossconnect using the modules is shown in FIG. 25. FIG. 25 shows four input routing modules 790-3, each with a respective input 790i-793i and four outputs 79001-79003 etc. and four output routing modules 794-7 each with four inputs and a respective single output 794o-797o to a respective output fibre. One output of each input module 790-3 forms a drop output. The input and output modules are associated together with input module 790 associated with output module 794, input module 791 associated with output module 795, input module 792 associated with output module 796 and input module 793 associated with output module 797. The remaining three outputs of each input module are cross-connected to the non associated output modules, so that for example the three non-drop outputs of input module 790 are coupled to respective inputs of output modules 795, 796 and 797. Specifically, output 79001 is connected to output module 795. Of the inputs to the four output modules, one per module is an add input and the remainder are connected to outputs of the input modules 790-3. In the example the routing function carried out by each input module 790-3 is to sort the incoming channels with respect to the selected output fibre 794o-797o for example, and with reference to the figure, all wavelength channels entering the cross-connect on input 790i that need to leave the cross-connect on 795o are routed by the input module 790 to the output 79001. This output carries these channels to the output module 795 which is collecting frequency channels for output 795o. The output module combines all incoming channels onto a respective single. output. In this architecture channel equalisation may be carried out independently for all channels routed through the cross connect. The cross connect architecture of FIG. 25 is modular in that it can be used to build a range of nodes of different connectivity and dimension. The modules can be used to assemble a node like that described above, starting with only 1 or 2 fibre pairs per link and adding in extra modules to allow more fibres per link. Extra modules can be added in and connected up as and when required, allowing the network operator to delay investment in infrastructure for as long as possible. When the node has reached, for example, 6 fibre pairs per link and the capacity begins to be exhausted there are three ways to upgrade the node. The first way is to upgrade the numbers of wavelength channels on particular fibres in each link. This requires replacing the associated modules with modules processing more channels. However the other modules (and the fibre interconnections) can remain in service. In contrast for the conventional architecture as well as upgrading the demultiplexers and multiplexers associated with the particular fibres to be upgraded, a whole set of N×N switches must be installed, one for every new system wavelength. These switches will remain under-utilised until all the fibre systems have been upgraded. A second way to upgrade the node is to replace selected modules with models providing an increased number of fibre choices per output link allowing more fibres per link. This requires the installation of more fibre groups inside the node. In contrast for the conventional architecture every N×N switch must be replaced meaning the associated system wavelengths would be out of service on every fibre entering or leaving the node. A third way to upgrade the node is to upgrade selected modules by cascading another module from a spare, or expansion output port, as shown in FIG. 26. FIG. 26 shows a somewhat similar arrangement to FIG. 24, and has an input module 860, with an input 861, five outputs 862-6, an optical amplifier 870 and an intermediate module 880 receiving the output of the optical amplifier 870 and providing four outputs 881-4. The input module has three outputs 862-4 to existing output modules, fourth output 865 to the optical amplifier 870 and fifth output as a drop output. The first to third outputs 881-3 of the intermediate module 880 connect to new or later output modules. The advantage of this third way is that service interruption is not required during installation. The smallest node can have as few as two modules, which would act as an add/drop node. Several pairs of such modules can service a stacked set of rings, allowing interconnection between different rings. Adjacent rings can also be interconnected. A hybrid ring/mesh network can be created. Hence the same modular system can be used for ring networks, mesh networks and mixes of the two. It can also allow re-use of existing plant and allow an add/drop node to grow and evolve into a wavelength-routing cross-connect. It will be clear to those skilled in the art that the use of reflective SLMs may allow optical folding to be accomplished and provide a compact system. Thus folding mirrors which may be found in some systems are replaced by SLMs that serve the dual function of folding and performance management for the system. The performance management may include managing direction change, focus correction, correction of non-focus aberration, power control and sampling. When taken together with the controller and sensors, the SLM can then act as an intelligent mirror. As an example, this application of SLMs would be attractive in the context of free-space wavelength demultiplexers as it would help to suppress the problems associated with long path lengths. Another example is to provide correction for alignment tolerances and manufacturing tolerances in systems requiring alignment between fibre arrays and lens arrays. In particular focal length errors in the lenses (due to chromatic aberration or manufacturing tolerance) can be compensated by focus correction at the SLM or SLMs, while transverse misalignment between a fibre and lens which leads to an error in the beam direction after the lens, can be compensated by beam deflection at the SLM or SLMs. It will also be clear to those skilled in the art that although the described embodiments refer to routing in the context of one-to-one, it would also be possible to devise holograms for multicast and broadcast, i.e. one-to-many and one-to-all, if desired. Although the invention has been described with reference to a number of embodiments, it will be understood that the invention is not limited to the described details. The skilled artisan will be aware that many alternatives may be employed within the general concepts of the invention as defined in the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>It has previously been proposed to use so-called spatial light modulators to control the routing of light beams within an optical system, for instance from selected ones of a number of input optical fibres to selected ones of output fibres. Optical systems are subject to performance impairments resulting from aberrations, phase distortions and component misalignment. An example is a multiway fibre connector, which although conceptually simple can often be a critical source of system failure or insertion loss due to the very tight alignment tolerances for optical fibres, especially for single-mode optical fibres. Every time a fibre connector is connected, it may provide a different alignment error. Another example is an optical switch in which aberrations, phase distortions and component misalignments result in poor optical coupling efficiency into the intended output optical fibres. This in turn may lead to high insertion loss. The aberrated propagating waves may diffract into intensity fluctuations creating significant unwanted coupling of light into other output optical fibres, leading to levels of crosstalk that impede operation. In some cases, particularly where long path lengths are involved, the component misalignment may occur due to ageing or temperature effects. Some prior systems seek to meet such problems by use of expensive components. For example in a communications context, known free-space wavelength multiplexers and demultiplexers use expensive thermally stable opto-mechanics to cope with the problems associated with long path lengths. Certain optical systems have a requirement for reconfigurability. Such reconfigurable systems include optical switches, add/drop multiplexers and other optical routing systems where the mapping of signals from input ports to output ports is dynamic. In such systems the path-dependent losses, aberrations and phase distortions encountered by optical beams may vary from beam to beam according to the route taken by the beam through the system. Therefore the path-dependent loss, aberrations and phase distortions may vary for each input beam or as a function of the required output port. The prior art does not adequately address this situation. Other optical systems are static in terms of input/output configuration. In such systems, effects such as assembly errors, manufacturing tolerances in the optics and also changes in the system behaviour due to temperature and ageing, create the desirability for dynamic direction control, aberration correction, phase distortion compensation or misalignment compensation. It should be noted that the features of dynamic direction control, phase distortion compensation and misalignment control are not restricted to systems using input beams coming from optical fibres. Such features may also be advantageous in a reconfigurable optical system. Another static system in which dynamic control of phase distortion, direction and (relative) misalignment would be advantageous is one in which the quality and/or position of the input beams is time-varying. Often the input and output beams for optical systems contain a multiplex of many optical signals at different wavelengths, and these signals may need to be separated and adaptively and individually processed inside the system. Sometimes, although the net aim of a system is not to separate optical signals according to their wavelength and then treat them separately, to do so increases the wavelength range of the system as a whole. Where this separation is effected, it is often advantageous for the device used to route each channel to have a low insertion loss and to operate quickly. It is an aim of some aspects of the present invention at least partly to mitigate difficulties of the prior art. It is desirable for certain applications that a method or device for addressing these issues should be polarisation-independent, or have low polarisation-dependence. SLMs have been proposed for use as adaptive optical components in the field of astronomical devices, for example as wavefront correctors. In this field of activity, the constraints are different to the present field—for example in communication and like devices, the need for consistent performance is paramount if data is to be passed without errors. Communication and like devices are desirably inexpensive, and desirably inhabit and successfully operate in environments that are not closely controlled. By contrast, astronomical devices may be used in conditions more akin to laboratory conditions, and cost constraints are less pressing. Astronomical devices are unlikely to need to select successive routings of light within a system, and variations in performance may be acceptable.

<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the invention, there is provided a method of operating an optical device comprising an SLM having a two-dimensional array of controllable phase-modulating elements, the method comprising delineating groups of individual phase-modulating elements; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. In some embodiments, the variation of the delineation and/or control data selection is in response to a signal or signals indicating a non-optimal performance of the device. In other embodiments, the variation is performed during a set up or training phase of the device. In yet other embodiments, the variation is in response to an operating signal, for example a signal giving the result of sensing non-performance system parameters such as temperature. An advantage of the method of this aspect of the invention is that stable operation can be achieved in the presence of effects such as ageing, temperature, component, change of path through the system and assembly tolerances. Preferably, control of said light beams is selected from the group comprising: control of direction, control of power, focussing, aberration compensation, sampling and beam shaping. Clearly in most situations more than one of these control types will be needed—for example in a routing device (such as a switch, filter or add/drop multiplexer) primary changes of direction are likely to be needed to cope with changes of routing as part of the main system but secondary correction will be needed to cope with effects such as temperature and ageing. Additionally such systems may also need to control power, and to allow sampling (both of which may in some cases be achieved by direction changes). Advantageously, each phase modulating element is responsive to a respective applied voltage to provide a corresponding phase shift to emergent light, and the method further comprises; controlling said phase-modulating elements of the spatial light modulator to provide respective actual holograms derived from the respective generated holograms, wherein the controlling step comprises; resolving the respective generated holograms modulo 2pi. The preferred SLM uses a liquid crystal material to provide phase shift and the liquid crystal material is not capable of large phase shifts beyond plus or minus 2pi. Some liquid crystal materials can only provide a smaller range of phase shifts, and if such materials are used, the resolution of the generated hologram is correspondingly smaller. Preferably the method comprises: providing a discrete number of voltages available for application to each phase modulating element; on the basis of the respective generated holograms, determining the desired level of phase modulation at a predetermined point on each phase modulating element and choosing for each phase modulating element the available voltage which corresponds most closely to the desired level. Where a digital control device is used, the resolution of the digital signal does not provide a continuous spectrum of available voltages. One way of coping with this is to determine the desired modulation for each pixel and to choose the individual voltage which will provide the closest modulation to the desired level. In another embodiment, the method comprises: providing a discrete number of voltages available for application to each phase modulating element; determining a subset of the available voltages which provides the best fit to the generated hologram. Another technique is to look at the pixels of the group as a whole and to select from the available voltages those that give rise to the nearest phase modulation across the whole group. Advantageously, the method further comprises the step of storing said control data wherein the step of storing said control data comprises calculating an initial hologram using a desired direction change of a beam of light, applying said initial hologram to a group of phase modulating elements, and correcting the initial hologram to obtain an improved result. The method may further comprise the step of providing sensors for detecting temperature change, and performing said varying step in response to the outputs of those sensors. The SLM may be integrated on a substrate and have an integral quarter-wave plate whereby it is substantially polarisation insensitive. Preferably the phase-modulating elements are substantially reflective, whereby emergent beams are deflected from the specular reflection direction. In some aspects, for at least one said group of pixels, the method comprises providing control data indicative of two holograms to be displayed by said group and generating a combined hologram before said resolving step. According to a second aspect of the invention there is provided an optical device comprising an SLM and a control circuit, the SLM having a two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged, to vary the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. An advantage of the device of this aspect of the invention is that stable operation can be achieved in the presence of effects such as ageing, temperature, component and assembly tolerances. Embodiments of the device can handle many light beams simultaneously. Embodiments can be wholly reconfigurable, for example compensating differently for a number of routing configurations. Preferably, the optical device has sensor devices arranged to detect light emergent from the SLM, the control circuit being responsive to signals from the sensors to vary said delineation and/or said selection. In some embodiments, the optical device has temperature responsive devices constructed and arranged to feed signals indicative of device temperature to said control circuit, whereby said delineation and/or selection is varied. In another aspect, the invention provides an optical routing device having at least first and second SLMs and a control circuit, the first SLM being disposed to receive respective light beams from an input fibre array, and the second SLM being disposed to receive emergent light from the first SLM and to provide light to an output fibre array, the first and second SLMs each having a respective two-dimensional array of controllable phase-modulating elements and the control circuit having a store constructed and arranged to hold plural items of control data, the control circuit being constructed and arranged to delineate groups of individual phase-modulating elements, to select, from stored control data, control data for each group of phase-modulating elements, and to generate from the respective selected control data a respective hologram at each group of phase-modulating elements, wherein the control circuit is further constructed and arranged, to vary the delineation of the groups and/or the selection of control data whereby upon illumination of said groups by respective light beams, respective emergent light beams from the groups are controllable independently of each other. In a further aspect, the invention provides a device for shaping one or more light beams in which the or each light beam is incident upon a respective group of pixels of a two-dimensional SLM, and the pixels of the or each respective group are controlled so that the corresponding beams emerging from the SLM are shaped as required. According to a further aspect of the invention there is provided an optical device comprising one or more optical inputs at respective locations, a diffraction grating constructed and arranged to receive light from the or each optical input, a focussing device and a continuous array of phase modulating elements, the diffraction grating and the array of phase modulating elements being disposed in the focal plane of the focussing device whereby diverging light from a single point on the diffraction grating passes via the focussing device to form beams at the array of phase modulating elements, the device further comprising one or more optical output at respective locations spatially separate from the or each optical input, whereby the diffraction grating is constructed and arranged to output light to the or each optical output. This device allows multiwavelength input light to be distributed in wavelength terms across different groups of phase-modulating elements. This allows different processing effects to be applied to any desired part or parts of the spectrum. According to a still further aspect of the invention there is provided a method of filtering light comprising applying a beam of said light to a diffraction grating whereby emerging light from the grating is angularly dispersed by wavelength, forming respective beams from said emerging light by passing the emerging light to a focussing device having the grating at its focal plane, passing the respective beams to an SLM at the focal plane of the focussing device, the SLM having a two-dimensional array of controllable phase-modulating elements, selectively reflecting light from different locations of said SLM and passing said reflected light to said focussing element and then to said grating. Preferably the method comprises delineating groups of individual phase-modulating elements to receive beams of light of differing wavelength; selecting, from stored control data, control data for each group of phase-modulating elements; generating from the respective selected control data a respective hologram at each group of phase-modulating elements; and varying the delineation of the groups and/or the selection of control data. According to a still further aspect of the invention there is provided an optical add/drop multiplexer having a reflective SLM having a two-dimensional array of controllable phase-modulating elements, a diffraction device and a focussing device wherein light beams from a common point on the diffraction device are mutually parallel when incident upon the SLM, and wherein the SLM displays respective holograms at locations of incidence of light to provide emergent beams whose direction deviates from the direction of specular reflection. In a yet further aspect, the invention provides a test or monitoring device comprising an SLM having a two-dimensional array of pixels, and operable to cause incident light to emerge in a direction deviating from the specular direction, the device having light sensors at predetermined locations arranged to provide signals indicative of said emerging light. The test or monitoring device may further comprise further sensors arranged to provide signals indicative of light emerging in the specular directions. Yet a further aspect of the invention relates to a power control device for one or more beams of lights in which the said beams are incident on respective groups of pixels of a two-dimensional SLM, and holograms are applied to the respective group so that the emergent beams have power reduced by comparison to the respective incident beams. The invention further relates to an optical routing module having at least one input and at least two outputs and operable to select between the outputs, the module comprising a two dimensional SLM having an array of pixels, with circuitry constructed and arranged to display holograms on the pixels to route beams of different frequency to respective outputs. According to a later aspect of the invention there is provided an optoelectronic device comprising an integrated multiple phase spatial light modulator (SLM) having a plurality of pixels, wherein each pixel can phase modulate light by a phase shift having an upper and a lower limit, and wherein each pixel has an input and is responsive to a value at said input to provide a phase modulation determined by said value, and a controller for the SLM, wherein the controller has a control input receiving data indicative of a desired phase modulation characteristic across an array of said pixels for achieving a desired control of light incident on said array, the controller has outputs to each pixel, each output being capable of assuming only a discrete number of possible values, and the controller comprises a processor constructed and arranged to derive, from said desired phase modulation characteristic, a non-monotonic phase modulation not extending outside said upper and lower limits, and a switch constructed and arranged to select between the possible values to provide a respective one value at each output whereby the SLM provides said non-monotonic phase modulation. Some or all of the circuitry may be on-chip leading to built-in intelligence. This leads to more compact and ultimately low-cost devices. In some embodiments, some or all on-chip circuitry may operate in parallel for each pixel which may provide huge time advantages; in any event the avoidance of the need to transfer data off chip and thereafter to read in to a computer allows configuration and reconfiguration to be faster. According to another aspect of the invention there is provided a method of controlling a light beam using a spatial light modulator (SLM) having an array of pixels, the method comprising: determining a desired phase modulation characteristic across a sub-array of said pixels for achieving the desired control of said beam; controlling said pixels to provide a phase modulation derived from the desired phase modulation, wherein the controlling step comprises providing a population of available phase modulation levels for each pixel, said population comprising a discrete number of said phase modulation levels; on the basis of the desired phase modulation, a level selecting step of selecting for each pixel a respective one of said phase modulation levels; and causing each said pixel to provide the respective one of said phase modulation levels. The SLM may be a multiple phase liquid crystal over silicon spatial light modulator having plural pixels, of a type having an integrated wave plate and a reflective element, such that successive passes of a beam through the liquid crystal subject each orthogonally polarised component to a substantially similar electrically-set phase change. If a non-integrated wave plate is used instead, a beam after reflection and passage through the external wave plate will not pass through the same zone of the SLM, unless it is following the input path, in which case the zero order component of said beam will re-enter the input fibre. The use of the wave plate and the successive pass architecture allows the SLM to be substantially polarisation independent. In one embodiment the desired phase modulation at least includes a linear component. Linear phase modulation, or an approximation to linear phase modulation may be used to route a beam of light, i.e. to select a new direction of propagation for the beam. In many routing applications, two SLMs are used in series, and the displayed information on the one has the inverse effect to the information displayed on the other. Since the information represents phase change data, it may be regarded as a hologram. Hence an output SLM may display a hologram that is the inverse of that displayed on the input SLM. Routing may also be “one-to-many” (i.e. multicasting) or “one-to-all” (i.e. broadcasting) rather than the more usual one-to-one in many routing devices. This may be achieved by correct selection of the relevant holograms. Preferably the linear modulation is resolved modulo 2pi to provide a periodic ramp. In another embodiment the desired phase modulation includes a non-linear component. Preferably the method further comprises selecting, from said array of pixels, a sub-array of pixels for incidence by said light beam. The size of a selected sub-array may vary from switch to switch according to the physical size of the switch and of the pixels. However, a typical routing device may have pixel arrays of between 100×100 and 200×200, and other devices such as add/drop multiplexers may have arrays of between 10×10 and 50×50. Square arrays are not essential. In one embodiment the level-selecting step comprises determining the desired level of phase modulation at a predetermined point on each pixel and choosing for each pixel, the available level which corresponds most closely to the desired level. In another embodiment, the level-selecting step comprises determining a subset of the available levels, which provides the best fit to the desired characteristic. The subset may comprise a subset of possible levels for each pixel. Alternatively the subset may comprise a set of level distributions, each having a particular level for each pixel. In one embodiment, the causing step includes providing a respective voltage to an electrode of each pixel, wherein said electrode extends across substantially the whole of the pixel. Preferably again the level selecting step comprises selecting the level by a modulo 2pi comparison with the desired phase modulation. The actual phase excursion may be from A to A+2pi where A is an arbitrary angle. Preferably the step of determining the desired phase modulation comprises calculating a direction change of a beam of light. Conveniently, after the step of calculating a direction change, the step of determining the desired phase modulation further comprises correcting the phase modulation obtained from the calculating step to obtain an improved result. Advantageously, the correction step is retroactive. In another embodiment the step of determining the desired phase modulation is retroactive, whereby parameters of the phase modulation are varied in response to a sensed error to reduce the error. A first class of embodiments relates to the simulation/synthesis of generally corrective elements. In some members of the first class, the method of the invention is performed to provide a device, referred to hereinafter as an accommodation element for altering the focus of the light beam. An example of an accommodation element is a lens. An accommodation element may also be an anti-astigmatic device, for instance comprising the superposition of two cylindrical lenses at arbitrary orientations. In other members of the first class, the method of the invention is performed to provide an aberration correction device for correcting greater than quadratic aberrations. The sub-array selecting step may assign a sub-array of pixels to a beam based on the predicted path of the beam as it approaches the SLM just prior to incidence. Advantageously, after the sub-array is assigned using the predicted path, it is determined whether the assignment is correct, and if not a different sub-array is assigned. The assignment may need to be varied in the event of temperature, ageing or other physical changes. The sub-array selection is limited in resolution only by the pixel size. By contrast other array devices such as MEMS have fixed physical edges to their beam steering elements. An element of this type may be used in a routing device to compensate for aberrations, phase distortions and component misalignment in the system. By providing sensing devices a controller may be used to retroactively control the element and the element may maintain an optimum performance of the system. In one embodiment of this first class, the method includes both causing the SLM to route a beam and causing the SLM to emulate a corrective element to correct for errors, whereby the SLM receives a discrete approximation of the combination of both a linear phase modulation applied to it to route the beam and a non-linear phase modulation for said corrections. Synthesising a lens using an SLM can be used to change the position of the beam focused spot and therefore correct for a position error or manufacturing tolerance in one or more other lenses or reflective (as opposed to transmissive) optical elements such as a curved mirror. The method of the invention may be used to correct for aberrations such as field curvature in which the output ‘plane’ of the image(s) from an optical system is curved, rather than flat. In another embodiment of the first class, intelligence may be integrated with sensors that detect the temperature changes and apply data from a look-up table to apply corrections. In yet another embodiment of this class, misalignment and focus errors are detected by measuring the power coupled into strategically placed sensing devices, such as photodiode arrays, monitor fibres or a wavefront sensor. Compensating holograms are formed as a result of the discrete approximations of the non-linear modulation. Changes or adjustments may then be made to these holograms, for example by applying a stimulus and then correcting the holograms according to the sensed response until the system alignment is measured to be optimised. In embodiments where the method provides routing functions by approximated linear modulation, adaptation of non-linear modulation due to changes in the path taken through the system desirably takes place on a timescale equivalent to that required to change the hologram routing, i.e. of the order of milliseconds. A control algorithm may use one or more of several types of compensation. In one embodiment a look-up table is used with pre-calculated ‘expected’ values of the compensation taking account of the different routes through the system. In another embodiment the system is trained before first being operated, by repeated changes of, or adjustments to, the compensating holograms to learn how the system is misaligned. A further embodiment employs intelligence attached to the monitor fibres for monitoring and calculation of how these compensating holograms should adapt with time to accommodate changes in the system alignment. This is achieved in some embodiments by integrating circuitry components into the silicon backplane of the SLM. In many optical systems there is a need to control and adapt the power or shape of an optical beam as well as its direction or route through the optical system. In communications applications, power control is required for network management reasons. In general, optical systems require the levelling out or compensation for path and wavelength-dependent losses inside the optical system. It is usually desirable that power control should not introduce or accentuate other performance impairments. Thus in a second class of embodiments, the modulation applied is modified for controlling the attenuation of an optical channel subjected to the SLM. In one particular embodiment, the ideal value of phase modulation is calculated for every pixel, and then multiplied by a coefficient having a value between 0 and 1, selected according to the desired attenuation and the result is compared to the closest available phase level to provide the value applied to the pixels. In another embodiment, the method further comprises selecting by a discrete approximation to a linear phase modulation, a routing hologram for display by the SLM whereby the beams may be correctly routed; selecting by a discrete approximation to a non-linear phase modulation, a further hologram for separating each beam into main and subsidiary beams, wherein the main beam is routed through the system and the or each subsidiary beam is diffracted out of the system; combining the routing and further holograms together to provide a resultant hologram; and causing the SLM to provide the resultant hologram. The non-linear phase modulation may be oscillatory. In yet another embodiment, the method further comprises selecting by a discrete approximation to a linear phase modulation, a routing hologram for display by the SLM whereby the beams may be correctly routed; selecting by a discrete approximation to a non-linear phase modulation, a further hologram for separating each beam into main and subsidiary beams, wherein the main beam is routed through the system and at least one subsidiary beam is incident on an output at an angle such that its contribution is insignificant; combining the routing and further holograms together to provide resultant hologram; and causing the SLM to display the resultant hologram. The non-linear phase modulation may be oscillatory. In a closely allied class of embodiments, light may be selectively routed to a sensor device for monitoring the light in the system. The technique used may be a power control technique in which light diverted from the beam transmitted through the system to reduce its magnitude is made incident on the sensor device. In another class of embodiments, a non-linear phase modulation profile is selected to provide beam shaping, for example so as to reduce cross-talk effects due to width clipping. This may use a pseudo amplitude modulation technique. In a further class of embodiments, the method uses a non-linear modulation profile chosen to provide wavelength dependent effects. The light may be at a telecommunications wavelength, for example 850 nm, 1300 nm or in the range 1530 nm to 1620 nm.

20040910

20061205

20050127

57770.0

BEN, LOHA

OPTICAL PROCESSING

UNDISCOUNTED

ACCEPTED

ACCEPTED

Production of biopolymer film, fibre, foam and adhesive materials from soluble s-sulfonated keratin derivatives

Film, fibre, foam and adhesive materials are produced from soluble S-sulfonated keratins. Once formed, the films, fibres, foams or adhesives are treated to modify the properties of the materials, in particular to improve the wet strength of the materials. Treatments used include removal of the S-sulfonate group by treatment with a reducing agent, treatment with an acid or treatment with a common protein crosslinking agent or treatment with a reduced form of keratin or keratin protein. The films are made by solvent casting a solution of S-sulfonated keratin proteins, the foam made by freeze-drying a solution of S-sulfonated keratin proteins and the fibres made by extruding a solution of a S-sulfonated keratin protein.

1. A foam or adhesive material derived from S-sulfonated proteins. 2. A foam or adhesive material derived primarily from S-sulfonated wool keratin intermediate filament proteins. 3. A foam or adhesive material as claimed in claim 1 or claim 2 wherein the keratin proteins are reconstituted from a solution. 4. A method for making protein films by solvent casting a solution of S-sulfonated keratin proteins. 5. A method for improving the wet strength of a film produced by the method in claim 4, by introducing disulfide crosslinks into the film through a treatment with a reductant to remove the sulfonate group and reform disulfide links. 6. A method as claimed in claim 5 wherein the reductant is a thiol or a phosphine. 7. A method for improving the wet strength of the film produced by the method of claim 4, by introducing disulfide crosslinks into the film through a treatment with a reduced form of keratin or a reduced form of keratin peptide. 8. A method for improving the wet strength of the film produced by the method of claim 4, by protonating the S-sulfonate groups within the protein and any other polar groups through treatment of the film with acid. 9. A method for improving the wet strength of the film produced by the method of claim 4, by introducing crosslinks into the film through the use of common protein crosslinking agents, such as formaldehyde, glutaraldehyde and other species reactive with proteins. 10. A film made by the solvent casting of S-sulfonated keratin protein, and subsequently modified by the method claimed in claim 5. 11. A method for making protein films by solvent casting a solution containing a mixture of S-sulfonated keratin with a reduced form of keratin or keratin peptides. 12. A film produced by the method described in claim 11. 13. A method for making protein fibres by extruding a solution of S-sulfonated keratins into an aqueous solution containing salts and a reductant that causes the protein in solution to become insoluble. 14. A method as claimed in claim 13 wherein the reductant is a thiol or thioglycollate salt. 15. A method for making protein fibres by extruding a solution of S-sulfonated keratins into an aqueous solution containing salts, a reductant and a crosslinking agent that causes the protein in solution to become insoluble. 16. A method as claimed in claim 15 wherein the reductant is thiol or thioglycollate salt. 17. A method as claimed in claim 15 or claim 16 wherein the crosslinking agent is formaldehyde. 18. A method for making protein fibres by extruding a solution of S-sulfonated keratins into an aqueous solution containing salts and an acid that causes the protein in solution to become insoluble. 19. A method as claimed in claim 18 wherein the acid is sulfuric acid. 20. A method for making protein fibres by extruding a solution of S-sulfonated keratins into a hot environment and evaporating away the solvent rapidly, to leave a fibrous material behind. 21. Application of a chemical treatment method claimed in claim 5 to the fibrous product made by extruding a solution of S-sulfonated keratin into a hot environment and evaporating away the solvent rapidly, to leave a fibrous material. 22. Fibres derived from S-sulfonated keratin produced by methods described in claim 15. 23. A method for making protein foams by freeze drying a solution of S-sulfonated keratin protein. 24. A method for improving the wet strength of a foam produced by the method in claim 23, by introducing disulfide crosslinks into the foam through a treatment with reductant to remove the sulfonate group and reform disulfide links. 25. A method as claimed in claim 24 wherein the reductant is a thiol or a phosphine. 26. A method for improving the wet strength of the foam produced by the method in claim 23, by introducing disulfide crosslinks into the foam through a treatment with a reduced form of keratin or a reduced form of keratin peptide. 27. A method for improving the wet strength of the foam produced by the method in claim 23, by protonating the S-sulfonate groups within the protein and any other polar groups through treatment of the film with acid. 28. A method for improving the wet strength of the foam produced by the method in claim 23, by introducing crosslinks into the film through the use of common protein crosslinking agents, such as formaldehyde, glutaraldehyde and other species reactive with proteins. 29. A foam made by freeze drying a solution of S-sulfonated keratin protein and subsequently modified by introducing disulfide crosslinks into the foam through a treatment with a reductant to remove the sulfonate group and reform disulfide links. 30. A method for modifying the flexibility of films, foams or fibres by including in the keratin solution plasticizing agents, such as those from the glycerol and polyethylene glycol families. 31. An adhesive including a solution of S-sulfonated keratins. 32. An adhesive including a solution of S-sulfonated keratins and a reductant, such as a phosphine or a thiol that has greater wet strength properties than the adhesive described in claim 31. 33. A two pot adhesive formulation in which one component is a solution of S-sulfonated keratin protein and the other component is a solution of reduced keratins or reduced keratin pepetides, that on combination react to form a crosslinked network and subsequently an adhesive with greater wet strength to that described in claim 31. 34. A film, fibre, foam or adhesive material derived from keratin derivates of high molecular weight by a process involving a first stage digestion step of sulfonating a keratin source by oxidative sulfitolysis followed by a second stage repetitive aqueous extraction involving separation of soluble and insoluble keratin and subsequent re-extraction of the insoluble keratin to thereby produce a highly S-sulfonated keratin derivative. 35. A film, fibre, foam or adhesive material as claimed in claim 34 wherein the protein source is source is naturally occurring protein source. 36. A film, fibre, foam or adhesive material derived from highly S-sulfonated keratin intermediate filament proteins by a first stage digestion step of sulfonating a keratin source by oxidative sulfitolysis followed by a second stage repetitive aqueous extraction involving separation of soluble and insoluble keratin and subsequent re-extraction of the insoluble keratin to thereby produce a highly S-sulfonated keratin derivative. 37. A film, fibre, foam or adhesive material derived from soluble keratin peptides by the process claimed in claim 34. 38. A method for making protein films, fibres, foams or adhesive materials for modifying the flexibility of films, foams or fibres, by solvent casting a solution of S-sulfonated keratin protein that uses a combination of engineering solutions to produce a film, fibre, foam or adhesive material derived from S-sulfonated keratin proteins. 39. A film, fibre, foam or adhesive derived from a purified protein with little or no damage to the structural integrity of the protein as produced from an impure protein source by the process claimed in claim 34. 40. A film, fibre, foam or adhesive material obtained from a protein produced from a large scale recovery method as claimed in claim 34. 41. A film, fibre, foam or adhesive material made according to the method of claim 4.

FIELD OF THE INVENTION This invention relates to the preparation and use of soluble keratin derivatives in the production of a range of biopolymer materials such as films, fibres, foams and adhesives, and the improvement of those materials using further chemical treatments. BACKGROUND TO THE INVENTION Keratins are a class of structural proteins widely represented in biological structures, especially in epithelial tissues of higher vertebrates. Keratins may be divided into two major classes, the soft keratins (occurring in skin and a few other tissues) and hard keratins, forming the material of nails, claws, hair, horn and (in birds and reptiles) feathers and scales. The hard keratins may in turn be further subdivided into structural types described as α-keratin, β-keratin, or feather keratin. Keratins of the α and β types have different predominant structural motifs in their proteins, in the former case supramolecular structures based on the α-helix secondary structure of protein chains, and in the latter case on the β-pleated sheet motif. All keratins are characterised by a high level of the sulphur-containing diamino-acid cystine, which acts as a cross-linking point between protein chains. This feature of a high-level of interchain crosslinking through cystine gives the keratins, especially the hard keratins, their characteristics of toughness, durability, resistance to degradation, and desirable mechanical properties. Cystine contents vary widely in the keratins, which is reflected in their variation in mechanical properties. Wool and hair are examples of hard α-keratin. However, even in a given α-keratin, there are many classes of structural protein present, and the mechanical properties arise from a sophisticated supramolecular organisation of proteins of many different types to create a complex morphology with a correspondingly complex mechanical behaviour. An object of the invention is to provide biopolymer materials derived from soluble keratin derivatives and production methods for producing the biopolymer materials. SUMMARY OF THE INVENTION According to a broadest aspect of the invention there are provided materials derived from S-sulfonated keratin proteins, as herein defined, in the form of films, fibres, foams or adhesives. The S-sulfonated keratin proteins can be derived from wool keratin and be enriched in intermediate filament protein(s). According to another aspect of the invention there is provided a process method for the formation of films from S-sulfonated keratin proteins in which a solution of the proteins is cast and the solution solvents evaporated to leave a protein film. The solution(s) used can be aqueous based, including some proportion of organic solvents. The films produced by this process method are inherently soluble in water or the solvent mix used for casting the film. Another aspect of the invention describes a method for improving the wet strength of films, produced by the process method, by using chemical agents, such as thiols and phosphines, that remove the sulfonate group and allow the formation of disulfide bonds within the protein film. The difsulfide bonds provide the film with wet strength. Another method of improving the wet strength of a film, produced by the process method, is described in which acidic solutions are used to treat the protein film, and through a process of protonation of the sulfonate groups and any other suitable polar groups within the protein, the film becomes insoluble in water and has significant wet strength. Another aspect of the invention describes introduction of crosslinks into a film, produced by the process method, through the use of crosslinking agents such as those commonly used in protein modifications, that target a range of functional groups present within the protein. A further aspect of the invention is a method for the production of protein films using a solution comprising a combination S-sulfonated keratin proteins and reduced keratin proteins or peptides containing reactive cysteine residues. The two species combine to form a crosslinked keratin network and subsequently a protein film with good wet strength properties. This approach of combining S-sulfonated and reduced keratins can also be applied to the production of keratin fibres, foams and adhesives. A further aspect of the invention is a method for the production of keratin fibres through the extrusion of a solution comprising of S-sulfonated keratin proteins through a spinnerette into a coagulation bath that causes the protein to become insoluble. In particular the coagulation bath may contain reductants, such as thiols or phosphines, that cause the removal of the sulfonate group from the protein and lead to disulfide groups forming. In addition the coagulation bath can contain crosslinking agents, such as formaldehyde or glutaraldehyde, which cause the protein(s) to become insoluble on contact with the coagulation bath. In addition the coagulation bath can be at acidic pH, which also causes the protein solution to become insoluble. A further aspect of the invention is a method for the production of keratin fibres through the extrusion of a solution comprising of S-sulfonated keratin proteins through a spinnerette into a hot environment through which the solvent is rapidly removed and a fibrous keratin material remains. Fibres produced in this way can be further processed through wet chemical treatments to improve the wet strength of the fibres through the formation of crosslinks, or by protonation of the protein in manners similar to those described above for keratin films. A further aspect of the invention is a method for the production of keratin foams through the freeze drying of a solution of S-sulfonated keratin proteins. Foams produced in this way can be modified using similar methods to those described for keratin films, that is through the use of a reductant such as a thiol or phosphine to remove the S-sulfonate group, through the use of reduced keratin proteins or peptides to remove the S-sulfonate group, through the use of an acidic solution to protonate the S-sulfonate group and the protein, or through the use of crosslinking agents such as formaldehyde and glutaraldehyde to modify the protein. A further aspect of the invention is a range of keratin based adhesives, comprising at least in part a solution of S-sulfonated keratin proteins. These adhesives can be made to have superior wet strength properties through the use of reducing agents, such as thiols or phosphines. Alternatively wet strength can be imparted through the use of a reduced keratin protein or reduced keratin peptide, to create a crosslinked keratin network. These two sets of reagents can form a ‘two pot’ adhesive. The flexibility of the films, fibres, foams and adhesives produced by the methods described can be modified through the use of plasticizers such as those from the glycerol or polyethylene glycol families. According to further aspect of the invention there is provided a film, fibre, foam or adhesive material derived from keratin derivates of high molecular weight as described and claimed in PCT/NZ02/00125 whereby the process includes a first stage digestion step of sulfonating a keratin source by oxidative sulfitolysis followed by a second stage repetitive aqueous extraction involving separation of soluble and insoluble keratin and subsequent re-extraction of the insoluble keratin to thereby produce a highly S-sulfonated keratin derivative. The protein keratin source can be a naturally occurring protein source. According to yet a further aspect of the invention there is provided a film, fibre, foam or adhesive material derived from either highly S-sulfonated keratin intermediate filament proteins, soluble keratin peptides or a purified protein with little or no damage to the structural integrity of the protein as produced from an impure protein source as described above. According to yet a further aspect of the invention there is provided a combination of engineering solutions to produce a film, fibre, foam or adhesive material derived from S-sulfonated keratin proteins. According to yet another aspect of the invention there is provided a film, fibre, foam or adhesive material obtained from a protein produced from a large scale recovery method as described and claimed in PCT/NZ02/00125. DESCRIPTION OF PREFERRED EXAMPLES The features of this invention specifically cite some methods and applications based on hard α-keratins from wool. However, the principle can equally well apply to alternative α-keratins, or any source of keratin which is able to yield proteins of the intermediate filament (IF) type. Similar preparative methods have been applied by the applicants to other keratin sources such as feathers, to produce materials equally well suited for some of the applications described below. The features of this invention are intended to cover the utilisation of such keratins as well, in applications which are not dependent on the presence of proteins of the α-type (IF proteins). This includes applications where preparations based on β or feather keratin may be combined with IF proteins. The characteristics of toughness and insolubility typical of hard keratins are desirable properties in many industrial materials. In addition, keratin materials are biodegradable and produced from a sustainable resource and as such they have significant potential for use as a substitute for oil-based polymers in many applications, such as films, fibres and adhesives. Their use in cosmetics and personal care applications is already well established and an extension to medical materials is proposed using materials such as those outlined in this specification. Wool represents a convenient source of hard α-keratins, although any other animal fibre, or horns, or hooves, would serve equally well as a source of the desired proteins. Wool is composed of approximately 95% keratin, which can be broadly divided into three protein classes. The intermediate filament proteins are typically of high molecular weight (45-60 kD), with a partly fibrillar tertiary structure and a cysteine content of the order of 6%. They account for approximately 58% of the wool fibre by mass although only part of this mass is actually helix-forming in structure. The high- and ultra-high-sulphur proteins, approximately 26% of the wool fibre, are globular in structure, have a molecular weight range of 10-40 kD and can contain cysteine levels up to 30 mol %. The high-glycine-tyrosine proteins are a minor class comprising 6% of the wool fibre, have molecular weights of the order of 10 kD and are characterised by their high content of glycine and tyrosine amino acid residues. Proteins from the different classes of wool keratins possess characteristics that will give them unique advantages in specific applications. This invention pertains largely to the use of intermediate filament proteins, and the use of them to produce films, fibres, foams and adhesives. Nonetheless the other non-fibrillar proteins have applications in their own right in more restricted fields. Likewise feather keratins, derived by extractive procedures similar to those applied to wool, have specific valuable applications in certain areas as defined below, but do not contain the IF proteins deemed to be desirable in some end-uses. The soluble keratin derivatives used in the method and subsequent chemical treatments described in this specification were obtained from wool or feathers either by reduction using sodium sulphide or by oxidative sulphitolysis. An example of process for the production of soluble keratin derivates is described in the applicant's PCT/NZ02/00125 patent specification, the description of which is incorporated herein by way of reference and outlined above. The reduction of wool or feather keratin using sodium sulphide involves dissolution in a dilute sodium sulphide solution (or other sulphide solution). The combination of high solution pH and sulphide ion concentration results in the keratin being degraded to some extent, with possible hydrolysis of some of the peptide bonds occuring, as well as the disulphide bonds being reduced to yield protein rich in thiol and polysulphide functionality. The rich thiol function of the isolated protein can be confirmed using reagents such as nitroprusside. Oxidative sulfitolysis involves the conversion of the cysteine in keratin to S-sulfocysteine by the action of sodium sulphite and an oxidant. No peptide hydrolysis occurs and the solublised keratin has a molecular weight distribution very similar to that in the unkeratinised state. Proteins derivatised in this way are referred to herein as S-sulfonated keratin proteins throughout the process methods, and are isolated from an oxidative sulfitolysis solution in the acid form, that is as kerateine S-sulfonic acid. S-sulfonated keratin protein is soluble only as the salt, which can be prepared by the addition of base to the S-sulfonated keratin protein. For the preparation of films from S-sulfonated wool keratin Intermediate filament protein it is convenient to prepare a 5% protein solution by suspending S-sulfonated keratin protein in water and adding base such as sodium hydroxide or ammonia to give a final composition of 1 ml 1M NaOH, or equivalent base, per gram of protein to a give a solution with a final pH In the range 9-10. Casting this solution onto a flat surface, such as a glass plate, and allowing the water and/or ammonia to evaporate at room temperature results in the formation of a keratin film. These keratin films have a high degree of clarity and have the physical properties detailed in Table 1 below. In untreated films there is likely to be little or no covalent bonding occurring between keratin proteins within the material as the disulphide bonds present in the original keratin have been converted to S-sulfocysteine. The hydrogen bonding and other non-covalent interactions occurring between the proteins are clearly significant, as the tensile strength of the material in the dry state is relatively high. The hydrogen bonding type interactions are overcome in the presence of water, reflected by the large decrease in tensile strength under wet conditions. The physical properties of the materials derived from S-sulfonated keratin proteins depend to a large extent on the nature of the interactions between the proteins comprising the material. These can be affected significantly by a range of chemical treatments, with one of the most significant of these treatments being the use of a reductant to remove the sulfonate group from the protein to leave a thiol function. Under atmospheric conditions, or in the presence of an oxidant such as dilute hydrogen peroxide, these thiol functions recombine to form disulfide bonds and return the chemical nature of the keratin material to one much closer to the original form, that is proteins containing a high proportion of cystine disulfide links. Treatment with a reducing agent, such as ammonium thioglycollate at pH 7 for 30 minutes, or tributylphosphine for 24 hours, is an effective way to remove the sulfonate function from S-sulfonated keratin. This can be confirmed using infra-red studies as the S-sulfonate group gives rise to a strong, sharp absorbance at 1022 cm−1 which is observed to disappear on exposure of the S-sulfonated to the reagents described. In one aspect of the invention the reductant used to remove the sulfonate function and introduce cystine disulfides is itself a keratin protein. Reduced keratin proteins, or keratin peptides, containing the thiol function can be readily produced by the process of sulphide dissolution described above. Keratin proteins prepared in this way contain the cysteine reducing group which may covalently attach directly to the S-sulfonate group to form a cystine disulfide. In this way a crosslinked keratin network is formed without the use of other agents. In the case of S-sulfonated wool keratin intermediate filament protein films reductive treatment significantly improves the wet strength properties of the material, as indicated by Table 1. The material retains a good degree of flexibility when wet. Other chemical treatments also affect the film properties. Treatment with an acid, such as 1M hydrochloric acid, protonates the basic groups within the protein and converts the S-sulfocysteine, present as the sodium or ammonium salt, to S-sulfonic acid. This can improve the hydrogen bonding interactions, as the wet strength of the film clearly improves and no covalent bonds have been introduced. The S-sulfonate functionality, as determined by infra-red absorption, remains intact. Standard protein crosslinking treatments, such as the use of formaldehyde or glutaraldehyde, also improve the wet strength of the film, and introduce rigidity in both the wet and dry states. This is achieved through crosslinking the proteins in a way that does not specifically target the sulfonate functionality and many of the amino acid residues containing nucleophilic side groups such as lysine, tyrosine and cystine may be involved in crosslinking. TABLE 1 Strength, extension and swelling data for protein films. Dry strength Wet strength % extension % extension Film and ×10−7Nm−2 ×10−7Nm−2 at break dry at break wet treatment (cv) (cv) (cv) (cv) Untreated 1.3 (11) 0.06 (15) 151 (24) 227 (20) Reductant 5.9 (7) 2.2 (21) 6 (16) 208 (15) Acid 6.1 (3) 1.6 (14) 6 (31) 387 (6) Glutaraldehyde 5.0 (8) 1.9 (14) 4 (11) 4 (8) Formaldehyde 2.8 (16) 0.96 (8) 7 (41) 13 (25) cv = coefficient of variation, %, n = 5 Solutions of S-sulfonated keratin proteins can be used to produce reconstituted keratin fibres by a variety of extrusion methods. Using a wet spinning approach, similar in concept to the spinning of viscose rayon in which a solution of a material is extruded into a coagulation bath in which the material is insoluble, solutions of S-sulfonated keratin proteins can be extruded into solutions containing chemicals that make the protein become insoluble. Any of the three approaches described for chemically treating S-sulfonated keratin films can be employed in the coagulation bath used to generate keratin fibres. By employing reductants, such as ammonium thioglycollate, in the coagulation bath, the S-sulfonated keratin proteins are converted back to keratins containing cystine disulfides through a wet spinning process, thereby producing reconstituted keratin fibres that have a multitude of disulfide links and good physical properties. By using acidic conditions the S-sulfonated keratin proteins become protonated and subsequently insoluble. By using crosslinking agents, such as formaldehyde or glutaraldehyde, the protein also becomes insoluble. The coagulation baths can also contain high concentrations of salt or solvent to assist the process of fibre formation. In each case precipitation of the extruded protein occurs, possibly only in an outer skin of the extruded filament, and a fibre is formed with sufficient mechanical integrity to allow it to be collected from the coagulation bath and subjected to further treatments such as drawing or other chemical processes. A dry spinning approach can also be employed for the production of reconstituted keratin fibres. The method is similar in concept to the formation of S-sulfonated keratin films described above, in which solvent is removed from an S-sulfonated keratin protein solution and a keratin material remains. In the formation of fibres this approach is employed by extruding a solution of S-sulfonated keratin protein that has a composition typically of 6-10% protein and up to 50% of a solvent such as acetone, ethanol or isopropylalcohol, with the remaining portion of the solution being water and a base such as sodium hydroxide to give a pH of 9-10. This solution is extruded downwards into a chamber containing a continuous downward hot air stream which causes the solvent to rapidly evaporate, and an S-sulfonated keratin fibre remains. Subsequent chemical treatments, such as the reductive, acidic or crosslinking treatments described for keratin films described above, can be employed to impart wet strength properties to keratin fibres produced by this method. Solutions of S-sulfonated keratins can be used to prepare highly porous protein foams. This is achieved by freeze drying a solution, prepared as described for the casting of keratin films. In order to produce foams the solution is cast onto an appropriate dish or surface and frozen, prior to being freeze dried. The resulting porous network is a foam of S-sulfonated keratin protein. As with the film and fibre forms of this material, applying chemical modifications to the protein has a significant effect on the wet properties of the material. In particular, applying reductants such as ammonium thioglycollate or tributylphosphine under similar conditions to those applied to the protein film, results in the removal of the S-sulfonate group and the formation of a network of disulfide bonds, and subsequently decreases the solubility and increases in the wet strength of the foam. A reduced form of keratin can also be used to similar effect, again resulting in the formation of foam comprising of a keratin protein interconnected through a network of disulfide bonds. Treatment of the foam with an acid, such as 1M hydrochloric acid, results in protonation of any available groups within the material, such as the S-sulfonate group, and a subsequent increase in the wet strength of the material. Crosslinking agents, such as formaldehyde or glutaraldehyde, can also be used to significantly modify the wet properties of the foam. All the above applications relate preferentially to the case of IF-type proteins prepared from hard α-keratins such as wool, but other applications such as the following one can use keratins from other sources, such as feather keratin. Solutions of keratins obtained from wool or feathers by either reduction using sodium sulphide or by oxidative sulphitolysis as described above show significant adhesive properties in various applications. However, the wet strength of both of these adhesives is limited. Keratin made soluble by sulphide reduction is degraded to some extent and contains protein chains of lower molecular weight than in the original wool. S-sulfonate derived keratin polymers contain no covalent crosslinks and hydrogen bonding interactions are weakened significantly in water, as demonstrated by the keratin films described above. However the wet strength and adhesive properties can be greatly enhanced by reforming disulphide cross-links, by adding an oxidant in the case of sulphide-derived proteins, or a reducing agent in the case of the S-sulfonated keratin proteins. By such means very effective adhesive bonding can be achieved, for example in wood-particle composites bonded with oxidised sulphide-derived proteins. A particular feature of this invention relates to the recognition that the sulphide-derived protein and the S-sulfonated keratin proteins can be used in conjunction to create highly cross-linked structures with very superior properties. As noted above, the former class of protein can be crosslinked by oxidation, and the latter by reduction. The two protein classes, one being in a reduced state and the other in an oxidised state, will when mixed form a self-crosslinking system. In effect, in such a system, an addition of sulphide-derived protein is acting as a reductant and crosslinking agent to convert the S-sulfonate groups in the other component to disulfide bonds. Such a two-pot self-crosslinking system is a particular aspect of the invention which will have applications in many forms of product, and has the advantage of eliminating volatile low molecular weight materials and the necessity to use solvents in some forms of product fabrication. Thus it is to be expected that such composites can be formed from mixtures of solids or viscous dispersions without shrinkage. In such two-component systems, the respective sulphide-derived and S-sulfonate keratin proteins can be produced from the same or different keratin sources. For example, if the mechanical property characteristics associated with IF proteins were desirable, the S-sulfonated keratin protein could be derived from a hard α-keratin such as wool, and the sulphide-derived protein from another keratin source such as feathers. An alternative two-component system is one which utilises a reductant from the thiol or phosphine family in addition to S-sulfonated keratin proteins. Combining solutions of these two materials results in the removal the sulfonate group and formation of cystine disulfudes in the manner described above for keratin films and fibres. This gives rise to an adhesive formulation with good wet strength properties. By such means, proteins from sources other than hard keratins can be incorporated into many of the product classes described above, and therefore the features in this invention encompass keratin sources in general and are not restricted to hard α-keratins. Polar, soluble reagents of low molecular weight, such as polyethylene glycol or glycerol, can be employed as plasticising agents to give keratin materials flexibility. These agents are best employed by inclusion in the keratin solutions used as the starting point for the formation of films, fibres or adhesives. EXAMPLES Example 1a Preparation of a Keratin Film In order to prepare an S-sulfonated keratin film, a 5% keratin protein solution was prepared by suspending 0.5 g S-sulfonated wool keratin intermediate filament protein in water, followed by the gradual addition of 0.5 ml of 1M sodium hydroxide to the vigorously stirred solution over approximately 2 hours. The pH of the solution was carefully monitored and observed to elevate to ˜pH10 upon immediate addition of base, and gradually fall as the base was absorbed by dissolution of the protein. A final pH of 9.5 was obtained. The protein solution was centrifuged at 34,000 g to remove any insoluble material and the resulting solution was cast onto a 100 mm square petri dish and allowed to dry under ambient conditions. Following drying a clear protein film remained which could be easily removed from the petri dish. Example 1b Disulfide Crosslinking of Protein Films In order to improve the wet strength of S-sulfonated keratin films, disulfide crosslinks were introduced to the film by immersing the films produced in Example 1a in a solution containing a reducing agent. One example is a solution comprising 0.25M ammonium thioglycollate and 0.1M potassium phosphate buffer adjusted to pH 7.0. Another example is a solution comprising 1M thioglycollic acid. Another example is a solution containing 85 microlitres of tributyl phosphine in 20 ml of 10% (v/v) 0.2M borate buffer in dimethyl formamide buffered to pH 9.0. Following immersion in the solution with gentle agitation for 30 minutes in the case of the thiols and 24 hours in the case of the phosphine, the keratin film was removed, rinsed briefly with water and allowed to dry under ambient conditions. Example 1c Protonation of Protein Films In order to improve the wet strength of S-sulfonated keratin films, acid was used to protonate all available sites on the proteins. This was achieved through immersion of the film produced in Example 1a in 1M hydrochloric acid for 30 minutes. Following a brief wash with water the film was allowed to dry under ambient conditions. Example 1d Non-Disulfide Crosslinking of Protein Films In order to improve the wet strength of S-sulfonated keratin films crosslinking agents were used to chemically bond proteins together. In one case this was achieved through the use of a solution of 8% formaldehyde in 0.1M phosphate buffer at pH 7.0. The film was immersed in this solution for 30 minutes, washed briefly with water and allowed to dry under ambient conditions. In another case, crosslinking was achieved through the use of a solution of 5% glutaraldehyde in 0.1M phosphate buffer at pH7.0. The film was immersed in this solution for 30 minutes, washed briefly with water and allowed to dry under ambient conditions for 30 minutes. Example 1e Plasticising of Protein Films In a variation of Example 1a, flexible protein films are made by incorporating glycerol or polyethylene glycol into the protein solution described in Example 1a at a level up to 0.2 g per g of protein prior to casting the film. The resulting films have a greater flexibility, as determined by extension at break measurements, than the analogous films containing no plasticiser. Example 2a Production of Keratin Fibres Through Wet Spinning and Disulfide Crosslinking In order to prepare fibres derived from S-sulfonated keratin proteins a spinning dope was prepared in a similar manner to that prepared in Example 1a, with the difference being that for the extrusion of fibres, the concentration of protein in the solution was in the range 6-15%. A plasticiser, such as those described in Example 1e, was added to the spinning dope. Following centrifuging to remove solids and entrained air the dope was forced, using a positive displacement pump such as a syringe or gear pump, or air pressure, through a spinnerette into a coagulation bath. The coagulation bath had a composition of 1M ammonium thioglycollate, 0.4M sodium phosphate, 0.25M sodium sulfate, 2% glycerol all set to pH 7.0. Example 2b Production of Keratin Fibres Through Wet Spinning and Non-Disulfide Crosslinking In a variation to Example 2a, fibres were extruded into a coagulation bath with a composition of 0.25M ammonium thioglycollate, 0.1M sodium phosphate, 8% formaldehyde and 2% glycerol. This served to form tough fibres without forming disulfide bonds, as shown by infra red analysis which clearly indicated the presence of the S-sulfonate group. Subsequent treatment of the fibres with solutions containing reductants, such as ammonium thioglycollate at a concentration of 0.25M and a pH of 7.0 with 0.1M potassium phosphate buffer, was sufficient to remove the S-sulfonate group and reform disulfide bonds. Example 2c Production of Keratin Fibres Through Dry Spinning In order to produce fibres through a dry spinning process, first a spinning dope was prepared in a similar manner to that described in Example 2a. In variation to the dope preparation a solvent such as acetone or isopropylacohol was added to the dope to give a final composition protein in the range 6-15%, solvent in the range 20-50% and plasticiser in the range 1-3%. The dope was extruded through a spinnerette, using similar technology to that described in Example 2a, downwards into a chamber with a continuous downwards hot air stream. This caused the solvent to rapidly evaporate leaving a keratin fibre. Subsequent wet processing of the fibre, through the use of acid, reductant and crosslinking agents, of the type described in Examples 1, was used to improve the wet strength properties of the fibre. Example 3a Production of a Keratin Foam A solution of S-sulfonated keratin protein, prepared to a protein concentration of 5% as described in Example 1a, was used to create a keratin foam by freezing the solution in a 100 mm square petri dish and freeze drying the resulting solid. Example 3b Chemical Modification of Keratin Foam Chemical solutions containing reductants, acids or crosslinking agents, of the described in Examples 1b, c, and d were applied to the keratin foam, in a manner identical to that described for the keratin film. A keratin foam with significantly reduced solubility and improved wet strength resulted. Example 4a Application of a Keratin Adhesive to Bind Wood A solution of S-sulfonated keratin protein, prepared to a protein concentration of 5% as described in Example 1a, was used to bind woodchips by mixing the keratin solution with woodchips in a ratio of 1 ml solution per gram of woodchips. The mixture was then pressed and heated in a similar manner to the production of commercial urea-formaldehyde bound particle board (3 MPa, 180° C., 300 s), and a solid wood keratin composite resulted. Example 4b Application of a Keratin Adhesive to Bind Textiles A solution of S-sulfonated keratin protein, prepared to a protein concentration of 5% as described in Example 1a, was used to bind woollen textiles by coating one of the textile surfaces with the keratin solution and pressing another textile onto the coated textile with the use of a pinch roller system. Following the drying of the composition at elevated temperature a bonded textile was produced. In a small variation, plasticiser was included in the protein solution, in a manner similar to that described in example 1d, to produce a flexible adhesive. Example 4c A Two Pot Adhesive System Using a Reductant An adhesive was made by combining a solution of S-sulfonated keratin protein, prepared in the manner described in Example 1a, with a solution of a reductant. The reductant solution contained 10% triscarboxyethylphosphine hydrochloride. When mixed in a ratio of 10 parts keratin solution to 1 part reductant solution and applied to two wood surfaces this two pot formulation dried over 12 hours to create a strong bond between the wooden surfaces that remained strong in a moist environment. In a variation of this application a reductant solution was used which contained 0.25M ammonium thioglycollate buffered to pH 7.0 with 0.1M potassium phosphate. When mixed in a ratio of 10 parts keratin solution to 1 part reductant solution and applied to two wood surfaces this two pot formulation dried over 12 hours to create a strong bond between the wooden surfaces that remained strong in a moist environment. Example 4d A Two Pot Adhesive System Using Two Forms of Keratin An adhesive was made by combining a solution of S-sulfonated keratin protein, prepared in the manner described in Example 1a, with a reduced keratin peptide solution which contained sulphur amino acids primarily in the form of cysteine and had a compositon of 5% protein and 2% sodium sulphide. When mixed in equal parts and applied to two wood surfaces this two pot formulation dried over 12 hours to create a strong bond between the wooden surfaces that remained strong in a moist environment. In a variation of this application, the reduced keratin peptide was used in the form of a solid and mixed with the S-sulfonated keratin protein solution in a ratio of 5 parts S-sulfonated keratin solution to 1 part reduced keratin solid and applied to two wood surfaces this two pot formulation dried over 12 hours to create a strong bond between the wooden surfaces that remained strong in a moist environment. Where in the description particular integers are mentioned it is to be appreciated that their equivalents can be substituted therefore as if they were set forth herein. Thus by the invention there is provided a method for the preparation and use of soluble keratin derivatives in the production of a range of biopolymer materials such as films, fibres, foams and adhesives, and the improvement of those materials using further chemical treatment. Particular examples of the invention have been described and it is envisaged that improvements and modifications can take place without departing from the scope of the attached claims.

<SOH> BACKGROUND TO THE INVENTION <EOH>Keratins are a class of structural proteins widely represented in biological structures, especially in epithelial tissues of higher vertebrates. Keratins may be divided into two major classes, the soft keratins (occurring in skin and a few other tissues) and hard keratins, forming the material of nails, claws, hair, horn and (in birds and reptiles) feathers and scales. The hard keratins may in turn be further subdivided into structural types described as α-keratin, β-keratin, or feather keratin. Keratins of the α and β types have different predominant structural motifs in their proteins, in the former case supramolecular structures based on the α-helix secondary structure of protein chains, and in the latter case on the β-pleated sheet motif. All keratins are characterised by a high level of the sulphur-containing diamino-acid cystine, which acts as a cross-linking point between protein chains. This feature of a high-level of interchain crosslinking through cystine gives the keratins, especially the hard keratins, their characteristics of toughness, durability, resistance to degradation, and desirable mechanical properties. Cystine contents vary widely in the keratins, which is reflected in their variation in mechanical properties. Wool and hair are examples of hard α-keratin. However, even in a given α-keratin, there are many classes of structural protein present, and the mechanical properties arise from a sophisticated supramolecular organisation of proteins of many different types to create a complex morphology with a correspondingly complex mechanical behaviour. An object of the invention is to provide biopolymer materials derived from soluble keratin derivatives and production methods for producing the biopolymer materials.

<SOH> SUMMARY OF THE INVENTION <EOH>According to a broadest aspect of the invention there are provided materials derived from S-sulfonated keratin proteins, as herein defined, in the form of films, fibres, foams or adhesives. The S-sulfonated keratin proteins can be derived from wool keratin and be enriched in intermediate filament protein(s). According to another aspect of the invention there is provided a process method for the formation of films from S-sulfonated keratin proteins in which a solution of the proteins is cast and the solution solvents evaporated to leave a protein film. The solution(s) used can be aqueous based, including some proportion of organic solvents. The films produced by this process method are inherently soluble in water or the solvent mix used for casting the film. Another aspect of the invention describes a method for improving the wet strength of films, produced by the process method, by using chemical agents, such as thiols and phosphines, that remove the sulfonate group and allow the formation of disulfide bonds within the protein film. The difsulfide bonds provide the film with wet strength. Another method of improving the wet strength of a film, produced by the process method, is described in which acidic solutions are used to treat the protein film, and through a process of protonation of the sulfonate groups and any other suitable polar groups within the protein, the film becomes insoluble in water and has significant wet strength. Another aspect of the invention describes introduction of crosslinks into a film, produced by the process method, through the use of crosslinking agents such as those commonly used in protein modifications, that target a range of functional groups present within the protein. A further aspect of the invention is a method for the production of protein films using a solution comprising a combination S-sulfonated keratin proteins and reduced keratin proteins or peptides containing reactive cysteine residues. The two species combine to form a crosslinked keratin network and subsequently a protein film with good wet strength properties. This approach of combining S-sulfonated and reduced keratins can also be applied to the production of keratin fibres, foams and adhesives. A further aspect of the invention is a method for the production of keratin fibres through the extrusion of a solution comprising of S-sulfonated keratin proteins through a spinnerette into a coagulation bath that causes the protein to become insoluble. In particular the coagulation bath may contain reductants, such as thiols or phosphines, that cause the removal of the sulfonate group from the protein and lead to disulfide groups forming. In addition the coagulation bath can contain crosslinking agents, such as formaldehyde or glutaraldehyde, which cause the protein(s) to become insoluble on contact with the coagulation bath. In addition the coagulation bath can be at acidic pH, which also causes the protein solution to become insoluble. A further aspect of the invention is a method for the production of keratin fibres through the extrusion of a solution comprising of S-sulfonated keratin proteins through a spinnerette into a hot environment through which the solvent is rapidly removed and a fibrous keratin material remains. Fibres produced in this way can be further processed through wet chemical treatments to improve the wet strength of the fibres through the formation of crosslinks, or by protonation of the protein in manners similar to those described above for keratin films. A further aspect of the invention is a method for the production of keratin foams through the freeze drying of a solution of S-sulfonated keratin proteins. Foams produced in this way can be modified using similar methods to those described for keratin films, that is through the use of a reductant such as a thiol or phosphine to remove the S-sulfonate group, through the use of reduced keratin proteins or peptides to remove the S-sulfonate group, through the use of an acidic solution to protonate the S-sulfonate group and the protein, or through the use of crosslinking agents such as formaldehyde and glutaraldehyde to modify the protein. A further aspect of the invention is a range of keratin based adhesives, comprising at least in part a solution of S-sulfonated keratin proteins. These adhesives can be made to have superior wet strength properties through the use of reducing agents, such as thiols or phosphines. Alternatively wet strength can be imparted through the use of a reduced keratin protein or reduced keratin peptide, to create a crosslinked keratin network. These two sets of reagents can form a ‘two pot’ adhesive. The flexibility of the films, fibres, foams and adhesives produced by the methods described can be modified through the use of plasticizers such as those from the glycerol or polyethylene glycol families. According to further aspect of the invention there is provided a film, fibre, foam or adhesive material derived from keratin derivates of high molecular weight as described and claimed in PCT/NZ02/00125 whereby the process includes a first stage digestion step of sulfonating a keratin source by oxidative sulfitolysis followed by a second stage repetitive aqueous extraction involving separation of soluble and insoluble keratin and subsequent re-extraction of the insoluble keratin to thereby produce a highly S-sulfonated keratin derivative. The protein keratin source can be a naturally occurring protein source. According to yet a further aspect of the invention there is provided a film, fibre, foam or adhesive material derived from either highly S-sulfonated keratin intermediate filament proteins, soluble keratin peptides or a purified protein with little or no damage to the structural integrity of the protein as produced from an impure protein source as described above. According to yet a further aspect of the invention there is provided a combination of engineering solutions to produce a film, fibre, foam or adhesive material derived from S-sulfonated keratin proteins. According to yet another aspect of the invention there is provided a film, fibre, foam or adhesive material obtained from a protein produced from a large scale recovery method as described and claimed in PCT/NZ02/00125. detailed-description description="Detailed Description" end="lead"?

20040301

20081216

20050310

91026.0

KOSSON, ROSANNE

PRODUCTION OF BIOPOLYMER FOAM AND ADHESIVE MATERIALS FROM SOLUBLE S-SULFONATED KERATIN DERIVATIVES

SMALL

ACCEPTED

ACCEPTED

Pulse radar arrangement

A pulse radar system has a high-frequency source, which supplies a continuous high-frequency signal and is connected on the one side with a transmission-side pulse modulator and on the other side with two separately controllable pulse modulators in at least one receive path. Mixers are situated downstream from pulse modulators, respectively. The mixers evaluate a radar pulse reflected by an object together with the signal of the high-frequency source. The pulse radar system allows different modes of operation that may be changed in a simple manner.

1-15. (Canceled). 16. A pulse radar system comprising: a high-frequency source for emitting a continuous high-frequency signal; a transmission-side pulse modulator coupled on a first side of the high-frequency source for emitting radar pulses; at least two reception-side mixers; and at least two separately controllable reception-side pulse modulators coupled on a second side of the high-frequency source in reception branches, the at least two pulse modulators being adapted to switch the continuous signal of the high-frequency source in each case to one of the at least two reception-side mixers. 17. The pulse radar system according to claim 16, wherein the system is for a close-range pulse radar application for a motor vehicle. 18. The pulse radar system according to claim 16, further comprising two pulse signal sources, each of which including a separate time-delay circuit, the two pulse signal sources being for controlling the reception-side pulse modulators. 19. The pulse radar system according to claim 16, further comprising a shared pulse signal source for controlling the reception-side pulse modulators, the shared pulse signal source being connected with each of separate time-delay circuits for each one of the reception-side pulse modulators. 20. The pulse radar system according to claim 19, wherein the shared pulse signal source also provides a pulse signal for the transmission-side pulse modulator. 21. The pulse radar system according to claim 16, further comprising a quadrature power splitter situated between a receiving antenna and the reception-side mixers, so that an in-phase received signal is supplied to one of the mixers and a quadrature received signal is supplied to another of the mixers. 22. The pulse radar system according to claim 16, further comprising a signal splitter device for splitting a continuous signal of the high-frequency source to the transmission-side pulse modulator and to the reception-side pulse modulators. 23. The pulse radar system according to claim 16, further comprising a separate pulse signal source for the transmission-side pulse modulator. 24. The pulse radar system according to claim 16, further comprising at least one further receive path with corresponding receiving antennas, reception-side mixers, reception-side pulse modulators, further signal splitters and pulse signal sources. 25. The pulse radar system according to claim 24, wherein the reception-side pulse modulators of the at least one further receive path are connected via the further signal splitters, which are downstream from the high-frequency source. 26. The pulse radar system according to claim 24, further comprising a plurality of receive paths and a plurality of evaluation devices for evaluating a plurality of distance cells at the same time. 27. The pulse radar system according to claim 16, further comprising transmission-side and reception-side pulse signal sources phase-coupled to one another. 28. The pulse radar system according to claim 16, further comprising transmission-side and reception-side pulse signal sources, the reception-side pulse signal sources being phase-coupled among one another, and further comprising a plurality of receive paths. 29. The pulse radar system according to claim 16, wherein pulse duty factors of radar pulses in a transmit path and at least one receive path are different. 30. The pulse radar system according to claim 16, wherein radar pulses are PN coded, and the reception-side pulse modulators are controlled using a reception sequence corresponding to a set distance. 31. The pulse radar system according to claim 16, wherein a cross echo analysis is provided, such that, with a plurality of receive paths, a reception-side device is set to a PN code of a neighboring device. 32. The pulse radar system according to claim 16, wherein a superimposition of two orthogonal codes is provided in a transmit path, and a reception branch/path evaluates in each case only one of transmitted orthogonal signals.

FIELD OF THE INVENTION The present invention is based on a pulse radar system, in particular for close-range pulse radar applications in motor vehicles. BACKGROUND INFORMATION Radar sensors are used in automotive engineering for measuring the distance to objects and/or the relative speed with respect to such objects outside of the motor vehicle. Examples of objects include preceding or parked motor vehicles, pedestrians, bicyclists, or devices within the vehicle's surroundings. The pulse radar functions, for example, at 24,125 GHz and may be used for the following functions, stop & go, precrash, blind spot detection, parking assistant, and backup aid. FIG. 1 shows a schematic representation of a radar device having a correlation receiver of the related art. A pulse generation 302 causes a transmitter 300 to transmit a transmission signal 306 via an antenna 304. Transmission signal 306 hits a target object 308 and is reflected. Received signal 310 is received by antenna 312. This antenna 312 may be identical to antenna 304. After received signal 310 is received by antenna 312, the signal is transmitted to receiver 314 and subsequently supplied via a unit 316 having low pass and analog/digital conversion to a signal evaluation 318. The special feature of a correlation receiver is that receiver 314 receives a reference signal 320 from pulse generation 302. Received signals 310, which are received by receiver 314, are mixed in receiver 314 with reference signal 320. As a result of the correlation, the time delay from the outside to reception of the radar impulses may be used as a basis for determining the distance of a target object, for example. A similar radar device is known from German Patent No. DE 199 26 787. In this context, a transmission switch is switched on and off by the impulses of a generator so that a high-frequency wave generated by an oscillator and conducted via a fork to the transmission switch is switched through to the transmission antenna during the pulse duration. A reception unit also receives the output signal of the generator. The received signal, i.e., a radar pulse reflected by an object, is combined with the oscillator signal, which reaches the mixer via a reception switch, and evaluated during a predefined time period. U.S. Pat. No. 6,067,040 also uses a transmission switch that is switched on and off by generator impulses. Separate paths for l/Q signals are provided for reception of the reflected radar pulses. Also in this instance, the received signal is only mixed and evaluated during a predefined time period. SUMMARY OF THE INVENTION The measures of the present invention enable the enhancement of the performance of known pulse radar systems. In the case of the solution according to U.S. Pat. No. 6,067,040, a reception-side pulse modulator or pulse switch is positioned upstream from a power splitter for splitting the LO (local oscillator) signal to the mixers in the reception-side IQ branches. This has the disadvantage that it is not possible to realize a multi-receiver system or to simultaneously evaluate a plurality of different reception cells. However, in the case of the solution of the present invention, two separately controllable, reception-side pulse modulators are provided via which the continuous signal of the high-frequency source, which also controls the transmission-side pulse modulator, may be switched to one respective reception-side mixer. This means that in this instance, as opposed to U.S. Pat. No. 6,067,040, the signal of the high-frequency source may be applied to every mixer in a reception branch at different instants, each mixer also being able to be connected to the signal of the high-frequency source for different durations. In this manner, different modes of operation are made possible and may also be changed quickly and flexibly. Such a change may be effected simply by varying the delay time of the time-delay circuits via which the reception-side pulse modulators may be controlled. A plurality of operating modes may also run automatically in a consecutive order according to a predefined scheme. If both pulse modulators/switches are switched at the same time, the receive path, which includes two reception branches of the pulse radar system, functions in the usual manner. If the switches are switched at different times or they have opening times of different durations, all capabilities of a multi-receiver system are available. A plurality of settings or modes may be set. A previous detection range of, for example, 7 m may now be divided, e.g. into 0 to 4 m and 4 to 7 m. An expansion of the detection range does not automatically result in an extension of the measurement times. One channel is able to cover the 0 to 4 m range, while the other channel having a longer measurement time, for example, covers the 7 to 14 m range. In special cases, the radar system of the present invention functions as a customary I/Q demodulator. Furthermore, parallel to the distance measurement, a channel may be responsible for the CV (closing velocity) measurement, which may be used to determine radial velocity. Therefore, in particular: a plurality of receiving channels may be operated in parallel; I/Q demodulator operation and individual operation are rendered possible; a plurality of antennas may be operated in parallel (multi-receiver principle); the pulse duty factor may be selected to be different in the transmit and receive paths; the pulse duty factor may be one (Doppler radar only); the radar pulses may vary with respect to their repetition frequency and/or pulse duration to increase the level of interference protection; a plurality of reception cells may be evaluated at the same time when using double or triple transmission pulse power; the power of the reception pulses may be split among a plurality of receive paths in the case of target objects that are too strong in close range so that overloading of subsequent received-signal amplifiers is prevented; a PN code may be provided with a reception sequence corresponding to the set distance; a cross echo analysis is possible; the superimposition of two orthogonal codes in the transmit path may be provided as well as evaluation of in each case only one of the transmitted orthogonal codes per reception branch on the reception side. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a schematic representation of a radar device of the related art. FIG. 2 shows a block diagram of a pulse radar system according to the present invention. FIG. 3 shows a block diagram of a pulse radar system according to the present invention having common pulse processing. FIG. 4 shows a block diagram of a pulse radar system according to the present invention having a plurality of receive paths. DETAILED DESCRIPTION The radar sensor of the present invention shown in FIG. 2 has a high-frequency source 1, which provides a continuous high-frequency signal (CW signal). Via a signal splitter in the form of a split connection 2, this high-frequency signal reaches on the one side the input of a transmission-side pulse modulator 3 for transmitting radar impulses to transmission antenna 61 and on the other side via a further signal splitter 8 directly to the inputs of two reception-side pulse modulators 71 and 72. The outputs of these pulse modulators 71 and 72 are connected to a mixer 4 and 5, respectively. The outputs of these mixers 4 and 5 are then connected via a power splitter 9, e.g. a 3 dB signal splitter, to receiving antenna 6. Two reception branches are provided with two pulse modulators 71, 72 and two mixers 4 and 5 in order to achieve I/Q (inphase/quadrature phase) capability of the radar system. Signal splitter 9 is used for the reception-side splitting of the antenna signal into the quadrature component signals I and Q. Mixers 4 and 5 are designed, for example, as balanced mixers in the form of a RAT-RACE hybrid (see in particular European Patent Application No. EP 685 9 30, which describes the system of such a RAT-RACE hybrid). The continuous signal of high-frequency source 1 may be switched via pulse modulators 71 and 72 in each case to one of mixers 4 and 5. Transmission-side pulse modulator/switch 3 is controlled via a pulse signal source 10 and a transmission gate circuit 101. Pulse modulators 71 and 72 are each controlled separately by pulse signal sources 11 and 12, to which a time-delay circuit 21 and 22 as well as a reception gate circuit 211 and 212 are respectively assigned. If a radar pulse reflected by an object travels from antenna 6 across power splitter 9 to mixers 4 or 5, the envelope curve of the received pulse (IF signal) is formed from the continuous signal of the high-frequency source and the reflected radar pulse during the time in which the pulse modulator allows the signal of high-frequency source 1 to pass. This mixed signal/envelope curve is amplified by an IF amplifier 411 or 412 with a bandwidth of, e.g. 10 kHz, and supplied to a reception scanner 413 or 414. This occurs separately for the I and the Q channel (separate receive and evaluation paths for the received I and Q signal). Time-delay circuits 21 and 22 are necessary to be able to compare the duration of the received radar pulse and to obtain distance information therefrom. After a defined time period following the generation of the transmission pulse that corresponds with the pulse duration for the desired distance cell, a particularly short scanning pulse is applied to a broadband scanner 413 and 414, respectively, and the scanner scans the output signal of IF amplifier 411 and 412, respectively, in the selected distance cell. In this context, the duration of the scanning pulse is in the order of magnitude of the transmission and IF pulse width. This occurs at the rate of transmission pulse generation, but accordingly delayed. The variation in delay time allows the scanning of the desired distance range in the same manner as SRR (short range radar). The scanner detects from 0 different voltages and thus detects the pulse return after the desired duration. Incoherent pulse integration is possible and is improved by the signal to noise ratio proportionally to SQRT (n), n being the number of integrated pulses. According to FIG. 3, the control pulses for pulse modulators 3, 71, 72 may also be jointly processed by a shared pulse signal source 100. Since the delay times of time-delay circuits 21 and 22 may be selected to be different, pulse modulators 71 and 72 may be controlled independently of one another also in this instance. Of course, in an alternative, only transmission-side pulse modulator 3 may have its own pulse signal source 10, a common pulse signal source then being provided for the reception-side pulse modulators. FIG. 4 shows an exemplary embodiment having a plurality of receive paths, two in this instance. The individual receive paths may be configured as shown in FIG. 2 or 3. As in FIGS. 2 and 3, every mixer 4, 5 and 41, 51, respectively, has a separate pulse modulator 71, 72 and 711, 721, respectively, which may be controlled independently of the respective other mixers of the same receive path via a corresponding pulse signal source 11, 12 and 111, 121, respectively, time-delay circuit 21, 22 and 211, 221, respectively, and reception gate 212, 213 and 214, 215, respectively. The individual receive paths may have either a common receiving antenna or each have a separate receiving antenna 62, 63. Additional downstream signal splitters 91, 92 are required to connect mixers 41, 51 of the further receive paths to high-frequency source 1, which is shared by all receive paths. As a result of the at least two receive paths and separate control of reception-side pulse modulators 71, 72 and 711, 712, respectively, each having adjustable time-delay circuits 21, 22, 211, 221 at different delay times, different modes of operation are possible as well as a faster change between these different modes of operation as a function of the needs of the vehicle operator. As a result, in particular: a plurality of channels (mixers) may be operated in parallel; a plurality of antennas may be operated in parallel (multi-receiver principle); the pulse duty factor may be selected to be different in the transmission and receive paths; the pulse duty factor may be one (Doppler radar only); the transmission pulses may vary with respect to their repetition frequency and/or pulse duration in particular to increase the level of interference protection; I/Q demodulator operation and individual channel operation are possible; a plurality of reception cells may be evaluated at the same time with the same degree of sensitivity when using double or triple transmission pulse power; the distance cells may be adjusted by scanning or masking the received signal; the reception pulse power may be split in the case of target objects that are too strong in close range so that in particular overloading of subsequent amplifiers is prevented; a cross echo analysis is possible; If coded sequences of pulses (PN coding) are transmitted, the modulators in the receive paths, e.g. phase rotators in this case, are controlled by a reception sequence corresponding with the set distance. This contributes significantly to the suppression of false targets. The channels monitor different distance ranges. In the event that a reception-side device is set to the PN code of a neighboring device, a cross echo analysis is possible. Superimposition of two orthogonal codes may be provided in the transmit path, and in each case only one of the transmitted orthogonal codes is evaluated per receive path. The transmission-side and reception-side pulse signal sources 10, 100, 11, 12, 111, 121 are phase-coupled to one another, or only the reception-side pulse signal sources 11, 12, 111, 121 are phase-coupled among one another, particularly in the case of a plurality of receive paths, in order to achieve defined time relationships particularly for the simultaneous monitoring of a plurality of reception cells. In the present invention, a plurality of operating modes may be set consecutively according to a predefined scheme. For this purpose, only a shared control switch 400 is needed for the pulse signal sources and/or the time-delay circuits that provide in each case the time window for transmission and evaluation of the radar pulses according to the predefined scheme. The different parameters for the individual modes of operation may be loaded in a memory module provided in the control circuit or supplied by a separate memory module 401. Of course, the control of the modes of operation may also be configured to be interactive, i.e., modified parameters may be provided in a first mode of operation for further modes of operation as a function of the evaluation.

<SOH> BACKGROUND INFORMATION <EOH>Radar sensors are used in automotive engineering for measuring the distance to objects and/or the relative speed with respect to such objects outside of the motor vehicle. Examples of objects include preceding or parked motor vehicles, pedestrians, bicyclists, or devices within the vehicle's surroundings. The pulse radar functions, for example, at 24,125 GHz and may be used for the following functions, stop & go, precrash, blind spot detection, parking assistant, and backup aid. FIG. 1 shows a schematic representation of a radar device having a correlation receiver of the related art. A pulse generation 302 causes a transmitter 300 to transmit a transmission signal 306 via an antenna 304 . Transmission signal 306 hits a target object 308 and is reflected. Received signal 310 is received by antenna 312 . This antenna 312 may be identical to antenna 304 . After received signal 310 is received by antenna 312 , the signal is transmitted to receiver 314 and subsequently supplied via a unit 316 having low pass and analog/digital conversion to a signal evaluation 318 . The special feature of a correlation receiver is that receiver 314 receives a reference signal 320 from pulse generation 302 . Received signals 310 , which are received by receiver 314 , are mixed in receiver 314 with reference signal 320 . As a result of the correlation, the time delay from the outside to reception of the radar impulses may be used as a basis for determining the distance of a target object, for example. A similar radar device is known from German Patent No. DE 199 26 787. In this context, a transmission switch is switched on and off by the impulses of a generator so that a high-frequency wave generated by an oscillator and conducted via a fork to the transmission switch is switched through to the transmission antenna during the pulse duration. A reception unit also receives the output signal of the generator. The received signal, i.e., a radar pulse reflected by an object, is combined with the oscillator signal, which reaches the mixer via a reception switch, and evaluated during a predefined time period. U.S. Pat. No. 6,067,040 also uses a transmission switch that is switched on and off by generator impulses. Separate paths for l/Q signals are provided for reception of the reflected radar pulses. Also in this instance, the received signal is only mixed and evaluated during a predefined time period.

<SOH> SUMMARY OF THE INVENTION <EOH>The measures of the present invention enable the enhancement of the performance of known pulse radar systems. In the case of the solution according to U.S. Pat. No. 6,067,040, a reception-side pulse modulator or pulse switch is positioned upstream from a power splitter for splitting the LO (local oscillator) signal to the mixers in the reception-side IQ branches. This has the disadvantage that it is not possible to realize a multi-receiver system or to simultaneously evaluate a plurality of different reception cells. However, in the case of the solution of the present invention, two separately controllable, reception-side pulse modulators are provided via which the continuous signal of the high-frequency source, which also controls the transmission-side pulse modulator, may be switched to one respective reception-side mixer. This means that in this instance, as opposed to U.S. Pat. No. 6,067,040, the signal of the high-frequency source may be applied to every mixer in a reception branch at different instants, each mixer also being able to be connected to the signal of the high-frequency source for different durations. In this manner, different modes of operation are made possible and may also be changed quickly and flexibly. Such a change may be effected simply by varying the delay time of the time-delay circuits via which the reception-side pulse modulators may be controlled. A plurality of operating modes may also run automatically in a consecutive order according to a predefined scheme. If both pulse modulators/switches are switched at the same time, the receive path, which includes two reception branches of the pulse radar system, functions in the usual manner. If the switches are switched at different times or they have opening times of different durations, all capabilities of a multi-receiver system are available. A plurality of settings or modes may be set. A previous detection range of, for example, 7 m may now be divided, e.g. into 0 to 4 m and 4 to 7 m. An expansion of the detection range does not automatically result in an extension of the measurement times. One channel is able to cover the 0 to 4 m range, while the other channel having a longer measurement time, for example, covers the 7 to 14 m range. In special cases, the radar system of the present invention functions as a customary I/Q demodulator. Furthermore, parallel to the distance measurement, a channel may be responsible for the CV (closing velocity) measurement, which may be used to determine radial velocity. Therefore, in particular: a plurality of receiving channels may be operated in parallel; I/Q demodulator operation and individual operation are rendered possible; a plurality of antennas may be operated in parallel (multi-receiver principle); the pulse duty factor may be selected to be different in the transmit and receive paths; the pulse duty factor may be one (Doppler radar only); the radar pulses may vary with respect to their repetition frequency and/or pulse duration to increase the level of interference protection; a plurality of reception cells may be evaluated at the same time when using double or triple transmission pulse power; the power of the reception pulses may be split among a plurality of receive paths in the case of target objects that are too strong in close range so that overloading of subsequent received-signal amplifiers is prevented; a PN code may be provided with a reception sequence corresponding to the set distance; a cross echo analysis is possible; the superimposition of two orthogonal codes in the transmit path may be provided as well as evaluation of in each case only one of the transmitted orthogonal codes per reception branch on the reception side.

20041004

20070123

20050217

69383.0

BARKER, MATTHEW M

PULSE RADAR ARRANGEMENT

UNDISCOUNTED

ACCEPTED

ACCEPTED

Reading, detection or quantification method, hybrids or complexes used in said method and the biochip using same

The invention relates to a method of reading, detecting or quantifying at least one biological reaction, on a support, between either a recognition molecule and a labeled target molecule or between a target molecule and a labeled detection molecule. The inventive method comprises treating the support under physicochemical conditions that allow the following: either the separation of the recognition molecule and the labeled target molecule or the separation of the target molecule and the labeled detection molecule. The inventive method further comprises producing images before and after the physicochemical treatment that can be used to determine the specific and non-specific bindings between the different molecules. The invention also relates to hybrids and complexes used in the inventive method and to a biochip containing the same which is used to carry out the inventive method. The invention is particularly suitable for use in the field of diagnosis.

1-23. (canceled) 24. A method of reading on a support at least one biological reaction, comprising: (a) bringing a support into contact with at least one first liquid sample comprising at least one group of identical biological recognition molecules so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (b) bringing the functionalized support into contact with at least one second liquid sample comprising at least one labeled target biological molecule so as to attach the target molecule(s) to the recognition molecules; (c) producing a first image of the support after the attachment of the target molecule(s); (d) treating the support under physicochemical conditions, thereby allowing for the separation of the target molecule(s) from the recognition molecules to which the target molecule(s) is(are) specifically attached; (e) producing a second image of the support after the separation in (d); and (f) analyzing the first and second images to determine the specific attachments between the recognition molecules and target molecule(s). 25. The method as claimed in claim 24, wherein at least one washing step is carried out after the attachment of the recognition molecules to the support and/or after the attachment of the target molecule(s) to the recognition molecules. 26. The method as claimed in claim 25, wherein the support comprises magnetic particles. 27. The method as claimed in claim 26, further comprising magnetizing the magnetic particles on the support during the physicochemical treatment of the support, during image production, or before any of the washing steps. 28. The method as claimed in claim 24, wherein the support is brought into contact with at least two different first liquid samples, thereby allowing for the attachment of at least two different groups of recognition molecules to the support in at least two distinct recognition zones, wherein the first liquid samples are combined prior to or after contact with the support. 29. The method as claimed in claim 24, further comprising: (g) bringing the functionalized and treated support, after the separation in (d), into contact with the same second liquid sample(s) so as to reattach the target molecule(s) to the recognition molecules from which it(they) had been separated, or into contact with another second liquid sample so as to attach the target molecule(s) to other recognition molecules from the same recognition zone; (h) producing a third image of the support after the attachment of the target molecule(s) in (g); and (i) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the recognition molecules and target molecule(s). 30. The method as claimed in claim 29, wherein in the other second liquid sample, the at least one labeled target biological molecule has a different marker from that contained in the initial second liquid sample(s). 31. The method as claimed in claim 24, wherein the physicochemical conditions are obtained by heating to a melting point. 32. The method as claimed in claim 24, wherein the target molecule(s) or recognition molecules comprise nucleic acids, antibodies, or antigens. 33. The method as claimed in claim 24, wherein the target molecule(s) is(are) labeled using a method selected from the group consisting of optical microscopy, fluorescence microscopy, dark field microscopy, atomic force microscopy, electron microscopy, and thermal lens microscopy. 34. The method as claimed in claim 24, wherein the target molecule(s) is(are) labeled using an enzyme having a precipitating product which produces a detectable signal or using a chromophore. 35. The method as claimed in claim 34, wherein the detectable signal is detected by fluorescence or luminescence. 36. The method as claimed in claim 34, wherein the enzyme is selected from the group consisting of horseradish peroxidase, alkaline phosphatase, β-galactosidase, and glucose-6-phosphate dehydrogenase. 37. The method as claimed in claim 34, wherein the chromophore is a fluorescent compound or a luminescent compound. 38. A method of reading on a support at least one biological reaction, comprising: (a) mixing at least one first liquid sample comprising at least one group of identical biological recognition molecules and at least one second liquid sample comprising at least one labeled target biological molecule so as to attach the target molecule(s) to the recognition molecules; (b) bringing a support into contact with the mixture of the first and second liquid samples so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (c) producing a first image of the support after the attachment of the target molecule(s); (d) treating the support under physicochemical conditions, thereby allowing for the separation of the target molecule(s) from the recognition molecules to which the target molecule(s) is(are) specifically attached; (e) producing a second image of the support after the separation in (d); and (f) analyzing the first and second images to determine the specific attachments between the recognition molecules and target molecule(s). 39. The method as claimed in claim 38, further comprising: (g) bringing the functionalized and treated support, after the separation in (d), into contact with the same second liquid sample(s) so as to reattach the target molecule(s) to the recognition molecules from which it(they) had been separated, or into contact with another second liquid sample so as to attach the target molecule(s) to other recognition molecules from the same recognition zone; (h) producing a third image of the support after the attachment of the target molecule(s) in (g); and (i) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the recognition molecules and target molecule(s). 40. The method as claimed in claim 39, wherein in the other second liquid sample, the at least one labeled target biological molecule has a different marker from that contained in the initial second liquid sample(s). 41. A method of reading on a support at least one biological reaction, comprising: (a) bringing a support into contact with at least one first liquid sample comprising at least one group of identical biological recognition molecules so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (b) bringing the functionalized support into contact with at least one second liquid sample comprising at least one biological target molecule so as to attach the target molecule(s) to the recognition molecules; (c) bringing the functionalized support into contact with at least one third liquid sample comprising at least one labeled detection molecule so as to attach the detection molecule(s) to the target molecule(s) attached to the recognition molecules; (d) producing a first image of the support after the attachment of the detection molecule(s); (e) treating the support under physicochemical conditions, thereby allowing for the separation of the detection molecule(s) from the target molecule(s) to which the detection molecule(s) is(are) specifically attached; (f) producing a second image of the support after the separation in (e); and (g) analyzing the first and second images to determine the specific attachments between the target molecule(s) and detection molecule(s). 42. The method as claimed in claim 41, wherein at least one washing step is carried out after the attachment of the recognition molecules to the support, after the attachment of the target molecule(s) to the recognition molecules, and/or after the attachment of the detection molecule(s) to the target molecule(s). 43. The method as claimed in claim 42, wherein the support comprises magnetic particles. 44. The method as claimed in claim 43, further comprising magnetizing the magnetic particles on the support during the physicochemical treatment of the support, during image production, or before any of the washing steps. 45. The method as claimed in claim 41, wherein the support is brought into contact with at least two different first liquid samples, thereby allowing for the attachment of at least two different groups of recognition molecules to the support in at least two distinct recognition zones, wherein the first liquid samples are combined prior to or after contact with the support. 46. The method as claimed claim 45, wherein the support is brought into contact with at least two different target molecules, thereby allowing for the quantification of said at least two different target molecules. 47. The method as claimed in claim 46, wherein the detection molecule(s) comprises(comprise) a molecule combined with at least one marker which produces images that allow individual visualization. 48. The method as claimed in claim 47, wherein the at least one marker is a nanoparticle. 49. The method as claimed in claim 41, further comprising: (h) bringing the functionalized and treated support, after separation in (e), into contact with the same third liquid sample(s) so as to reattach the detection molecule(s) and the target molecule(s) from which it(they) had been separated, or into contact with another third liquid sample so as to attach the detection molecule(s) to any other target molecule(s) attached to the recognition molecules from the same recognition zone; (i) producing a third image of the support after the attachment of the detection molecule(s) in (h); and (j) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the target molecule(s) and detection molecule(s). 50. The method as claimed in claim 49, wherein in the other third liquid sample, the at least one labeled detection molecule has a different marker from that contained in the initial third liquid sample(s). 51. The method as claimed in claim 41, wherein the physicochemical conditions are obtained by heating to a melting point. 52. The method as claimed in claim 41, wherein the target molecule(s), recognition molecules, or detection molecule(s) comprise nucleic acids, antibodies, or antigens. 53. The method as claimed in claim 41, wherein the detection molecule(s) is(are) labeled using a method selected from the group consisting of optical microscopy, fluorescence microscopy, dark field microscopy, atomic force microscopy, electron microscopy, and thermal lens microscopy. 54. The method as claimed in claim 41, wherein the detection molecule(s) is(are) labeled using an enzyme having a precipitating product which produces a detectable signal or using a chromophore. 55. The method as claimed in claim 54, wherein the detectable signal is detected by fluorescence or luminescence. 56. The method as claimed in claim 54, wherein the enzyme is selected from the group consisting of horseradish peroxidase, alkaline phosphatase, β-galactosidase, and glucose-6-phosphate dehydrogenase. 57. The method as claimed in claim 54, wherein the chromophore is a fluorescent compound or a luminescent compound. 58. A method of reading on a support at least one biological reaction, comprising: (a) mixing at least one first liquid sample comprising at least one group of identical biological recognition molecules and at least one second liquid sample comprising at least one biological target molecule so as to attach the target molecule(s) to the recognition molecules; (b) bringing a support into contact with the mixture of the first and second liquid samples so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (c) bringing the functionalized support into contact with at least one third liquid sample comprising at least one labeled detection molecule so as to attach the detection molecule(s) to the target molecule(s) attached to the recognition molecules; (d) producing a first image of the support after the attachment of the detection molecule(s); (e) treating the support under physicochemical conditions, thereby allowing for the separation of the detection molecule(s) from the target molecule(s) to which the detection molecule(s) is(are) specifically attached; (f) producing a second image of the support after the separation in (e); and (g) analyzing the first and second images to determine the specific attachments between the target molecule(s) and detection molecule(s). 59. The method as claimed in claim 58, further comprising: (h) bringing the functionalized and treated support, after separation in (e), into contact with the same third liquid sample(s) so as to reattach the detection molecule(s) and the target molecule(s) from which it(they) had been separated, or into contact with another third liquid sample so as to attach the detection molecule(s) to any other target molecule(s) attached to the recognition molecules from the same recognition zone; (i) producing a third image of the support after the attachment of the detection molecule(s) in (h); and (j) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the target molecule(s) and detection molecule(s). 60. The method as claimed in claim 59, wherein in the other third liquid sample, the at least one labeled detection molecule has a different marker from that contained in the initial third liquid sample(s). 61. A method of reading on a support at least one biological reaction, comprising: (a) mixing at least one first liquid sample comprising at least one group of identical biological recognition molecules and at least one second liquid sample comprising at least one biological target molecule so as to attach the target molecule(s) to the recognition molecules; (b) adding at least one third liquid sample comprising at least one labeled detection molecule to the mixture of the first and second liquid samples so as to attach the detection molecule(s) to the target molecule(s) attached to the recognition molecules; (c) bringing a support into contact with the mixture of the first, second, and third liquid samples so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (d) producing a first image of the support after the attachment of the recognition molecules; (e) treating the support under physicochemical conditions, thereby allowing for the separation of the detection molecule(s) from the target molecule(s) to which the detection molecule(s) is(are) specifically attached; (f) producing a second image of the support after the separation in (e); and (g) analyzing the first and second images to determine the specific attachments between the target molecule(s) and detection molecule(s). 62. The method as claimed in claim 61, further comprising: (h) bringing the functionalized and treated support, after separation in (e), into contact with the same third liquid sample(s) so as to reattach the detection molecule(s) and the target molecule(s) from which it(they) had been separated, or into contact with another third liquid sample so as to attach the detection molecule(s) to any other target molecule(s) attached to the recognition molecules from the same recognition zone; (i) producing a third image of the support after the attachment of the detection molecule(s) in (h); and (j) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the target molecule(s) and detection molecule(s). 63. The method as claimed in claim 62, wherein in the other third liquid sample, the at least one labeled detection molecule has a different marker from that contained in the initial third liquid sample(s). 64. A method of reading on a support at least one biological reaction, comprising: (a) mixing at least one second liquid sample comprising at least one target biological molecule and at least one third liquid sample comprising at least one labeled detection molecule so as to attach the target molecule(s) to the detection molecule(s); (b) adding at least one first liquid sample comprising at least one group of identical recognition molecules to the mixture of the second and third liquid samples so as to attach the recognition molecules to the target molecule(s); (c) bringing a support into contact with the mixture of the first, second, and third liquid samples so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (d) producing a first image of the support after the attachment of the detection molecule(s); (e) treating the support under physicochemical conditions, thereby allowing for the separation of the detection molecule(s) from the target molecule(s) to which the detection molecule(s) is(are) specifically attached; (f) producing a second image of the support after the separation in (e); and (g) analyzing the first and second images to determine the specific attachments between the target molecule(s) and detection molecule(s). 65. The method as claimed in claim 64, further comprising: (h) bringing the functionalized and treated support, after separation in (e), into contact with the same third liquid sample(s) so as to reattach the detection molecule(s) and the target molecule(s) from which it(they) had been separated, or into contact with another third liquid sample so as to attach the detection molecule(s) to any other target molecule(s) attached to the recognition molecules from the same recognition zone; (i) producing a third image of the support after the attachment of the detection molecule(s) in (h); and (j) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the target molecule(s) and detection molecule(s). 66. The method as claimed in claim 65, wherein in the other third liquid sample, the at least one labeled detection molecule has a different marker from that contained in the initial third liquid sample(s). 67. A method of reading on a support at least one biological reaction, comprising: (a) bringing a support into contact with at least one first liquid sample comprising at least one group of identical biological recognition molecules so as to attach the recognition molecules to the support at the level of a recognition zone, such that the support is functionalized; (b) mixing at least one second liquid sample comprising at least one target biological molecule and at least one third liquid sample comprising at least one labeled detection molecule so as to attach the target molecule(s) to the detection molecule(s); (c) bringing the mixture of the second and third liquid samples into contact with the support so as to attach the target molecule(s) to the recognition molecules; (d) producing a first image of the support after the attachment of the detection molecule(s); (e) treating the support under physicochemical conditions, thereby allowing for the separation of the detection molecule(s) from the target molecule(s) to which the detection molecule(s) is(are) specifically attached; (f) producing a second image of the support after the separation in (e); and (g) analyzing the first and second images to determine the specific attachments between the target molecule(s) and detection molecule(s). 68. The method as claimed in claim 67, further comprising: (h) bringing the functionalized and treated support, after separation in (e), into contact with the same third liquid sample(s) so as to reattach the detection molecule(s) and the target molecule(s) from which it(they) had been separated, or into contact with another third liquid sample so as to attach the detection molecule(s) to any other target molecule(s) attached to the recognition molecules from the same recognition zone; (i) producing a third image of the support after the attachment of the detection molecule(s) in (h); and (j) analyzing the third image with respect to the analysis of the first and second images to confirm the specific attachments between the target molecule(s) and detection molecule(s). 69. The method as claimed in claim 68, wherein in the other third liquid sample, the at least one labeled detection molecule has a different marker from that contained in the initial third liquid sample(s). 70. A hybrid or complex, produced by the method of claim 41, bound to a support by a biological recognition molecule, the hybrid or complex comprising the recognition molecule bound to a biological target molecule, which is bound to a labeled detection molecule, wherein the bond between the detection molecule and the target molecule is easier to dissociate under suitable physicochemical conditions than the bond between the target molecule and the recognition molecule, and wherein the bond between the target molecule and the recognition molecule is easier to dissociate under suitable physiochemical conditions than the bond between the recognition molecule and the support. 71. The hybrid or complex as claimed in claim 70, when the recognition molecule, target molecule, and detection molecule are nucleic acids, wherein the pairing between the detection molecule and the target molecule comprises fewer total base pairs and/or comprises fewer guanine-cytosine base pairs than the bond between the target molecule and the recognition molecule. 72. A biochip comprising a plurality of hybrids or complexes as claimed in claim 70. 73. The biochip as claimed in claim 72, wherein structurally identical hybrids or complexes are grouped together to form recognition zones.

The present invention relates to a method of reading, a method of detecting and a method of quantifying chemical or biological reactions performed on a support, which support may consist of a Petri dish, a microtiter plate, a biochip and the like. The present invention also relates to a support comprising a plurality of, that is to say at least two, zones of molecular recognition, each recognition zone containing at least one recognition molecule. While there are at least two recognition molecules per recognition zone, all the recognition molecules are structurally identical. The present invention finally relates to hybrids or complexes which may be used on such supports. The expression biochip is understood to mean a chip having at its surface a plurality of recognition zones, that is to say at least one hundred recognition zones, endowed with molecules having recognition properties. In the remainder of the text, and by a misuse of terminology, the term biochip is used independently of whether the chip is intended for chemical or biological analysis. The concept of biochip, more precisely of DNA chip, dates from the beginning of the 1990s. Nowadays, this concept has been extended since protein chips have started to be developed. It is based on a multidisciplinary technology incorporating microelectronics, nucleic acid chemistry, image analysis and computing. The principle of operation is based on a molecular biology foundation: the phenomenon of hybridization, that is to say the pairing by base complementarity of two DNA and/or RNA sequences. The biochip method is based on the use of probes (DNA sequences representing a portion of a gene or an oligonucleotide), attached to a solid support on which a sample of nucleic acids labeled directly or indirectly with fluorochromes is caused to act. However, it is quite possible to use other more conventional supports such as Petri dishes, microtiter plates which contain a number of separate wells, and the like. The expression support is understood to mean an analytical surface which contains only a few recognition zones, generally at most one hundred recognition zones. Each recognition zone comprises at least one molecule having recognition properties In all cases, the probes, also called recognition molecules, are positioned in a specific manner on the support or chip and each hybridization gives information on each gene represented. This information is cumulative, and makes it possible to detect the presence of a gene or to quantify the level of expression of this gene in the tissue studied. After hybridization, the support or chip is washed, read for example by a scanner and the analysis of the fluorescence is processed by a computer. The support or chip which serves to attach the probes generally consists of a flat or porous surface composed of materials, such as: glass, an inexpensive, inert and mechanically stable material; the surface may be covered with a Teflon screen which delimits hydrophilic and hydrophobic zones, polymers, silicon, and metals, in particular gold and platinum. However, it is also possible to use particles, for example magnetic particles, as described in patent applications WO-A-97/34909, WO-A-97/45202, WO-A-98/47000 and WO-A-99/35500 from one of the applicants. To attach the probes (or recognition molecules), three main types of manufacture are distinguishable. There is first of all a first technique which consists in depositing presynthesized probes. The attachment of the probes occurs by direct transfer, by means of micropipettes, microtips or by an ink-jet type device. This technique allows the attachment of probes having a size ranging from a few bases (5 to 10) up to relatively large sizes of 60 bases (imprinting) to a few hundreds of bases (microdeposition): Imprinting is an adaptation of the method used by ink-jet printers. It is based on the propelling of very small spheres of fluid (volume<1 nl) and at a rhythm which may be up to 4000 drops/second. Imprinting does not involve any contact between the system releasing the fluid and the surface on which it is deposited. Microdeposition consists in attaching probes which are a few tenths to a few hundredths of bases long to the surface of a glass slide. These probes are generally extracted from databases and exist in the form of amplified and purified products. This technique makes it possible to prepare chips called microarrays carrying about ten thousand spots, called recognition zones, of DNA on a surface of slightly less than 4 cm2. There should however not be forgotten the use of Nylon membranes, called “macroarrays”, which carry products which have been amplified, generally by PCR, with a diameter of 0.5 to 1 mm and the maximum density of which is 25 spots/cm2. This highly flexible technique is used by many laboratories. In the present invention, the latter technique is considered as forming part of biochips. It is possible however to deposit, at the bottom of a microtiter plate, a certain volume of sample into each well, as is the case in patent applications WO-A-00/71750 under priority of 20 May and of 6 Dec. 1999 and FR00/14896 of 17 Nov. 2000 from one of the applicants, or to deposit, at the bottom of the same Petri dish, a certain number of drops separated from each other, according to another patent application FR00/14691 of 15 Nov. 2000 from this same applicant. The second technique for attaching probes to the support or chip is called in situ synthesis. This technique results in the production of short probes directly at the surface of the chip. It is based on the synthesis of oligonucleotides in situ, invented by Edwin Southern, and is based on the method of oligonucleotide synthesizers. It consists in moving a reaction chamber, where the oligonucleotide extension reaction is taking place, along the surface of glass. Finally, the third technique is called photolithography, which is a method at the origin of the biochips developed by Affymetrix. It also involves an in situ synthesis. Photolithography is derived from microprocessor techniques. The surface of the chip is modified by the attachment of photolabile chemical groups which can be activated by light. Once illuminated, these groups are capable of reacting with the 3′ end of an oligonucleotide. By protecting this surface with masks of defined shapes, it is possible to illuminate and therefore activate selectively zones of the chip where it is desired to attach either of the four nucleotides. The successive use of different masks makes it possible to alternate protection/reaction cycles and therefore to produce the oligonucleotide probes on spots of about a few tenths of a square micrometer (μm2). This resolution makes it possible to create up to several hundreds of thousands of spots on a surface of a few square centimeters (cm2). Photolithography has advantages: massively parallel, it makes it possible to create a chip of N mers in only 4×N cycles. All these techniques can of course be used with the present invention. Methods using such supports or biochips can be essentially used for: searching for the presence or absence of a pathogenic agent, for example for a bacterium in meat, searching for the presence or absence of mutations. Knowing the molecular structure of the gene, oligonucleotides are manufactured which represent all or the complementary part of this gene. In the presence of the biological sample, hybridization will occur between all or part of said gene, which is generally labeled, for example by fluorescence, and the oligonucleotides, and the image obtained by fluorescence makes it possible to know if there is a mutation and in which position it is situated. In this application, the use of DNA chips is equivalent to sequencing for a diagnosis of mutation, with a huge advantage in terms of speed, and measuring the level of expression of genes in a tissue. The chip network carries a very large number of probes which correspond to all the genes of the species to be studied. A sample, for example of previously amplified mRNAs, which represents the active genes of the tissue, is hybridized. Fluorescence analysis makes it possible to know the level of expression of each gene. The efficiency of such supports and biochips was tested on well known biological systems such as yeast (cell cycle, respiratory metabolism, fermentation and the like). Comparison of the results obtained by the chips with those previously obtained by other approaches showed agreement for the genes whose expression was already well known in these biological systems. This work has thus made it possible to validate the technology of biochips in relation to the more conventional supports which we have mentioned. Moreover, companies are involved in novel methods which also allow genomic analyses to be performed in parallel. Thus, the microbead technique makes it possible to attach probes to microspheres carrying an individual “tag” or mark, and more precisely a genetic code. After reaction, the reading of this mark makes it possible to unambiguously identify a microbead and therefore the probe present at its surface. The microspheres are brought into contact with the test sample labeled with one or more fluorochromes. The mixture is then analyzed by flow cytometry which will, on the one hand, identify each bead according to its “tag”, and, on the other hand, measure the fluorescence indicating an effective hybridization reaction. DNA chips have paved the way to a novel instrumentation in molecular biology which can even incorporate various stages of analyses in miniaturized form, see in this regard patent applications WO-A-00/78452 under priority of 22 Jun. 1999 and FR00/10978 filed on 28 Aug. 2000 from one of the applicants. Furthermore, as already indicated above, the very high interest recently created by proteomics, the key post-genomics discipline, is accompanied by the emergence of the concept of protein chips. These also form part of the supports according to the invention. The recognition molecules may be, for example, oligonucleotides, polynucleotides, proteins such as antibodies or peptides, lectins or any other ligand-receptor type system. In particular, the recognition molecules may contain DNA or RNA fragments. When the support is brought into contact with a sample to be analyzed, the recognition molecules are capable of interacting, for example by hybridization in the case where they are nucleic acids or by formation of a complex in the case where they are antibodies or antigens, with target molecules present in a liquid biological sample. Thus, by equipping a biochip with a plurality of recognition zones with various different recognition molecules, where each recognition molecule is specific for a target molecule, it is possible to detect and possibly quantify a large variety of molecules contained in the sample. It is of course obvious that each recognition zone contains only one type of recognition molecules which are identical to each other. The support-recognition molecule-target molecule assembly can be detected by a detection molecule. The support-recognition molecule-target molecule-detection molecule assembly constitutes a test in a sandwich format. Tests in a sandwich format are widely used in diagnosis, whether in molecular diagnosis, ELOSA (Enzyme-Linked Oligo-Sorbent Assay) test for example, or in immunological diagnosis, for example ELISA (Enzyme-Linked Immuno-Sorbent Assay) test for example. In general, they comprise a recognition molecule, such as a nucleic acid probe or an antigen (case of an antigen sandwich) or an antibody (case of an antibody sandwich), which serves to capture a target, which will consist respectively of a nucleic acid probe or an antibody or an antigen. This recognition molecule is attached to a solid support in a manner known to a person skilled in the art, for example: either by adsorption, or by direct coupling, or via an intermediate protein, such as for example avidin or protein A, or via polymers. The recognition molecule and target molecule assembly is then detected by a detection molecule, which will respectively consist of a nucleic acid probe or an antibody or an antigen. This detection molecule carries or may be subsequently combined with a marker, which marker is necessary in order to allow detection and/or quantification. The detection molecule, whether still combined with a marker or not, will still be called detection molecule. In the text which follows, the term “hybridization” will be associated with the attachment of a nucleic acid to another nucleic acid, whereas the term “complexing” will be associated with the attachment of an antibody to an antigen. On the other hand, the term “attachment” will have a broader definition which may relate at the same time to: the attachment of a nucleic acid to another nucleic acid, the attachment of an antibody to an antigen, or the attachment of a biological molecule to a support. The tests currently available are tests such as those developed by one of the applicants for immunological assays or the DNA chips developed by the company Affymetrix (“Accessing Genetic Information with High-Density DNA arrays”, M. Shee et al., Science, 274, 610-614. “Light-generated oligonucleotide arrays for rapide DNA sequence analysis”, A. Caviani Pease et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 5022-5026), for medical diagnosis. In this technology, the capture probes are generally of small sizes, of around twenty nucleotides. In the ELOSA field, that is to say in the field of detection of nucleic acids, see in this regard the patent application filed by one of the applicants WO-A-91/19812, there are defined in the same manner a capture oligonucleotide (recognition molecule), a target nucleic acid (target molecule) which is either DNA or RNA, and a detection oligonucleotide (detection molecule). Capture and detection oligonucleotides are complementary to part of the target but at the level of the regions of the target which are respectively structurally and physically different, such that the capture and detection oligonucleotides cannot hybridize to one another. Whether in molecular diagnosis or in immunological assays, the detection elements carry a marker which allows the detection and/or the quantification of the target. The expressing labeling is understood to mean the attachment of a marker capable of directly or indirectly generating a detectable signal. Various markers have been developed with the permanent objective of improving sensitivity. They may be either radioactive, enzymatic, fluorescent, or, as described more recently, in the form of nanoparticles. These nanoparticles are different from microparticles, in particular in their size which remains considerably less than a micron. Because they are less trivial, they will be the subject of a more detailed disclosure later. A nonlimiting list of these markers, which makes it possible to carry out imaging with a single marker, will be described in the remainder of the description. Indirect systems may also be used, such as for example ligands capable of reacting with an antiligand. The ligand/antiligand pairs are well known to a person skilled in the art, which is the case for example of the following pairs: biotin/streptavidin, hapten/antibody, antigen/antibody, peptide/antibody, sugar/lectin, polynucleotide/complementary to the polynucleotide, successive histidine sequence, called “tag”, for a metal, for example nickel. In this case, it is the ligand which carries the linking agent. The antiligand may be detectable directly by the markers described in the preceding paragraph or may itself be detectable by a ligand/antiligand. These indirect detection systems can lead, under certain conditions, to a signal amplification. This signal amplification technique is well known to a person skilled in the art, and reference may be made to previous patent applications FR98/10084 or WO-A-95/08000 from one of the applicants or to the article J. Histochem. Cytochem. 45: 481-491, 1997. Moreover, the applicants have jointly filed a patent application PCT/FROO/03359 under French priority of 2 Dec. 1999 on a signal amplification technique. However, the latter does not function on the basis of the teachings drawn from the preceding documents, which increase the number of markers at the level of the sites of attachment of said markers, but rather uses a particular coating at the surface of the support, which coating is based on a thin layer of a material chosen from silicon nitride, silicon carbide, titanium oxides, aluminum oxide, ZrO2, ZrO4Ti, HfO2, Y2O3, diamond, MgO, oxynitrides (SixOyNz), fluorinated materials, YF3, MgF2. These two techniques may be cumulative. As mentioned above, the markers may also be in the form of nanoparticles. The first experiments using conjugates with nanoparticles date back to 1980. They were motivated by the search for ultrasensitive labeling techniques which avoid the use of radioactivity or the use of enzymatic labelings which require not only time but also the use of toxic reagents. They have been widely developed and used since then and many types of particle have been developed, such as microparticles, nanoparticles of latex or particles of colloidal gold or alternatively fluorescent particles. In the text which follows, the term “particles” will be used without distinction for microparticles or nanoparticles or other particles of different sizes. Many particles are now commercially available (Bangs, Milteny, Molecular Probes, Polyscience, Immunicon). Labeling experiments using nanoparticles were started in the field of immunological assays by J. H. W. Leuvering, P. J. H. M. Thal, M. Van der Waart and A. H. W. M. Schuurs, Sol Particle Immunoassay (SPIA). Journal of Immunoassay 1(1):77-91, 1980. The use of nanoparticles has allowed access to other technologies such as atomic force microscopy for reading immunological assays, with which technology, on a TSH detection model, a sandwich system mounted on a silicon support using anti-TSH detection antibody conjugates bound to gold nanoparticles has made it possible to obtain a sensitivity of the order of 1 pM. On this subject, reference may be made to the following two publications: Agnès Perrin, Alain Theretz, and Bernard Mandrand Thyroïd stimulating hormone assays based on the detection of gold conjugates by scanning force microscopy. Analytical biochemistry 256:200-206, 1998, and Agnès Perrin, Alain Theretz, Véronique Lanet, S. Vialle, and Bernard Mandrand Immunomagnetic concentration of antigens and detection based on a scanning force microscopic immunoassay. Journal of immunological methods 8313, 1999 The use of nanoparticles for the detection of nucleic acids has been observed since only very recently. The work carried out in the field of immunology finds its equivalent in the field of nucleic acids. There is no fundamental innovation either in the labeling methods or in the detection methods. Since the ELISA plate no longer exists, it is indeed replaced by a flat support. The nanoparticles are then detected by microscopy, by amplification for surface plasmon resonance, called “biosensor” technique, or by measurement using AFM. Overall, the biological models remain simple models. The work by Taton, T. A., Mirkin C. A. and Letsinger R. L. relating to: “Scanometric DNA array detection with nanoparticle probes” Science 2000 Sep. 8; 289(5485):1757-60, presents the use of gold nanoparticles coupled to detection oligonucleotides of 15 bases for detecting a target of 27 bases which is captured on a probe of 12 bases. The detection signal is amplified by labeling with silver. For high target concentrations of the order of 10 nanoMolar (nM), the detection of the particles is carried out by eye by observing the passage of a pink color. For the lowest concentrations, 100 picoMolar (pM) for example, the detection requires the use of a scanner. The sensitivity reached is of the order of 50 femtoMolar (fM). The authors are capable of dissociating the nanoparticles from the surface by heating, which tends to show the specificity of their labeling. However, according to the experiment of the applicants and because of the respective sizes of the detection oligonucleotides (15 bases), of the target oligonucleotides (27 bases) and of the capture oligonucleotides (12 bases), there must necessarily be dissociation between said nanoparticles and the detection oligonucleotides. This work is based, in addition, on a set of experiments which have been the subject of several publications (1996; 1997; 1997; 2000) and several patent applications and patents, such as WO-A-98/04740. These researchers carry out a dissociation of the nanoparticles which does not distinguish the nanoparticles combined with a detection molecule with no mismatch with the target and the nanoparticles combined with a detection molecule with a mismatch with said target. In the text that follows, the expression “dissociation” is understood to mean in particular the separation between the recognition molecule and the target molecule and/or the separation of the target molecule and the detection molecule. If this dissociation is thermal, the physical characteristic involved consists of the melting point (Tm) which corresponds to the temperature zone where the DNA or RNA molecules are denatured. More precisely, this temperature corresponds to a state where a population of identical oligonucleotides, in the presence of an identical quantity of complementary oligonucleotides, is 50% in double-stranded form, that is to say paired, and 50% in single-stranded form. While labelings with nanoparticles make it possible to obtain good sensitivity, there is nevertheless a compromise to be made between the increase in the specific signal and the decrease in the nonspecific signal. The nonspecific signal is of course limiting for improving the sensitivity and the dynamics of the method. The authors solve these problems by optimizing the experimental conditions. As a guide, some authors (Okano et al.; Anal. Biochem. 202:120-125; 1992) have optimized the concentration of detection oligonucleotides per particle, on the one hand, and the concentration of particles in the solution, on the other hand. They have also succeeded in reducing the nonspecific by adding BSA (bovine serum albumin). As regards the use of nanoparticles for amplifying a signal obtained on a biosensor, reference is made to the work of Lin He, Michael D. Musick, Scheila R. Nicewaener, Franck G. Salinas, Stephen J. Benkovic, Michael J. Natan, and Christine D. Keating. Colloidal Au-enhanced surface plasmon resonance for ultrasensitive detection of DNA hybridization. J. Am. Chem. Soc. 122:9071-9077, 2000. Detection oligonucleotides (12 bases) conjugated with nanoparticles of colloidal gold are used to amplify the detection of a small sized nucleic acid target (24 mers) by surface plasmon resonance. They obtained a sensitivity of 10 pM, that is to say a surface density of 8.108 molecules/cm2 with an improvement in signal intensity of a factor of 100000. They verified the hybridization specificity by dissociating the nanoparticles from the surface either by heating or by digesting with restriction enzymes if the restriction site is present on the hybridized sequence. In this case, the labeling is used to amplify the signal, and the dissociation serves to show that the labeling results from a specific hybridization. It is a verification of hybridization. Either the nanoparticles are separated by heating, in which case the scenario described by Taton (2000) exists and there is no specificity in the removal of the marker, or the nanoparticles are separated by restriction enzymes, in this case the nanoparticles are removed, for example by washing, while remaining combined with all or part of the detection molecule and/or the hybrid. There is an oriented character of this separation, but without dissociation or with a partial dissociation of the double strands. Among the state of the art methods using nanoparticles, the document by Kubitschko S., Spinke J., Bruckner T., Pohl S. and Oranth N. “Sensitivity enhancement of optical immunosensors with nanoparticles.” Anal. Biochem. 253(1):112-122 from 1997 evokes, in immunological diagnosis, the dissociation of the antibody conjugates in relation to the antigens. This dissociation is achieved with formic acid which serves to regenerate a microcomponent which still contains the antibodies for subsequent uses of the microcomponent. It is more a method of cleaning a microcomponent; as a result, no de facto discrimination is made when the dissociation of the antibody conjugates is carried out in relation to the antigens which may be combined with the nanoparticles. U.S. Pat. No. 6,093,370 provides another method which has the objective of recovering a DNA captured on a DNA chip. It is a photothermal dissociation carried out with an infrared (IR) laser at 1053 nanometers (nm) which irradiates with a power of between 10 and 100 mW the region of the chip on which it is desired to recover the DNA. The DNA redissolved in solution is amplified by PCR. The authors show that they are capable of extracting at least one DNA molecule per 169 nm2, that is 10-17 mol/1000 μm2. However, they do not use a physicochemical dissociation for determining the hybridizations which are real because they are specific (true positives) from the other hybridizations. In addition to the dissociation techniques mentioned above, that is to say by thermal denaturation (heating), by photothermal denaturation (IR laser), by digestion (restriction enzymes), by chemistry (formic acid), other methods of dissociating nucleic acids exist in the state of the art. Thus, it is possible to modify the ionic strength of the hybridization buffer in order to dissociate the detection oligonucleotide from the target. Indeed, the melting point of the oligonucleotides varies according to the ionic strength of the buffer. The lower the ionic strength of the buffer, the less stable the oligonucleotide. It is also possible to combine the action of temperature with the buffer conditions. It is also possible to use PNA (Peptide Nucleic Acid) or any other molecules used in the state of the art for capturing a nucleic acid. The PNA/oligonucleotide hybrids have the same thermal stability regardless of the ionic strength, that is to say that their melting point does not vary according to the ionic strength of the hybridization buffer. If the capture probe is a PNA and the detection probe is an oligonucleotide, on using a low ionic strength, the detection probe dissociates from the target whereas the target remains hybridized with the capture probe (PNA). It is possible to chemically modify the detection probes in order to carry out the dissociation of the DNA under certain conditions. These dissociation methods do not relate to the particles which interact with the surface via the surface properties of the nanoparticles and of the support. It is also possible to modify a base of the oligonucleotide, as described for example by Dreyer et al. (Proc. Natl. Acad. Sci., 82: 968-972; 1985). An EDTA group is coupled to a thymidine. In the presence of DTT, Fe(II) and O2, a cleavage of the DNA occurs at the level of the thymidine carrying the EDTA. As it is possible to couple a biotin to the detection oligonucleotide, for subsequent attachment to an avidin, it is also possible to couple a chemical group of the homobifunctional or heterobifunctional type (chemical functional groups necessary for its attachment to the oligonucleotide and to the support) which contains an additional chemical functional group which may be cleaved under certain conditions: for example a photocleavable group or alternatively a group reduced by DTT. In the case of a photocleavable group, exposing the oligonucleotide to a given wavelength cleaves the functional group and dissociates the oligonucleotide from its support. Another method may also consist in adding a known sequence having a small size, called “tag”, which has the property of forming a chelate with a chelating group present on the nanoparticle, via a metal ion. The tag may be a Histidine tag or any other molecule described by the state of the art. The chelating group may be an NTA (nitrilotriacetic acid) or any other group described by the state of the art. The dissociation will consist in using the methods described by the state of the art for dissociating the tag-metal-chelating group interaction (for example use of EDTA). The dissociation may also be performed by displacing the detection probe, present on the nanoparticle, by oligonucleotides having identical sequences. These oligonucleotides may have either a shorter sequence or the same sequence with an additional sequence complementary to the target. Also, it is possible to use nucleic acid analogs for this displacement by competition, for example PNAs (Peptide Nucleic Acids) or another analog having the advantage of a neutral backbone. As regards the dissociation of protein molecules such as antigens and/or antibodies, it is possible to apply any of the methods described in the state of the art for dissociating the interactions between an antigen and an antibody (numerous techniques known in the field of affinity chromatography). By way of example, it is thus possible to carry out the dissociation by applying acid solutions such as a glycine buffer at acidic pH or solutions with high ionic strength such as 5M LiCl (Kubitschko et al., Anal. Biochem. 253(1):112-122; 1997). It is also possible to use denaturing agents such as guanidium chloride, urea or alternatively solutions containing detergents; or methods for digesting proteins with proteases or even endoproteases specific for the antigen or the antibody or alternatively nonspecific for the antigens or the antibodies. In the case of a double labeling, the dissociation should be oriented, without being denaturing for the proteins so as to allow a second labeling. This may be carried out for example by displacement by the use of synthetic peptides, whose sequence corresponds to the sequence of the epitopes of monoclonal antibodies but with a higher affinity. It is also possible to modify, chemically or by genetic engineering techniques, antigens and antibodies in order to carry out the dissociation under certain conditions. These methods do not relate, however, to the protein molecules which interact directly with the surface in a nonspecific manner. Thus, the modification may relate to one of the proteins (antigen or antibody) by inserting, for example by genetic engineering, a sequence for cleavage by an endoprotease. In the presence of the enzyme, there is cleavage of the protein to be detected. The second labeling is performed using a second monoclonal antibody specific for the remaining protein sequence. The modification may relate to the end of the protein by adding, for example by genetic engineering, a tag. This tag may be recognized by monoclonal antibodies, the dissociation is then made by displacement using competitor peptides or antibodies. As a guide, the tag added may be a “poly-Histidine” sequence, may contain a sequence for cleavage by endoproteases which does not exist in the sequence, the dissociation is then carried out by enzymatic cleavage. Other sequences such as protein “splice” sequences may also be integrated into the protein. The cleavage is made in the presence of DTT for example. Finally, it is also possible to add to the detection protein a nucleic acid sequence. A tag is then obtained, as above, which can be recognized by a nucleic probe which is itself conjugated with a nanoparticle. The dissociation, oriented or otherwise, can then be carried out by one of the techniques described for nucleic acids, provided that the protein assembly is not denatured in the case of an oriented dissociation. Competition methods are advantageous from this point of view. All these elements mentioned above are capable of being incorporated into the invention in order to further improve the performance thereof. According to patent application WO-A-99/65926, from one of the applicants, it is also possible to dispense with the detection molecule proper in the case of nucleic acids. Each target can be cleaved chemically, enzymatically or physically, while undergoing simultaneous labeling or otherwise. The presence of a detection molecule is then no longer necessary since the target molecule is labeled, see in particular patent application PCT/FR99/03192. Devices exist for reading molecules which are labeled or otherwise, and which may be present in the recognition zones of the chip. The reading of the recognition zones may indeed also be carried out without the presence of the marker, such a technology already being known in the state of the art. The applicants have in fact jointly filed a patent application PCT/FR00/02703 under French priority of 30 Sep. 1999 on such a reading technique, which uses a photothermal method. Among the direct methods for detection of hybridization, it is possible to distinguish in particular the detection of the variation in mass, of the variation in thickness and of the variation in index. Photothermal methods are also known which are described in the document by S. E. Bialkowski, vol. 137, under the title: “Photothermal spectrocopy methods for chemical analysis” taken from Chemical analysis: a series of monographs on analytical chemistry and its application, Wiley. Finally, the document U.S. Pat. No. 4,299,494 describes a technique for photothermal deflection. Thus, the invention finds applications in the fields of biological and chemical analysis. In general, the reading of the molecular or immunological diagnosis mentioned above has the main disadvantage of being limited by false-positives, that is to say hybrids or complexes which form when they should not have hybridized or formed a complex, and/or false-negatives, that is to say hybrids or complexes which do not form when they should have hybridized or formed a complex. This presence of false-positives or of false-negatives causes another disadvantage, which is the consequence of the first disadvantage mentioned above; the molecular diagnosis or the immunological assays lack sensitivity (power to identify the hybrid or the complex sought when it is present in a small quantity in a biological sample to be tested) and/or specificity (power to detect the hybrid or the complex sought in the biological sample to be tested containing other hybrids or complexes). This can cause diagnostic errors which are not acceptable for patients, practitioners and the companies manufacturing such tests. The present invention proposes to solve all the disadvantages of the prior art mentioned above by providing a method of reading which is little or not influenced by the presence of false-positives and which therefore very substantially improves the sensitivity and specificity of diagnostic tests. To this effect, the present invention relates, according to a first embodiment, to a method of reading on a support at least one biological reaction, which consists in: bringing the support into contact with at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, so as to attach these recognition molecules to the support, preferably at the level of a recognition zone, bringing the functionalized support into contact with at least a second liquid sample containing at least one labeled target biological molecule so as to attach this or these target molecule(s) to said recognition molecule(s), producing a first image of said support after this attachment of the labeled target molecule(s), treating the support under physicochemical conditions allowing the separation of each target molecule with respect to a recognition molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the recognition and target molecule(s). According to a second embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, into contact with at least a second liquid sample containing at least one labeled target biological molecule so as to attach this or these target molecule(s) to said recognition molecule(s), bringing the support into contact with the mixture of the at least two first and second liquid samples containing at least the group of biological recognition molecules optionally complexed with at least one target molecule so as to attach this or these recognition molecules or complex(es) to the support, preferably at the level of a recognition zone, producing a first image of said support after this attachment of the labeled target molecule(s), treating the support under physicochemical conditions allowing the separation of each target molecule with respect to a recognition molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the recognition and target molecule(s). In the preceding two cases, the method may additionally comprise the following additional subsequent steps: bringing the functionalized and treated support, after specific separation, into contact with the second liquid sample or with another liquid sample so as to again attach at least one labeled target biological molecule to: the biological recognition molecule(s) from which it or they had been separated, and/or any other recognition molecule(s) derived from the same recognition zone, producing a third image of said support after this new attachment of target molecule(s), analyzing the third image with respect to the preceding analysis of the two first images in order to confirm the specific attachments between the recognition and target molecule(s). According to a third embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing the support into contact with at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, so as to attach these identical recognition molecules to the support, preferably at the level of a recognition zone, bringing the functionalized support into contact with at least a second liquid sample containing at least one biological target molecule so as to attach this or these target molecule(s) to said recognition molecule(s), bringing the functionalized and treated support into contact with at least a third liquid sample containing at least one labeled detection molecule so as to attach this or these detection molecule(s) to said target molecule(s) attached to the recognition molecule(s), producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). According to a fourth embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, into contact with at least a second liquid sample containing at least one biological target molecule so as to attach this or these target molecule(s) to said recognition molecule(s), bringing the support into contact with the mixture of the at least two first and second liquid samples containing at least one group of identical biological recognition molecules, which recognition molecule(s) is (are) optionally complexed with at least one target molecule, so as to attach this or these recognition molecule(s) and/or complex(es) to the support, preferably at the level of a recognition zone, bringing the functionalized and treated support into contact with at least a third liquid sample containing at least one labeled detection molecule so as to attach this or these detection molecule(s) to said target molecule(s) attached to the recognition molecule(s), producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). According to a fifth embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, into contact with at least a second liquid sample containing at least one biological target molecule so as to attach this or these target molecule(s) to said recognition molecule(s), bringing the mixture of the two first and second liquid samples into contact with at least a third liquid sample containing at least one labeled detection molecule so as to attach this or these detection molecule(s) to said target molecule(s) attached to the recognition molecule(s), bringing the support into contact with the mixture of the at least three first, second and third liquid samples containing at least the group of identical biological recognition molecules, which recognition molecule(s) is (are) optionally complexed with at least one target molecule which is itself optionally complexed with at least one detection molecule so as to attach this or these recognition molecules or complex(es) to the support, preferably at the level of a recognition zone, producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). According to a sixth embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing at least a second liquid sample containing at least one target biological molecule into contact with at least a third liquid sample containing at least one biological detection molecule, so as to attach this or these target molecule(s) to the detection molecule(s), bringing the mixture of the two second and third liquid samples into contact with at least a first liquid sample containing at least one group of recognition molecules, which are identical to each other, so as to attach this or these recognition molecule(s) to said target molecule(s), optionally attached to said detection molecule(s), bringing the support into contact with the mixture of the at least three first, second and third liquid samples containing at least the group of identical biological recognition molecules, which recognition molecule(s) is (are) optionally complexed with at least one target molecule which is itself optionally complexed with at least one detection molecule so as to attach this or these recognition molecules or complex(es) to the support, preferably at the level of a recognition zone, producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). According to a seventh embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing the support into contact with at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, so as to attach these identical recognition molecules to the support, preferably at the level of a recognition zone, bringing at least a second liquid sample containing at least one target biological molecule into contact with at least a third liquid sample containing at least one biological detection molecule, so as to attach this or these target molecule(s) to the detection molecule(s), bringing the mixture of the at least two second and third liquid samples containing at least one optionally complexed target molecule into contact with a detection molecule so as to attach this or these target molecule(s) to said recognition molecule(s), producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). According to an eighth embodiment, the present invention relates to a method of reading on a support at least one biological reaction, which consists in: bringing at least a second liquid sample containing at least one target biological molecule into contact with at least a third liquid sample containing at least one biological detection molecule, so as to attach this or these target molecule(s) to the detection molecule(s), bringing at least a first liquid sample containing at least one group of biological recognition molecules, which are identical to each other, into contact with the mixture of the at least two second and third liquid samples containing at least one target molecule optionally complexed with a detection molecule so as to attach this or these target molecule(s) to said recognition molecule(s), bringing the support into contact with the mixture of the at least three first, second and third liquid samples containing at least one group of biological recognition molecules, which are identical to each other, which recognition molecule(s) is (are) optionally complexed with at least one target molecule, which is itself optionally complexed with a detection molecule, so as to attach these identical recognition molecules to the support, preferably at the level of a recognition zone, producing a first image of said support after this attachment of the labeled detection molecule(s), treating the support under physicochemical conditions allowing the separation of each detection molecule with respect to a target molecule to which it is specifically attached, producing a second image of said support after this separation, and analyzing the two images in order to determine the specific attachments between the target and detection molecule(s). In the preceding five cases, the method may comprise the following additional subsequent steps: bringing the functionalized and treated support, after specific separation, into contact with the third liquid sample or with another liquid sample, so as to again attach at least one labeled detection molecule to: the target molecule(s) from which it or they had been separated, and/or any other target molecule(s) (3) attached to one or more of the recognition molecules (2) derived from the same recognition zone, producing a third image of said support after this new attachment of detection molecule(s), analyzing the third image with respect to the preceding analysis of the two first images in order to confirm the specific attachments between the target and detection molecule(s). According to a first variant embodiment of the invention, at least one washing is carried out after attachment: of the recognition molecules to the support, the recognition molecules being optionally attached to labeled target molecules and/or to nonlabeled target molecules, the latter being optionally attached to detection molecules, and/or of the labeled target molecules and/or of the nonlabeled target molecules to the recognition molecules, which are themselves attached beforehand to said support, the target molecules being optionally attached to detection molecules, and/or of the detection molecules to nonlabeled target molecules, the latter being attached to recognition molecules, which are themselves attached to the support. According to a second variant embodiment of said invention, the support consists of magnetic particles, and the method comprises steps of magnetizing said magnetic particles, which are preferably put in place: during any step(s) of physicochemical treatment and/or of producing an image, as described above, and/or before any washing step, as described above. According to a third variant embodiment of the invention, the bringing of the support into contact with at least two different first liquid samples, optionally mixed beforehand, allows the attachment of at least two different recognition molecules to said support in at least two distinct recognition zones. Regardless of the variant, when it is desired to quantify at least two optionally different target molecules, the detection molecule consists of a molecule combined directly or indirectly with at least one marker, such as a nanoparticle, whose means, which produce the images, allow individual visualization, despite the presence of other neighboring detection molecules and the like. In all cases, the physicochemical conditions allowing the separation of the labeled target molecules with respect to the recognition molecules or of the detection molecules with respect to the target molecules may be obtained by heating to a melting point. According to a preferred embodiment, the labeled target molecules, the recognition molecules or the target molecules consist of or the detection molecules comprise nucleic acids. According to another preferred embodiment, the labeled target molecules, the recognition molecules or the target molecules consist of or the detection molecules comprise antibodies and/or antigens. Whatever the case, the labeling of the target molecules or of the detection molecules may be carried out by: particles which can be visualized by conventional optical microscopy, fluorescence microscopy, dark field microscopy or atomic force microscopy, molecules which can be visualized by atomic force microscopy, enzymes with precipitating product which produce a detectable signal, for example by fluorescence, luminescence, such as horseradish peroxidase, alkaline phosphatase, β-galactosidase or glucose-6-phosphate dehydrogenase, chromophores such as fluorescent or luminescent compounds, electronic markers which can be detected by electron microscopy, absorbent molecules which can be visualized by thermal lens microscopy. In the case where three successive images of the support are produced, the other liquid sample, in place either of the second or of the third liquid sample, for bringing into contact the functionalized and treated support, after specific separation, comprises a different marker from that contained in said second or third liquid sample. The present invention also relates to a hybrid or complex obtained during the implementation of the method disclosed above, which is bound to a support by a recognition molecule, the hybrid or complex consisting of the recognition molecule bound to a target molecule which is itself bound to a detection molecule. In this case, the bond between the detection molecule and the target molecule is easier to dissociate under suitable physicochemical conditions than the bond between said target molecule and the recognition molecule, and the bond between the target molecule and the recognition molecule is easier to dissociate under suitable physicochemical conditions than the bond between said recognition molecule and the support. In this case, when the recognition, target and detection molecules are based on nucleic acids, the pairing between the detection molecule and the target molecule comprises fewer total paired bases and/or comprises fewer paired Guanine-Cytosine bases than the bond between the target molecule and the recognition molecule. Preferably, the number of total paired bases between the detection molecule and the target molecule is between five and fifty, preferably between ten and twenty five and still more preferably between twelve and twenty, and the number of total paired bases between the target molecule and the recognition molecule is between ten and one hundred, preferably between fifteen and fifty and more preferably still between twenty and thirty. Furthermore, the proportion of paired Guanine-Cytosine bases involved in the binding between the detection molecule and the target molecule is less than or equal to 50%, preferably less than or equal to 45%, and the proportion of paired Guanine-Cytosine bases involved in the binding between the target molecule and the recognition molecule is greater than or equal to 50%, preferably greater than or equal to 55%. The present invention finally relates to a biochip consisting of a plurality of hybrids or complexes, as described above, attached to at least one support, as mentioned above. On this biochip, the structurally identical hybrids or complexes are grouped together to form recognition zones. The accompanying figures and examples are given by way of an explanatory example and do not imply any limitation. They will make it possible to better understand the invention. FIG. 1 represents a step of the method of reading consisting in the introduction of a second liquid containing target molecules into a biochip which carries, for its part, recognition molecules. FIG. 2 represents a step of the method of reading consisting in a washing to remove the nonhybridized or noncomplexed target molecules, that is to say which are not attached within the biochip. FIG. 3 represents a step of the method of reading consisting in the introduction of a third liquid containing detection molecules into a biochip which carries both recognition molecules and target molecules. FIG. 4 represents a step of the method of reading consisting in a washing to remove the nonhybridized or noncomplexed detection molecules, that is to say which are not attached within the biochip. FIG. 5 represents a step of the method of reading consisting in producing a first image which represents the hybrids or complexes detected on the biochip after the steps represented in FIGS. 1 to 4 above. FIG. 6 represents a step of the method of reading consisting in an oriented cleavage allowing dissociation between the target molecules and the detection molecules. FIG. 7 represents a step of the method of reading consisting in the production of a second image which represents the hybrids or complexes detected on the biochip after the step represented in FIG. 6 above. FIG. 8 represents a step of the method of reading consisting in the reintroduction of the third liquid containing detection molecules into a biochip which carries both recognition molecules and target molecules. FIG. 9 represents a step of the method of reading consisting in a washing to remove the detection molecules which have not become attached within the biochip. FIG. 10 represents a step of the method of reading consisting in producing a third image which represents the hybrids or complexes detected on the biochip after the step represented in FIGS. 8 and 9 above. Finally, FIG. 11 represents the last step of the method of reading according to the invention, this step consists in the simultaneous analysis of the second and third images in order to obtain a fourth image which is truly representative of the hybrids or complexes detected on the biochip. The examples above will also make it possible to better understand the invention. EXAMPLE 1 Specific Dissociation of the Detection Molecules Combined with Magnetic Nanoparticles in Relation to Target Molecules The model, chosen from HIV sequences, consists of: a recognition molecule 2, biotinylated in 5′, to allow its attachment to a support 1, corresponding to the sequence SEQ ID N°1, 5′-TCACTATTAT CTTGTATTAC TACTGCCCCT TCACCTTTCC AGAGGAGCTT TGCTGCTCCT TTCCAAAGTG-3′ (length: 70 nucleotides), a target molecule 3, corresponding to the sequence SEQ ID N°2: 5′-ACAGCAGTAC AAATGGCAGT ATTCATCCAC AATTTTAAAA GAAAAGGGGG GATTGGGGGG TACAGTGCAG GGGAAAGAAT AGTAGACATA ATAGCAACAG ACATACAAAC TAAAGAATTA CAAAAACAAA TTACAAAAAT TCAAAATTTT CGGGTTTATT ACAGGGACAG CAGAAATCCA CTTTGGAAAG GACCAGCAAA GCTCCTCTGG AAAGGTGAAG GGGCAGTAGT AATACAAGAT AATAGTGACA TAAAAGTAGT GCCAAGAAGA AAAGCAAAGA TCATTAGGGA TTATGGAAAA CAGATGGCAG GTGATGATTG TGTGGCAAGT AGACAGGATG AGATTAGAAC ATGGAAAAGT TTAGTAAAAC ACCATATGTA TGTTTCAGGG AAAGCTAGGG GATGGTTTTA TAGACATCAC TATGAAAGCC CTCATCCAAG AATAAGTTCA GAAGTAAATC GAATTCCCGC GGCCATGGCG GCCGGGAGCA TGCGACGTCG GGCCCAATTC GCCC-3′ (length: 514 nucleotides), and a detection molecule 4, comprising an oligonucleotide biotinylated at its 3′ end, corresponding to the sequence SEQ ID N°3: 5′-TTCTGAACTT ATTCTT-3′ (length: 16 nucleotides), and a marker. In SEQ ID N°2, part of the sequence is represented in bold and underlined, this part corresponds to the sequence complementary to SEQ ID N°1 of the recognition molecule 2. Another part of the sequence is represented solely underlined, this part corresponds to the sequence complementary to SEQ ID N°3 of the detection molecule 4. First Step: Immnobilization of the Recognition Molecules on the Support: The support 1 used is a Corning glass slide (reference 0211) format 18 mm×18 mm, silanized beforehand with 1% AMPMES (Amino-propyl-dimethyl-ethoxysilane). Onto this support 1 is grafted neutravidin (Neutravidin biotin-binding Protein Pierce reference 31000AH) via PDC (Phenylene diisothiocyanate) at a concentration of 1 mg/ml of PBS (Phosphate Buffer Saline) in the form of a deposit of 2 μl, that is 2 mm in diameter. This preliminary step, not represented in the figures, allows subsequent attachment of the recognition molecules 2 to the support 1, by immobilization of the biotinylated end of said recognition molecules 2 to the neutravidin present on said support 1. After washing with a solution of 1% aqueous ammonia, 1 M NaCl, 1% BSA (Bovine Serum Albumin) and incubating in this same buffer for 10 minutes, the support 1 is washed with water and then with TE buffer (10 mM Tris at pH 8, 1 mM EDTA), 1 M NaCl, in order to remove the neutravidin not attached. The support 1 onto which the neutravidin is attached is then incubated for 20 minutes at room temperature in the presence of recognition molecules 2, in solution in TE, 1 M NaCl, at a concentration of 5 μm. The support 1 is washed in a solution of 1% aqueous ammonia, 1 M NaCl, 1% BSA by an incubation of 10 minutes. This support 1 is then immersed into this same solution so as to saturate the totality of the recognition zones, for 20 minutes, washed with water and then with TE, so as to promote the removal of the recognition molecules 2 not attached to the neutravidin. The step of attachment of the recognition molecules 2 to the support 1 via their biotinylated 5′ end is not represented in the figures, since the support 1, according to FIG. 1, is already functionalized to receive the target molecules 3. Second Step: Hybridization of the Target Molecules to the Recognition Molecules: After immobilization of the recognition molecules 2, the hybridization thereof 2 with the target molecules 3 is carried out by incubation of the support in TE 1 M NaCl, 0.05% Triton X100 overnight at 35° C., which corresponds to FIG. 1. In the present case, 70 complementary base pairs are hybridized. The support 1 is then taken up, washed in this same buffer for 15 minutes at room temperature, as represented in FIG. 2, which makes it possible to remove the target molecules 6 not hybridized. It is interesting to note that according to one variant of the invention, the recognition molecules 2 may be hybridized beforehand with the target molecules 3 and the mixture is then brought into contact directly with the support 1. Third Step: Labeling of the Oligonucleotides with Nanoparticles in Order to Synthesize the Detection Molecules: To detect the target molecules 3 hybridized with the recognition molecules 2, detection molecules 4 are labeled beforehand with magnetic nanoparticles from Immunicon (Huntingdon Valley, USA; ref.: F3106). These nanoparticles have a diameter of 145 nm and are functionalized with streptavidin, generally 6000 to 20000 molecules of streptavidin are attached to a single nanoparticle, each streptavidin allowing the attachment of four biotins. These nanoparticles are incubated at a concentration of 109 particles/ml at 4° C. overnight in TE buffer containing 1 M NaCl, 0.14 mg/ml salmon DNA, 0.05% Triton X100. The oligonucleotide, forming the basis of the detection molecule 4, biotinylated at one of its ends, is then added to the solution of nanoparticles, at the rate of one thousand detection oligonucleotides per nanoparticle, and then incubated for 30 minutes at 35° C. Each detection oligonucleotide combined with a nanoparticle constitutes a detection molecule 4. Fourth Step: 1st Hybridization of the Detection Molecules with the Target Molecules: Each step, represented in FIG. 3, consists in bringing the target molecules 3 hybridized with the recognition molecules 2 into contact with the detection molecules 4. For this, the support 1, onto which are attached the target molecules 3 hybridized with the recognition molecules 2, is incubated with 1 ml of the solution of detection molecules 4, prepared according to the preceding step, at the rate of 109 nanoparticles/ml for 1 hour at room temperature. The hybridization is performed on 16 complementary base pairs. The support 1 is then washed in TE buffer containing 1 M NaCl, 0.05% Triton X100 for 15 minutes at room temperature so as to promote the removal of the detection molecules not hybridized with the target molecules 3, as represented in FIG. 4. It is advantageous to note that according to one variant of the invention, the detection molecules 4 may be hybridized beforehand with the target molecules 3 and the mixture is then directly brought into contact with the support 1 to which the recognition molecules 2 are attached. Fifth Step: Production of a 1st Image: A first image 10 is produced by dark field microscopy (twenty (20) times magnification with a dark field lens) which makes it possible to visualize nonfluorescent small sized nanoparticles, which corresponds to FIG. 5. Sixth Step: Thermal Dissociation of the Target Molecules and of the Detection Molecules: This dissociation step is represented in FIG. 6. The detection molecule 4 possesses a melting point of 51° C. whereas the recognition molecule 2 has a measured melting point of 90.5° C. A temperature of 60° C. constitutes a temperature greater than the melting point of the detection molecule 4 and less than the melting point of the recognition molecule 2, allowing dissociation between the target molecule 3 and the detection molecule 4. The dissociation of the detection molecules 4 is thus performed by treating the support 1 in a TE buffer containing 0.05% Triton X100 at 60° C. for 1 hour. Some detection molecules 4 remain at the surface, but those which remain correspond to the detection molecules not specifically adsorbed at the surface. This dissociation may also be obtained by incubating the support 1 in Sodium Phosphate buffer at pH 5.5 at a concentration of 100 mM, containing 1 mM EDTA, 0.05% Triton X100 for 1 hour at 60° C. The dissociation does not depend on the nature of the buffer used for the hybridization (Sodium Phosphate buffer at pH 5.5 and 100 mM, 1 M NaCl, 1 mM EDTA, 0.05% Triton X100, or Sodium Phosphate buffer at pH 5.5 and 100 mM, 0.1 M NaCl, 1 mM EDTA, 0.05% Triton X100). The conditions necessary are the use of a low ionic strength, or even salt-free, buffer and heating for 1 hour at 60° C. Seventh Step: Production of a Second Image: There is produced by dark field microscopy a second image 11 which makes it possible to observe that most of the detection molecules 4 hybridized beforehand with the target molecules, which constituted true-positives, have disappeared. That is what is represented in FIG. 7. This 2nd image 11 thus makes it possible to detect the detection molecules 4 which are only adsorbed at the surface or which were not properly hybridized with the target molecules 3, that is to say without mismatch, which constitute false-positives. By subtracting the detection spots present on the 1st image 10 from those of the 2nd image 11, it is possible to thus distinguish the presence of true-positives and false-positives. Eighth Step: 2nd Hybridization of the Detection Molecules with the Target Molecules: With the aim of further refining the results of the preceding steps, the support 1 is incubated a second time with the detection molecules 4 under identical conditions to the first hybridization described above in the fourth step, so as to reconstitute the labeling of the target molecules 3, already hybridized with the recognition molecules 2, with the detection molecules 4. That is what is indeed represented in FIG. 8. The support 1 is then washed in TE buffer containing 1 M NaCl, 0.05% Triton X100 for 15 minutes at room temperature, which corresponds to FIG. 9. Ninth step: Production of a 3rd Image: This 3rd image 12 makes it possible to refine the distinction made during the seventh step between the true-positives and the false-positives. Furthermore, the detection molecules 4 being specific for the target molecules 3, this 3rd image 12 makes it possible to verify, as represented in FIG. 10, that said target molecules 3 are still present on said recognition molecules 2, since the same intensity of the detection signal is obtained as that for the 1st image. Consequently, the target molecules 3 are not dissociated from the recognition molecules 2 during the treatment with TE containing Triton X100 at 60° C.: the dissociation is oriented. It is also possible to carry out a final step corresponding to FIG. 11, where computer means can process the three images obtained 10, 11 and 12 so as to precisely define the detection spots 18 really corresponding to detection molecules 4 hybridized with recognition molecule 2—target molecule 3 hybrids. EXAMPLE 2 Oriented Dissociation of the Detection Molecules Combined with Fluorescent Nanoparticles in Relation to Target Molecules This example uses the biological model described in Example 1. The two first steps described in Example 1, which correspond respectively to the immobilization of the recognition molecules 2 on the support 1, and the hybridization of the target molecules 3 with the recognition molecules 2 are performed in a comparable manner in this example. The third step, which corresponds to the labeling of the detection molecules on the other hand differs from Example 1 since the nanoparticles which were used for labeling the detection molecules 4 are fluorescent nanoparticles supplied by Molecular Probe (Eugene Oreg. USA ref.: T8860) of 100 nm in diameter, already functionalized with neutravidin. The detection molecules 4 thus obtained are purified on Microcon YM30 (Amicon MILLIPORE ref.: 42409). The 1st hybridization of the detection molecules 4 with the target molecules is carried out as described in the fourth step of Example 1. The counting of the detection spots is carried out by means of a 1st image 10, obtained by fluorescence microscopy according to FIG. 5. The dissociation step is carried out in TE buffer containing 0.05% Triton X100 at 60° C. for one hour, as represented in FIG. 7, as described above in the sixth step of Example 1. A second image 11 is produced by fluorescence microscopy. By subtracting the intensity of fluorescence obtained in the first image from that obtained in the second image, it is possible to deduce therefrom the fluorescence intensity due to the presence of false-positives. In a comparable manner to what is described in Example 1, a 2nd hybridization of the detection molecules 4 with the target molecules 3 followed by a third image 12 makes it possible to check that a fluorescence intensity is indeed obtained which is comparable to that detected in the first image 10, demonstrating once again that the dissociation is indeed oriented. The dissociation can therefore be performed with detection molecules 4 labeled with nanoparticles of a different nature. EXAMPLE 3 Oriented Dissociation of a Target Molecule Hybridized Between Two Oligonucleotides Combined with Nanoparticles The sequences of the recognition molecules 2, target molecules 3 and detection molecules 4 used in this example are identical to those described in Example 1. In this example, the invention is used with a double hybrid combining the target molecule 3 with: the recognition molecule 2, itself 2 combined with a magnetic particle, and the detection molecule 4 labeled with a fluorescent nanoparticle. The use of a magnetic particle, which does not serve here as a marker, makes it possible to use a simple purification protocol by mere magnetization, and the use of a fluorescent particle makes it possible to use fluorescence as the sensitive method for detecting and counting the hybrids manufactured. Thus, the recognition molecules 2 are combined with magnetic particles (Immunicon Streptavidine; Huntingdon Valley, USA, ref. F3106; diameter 145 nm; concentration 109 p/ml) while the detection molecules 4 are combined with fluorescent nanoparticles (Molecular Probes Neutravidine; diameter 100 nm; concentration 109 p/ml). In a first stage, the target molecules 3 are hybridized with the fluorescent detection molecules 4. The target molecules 3 (concentration: 106 p/μl) are incubated at room temperature for 4 hours with the detection molecules 4 (concentration: 1 nM) in TE buffer containing 1 M NaCl and 0.05% Triton (final volume: 20 μl). In a second stage, the target molecules 3 hybridized with the detection molecules 4 are incubated for 1 hour at room temperature with the recognition molecules 2 combined with the magnetic particles. The target molecules 3 are thus sandwiched between a magnetizable recognition molecule 2 and a fluorescent detection molecule 4. In a third stage, the double hybrids are observed under a microscope with epifluorescence illumination or with dark field illumination. A device with a permanent magnet, placed under the plate of the microscope, makes it possible to apply a magnetic field of 300 Gauss. Under the action of this magnetic field, the magnetic particles assemble in the form of rods into which fluorescent particles may be incorporated. However, at this stage of the test, it cannot be concluded whether these conjugates incorporate a target molecule or otherwise. In a fourth stage, this uncertainty is removed at an oriented dissociation stage. For this, the buffer for suspending the particles is replaced, under a magnetic confining field, by a low ionic strength TE buffer containing 0.05% Triton X100, and the particles are heated at 70° C. for 30 minutes. Immediately afterwards, a magnetic washing is carried out. The suspension obtained is examined under a microscope, still under a magnetic field of 300 Gauss. The combination of the ionic strength and the temperature therefore made it possible to separate the target molecules 3 from the detection molecules 4. The level of dissociation depends on the exact nature of the functionalizations of the two types of nanoparticles and also on the length and the sequence of the DNA molecules, and on the composition of the buffer. This mode of application of oriented dissociation between a fluorescent particle and a magnetic particle, or more precisely between a target molecule 3 and a detection molecule 4, can be carried out with other types of nonmagnetic or nonfluorescent particles, or with particles whose functionalization is different, or with particles of different sizes. EXAMPLE 4 Oriented Dissociation of the Labeled Target Molecules in Relation to the Recognition Molecules The main characteristic of this example is to directly use labeled target molecules without having recourse to detection molecules for detecting the hybridization between the recognition molecules and the target molecules. The model consists of: a recognition molecule, whose sequence is identical to that described in Example 1 a target molecule, whose sequence is identical to that described in Example 1, fragmented and labeled beforehand according to the protocol described in patent application PCT/FR99/03192. Using this method, fragments of about 50 nucleotides, labeled at their 3′ end with a fluorescent marker, are obtained. One of these fragments, called detection fragment can hybridize by complementarity with the recognition molecule according to a protocol similar to that which is described in Example 1. Thus, the immobilization of the recognition molecules on the support is carried out as described in the first stage of Example 1. After immobilization of the recognition molecules, the hybridization of the recognition molecules with the labeled target molecules is carried out by incubating the support in TE containing 1 M NaCl. The support 1 is then taken up, washed in this same buffer for 15 minutes at room temperature. This washing step is very important since it makes it possible to remove the fragments obtained by this method, which are the detection fragments which are not hybridized, and the fragments which do not possess the region complementary to the recognition molecule. A first image is produced by fluorescence microscopy, as described in Example 2, which makes it possible to obtain the level of fluorescence due to the presence of true-positives, but also of false-positives. The dissociation of the target molecules labeled with the recognition molecules is then carried out by incubating the support in a TE buffer containing 0.05% Triton X100, at 95° C. for 1 h. A second image is then produced which makes it possible to detect the detection fragments which are only adsorbed at the surface and which were not properly hybridized with the recognition molecules, which constitute false-positives. As described in Example 1, by subtracting the detection spots present on the 1st image from those of the 2nd image, it is possible to distinguish between the presence of true-positives and false-positives. Still with the aim of checking the results obtained in the preceding stages, the support to which the recognition molecules are attached is incubated a second time with the target molecules under conditions identical to the first recognition molecule—target molecule hybridization described above, and the support is washed in TE buffer containing 1 M NaCl, 0.05% Triton X100 for 15 minutes at room temperature. A 3rd image makes it possible to verify the distinction made between the true-positives and the false-positives. Furthermore, this 3rd image makes it possible to verify that said recognition molecules are still present on the support since the same intensity of the detection signal is obtained as that for the 1st image. Consequently, the recognition molecules need not become dissociated from the support. REFERENCES 1. Biochip support 5 2. Recognition molecule 3. Target molecule 4. Detection molecule 5. Biochip 6. Nonhybridized or noncomplexed target molecule 7. Target molecule hybridized or complexed elsewhere than on a recognition molecule 2 8. Nonhybridized or noncomplexed detection molecule 9. Detection molecule adsorbed or complexed elsewhere than on a target molecule 3 10. First image 11. Second image 12. Third image 13. Fourth image 14. Detection spot corresponding to a detection molecule 4, 8 or 9 15. Position of a detection spot which has disappeared, corresponding to a detection molecule 4 16. Detection spot corresponding to a detection molecule 9 17. Detection spot which has just appeared, corresponding to a detection molecule 9 18. Detection spot corresponding to a detection molecule 4

20040401

20090630

20050630

62590.0

CROW, ROBERT THOMAS

READING, DETECTION OR QUANTIFICATION METHOD, HYBRIDS OR COMPLEXES USED IN SAID METHOD AND THE BIOCHIP USING SAME

UNDISCOUNTED

ACCEPTED

ACCEPTED

Conjugated polymers containing spirobifluorene units and the use thereof

The present invention relates to novel conjugated polymers comprising spirobifluorene units and their use in optoelectronic devices, preferably in, for example, displays based on polymeric organic light-emitting diodes.

1. A conjugated polymers which comprise units of the formula (I) together with one or more units selected from the following groups: group 1: units which significantly increase the hole injection or transport properties of the polymers; group 2: units which significantly increase the electron injection or transport properties of the polymers; group 3: units which comprise combinations of individual units of group 1 and group 2; group 4: units which alter the emission characteristics so that phosphorescence can be obtained instead of fluorescence; where the symbols and indices have the following meanings: X is identical or different on each occurrence and is in each case CH, CR1 or N, Z is identical or different on each occurrence and is in each case a single chemical bond, a CR3R4 group, a —CR3R4—CR3R4— group, a —CR3═CR4— group, O, S, N—R5, C═, C═CR3R4 or SiR3R4; R1 is identical or different on each occurrence and is in each case a linear, branched or cyclic alkyl or alkoxy chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms is optionally replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms is optionally replaced by fluorine, or is an aryl or aryloxy group which has from 5 to 40 carbon atoms and in which one or more carbon atoms is optionally replaced by O, S or N, which is optionally substituted by one or more nonaromatic radicals R1, or is Cl, F, CN, N(R5)2, N(R5)3+, where two or more radicals R1 together form a ring system; R2 is identical or different on each occurrence and is in each case a linear, branched or cyclic alkyl or alkoxy chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms is optionally replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms is optionally replaced by fluorine, or is an aryl or aryloxy group which has from 5 to 40 carbon atoms and in which one or more carbon atoms is optionally replaced by O, S or N which is optionally substituted by one or more nonaromatic radicals R1, or is CN; R3 and R4 are identical or different on each occurrence and are each H, a linear, branched or cyclic alkyl chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms is optionally replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms is optionally replaced by fluorine, or are each an aryl group which has from 5 to 40 carbon atoms and in which one or more carbon atoms is optionally replaced by O, S or N, which is optionally substituted by one or more nonaromatic radicals R1, or are each CN; where a plurality of adjacent radicals R3 and/or R4 may together also form a ring; R5 is identical or different on each occurrence and is in each case H, a linear, branched or cyclic alkyl chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms is optionally replaced by O, S, —CO—O—, O—CO—O, where one or more H atoms is optionally replaced by fluorine, or is an aryl group which has from 5 to 40 carbon atoms and in which one or more carbon atoms is optionally replaced by O, S or N, which is optionally substituted by one or more nonaromatic radicals R1; m is identical or different on each occurrence and is in each case 0, 1, 2, or 3; n is identical or different on each occurrence and is in each case 0, 1, 2, 3 or 4; with the proviso that repeating units of the formula (I) and units of groups 1 to 4 together make up at least 40% of all repeating units in the polymer and that the ratio of repeating units of the formula (I) to the sum of those of groups 1 to 4 is in the range from 20:1 to 1:2. 2. A polymer as claimed in claim 1, characterized in that the units of group 1 are selected from among the units of the formulae (II) to (XIX), where the symbols R1, R2, R4, R5 and the indices n and m are as defined under the formula (I) in claim 1 and Ar1, Ar2, Ar3 are identical or different on each occurrence and are aromatic or heteroaromatic hydrocarbons which have from 2 to 40 carbon atoms and is optionally substituted by one or more nonaromatic radicals R1; o is 1, 2 or 3. 3. A polymer as claimed in claim 1, characterized in that the units of group 2 are selected from among units of the formulae (XX) to (XXX), where the symbols R1 and indices m and n are as defined under the formula (I) in claim 1 and p is 0, 1 or 2. 4. A polymer as claimed in claim 1, wherein the units of group 3 are selected from among units of the formulae (XXXI) to (XXXXVI), where the symbols Ar1, R1, R2, R3, R4, R5, Z and the indices m, n and p are as defined in claim 1 and o is 1, 2 or 3; and p is 0, 1 or 2. 5. A polymer as claimed in claim 1, wherein the units of group 4 are selected from among units of the formulae (XXXXVII) to (XXXXX), where the symbols R1, R3 and the indices m and n are as defined in claim 1 and M is Rh or Ir XX corresponds to the point of linkage in the polymer, and YY is identical or different on each occurrence and is in each case O, S or Se. 6. A polymer as claimed in claim 1, which comprises both structural units of the formula (I) and at least two groups selected from groups 1 to 4. 7. A polymer as claimed in claim 6, characterized in that both structural units of the formula (I) and further units of groups 1 and 2, or 1 and 3, or 1 and 4, or 2 and 3, or 2 and 4, or 3 and 4 are present. 8. A polymer as claimed in claim 6, characterized in that both structural units of the formula (I) and further structures from groups 1 and 2 and 3, or 1 and 2 and 4, or 2 and 3 and 4 are present. 9. cancelled 10. A polymer as claimed in claim 2, wherein more than one structural unit from a group are simultaneously present. 11. A polymer as claimed in claim 1, wherein X=C—H or C—R1. 12. A polymer as claimed in claim 1, wherein Z represents a single chemical bond. 13. A polymer as claimed in claim 1, wherein: R1 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 8 carbon atoms, or is an aryl group having from 6 to 10 carbon atoms, which are also substituted by one or more nonaromatic radicals R1; n are identical or different and are each 1 or 2. 14. A polymer as claimed in claim 1, wherein: R1 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 8 carbon atoms, or is an aryl group having from 6 to 10 carbon atoms, which are also substituted by one or more nonaromatic radicals R1; n are identical or different and are each 1 or 2. 15. A polymer as claimed in claim 1, which further comprises at least one additional aromatic or other conjugated structure which does not come under groups 1 to 4. 16. A polymer as claimed in claim 15, wherein the polymer comprises aromatic structures having from 6 to 40 carbon atoms or stilbene or bisstyrylarylene derivatives which is optionally substituted by one or more nonaromatic radicals R1. 17. A polymer as claimed in claim 15, wherein 1,4-phenylene, 1,4-naphthylene, 1,4- or 9,10-anthracenylene, 1,6- or 2,7- or 4,9-pyrene, 3,9- or 3,10-perylene, 2,7- or 3,6-phenanthrene, 4,4′-biphenylene, 4,4″-terphenylene, 4,4′-bi-1,1′-naphthylene, 4,4′-stilbene or 4,4″-bisstyrylarylene derivatives are incorporated. 18. (cancelled) 19. A PLED having one or more active layers of which at least one comprises one or more polymers as claimed in claim 1. 20. An electronic component (device) comprising one or more polymers as claimed in claim 1. 21. An organic integrated circuit (O-IC), organic field effect transistor (OFET), organic thin film transistor (OTFT), organic solar cell (O-SC) or organic laser diode (O-laser), characterized in that it comprises one or more polymers as claimed in claim 1. 22. A solution comprising one or more polymers as claimed in claim 1. 23. A polymer as claimed in claim 3, wherein both structural units of the formula (I) and further units of the formulae (II) to (V) and units of the formulae (XXIV) or (XXVI) to (XXX) are present. 24. A polymer as claimed in claim 4, wherein o is 1 or 2 and p is 0 or 1.

The present patent application relates to novel conjugated polymers and their use in optoelectronic devices, preferably in, for example, displays based on polymeric organic light-emitting diodes. Wide-ranging research on the commercialization of display and lighting elements based on polymeric (organic) light-emitting diodes (PLEDs) has been carried on for about 10 years. This development was achieved by the fundamental developments disclosed in EP 423 283 (WO 90/13148). In contrast to low molecular weight organic light-emitting diodes (OLEDs), which have already been introduced on the market, as demonstrated by the commercially available car radios with an “organic display” from Pioneer, the PLEDs have still to be introduced on the market. Significant improvements are still necessary to make these displays genuinely competitive or superior to the liquid crystal displays (LCDs) which currently dominate the market. EP-A-0 423 283, EP-A-0 443 861, WO98/27136, EP-A-1 025 183 and WO 99/24526 disclose polyarylene-vinylene derivatives as conjugated polymeric emitters. EP-A-0 842 208, WO 99/54385, WO 00/22027, WO 00/22026 and WO 00/46321 disclose polyfluorene derivatives as conjugated polymeric emitters. EP-A-0 707 020 and EP-A-0 894 107 disclose polyspirobifluorene derivatives as conjugated polymeric emitters. For the purposes of the present invention, conjugated polymers are polymers which contain mainly sp2-hybridized carbon atoms, which may also be replaced by appropriate heteroatoms, in the main chain. This is equivalent to the alternating presence of double and single bonds in the main chain. “Mainly” means that naturally occurring defects which lead to interruptions to the conjugation do not invalidate the term “conjugated polymers”. However, the term does not include polymers which contain relatively large amounts of deliberately introduced nonconjugated segments. Furthermore, for the purposes of the present text, the term conjugated is likewise used when, for example, arylamine units and/or particular heterocycles (i.e. conjugation by N, O or S atoms) and/or organometallic complexes (i.e. conjugation via the metal atom) are present in the main chain. In contrast, units such as simple (thio)ether bridges, ester linkages, amide or imide linkages are clearly defined as nonconjugated segments. The general structure of PLEDs is disclosed in the abovementioned patent applications or patents and is also described in more detail below. Further refinements (for example passive matrix addressing, active matrix addressing) are likewise known but are not of critical importance for the further description of the present patent application. At present, the commercialization of both single-color and multicolor or full-color displays based on PLEDs is being evaluated. While single-color displays may be able to be produced by means of simple coating technologies (e.g. doctor blade coating, spin coating), multicolor and full-color display elements will very probably require the use of printing processes (e.g. ink jet printing, offset printing, gravure printing processes, screen printing processes). However, all these processes require soluble polymers. Some of the conjugated polymers disclosed in the abovementioned patent applications display good properties for the applications mentioned. Important properties include, in particular, the following: High luminous efficiency and energy efficiency when used in PLEDs. Long operating life when used in PLEDs. Low operating voltage. Good storage stability, both when used in PLEDs and also before introduction into corresponding devices. Good solubility in organic solvents in order to make an appropriate coating process possible at all. Reasonable availability to make economical use in mass-produced products possible. Ability to achieve various colors to make full-color displays possible. It has now surprisingly been found that an improved, further-developed novel class of conjugated polymers has very good properties which are superior to the abovementioned prior art. These polymers and their use in PLEDs are subject matter of the present invention. The invention provides conjugated polymers which comprise units of the formula (I) together with one or more units selected from the following groups: group 1: units which significantly increase the hole injection or transport properties of the polymers; group 2: units which significantly increase the electron injection or transport properties of the polymers; group 3: units which comprise combinations of individual units of group 1 and group 2; group 4: units which alter the emission characteristics so that phosphorescence can be obtained instead of fluorescence; where the symbols and indices have the following meanings: X is identical or different on each occurrence and is in each case CH, CR1 or N, Z is identical or different on each occurrence and is in each case a single chemical bond, a CR3R4 group, a —CR3R4—CR3R4— group, a —CR3═CR4— group, O, S, N—R5, C═O, C═CR3R4 or SiR3R4; R1 is identical or different on each occurrence and is in each case a linear, branched or cyclic alkyl or alkoxy chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms may also be replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms may also be replaced by fluorine, or is an aryl or aryloxy group which has from 5 to 40 carbon atoms and in which one or more carbon atoms may also be replaced by O, S or N, which may also be substituted by one or more nonaromatic radicals R1, or is Cl, F, CN, N(R5)2, N(R5)3+, where two or more radicals R1 may also together form a ring system; R2 is identical or different on each occurrence and is in each case a linear, branched or cyclic alkyl or alkoxy chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms may also be replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms may also be replaced by fluorine, or is an aryl or aryloxy group which has from 5 to 40 carbon atoms and in which one or more carbon atoms may also be replaced by O, S or N which may also be substituted by one or more nonaromatic radicals R1, or is CN; R3, R4 are identical or different on each occurrence and are each H, a linear, branched or cyclic alkyl chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms may also be replaced by N—R5, O, S, —CO—O—, O—CO—O, where one or more H atoms may also be replaced by fluorine, or are each an aryl group which has from 5 to 40 carbon atoms and in which one or more carbon atoms may also be replaced by O, S or N, which may also be substituted by one or more nonaromatic radicals R1, or are each CN; where a plurality of adjacent radicals R3 and/or R4 may together also form a ring; R5 is identical or different on each occurrence and is in each case H, a linear, branched or cyclic alkyl chain which has from 1 to 22 carbon atoms and in which one or more nonadjacent carbon atoms may also be replaced by O, S, —CO—O—, O—CO—O, where one or more H atoms may also be replaced by fluorine, or is an aryl group which has from 5 to 40 carbon atoms and in which one or more carbon atoms may also be replaced by O, S or N, which may also be substituted by one or more nonaromatic radicals R1; m is identical or different on each occurrence and is in each case 0, 1, 2, or 3, preferably 0, 1 or 2, particularly preferably 0 or 1; n is identical or different on each occurrence and is in each case 0, 1, 2, 3 or 4, preferably 0, 1 or 2, particularly preferably 1 or 2; with the proviso that repeating units of the formula (I) and units of groups 1 to 4 together make up at least 40%, preferably at least 60%, particularly preferably at least 80%, of all repeating units in the polymer and that the ratio of repeating units of the formula (I) to the sum of those of groups 1 to 4 is in the range from 20:1 to 1:2, preferably from 5:1 to 1:2, particularly preferably from 3:1 to 1:1. Preferred units of group 1 are those of the formulae (II) to (XIX), where the symbols R1, R2, R4, R5 and the indices n and m are as defined under the formula (I) and Ar1, Ar2, Ar3 are identical or different on each occurrence and are aromatic or heteroaromatic hydrocarbons which have from 2 to 40 carbon atoms and may be substituted by one or more nonaromatic radicals R1; preferably substituted or unsubstituted aromatic hydrocarbons having from 6 to 20 carbon atoms, very particularly preferably appropriate benzene, naphthalene, anthracene, pyrene or perylene derivatives; o is 1, 2 or 3, preferably 1 or 2. Preferred units of group 2 are those of the formulae (XX) to (XXX), where the symbols R1 and indices m and n are as defined under the formula (I) and p is 0, 1 or 2, preferably o or 1. Preferred units of group 3 are those of the formulae (XXXI) to (XXXXVI), where the symbols Ar1, R1, R2, R3, R4, R5, Z and the indices m, n and p are as defined under the formula (I) and o is 1, 2 or 3, preferably 1 or 2; p is 0, 1 or 2, preferably 0 or 1. Preferred units of group 4 are those of the formulae (XXXXVII) to (XXXXX), where the symbols R1, R3 and the indices m and n are as defined under the formula (I) and M is Rh or Ir XX corresponds to the point of linkage in the polymer, YY is identical or different on each occurrence and is in each case O, S or Se. Preference is given to polymers according to the invention in which structural units of the formula (1) are present together with structural units of at least two of the groups 1 to 4. Particular preference is in this case given to the simultaneous presence of units of groups 1 and 2, or 1 and 3, or 1 and 4, or 2 and 3, or 2 and 4, or 3 and 4. Preference is also given to the simultaneous presence of structures from groups 1 and 2 and 3, or 1 and 2 and 4, or 2 and 3 and 4. It is thus likewise particularly preferred for units of the formulae (II) to (V) and units of the formulae (XXIV) or (XXVI) to (XXX) to be present simultaneously. Furthermore, it is likewise preferred for more than one structural unit from one group to be simultaneously present. Thus, preference is given to at least two structural units from group 1, or from group 2, or from group 3, or from group 4 being present simultaneously. Even when not indicated by the description, it may here be explicitly stated that the structural units of the formula (I) can be unsymmetrically substituted, i.e. different substituents R1 and/or R2 can be present on one unit, or these can also have different positions on each of the two sides. The synthesis of the corresponding monomers is, for example, described in detail in the abovementioned patent applications and patents. Thus, for example, monomers which then give structures of the formula (I) in the polymer can be synthesized as described in EP-A-0676461, EP-A-0707020, EP-A-0894107 and the literature references cited therein. The polymers of the invention are different from the previously known polyspirobifluorenes (as described in EP-A-0 707 020 and EP-A-0 894 107): although these patent applications described polymers which can comprise structures of the formula (I), no mention is made of the formulae (II) to (XXXXX). Although copolymers in which these are present are disclosed, these copolymers comprise, according to the descriptions, mainly arylene or vinylene structures in addition to the structures of the formula (I). The presence of elements of the structures (II) to (XXXXX) brings the following surprising advantages: (1) If structures of the formulae (II) to (XIX) are present, improved charge injection and transport, especially for holes, is observed. In use, this leads to a higher current and thus also a higher luminance being achieved at a given voltage. This is of critical importance especially for mobile applications (e.g. displays for mobile telephones, PDAs, etc.), since the maximum operating voltage is restricted here. For further details, see Example P1 (comparison: C1-C3); also P2-P19, P21-P23, P25-P32, P34-P41. (2) If structures of the formulae (XX) to (XXX) are present, an analogous situation is observed for electrons. This can have advantages similar to those described under (1). If both structures of the formulae (II) to (XIX) and structures of the formulae (XX) to (XXX) are present, this can further increase the effect. For further details, see Examples P12-P24, P40, P41 (comparison: C1-C3). (3) Structures of the formulae (XXIX) to (XXXXV) make variation of the electronic band gap possible, and thus allow alteration of the color properties. While mainly blue emission is mentioned in the abovementioned applications, the use of these structures makes it possible to achieve blue-green, green, yellow, orange and red emission as well. For further details, see P12-P35, P40, P41 (comparison: C1). (4) The structures of the formulae (XXXXVII) to (XXXXX) lead to a different type of emission (known as phosphorescence) occurring. This can give a higher quantum efficiency and thus also contribute to an improvement in corresponding components. The polymers of the invention generally have from 10 to 10 000, preferably from 50 to 5000, particularly preferably from 50 to 2000, repeating units. The necessary solubility is ensured, in particular, by the substituents R1, R3 and/or R4. If substituents R2 are present, these also contribute to the solubility. To ensure sufficient solubility, it is necessary for on average at least 2 nonaromatic carbon atoms per repeating unit to be present in the substituents. Preference is given to at least 4, particularly preferably at least 8, carbon atoms. Some of these carbon atoms may also be replaced by O or S. This can, however, mean that a certain proportion of repeating units, both of the formulae (I) to (XXXXX) and of other structural types, bear no further nonaromatic substituents. To prevent morphology of the film being impaired, it is preferred that there are no long-chain substituents having more than 12 carbon atoms in a linear chain, preferably none having more than 8 carbon atoms, particularly preferably none having more than 6 carbon atoms. Nonaromatic carbon atoms are, as in the description of, for example, R1, present in appropriate linear, branched or cyclic alkyl or alkoxy chains. Preference is given to polymers according to the invention in which X=C—H or C—R1. Preference is also given to polymers according to the invention in which the symbol Z represents a single chemical bond. Furthermore, preference is given to polymers according to the invention in which: R1 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 8 carbon atoms, or is an aryl group having from 6 to 10 carbon atoms, which are also substituted by one or more nonaromatic radicals R1; n are identical or different and are each 1 or 2. Furthermore, particular preference is given to polymers according to the invention in which: R1 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 8 carbon atoms, or is an aryl group having from 6 to 10 carbon atoms, which are also substituted by one or more nonaromatic radicals R1; n are identical or different and are each 1 or 2. Furthermore, preference is given to polymers according to the invention in which: R2 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 10 carbon atoms, where one or more H atoms may also be replaced by fluorine, or is an aryl or aryloxy group having from 6 to 14 carbon atoms, which may also be substituted by one or more nonaromatic radicals R1, or is CN; m is identical or different on each occurrence and is in each case 0 or 1. Furthermore, particular preference is given to polymers according to the invention in which: R2 is identical or different on each occurrence and is in each case a linear or branched alkyl or alkoxy chain having from 1 to 8 carbon atoms, where one or more H atoms may also be replaced by fluorine, or is an aryl group having from 6 to 10 carbon atoms, which may also be substituted by one or more nonaromatic radicals R1; m is identical or different on each occurrence and is in each case 0 or 1, where m is equal to 0 for at least 50%, preferably at least 70%, very particularly preferably at least 90%, of all repeating units of the formula (I) or (VI) to (XIII) present in the polymer. Preference is also given to polymers according to the invention in which: R3, R4 are identical or different on each occurrence and are each a linear, branched or cyclic alkyl chain which has from 1 to 10 carbon atoms and in which one or more nonadjacent carbon atoms may also be replaced by O, where one or more H atoms may also be replaced by fluorine, or are each an aryl group which has from 5 to 40 carbon atoms and in which one or more carbon atoms may also be replaced by O, S or N, which may also be substituted by one or more aromatic radicals R1. The polymers of the invention are per se copolymers which have at least two different repeating units (one of the formula (I), one selected from among the formulae (II) to (XXXXX). The copolymers of the invention can have random, alternating or block structures, or have a plurality of these structures present in an alternating fashion. However, preference is also given to copolymers according to the invention which have one or more different structures of the formula (I) and/or one or more different structures of the formulae (II) to (XXXXX). The use of a plurality of different structural elements enables properties such as solubility, solid-state morphology, color, charge injection and transport properties, thermal stability, electrooptical characteristics, etc., to be adjusted. Preferred polymers according to the invention are polymers in which at least one structural element has charge transport properties. For the purposes of the present patent application, such structural elements are as follows: if HOMOPOLYMERS or OLIGOMERS were produced from these structural elements, they would have a higher charge carrier mobility, at least for one charge carrier, i.e. either electrons or holes, as is the case for a polymer consisting exclusively of structural elements of the formula (I). The charge carrier mobility (measured in cm2/(V*s)) is preferably at least a factor of 10 higher, particularly preferably a factor of at least 50 higher. Structural elements which have hole transport properties are, for example, triarylamine derivatives, benzidine derivatives, tetraarylene-para-phenylenediamine derivatives, phenothiazine derivatives, phenoxazine derivatives, dihydrophenazine derivatives, thianthrene derivatives, benzo-p-dioxin derivatives, phenoxathiine derivatives, carbazole derivatives, azulene derivatives, thiophene derivatives, pyrrole derivatives, furan derivatives and further O, S or N-containing heterocycles having a high HOMO (HOMO=highest occupied molecular orbital); these heterocycles preferably lead to an HOMO in the polymer of less than 5.8 eV (relative to vacuum level), particularly preferably less than 5.5 eV. Preference is given to polymers according to the invention which further comprise at least one structural unit of the formulae (II) to (XXX). The proportion of these structural elements is at least 1%, preferably at least 5%. The maximum proportion is 50%, preferably 30%. These structural units, too, can be incorporated randomly, in an alternating fashion or as blocks in the polymer. The way in which the structures are incorporated has already been indicated directly for many of them (cf., for example, formulae (II) to (V) and formulae (XIII) to (XIX)). In the case of other structures, a number of possibilities are in each case possible according to the invention. However, in these cases there are also preferred ways in which they can be incorporated: In the case of the N-containing tricyclic heterocycles (formula (VI) to formula (VIII)), linkage via carbon atoms in the para position relative to the nitrogen (i.e. in the case of phenothiazine and phenoxazine derivatives: 3,7 positions; in the case of dihydrophenazine derivatives: 2,7 or 3,7 positions) is preferred in each case. An analogous situation applies to carbazole derivatives (formula (XII)). On the other hand, in the case of the O- and/or S-containing tricycles (formulae (IX) to (XI)), both ortho and para positions relative to one of the heteroatoms are preferred. In the case of heterocycles in which more than the ring is present, linkage to the polymer via only one ring or via two rings is possible. Monomers for the incorporation of structural units of formula (II), formula (III), formula (IV) and formula (V) can be synthesized, for example, as described in WO98/06773. Monomers for the incorporation of structural units of formula (VI), formula (VII) and formula (VIII) can be synthesized, for example, as described by M. Jovanovic et al., J. Org. Chem. 1984, 49, 1905, and H. J. Shine et al., J. Org. Chem. 1979, 44, 3310. Monomers for the incorporation of structural units of formula (IX) and formula (X) can be synthesized, for example, as described in J. Lovell et al., Tetrahedron 1996, 52, 4745, U.S. Pat. No. 4,505,841 and the references cited therein. Monomers for the incorporation of structural units of formula (XI) can be synthesized, for example, as described by A. D. Kuntsevich et al., Zh. Obshch. Khim. 1994, 64, 1722, and A. D. Kuntsevich et al., Dokl. Akad. Nauk 1993, 332, 461. Many halogenated monomers for the incorporation of structural units of the formula (XII) are known from the literature and some of them are even commercially available. A listing of all possible methods would go beyond the scope of the present patent application. Monomers for the incorporation of structural units of the formula (XIII) can, for example, be synthesized as described by R. H. Mitchell et al., Org. Prep. Proced. Int. 1997, 29, 715. Many halogenated monomers for the incorporation of structural units of the formula (XIV) are known from the literature and some of them are even commercially available. A listing of all possible methods would go beyond the scope of the present patent application. Monomers for the incorporation of structural units of the formula (XV) can be synthesized, for example, as described by H. M. Gilow et al., J. Org. Chem. 1981, 46, 2221, and G. A. Cordell, J. Org. Chem. 1975, 40, 3161. Monomers for the incorporation of structural units of the formula (XVI) can be synthesized, for example, as described by M. A. Keegstra et al., Synth. Commun. 1990, 20, 3371, and R. Sornay et al., Bull. Soc. Chim. Fr. 1971, 3, 990, and some of them are also commercially available. Some monomers for the incorporation of structural units of the formula (XVII) are commercially available. Monomers for the incorporation of structural units of the formula (XVIII) can be synthesized, for example, as described in JP 63-250385. Monomers for the incorporation of structural units of the formula (XIX) can be synthesized, for example, as described by M. El Borai et al., Pol. J. Chem. 1981, 55, 1659, and some of them are also commercially available. The literature references listed here for the synthesis of monomers which in the polymer give structures of the formulae (II) to (XIX) describe mainly the synthesis of halogen derivatives, preferably bromine derivatives. From these, a person skilled in the art can easily prepare, for example, boronic acid derivatives or stannates. This can be achieved, for example, by metallation (e.g. by means of Mg (Grignard reaction) or Li (e.g. by means of Bu-Li)) and subsequent reaction with appropriate boron or tin derivatives, e.g. trialkyl borates or trialkyltin halides. It is, however, naturally also possible to produce boronic acid derivatives from the corresponding bromides in the presence of transition metal catalysts using boranes or diboranes. There is a great variety of further methods known from the literature and these can naturally also be used by a person skilled in the art. Structural elements of group 2 are, for example, pyridine derivatives, pyrimidine derivatives, pyridazine derivatives, pyrazine derivatives, oxadiazole derivatives, quinoline derivatives, quinoxaline derivatives, phenazine derivatives and further O-, S- or N-containing heterocycles having a low LUMO (LUMO=lowest unoccupied molecular orbital); these heterocycles preferably lead to an LUMO in the polymer of more than 2.7 eV (relative to vacuum level), particularly preferably more than 3.0 eV. Preference is given to polymers according to the invention which contain at least one structural unit of the formulae (XX) to (XXX). The proportion of these structural elements is at least one 1%, preferably at least 5%. The maximum proportion is 70%, preferably 50%. These structural units, too, can be incorporated randomly, in an alternating fashion or in blocks in the polymer. The way in which the structures are incorporated has already been indicated directly for many of them (cf., for example, formulae (XXIV), (XXIX) und (XXX)). In the case of other structures, a number of possibilities are in each case possible according to the invention. However, in these cases there are also preferred ways in which they can be incorporated: In the case of pyridine derivatives, linkage via the 2,5 or 2,6 positions is preferred, in the case of pyrazine and pyrimidine derivatives that via the 2,5 positions is preferred and in the case of pyridazine derivatives that via the 3,6 positions is preferred. In the case of the bicyclic heterocycles, a plurality of linkages are generally possible and also preferred. However, in the case of quinoxaline, linkage via the 5,8 positions is unambiguously preferred. In the case of phenazine, it may, as indicated, be preferred that linkage occurs via the two outer rings or that incorporation is via only one ring. Preferred positions are therefore incorporation at carbon atoms 1,4 or 2,3 or 2,7 or 3,7. The chemistry of pyridine derivatives (XX) has been examined in great detail. Thus, the preparation of 2,5- and 2,6-dihalopyridines is likewise known. Reference may here be made to the numerous standard works on heterocyclic chemistry. Furthermore, many of the compounds are also commercially available. Monomers for the incorporation of structural units of the formula (XXI) can be synthesized, for example, as described in Arantz et al., J. Chem. Soc. C 1971, 1889. Monomers for the incorporation of structural units of the formula (XXII) can be synthesized, for example, as described in Pedrali et al., J. Org. Synth. 1958, 23, 778. Monomers for the incorporation of structural units of the formula (XXIII) can be synthesized, for example, as described by Ellingson et al., J. Am. Chem. Soc. 1949, 71, 2798. Monomers for the incorporation of structural units of the formula (XXIV) can be synthesized, for example, as described in Stolle et al., J. Prakt. Chem. 1904, 69, 480. Monomers for the incorporation of structural units of the formula (XXV) can be synthesized, for example, as described in Metzger, Chem. Ber. 1884, 17, 187, and A. I. Tochilkin et al., Chem. Heterocycl. Compd. (Engl. Transl) 1988, 892. Monomers for the incorporation of structural units of the formula (XXVI) can be synthesized, for example, as described in Calhane et al., J. Am. Chem. Soc. 1899, 22, 457, and T. Yamamoto et al., J. Am. Chem. Soc. 1996, 118, 3930. Monomers for the incorporation of structural units of the formulae (XXVII) and (XXVIII) can be synthesized, for example, as described in L. Horner et al., J. Liebigs Ann. Chem., 1955, 597, 1, and P. R. Buckland et al., J. Chem. Res. Miniprint 1981, 12, 4201. Monomers for the incorporation of structural units of the formula (XXIX) can be synthesized, for example, as described in K. Pilgram et al., J. Heterocycl. Chem. 1970, 7, 629, and WO 00/55927. Monomers for the incorporation of structural units of the formula (XXX) can be synthesized, for example, as described in Hammick et al., J. Chem. Soc. 1931, 3308, and K. Pilgram et al., J. Heterocycl. Chem. 1974, 11, 813. The references cited here for the synthesis of monomers which in the polymer gives structures of the formulae (XX) to (XXX) also describe mainly the synthesis of halogen derivatives, preferably bromine derivatives. Using these as a starting point, a person skilled in the art can, as also described above for the properties which increase hole mobility, carry out further transformations, e.g. to give boronic acid derivatives or stannates. Furthermore, preference is also given to polymers according to the invention in which units of group 3 are present. Particular preference is accordingly given to polymers according to the invention which comprise both one or more structures of the formulae (II) to (XIX) and one or more structures of the formulae (XX) to (XXX). The abovementioned limits for the respective proportion continue to apply here. It can be very particularly preferred for the polymers of the invention to comprise units in which structures which increase hole mobility and electron mobility follow one another directly or alternate, as is the case, for example, for the formulae (XXXI) to (XXXXV) and is indicated somewhat more generally for the formula (XXXXVI). Monomers of the formulae (XXXI) to (XXXXVI) can be synthesized by the methods indicated for the formulae (III) to (XXX) by appropriate combination of the appropriate precursors. It may also be pointed out that at least some examples of syntheses are given in the abovementioned patent applications WO 00/46321 and WO 00/55927. Such structures are also reported in, for example, in H. A. M. Mullekom et al., Chem. Eur. J., 1998, 4, 1235. It may be pointed out that the structures of the formulae (XXXI) to (XXXXVI) do not in any way restrict the invention thereto, but it is naturally simple for a person skilled in the art to synthesize suitable combinations of the abovementioned structures (III) to (XIX) or (XX) to (XXX) and to incorporate these into the polymers of the invention. Preference is also given to copolymers whose emission characteristics have been altered so that phosphorescence takes place instead of fluorescence. This is, in particular, the case when organometallic complexes have been incorporated in the main chain. Particular preference is in this case given to complexes of the d series transition metals, very particularly preferably those of the higher metals of the iron, cobalt and nickel triads, i.e. complexes of ruthenium, osmium, rhodium, iridium, palladium and platinum. Such complexes are frequently able to emit light from excited triplet states, which frequently increases the energy efficiency. The use of such complexes in low molecular weight OLEDs is described, for example, in M. A. Baldo, S. Lamansky, P. E. Burrows, M. E. Thompson, S. R. Forrest, Applied Physics Letters, 1999, 75, 4-6. Nothing has yet been reported about the incorporation of these compounds in polymers. Corresponding monomers are described in the as yet unpublished patent application DE 10109027.7. Such structural elements can also have a substantial influence on the emission color and the energy efficiency of the resulting polymers. Examples for particularly preferred complexes which can be incorporated into the polymers of the invention are the abovementioned compounds of the formulae (XXXXVII) to (XXXXX). The preparation of corresponding monomers is described in the above-mentioned unpublished patent application DE 10109027.7, which is hereby incorporated by reference into this disclosure of the present invention. Preferred copolymers which further comprise additional structural elements in addition to those of the formula (I) and the formulae (II) to (XXXXX) also include ones which comprise at least one further aromatic structure or another conjugated structure which does not come under one of the abovementioned groups, i.e. has little if any influence on the charge carrier mobilities or is not an organometallic complex. Such structural elements can influence the morphology and also the emission color of the resulting polymers. Preference is given to aromatic structures which have from 6 to 40 carbon atoms or stilbene or bisstyrylarylene derivatives which may each be substituted by one or more nonaromatic radicals R1. Particular preference is given to the incorporation of 1,4-phenylene, 1,4-naphthylene, 1,4- or 9,10-anthracenylene, 1,6- or 2,7- or 4,9-pyrene, 3,9- or 3,10-perylene, 2,7- or 3,6-phenanthrene, 4,4′-biphenylene, 4,4″-terphenylene, 4,4′-bi-1,1′-naphthylene, 4,4′-stilbene or 4,4″-bisstyrylarylene derivatives. These structures are also mentioned in the patent applications EP-A-0 707 020 and EP-A-0 894 107 cited at the outset, but in contrast to the information given there, these are introduced into the present novel polymers only as additional possibilities for obtaining further modifications. Such structures are widely known in the literature and most are also commercially available. A listing of all possible synthetic variants would go far beyond the scope of the present patent application. The polymers of the invention are generally prepared by polymerization of two or more monomers of which at least one subsequently gives structures of the formula (I) and at least one more gives structures selected from among the formulae (II) to (XXXXX). There are in principle a relatively large number of different polymerization reactions which can be used, but the types listed below have been found to be particularly useful. In principle, all these reaction types give C—C linkages: (A) Polymerization by the SUZUKI method: Here, monomers used are, firstly, bishalides and, secondly, bisboronic acids and corresponding derivatives, or corresponding monohalide-monoboronic acid derivatives, and these are coupled in the presence of palladium catalysts and solvents under basic conditions. Reactions of this type which lead to conjugated polymers have been described many times. There is a series of proposals for making such reactions proceed efficiently and lead to high molecular weight polymers; these are described, inter alia, in the following references: (i) EP 707.020, (ii) EP 842.208, (iii) EP 1.025.142, (iv) WO 00/53656 and (v) in the references cited therein. The corresponding descriptions are hereby incorporated by reference into the disclosure of the present patent application. (B) Polymerizations by the YAMAMOTO method: Here, exclusively bishalides are used as monomers. The polymerizations are carried out in the presence of solvents, a nickel compound, possibly a base and, if desired, a reducing agent and also further ligands. Reactions of this type which lead to conjugated polymers have been described relatively often. There are some proposals for making such reactions proceed efficiently and lead to high molecular weight polymers; these are described, inter alia, in the following references: (i) M. Ueda et al., Macromolecules, 1991, 24, 2694, (ii) T. Yamamoto et al., Macromolecules 1992, 25, 1214, (iii) T. Yamamoto et al., Synth. Met. 1995, 69, 529-31, (iv), T. Yamamoto et al., J. Organometallic Chem. 1992, 428, 223, (v) I. Colon et al., J. Poly. Sci.: Part A: Poly. Chem. 1990, 28, 367, (vi) T. Yamamoto et al., Macromol. Chem. Phys. 1997, 198, 341. The corresponding descriptions are hereby incorporated by reference into the disclosure of the present patent application. (C) Polymerizations by the STILLE method: Monomers used here are, firstly, bishalides and, secondly, bisstannanes, or corresponding monohalide-monostannanes, and these are coupled in the presence of palladium catalysts and solvents, possibly under basic conditions. Reactions of this type which lead to conjugated polymers have been described in the literature. However, they have not been examined to the same extent as the SUZUKI or YAMAMOTO coupling. A conjugated polymer obtained by STILLE coupling is described, for example, in W. Schorf et al., J. Opt. Soc. Am. B 1998, 15, 889. A review of the possibilities and the difficulties of the STILLE reaction is given, inter alia, in V. Farina, V. Krishnamurthy, W. J. Scott (editors) “The Stille Reaction” 1998, Wiley, New York, N.Y. The corresponding descriptions are hereby incorporated by reference into the disclosure of the present patent application. After the polymerization (polycondensation) has been carried out, the polymers synthesized firstly have to be separated off from the reaction medium. This is generally achieved by precipitation in a nonsolvent. The polymers obtained subsequently have to be purified, since especially the content of low molecular weight organic impurities and also the ion content or content of other inorganic impurities sometimes have very strong effects on the use properties of the polymers in PLEDs. Thus, low molecular weight constituents can considerably reduce the efficiency and also cause a dramatic deterioration in the operating life. The presence of inorganic impurities has an analogous effect. Suitable purification methods include, firstly, precipitation procedures in which the polymer is repeatedly dissolved and precipitated in a nonsolvent. It is advantageous to pass the polymer solution through a filter in order to separate off undissolved constituents (gel particles) and also dust particles. A further possibility is the use of ion exchangers to lower the content of ions. Stirring a polymer solution with an aqueous solution containing, for example, chelating ligands, can also be helpful. Further organic or inorganic extraction processes, e.g. with solvent/nonsolvent mixtures, or using supercritical CO2 can also result in considerable improvements here. The novel polymers obtained in this way can then be used in PLEDs. This is usually done using the following general method, which then naturally has to be adapted appropriately to the specific case: A substrate (e.g. glass or a plastic such as specially treated PET) is coated with a transparent anode material (for example indium-tin oxide, ITO); the anode is subsequently structured (e.g. photolithographically) and connected according to the desired application. It is also possible for the entire substrate and the appropriate circuitry firstly to be produced by a quite complicated process to make active matrix control possible. After this, a conductive polymer, e.g. a doped polythiophene or polyaniline derivative, is generally firstly applied either over the entire area or only to the active (=anodic) places. This is generally carried out by coating methods in which a dispersion of the appropriate polymer is applied. This can in principle be carried out using the methods described below for the light-emitting polymer. The thickness of this polymer layer can vary within a wide range, but for practical use will be in the range from 10 to 1000 nm, preferably from 20 to 500 nm. A solution of a polymer according to the invention is then applied, depending on the intended use. For multicolor or full-color displays, a plurality of different solutions are then applied in various regions to produce appropriate colors. The polymers of the invention are for this purpose firstly dissolved individually (it can also be advisable to use blends of two or more polymers) in a solvent or solvent mixture, possibly mechanically after-treated and subsequently filtered. Since the organic polymers and especially the interfaces in the PLED are sometimes extremely sensitive to oxygen or other constituents of the air, it is advisable to carry out this operation under protective gas. Suitable solvents include aromatic liquids such as toluene, xylenes, anisole, chlorobenzene, and also others such as cyclic ethers (e.g. dioxane, methyldioxane) or amides, for example NMP or DMF, and also solvent mixtures, as are described in the unpublished patent application DE 10111633.0. The above-described supports can then be coated with the solutions, either over their entire area, e.g. by spin coating or doctor blade techniques, or else in a resolved manner by means of printing processes such as ink jet printing, offset printing, screen printing processes, gravure printing processes, and the like. These abovementioned solutions are novel and are thus likewise subject matter of the present invention. If desired, electron injection materials can then be applied to these polymer layers, e.g. by vapor deposition or from solution using methods as have been described for the emitting polymers; As electron injection materials, it is possible to use, for example, low molecular weight compounds such as triarylborane compounds or aluminum trishydroxyquinolinate (Alq3) or appropriate polymers such as polypyridine derivatives and the like. It is also possible to convert thin layers of the emitting polymers into electron injection layers by appropriate doping. A cathode is subsequently applied by vapor deposition. This is generally carried out by means of a vacuum process and can, for example, be achieved either by thermal vapor deposition or by plasma spraying (sputtering). The cathode can be applied over the entire area or in a structured fashion by means of a mask. As cathode, use is generally made of metals having a low work function, e.g. alkali metals, alkaline earth metals and f series transition metals, e.g. Li, Ca, Mg, Sr, Ba, Yb, Sm, or else aluminum or alloys of metals, or multilayer structures comprising various metals. In the latter case, metals having a relatively high work function, e.g. Ag, can be concomitantly used. It can also be preferred to introduce a very thin dielectric layer (e.g. LiF or the like) between the metal and the emitting polymer or the electron injection layer. The cathodes generally have a thickness of from 10 to 10 000 nm, preferably from 20 to 1000 nm. The PLEDs or displays produced in this way are subsequently provided with appropriate electrical connections and encapsulated, and then tested or used. As described above, the polymers of the invention are especially useful as electroluminescence materials in the PLEDs or displays produced in the manner described. For the purposes of the invention, electroluminescence materials are materials which can be used as active layer in a PLED. Active layer means, in the present context, that the layer is capable of emitting light (light-emitting layer) on application of an electric field and/or that it improves the injection and/or transport of the positive and/or negative charges (charge injection layer or charge transport layer). The invention therefore also provides for the use of a polymer according to the invention in a PLED, in particular as electroluminescence material. The invention thus likewise provides a PLED having one or more active layers of which at least one comprises one or more polymers according to the invention. The active layer can, for example, be a light-emitting layer and/or a transport layer and/or a charge injection layer. PLEDs are employed, for example, as self-illuminating display elements such as control lamps, alphanumeric displays, multicolor or full-color displays, information signs and in optoelectronic couplers. The present description and the examples below describe the use of polymers according to the invention or blends of polymers according to the invention in PLEDs and the corresponding displays. Despite this restriction of the description, a person skilled in the art will easily be able, without making a further inventive step, to utilize the polymers of the invention for further applications in other electronic devices, e.g. for organic integrated circuits (O-ICs), in organic field effect transistors (OFETs), in organic thin film transistors (OTFTs), for organic solar cells (O-SCs) or organic laser diodes (O-lasers), to name only a few applications. The present invention is illustrated by the following examples without being restricted thereto. A person skilled in the art will be able, on the basis of the description and the examples provided, to prepare further solutions according to the invention and employ these for producing layers without having to make an inventive step. Part A: Synthesis of the Monomers: A1: Monomers for Units of the Formula (I) (Spiro Compounds) A1.1. Preparation of Symmetrical Spiro Monomers Preparation of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1) and the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid (S-SY2) Preparation of 2,7-dibrom-2′,7′-di-tert-butylspirobifluorene (S-SY3) Preparation of the glycol ester of 2′,7′-di-t-butylspirobifluorene-2,7-bisboronic acid (S-SY4) The synthesis is described in the unpublished German patent application DE 10114477.6. A1.2. Preparation of Unsymmetrical Spiro Monomers The preparation of the unsymmetrical spirobifluorene monomers was carried out according to the following scheme: The synthesis will be described in detail for the monomer S-US1; the further monomers were prepared by an analogous method. Preparation of 2,7-dibromo-8′-t-butyl-5′-(4″-t-butylphenyl)-2′,3′-bis(2-methylbutyloxy)spirobifluorene (S-US1) Preparation of 5′-t-butyl-2′-(4″-t-butylphenyl)-2,3-bis(2-methylbutyloxy)biphenyl 205.5 g (0.595 mol) of 2-bromo-4,4′-di-t-butylbiphenyl, 188.7 g (0.641 mol) of 3,4-bis(2-methylbutyloxy)benzeneboronic acid and 177.2 g (1.282 mol) of K2CO3 were suspended in 840 ml of toluene and 840 ml of H2O and the mixture was saturated with N2 for 1 hour. 1.48 g (1.28 mmol) of Pd(PPh3)4 were subsequently added under protective gas and the mixture was stirred vigorously under reflux for about 8 hours under a blanket of protective gas. 630 ml of 1% strength NaCN solution were added and the mixture was stirred for 2 hours. The organic phase was washed three times with water, dried over Na2SO4, filtered and subsequently evaporated completely on a rotary evaporator. This gave 300.2 g (98%) of a light-brown oil which, according to 1H NMR, had a purity of 97% and was used directly in the subsequent reaction. 1H NMR (CDCl3, 500 MHz): [ppm]=7.5-7.3 (m, 3H); 7.23 (m, 2H); 7.08 (m, 2H); 6.81-6.87 (m, 2H); 6.51 (d, 1H); 3.87-3.7 (m, 2H, OCH2); 3.44-3.30 (m, 2H, OCH2); 1.88 (m, 1H, H—C); 1.71 (m, 1H, H—C); 1.62-1.42 (m, 2H, CH2); 1.39 (s, 9H, C(CH3)3); 1.29 (s, 9H, C(CH3)3); 1.10-1.33 (m, 4H, CH2); 1.07-0.83 (m, 12H, 4×CH3). Preparation of 2-bromo-5′-t-butyl-2′-(4″-t-butylphenyl)-4,5-bis(2-methylbutyloxy)biphenyl 300.2 g (0.583 mol) of 5′-t-butyl-2′-(4″-t-butylphenyl)-2,3-bis(2-methylbutyloxy)biphenyl were dissolved in 500 ml of ethyl acetate under protective gas and cooled to 0° C. 103.8 g (0.583 mol) of N-bromosuccinimide were then added as a solid and the mixture was warmed to room temperature. The reaction was complete after 1 hour. The organic phase was washed three times with water, dried, evaporated on a rotary evaporator and subsequently recrystallized from ethanol. This gave 294.1 g (85%) of a colorless solid which had a purity of >99% according to 1H-NMR and of 99.7% according to HPLC. 1H NMR (CDCl3, 500 MHz): [ppm]=7.45-7.35 (m, 3H); 7.19 (m, 2H); 7.06 (m, 3H); 6.50 (d, 1H); 3.87-3.70 (m, 2H, OCH2); 3.55-3.25 (m, 2H, OCH2); 1.88 (m, 1H, H—C); 1.67 (m, 1H, H—C); 1.62-1.42 (m, 1H, CH2); 1.38 (s+m, 10H, C(CH3)3+1H); 1.27 (s+m, 10H, C(CH3)3+1H); 1.15 (m, 1H, CH2); 1.12 (d, 3H, CH3); 0.95 (t, 3H, CH3); 0.9-0.8 (m, 6H, 2×CH3). Preparation of 2,7-dibromo-8′-t-butyl-5′-(4″-t-butylphenyl)-2′,3′-bis(2-methylbutyloxy)spirobifluorene (S-US1) 294 g (0.495 mol) of 2-bromo-5′-t-butyl-2′-(4″-t-butylphenyl)4,5-bis(2-methylbutyloxy)biphenyl were dissolved in 700 ml of distilled THF. 12.4 g (0.510 mol) of magnesium turnings and a few crystals of iodine were placed in a flask kept under protective gas. The mixture was heated briefly and 10% of the amount of starting material in THF was added. After the reaction had started, the remainder was added at such a rate that the reaction mixture refluxed without further introduction of heat (one hour). The mixture was refluxed for a further 3 hours and a further 100 ml of distilled THF were then added. A suspension of 189.7 g (561.2 mmol) of 2,7-dibromfluoren-9-one in 500 ml of distilled THF was cooled to 0° C. The Grignard solution was then added dropwise to the suspension at a temperature of 0-5° C. The mixture was subsequently refluxed for 90 minutes. After cooling to room temperature, the reaction mixture was admixed with a mixture of 600 ml of ice water, 33.2 ml of HCl and 900 ml of ethyl acetate and the organic phase was washed twice with NaHCO3 solution and water, subsequently dried and evaporated on a rotary evaporator. This light-brown oil was heated to boiling with 3000 ml of glacial acetic acid and 21 ml of 37% hydrochloric acid under protective gas, resulting in precipitation of a colorless solid. The mixture was heated for another 2 hours, cooled to RT, the solid was filtered off with suction and washed with 1500 ml of glacial acetic acid. A single recrystallization from 2-butanone gave 310.1 g (75%) of the product, which had a purity of >99.5% according to 1H-NMR and of 99.8% according to HPLC. 1H NMR (CDCl3, 500 MHz): [ppm]=7.67 (d, 2H); 7.55 (d, 2H); 7.53-7.43 (m, 5H); 7.26 (d, 1H); 6.97 (s, 1H); 6.27 (s, 1H); 5.60 (s, 1H), 3.40-3.21 (m, 4H, OCH2); 1.67-1.55 (m, 2H, H—C); 1.42 (s+m, 1H, C(CH3)3+2H); 1.19-1-01 (m, 2H); 1.27 (s+m, 10H, C(CH3)3+1H); 1.15 (m, 1H, CH2); 1.12 (d, 3H, CH3); 0.95 (t, 3H, CH3); 0.82 (s+m, 21H, 1×C(CH3)3+4×CH3). The further monomers are summarized in the following table: Total yield at the end Purity according to Starting aryl of the above HPLC Monomer bromide scheme [%] [%] S-US1 62.5 99.8 S-US2 60.3 99.6 S-US3 27.8 99.8 (as a mixture of 2 isomers in a ratio of about 70/30) S-US4 44.2 99.3 To give an overview, the monomers of the formula (I) whose preparation is carried out here are summarized below: A2: Monomers for Units of the Formulae (II) to (V) (Triarylamines, Phenylenediamine Derivatives and Tetraarylbenzidines) Preparation of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1) Preparation of N,N′-bis(4-bromophenyl)-N,N′-bis(4-methoxyphenyl)benzidine (AM2) Preparation of 4,4′-dibromotriphenylamine (AM3) The synthesis is described in the unpublished German patent application DE 10114477.6. To give an overview, the monomers of the formulae (II) to (V) whose preparation is carried out here are summarized below: A3: Monomers for Units of the Formula (XXVI) The preparation of substituted quinoxaline monomers was carried out according to the following scheme: Preparation of 5,8-dibromodiphenylquinoxaline (CH-b) A solution of 5.3 g (20 mmol) of 3,6-dibromo-1,2-phenylenediamine 1, 4 g (19 mmol) of benzil 2b, 4.2 g of sodium acetate and 150 ml of glacial acetic acid were refluxed for 4 hours. The precipitate was filtered off, washed with 100 ml of water and recrystallized twice from dioxane. Drying under reduced pressure at 50° C. gave the pure product in the form of colorless crystals, which according to HPLC had a purity of about 99.5%. The yield was 6.45 g (73%). 1H NMR (CDCl3, 500 MHz): [ppm]=7.92 (s, 2H), 7.67 (d, 3JHH=1.67 Hz, 2H), 6.66 (d, 3JHH=1.67 Hz, 2H), 7.37 (m, 6H). The other quinoxaline monomers CH-a and CH-c to CH-m were prepared in an analogous manner. The individual quinoxaline monomers are indicated in the scheme above. A4: Monomers for Units of the Formulae (XXIX) and (XXX) Preparation of 4,7-dibromobenzo[1,2,5]thiadiazole (N2S-1) Preparation of 4,7-dibromobenzofurazone (N2O-1) The synthesis described in the unpublished German application DE 10114477.6. To give a better overview, the monomers described, of the formulae (XXIX) and (XXX), are depicted below. A5: Monomers for Units of the Formulae (XXXI) to (XXXXVI) Such monomers were prepared according to the following scheme: Preparation of bis-4,7-(2′-bromo-5′-thienyl)-2,1,3-benzothiadiazole (N2S-1)-T2-Br2. Preparation of bis-4,7-(thien-2-yl)-2,1,3-benzothiadiazole 13.5 g (11.7 mmol, 0.065 eq.) of Pd(PPh3)4 were added to a nitrogen-saturated mixture consisting of 52.92 g (180 mmol) of 1′,4′-dibromo-2,1,3-benzothiadiazole, 60 g (468.9 mmol, 2.6 eq.) of thiophene-2-boronic acid, 149 g (702 mmol, 3.9 eq.) of K3PO4, 1 l of dioxane and 1 l of water and the suspension was heated at 80° C. for 7 hours. 0.8 g of NaCN was then added and the aqueous phase was separated off. The organic phase was washed twice with H2O and subsequently dried over Na2SO4. The solvent wass removed and the residue was recrystallized twice from CH2Cl2/MeOH to give dark red needles which according to HPLC had a purity of about 99%. The yield was 43 g (80%). 1H NMR (CDCl3, 500 MHz): [ppm]=8.11 (dd, 3JHH=3.68 Hz, 2H), 7.89 (s, 2H), 7.46 (dd, 3JHH=5.2 Hz, 2H), 7.21 (dd, 3JHH=5.2 Hz, 2H). Preparation of bis-4,7-(2′-bromo-5′-thienyl)-2,1,3-benzothiadiazole (N2S-1)-T2-Br2 9.51 g (54 mmol) of N-bromosuccinimide were added to a solution of 7.72 g (25.7 mmol) of bis-4,7-(thien-2-yl)-2,1,3-benzothiadiazoline in 770 ml of chloroform over a period of 15 minutes at RT in a protective gas atmosphere and with exclusion of light. The mixture was stirred for 6 hours, and 80 ml of saturated Na2CO3 solution were subsequently added, the organic phase was separated off and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from DMF/EtOH. Drying at 50° C. under reduced pressure gave the product in the form of yellow-orange crystals which according to HPLC had a purity of about 99.6%. The yield was 10 g (85%). 1H NMR (DMSO-d6, 500 MHz): [ppm]=8.17 (s, 2H), 7.95 (d, 3JHH=4.2 Hz, 2 H), 7.40 (d, 3JHH=4.2 Hz, 2H). The compounds (CH-a to CH-m, 5, 6)-T2-Br2 could be prepared analogously. Preparation of 4-bromo-7-(2′-bromo-5′-thienyl)-2,1,3-benzothiadiazole (N2S-1)-T1-Br2 Preparation of 4-bromo-7-(thien-2-yl)-2,1,3-benzothiadiazole 6.75 g (5.85 mmol, 0.032 eq.) of Pd(PPh3)4 were added to a nitrogen-saturated mixture consisting of 52.92 g (180 mmol) of 1′,4′-dibromo-2,1,3-benzothiadiazole, 30 g (234.4 mmol, 1.3 eq.) of thiophene-2-boronic acid, 74.5 g (351 mmol, 1.95 eq.) of K3PO4, 2 l of dioxane and 2 l of water and the suspension was heated at 80° C. for seven hours. 0.8 g of NaCN were then added and the aqueous phase was separated off. The organic phase was washed twice with H2O and subsequently dried over Na2SO4. The solvent was removed and the residue was recrystallized twice from CH2Cl2/MeOH to give dark red needles which according to HPLC had a purity of about 99%. The yield was 30 g (60%). 1H NMR (CDCl3, 500 MHz): [ppm]=8.01 (d, 3JHH=3.9 Hz, 2H), 7.79 (d, 3JHH=7.7 Hz, 2H), 6.64 (d, 3JHH=7.7 Hz, 2H), 7.40 (dd, 3JHH=5.2 Hz, 2H), 7.12 (dd, 3JHH=5.2 Hz, 2H). Preparation of 4-bromo-7-(2′-bromo-5′-thienyl)-2,1,3-benzothiadiazole (N2S-1)-T1-Br2 2.1 g (11.38 mmol) of N-bromosuccinimide were added to a solution of 2.93 g (9.9 mmol) of 4-bromo-7-(thien-2-yl)-2,1,3-benzothiadiazoline in 250 ml of chloroform and 150 ml of ethyl acetate over a period of 15 minutes at RT in a protective gas atmosphere and with exclusion of, light. The mixture was stirred for 6 hours, and 50 ml of saturated Na2CO3 solution were subsequently added, the organic phase was separated off and dried over Na2SO4. After removal of the solvent, the residue was recrystallized from DMF/EtOH. Drying at 50° C. under reduced pressure gave the dibromo compound in the form of yellow-orange crystals which according to HPLC had a purity of about 99.6%. The yield was 3.2 g (87%). 1H NMR (CDCl3, 500 MHz): [ppm]=8.07 (d, 3JHH=7.7 Hz, 1H), 8.01 (d, 3JHH=7.7 Hz, 1H), 7.93 (d, 3JHH=4.0 Hz, 1H), 7.38 (d, 3JHH=4.0 Hz, 1H). The compounds (CH-a to CH-m, 5, 6)-T1-Br2 could be prepared analogously. A6: Preparation of Further Monomers which can be used in Copolymers: Preparation of 1-(2-ethylhexyloxy)-4-methoxy-2,5-bis(4-bromo-2,5-dimethoxystyryl)-benzene (MX-1) 10.5 g (19.5 mmol) of 1-(2-ethylhexyloxy)-4-methoxy-2,5-methylenephosphonate were dissolved in 85 ml of dry DMF and admixed under nitrogen with 2.4 g (43 mmol) of NaOMe and subsequently with 10.6 g (43 mmol) of 4-bromo-2,5-dimethoxybenzaldehyde. The orange suspension was stirred at RT for 5 hours, poured into water, the yellow precipitate was filtered off, washed with MeOH and n-hexane and recrystallized twice from toluene/hexane. This gave 11.8 g (83%) of the bisphenylenevinylene as yellow needles having a purity of 99.8%, determined by RP-HPLC. 1H NMR (CDCl3, 500 MHz): [ppm]=7.43 (m, 4H), 7.18 (s, 1H), 7.17 (s, 1H), 7.14 (s, 2H), 7.10 (s, 2H), 3.97 (m, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.85 (s, 6H), 1.81 (m, 1H), 1.61 (m, 4H), 1.35 (m, 4H), 0.98 (t, 3JHH=7.4 Hz, 3H), 0.89 (t, 3JHH=7.3 Hz, 3H). Preparation of 2,3,6,7-tetra-(2-methylbutyloxy)-2′,7′-(4-bromostyryl)-9,9′-spirobifluorene (MX-2) 12.8 g (13.8 mmol) of 2,3,6,7-(2-methylbutyloxy)-9,9′-spirobifluorene-2′,7′-methylenephosphonate were dissolved in 60 ml of dry DMF, and 1.7 g of NaOMe and 5.6 g (30.4 mmol) of bromobenzaldehyde in 20 ml of dry DMF were added one after the other. The mixture was heated at 90° C. for 6 hours, subsequently poured into water, the precipitate was filtered off with suction, washed with H2O, MeOH and hexane and recrystallized twice from toluene/hexane. This gave the spirobifluorene in the form of yellow platelets having a purity of 99.7%, determined by RP-HPLC. 1H NMR (CDCl3, 500 MHz): [ppm]=7.78 (d, 3JHH=7.7 Hz, 2H, spiro), 7.49 (dd, 3JHH=8.0 Hz, 4JHH=1.4 Hz, 2H, spiro), 7.40 (d, 3JHH=9.0 Hz, 4H phenylene), 7.26 (m, 6H, phenylene, spiro), 6.91 (2 d, 3JHH=16.1 Hz, 4H, olefin), 6.88 (s, 2H, spiro), 6.2 (s, 2H, spiro), 3.95 (m, 4H, CH2), 3.55 (m, 4H, CH2), 1.95 (m, 2H, CH2), 1.75 (m, 2H, CH2), 1.64 (m, 2H, CH), 1.48 (m, 2H, CH), 1.34 (m, 2H, CH2), 1.18 (m, 2H, CH2), 1.09 (d, 3JHH=6.7 Hz, 6H, CH3), 0.99 (t, 3JHH=7.3 Hz, 6H, CH3), 0.93 (d, 3JHH=9.7 Hz, 6H, CH3), 0.86 (t, 3JHH=7.5 Hz, 6H, CH3). Preparation of 1,4-dibromo-2,5-(4-fluorostyryl)benzene (MX-3) 15.3 g of 1,4-dibromobenzene-2,5-methylenephosphonate were dissolved in 60 ml of DMF, 3.3 g (60 mmol) of NaOMe were added and a solution of 7.1 g (57 mmol) in 10 ml of DMF was subsequently added dropwise with evolution of heat. After 10 minutes, the yellow solution was poured into water and the yellow, felt-like solid was filtered off with suction and washed with water, MeOH and hexane. The solid was recrystallized three times from CHCl3 to give 10 g (70%) of yellow needles having a purity of 99.9% (RP-HPLC). 1H NMR (d2-tetrachloroethane 500 MHz): [ppm]=7.85 (s, 2H, dibromophenyl), 7.53 (m, 4H, phenylene), 7.28 (d, 3JHH=16.1 Hz, 2H, olefin), 7.09 (m, 4H, phenylene), 7.04 (d, 3JHH=16.1, Hz, 2H, olefin). Preparation of 2,7-dibromo-2,7′-N,N-diphenylamino-9,9′-spirobifluorene (MX-4) (A) 2,7-Diiodo-2′,7′-dibromo-9,9′-spirobifluorene: 92.0 g (194.1 mmol) of 2,7-dibromospirobifluorene were dissolved in 200 ml of CHCl3, after which 100.1 g (233 mmol) of bis(trifluoroacetoxy)iodobenzene and 59.0 g of 12 were added and the mixture was stirred at RT under nitrogen for 12 hours. The suspension was filtered, the residue was washed with CHCl3 and recrystallized twice from 1,4-dioxane. The yield of the diiodated spirobifluorene was 121.4 g (86%) at a purity of >99% (1H-NMR). 1H NMR (DMSO-d6, 500 MHz): 8.04 (d, 3JHH=7.9 Hz, 2H), 7.88 (d, 3JHH=7.9 Hz, 2H), 7.82 (dd, 3JHH=7.9 Hz, 4JHH=1.5 Hz, 2H), 7.66 (dd, 3JHH=8.3 Hz, 4JHH=1.9 Hz, 2H), 6.98 (d, 4JHH=1.2 Hz, 2H), 6.83 (d, 4JHH=1.5 Hz, 2H). (B) 2,7-Dibromo-2′,7′-N,N-diphenylamino-9,9′-spirobifluorene (MX4) 30.0 g (41 mmol) of 2,7-diiodo-2′,7′-dibromo-9,9′-spirobifluorene and 15.1 g (93 mmol) of diphenylamine were dissolved in toluene and the solution was saturated with N2, after which 93 mg (0.41 mmol) of Pd(OAc)2, 167 mg (0.82 mmol) of tris-o-tolylphosphine and 11 g (115 mmol) of NaOtBu were added in succession and the resulting suspension was heated at 70° C. for 12 hours. After this time, 20 ml of 1% strength NaCN solution were added dropwise, the mixture was stirred for 2 hours and the solid which precipitated was filtered off with suction. The solid was washed with H2O and EtOH and recrystallized three times with toluene. This gave is 21.7 g (65%) of the diamine in the form of colorless crystals having a purity of 99.6% (RP-HPLC). 1H NMR (DMSO-d6, 500 MHz): [ppm]=7.83 (m, 4H, spiro), 7.56 (dd, 3JHH=8.1 Hz, 4JHH=2.0 Hz, 2H, spiro), 7.18 (m, 8H, N-phenyl), 6.96 (m, 6H, N-phenyl, spiro), 6.88 (m, 10H, N-phenyl, spiro), 6.19 (d, 4JHH=2.0 Hz, 2H, spiro). To give a better overview, the monomers described in A6 are depicted below: Part B: Preparation of the Polymers Copolymerization of 87.5 mol % of 2,7-dibromo-2′,3′, 6′, 7′-tetra(2-methylbutyloxy)-spirobifluorene (S-SY1) and 12.5 mol % of N,N′-bis(4-bromo)phenyl-N,N′-bis(4-tert-butylphenyl)benzidine (AM1) by Yamamoto Coupling (Polymer P1) 1.53 g (5.57 mmol) of Ni(COD)2 and 0.87 g (5.57 mmol) of 2,2′-bipyridyl were introduced under argon into a Schlenk vessel. 25 ml of dimethylformamide and 80 ml of toluene were added and the mixture was heated to 80° C. After 30 minutes, firstly 0.379 g (3.51 mmol, 0.43 ml) of 1,5-cyclooctadiene and then a solution of 1.768 g (2.11 mmol) of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1) and 0.183 g (0.242 mmol) of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)-benzidine (AM1) in 20 ml of toluene were added. After 144 hours, the mixture was cooled, 5 ml of HCl in dioxane were added and the reaction mixture was stirred for 15 minutes. 50 ml of chloroform were added and the mixture was stirred for 15 minutes. The organic phase was washed twice with 100 ml each time of 5M HCl and once with 100 ml of saturated NaHCO3 solution. The solution was precipitated in 450 ml of methanol and the crude polymer was filtered off with suction. It was reprecipitated twice from 100 ml of THF/150 ml of methanol in each case. This gave 1.30 g (2.24 mmol, 83%) of fibrous, light-yellow polymer P1. 1H NMR (CDCl3): [ppm]=7.7-6.7 (m, 9.4H, spiro, TAD); 6.2-6.0 (m, 2H, spiro); 4.0-3.2 (2×m, 7.2H, OCH2); 1.9-0.7 (m, alkyl H, including t-butyl at 1.30). GPC: THF; 1 ml/min, Plgel 10 μm Mixed-B 2×300×7.5 mm2, 35° C., RI detection: Mw=155 000 g/mol, Mn=53 000 g/mol Copolymerization of 50 mol % of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic Acid (S-SY2), 40 mol % of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1) and 10 mol % of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1) by Means of the Suzuki Reaction (polymer P2). 8.0065 g (1-0.00 mmol) of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid (S-SY2), 6.5499 g (8.00 mmol) of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1), 1.5173 g (2.00 mmol) of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1), 9.67 g (42 mmol) of K3PO4.H2O, 30 ml of toluene, 15 ml of water and 0.25 ml of ethanol were degassed for 30 minutes by passing N2 through the mixture. 175 mg (0.15 mmol) of Pd(PPh3)4 were subsequently added under protective gas. The suspension was stirred vigorously under a blanket of N2 at an internal temperature of 87° C. (gentle reflux). After 4 days, a further 0.30 g of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid was added. After heating for a further 6 hours, 0.3 ml of bromobenzene was added and the mixture was refluxed for another 3 hours. The reaction solution was diluted with 200 ml of toluene and was then stirred with 200 ml of 2% strength aqueous NaCN solution for 3 hours. The mixture became virtually colorless during this time. The organic phase was washed with H2O and precipitated by dropwise addition to 800 ml of ethanol. The polymer was dissolved in 200 ml of THF at 40° C. over a period of 1 hour, precipitated with 250 ml of MeOH, washed and dried under reduced pressure. The solid was reprecipitated once more in 200 ml of THF/250 ml of methanol, filtered off with suction and dried to constant mass. This gave 12.25 g (18.8 mmol, 94%) of the polymer P2 as a light-yellow solid. 1H NMR (CDCl3): [ppm]=7.7-6.7 (m, 9.4H, spiro, TAD); 6.2-6.0 (m, 2H, spiro); 4.0-3.2 (2×m, 7.2H, OCH2); 1.9-0.7 (m, alkyl H, including t-butyl at 1.30). GPC: THF; 1 ml/min, PLgel 10 μm Mixed-B 2×300×7.5 mm2, 35° C., RI detection: Mw=124 000 g/mol, Mn=39 000 g/mol. Example P3 Copolymerization of 50 mol % of the ethylene glycol ester of 2′,3′, 6′, 7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid (S-SY2), 30 mol % of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1), 10 mol % of 5,8-dibromodiphenylquinoxaline (CH-b) and 10 mol % of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1) by means of the Suzuki Reaction (Polymer P13). 4.9124 g (6.00 mmol) of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid (S-SY2), 8.0065 g (10.00 mmol) of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1), 0.8803 g (2.00) of 5,8-dibromodiphenylquinoxaline (CH-b), 1.5173 g (2.00 mmol) of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1), 9.67 g (42 mmol) of K3PO4.H2O, 30 ml of toluene, 15 ml of water and 0.25 ml of ethanol were degassed for 30 minutes by passing N2 through the mixture. 175 mg (0.15 mmol) of Pd(PPh3)4 were subsequently added under protective gas. The suspension was stirred vigorously under a blanket of N2 at an internal temperature of 87° C. (gentle reflux). After 4 days, a further 0.30 g of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid was added. After heating for a further 6 hours, 0.3 ml of bromobenzene was added and the mixture was refluxed for another 3 hours. The reaction solution was diluted with 200 ml of toluene and stirred with 200 ml of 2% strength aqueous NaCN solution for 3 hours. The mixture became virtually colorless during this time. The organic phase was washed with H2O and precipitated by adding it dropwise to 800 ml of ethanol. The polymer was dissolved in 200 ml of THF at 40° C. over a period of 1 hour, precipitated with 250 ml of MeOH, washed and dried under reduced pressure. The solid was reprecipitated once more in 200 ml of THF/250 ml of methanol, filtered off with suction and dried to constant mass. This gave 17.8 g (18.6 mmol, 93%) of the polymer P13 as a light-yellow solid. 1H NMR (CDCl3): [ppm]=7.8-6.7 (m, 9.6H, spiro, TAD); 6.4-6.0 (m, 2H, spiro); 4.0-3.4 (2×m, 6.4H, OCH2); 1.9-0.7 (m, alkyl H, including t-butyl at 1.30). GPC: THF; 1 ml/min, PLgel 10 μm Mixed-B 2×300×7.5 mm2, 35° C., RI detection: Mw=54 000 g/mol, Mn=22 000 g/mol. Example P4 Copolymerization of 50 mol % of the ethylene glycol ester of 2′,3′, 6′, 7′-tetra(2-methylbutyloxy)spirobifluorene-2,7-bisboronic acid (S-SY2), 30 mol % of 2,7-dibromo-2′,3′, 6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1), 10 mol % of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1) and 10 mol % of 2,3,6,7-tetra(2-methylbutyloxy)-2′,7′-(4-bromostyryl)-9,9-spirobifluorene (MX-2) by Means of the Suzuki Reaction (Improved Version) (Polymer P35*). Polymerization Method as Described in the Unpublished Patent Application DE 10159946.3: 16.0131 g (20.00 mmol) of the ethylene glycol ester of 2′,3′,6′,7′-tetra(2-methylbutyl-oxy)spirobifluorene-2,7-bisboronic acid (S-SY2), 9.8249 g (12.00 mmol) of 2,7-dibromo-2′,3′,6′,7′-tetra(2-methylbutyloxy)spirobifluorene (S-SY1), 3.0346 g (4.00 mmol) of N,N′-bis(4-bromophenyl)-N,N′-bis(4-tert-butylphenyl)benzidine (AM1), 4.0923 g (4.00 mmol) of 2,3,6,7-tetra(2-methylbutyloxy)-2′,7′-(4-bromostyryl)-9,9′-spirobifluorene (MX-2), 19.57 g (85 mmol) of K3PO4.H2O, 250 ml of toluene, 250 ml of dioxane, 40 ml of water were degassed for 30 minutes by passing argon through the mixture. A mixture of 2.25 mg (0.01 mmol) of PdAc2 and 18.3 mg (0.06 mmol) of P(o-tolyl)3 in 1 ml of toluene was subsequently added under protective gas. The suspension was stirred vigorously under a blanket of argon for about 5 hours under gentle reflux. During this time, the reaction mixture became viscous and displayed a bluish fluorescence. 118 mg (0.4 mmol) of 3,4-bis(2-methylbutyloxy)benzeneboronic acid in 150 ml of toluene were subsequently added and the mixture was refluxed for another one hour. Finally, 165 mg (0.5 mmol) of 3,4-bis(2-methylbutyloxy)-bromobenzene in a further 100 ml were added and the mixture was refluxed for another one hour. The reaction mixture was cooled, the aqueous phase was separated off and was subsequently stirred twice with 250 ml each time of a 5% strength sodium diethyldithiocarbamate solution in water at 60° C. It was subsequently stirred three times with 250 ml each time of water, diluted with 750 ml of THF and the crude polymer was finally precipitated by addition of 2 l of methanol. This was purified further by being reprecipitated twice from THF (1% strength solution) in methanol. Final purification was carried out by Soxhlet extraction with methanol/THF (1:1) for about 48 hours. 24.14 g (90%) of polymer were obtained as yellow fibers. 1H NMR (CDCl3): 7.8-6.2 (m, 12.6H, spiro, vinyl, TAD); 4.0-3.3 (2×m, 7.2H, OCH2); 1.9-0.7 (m, 34.2H, alkyl H, including t-butyl at 1.25). GPC: THF; 1 ml/min, PLgel 10 μm Mixed-B 2×300×7.5 mm2, 35° C., RI detection: Mw=830 000 g/mol, Mn=220 000 g/mol. This polymer had a higher molecular weight than the polymer P35 listed in the table (see below), which had been prepared by the old polymerization method. This also enabled a few property changes to be achieved; some further data: Viscosity data: solution (P35*) in anisole/o-xylene (14 g/l): 20.8 mPas (@ 40 s−1); solution (P35*) in tetralin (8 g/l): 15.8 mPas (@ 40 s−1). EL data: max. eff.: 5.35 Cd/A; 3.8 V @ 100 Cd/mr2; color: light blue (CIE-1931: x/y=0.18, 0.25); operating life (@100 Cd/m2): 4000 h. Further polymers were prepared by methods analogous to those described for P1, P2 and P13. The chemical properties are summarized in the following table. All these polymers were also examined for use in PLEDs. The way in which PLEDs can be produced has been indicated above and is described in more detail in part C. The most important device properties (color, efficiency and life) are also listed in the table. Electroluminescence*** GPC** Voltage Life at Visco.**** MW MN Max. at 100 100 Gel Polymer Proportion of the monomers in the polymerization [%] (1000 (1000 λmax eff Cd/m2 EL Cd/m2 temp. (Type)* Monom. 1 Monom. 2 Monom. 3 Monom. 4 g/mol) g/mol) [nm] [Cd/A] [V] color [h] [° C.] P1 (Y) 87.5% S-SY1 12.5% AM1 155 53 465 2.7 4.0 blue 800 <0° C. P2 (S) 50% S-SY2 40% S-SY1 10% AM1 124 39 463 2.8 4.5 blue 1250 <0° C. P3 (S) 50% S-SY2 40% S-US1 10% AM1 101 41 465 2.6 4.5 blue 1150 <0° C. P4 (S) 50% S-SY2 40% S-US2 10% AM1 90 40 470 3.0 4.7 blue 1550 10° C. P5 (S) 50% S-SY2 40% S-US3 10% AM1 115 45 473 3.2 4.2 blue 2250 <0° C. P6 (S) 50% S-SY2 40% S-US4 10% AM1 87 36 472 2.8 4.5 blue 1250 <0° C. P7 (S) 50% S-SY2 40% S-SY3 10% AM1 120 46 467 1.9 5.1 blue 610 10° C. P8 (S) 50% S-SY4 40% S-SY1 10% AM1 110 38 468 1.8 5.3 blue 410 15° C. P9 (S) 50% S-SY2 40% S-SY1 10% AM2 89 30 470 2.2 5.0 blue 900 <0° C. P10 (S) 50% S-SY2 40% S-SY1 10% AM3 83 29 465 1.6 5.8 blue 800 <0° C. P11 (S) 50% S-SY2 40% S-SY1 10% AM1 124 39 463 2.8 4.5 blue 1250 <0° C. P12 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-a 98 48 509 6.8 5.8 green 3000 <0° C. P13 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-b 77 32 516 7.6 4.6 green 4300 <0° C. P14 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-c 99 29 516 5.9 5.8 green 2800 <0° C. P15 (S) 50% S-SY2 30% S-SYI 10% AM1 10% CH-d 110 51 545 6.9 4.7 green- 4000 <0° C. yellow P16 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-e 105 37 527 7.7 3.9 green >5000 <0° C. P17 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-f 120 48 525 6.0 4.9 green 2100 <0° C. P18 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-g 29 10 525 3.1 7.1# green — ˜20° C. P19 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-h 91 29 535 6.7 3.8 green >5000 <0° C. P20 (S) 50% S-SY2 30% S-SY1 20% CH-h 87 36 534 6.1 4.1 green 4000 <0° C. P21 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-i 124 63 553 6.5 4.8 green- 2500 <0° C. yellow P22 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-k 54 20 541 2.2 5.8 green- — ˜5° C. yellow P23 (S) 50% S-SY2 30% S-SY1 10% AM1 10% CH-l 111 54 524 5.9 5.1 green 1800 <0° C. P24 (S) 50% S-SY2 20% S-SY1 20% MX-4 10% CH-b 138 56 516 8.8 3.8 green >5000 <0° C. P25 (S) 50% S-SY2 30% S-SY1 10% AM1 10% N2S-1 98 37 551 7.1 4.9 green- 1600 <0° C. yellow P26 (S) 50% S-SY2 30% S-SY1 10% AM1 10% N2O-1 87 39 575 6.2 5.4 yellow 1200 <0° C. Electroluminescence*** GPC** Voltage Life at Visco.**** MW MN Max. at 100 100 Gel Polymer Proportion of the monomers in the polymerization (1000 (1000 λmax eff. Cd/m2 EL- Cd/m2 temp. (Type)* Monom. 1 Monom. 2 Monom. 3 Monom. 4 g/mol) g/mol) [nm] [Cd/A] [V] Farbe [h] [° C.] P27 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (N2S- 89 40 632 1.5 3.6 red >5000 <0° C. 1)-T2-Br2 P28 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (N2S- 112 45 597 1.6 4.9 red- >5000 <0° C. 1)-T1-Br2 orange P29 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (CH-b)- 56 20 619 1.5 3.5 red >5000 <0° C. T2-Br2 P30 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (CH-b)- 89 45 590 1.9 3.9 red- >5000 <0° C. T1-Br2 orange P31 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (5)- 120 62 560 3.2 4.9 yellow- — <0° C. T2-Br2 orange P32 (S) 50% S-SY2 10% AM1 35% N2S-1 5% (6)- 79 30 575 1.0 6.9 yellow- — <0° C. T2-Br2 orange P33 (S) 50% S-SY2 10% MX-1 35% N2S-1 5% (N2S- 117 48 642 1.9 3.0 red >5000 <0° C. 1)-T2-Br2 P34 (S) 50% S-SY2 30% S-SY1 10% AM1 10% MX-1 135 53 520 9.8 3.5 green >5000 <0° C. P35 (S) 50% S-SY2 30% S-SY1 10% AM1 10% MX-2 102 45 475 4.0 4.2 blue- 2100 <0° C. green P36 (S) 50% S-SY2 30% S-SY1 10% AM1 10% MX-3 65 25 460 2.0 4.4 blue 1200 <0° C. P37 (S) 50% S-SY2 30% S-SY1 10% AM1 10% MX-4 128 60 468 3.2 4.0 blue 2000 <0° C. P38 (S) 50% S-SY2 20% S-SY1 10% AM1 20% MX-4 99 39 468 3.2 3.8 blue 1900 <0° C. P39 (Y) 80% S-SY1 10% AM1 10% MX-4 176 76 466 3.3 4.0 blue 2500 <0° C. P40 (S) 50% S-SY2 20% S-SY1 10% AM1 10% MX-4 112 60 517 10.2 3.0 green >5000 <0° C. 10% CH-b P41 (S) 50% S-SY2 20% S-SY1 10% AM1 10% MX-1 122 62 515 11.2 2.9 green >5000 <0° C. 10% CH-b V1 (S) 50% S-SY2 50% S-SY1 142 62 451 0.1 8.9 blue — <0° C. V2 (S) 50% S-SY2 40% S-SY1 10% MX-1 102 60 518 2.1 9.3 green 100 h <0° C. V3 (S) 50% S-SY2 25% S-SY1 25% MX-1 99 38 523 2.0 9.2 green 80 h <0° C. *S = Prepared by Suzuki polymerization (cf. Ex. P2), Y = prepared by Yamamoto polymerization (cf. Ex. P1) **GPC measurements in THF; 1 ml/min, Plgel 10 μm Mixed-B 2 × 300 × 75 mm2, 35° C., RI detection was calibrated against polystyrene ***For preparation of the polymeric LEDs, see part C ****Solutions of the polymer (10 mg/ml) in toluene were heated to 60° C., cooled at 1° C./minute and the viscosity was measured on a Brookfield LVDV-III rheometer (CP-41). At the gel temperature determined in this way, a sharp increase in the viscosity occurred. #Owing to the poor solubility, the PLEDs were produced from chlorobenzene. Part C: Production and Characterization of LEDs: LEDs were produced by the general method outlined below. This naturally had to be adapted in each individual case to the particular circumstances (e.g. polymer viscosity and optimal layer thickness of the polymer in the device). The LEDs described below were in each case two-layer systems, i.e. substrate//ITO//PEDOT//polymer//cathode. PEDOT is a polythiophene derivative which can, for example, be procured from BAYER AG as Baytron P™. General Method of Producing Highly Efficient, Long-Life LEDs: After the ITO-coated substrates (e.g. glass support, PET film) have been cut to the correct size, they are cleaned in a number of cleaning steps in an ultrasonic bath (e.g. soap solution, Millipore water, isopropanol). They are dried by blowing with an N2 gun and stored in a desiccator. Before coating with the polymer, they are treated in an ozone plasma apparatus for about 20 minutes. A solution of the respective polymer (generally with a concentration of 4-25 mg/ml in, for example, toluene, chlorobenzene, xylene:cyclohexanone (4:1)) is made up and dissolved by stirring at room temperature. Depending on the polymer, it can also be advantageous to stir at 50-70° C. for some time. When the polymer has dissolved completely, the solution is filtered through a 5 μm filter and applied by means of a spin coater at varying speeds (400-6000). The layer thicknesses can in this way be varied in a range from about 50 to 300 nm. The measurements are carried out using a Dektak instrument as described in EP 1029019. A conductive polymer, preferably doped PEDOT or PANI, is usually applied to the (structured) ITO beforehand. Electrodes are then applied to the polymer films. This is generally carried out by thermal vapor deposition (Balzer BA360 or Pfeiffer PL S 500). The transparent ITO electrode is then connected as anode and the metal electrode (e.g. Ba, Yb, Ca) is connected as cathode and the device parameters are determined. The results obtained using the polymers described are summarized in the table in part B.

20040910

20080129

20050217

86750.0

TRUONG, DUC

CONJUGATED POLYMERS CONTAINING SPIROBIFLUORENE UNITS AND THE USE THEREOF

UNDISCOUNTED

ACCEPTED

ACCEPTED

Program detail information display apparatus and method thereof

A program detail information display apparatus comprises a display unit, a storage unit for storing program data including program detail information, a program detail information extracting unit for extracting at least program detail information from the program data stored in the storage unit, and a program detail information sequential display control unit for issuing the program detail information extracted by the program detail information extracting means sequentially to the display unit. The program detail information display apparatus can enhance the efficiency of selection of programs by the viewer.

1. A program detail information display apparatus comprising: display means; storage means for storing program data; program detail information extracting means for extracting program detail information greater than a specified size from the program data stored in the storage means; and program detail information sequential display control means for issuing the program detail information extracted by the program detail information extracting means sequentially to the display means. 2. The program detail information display apparatus of claim 1, wherein the program detail information sequential display control means issues the program detail information extracted by the program detail information extracting means automatically and sequentially to the display means at specified time intervals. 3. The program detail information display apparatus of claim 1, further comprising command receiving means for receiving a command, wherein the program detail information sequential display control means issues the program detail information extracted by the program detail information extracting means sequentially to the display means at the timing controlled by the command receiving means. 4. The program detail information display apparatus of claim 1, wherein the program detail information extracting means extracts further related information relating to the program detail information greater than a specified size from the program data; and wherein the program detail information sequential display control means issues the program detail information and related information extracted by the program detail information extracting means sequentially to the display means. 5. The program detail information display apparatus of claim 1, wherein the display means comprises: a video processor for restoring video signal on the basis of video data stream; a synthesizer; a video output part for displaying the image by receiving the output from the synthesizer; an audio processor for restoring audio signal on the basis of audio data stream; and an audio output part for issuing a voice by receiving the audio signal, wherein the storage means is composed of a memory part controlled by a controller; wherein the program detail information extracting means comprises: the controller; and a program detail information extractor for extracting program detail information greater than a specified size from the memory part by an instruction from the controller; and wherein the program detail information sequential display control means comprises; the controller; and a program detail information sequence controller for sequentially controlling the program detail information from the program detail information extractor by an instruction from the controller; and wherein the synthesizer synthesizes the output of the video processor and the output of the program detail information sequence controller. 6. The program detail information display apparatus of claim 1, wherein the display means comprises: a video processor for restoring video signal on the basis of video data stream; a synthesizer; a video output part for displaying an image by receiving the output from the synthesizer; an audio processor for restoring audio signal on the basis of audio data stream; an audio changeover part for changing over audio signals; and an audio output part for issuing a voice by receiving the audio signal from the audio changeover part, wherein the storage means is composed of a memory part controlled by a controller; wherein the program detail information extracting means comprises: the controller; and a program detail information extractor for extracting the program detail information greater than a specified size from the memory part by an instruction from the controller; wherein the program detail information sequential display control means comprises: the controller; and a program detail information sequence controller for sequentially controlling the program detail information from the program detail information extractor by an instruction from the controller, further comprising an audio converter for converting into an audio signal on the basis of the information from the program detail information sequence controller, wherein the synthesizer synthesizes the output of the video processor and the output of the program detail information sequence controller; and wherein the audio changeover part changes over the output of the audio processor and the output of the audio converter. 7. The program detail information display apparatus of claim 5, wherein the synthesizer replaces part of the output of the video processor with the output of the program detail information sequence controller. 8. The program detail information display apparatus of claim 5, wherein the synthesizer sums the output of the video processor and the output of the program detail information sequence controller by weighting. 9. The program detail information display apparatus of claim 5, wherein the synthesizer processes the output of the video processor and the output of the program detail information sequence controller by keying. 10. The program detail information display apparatus of claim 5, wherein the synthesizer has a function of displaying the output image of the video processor by compressing one-dimensionally or two-dimensionally, and a vacant space produced by compression is replaced by the output of the program detail information sequence controller. 11. A program detail information display method comprising: a step of displaying at least video data; a step of storing program data; a step of extracting program detail information greater than a specified size from the program data stored at the step of storing; and a step of controlling sequentially so as to issue sequentially the program detail information extracted at the step of extracting the program detail information to the step of displaying. 12. The program detail information display method of claim 11, wherein the step of extracting the program detail information extracts further the related information relating to the program detail information greater than a specified size from the program data; and wherein the step of controlling sequentially issues the program detail information and related information extracted at the step of extracting the program detail information sequentially to the step of displaying. 13. (Canceled) 14. (Canceled) 15. (Canceled) 16. The program detail information display apparatus of claim 6, wherein the synthesizer replaces part of the output of the video processor with the output of the program detail information sequence controller. 17. The program detail information display apparatus of claim 6, wherein the synthesizer sums the output of the video processor and the output of the program detail information sequence controller by weighting. 18. The program detail information display apparatus of claim 6, wherein the synthesizer processes the output of the video processor and the output of the program detail information sequence controller by keying. 19. The program detail information display apparatus of claim 6, wherein the synthesizer has a function of displaying the output image of the video processor by compressing one-dimensionally or two-dimensionally, and a vacant space produced by compression is replaced by the output of the program detail information sequence controller.

TECHNICAL FIELD The present invention relates to a display apparatus of television program detail information or the like. BACKGROUND ART A conventional program detail information display apparatus is designed to display the program detail information by the manipulation of the viewer to designate a desired program, obtain the detail information of the program, and instruct to display. That is, the viewer manipulates in this manner to display the program detail information transmitted in every program of every channel, and selects the program by referring to the displayed program detail information. This program detail information is the information including the synopsis, names of the cast, etc. In other method, the user designates a desired program actively by using the display function of program list and program retrieval function by program genre. In these methods, however, the program detail information display screen is displayed in a separate screen from the program list, or the screen is changed over from the program list to the program detail information display screen, and it is hard to understand the correspondence between the program detail information and program. Besides, the user's operation is complicated. To solve such problems, a apparatus for displaying the program detail information directly in the program list is proposed in Japanese Laid-open Patent No. H11-155110. The conventional methods are explained below by referring to FIG. 12. FIG. 12 shows a screen displaying program detail information in the program list. In the diagram, the vertical direction at the right side of a screen 1200 is a channel column 1210, and the lateral direction is a time column 1260. Channels 1220, 1230, 1240, 1250 are individual channels. In channel 1220, programs are displayed along the time column 1260 in the lateral direction. For example, from time 12:00 to time 13:00, a program 1221 is broadcast. Similarly, a program 1231 is one of the programs broadcasted in channel 1230, a program 1241 is one of the programs broadcasted in channel 1240, and a program 1251 is one of the programs broadcast in channel 1250. Upon start of display of the program list, display frames are formed in each channel by dividing in a uniform width in the vertical axis direction (direction of channel column 1210) and in uniform time unit width in the lateral axis direction (direction of time column 1260). The viewer designates a program by moving the cursor to the position of a program name desired to know the detail information out of the program names displayed in the program list displayed on the screen 1200. At this moment, the detail information of the program corresponding to the cursor position is taken out from a specified database, and displayed as program detail information. The column of the program corresponding to the cursor position is magnified in the direction of the channel column 1210 and in the direction of the time column 1260 so that the program detail information and program name may be displayed in a proper size. In FIG. 12, the cursor is positioned at the program 1241, and the program 1241 is designated. The viewer does not designate the program 1221, program 1231 or program 1251, only the program titles are displayed in these columns. On the other hand, the column of the program 1241 displays the program detail information such as the synopsis and the cast, together with the program title. In such apparatus, the user must designate a desired program by moving the cursor to each program and display the program detail information, out of a tremendous number of programs displayed on the program list, and select the program by referring to the displayed program detail information. In such method, the operation is very complicated and practically difficult. In another prior art, the viewer is not required to select each program from the program list, but by using the viewer's preference information, preferred programs for the viewer are selected and recommended from a huge list of programs. This prior art is based on the preference of the viewer. In other words, programs recommended by the program provider cannot be presented to the user without requiring the viewer's preference information. In the multichannel trend of television broadcast, the number of programs is increasing enormously, and these problems will become more and more serious. It is hence extremely difficult for the viewer to designate a program actively from the program list by program retrieval by program list or program genre, and display the program detail information and select a program. Yet, the conventional program detail information display apparatus has no means for telling the programs recommended by the program provider. DISCLOSURE OF THE INVENTION A program detail information display apparatus comprises at least: display means, storage means for storing program data, program detail information extracting means for extracting at least program detail information from the program data stored in the storage means, and program detail information sequential display control means for displaying the program detail information extracted by the program detail information extracting means sequentially in the display means. A program detail information display method comprises at least: a step of displaying video data and the like, a step of storing program data, a step of extracting at least program detail information from the program data stored at the step of storing, and a step of controlling sequentially so as to display sequentially the program detail information extracted at the step of extracting the program detail information. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a system block diagram of program detail information display apparatus in a preferred embodiment of the invention. FIG. 2 is a specific system block diagram of program detail information display apparatus in preferred embodiment 1 of the invention. FIG. 3 is a conceptual diagram of data composition of program data in preferred embodiment 1 of the invention. FIG. 4 is an operation flowchart of program detail information extracting process in preferred embodiment 1 of the invention. FIG. 5 is an example of program detail list for display in program detail information display apparatus in preferred embodiment 1. FIG. 6 is a flowchart of making process of program detail data for display in program detail information display apparatus in preferred embodiment 1. FIG. 7 is an example of display screen of program detail information in program detail information display apparatus in preferred embodiment 1. FIG. 8 is a diagram showing an example of a further specific display screen of program detail information in preferred embodiment 1 of the invention. FIG. 9 is a diagram showing other example of a further specific display screen of program detail information in preferred embodiment 1 of the invention. FIG. 10 is a specific system block diagram of program detail information display apparatus in preferred embodiment 2 of the invention. FIG. 11 is a diagram showing an example of a display screen of program detail information in program detail information display apparatus in preferred embodiment 2 of the invention. FIG. 12 is a diagram showing a display screen of program detail information in program detail information display apparatus in a prior art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The program detail information display apparatus of the invention is intended to enhance the efficiency of selection of programs by the viewer by sequential output of extracted program detail information in the display means. Further, by extracting only the program detail information larger than a specific size, recommended programs can be efficiently presented to the viewer. Considering that program detail information is not provided in all programs, and that a greater quantity of program detail information is added to the programs recommended by the program provider, the invention is intended to enhance the efficiency of selection of programs by the viewer by displaying the program detail information of programs with a greater quantity of program detail information to the viewer. Besides, by processing the program detail information by using video and audio data, and sequentially displaying on the same screen as ordinary television program, the invention is intended to allow the viewer to acquire the program detail information passively for the ease of selection of programs. Preferred Embodiment 1 Preferred embodiment 1 is described below while referring to FIG. 1 to FIG. 9. FIG. 1 is a system block diagram of program detail information display apparatus in preferred embodiment 1 and preferred embodiment 2. In FIG. 1, a program detail display apparatus 100 comprises storage means 110, program detail information control means 120, display means 130, and command receiving means 140. The program detail information control means 120 is composed of program detail information extracting means 150 and program detail information sequential display control means 160. The storage means 110 stores the program data, and the program detail information extracting means 150 extracts the program detail information from the program data stored in the memory means 110. The program detail information sequential display control means 160 receives the program detail information extracted by the program detail information extracting means 150. Consequently, the program detail information sequential display means 160 operates so that the display means 130 may sequentially execute display and notice of program detail information and others. The display means 130, receiving the output of the program detail information sequential display control means 160, executes display and notice of program detail information and others. The command receiving means 140 receives program detail information display command from a remote controller or the like, and controls the operation of the program detail information control means 120 on the basis of the received data. The system block diagram in FIG. 1 is further specifically shown in a system block diagram in FIG. 2, and a detailed description is given below together with FIG. 2. In FIG. 2, the program detail information display apparatus 100 comprises an antenna 104, a tuner 101, a separator 102, a controller 103, a memory 111, a program detail information extractor 151, program detail information sequence controller 161, a video processor 131, a synthesizer 132, a video output unit 133, an audio processor 134, an audio output unit 135, and an input unit 141. The command receiving means 140 is composed of the input unit 141 and controller 103, and the storage means 110 is composed of the memory 111. The program detail information extracting means 150 is composed of the controller 103 and the program detail information extractor 151, and the program detail information sequential display control means 160 is composed of the controller 103 and program detail information sequence controller 161. The display means 130 is composed of the video processor 131, synthesizer 132, video output unit 133, audio processor 134, and audio output unit 135. The program detail information control means 120 is composed of the program detail information extracting means 150 and program detail information sequential display control means 160. The command receiving means 140, storage means 110, program detail information extracting means 150, program detail information sequential display control means 160, display means 130, and program detail information control means 120 correspond respectively to the command receiving means 140, storage means 110, program detail information extracting means 150, program detail information sequential display control means 160, display means 130, and program detail information control means 120 shown in FIG. 1. The antenna 104 receives an incoming radio wave, converts into an electric signal of radio frequency, and supplies into the tuner 101. The electric signal of radio frequency entered from the antenna 104 to the tuner 101 is a signal of broad frequency band enveloping multiple carrier channels. First of all, the tuner 101 receives a tuning start command from the controller 103, and extracts a signal corresponding to a desired carrier channel. The extracted radio frequency signal of carrier channel is processed by channel decoding. Channel decoding is demodulation from so-called digital modulation. Generally, PSK modulation of higher order or QAM modulation of higher order is employed. Channel decoding is to restore the digital data before modulation from the signal modulated in such modulating system. The tuner 101 also executes error correction decoding process, and a transport stream is restored and sent to the separator 102. The separator 102 decodes the transport stream entered from the tuner 101. The transport stream entered from the tuner 101 is a data stream having various pieces of information multiplexed in time in transport stream packet units. That is, the transport stream is a time multiplexed composition of packet of digital video data, packet of digital audio data, packet of program data, and others. The separator 102 separates the entered transport stream into a packet of digital video signal, a packet of digital audio signal, and a packet of program data. The separated packet of digital video signal is converted into a digital video signal data stream, and is put into the video processor 131. The separated packet of digital audio signal is converted into a digital audio signal data stream, and is put into the audio processor 134. The separated packet of program data is put into the controller 103 as program data. The controller 103 delivers the program data entered from the separator 102 into the memory 111. The controller 103 also command tuning start to the tuner 101 on the basis of channel selection request from the input unit 141. Further, the controller 103 feeds a program detail information extraction request to the program detail information extractor 151 on the basis of the recommended program display request or the like from the input unit 141. In this preferred embodiment, an example of recommended program display request is used as program detail information display command. The memory 111 stores the program data entered from the controller 103. The program detail information extractor 151 acquires program data from the memory 111 and extracts the program detail information when program detail information extraction is requested from the controller 103. A list of program detail for display obtained as a result of program detail information extraction process is sent out to the program detail information sequence controller 161. The program detail information sequence controller 161 compiles program detail data for display on the basis of the list of program detail for display from the program detail information extractor 151, converts the program detail data for display into program detail signal for display of analog video signal format, and issues sequentially to the synthesizer 132. Generally, the program detail list information for display issued from the program detail information extractor 151 is data coded as specified. Therefore, the program detail information sequence controller 161 also has a function of decoding the coded data into characters, and further converting into video data. The coded data may include moving image, still image, and other related information. The program detail information sequence controller 161 further has a function of decoding such related information, and converting into video data. The video processor 131 decodes the video signal data stream entered from the separator 102. In digital television broadcast, the video signal is compressed by a specified video compression method (so-called source coding), and composed into a video signal data stream of specified format. Decoding executed in the video processor 131 is decoding of video data before compression on the basis of the above video signal data stream, which is so-called source decoding. The video processor 131 processes in this manner, and converts into analog video signal, and issues to the synthesizer 132. The synthesizer 132 synthesizes the analog video signal from the video processor 131 and the program detail signal for display from the program detail information sequence controller 161, and issues the synthesized analog video signal to the video output unit 133. The video output unit 133 is a display apparatus composed of monitor and others, and displays the analog video signal from the synthesizer 132. The audio processor 134 decodes the digital audio signal data stream entered from the separator 102. In digital television broadcast, the audio signal is compressed by a specified audio compression method (so-called source coding), and composed into an audio signal data stream of specified format. Decoding executed in the audio processor 134 is decoding of audio data before compression on the basis of the above audio signal data stream, which is so-called source decoding. The audio processor 134 processes in this manner, and converts into analog audio signal, and issues to the audio output unit 135. The audio output unit 135 is an audio output apparatus composed of loudspeaker and others, and delivers analog audio signal from the audio processor 134. The input unit 141 sends the channel selection request from the viewer or program display request to the controller 103. In this explanation, the synthesizer 132 synthesizes the analog video signal from the video processor 131 and the program detail signal for display of analog video signal from the program detail information sequence controller 161. Alternatively, however, the video processor 131 may issue a digital video signal, the program detail information sequence controller 161 may issue a program detail signal for display of digital video signal, and the synthesizer 132 may synthesize the digital video signal from the video processor 131 and the program detail signal for display of digital video signal from the program detail information sequence controller 161. Synthesizing process in the synthesizer 132 includes a method of replacing part of the video signal form the video processor 131 with the program detail signal for display from the program detail information sequence controller 161, a superimposing method by weighted sum of both signals, chroma key or other keying method. When merely synthesizing both signals, part of the video signal from the video processor 131 may be missing or may be hard to see due to the program detail signal for display. To avoid such inconvenience, the synthesizer 132 compresses the video signal from the video processor 131 one-dimensionally or two-dimensionally within the plane, and the program detail signal for display from the program detail information sequence controller 161 may be positioned in the vacant region resulting from the compression. The synthesizer 132 in this preferred embodiment may also synthesize in such process. The data composition of the program data in the preferred embodiment, that is, the data composition of the program data issued from the separator 102 is explained by referring to FIG. 3. FIG. 3 is a conceptual diagram of data composition of program data in the preferred embodiment. In FIG. 3, program data 300 is composed of channel information 310, 320, 330, program information 311, 313, 315, 317, 321, 323, 325, 327, and program detail information 316, 318, 324, 328. The channel information 310, 320, 330 are composed of channel number and channel name relating to each channel. The program information 311, 313, 315, 317, 321, 323, 325, 327 are composed of the title and on-air time of the program broadcast in each channel. The program detail information 316, 318, 324, 328 are additional information to the program information, and are composed of synopsis and highlight scenes. The channel information 310 has the data meaning the channel number of 022 and channel name of □□ Broadcast, the channel information 320 has the data meaning the channel number of 034 and channel name of □□ Broadcast, and the channel information 330 has the data meaning the channel number of 077 and channel name of □□ Broadcast. The channel information 310 includes program information 311, 313, 315, 317, and the program information 315, 317 have program detail information 316, 318, respectively. However, the program information 311, 313 do not have program detail information. Similarly, the channel information 320 includes program information 321, 323, 325, 327, and the program information 323, 325 have program detail information 324, 328, respectively. However, the program information 321, 325 do not have program detail information. For example, in the case of the program information 315, the program information and program detail information are explained. The program information 315 has the data meaning the program title of Movie theater and the on-air time of 21:00 to 22:55, and also has the program detail information 316. The program detail information 316 has the data meaning the synopsis “Synopsis: ◯◯◯◯◯◯◯◯”. Other detail information and program detail information are same as in the program information 315 and program detail information 316, and specific description is omitted. Herein, it is assumed that the program detail information 316, 324, 328 have a data quantity not less than the specified size, while the program detail information 318 has a data quantity smaller than the specified size. The program data 300 has the data composition as described above. The display operation of the program detail information in the preferred embodiment is explained below by referring to FIG. 1 in the first place. In the program detail information display apparatus 100 in FIG. 1, the command receiving means 140 receives a recommended program display request or the like as one of the program detail information display commands from the remote controller or the like, and it is noticed to the program control means 120. The program detail information extracting means 150 of the program information control means 120 receiving the notice of reception of program detail information display command acquires the program information stored in the memory 110. The program detail information extracting means 150 extracts the channel information, program information, and program detail information in the procedure shown in FIG. 4, and compiles a program detail list for display. The program detail information sequential display control means 160 compiles program detail data for display from the channel information, program information, and program detail information extracted by the program detail information extracting means 150, and sequentially issues to the display means 130. The display means 130 receives the output of the program detail information sequential display control means 160, and displays sequentially. Referring now to FIG. 4, an outline of operation of the program detail information extracting means 150 in FIG. 1 is explained below. To begin with, the program detail information extracting means 150 extracts the channel information from the program data (S403). Next, the program detail information extracting means 150 checks the channel number of the extracted channel information, and extracts the corresponding program information (S404). The program detail information extracting means 150 further checks if the program detail information corresponding to the extracted program information is present or not (S405). If the program detail information is present, the program detail information extracting means 150 detects the size of the program detail information (S406). If the program detail information is not present, the program detail information extracting means 150 judges if the program information is the final program information or not (S408). When the size of the program detail information is more than a specified number of bytes, the program detail information extracting means 150 registers this program detail information in the program detail list for display (S407). If not more than the specified number of bytes, the program detail information extracting means 150 judges if the program information is the final program information or not (S408). The program detail information extracting means 150 checks if the program information being checked at the present is the final program information about the channel or not (S408). If final, the program detail information extracting means 150 detects whether the channel information being checked is the final channel information in the number data or not (S409). If not final, the program detail information extracting means 150 extracts new program information (S404). If the channel number being checked is not the final channel information in the number data, the program detail information extracting means 150 extracts new channel information (S403). If the channel number being checked is final, the program detail information extracting means 150 terminates the processing (End). Referring next to FIG. 4, the operation of the program detail information extractor 151 shown in FIG. 2 is explained below. In the program detail information display apparatus 100 in FIG. 2, the input unit 141 operating as the command receiving means 140 receives a recommended program display request or the like as one of the program detail information display commands from the remote controller or the like, and it is notice to the controller 103 in the program control means 120. The controller 103 consequently starts operation of the program detail information extractor 151. The program detail information extractor 151 acquires the program data stored in the memory 111, and extracts channel information, program information, and program detail information. FIG. 4 shows this operation procedure. In FIG. 4, the program detail information extractor 151 starts processing according to the instruction from the controller 103 (Start). As a result, the program detail information extractor 151 initializes the program detail list for display (S401). The program detail information extractor 151 acquires program data stored in the memory 111 (S402). The program detail information extractor 151 extracts channel information from the acquired program data (S403). The program detail information extractor 151 extracts program information about the extracted channel information (S404). The program detail information extractor 151 judges if the program detail information about the extracted program information is present or not (S405). When it is judged that the program detail information bout the extracted program information is present (Yes), the program detail information extractor 151 judges if the program detail information is more than a specified size or not (S406). When the program detail information is judged to be larger than the specified size (Yes), the program detail information extractor 151 registers this program detail information in the program detail list for display (S407). Further, the program detail information extractor 151 judges if the program information is the final program information or not (S408). If it is judged that the program detail information about the extracted program information is not present (No), or if it is judged the program detail information about the extracted program information is not larger than the specified size (No), the program detail information extractor 151 judges if the program information is the final program information or not (S408). When the program information is not judged to the final program information (No), the program detail information extractor 151 extracts next program information newly (S404). On the other hand, if the program information is judged to be the final program information, the program detail information extractor 151 judges if the channel information is the final channel information or not (S409). When the channel information is not judged to be the final channel information (No), the program detail information extractor 151 extracts next channel information newly (S403). On the other hand, when the channel information is judged to be the final channel information (Yes), the program detail information extractor 151 issues the program detail list for display to the program detail information sequential display controller 161 (S410). Finally, a series of processing of the program detail information extractor 151 is over (End). FIG. 5 shows a program detail list for display created in the program detail information extractor 151 and entered in the program detail information sequential display controller 161. In the diagram, the left end row of the program detail list for display 501 is a channel information column 510, the middle row is a program information column 520, and the right end row is a program detail information column 530. As clear from the explanation of the flowchart shown in FIG. 4, the program detail information extractor 151 compiles a program detail list for display by extracting when the program detail information has a quantity of data larger than a specified size. That is, among the program data 300 shown in FIG. 3, the program information 315 and program detail information 316 of channel information 310, the program information 323 and program detail information 324 of channel information 320, and the program information 327 and program detail information 328 of channel information 320 are extracted, and registered in the program detail list for display 501. The program detail information 318 of which program detail information is not more than the specified data quantity is not hence registered in the program detail list for display 501. Therefore, the channel information 310, program information 315 and program detail information 316 in FIG. 3 correspond respectively to the channel information 511, program information 521 and program detail information 531 in FIG. 5. Similarly, the channel information 320, program information 323 and program detail information 324 in FIG. 3 correspond respectively to the channel information 512, program information 522 and program detail information 532 in FIG. 5. Also, the channel information 320, program information 327 and program detail information 328 in FIG. 3 correspond respectively to the channel information 513, program information 523 and program detail information 533 in FIG. 5. Processing in the program detail information sequential display controller 161 is explained below while referring to FIG. 6. In FIG. 6, the program detail information sequential display controller 161 in FIG. 2 receives an instruction from the controller 103, and starts processing (Start). The program detail information sequential display controller 161 acquires a program detail list for display created in the program detail information extractor 151 (S601). Further, the program detail information sequential display controller 161 detects the total number of list items included in the acquired program detail list for display. The detected total number is supposed to be N (S602). In this preferred embodiment, the program detail list for display is as shown in FIG. 5. The total number of list items N is 3 in this case. In succession, the program detail information sequential display controller 161 resets the own counter number (COUNT) to 0 (S603). In the preferred embodiment, the program detail list for display is as shown in FIG. 5. Therefore, the COUNT value of 0 corresponds to channel information 511, program information 521, and program detail information 531 in FIG. 5. Similarly, the COUNT value of 1 corresponds to channel information 512, program information 522, and program detail information 532 in FIG. 5, and the COUNT value of 2 corresponds to channel information 513, program information 523, and program detail information 533 in FIG. 5. Next, the program detail information sequential display controller 161 judges if the present COUNT value is smaller than N or not (S604). When the present COUNT value is judged to be smaller than N (Yes), the program detail information sequential display controller 161 creates program detail data for display corresponding to the COUNT value on the basis of the information corresponding to the COUNT value in the program detail list for display (S605). At this moment, the COUNT value is still 0, and the program detail data for display corresponding to channel information 511, program information 521, and program detail information 531 in FIG. 5 is created. Further, the program detail information sequential display controller 161 sends the created program detail data for display to the synthesizer 132 (S606). Successively, the program detail information sequential display controller 161 increments by adding 1 to the COUNT value (S607). Next, the program detail information sequential display controller 161 judges if the newly incremented COUNT value is smaller than N or not (S604). Such process is repeated, and finally the newly incremented COUNT value is not judged to be smaller than N (No). When the COUNT value is not judged to be smaller than N, the program detail information sequential display controller 161 terminates the processing (End). In this way, the program detail information sequential display controller 161 issues the created program detail data for display sequentially to the synthesizer 132. In this description, the program detail information sequential display controller 161 issues the program detail data for display to the synthesizer 132 sequentially every time the program detail data for display is created (S606). However, preferred embodiment 1 of the invention is not limited to such system alone. That is, while storing the created program detail data for display, the controller 103 may display the desired data from the stored program detail data for display at a desired timing, on the basis of an input signal entering the input unit 141 or the like. A display screen example of thus composed program detail information is explained briefly below by referring to FIG. 7. In FIG. 7, a display apparatus such as television receiver 701 is controlled by a remote controller 703. A display screen 702 is controlled by the remote controller 703, and displays the broadcast image, channel information, and program detail information. Display procedure of program detail information includes display during commercial message, display in no-signal time, automatic display in such cases, display when “Recommended Program” button is pressed, etc. The viewer decides and sets to execute which display procedure by manipulating the remote controller 703. A further specific example of display screen of program detail information is described below. FIG. 8 is an example of screen display in the video output unit 133 in FIG. 2. In FIG. 8, screens 810, 820, 830 are screens at different times of the display screen 702 in FIG. 7. An image region 811 is a region for display of an output image from the video processor 131 in FIG. 2, and an image region 812 is a region for display of information from the program detail information sequential display controller 161. Similarly, image regions 821 and 831 are regions for display of output images from the video processor 131 in FIG. 2, and regions 822 and 832 are regions for display of information from the program detail information sequential display controller 161. The screen 810 shows a state of display of channel information 511, program information 521, and program detail information 531 shown in FIG. 5 issued from the program detail information sequential display controller 161. Similarly, the screen 820 shows a state of display of channel information 512, program information 522, and program detail information 532 shown in FIG. 5, and the screen 830 shows a state of display of channel information 513, program information 523, and program detail information 533 shown in FIG. 5. Thus, the information from the program detail information sequential display controller 161 is sequentially shown in part of the screen at specific time intervals. As explained already, the synthesizer 132 in the preferred embodiment can be realized in various synthesizing processing methods. In the case that the synthesizer 132 replaces part of the video signal from the video processor 131 merely with program detail signal for display from the program detail information sequential display controller 161, part of the video signal from the video processor 131 may be missing, and the program detail signal for display from the program detail information sequential display controller 161 is fitted in the vacant area. In the case of the synthesizer 132 operating on a superimposing system by weighted summation of video signal and program detail signal for display, the video signal from the video processor 131 is intact, and the program detail signal for display is weighted and superimposed in part of the video signal. In the case of the synthesizer 132 operating on the keying system by chroma key or the like, only the pixel portion having characters or the like of the program detail signal for display is replaced with video signal. In the case of the synthesizer 132 having a function of compressing the video signal from the video processor 131 one-dimensionally or two-dimensionally within the screen, the video signal is compressed one-dimensionally or two-dimensionally in the screen, and the program detail signal for display is fitted in the vacant region formed by this compression. In FIG. 8, only texts are displayed in the image regions 812, 822, 832. Not limited to texts, in preferred embodiment 1, drawings, moving image and other video information can be also displayed. As mentioned above, the program detail list information for display issued from the program detail information extractor 151 is specified coded data. Therefore, the program detail information sequential display controller 161 has a function of decoding the coded data into characters, and further converting into image data. The coded data may include related information such as moving image and still image. The program detail information sequential display controller 161 further has a function of decoding such related information and converting into image data. Examples of displaying drawings, moving image and other video information as well as texts in the image regions 812, 822, 823 are explained by referring to FIG. 2 and FIG. 9. In FIG. 9, what differs from FIG. 8 is moving images 901 to 903. The moving images 901 to 903 are examples of the video information. In FIG. 9, same parts as in FIG. 8 are identified with same reference numerals, and duplicate explanation is omitted. As described above, the program detail list information for display issued from the program detail information extractor 151 in FIG. 2 is specified coded data of characters, still image, moving image or objects. Therefore, the program detail information sequential display controller 161 in FIG. 2 has a function of decoding the coded data into characters, still image, moving image or objects, and converting further into image data. Suppose the program detail list information for display includes information of character and information of moving image. In this case, the program detail information sequential display controller 161 decodes also the information of moving image, and converts into video signal and sends out into the synthesizer 132. The synthesizer 132 synthesizes the character and moving image from the program detail information sequential display controller 161 and the video signal from the video processor 131. That is, in the regions 812, 822, 823 in FIG. 9, moving images 901, 902, 903 are displayed in part respectively. Thus, by displaying not only characters but also drawings, moving images and other video information, a further wide variety of program information notice is realized. Preferred Embodiment 2 The foregoing preferred embodiment 1 shows a program detail information display apparatus handling character information or video information as program detail signal for display. This preferred embodiment 2 shows a program detail information display apparatus handling not only character information and video information but also audio information as program detail signal for display. The preferred embodiment 2 is explained by referring to FIG. 10 and FIG. 11. FIG. 10 is a system block diagram of program detail information display apparatus in preferred embodiment 2 of the invention. In FIG. 10, what differs from FIG. 2 lies in an audio converter 1001 and an audio changeover unit 1002. In FIG. 10, same parts as in FIG. 2 are identified with same reference numerals and duplicate explanation is omitted. The program detail information sequential display controller 161 creates program detail data for display on the basis of the program detail list information for display from the program detail information extractor 151, and converts the program detail data for display into program detail signal for display, and issues to the synthesizer 132. The program detail information sequential display controller 161 further feeds the created program detail data for display to the audio converter 1001. The audio converter 1001 converts the portion of character information contained in the input data of program detail data for display into audio information corresponding to the characters. That is, the audio converter 1001 has a so-called voice synthesizing function. The audio converter 1001 converts the created audio information into analog audio signal, and sends to the audio changeover unit 1002. The audio processor 134 decodes the digital audio signal data stream supplied from the separator 102, and issues analog audio signal to the audio changeover unit 1002. The audio changeover unit 1002 changes over the audio signal entered from the audio converter 1001 and the audio signal entered from the audio processor 134 properly, and sends to the audio output unit 135. The audio changeover unit 1002 in this preferred embodiment 2 operates in various systems, including a system of merely changing over the audio signal entered from the audio converter 1001 and the audio signal entered from the audio processor 134, a system of changing over these two audio signals by fade-in and fade-out method, and a system of synthesizing these two audio signals by weighted summation. In the system of changing them over merely, the audio changeover unit 1002 is composed of a single selection circuit of the audio signal entered from the audio converter 1001 and the audio signal entered from the audio processor 134. In the changeover system by fade-in and fade-out method, the audio changeover unit 1002 is composed of a circuit for changing over by adding while changing the gain of the two at the changeover timing of the audio signal entered from the audio converter 1001 and the audio signal entered from the audio processor 134. In the system of weighted summation of the two, the audio changeover unit 1002 is composed of a circuit for adding by weighting the both signals in the input period of the signal from the audio converter 1001. In this explanation, the audio changeover unit 1002 changes over the analog audio signal from the audio processor 134 and the analog audio signal from the audio converter 1001. However, the audio processor 134 may issue a digital audio signal and the audio converter 1001 may also issue a digital audio signal, and the audio changeover unit 1002 can also change over the digital audio signal from the audio processor 134 and the digital audio signal from the audio converter 1001. An example of screen displayed in the video output unit 133 and voice produced from the audio output unit 135 in FIG. 10 is explained by referring also to FIG. 11. In FIG. 11, what differs from FIG. 8 and FIG. 9 lies in voice 1101 to 1103 and audio output unit 135. The audio output unit 135 is same as the audio output unit 135 shown in FIG. 10. In FIG. 11, same parts as in FIG. 8 and FIG. 9 are identified with same reference numerals and duplicate explanation is omitted. As shown in FIG. 11, while the information from the program detail information sequential display controller 161 is displayed in the image region 812, the voice 1101 corresponding to the display content is delivered from the audio output unit 135. Similarly, while the information from the program detail information sequential display controller 161 is displayed in the image region 822, the voice 1102 corresponding to the display content is delivered from the audio output unit 135, and while the information from the program detail information sequential display controller 161 is displayed in the image region 832, the voice 1103 corresponding to the display content is delivered from the audio output unit 135. Thus, in preferred embodiment 2, not only the information from the program detail information sequential display controller 161 is displayed in the video output unit 133, but also the voice corresponding to the display content is delivered from the audio output unit 135, so that the function for getting information about the program by the user is further enhanced. As explained herein, the program detail information display apparatus of the invention is enhance in efficiency of selection of program by the viewer by receiving a program detail information display command from the viewer by remote control or other operation, extracting the program detail information from the program data stored in the storage means, creating program detail data for display using image or voice together with the channel information and program information, and displaying sequentially. Further, by displaying only the program detail information greater than specified data quantity, a special program recommended by the program provider can be efficiently presented to the viewer as recommended program. Simultaneously with the on-air image, the program detail information can be also displayed. Industrial Applicability The program detail information display apparatus of the invention comprises program detail information sequential display control means for issuing the program detail information extracted by the program detail information extracting means sequentially to the display means, and hence the efficiency of selection of program by the viewer can be enhanced. Further, the program detail information extracting means of the program detail information display apparatus of the invention extracts only the program detail information greater than specified size, so that a recommended program can be efficiently presented to the viewer. Reference Numerals in the Drawings 100 Program detail information display device 101 Tuner 102 Separator 103 Controller 104 Antenna 110 Storage means 111 Memory 120 Program information control means 130 Display means 131 Video processor 132 Synthesizer 133 Video output unit 134 Audio processor 135 Audio output unit 140 Command receiving means 141 Input unit 150 Program detail information extracting means 151 Program detail information extractor 160 Program detail information sequential display control means 161 Program detail information sequential display controller 300 Program data 310, 320, 330 Channel information 311, 313, 315, 317, 321, 322, 325, 327 Program information 316, 318, 324, 328 Program detail information 510 Channel information column 520 Program information column 530 Program detail information column 511, 512, 513 Channel information 521, 522, 523 Program information 531, 532, 533 Program detail information 701 Television receiver 702 Display screen 703 Remote controller 810, 820, 830 Screen 811, 821, 831, 812, 822, 832 Image region 901, 902, 903 Moving image 1001 Audio converter 1002 Audio changeover unit 1101, 1102,1103 Voice

<SOH> BACKGROUND ART <EOH>A conventional program detail information display apparatus is designed to display the program detail information by the manipulation of the viewer to designate a desired program, obtain the detail information of the program, and instruct to display. That is, the viewer manipulates in this manner to display the program detail information transmitted in every program of every channel, and selects the program by referring to the displayed program detail information. This program detail information is the information including the synopsis, names of the cast, etc. In other method, the user designates a desired program actively by using the display function of program list and program retrieval function by program genre. In these methods, however, the program detail information display screen is displayed in a separate screen from the program list, or the screen is changed over from the program list to the program detail information display screen, and it is hard to understand the correspondence between the program detail information and program. Besides, the user's operation is complicated. To solve such problems, a apparatus for displaying the program detail information directly in the program list is proposed in Japanese Laid-open Patent No. H11-155110. The conventional methods are explained below by referring to FIG. 12 . FIG. 12 shows a screen displaying program detail information in the program list. In the diagram, the vertical direction at the right side of a screen 1200 is a channel column 1210 , and the lateral direction is a time column 1260 . Channels 1220 , 1230 , 1240 , 1250 are individual channels. In channel 1220 , programs are displayed along the time column 1260 in the lateral direction. For example, from time 12:00 to time 13:00, a program 1221 is broadcast. Similarly, a program 1231 is one of the programs broadcasted in channel 1230 , a program 1241 is one of the programs broadcasted in channel 1240 , and a program 1251 is one of the programs broadcast in channel 1250 . Upon start of display of the program list, display frames are formed in each channel by dividing in a uniform width in the vertical axis direction (direction of channel column 1210 ) and in uniform time unit width in the lateral axis direction (direction of time column 1260 ). The viewer designates a program by moving the cursor to the position of a program name desired to know the detail information out of the program names displayed in the program list displayed on the screen 1200 . At this moment, the detail information of the program corresponding to the cursor position is taken out from a specified database, and displayed as program detail information. The column of the program corresponding to the cursor position is magnified in the direction of the channel column 1210 and in the direction of the time column 1260 so that the program detail information and program name may be displayed in a proper size. In FIG. 12 , the cursor is positioned at the program 1241 , and the program 1241 is designated. The viewer does not designate the program 1221 , program 1231 or program 1251 , only the program titles are displayed in these columns. On the other hand, the column of the program 1241 displays the program detail information such as the synopsis and the cast, together with the program title. In such apparatus, the user must designate a desired program by moving the cursor to each program and display the program detail information, out of a tremendous number of programs displayed on the program list, and select the program by referring to the displayed program detail information. In such method, the operation is very complicated and practically difficult. In another prior art, the viewer is not required to select each program from the program list, but by using the viewer's preference information, preferred programs for the viewer are selected and recommended from a huge list of programs. This prior art is based on the preference of the viewer. In other words, programs recommended by the program provider cannot be presented to the user without requiring the viewer's preference information. In the multichannel trend of television broadcast, the number of programs is increasing enormously, and these problems will become more and more serious. It is hence extremely difficult for the viewer to designate a program actively from the program list by program retrieval by program list or program genre, and display the program detail information and select a program. Yet, the conventional program detail information display apparatus has no means for telling the programs recommended by the program provider.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a system block diagram of program detail information display apparatus in a preferred embodiment of the invention. FIG. 2 is a specific system block diagram of program detail information display apparatus in preferred embodiment 1 of the invention. FIG. 3 is a conceptual diagram of data composition of program data in preferred embodiment 1 of the invention. FIG. 4 is an operation flowchart of program detail information extracting process in preferred embodiment 1 of the invention. FIG. 5 is an example of program detail list for display in program detail information display apparatus in preferred embodiment 1. FIG. 6 is a flowchart of making process of program detail data for display in program detail information display apparatus in preferred embodiment 1. FIG. 7 is an example of display screen of program detail information in program detail information display apparatus in preferred embodiment 1. FIG. 8 is a diagram showing an example of a further specific display screen of program detail information in preferred embodiment 1 of the invention. FIG. 9 is a diagram showing other example of a further specific display screen of program detail information in preferred embodiment 1 of the invention. FIG. 10 is a specific system block diagram of program detail information display apparatus in preferred embodiment 2 of the invention. FIG. 11 is a diagram showing an example of a display screen of program detail information in program detail information display apparatus in preferred embodiment 2 of the invention. FIG. 12 is a diagram showing a display screen of program detail information in program detail information display apparatus in a prior art. detailed-description description="Detailed Description" end="lead"?

20041013

20091006

20050324

58620.0

HICKS, CHARLES N

PROGRAM DETAIL INFORMATION DISPLAY APPARATUS AND METHOD THEREOF

UNDISCOUNTED

ACCEPTED

ACCEPTED

Comfort pillow

A pillow including a viscoelastic sleeve defining a cavity and filler material positioned within the cavity.

1. A pillow comprising: a viscoelastic sleeve defining a cavity; and filler material positioned within the cavity. 2. The pillow of claim 1, wherein the sleeve includes a first viscoelastic layer; and a second viscoelastic layer, the first and second viscoelastic layers being connected together to form the cavity therebetween, wherein the filler material is positioned between the first and second viscoelastic layers. 3. The pillow of claim 2, wherein the first viscoelastic layer and the second viscoelastic layer are between about 5 mm and 15 mm thick. 4. The pillow of claim 3, wherein the first viscoelastic layer and the second viscoelastic layer are about 10 mm thick. 5. The pillow of claim 2, wherein the first viscoelastic layer and the second viscoelastic layer have a density between about 30 kg/m3 and about 140 kg/m3. 6. The pillow of claim 5, wherein the first viscoelastic layer and the second viscoelastic layer have a density of about 85 kg/m3. 7. The pillow of claim 2, further comprising a first fabric layer covering the first viscoelastic layer; and a second fabric layer covering the second viscoelastic layer. 8. The pillow of claim 7, wherein the first and second fabric layers are connected to the first and second viscoelastic layers, respectively. 9. The pillow of claim 8, wherein the first and second fabric layers are stitched to the first and second viscoelastic layers, respectively. 10. The pillow of claim 1, further comprising a cover encasing the viscoelastic sleeve, the cover including a re-sealable slot. 11. The pillow of claim 1, wherein the filler material includes granulated viscoelastic foam. 12. The pillow of claim 11, wherein the granulated viscoelastic foam has a density between about 30 kg/m3 and about 140 kg/m3. 13. The pillow of claim 12, wherein the granulated viscoelastic foam has a density of about 85 kg/m3. 14. The pillow of claim 11, wherein the granulated viscoelastic foam has a nominal length between about 0.6 cm and about 2 cm. 15. The pillow of claim 14, wherein the granulated viscoelastic foam has a nominal length of about 1.3 cm. 16. The pillow of claim 11, wherein approximately 16% to 20% of the granulated viscoelastic foam include lengths longer than about 2 cm. 17. The pillow of claim 11, wherein between approximately 38% to 42% of the granulated viscoelastic foam include lengths between about 1 cm and about 2 cm. 18. The pillow of claim 11, wherein approximately 38% to 42% of the granulated viscoelastic foam include lengths shorter than about 1 cm. 19. The pillow of claim 1, wherein the filler material includes granulated viscoelastic foam and polystyrene balls. 20. The pillow of claim 1, wherein the filler material includes granulated viscoelastic foam and granulated highly-elastic foam. 21. A method for manufacturing a pillow, the method comprising: providing a viscoelastic sleeve that defines a cavity; inserting filler material within the cavity; and closing the sleeve to maintain the filer material within the cavity. 22. The method of claim 21, further comprising overlying a first viscoelastic layer with a second viscoelastic layer; connecting a portion of the first and second viscoelastic layers to form the sleeve containing the filler material; and connecting a remaining portion of the first and second viscoelastic layers to close the sleeve and maintain the filler material within the cavity. 23. The method of claim 22, further comprising covering the first viscoelastic layer with a first fabric layer; and covering the second viscoelastic layer with a second fabric layer. 24. The method of claim 23, further comprising connecting the first fabric layer to the first viscoelastic layer; and connecting the second fabric layer to the second viscoelastic layer. 25. The method of claim 24, wherein connecting the first fabric layer with the first viscoelastic layer includes stitching together the first fabric layer with the first viscoelastic layer, and wherein connecting the second fabric layer with the second viscoelastic layer includes stitching together the second fabric layer with the second viscoelastic layer. 26. The method of claim 21, further comprising inserting the viscoelastic sleeve into a cover through a re-sealable slot; and sealing the slot to secure the viscoelastic sleeve within the cover. 27. The method of claim 21, further comprising shredding viscoelastic material into individual lengths to form the filler material. 28. A method for manufacturing a pillow, the method comprising: providing at least two opposing viscoelastic foam layers and at least two reinforcing fabric layers covering the opposing viscoelastic foam layers; sewing together the viscoelastic foam layers and the reinforcing fabric layers to form a casing having an open end, the viscoelastic foam layers comprising respective inner layers of the casing, and the reinforcing fabric layers comprising respective outer layers of the casing; inserting filler material through the open end of the casing; and sewing together the open end of the casing to close the casing and secure therein the filler material.

RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/383,169 filed on May 24, 2002, the entire contents of which is incorporated herein by reference. FIELD OF THE INVENTION This invention relates generally to pillows or cushions, and more particularly to a pillow or cushion for therapeutic use. BACKGROUND OF THE INVENTION The neck of a person lying in a supine or sidelying position is often out of alignment with the person's spine. This is commonly the case when the person's neck is supported by a pillow or multiple pillows such that the neck lies at an angle defined by the deflected height of the pillow(s), and this angle is typically not co-planar with the spine. The deflected height of the pillow is closely related to its stiffness, which is conventionally provided by filling material disposed within a fabric covering. Conventional filling material can include feathers, cotton, or a synthetic filler. SUMMARY OF THE INVENTION To provide a pillow structure more likely to properly align the user's neck and spine, the invention provides a pillow having multiple foam components. One embodiment of the present invention includes a pillow having a viscoelastic sleeve defining a cavity and filler material positioned within the cavity. Another embodiment of the present invention includes a pillow having outer layers and a filler material comprised of granulated viscoelastic foam disposed between the outer layers. Yet another embodiment of the present invention includes a pillow having outer layers of reinforcing fabric, intermediate layers of viscoelastic foam, and a filler material comprised of granulated viscoelastic foam disposed between the intermediate layers. The present invention also includes a method for manufacturing a pillow. The method includes providing a viscoelastic sleeve that defines a cavity, inserting filler material within the cavity, and closing the sleeve to maintain the filer material within the cavity. The viscoelastic foam responds to changes in temperature such that body heat molds the pillow to conform to the curves of a body for comfort and support. This allows the shape of the pillow to more closely follow the contours of the body and to promote an improved alignment of the neck and spine when a person is in a supine or sidelying position. A cover preferably encases the pillow and contours to the shape of the pillow. The cover is removable, washable, and has a resealable slot through which the pillow may be inserted or removed. The slot extends across an edge portion of the pillow and is preferably opened and closed by a zipper. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view illustrating a pillow embodying the present invention. FIG. 2 is an exploded view of the pillow shown in FIG. 1. FIG. 3 is a partial cross-sectional view of the pillow shown in FIG. 1. Before the embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangements of components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT FIGS. 1-3 illustrate a pillow 10 of the present invention having a sleeve construction formed of multiple layers. The pillow 10 comprises a filler material 14 disposed between layers of viscoelastic foam 18. The viscoelastic foam layers 18 possess specific thermally responsive properties which cause the pillow 10 to conform to the shape of the portion of a person's body that contacts the pillow 10. The viscoelastic foam layers 18 have a lower stiffness or hardness at an elevated temperature as compared to the stiffness at a cooler temperature. Conversely, conventional pillow filler materials typically have a constant stiffness with respect to a changing temperature. The body heat of the person acts to soften the portion of the pillow 10 in contact with the body, while the portion of the pillow 10 not contacting the body remains more firm. As a result, the pillow 10 embodying the present invention allows for greater comfort over a conventional pillow by accommodating each user's body form. In one embodiment of the present invention, the filler material 14 is granulated, or shredded, viscoelastic foam having a density of about 85 kg/m3. However, a suitable density for the viscoelastic foam filler material 14 for an average weight pillow 10, for example, can be between about 30 and about 140 kg/m3. Further, a suitable density for the viscoelastic foam filler material 14 for a light-weight pillow 10, for example, can be less than about 40 kg/m3. Likewise, a suitable density for the viscoelastic foam filler material 14 for a heavy-weight pillow 10, for example, can be greater than about 130 kg/m3. Alternatively, the granulated viscoelastic foam utilized as the filler material 14 can have any density in accordance with the desired characteristics of the pillow 10. In addition, a suitable viscoelastic foam filler material 14 possesses an indentation load deflection, or “LD,” of 65% between 100-500 N loading, and a maximum 10% rebound according to the test procedure governed by the ASTM-D-1564 standard. The granulated filler material 14 can be made up of recycled, virgin, or scrap viscoelastic material. The granulated filler material 14 may consist of pieces of a nominal length, or the granulated filler material 14 may consist of pieces of varying lengths. For example, granulated filler material 14 may have a nominal length of about 1.3 cm. Also, granulated filler material 14 may consist of varying lengths between about 0.6 cm and about 2 cm. The granulated filler material 14 can be as short as 0.3 cm and as long as 4 cm., or the filler material 14 can be any length in accordance with the desired characteristics of the pillow 10. In one preferred embodiment of the invention, the granulated filler material 14 is comprised of 16-20% having a length longer than 2 cm, 38-42% having a length between 1 and 2 cm, and 38-42% of the pieces shorter than 1 cm. Significant cost savings and waste reduction can be realized by using scrap or recycled filler material 14 rather than virgin filler material 14. The viscoelastic foam used as the filler material 14 is made from a polyurethane foam material, however, the filler material 14 can be made from any other viscoelastic polymer material that exhibits similar thermally-responsive properties. The composition of the filler material 14 can be varied to alter the characteristics of the pillow 10 and the cost of the pillow 10. In another embodiment of the present invention, the filler material 14 is a combination of granulated viscoelastic foam and a fiber material. The fiber material can be made from any kind of textile, such as an organic textile (cotton) or a synthetic textile, which is often less expensive than viscoelastic foam. In one embodiment of the present invention, the fiber material has a density of about 1 g/cm3. However, a suitable density for the fiber material for an average weight pillow 10, for example, is 0.1-2 g/cm3. Further, a suitable density for the fiber material for a light-weight pillow 10, for example, can be less than about 0.3 g/cm3. Likewise, a suitable density for the fiber material for a heavy-weight pillow 10, for example, can be greater than about 1.8 g/cm3. Alternatively, the fiber material utilized in combination with the granulated viscoelastic foam as the filler material 14 can have any density in accordance with the desired characteristics of the pillow 10. In one preferred embodiment of the invention, the filler material 14 is comprised of about 50% fiber material, while the remaining composition includes the granulated viscoelastic foam. However, a suitable range of fiber material in the filler material 14 for an average-cost pillow 10, for example, can be between about 20% and about 80%. Further, a suitable range of fiber material in the filler material 14 for a more expensive pillow 10, for example, can be more than about 30% of the filler material 14. Likewise, a suitable range of fiber material in the filler material 14 for a less expensive pillow 10, for example, can be greater than about 70% of the filler material 14. In yet another embodiment of the present invention, the filler material 14 is a combination of granulated viscoelastic foam and polystyrene balls, which are often less expensive than viscoelastic foam. The filler material 14 of this embodiment can also include an organic or synthetic fiber material depending on the desired characteristics of the pillow 10. The polystyrene balls may consist of balls of a nominal diameter, or the polystyrene balls may consist of balls of varying diameters. For example, the polystyrene balls may have a nominal diameter of about 5 mm. Also, the polystyrene balls may consist of varying diameters between about 1 mm and about 10 mm. The polystyrene balls can also be as small as 0.5 mm and as long as 20 mm, or the polystyrene balls can be any length in accordance with the desired characteristics of the pillow 10. In one preferred embodiment of the invention, the filler material 14 is comprised of about 50% polystyrene balls, while the remaining composition includes the granulated viscoelastic foam. However, a suitable range of polystyrene balls in the filler material 14 for an average-cost pillow 10, for example, can be between about 20% and about 80%. Further, a suitable range of polystyrene balls in the filler material 14 for a more expensive pillow 10, for example, can be less than about 30% of the filler material 14. Likewise, a suitable range of polystyrene balls in the filler material 14 for a less expensive pillow 10, for example, can be greater than about 70% of the filler material 14. In another embodiment of the present invention, the filler material 14 can also include granulated highly-elastic (“HE”) foam in addition to the granulated viscoelastic foam. HE foam is often less expensive than viscoelastic foam, thus yielding a potentially less expensive pillow 10. The filler material can be comprised of any single filler described above or any combination of the fillers. Alternatively, the filler material 14 can also include any conventional materials, such as feathers, granulated cotton, cotton fibers, etc. In one embodiment of the present invention, the filler material 14 includes HE foam having a density of about 35 kg/m3. However, a suitable density for the HE foam for an average weight pillow 10, for example, can be between about 20 and about 50 kg/m3. Further, a suitable density for the HE foam for a lightweight pillow 10, for example, can be less than about 25 kg/m3. Likewise, a suitable density for the HE foam for a heavyweight pillow 10, for example, can be greater than about 45 kg/m3. Alternatively, the HE foam utilized in the filler material 14 can have any density in accordance with the desired characteristics of the pillow 10. The granulated HE foam may consist of pieces of a nominal length, or the granulated HE foam may consist of pieces of varying lengths. For example, the granulated HE foam may have a nominal length of about 1.3 cm. Also, the granulated HE foam may consist of varying lengths between about 0.6 cm and about 2 cm. The granulated HE foam can be as short as 0.3 cm and as long as 4 cm., or the granulated HE foam can be any length in accordance with the desired characteristics of the pillow 10. In one preferred embodiment of the invention, the granulated HE foam is comprised of 16-20% having a length longer than 2 cm, 38-42% having a length between 1 and 2 cm, and 38-42% of the pieces shorter than 1 cm. In one preferred embodiment of the invention, the filler material 14 is comprised of about 50% granulated HE foam, while the remaining composition includes the granulated viscoelastic foam. However, a suitable range of HE foam in the filler material 14 for an average cost pillow 10, for example, is 20%-80%. Further, a suitable range of granulated HE foam in the filler material 14 for a more expensive pillow 10, for example, can be less than about 30% of the filler material 14. Likewise, a suitable range of granulated HE foam in the filler material 14 for a less expensive pillow 10, for example, can be greater than about 70% of the filler material 14. As previously mentioned, the filler material 14 is disposed between layers of viscoelastic foam 18. In one embodiment of the present invention, the layers of viscoelastic foam 18 have a density of about 85 kg/m3. However, a suitable density for the layers of viscoelastic foam 18 for an average weight pillow 10, for example, can be between about 30 and about 140 kg/m3. Further, a suitable density for the layers of viscoelastic foam 18 for a lightweight pillow 10, for example, can be less than about 40 kg/m3. Likewise, a suitable density for the layers of viscoelastic foam 18 for a heavyweight pillow 10, for example, can be greater than about 130 kg/m3. Alternatively, the layers of viscoelastic foam 18 can have any density in accordance with the desired characteristics of the pillow 10. The layers of viscoelastic foam 18 are preferably about 10 mm thick and have thermally-responsive properties similar to the granulated viscoelastic foam of the filler material 14. Likewise, a suitable thickness for the layers of viscoelastic foam 18 for an average weight pillow 10, for example, can be between about 5 mm and 15 mm. However, a suitable thickness for the layers of viscoelastic foam 18 for a lightweight pillow 10, for example, can be less than about 7 mm. Further, a suitable thickness for the layers of viscoelastic foam 18 for a heavyweight pillow 10, for example, can be greater than about 13 mm. The layers of viscoelastic foam 18 are made from a polyurethane foam material, however, the layers of viscoelastic foam 18 can be made from any other viscoelastic polymer material that exhibits similar thermally-responsive properties. The overall stiffness or hardness of the pillow 10 is dependent on the stiffness of the individual viscoelastic foam layers 18 and the filler material 14. As such, the overall stiffness or hardness of the pillow 10 may be affected by varying the stiffness of the individual viscoelastic foam layers 18 and/or the filler material 14. As shown in FIGS. 1-3, reinforcing fabric layers 22 are positioned on the outside of the layers of viscoelastic foam 18. The reinforcing fabric 22 acts as an anchor for stitches 26 that secure together the layers of reinforcing fabric 22 and the layers of viscoelastic foam 18. Without the reinforcing fabric layers 22, the viscoelastic foam layers 18, which are less durable than the layers of reinforcing fabric 22, would have to directly anchor the stitches 26 such that the filler material 14 is secured between the viscoelastic foam layers 18. In a pillow having this construction (not shown), the viscoelastic foam layers 18 would likely tear near the stitches 26 as a result of normal use of the pillow. Further, if the viscoelastic foam layers 18 were to tear, then the filler material 14 would spill out. Therefore, the reinforcing fabric layers 22 provide a measure of durability to the pillow 10. The reinforcing fabric 22 is preferably made from a durable material, such as a cotton/polyester blend. A cover 30 surrounds and encases the pillow 10, and conforms to the shape of the pillow 10. The cover 30 is preferably made from a durable and washable fabric material, such as a cotton/polyester blend. As shown in FIG. 1, a slot 34 extends across the cover 30 along the cover's edge. The pillow 10 may be inserted into the cover 30 through the slot 34. The pillow 10 may also be removed from the cover 30 through the slot 34 to facilitate cleaning of the cover 30. The slot 34 is resealable to close the cover 30 around the pillow 10 and to open the cover 30 for removing the pillow 10. A closure device is used to open and close the slot 34. In the preferred embodiment, the closure device is a zipper 38, although the closure device could also comprise snaps, buttons, hook and loop fasteners, overlapping flaps, laces, or other similar fasteners. During manufacture, the layers of viscoelastic foam 18 are sewn together with the layers of reinforcing fabric 22 to form a sleeve or casing having an open end, wherein the layers of viscoelastic foam 18 comprise the inner layers of the casing and the layers of reinforcing fabric 22 comprise the outer layers of the casing. The filler material 14 is then inserted through the open end of the casing until the desired amount of filler material 14 is reached within the casing. The open end is then sewn closed, thereby encasing the filler material 14 within the casing and defining a pillow 10. The pillow 10 is then inserted within the cover 30 and the cover 30 is closed by the zipper 38.

<SOH> BACKGROUND OF THE INVENTION <EOH>The neck of a person lying in a supine or sidelying position is often out of alignment with the person's spine. This is commonly the case when the person's neck is supported by a pillow or multiple pillows such that the neck lies at an angle defined by the deflected height of the pillow(s), and this angle is typically not co-planar with the spine. The deflected height of the pillow is closely related to its stiffness, which is conventionally provided by filling material disposed within a fabric covering. Conventional filling material can include feathers, cotton, or a synthetic filler.

<SOH> SUMMARY OF THE INVENTION <EOH>To provide a pillow structure more likely to properly align the user's neck and spine, the invention provides a pillow having multiple foam components. One embodiment of the present invention includes a pillow having a viscoelastic sleeve defining a cavity and filler material positioned within the cavity. Another embodiment of the present invention includes a pillow having outer layers and a filler material comprised of granulated viscoelastic foam disposed between the outer layers. Yet another embodiment of the present invention includes a pillow having outer layers of reinforcing fabric, intermediate layers of viscoelastic foam, and a filler material comprised of granulated viscoelastic foam disposed between the intermediate layers. The present invention also includes a method for manufacturing a pillow. The method includes providing a viscoelastic sleeve that defines a cavity, inserting filler material within the cavity, and closing the sleeve to maintain the filer material within the cavity. The viscoelastic foam responds to changes in temperature such that body heat molds the pillow to conform to the curves of a body for comfort and support. This allows the shape of the pillow to more closely follow the contours of the body and to promote an improved alignment of the neck and spine when a person is in a supine or sidelying position. A cover preferably encases the pillow and contours to the shape of the pillow. The cover is removable, washable, and has a resealable slot through which the pillow may be inserted or removed. The slot extends across an edge portion of the pillow and is preferably opened and closed by a zipper.

20040310

20060530

20050414

59549.0

SANTOS, ROBERT G

COMFORT PILLOW

UNDISCOUNTED

ACCEPTED

ACCEPTED

Refrigeration equipment

In a refrigerating apparatus in which a plurality of application-side heat exchangers (41, 45, 51) are connected to a heat-source side heat exchanger (4), liquid lines for a plurality of channels in a refrigerant circuit (1E) share a liquid side communication pipe (11) in order to reduce the number of pipes. Further, the liquid side communication pipe (11) is provided adjacent to a low-pressure gas side communication pipe (15) for at least one channel so as to contact it in order to supercool a liquid refrigerant by a low-pressure gas refrigerant. Thus, workability for connecting the pipes is improved and a refrigerating ability may not be decreased even if communication pipes (11, 15, 17) become long.

1. A refrigerating apparatus which comprises a refrigerant circuit (1E) in which compression mechanisms (2D, 2E), a heat-source side heat exchanger (4), expansion mechanisms (26, 42, 46, 52) and application-side heat exchangers (41, 45, 51) are connected together, and in which the application-side heat exchangers (41, 45, 51) for a plurality of channels are connected in parallel to the compression mechanisms (2D, 2E) and the heat-source side heat exchanger (4), wherein liquid lines for the plurality of channels in the refrigerant circuit (1E) share a liquid side communication pipe (11), and the liquid side communication pipe (11) is provided adjacent to a low-pressure gas side communication pipe (15) for a gas line of at least one channel so as to contact it. 2. A refrigerating apparatus which comprises a refrigerant circuit (1E) in which compression mechanisms (2D, 2E), a heat-source side heat exchanger (4), expansion mechanisms (26, 42, 46, 52) and application-side heat exchangers (41, 45, 51) are connected together, and in which the application-side heat exchangers (45, 51) for a cold-storage/freezing channel and the application-side heat exchanger (41) for an air-conditioning channel are connected in parallel to the compression mechanism (2D, 2E) and the heat-source side heat exchanger (4) and the compression mechanisms (2D, 2E) are configured so as to be capable of switching a plurality of compressors (2A, 2B, 2C) between for the cold-storage/freezing channel and for the air-conditioning channel, wherein liquid lines for both of the channels share a liquid side communication pipe (11), and the liquid side communication pipe (11) is provided adjacent to a low-pressure gas side communication pipe (15) for a gas line in the cold-storage/freezing channel so as to contact it. 3. The refrigerating apparatus of claim 1 or 2 further comprising a liquid injection pipe (27) for supplying a part of liquid refrigerant circulating in the refrigerant circuit (1E) to suction sides of the compression mechanisms (2D, 2E). 4. The refrigerating apparatus of claim 1 or 2, wherein the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15) which are disposed adjacent to each other are surrounded by a heat transfer material (12). 5. The refrigerating apparatus of claim 4, wherein an aluminum tape material (12) is wound, as a heat transfer material, around the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15).

TECHNICAL FIELD The present invention relates to a refrigerating apparatus, and in particular to, a refrigerating apparatus which has application-side heat exchangers for a plurality of channels as cold-storage/freezing and air-conditioning heat exchangers. BACKGROUND ART Refrigerating apparatuses which perform a refrigerating cycle are conventionally known. The refrigerating apparatuses are widely utilized as an air-conditioning machine for performing air-cooling/heating in a room or a cooling machine such as a refrigerator for storing foods. Among the refrigerating apparatuses, there is a refrigerating apparatus which performs air-conditioning and cold-storage/freezing as disclosed in Japanese Patent Application Laid-Open (JP-A) No. 2001-280749. In this type of refrigerating apparatus, application-side heat exchangers provided in application-side units including cold-storage/freezing showcases and an air-conditioning indoor machine are connected in parallel to a heat-source side heat exchanger in a heat-source side unit installed outdoor by liquid side communication pipes and gas side communication pipes, respectively. This refrigerating apparatus is installed at e.g., a convenience store and the like. By installing one refrigerating apparatus, air-conditioning within a store and cooling for showcases can be performed. —Problems to be Solved— In accordance with the refrigerating apparatus, communication pipes having diameters depending on the amount of refrigerant circulated and their lengths are selected. Nevertheless, when the length of the pipes is extremely long, a pressure loss for the refrigerant becomes large and thus a refrigerating ability may be easily decreased. In the refrigerating apparatus, a refrigerant circuit is configured so as to have two channels, i.e., a cold-storage/freezing channel and an air-conditioning channel. Two communication pipes are used for a liquid line and a gas line, respectively and thus the number of pipes becomes large. Work for connecting such pipes is complicated and the pipes may be connected in a wrong manner. The present invention was developed in view of such problems, and an object of the present invention is to improve workability of connecting pipes and to prevent a decrease in refrigerating ability even if the length of the pipes becomes long in a refrigerating apparatus in which a plurality of application-side heat exchangers are connected to a compression mechanism and a heat-source side heat exchanger. DISCLOSURE OF INVENTION In accordance with the present invention, a plurality of liquid lines are integrated into a liquid side communication pipe. The liquid side communication pipe is disposed adjacent to a low-pressure gas side communication pipe for a gas line so as to contact it. As a result, a liquid refrigerant can heat-exchange with a gas refrigerant to be supercooled by the gas refrigerant at the suction side. Specifically, in accordance with a first invention, it is presupposed to provide a refrigerating apparatus which comprises a refrigerant circuit (1E) in which compression mechanisms (2D, 2E), a heat-source side heat exchanger (4), expansion mechanisms (26, 42, 46, 52) and application-side heat exchangers (41, 45, 51) are connected together, and in which the application-side heat exchangers (41, 45, 51) for a plurality of channels are connected in parallel to the compression mechanisms (2D, 2E) and the heat-source side heat exchanger (4). In the refrigerating apparatus, liquid lines for the plurality of channels in the refrigerant circuit (1E) share a liquid side communication pipe (11), and the liquid side communication pipe (11) is provided adjacent to a low-pressure gas side communication pipe (15) for a gas line of at least one channel so as to contact it. In accordance with the first invention, a refrigerant is circulated within a refrigerant circuit (1E) by being branched into a plurality of channels. On the other hand, in a liquid line, refrigerants from the plurality of channels are joined and the joined refrigerant flows in one liquid side communication pipe (11). As the liquid side communication pipe (11) is provided adjacent to the low-pressure gas side communication pipe (15) for a gas line of at least one channel so as to contact it, a liquid refrigerant flowing in the liquid side communication pipe (11) heat-exchanges with a refrigerant flowing in the low-pressure gas side communication pipe (15) so as to be supercooled. In accordance with a second invention, it is presupposed to provide a refrigerating apparatus which comprises a refrigerant circuit (1E) in which compression mechanisms (2D, 2E), a heat-source side heat exchanger (4), expansion mechanisms (26, 42, 46, 52) and application-side heat exchangers (41, 45, 51) are connected together, and in which the application-side heat exchangers (45, 51) for a cold-storage/freezing channel and the application-side heat exchanger (41) for an air-conditioning channel are connected in parallel to the compression mechanism (2D, 2E) and the heat-source side heat exchanger (4) and the compression mechanisms (2D, 2E) are configured so as to be capable of switching a plurality of compressors (2A, 2B, 2C) between for the cold-storage/freezing channel and for the air-conditioning channel. In accordance with this refrigerating apparatus, liquid lines for both of the channels share a liquid side communication pipe (11), and the liquid side communication pipe (11) is provided adjacent to a low-pressure gas side communication pipe (15) for a gas line in the cold-storage/freezing channel so as to contact it. In accordance with the second invention, a refrigerant is circulated in the refrigerant circuit (1E) by branched into the cold-storage/freezing channel and the air-conditioning channel. In a liquid line, branched refrigerants join and the joined refrigerant flows in one liquid side communication pipe (11). As the liquid side communication pipe (11) is provided adjacent to the low-pressure gas side communication pipe (15) for a gas line of the cold-storage/freezing channel so as to contact it, a liquid refrigerant flowing in the liquid side communication pipe (11) heat-exchanges with a refrigerant flowing in the low-pressure gas side communication pipe (15) for the cold-storage/freezing channel so as to be supercooled. In accordance with a third invention, the refrigerating apparatus of the first or second invention further comprises a liquid injection pipe (27) for supplying a part of liquid refrigerant circulating in the refrigerant circuit (1E) to suction sides of the compression mechanisms (2D, 2E). In accordance with the third invention, when the liquid refrigerant is supercooled by the gas refrigerant at the suction side, the gas refrigerant is superheated. Even if a gas refrigerant with a large degree of superheat is sucked by the compression mechanisms (2D, 2E), it is possible to prevent the degree of superheat from being excessively large by performing liquid injection. In accordance with a fourth invention, in the refrigerating apparatus of the first or second invention, the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15) which are disposed adjacent to each other are surrounded by a heat transfer material (12). In accordance with a fifth invention, in the refrigerating apparatus of the fourth invention, an aluminum tape material (12) is wound, as a heat transfer material, around the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15). In accordance with the fourth and fifth inventions, a liquid refrigerant is efficiently supercooled by a gas refrigerant at the suction side via the heat transfer material (12) such as, e.g., an aluminum tape material. —Effects— In accordance with the first invention, liquid lines for a plurality of channels in the refrigerant circuit (1E) share one liquid side communication pipe (11), and the liquid side communication pipe (11) is provided adjacent to the low-pressure gas side communication pipe (15) for a gas line of at least one channel so as to contact it in order to supercool a liquid refrigerant by a gas refrigerant. Thus, a refrigerant having lower enthalpy can be supplied to the application-side heat exchangers (41, 45, 51). For this reason, the difference in enthalpy between refrigerants at entrances/exits for the application-side heat exchangers (41, 45, 51) becomes large, and a decrease in refrigerating ability can be prevented even if pipes are long. As liquid lines for a plurality of channels are integrated into one liquid side communication liquid pipe (11), the total number of communication pipes is reduced. Accordingly, work for connecting pipes is easily performed and the possibility of connecting wrong pipes is reduced. Namely, workability for piping is improved. In accordance with the second invention, in the refrigerant circuit (1E) having the cold-storage/freezing-channel and the air-conditioning channel, a joined liquid refrigerant from both of the channels is supercooled by a sucked gas refrigerant for the cold-storage/freezing channel. A decrease in ability can be prevented and the workability for piping can be improved. In the case of the apparatus having the cold-storage/freezing channel and the air-conditioning channel separately, a direction that a refrigerant is circulated is fixed in the cold-storage/freezing channel and a gas line is not switched between the discharge side and the suction side. Accordingly, the low-pressure gas side communication pipe (15) for the cold-storage/freezing channel and the joined liquid side communication pipe (11) for both of the channels can be easily provided adjacent to each other. As the communication pipe (17) in a gas line for the air-conditioning channel is not provided adjacent to the liquid side communication pipe (11), it can be configured so as to perform air-cooling/air-heating by switching directions in which a refrigerant circulates. In accordance with the third invention, there is provided the liquid injection pipe (27) for supplying a part of liquid refrigerant circulating in the refrigerant circuit (1E) to the suction sides of the compression mechanisms (2D, 2E). Thus, even if a degree of superheat of the gas refrigerant at the suction side becomes large when a liquid refrigerant is supercooled by the gas refrigerant at the suction side, performing liquid injection can prevent the degree of superheat from being excessively large in a compression process. As a result, because of structures of the first and second inventions, a refrigerating apparatus in which a decease in workability is suppressed while a decrease in ability is prevented can be reliably put to practical use. In accordance with the fourth invention, the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15) are surrounded by the heat transfer material (12). Accordingly, a liquid refrigerant can be reliably supercooled by a gas refrigerant via the heat transfer material (12). Further, a heat exchanger dedicated to supercooling of a liquid refrigerant is not required and thus the structure cannot be complicated. In accordance with the fifth invention, the aluminum tape material (12) is wound, as a heat transfer material, around the liquid side communication pipe (11) and the low-pressure gas side communication pipe (15). Thus, supercooling of a liquid refrigerant by a low-pressure gas refrigerant can be realized by an extremely simple structure. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a refrigerant circuit diagram of a refrigerating apparatus relating to an embodiment of the present invention. FIG. 2 is a refrigerant circuit diagram illustrating the operation of an air-cooling operation. FIG. 3 is a refrigerant circuit diagram illustrating the operation of a freezing operation. FIG. 4 is a refrigerant circuit diagram illustrating the operation of a first air-cooling/freezing operation. FIG. 5 is a Mollier chart illustrating the behavior of a refrigerant at the time of the first air-cooling/freezing operation. FIG. 6 is a refrigerant circuit diagram illustrating the operation of a second air-cooling/freezing operation. FIG. 7 is a refrigerant circuit diagram illustrating the operation of an air-heating operation. FIG. 8 is a refrigerant circuit diagram illustrating the operation of a first air-heating/freezing operation. FIG. 9 is a refrigerant circuit diagram illustrating the operation of a second air-heating/freezing operation. FIG. 10 is a Mollier chart illustrating the behavior of a refrigerant at the time of the second air-heating/freezing operation. FIG. 11 is a refrigerant circuit diagram illustrating the operation of a third air-heating/freezing operation. FIG. 12 is a Mollier chart illustrating the behavior of a refrigerant at the time of the third air-heating/freezing operation. BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described in detail hereinafter based on the drawings. As shown in FIG. 1, a refrigerating apparatus (1) relating to this embodiment is installed at convenience stores and is used to perform cooling of cold-storage showcases and freezing showcases and air-cooling/heating in the stores. The refrigerating apparatus (1) has an outdoor unit (1A), an indoor unit (1B), a cold-storage unit (1C) and a freezing unit (1D), and comprises a refrigerant circuit (1E) performing a vapor-compression refrigerating cycle. The refrigerant circuit (1E) is provided with a first channel side circuit for cold-storage/freezing and a second channel side circuit for air-conditioning. The refrigerant circuit (1E) is configured so as to be switched between an air-cooling cycle and an air-heating cycle. The indoor unit (1B) is configured to perform an air-cooling operation and an air-heating operation by switching such operations and is installed at, e.g., salesrooms. The cold-storage unit (1C) is installed at cold-storage showcases to cool air within the showcases. The freezing unit (1D) is installed at freezing showcases to cool air within the showcases. Although only one indoor unit (1B), one cold-storage unit (1C) and one freezing unit (1D) are illustrated in the figure, two indoor units (1B), eight cold-storage units (1C) and one freezing unit (1D) are connected in this embodiment. <Outdoor Unit> The outdoor unit (1A) comprises an inverter compressor (2A) serving as a first compressor, a first non-inverter compressor (2B) serving as a second compressor and a second non-inverter compressor (2C) serving as a third compressor. Further, the outdoor unit (1A) comprises a first four-way selector valve (3A), a second four-way selector valve (3B), a third four-way selector valve (3C) and an outdoor heat exchanger (4) serving as a heat-source side heat exchanger. Each of the compressors (2A, 2B, 2C) is configured by a closed type high-pressure dome scroll compressor. The inverter compressor (2A) is a compressor having a variable capacity in which an electric motor is controlled by an inverter such that the capacity is varied continuously or stepwise. The first non-inverter compressor (2B) and the second non-inverter compressor (2C) are compressors having a constant capacity in which an electric motor is always driven at a certain revolution. The inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) constitute compression mechanisms (2D, 2E) for the refrigerating apparatus (1). The compression mechanisms (2D, 2E) are configured by a compression mechanism (2D) for the first channel and a compression mechanism (2E) for the second channel. Specifically, in accordance with the compression mechanisms (2D, 2E), during operation, there are provided a case in which the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel and a case in which the inverter compressor (2A) constitutes the compression mechanism (2D) for the first channel and the first non-inverter compressor (2B) and the second non-inverter compressor (2C) constitute the compression mechanism (2E) for the second channel. Namely, while the inverter compressor (2A) is used for the first channel side circuit for cold-storage/freezing and the second non-inverter compressor (2C) is used for the second channel side circuit for air conditioning in a fixed manner, the first non-inverter compressor (2B) is used so as to be switched between for the first channel side circuit and for the second channel side circuit. Discharge pipes (5a, 5b, 5c) for the above-described inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) are connected to a high-pressure gas pipe (discharge pipe) (8), and the high-pressure gas pipe (8) is connected to a port of the first four-way selector valve (3A). The discharge pipe (5b) for the first non-inverter compressor (2B) and the discharge pipe (5c) for the second non-inverter compressor (2C) are respectively provided with a check valve (7). A gas side end portion of the outdoor heat exchanger (4) is connected to a port of the first four-way selector valve (3A) by an outdoor gas pipe (9). Connected to a liquid side end portion of the outdoor heat exchanger (4) is one end of a liquid pipe (10) serving as a liquid line. A receiver (14) is provided in the half way of the liquid pipe (10). The other end of the liquid pipe (10) is connected to a communication liquid pipe (liquid side communication pipe) (11). The outdoor heat exchanger (4) is, e.g., a fin-and-tube heat exchanger of cross-fin type, and an outdoor fan (4F) serving as a heat source fan is disposed so as to be adjacent to the exchanger (4). Connected to a port for the first four-way selector valve (3A) is a communication gas pipe (17). A port for the first four-way selector valve (3A) is connected to a port for the second four-way selector valve (3B) by a connecting pipe (18). A port for the second four-way selector valve (3B) is connected to the discharge pipe (5c) for the second non-inverter compressor (2C) by an auxiliary gas pipe (19). A port for the second four-way selector valve (3B) is connected to a suction pipe (6c) for the second non-inverter compressor (2C). A port for the second four-way selector valve (3B) is configured as a closed port. Namely, the second four-way selector valve (3B) may be a three-way selector valve. The first four-way selector valve (3A) is configured so as to be switched between a first state (see the solid lines in FIG. 1) in which the high-pressure gas pipe (8) communicates with the outdoor gas pipe (9) and the connecting pipe (18) communicates with the communication gas pipe (17) and a second state (see the broken lines in FIG. 1) in which the high-pressure gas pipe (8) communicates with the communication gas pipe (17) and the connecting pipe (18) communicates with the outdoor gas pipe (9). The second four-way selector valve (3B) is configured so as to be switched between a first state (see the solid lines in FIG. 1) in which the auxiliary gas pipe (19) communicates with the closed port and the connecting pipe (18) communicates with the suction pipe (6c) for the second non-inverter compressor (2C) and a second state (see the broken lines in FIG. 1) in which the auxiliary gas pipe (19) communicates with the connecting pipe (18) and the suction pipe (6c) communicates with the closed port. A suction pipe (6a) for the inverter compressor (2A) is connected to a low-pressure gas pipe (low-pressure gas side communication pipe) (15) for the first channel side circuit. The suction pipe (6c) for the second non-inverter compressor (2C) is connected via the first and second four-way selector valves (3A, 3B) to the low-pressure gas pipe for the second channel side circuit (the communication gas pipe (17) or the outdoor gas pipe (9)). A suction pipe (6b) for the first non-inverter compressor (2B) is connected via the third four-way selector valve (3C) to be described later to the suction pipe (6a) for the inverter compressor (2A) and the suction pipe (6c) for the second non-inverter compressor (2C). Specifically, connected to the suction pipe (6a) for the inverter compressor (2A) is a branch pipe (6d), and connected to the suction pipe (6c) for the second non-inverter compressor (2C) is a branch pipe (6e). The branch pipe (6d) from the suction pipe (6a) for the inverter compressor (2A) is connected via the check valve (7) to a first port (P1) for the third four-way selector valve (3C). The suction pipe (6b) for the first non-inverter compressor (2B) is connected to a second port (P2) for the third four-way selector valve (3C). The branch pipe (6e) from the suction pipe (6c) for the second non-inverter compressor (2C) is connected via the check valve (7) to a third port (P3) for the third four-way selector valve (3C). Further, connected to a fourth port (P4) for the third four-way selector valve (3C) is a branch pipe (28a) from a gas vent pipe (28) from the receiver (14) to be described later. The check valves provided on the branch pipes (6d, 6e) allow only a refrigerant flow toward the third four-way selector valve (3C). The third four-way selector valve (3C) is configured so as to be switched between a first state (see the solid lines in the figure) in which the first port (P1) communicates with the second port (P2) and the third port (P3) communicates with the fourth port (P4) and a second state (see the broken lines in the figure) in which the first port (P1) communicates with the fourth port (P4) and the second port (P2) communicates with the third port (P3). The discharge pipes (5a, 5b, 5c), the high-pressure gas pipe (8) and the outdoor gas pipe (9) constitute a high-pressure gas line (1L) at the time of air-cooling operation. The discharge pipes (5a, 5b, 5c), the high-pressure gas pipe (8) and the communication gas pipe (17) constitute a high-pressure gas line (1N) at the time of air-heating operation. The low-pressure gas pipe (15) and the suction pipes (6a, 6b) for the compression mechanism (2D) for the first channel constitute a first low-pressure gas line (1M). The communication gas pipe (17) and the suction pipe (6c) for the compression mechanism (2E) for the second channel constitute a low-pressure gas line (1N) at the time of the air-cooling operation. The outdoor gas pipe (9) and the suction pipe (6c) constitute a low-pressure gas line (1L) at the time of the air-heating operation. The communication gas pipe (17) is switched to be high-pressure gas line or the low-pressure gas line depending on operational states. The low-pressure gas pipe (15) is always a low-pressure gas line when a refrigerant flows therethrough regardless of the operational states. The communication liquid pipe (11), the communication gas pipe (17) and the low-pressure gas pipe (15) are extended outside from the outdoor unit (1A). Stop valves (20) are provided within the outdoor unit (1A) so as to correspond to such pipes. An auxiliary liquid pipe (25) for bypassing the receiver (14) is connected to the liquid pipe (10). A refrigerant flows in the auxiliary liquid pipe (25) mainly at the time of air-heating. The auxiliary liquid pipe (25) is provided with an outdoor expansion valve (26) serving as an expansion mechanism. The check valve (7) allowing only a refrigerant flow toward the receiver (14) is provided on the liquid pipe (10) between the outdoor heat exchanger (4) and the receiver (14). The check valve (7) is placed between a connecting point with the auxiliary liquid pipe (25) and the receiver (14) on the liquid pipe (10). The liquid pipe (10) is branched between the check valve (7) and the receiver (14) (into a branch liquid pipe (36)). The branch liquid pipe (36) is connected between the stop valve (20) and the check valve (7) to be described later on the liquid pipe (10). The branch liquid pipe (36) is provided with the check valve (7) allowing a refrigerant flow from a connecting point with the liquid pipe (10) toward the receiver (14). The liquid pipe (10) is provided with the check valve (7) between a connecting point with the auxiliary liquid pipe (25) and the stop valve (20). This check valve (7) allows only a refrigerant flow from the receiver (14) toward the stop valve (20). A liquid injection pipe (27) is connected between the auxiliary liquid pipe (25) and the low-pressure gas pipe (15). The liquid injection pipe (27) is provided with an electronic expansion valve (29). A gas vent pipe (28) is connected between the upper portion of the receiver (14) and the discharge pipe (5a) for the inverter compressor (2A). The gas vent pipe (28) is provided with the check valve (7) allowing only a refrigerant flow from the receiver (14) toward the discharge pipe (5a). As described above, the branch pipe (28a) from the gas vent pipe (28) is connected to the fourth port (P4) of the third four-way selector valve (3C). An oil separator (30) is provided at the high-pressure gas pipe (8). One end of an oil return pipe (31) is connected to the oil separator (30). The other end of the oil return pipe (31) is branched into a first oil return pipe (31a) and a second oil return pipe (31b). The first oil return pipe (31a) is provided with a solenoid valve (SV0) and is connected via the liquid injection pipe (27) to the suction pipe (6a) for the inverter compressor (2A). The second oil return pipe (31b) is provided with a solenoid valve (SV4) and is connected to the suction pipe (6c) for the second non-inverter compressor (2C). A first oil-level equalizing pipe (32) is connected between the dome (oil pool) of the inverter compressor (2A) and the suction pipe (6b) for the first non-inverter compressor (2B). A second oil-level equalizing pipe (33) is connected between the dome of the first non-inverter compressor (2B) and the suction pipe (6c) for the second non-inverter compressor (2C). A third oil-level equalizing pipe (34) is connected between the dome of the second non-inverter compressor (2C) and the suction pipe (6a) for the inverter compressor (2A). The first oil-level equalizing pipe (32), the second oil-level equalizing pipe (33) and the third oil-level equalizing pipe (34) are respectively provided with solenoid valves (SV1, SV2, SV3) as open/close mechanisms. The second oil-level equalizing pipe (33) is branched into a fourth oil-level equalizing pipe (35) between the dome of the first non-inverter compressor (2B) and the solenoid valve (SV2). The fourth oil-level equalizing pipe (35) is provided with a solenoid valve (SV5) and joins the suction pipe (6a) for the first compressor (2A). <Indoor Unit> The indoor unit (1B) includes an indoor heat exchanger (air-conditioning heat exchanger) (41) serving as an application-side heat exchanger and an indoor expansion valve (42) serving as an expansion mechanism. The gas side of the indoor heat exchanger (41) is connected to the communication gas pipe (17). The liquid side of the indoor heat exchanger (41) is connected via the indoor expansion valve (42) to a second branch pipe (11b) from the communication liquid pipe (11). The indoor heat exchanger (41) is, e.g., a fin-and-tube heat exchanger of cross-fin type. An indoor fan (43) serving as an application-side fan is disposed in the vicinity of the indoor heat exchanger (41). The indoor expansion valve (42) is configured by an electronic expansion valve. <Cold-Storage Unit> The cold-storage unit (1C) includes a cold-storage heat exchanger (45) serving as a cooling heat exchanger (evaporator) and a cold-storage expansion valve (46) serving as an expansion mechanism. The liquid side of the cold-storage heat exchanger (45) is connected via a solenoid valve (7a) and the cold-storage expansion valve (46) to the first branch pipe (11a) of the communication liquid pipe (11). Namely, the cold-storage expansion valve (46) and the solenoid valve (7a) serving as an open/close valve are provided at the upstream side of the cold-storage heat exchanger (45). The solenoid valve (7a) is used to stop a refrigerant flow at the time of a thermo-off operation. The gas side of the cold-storage heat exchanger (45) is connected to the low-pressure gas pipe (15). The cold-storage heat exchanger (45) communicates with the suction side of the compression mechanism (2D) for the first channel. The indoor heat exchanger (41) communicates with the suction side of the second non-inverter compressor (2C) during the air-cooling operation. A refrigerant pressure (evaporation pressure) of the cold-storage heat exchanger (45) is lower than that of the indoor heat exchanger (41). As a result, a refrigerant evaporation temperature of the cold-storage heat exchanger (45) is, e.g., −10° C., and the refrigerant evaporation temperature of the indoor heat exchanger (41) is, e.g., +5° C.. The refrigerant circuit (1E) structures a circuit for performing evaporation at different temperatures. The cold-storage expansion valve (46) is a temperature-sensitive expansion valve and a temperature sensing bulb is mounted to the gas side of the cold-storage heat exchanger (45). The opening of the cold-storage expansion valve (46) is adjusted on the basis of a refrigerant temperature at the exit side of the cold-storage heat exchanger (45). The cold-storage heat exchanger (45) is, e.g., a fin-and-tube heat exchanger of cross-fin type. A cold-storage fan (47) serving as a cooling fan is disposed in the vicinity of the cold-storage heat exchanger (45). <Freezing Unit> The freezing unit (1D) includes a freezing heat exchanger (51) serving as a cooling heat exchanger, a freezing expansion valve (52) serving as an expansion mechanism and a booster compressor (53) serving as a freezing compressor. Connected to the liquid side of the freezing heat exchanger (51) is a branch liquid pipe (13) branched from the first branch pipe (11a) of the communication liquid pipe (11) via a solenoid valve (7b) and the freezing expansion valve (52). The gas side of the freezing heat exchanger (51) is connected to the suction side of the booster compressor (53) by a connecting gas pipe (54). A branch gas pipe (16) branched from the low-pressure gas pipe (15) is connected to the discharge side of the booster compressor (53). The branch gas pipe (16) is provided with the check valve (7) and an oil separator (55). An oil return pipe (57) having a capillary tube (56) is connected between the oil separator (55) and the connecting gas pipe (54). The booster compressor (53) compresses a refrigerant by two steps with the compression mechanism (2D) for the first channel so that the refrigerant evaporation temperature of the freezing heat exchanger (51) is lower than that of the cold-storage heat exchanger (45). The refrigerant evaporation temperature of the freezing heat exchanger (51) is set to be, e.g., −35° C.. The freezing expansion valve (52) is a temperature-sensitive expansion valve and a temperature sensing bulb is mounted to the gas side of the cold-storage heat exchanger (45). The freezing heat exchanger (51) is, e.g., a fin-and-tube heat exchanger of cross-fin type. A freezing fan (58) serving as a cooling fan is disposed in the vicinity of the freezing heat exchanger (51). A bypass pipe (59) having the check valve (7) is connected between the connecting gas pipe (54) at the suction side of the booster compressor (53) and the downstream side of the check valve (7) on the branch gas pipe (16) at the discharge side of the booster compressor (53). The bypass pipe (59) is configured so as to bypass the booster compressor (53) to enable flowing of a refrigerant when the booster compressor (53) is stopped because of failures. <Control Channel> The refrigerant circuit (1E) is provided with various sensors and switches. The high-pressure gas pipe (8) in the outdoor unit (1A) is provided with a high-pressure sensor (61) serving as pressure detection means for detecting a high-level refrigerant pressure and a discharge temperature sensor (62) serving as temperature detection means for detecting a high-pressure refrigerant temperature. The discharge pipe (6c) for the second non-inverter compressor (2C) is provided with a discharge temperature sensor (63) serving as temperature detection means for detecting a high-pressure refrigerant temperature. The discharge pipes (5a, 5b, 5c) for the inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) are respectively provided with a pressure switch (64) which is opened when the high-level refrigerant pressure reaches a predetermined value. The suction pipes (6a, 6c) of the inverter compressor (2A) and the second non-inverter compressor (2C) are respectively provided with low-pressure sensors (65, 66) serving as pressure detection means for detecting a low-level refrigerant pressure and suction temperature sensors (67, 68) serving as temperature detection means for detecting a low-pressure refrigerant temperature. The outdoor heat exchanger (4) is provided with an outdoor heat exchanger sensor (69) serving as temperature detection means for detecting an evaporation temperature or condensation temperature which is a refrigerant temperature in the outdoor heat exchanger (4). The outdoor unit (1A) is provided with an outside air temperature sensor (70) serving as temperature detection means for detecting an outdoor air temperature. The indoor heat exchanger (41) is provided with an indoor heat exchanger sensor (71) serving as temperature detection means for detecting an evaporation temperature or condensation temperature which is a refrigerant temperature in the indoor heat exchanger (41). Further, a gas temperature sensor (72) serving as temperature detection means for detecting a gas refrigerant temperature is provided at the gas side of the indoor heat exchanger (41). Moreover, the indoor unit (1B) is provided with a room temperature sensor (73) serving as temperature detection means for detecting an indoor air temperature. A cold-storage temperature sensor (74) serving as temperature detection means for detecting a temperature within cold-storage showcases is provided in the cold-storage unit (1C). A freezing temperature sensor (75) serving as temperature detection means for detecting a temperature within freezing showcases is provided in the freezing unit (1D). The pressure switch (64) which is opened when the pressure of a discharged refrigerant reaches a predetermined value is provided at the discharge side of the booster compressor (53). Output signals from various sensors and switches are inputted to a controller (80). This controller (80) is configured so as to control the operation of the refrigerant circuit (1E) and to perform control by switching eight kinds of operation modes to be described later. The controller (80) controls, at the time of operation, start, stop and capacity control for the inverter compressor (2A), start and stop for the first non-inverter compressor (2B) and the second non-inverter compressor (2C) and opening adjustment for the outdoor expansion valve (26) and the indoor expansion valve (42). Further, the controller (80) also performs switching of the four-way selector valves (3A, 3B, 3C), open/close operation for the solenoid valves (SV0, SV1, SV2, SV3, SV4, SV5) of the oil return pipes (31a, 31b) and the oil-level equalizing pipes (32, 33, 34, 35) and opening adjustment for the electronic expansion valve (29) of the liquid injection pipe (27). <Communication Pipes> One communication liquid pipe (11) is provided at the exit of the outdoor unit (1A). Two liquid lines for the first channel side circuit for cold-storage/freezing and the second channel side circuit for air-conditioning are integrated into the one communication liquid pipe (11). The communication liquid pipe (11) is branched into the branch pipes (11a, 11b) for the respective channels in the vicinity of the application-side units (1B, 1C, 1D). The communication liquid pipe (11) is provided adjacent to the low-pressure gas pipe (15) serving as a suction gas line in the first channel side circuit for cold-storage/freezing so as to contact it. An aluminum tape material (12) serving as a heat transfer material is wound around the communication liquid pipe (11) and the low-pressure gas pipe (15), so that these two communication pipes (11, 15) are surrounded by the heat transfer material (12). The contacted portion of the communication pipes (11, 15) constitutes a heat exchanger in which a liquid refrigerant heat-exchanges with a low-pressure gas refrigerant. In accordance with the refrigerating apparatus (1), the outdoor unit (1A), the indoor unit (1B), the cold-storage unit (1C) and the freezing unit (1D) are respectively installed. Then, the units (1A, 1B, 1C, 1D) are connected together by three communication pipes (11, 15, 17) and the stop valves (20) are opened. As a result, a refrigerant can be circulated in the refrigerant circuit (1E). In accordance with the refrigerating apparatus (1), the refrigerant circuit (1E) includes a first channel for cold-storage/freezing and a second channel for air-conditioning. Nevertheless, the communication liquid pipe (11) is common to the respective channels. Consequently, work for connecting pipes can be easily carried out as compared to the case that communication liquid pipes are separately provided for the respective channels. —Operation— Next, operations performed by the above-described refrigerating apparatus (1) will be described respectively. In accordance with this embodiment, it is configured so as to be capable of setting eight kinds of operation modes as follows. Specifically, it is configured so as to be capable of performing {circle over (1)} air-cooling operation of performing only air-cooling in the indoor unit (1B), {circle over (2)} freezing operation of only performing cooling in the cold-storage unit (1C) and the freezing unit (1D), {circle over (3)} first air-cooling/freezing operation of simultaneously performing air-cooling in the indoor unit (1B) and cooling in the cold-storage unit (1C) and the freezing unit (1D), {circle over (4)} second air-cooling/freezing operation performed when an air-cooling ability of the indoor unit (1B) is insufficient at the time of the first air-cooling/freezing operation, {circle over (5)} air-heating operation of performing only air-heating in the indoor unit (1B), {circle over (6)} first air-heating/freezing operation of performing air-heating in the indoor unit (1B) and cooling in the cold-storage unit (1C) and the freezing unit (1D) by a heat recovery operation without using the outdoor heat exchanger (4), {circle over (7)} second air-heating/freezing operation with excessive air-heating ability performed when an air-heating ability of the indoor unit (1B) is superfluous at the time of the first air-heating/freezing operation and {circle over (8)} third air-heating/freezing operation with insufficient air-heating ability performed when the air-heating ability of the indoor unit (1B) is insufficient during the first air-heating/freezing operation. The respective operations will be described specifically. <Air-Cooling Operation> The air-cooling operation is an operation of performing only air-cooling in the indoor unit (1B). At the time of the air-cooling operation, as shown in FIG. 2, the inverter compressor (2A) constitutes the compression mechanism (2D) for the first channel, and the first non-inverter compressor (2B) and the second non-inverter compressor (2C) constitute the compression mechanism (2E) for the second channel. Only the first non-inverter compressor (2B) and the second non-inverter compressor (2C) in the compression mechanism (2E) for the second channel are driven. As shown by the solid lines in FIG. 2, the first four-way selector valve (3A) and the second four-way selector valve (3B) are switched to be in the first state. The third four-way selector valve (3C) is switched to be in the second state. Further, the outdoor expansion valve (26), the electronic expansion valve (29) of the liquid injection pipe (27), the solenoid valve (7a) in the cold-storage unit (1C) and the solenoid valve (7b) in the freezing unit (1D) are closed. Under this state, a refrigerant discharged from the first non-inverter compressor (2B) and the second non-inverter compressor (2C) flows from the first four-way selector valve (3A) through the outdoor gas pipe (9) into the outdoor heat exchanger (4) and is condensed therein. The condensed liquid refrigerant flows in the liquid pipe (10). Further, the liquid refrigerant flows through the receiver (14), the communication liquid pipe (11), the second branch pipe (11b) and the indoor expansion valve (42) into the indoor heat exchanger (41) and then is evaporated. The evaporated gas refrigerant flows from the communication gas pipe (17) through the first four-way selector valve (3A) and the second four-way selector valve (3B) into the suction pipe (6c) for the second non-inverter compressor (2C). A part of the low-pressure gas refrigerant returns to the second non-inverter compressor (2C). The remainder thereof flows from the suction pipe (6c) for the second non-inverter compressor (2C) into the branch pipe (6e). Then, the remaining gas refrigerant returns through the third four-way selector valve (3C) to the first non-inverter compressor (2B). By the refrigerant repeating such circulation, air-cooling within a store is performed. Under this operational state, start and stop for the first non-inverter compressor (2B) and the second non-inverter compressor (2C) and the opening of the indoor expansion valve (42) are controlled depending on an air-cooling load within the store. Only one of the compressors (2B, 2C) may be operated. <Freezing Operation> The freezing operation is an operation of performing only cooling in the cold-storage unit (1C) and the freezing unit (1D). During the freezing operation, as shown in FIG. 3, the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel, and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel. The inverter compressor (2A) and the first non-inverter compressor (2B) in the compression mechanism (2D) for the first channel are driven and the booster compressor (53) is also driven, but the second non-inverter compressor (2C) is stopped. As shown by the solid lines in FIG. 3, the first four-way selector valve (3A) and the second four-way selector valve (3B) are switched to be in the first state, and the third four-way selector valve (3C) is also switched to be in the first state. The solenoid valve (7a) of the cold-storage unit (1C) and the solenoid valve (7b) of the freezing unit (1D) are opened, while the outdoor expansion valve (26) and the indoor expansion valve (42) are closed. The opening of the electronic expansion valve (29) of the liquid injection pipe (27) is adjusted to a predetermined value so as to enable a liquid refrigerant flow with a predetermined flow rate. Under this state, a refrigerant discharged from the inverter compressor (2A) and the first non-inverter compressor (2B) flows from the first four-way selector valve (3A) through the outdoor gas pipe (9) into the outdoor heat exchanger (4) and then is condensed therein. The condensed liquid refrigerant flows through the liquid pipe (10), the receiver (14) and the communication liquid pipe (11) into the first branch pipe (11a). Then, a part of the condensed liquid refrigerant flows through the cold-storage expansion valve (46) into the cold-storage heat exchanger (45) and then is evaporated therein. The other part of the liquid refrigerant flowing in the communication liquid pipe (11) flows through the branch liquid pipe (13) and the freezing expansion valve (52) into the freezing heat exchanger (51) and then is evaporated therein. The gas refrigerant evaporated in the freezing heat exchanger (51) is sucked by the booster compressor (53), compressed thereat and then discharged into the branch gas pipe (16). The gas refrigerant evaporated by the cold-storage heat exchanger (45) joins the gas refrigerant discharged from the booster compressor (53) at the low-pressure gas pipe (15). The joined gas refrigerant returns to the inverter compressor (2A) and the first non-inverter compressor (2B). By the refrigerant repeating such circulation, cold-storage showcases and freezing showcases are cooled. The refrigerant pressure of the freezing heat exchanger (51) is lower than that of the cold-storage heat exchanger (45) because the refrigerant is sucked by the booster compressor (53). As a result, the refrigerant temperature (evaporation temperature) in the freezing heat exchanger (51) is, e.g., −35° C., and the refrigerant temperature (evaporation temperature) in the cold-storage heat exchanger (45) is, e.g., −10° C. During the freezing operation, start and stop for the first non-inverter compressor (2B) and start, stop and capacity control for the inverter compressor (2A) are performed depending on, e.g., a low refrigerant pressure (LP) detected by the low-pressure sensor (65), and the operation is performed depending on a freezing load. For the control for increasing the capacity of the compression mechanism (2D), the inverter compressor (2A) is driven while the first non-inverter compressor (2B) is stopped. When the inverter compressor (2A) reaches its maximum capacity and then a load is further increased, the first non-inverter compressor (2B) is driven and the capacity of the inverter compressor (2A) is reduced to its minimum capacity. When a load is even further increased, the capacity of the inverter compressor (2A) is increased while the first non-inverter compressor (2B) is activated. For the control for reducing the capacity of the compressor, the operation opposite to the control for increasing the capacity is carried out. A degree-of-superheat control utilizing a temperature sensing bulb is performed for the opening of the cold-storage expansion valve (46) and the freezing expansion valve (52). This is also performed in the following operations. When a refrigerant is circulated in the refrigerant circuit (1E) during the freezing operation, a liquid refrigerant flowing in the communication liquid pipe (11) heat-exchanges with a low-pressure gas refrigerant flowing in the low-pressure gas pipe (15) and thus is supercooled. For this reason, the difference in enthalpy between refrigerants in the cold-storage heat exchanger (45) and the freezing heat exchanger (51) is larger than that of the case that supercooling is not performed. As a result, high refrigerating ability is exhibited. The degree of superheat of a gas refrigerant at the suction side becomes large because it heat-exchanges with the liquid refrigerant. The gas refrigerant is mixed with the liquid refrigerant from the liquid injection pipe (27) and thus it is possible to prevent the degree of superheat of the gas refrigerant from becoming significantly large in the compression mechanism (2D). <First Air-Cooling/Freezing Operation> This first air-cooling/freezing operation is an operation of simultaneously performing air-cooling in the indoor unit (1B) and cooling in the cold-storage unit (1C) and the freezing unit (1D). During the first air-cooling/freezing operation, as shown in FIG. 4, the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel, and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel. The inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) are driven, and the booster compressor (53) is also driven. As shown by the solid lines in FIG. 4, the first four-way selector valve (3A), the second four-way selector valve (3B) and the third four-way selector valve (3C) are switched to be in the first state. The solenoid valve (7a) in the cold-storage unit (1C) and the solenoid valve (7b) in the freezing unit (1D) are opened, and the outdoor expansion valve (26) is closed. The opening of the electronic expansion valve (29) on the liquid injection pipe (27) is adjusted so as to supply a predetermined flow rate of liquid refrigerant to the suction side of the compression mechanism (2D). Under this state, refrigerants discharged from the inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) join at the high-pressure gas pipe (8). The resultant joined refrigerant flows from the first four-way selector valve (3A) through the outdoor gas pipe (9) into the outdoor heat exchanger (4), and then is condensed therein. The condensed refrigerant flows through the liquid pipe (10) and the receiver (14), and then into the communication liquid pipe (11). A part of the liquid refrigerant flowing in the communication liquid pipe (11) is branched into the second branch pipe (11b). The branched liquid refrigerant flows through the indoor expansion valve (42) into the indoor heat exchanger (41), and then is evaporated therein. The evaporated gas refrigerant flows from the communication gas pipe (17) through the first four-way selector valve (3A) and the second four-way selector valve (3B) into the suction pipe (6c). Finally, the evaporated gas refrigerant returns to the second non-inverter compressor (2C). The other part of the liquid refrigerant flowing in the communication liquid pipe (11) is branched into the first branch pipe (11a). A part of the branched liquid refrigerant flows through the cold-storage expansion valve (46) into the cold-storage heat exchanger (45) and then is evaporated therein. The other part of the liquid refrigerant flowing in the first branch pipe (11a) flows through the branch liquid pipe (13) and the freezing expansion valve (52) into the freezing heat exchanger (51) and then is evaporated therein. The gas refrigerant evaporated by the freezing heat exchanger (51) is sucked by the booster compressor (53), compressed therein and then discharged into the branch gas pipe (16). The gas refrigerant evaporated by the cold-storage heat exchanger (45) joins the gas refrigerant discharged from the booster compressor (53) at the low-pressure gas pipe (15) and the joined gas refrigerant returns to the inverter compressor (2A) and the first non-inverter compressor (2B). By the refrigerant repeating such circulation, air-cooling within a store is performed and the interiors of cold-storage showcases and freezing showcases are cooled. The behavior of refrigerant during the first air-cooling/freezing operation will be described based on a Mollier chart shown in FIG. 5. Firstly, a refrigerant is compressed to a point A by the second non-inverter compressor (2C). A refrigerant is compressed to a point B by the inverter compressor (2A) and the first non-inverter compressor (2B). The refrigerant at the point A joins the refrigerant at the point B, and the joined refrigerant is condensed into a point C1. The refrigerant at the point C1 heat-exchanges with a gas refrigerant sucked into the inverter compressor (2A) and the first non-inverter compressor (2B) so as to be in a supercooled state (point C2). The pressure of a part of the refrigerant at the point C2 is reduced to a point D by the indoor expansion valve (42). This refrigerant is evaporated at, e.g., +5° C. and sucked into the second non-inverter compressor (2C) at a point E. The pressure of a part of the refrigerant at the point C2 is reduced to a point F by the cold-storage expansion valve (46). This refrigerant is evaporated at, e.g., −10° C. and its state is changed to a point G. Because a part of the refrigerant at the point C2 is sucked by the booster compressor (53), the pressure of this refrigerant is reduced to a point H by the freezing expansion valve (52). This refrigerant is evaporated at, e.g., −35° C. and sucked by the booster compressor (53) at a point I. The refrigerant compressed to a point J by the booster compressor (53) joins the refrigerant from the cold-storage heat exchanger (45) and the state of the resultant joined refrigerant is changed to the point G. The gas refrigerant at the point G heat-exchanges with the liquid refrigerant at the point C1 and is superheated to a point K. The liquid refrigerant is supercooled to the point C2. The state of the gas refrigerant is changed to a point M by mixing this gas refrigerant with a refrigerant obtained by reducing the pressure of a part of the liquid refrigerant at the point C1 to a point L by the electronic expansion valve (29) (by performing liquid injection), and then the resultant refrigerant is sucked by the inverter compressor (2A) and the first non-inverter compressor (2B). As described above, the refrigerant in the refrigerant circuit (1E) is evaporated at different temperatures by the compression mechanism (2D) for the first channel and the compression mechanism (2E) for the second channel. Further, the refrigerant is compressed by two steps by the booster compressor (53) and thus has three kinds of evaporation temperatures. When the refrigerant is circulated during the first air-cooling/freezing operation, a liquid refrigerant flowing in the communication liquid pipe (11) heat-exchanges with a low-pressure gas refrigerant flowing in the low-pressure gas pipe (15) and thus is supercooled. For this reason, the differences in enthalpy of refrigerants in the air-conditioning heat exchanger (41), the cold-storage heat exchanger (45) and the freezing heat exchanger (51) are larger than those of the case that supercooling is not performed. As a result, high refrigerating ability is exhibited. The gas refrigerant at the suction side is mixed with the liquid refrigerant by performing liquid injection and thus the degree of superheat of the refrigerant cannot be excessively large in the compression process. <Second Air-Cooling/Freezing Operation> The second air-cooling/freezing operation is an operation performed when the air-cooling ability of the indoor unit (1B) becomes insufficient during the first air-cooling/freezing operation and in which the first non-inverter compressor (2B) is switched to the air-conditioning side. Settings for the second air-cooling/freezing operation are basically the same as in the first air-cooling/freezing operation as shown in FIG. 6. Nevertheless, the second air-cooling/freezing operation is different from the first air-cooling/freezing operation in that the third four-way selector valve (3C) is switched to be in the second state. In accordance with the second air-cooling/freezing operation, as in the first air-cooling/freezing operation, a refrigerant discharged from the inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) is condensed in the outdoor heat exchanger (4) and then is evaporated in the indoor heat exchanger (41), the cold-storage heat exchanger (45) and the freezing heat exchanger (51). The refrigerant evaporated in the indoor heat exchanger (41) returns to the first non-inverter compressor (2B) and the second non-inverter compressor (2C). The refrigerant evaporated in the cold-storage heat exchanger (45) and the freezing heat exchanger (51) returns to the inverter compressor (2A). Because two compressors (2B, 2C) are used at the air-conditioning side, the lack of the air-cooling ability is compensated. A description about specific switching control between the first air-cooling/freezing operation and the second air-cooling/freezing operation will be omitted. In the second air-cooling/freezing operation, an improvement in ability can be accomplished by supercooling a liquid refrigerant. <Air-Heating Operation> The air-heating operation is an operation of performing only air-heating in the indoor unit (1B). At the time of the air-heating operation, as shown in FIG. 7, the inverter compressor (2A) constitutes the compression mechanism (2D) for the first channel, and the first non-inverter compressor (2B) and the second non-inverter compressor (2C) constitute the compression mechanism (2E) for the second channel. Only the first non-inverter compressor (2B) and the second non-inverter compressor (2C) in the compression mechanism (2E) for the second channel are driven. As shown by the solid lines in FIG. 7, the first four-way selector valve (3A) is switched to be in the second state, the second four-way selector valve (3B) is switched to be in the first state and the third four-way selector valve (3C) is switched to be in the second state. The electronic expansion valve (29) on the liquid injection pipe (27), solenoid valve (7a) in the cold-storage unit (1C) and the solenoid valve (7b) in the freezing unit (1D) are closed. Openings of the outdoor expansion valve (26) and the indoor expansion valve (42) are controlled to predetermined values. Under this state, a refrigerant discharged from the first non-inverter compressor (2B) and the second non-inverter compressor (2C) flows from the first four-way selector valve (3A) through the communication gas pipe (17) into the indoor heat exchanger (41) and then is condensed therein. The condensed liquid refrigerant flows through the communication liquid pipe (11) and the branch liquid pipe (36) into the receiver (14). Then, the liquid refrigerant flows through the outdoor expansion valve (26) on the auxiliary liquid pipe (25) into the outdoor heat exchanger (4), and then is evaporated therein. The evaporated gas refrigerant flows from the outdoor gas pipe (9) through the first four-way selector valve (3A) and the second four-way selector valve (3B) into the suction pipe (6c) for the second non-inverter compressor (2C). Finally, the evaporated gas refrigerant returns to the first non-inverter compressor (2B) and the second non-inverter compressor (2C). By repeating such circulation, air-heating within a store is performed. As in the air-cooling operation, one of the compressors (2A, 2B) may be operated. <First Air-Heating/Freezing Operation> The first air-heating/freezing operation is a heat recovery operation of performing air-heating in the indoor unit (1B) and cooling in the cold-storage unit (1C) and the freezing unit (1D) without using the outdoor heat exchanger (4). In accordance with the first air-heating/freezing operation, as shown in FIG. 8, the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel, and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel. The inverter compressor (2A) and the first non-inverter compressor (2B) are driven and the booster (53) is also driven. The second non-inverter compressor (2C) is stopped. As shown by the solid lines in FIG. 8, the first four-way selector valve (3A) is switched to be in the second state, the second four-way selector valve (3B) and the third four-way selector valve (3C) are switched to be in the first state. The solenoid valve (7a) in the cold-storage unit (1C) and the solenoid valve (7b) in the freezing unit (1D) are opened, and the outdoor expansion valve (26) is closed. The opening of the electronic expansion valve (29) on the liquid injection pipe (27) is controlled to a predetermined value in order to adjust the flow rate of a refrigerant. Under this state, a refrigerant discharged from the inverter compressor (2A) and the first non-inverter compressor (2B) flows from the first four-way selector valve (3A) through the communication gas pipe (17) into the indoor heat exchanger (41) and then is condensed therein. The condensed liquid refrigerant flows from the second branch pipe (11b) to the first branch pipe (11a) before the communication liquid pipe (11). A part of the liquid refrigerant flowing in the first branch pipe (11a) flows through the cold-storage expansion valve (46) into the cold-storage heat exchanger (45) and then is evaporated therein. The other part of the liquid refrigerant flowing in the first branch pipe (11a) flows through the branch liquid pipe (13) and the freezing expansion valve (52) into the freezing heat exchanger (51) and then is evaporated therein. The gas refrigerant evaporated by the freezing heat exchanger (51) is sucked by the booster compressor (53), compressed thereby and discharged into the branch gas pipe (16). The gas refrigerant evaporated in the cold-storage heat exchanger (45) joins the gas refrigerant discharged from the booster compressor (53) at the low-pressure gas pipe (15). The joined gas refrigerant returns to the inverter compressor (2A) and the first non-inverter compressor (2B). By the refrigerant repeating such circulation, air-heating within a store is performed, and the interiors of cold-storage showcases and freezing showcases are cooled. During the first air-heating/freezing operation, a cooling ability (amount of heat evaporated) for the cold-storage unit (1C) and the freezing unit (1D) is balanced with an air-heating ability (amount of heat condensed) for the indoor unit (1B), so that 100% of heat is recovered. If the amount of the liquid refrigerant flowing from the second branch pipe (11b) to the first branch pipe (11a) is insufficient, the liquid refrigerant is sucked from the receiver (14) through the communication liquid pipe (11) into the first branch pipe (11a). The liquid refrigerant is supercooled by a low-pressure gas refrigerant at the portion that the communication liquid pipe (11) and the low-pressure gas pipe (15) are provided adjacent to each other, and the resultant supercooled refrigerant flows toward the cold-storage heat exchanger (45) and the freezing heat exchanger (51). Accordingly, even if a part of the liquid refrigerant from the second branch pipe (11b) to the first branch pipe (11a) is flashed, a flash gas is condensed into a liquid and then the liquid is supplied to the heat exchangers (45, 51). <Second Air-Heating/Freezing Operation> The second air-heating/freezing operation is an operation with excess air-heating ability in which during the first air-heating/freezing operation, the air-heating ability for the indoor unit (1B) is superfluous. During the second air-heating/freezing operation, as shown in FIG. 9, the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel, and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel. The inverter compressor (2A), the first non-inverter compressor (2B) and the booster compressor (53) are driven. The second non-inverter compressor (2C) is stopped. The second air-heating/freezing operation is an operation in which the air-heating ability is superfluous during the first air-heating/freezing operation, and is the same as the first air-heating/freezing operation except that the second four-way selector valve (3B) is switched to be in the second state as shown by the solid lines in FIG. 9. A part of refrigerant discharged from the inverter compressor (2A) and the first non-inverter compressor (2B) flows in the indoor heat exchanger (41) and then is condensed therein as in the first air-heating/freezing operation. The condensed liquid refrigerant flows from the second branch pipe (11b) to the first branch pipe (11a) before the communication liquid pipe (11). The other part of the refrigerant discharged from the inverter compressor (2A) and the first non-inverter compressor (2B) flows from the auxiliary gas pipe (19) through the second four-way selector valve (3B) and the first four-way selector valve (3A) to the outdoor gas pipe (9). Then, the refrigerant is condensed in the outdoor heat exchanger (4). The condensed liquid refrigerant passes through the receiver (14) when flowing in the liquid pipe (10). Further, the liquid refrigerant flows through the communication liquid pipe (11) into the first branch pipe (11a), and joins the refrigerant from the second branch pipe (11b). A part of the liquid refrigerant flowing in the first branch pipe (11a) flows in the cold-storage heat exchanger (45) and is evaporated therein. The other part of the liquid refrigerant flowing in the first branch pipe (11a) flows in the freezing heat exchanger (51), is evaporated and sucked into the booster compressor (53). The gas refrigerant evaporated in the cold-storage heat exchanger (45) joins the gas refrigerant discharged from the booster compressor (53) at the low-pressure gas pipe (15). The joined refrigerant returns to the inverter compressor (2A) and the first non-inverter compressor (2B). While the suction side gas refrigerant flows in the low-pressure gas pipe (15), it heat-exchanges with the liquid refrigerant flowing in the communication liquid pipe (11) and thus the liquid refrigerant flowing in the communication liquid pipe (11) is supercooled. This liquid refrigerant joins the liquid refrigerant from the second branch pipe (11b) and the joined liquid refrigerant flows in the cold-storage heat exchanger (45) and the freezing heat exchanger (51). Accordingly, the differences in enthalpy of the refrigerants in the cold-storage heat exchanger (45) and the freezing heat exchanger (51) become larger than those of the case in which supercooling is not performed, so that high refrigerating ability is exhibited. Although the gas refrigerant is superheated because of heat-exchange with the liquid refrigerant, it is mixed with the liquid refrigerant by liquid injection. Thus, it is possible to prevent the degree of superheat of the gas refrigerant from being excessively large in a compression process. The behavior of refrigerant during the second air-heating/freezing operation will be described based on a Mollier chart shown in FIG. 10. A refrigerant is compressed to a point A by the inverter compressor (2A) and the first non-inverter compressor (2B). A part of the refrigerant at the point A is condensed by the indoor heat exchanger (41) to a point C1. The other part of the refrigerant at the point A is condensed by the outdoor heat exchanger (4) to the point Cl, and then heat-exchanges with the gas refrigerant (refrigerant at a point G) sucked into the inverter compressor (2A) and the first non-inverter compressor (2B) during its flowing in the communication liquid pipe (11) in order to be supercooled to a point C2. The refrigerant at the point C1 joins the refrigerant at the point C2 and the joined refrigerant is changed to a point C3. The pressure of a part of the refrigerant at the point C3 is reduced to a point F by the cold-storage expansion valve (46). Then, this refrigerant is evaporated at, e.g., −10° C. and its state is changed to the point G. A part of the refrigerant at the point C3 is sucked by the booster compressor (53). Thus, the pressure of this refrigerant is reduced to a point H at the freezing expansion valves (52). Further, this refrigerant is evaporated at, e.g., −35° C. and sucked into the booster compressor (53) at a point I. The refrigerant compressed by the booster compressor (53) to a point J joins the refrigerant from the cold-storage heat exchanger (45) and the state of the joined refrigerant is changed to the point G. The gas refrigerant at the point G heat-exchanges with the liquid refrigerant at the point C1 to be superheated to a point K. The liquid refrigerant is supercooled to the point C2. This gas refrigerant is mixed with a refrigerant obtained by reducing the pressure of a part of the liquid refrigerant at the point C1 to the point L by the electronic expansion valve (29) (by performing liquid injection), so that its state is changed to a point M. Thereafter, the resultant gas refrigerant is sucked by the inverter compressor (2A) and the first inverter compressor (2B). By repeating such circulation during the second air-heating/freezing operation, air-heating within a store is performed and the interiors of cold-storage showcases and freezing showcases are cooled. At this time, the cooling ability (amount of heat evaporated) for the cold-storage unit (1C) and the freezing unit (1D) is not balanced with the air-heating ability (amount of heat condensed) for the indoor unit (1B), and excess condensed heat is discharged outdoor by the outdoor heat exchanger (4). <Third Air-Heating/Freezing Operation> The third air-heating/freezing operation is an operation with insufficient air-heating ability in which during the first air-heating/freezing operation, the air-heating ability for the indoor unit (1B) is insufficient. In accordance with the third air-heating/freezing operation, as shown in FIG. 11, the inverter compressor (2A) and the first non-inverter compressor (2B) constitute the compression mechanism (2D) for the first channel, and the second non-inverter compressor (2C) constitutes the compression mechanism (2E) for the second channel. The inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) are driven. Further, the booster compressor (53) is also driven. The third air-heating/freezing operation is performed when the air-heating ability is insufficient in the first air-heating/freezing operation, i.e., is performed when an amount of heat evaporated is insufficient. The third air-heating/freezing operation is the same as the first air-heating/freezing operation except that the opening of the outdoor expansion valve (26) is controlled and the second non-inverter compressor (2C) is driven. A refrigerant discharged from the inverter compressor (2A), the first non-inverter compressor (2B) and the second non-inverter compressor (2C) flows through the communication gas pipe (17) into the indoor heat exchanger (41) and then is condensed therein, as in the first air-heating/freezing operation. The condensed liquid refrigerant is branched from the second branch pipe ( lb) into the first branch pipe (11a) and the communication liquid pipe (11). A part of the liquid refrigerant flowing in the first branch pipe (11a) flows in the cold-storage heat exchanger (45) and is evaporated therein. The other part of the liquid refrigerant flowing in the first branch pipe (11a) flows in the freezing heat exchanger (51), is evaporated therein, and sucked into the booster compressor (53). The gas refrigerant evaporated by the cold-storage heat exchanger (45) joins the gas refrigerant discharged from the booster compressor (53) at the low-pressure gas pipe (15), and the joined gas refrigerant returns to the inverter compressor (2A) and the first non-inverter compressor (2B). The liquid refrigerant which is condensed in the indoor heat exchanger (41) and then flows in the communication liquid pipe (11) flows from the branch liquid pipe (36) through the receiver (14) and the outdoor expansion valve (26) to the outdoor heat exchanger (4), and then is evaporated therein. The evaporated gas refrigerant flows in the outdoor gas pipe (9). Further, the evaporated gas refrigerant flows through the first four-way selector valve (3A) and the second four-way selector valve (3B) into the suction pipe (6c) for the second non-inverter compressor (2C) and then returns to the second non-inverter compressor (2C). The behavior of refrigerant during the third air-heating/freezing operation will be described based on a Mollier chart shown in FIG. 12. A refrigerant is compressed to a point A by the second non-inverter compressor (2C). A refrigerant is compressed to a point B by the inverter compressor (2A) and the first non-inverter compressor (2B). The refrigerant at the point A joins the refrigerant at the point B, and the joined refrigerant is condensed to a point C1 by the indoor heat exchanger (41). The pressure of a part of the refrigerant at the point C1 is reduced to a point F by the cold-storage expansion valve (46). Then, this refrigerant is evaporated at, e.g., −10° C. and its state is changed to a point G. A part of the refrigerant at the point C1 is sucked by the booster compressor (53). Thus, the pressure of this refrigerant is reduced to a point H by the freezing expansion valve (52). This refrigerant is evaporated at, e.g., −35° C. and sucked into the booster compressor (53) at a point I. The refrigerant compressed by the booster compressor (53) to a point J joins the refrigerant from the cold-storage heat exchanger (45) and the state of the joined refrigerant is changed to the point G. The gas refrigerant at the point G heat-exchanges with the liquid refrigerant at the point C1 flowing from the indoor heat exchanger (41) in the communication pipe (11). The liquid refrigerant flowing in the communication pipe (11) is supercooled to the point C2. The gas refrigerant flowing in the low-pressure gas pipe (15) is superheated to a point K. The pressure of the refrigerant at the point C2 is reduced to a point D by the outdoor expansion valve (26). This refrigerant is evaporated at, e.g., −5° C. and sucked to the second inverter compressor (2C) at a point E. The gas refrigerant at the point K is mixed with a refrigerant obtained by reducing the pressure of the liquid refrigerant at the point C2 to the point L by the electronic expansion valve (29), so that its state is changed to a point M. Thereafter, the resultant refrigerant at the point M is sucked by the inverter compressor (2A) and the first inverter compressor (2B). By repeating such circulation, air-heating within a store is performed and the interiors of cold-storage showcases and freezing showcases are cooled. Namely, the cooling ability (amount of heat evaporated) for the cold-storage unit (1C) and the freezing unit (1D) is not balanced with the air-heating ability (amount of heat condensed) for the indoor unit (1B), and insufficient evaporated heat is obtained from the outdoor heat exchanger (4). EFFECTS OF EMBODIMENTS In accordance with this embodiment, the liquid line for cold-storage/freezing channel and the liquid line for the air-conditioning channel share one communication liquid pipe (11), and the communication liquid pipe (11) is provided adjacent to the low-pressure gas pipe (15) serving as a gas line for the cold-storage/freezing channel so as to contact it. Thus, a liquid refrigerant is supercooled by a low-pressure gas refrigerant, so that a refrigerant having lower enthalpy can be supplied to the application-side heat exchangers (41, 45, 51). Consequently, the differences in enthalpy between refrigerants at entrances/exits of the respective application-side heat exchangers (41, 45, 51) become large, and a decrease in refrigerating ability can be prevented even if pipes are long. As liquid lines for a plurality of channels are integrated into one communication liquid pipe (11), the total number of communication pipes is reduced. Accordingly, work for connecting pipes is easily performed and the possibility of connecting wrong pipes may be reduced. Further, there is provided the liquid injection pipe (27) for supplying a part of liquid refrigerant circulating in the refrigerant circuit (1E) to the suction sides of the compression mechanisms (2D, 2E). Accordingly, even if the degree of superheat of gas refrigerant at the suction side becomes large when a liquid refrigerant is supercooled by the gas refrigerant, liquid injection can prevent the degree of superheat of the refrigerant from being excessively large in a compression step. The aluminum tape material (12) serving as a heat transfer material is wound around the communication liquid pipe (11) and the low-pressure gas pipe (15) so that the pipes (11, 15) are surrounded by the heat transfer material (12). Thus, a liquid refrigerant can be reliably supercooled by a gas refrigerant through the heat transfer material (12). In accordance with such a structure, a heat exchanger dedicated to supercooling of liquid refrigerant is not required and thus the structure is not complicated. OTHER EMBODIMENTS The present invention may be structured as follows with respect to the above-described embodiment. For example, the refrigerating apparatus (1) which has the cold-storage/freezing channel and the air-conditioning channel capable of performing air-cooling/air-heating has been described in the above embodiment. Nevertheless, the present invention may be applied to apparatus having a cold-storage/freezing channel and an air-conditioning channel dedicated to air-cooling or apparatus having a plurality of cold-storage/freezing channels. In such cases, gas lines are not switched between a low-pressure side and a high-pressure side in both of the channels. Thus, gas lines, as well as liquid lines, may be integrated. Specific structure of the application-side or the heat-source side may be appropriately changed. Namely, in accordance with the present invention, the structure only has to be such that a liquid refrigerant in a liquid side communication pipe can be supercooled by a low-pressure gas refrigerant in a low-pressure gas side communication pipe. Industrial Applicability As described above, the present invention is useful for a refrigerating apparatus.

<SOH> BACKGROUND ART <EOH>Refrigerating apparatuses which perform a refrigerating cycle are conventionally known. The refrigerating apparatuses are widely utilized as an air-conditioning machine for performing air-cooling/heating in a room or a cooling machine such as a refrigerator for storing foods. Among the refrigerating apparatuses, there is a refrigerating apparatus which performs air-conditioning and cold-storage/freezing as disclosed in Japanese Patent Application Laid-Open (JP-A) No. 2001-280749. In this type of refrigerating apparatus, application-side heat exchangers provided in application-side units including cold-storage/freezing showcases and an air-conditioning indoor machine are connected in parallel to a heat-source side heat exchanger in a heat-source side unit installed outdoor by liquid side communication pipes and gas side communication pipes, respectively. This refrigerating apparatus is installed at e.g., a convenience store and the like. By installing one refrigerating apparatus, air-conditioning within a store and cooling for showcases can be performed. —Problems to be Solved— In accordance with the refrigerating apparatus, communication pipes having diameters depending on the amount of refrigerant circulated and their lengths are selected. Nevertheless, when the length of the pipes is extremely long, a pressure loss for the refrigerant becomes large and thus a refrigerating ability may be easily decreased. In the refrigerating apparatus, a refrigerant circuit is configured so as to have two channels, i.e., a cold-storage/freezing channel and an air-conditioning channel. Two communication pipes are used for a liquid line and a gas line, respectively and thus the number of pipes becomes large. Work for connecting such pipes is complicated and the pipes may be connected in a wrong manner. The present invention was developed in view of such problems, and an object of the present invention is to improve workability of connecting pipes and to prevent a decrease in refrigerating ability even if the length of the pipes becomes long in a refrigerating apparatus in which a plurality of application-side heat exchangers are connected to a compression mechanism and a heat-source side heat exchanger.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a refrigerant circuit diagram of a refrigerating apparatus relating to an embodiment of the present invention. FIG. 2 is a refrigerant circuit diagram illustrating the operation of an air-cooling operation. FIG. 3 is a refrigerant circuit diagram illustrating the operation of a freezing operation. FIG. 4 is a refrigerant circuit diagram illustrating the operation of a first air-cooling/freezing operation. FIG. 5 is a Mollier chart illustrating the behavior of a refrigerant at the time of the first air-cooling/freezing operation. FIG. 6 is a refrigerant circuit diagram illustrating the operation of a second air-cooling/freezing operation. FIG. 7 is a refrigerant circuit diagram illustrating the operation of an air-heating operation. FIG. 8 is a refrigerant circuit diagram illustrating the operation of a first air-heating/freezing operation. FIG. 9 is a refrigerant circuit diagram illustrating the operation of a second air-heating/freezing operation. FIG. 10 is a Mollier chart illustrating the behavior of a refrigerant at the time of the second air-heating/freezing operation. FIG. 11 is a refrigerant circuit diagram illustrating the operation of a third air-heating/freezing operation. FIG. 12 is a Mollier chart illustrating the behavior of a refrigerant at the time of the third air-heating/freezing operation. detailed-description description="Detailed Description" end="lead"?

20040311

20070102

20050602

68968.0

JIANG, CHEN WEN

REGRIGERATING APPARATUS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Microfluidic devices having a reduced number of input and output connections

A system and method for reducing the number of input/output connections required to connect a microfluidic substrate to an external controller for controlling the substrate. In one example, a microfluidic processing device is fabricated on a substrate having a plurality of N independently controllable components, (e.g., a resistive heating elements) each having at least two terminals. The substrate includes a plurality of input/output contacts for connecting the substrate to an external controller, and a plurality of leads for connecting the contacts to the terminals of the components. The leads are arranged to allow the external controller to supply control signals to the terminals of the components via the contacts using substantially fewer contacts than the total number of component terminals. For example, in one embodiment, each lead connects a corresponding contact to a plurality of terminals to allow the controller to supply to signals to the terminals without requiring a separate contact for each terminal. However, to assure that the components can each be controlled independently of the others, the leads are also arranged so that each component's terminals are connected to a unique combination of contacts. Thus, the external controller can activate a selected component by supplying control signals to the combination of contacts uniquely associated with that component.

1. A microfluidic processing device, comprising: a substrate comprising a plurality of N independently controllable components, each having at least two terminals; a plurality of input/output contacts for connecting said substrate to an external controller, and a plurality of leads for connecting said contacts to said terminals, whereby the number of contacts required to independently control said N components is substantially less than the total number of terminals without requiring a separate lead for each said terminal, and wherein said controller can thereby control each said component independently of each other component. 2. The microfluidic device of claim 1 wherein each said lead connects a corresponding contact to a plurality of terminals to allow said controller to provide signals to said terminals without requiring a separate contact for each terminal, and wherein the terminals of each said component are connected to a unique combination of contacts, so that said external controller can thereby control each said component independently of the other components. 3. The microfluidic processing device according to claim 2, wherein the number of contacts is related to the number of said components by the formula, 2{square root}N. 4. The microfluidic processing device according to claim 1, wherein at least a subset of the N components are resistive heating elements. 5. The microfluidic processing device according to claim 1, wherein at least a subset of the N components are resistive sensing elements. 6. The microfluidic processing device of claim 1 wherein at least one of said independently controllable components comprises a plurality of sub-components that are all activated by said external controller using the unique combination of contacts associated with said at least one independently controllable component. 7. The microfluidic device of claim 1, wherein the device includes a plurality of current flow directional elements configured to allow current to flow in essentially only one direction through the components. 8. The microfluidic device of claim 1, wherein the substrate includes a thermally actuated valve and at least one of the N independently controllable components is a heating element in thermal communication with the thermally actuated valve. 9. The microfluidic device of claim 8, wherein the substrate includes a plurality of thermally actuated valves and each component of a subset of the N independently controllable components is a heating element in thermal communication with a respective thermally actuated valve. 10. The microfluidic device of claim 1, wherein the substrate includes a thermally actuated pump comprising a volume of fluid and at least one of the N independently controllable components is a heating element in thermal communication with the volume of fluid, whereby actuation of the heating element heats the fluid and actuates the thermally actuated pump. 11. The microfluidic device of claim 10, wherein the substrate includes a plurality of thermally actuated pumps each comprising a volume of fluid and, wherein each component of a subset of the N independently controllable components is a heating element in thermal communication with the volume of fluid of a respective thermally actuated pump. 12. A method for fabricating a microfluidic processing device comprising: providing a substrate having a plurality of components each having at least two terminals; providing a plurality of input/output contacts for connecting said substrate to an external controller; and providing a plurality of leads for connecting said contacts to said terminals, whereby the number of contacts required to independently control said N components is substantially less than the total number of terminals without requiring a separate lead for each said terminals, and wherein said controller can thereby control each said component independently of each other component. 13. A method according to claim 12, wherein each lead connects a corresponding contact to a plurality of said terminals. 14. A method according to claim 12, wherein the number of contacts is related to the number of said components by the formula, 2{square root}N. 15. A method according to claim 12, wherein the component is a resistive heating element. 16. The method according to claim 12 wherein at least one of said independently controllable components comprises a plurality of sub-components that are all activated by said external controller using the unique combination of contacts associated with said at least one independently controllable component. 17. A method according to claim 12, wherein the component is a resistive sensing element.

1. FIELD OF THE INVENTION The present invention relates to microfluidic devices, and more particularly to techniques for reducing the number of input and output connections required to connect a microfluidic device to an external controller for controlling the microfluidic device. 2. BACKGROUND OF THE INVENTION Micro/nano technology devices are known in the art as devices with components on the scale of 1 μm to 100s of μm that cooperate to perform various desired functions. In particular, microfluidic devices are micro/nano technology devices that perform fluid handling functions which, for example, cooperate to carry out a chemical or biochemical reaction or analysis. Microfluidic devices include a variety of components for manipulating and analyzing the fluid within the devices. Typically, these elements are microfabricated from substrates made of silicon, glass, ceramic, plastic, and/or quartz. These various fluid-processing components are linked by microchannels, etched into the same substrate, through which the fluid flows under the control of a fluid propulsion mechanism. Electronic components may also be fabricated on the substrate, allowing sensors and controlling circuitry to be incorporated in the same device. Because all of the components are made using conventional photolithographic techniques, multi-component devices can be readily assembled into complex, integrated systems. Most microfluidic devices in the prior art are based on fluid flowing through micro-scale passages and chambers, either continuously or in relatively large aliquots. Fluid flow is usually initiated and controlled by electro-osmotic and electrophoretic forces. See, e.g., U.S. Pat. No. 5,632,876, issued Apr. 27, 1997 and entitled “Apparatus and Methods for Controlling Fluid Flow in Microchannels;” U.S. Pat. No. 5,992,820, issued Nov. 30, 1999 and entitled “Flow Control in Microfluidics Devices by Controlled Bubble Formation;” U.S. Pat. No. 5,637,469, issued Jun. 10, 1997 and entitled “Methods and Apparatus for the Detection of an Analyte Utilizing Mesoscale Flow Systems;” U.S. Pat. No. 5,800,690, issued Sep. 1, 1998 and entitled “Variable Control of Electroosmotic and/or Electrophoretic Forces Within a Fluid-Containing Structure Via Electrical Forces;” and U.S. Pat. No. 6,001,231, issued Dec. 14, 1999 and entitled “Methods and Systems for Monitoring and Controlling Fluid Flow Rates in Microfluidic Systems.” See also products from, e.g., Orchid, Inc. (www.orchid.com) and Caliper Technologies, Inc. (www.calipertech.com). Microfluidic devices that manipulate very small aliquots of fluids (known herein as “micro-droplets”) in micro-scale passages rely principally on pressure and other non-electric forces to move the liquid volume. These devices are advantageous because smaller volumes of reagents are required and because non-electric propulsion forces can be generated using relatively small voltages, on the same order of magnitude as voltages required by standard microelectronic components. See, ie. the following patents, the contents of which are incorporated herein in their entirety by reference: U.S. Pat. No. 6,057,149, issued May 2, 2000 and entitled “Microscale Devices And Reactions In Microscale Devices;” U.S. Pat. No. 6,048,734, issued Apr. 11, 2000 and entitled “Thermal Microvalves in a Fluid Flow Method;” and U.S. Pat. No. 6,130,098, issued Oct. 10, 2000. (Citation or identification of any reference in this section or any section of this application shall not be construed that such reference is available as prior art to the present invention). U.S. Pat. No. 6,130,098 (“the '098 patent”), for example, discloses microfluidic devices that include micro-droplet channels for transporting fluid droplets through a fluid processing system. The system includes a variety of micro-scale components for processing the fluid droplets, including micro-reaction chambers, electrophoresis modules, and detectors (such as radiation detectors). In some embodiments, the devices also include air chambers coupled to resistive heaters to internally generate air pressure to automatically withdraw a measured volume of fluid from an input port, and to propel the measured micro-droplet through the microfluidic device. These components are connected to input/output (I/O) pins at the edge of the micro-fluid device which mate with corresponding I/O pins of the external controller. The external controller operates these components by sending and receiving control signals via the input/output pins. For example, a control device, external to the microfluidic device, activates a resistive heater within a microfluidic device by supplying current to the heater through the input/output pins. Microfluidic devices can include a large number of such components which are controlled by external devices. Accordingly, an object of the present invention is to reduce the number of input/output pins required for controlling such microfluidic devices from such external controllers. 3. SUMMARY OF THE INVENTION The invention relates generally to techniques for reducing the number of input/output connections required to connect a microfluidic substrate to an external controller for controlling the substrate. In one aspect, the invention involves a microfluidic processing device fabricated on a substrate having a plurality of N independently controllable components, (e.g., resistive heating elements) each having at least two terminals. The substrate includes a plurality of input/output contacts for connecting the substrate to an external controller, and a plurality of leads for connecting the contacts to the terminals of the components. The leads are arranged to allow the external controller to supply control signals to the terminals of the components via the contacts using substantially fewer contacts than the total number of component terminals. For example, in one embodiment, each lead connects a corresponding contact to a plurality of terminals to allow the controller to supply to signals to the terminals without requiring a separate contact for each terminal. The number of contacts may be less than about 50% of the number of components. However, to assure that the components can each be controlled independently of the others, the leads are also arranged so that each component's terminals are connected to a unique combination of contacts. Thus, the external controller can activate a selected component by supplying control signals to the combination of contacts uniquely associated with that component. The substrate of the microfabricated device preferably includes elements such as valves or pumps, which cooperate to manipulate fluid within channels and chambers of the substrate. For example, the substrate may include a thermally actuated valve. At least one of the N independently controllable components is a heating element in thermal communication with the thermally actuated valve. Actuation of the heating element actuates the valve, whereupon the valve opens or closes. The substrate may include a plurality of thermally actuated valves and a plurality of the N independently controllable components are heating elements in thermal communication with respective thermally actuated valves. The substrate may include a thermally actuated pump comprising a volume of fluid. At least one of the N independently controllable components is a heating element in thermal communication with the volume of fluid, whereby actuation of the heating element heats the fluid and actuates the thermally actuated pump. For example, the fluid may be a gas, whereby expansion of the gas propels a microfluidic sample along a channel of the substrate. The substrate may include a plurality of thermally actuated pumps. Fluid of each pump is in thermal communication with at least one heating element. The substrate may include at least one microfabricated reaction chamber, such as a chamber configured to perform a polymerase chain reaction. At least one of the N independently controllable components is a heating element in thermal communication with the reaction chamber, whereby actuation of the heating element may raise a temperature of material present in the reaction chamber. At least one of the N independently controllable components may be a heat sensor in thermal communication with the reaction chamber, whereby the temperature of the material present in the reaction chamber may be determined. 4. BRIEF DESCRIPTION OF THE FIGURES The present invention may be understood more fully by reference to the following detailed description of the preferred embodiment of the present invention, illustrative examples of specific embodiments of the invention, and the appended figures wherein: FIG. 1 illustrates a microfluidic control system having a discrete droplet microfluidic processing device, an external controller, and a general purpose computer, FIG. 2 illustrates the discrete droplet microfluidic processing device of FIG. 1; FIG. 3 illustrates the external controller of FIG. 1; FIGS. 4A-B illustrate a micro-valve actuator; FIG. 5 illustrates a heating component having resistive temperature detectors; FIGS. 6A-B illustrate a micro-valve actuator having a reduced number of I/O contacts. FIGS. 7A-B illustrate a technique for sharing conductive leads that supply current to resistive heaters within a microfluidic processing device; FIGS. 8A-B illustrate a technique for sharing conductive leads for resistive temperature detectors (“RTDs”); FIGS. 9A-B illustrate a technique for sharing conductive leads for resistive heaters and RTDs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT System Overview FIG. 1 depicts a microfluidic processing system that includes a microfluidic substrate 10, a chip carrier cartridge 20, a data acquisition and control board (“DAQ”) 26, and a portable computer 27 such as a laptop or palmtop computer. Microfluidic substrate 10 has microchannels and fluid control elements formed in a solid substrate such as silicon, glass, or other suitable material, preferably microfabricated using conventional photolithographic techniques. The microfluidic substrate 10 is mounted on the chip carrier cartridge 20. The microfluidic substrate 10 has electrical and optical connections 12 with the chip carrier cartridge for carrying electrical and optical signals between the microfluidic substrate and the chip carrier. For example, the electrical connections can be formed with well-known wire bonding techniques. Furthermore, the chip carrier cartridge 20 has electrical and optical contacts 21 for carrying electrical and optical signals between the microfluidic substrate and the data acquisition board 26. The chip carrier cartridge 20 is shown being inserted into (or removed from) an interface hardware receptacle of DAQ 26 having electrical and optical contacts 25 standardized to mate with a corresponding contacts 21 of the chip carrier cartridge. Most contacts are for electrical signals, while certain are for optical signals (IR, visible, UV, etc.) in the case of optically-monitored or optically-excited microfluidic processors. Alternatively (not shown), the entire data acquisition and control board 26 may be a single ASIC chip that is incorporated into the chip carrier cartridge 20, wherein contacts 21, 25 would become lines on a printed circuit board. In general, DAQ 26 controls the operation of microfluidic substrate 10 via contacts 12, 21, 25 using electrical and optical signals. Portable computer 27 typically performs high level functions, such as supplying a user interface that allows the user to select desired operations and to view the results of such operations. As shown in FIG. 1, the computer 27 is connected to DAQ 26 via connection 28, which provides data I/O, power, ground, reset, and other function connectivity. Computer 27 can also, as shown, be used to control a laboratory robot 24 via link 31. Alternatively, a wireless link 32 between the computer 27 and the DAQ 26 may be provided for data and control signal exchange via wireless elements 32(a) and 32(b). Where the data link is a wireless link, for example, the DAQ 26 may have separate power source such as, for example, a battery. The present invention is directed to techniques for reducing the number of contacts 12, 21, 25 required for communication between the microfluidic substrate 10, chip carrier cartridge 20, and the external controller or controllers such as DAQ 26. As explained below, the number of such contacts can become extremely large for microfluidic substrates that include many components which are independently controlled by an external controller. The following description of the operation of a microfluidic substrate 10 and DAQ 26 demonstrates the relationship between the complexity of the microfluidic substrate and the requisite number of contacts 12, 21, 25. Structure of Microfluidic Processor In the example shown in FIG. 1, a microfluidic substrate 10 includes three inlet ports 22 for accepting fluid reagents or samples. Preferably, these inlet ports are in a standard position on the substrate so that laboratory robot 24, where available, may be easily programmed for automatic loading of ports of several types of microfluidic processors. Otherwise, the ports should be accessible for manual loading. Where possible, reagents may also be pre-packaged on the microfluidic substrate and/or the chip carrier 20. Additionally, chip carrier 20 has micro-circuit 23 accessible through standard connectors for storing, for example, self-descriptive processor information. Alternately, chip carrier 20 may bear indicia such as a bar code to indicate the device type or further information. FIG. 2 illustrates, schematically and not to scale, the general structure of an exemplary integrated microfluidic substrate. This microfluidic substrate is constructed from three types of sub-assemblies. In particular, this substrate has four separate sub-assemblies: two micro-droplet metering sub-assemblies, metering1 and metering2; one mixing sub-assembly, mixing 1; and one reaction/detection sub-assembly, reaction/detection1. These sub-assemblies are constructed from a variety of components or actuators as shown. The components include heater actuators, valve actuators, and an optical detector, all interconnected with passive inlets, overflows, vents, and reservoirs. More specifically, sub-assembly metering1 includes inlet1, overflow1, valve1, heater1, and passage1. Similarly, sub-assembly metering2 includes inlet2, overflow2, valve2, heater2, and passage2. The mixing subassembly, mixing 1, includes heater1, heater2, valve3, valve4, vent1, vent2, Y-shaped passage3, and passage4. Finally, reaction/detection1 sub-assembly includes valves, valve6, heater3, and passage5. Operations of the sub-assemblies result from the coordinated operations of their component actuators under the control of an external controller, DAQ 26. The specific operation of microfluidic substrate 10 is described in greater detail in co-pending application Ser. No. 09/819,105, which is incorporated herein by reference. However, the following describes the general operation of the fluid processor under the control of DAQ 26. First, fluid is introduced into inlet1, for example, by an external robotic device, and flows up to the stable position created by the first hydrophobic region h3 just beyond the widening of passage 1. Any excess fluid flows out through port overflow1. Next, DAQ 26 instructs sub-assembly metering1 to measure a micro-droplet of determined volume from an aliquot of fluid introduced through port inlet1, as described in co-pending application Ser. No. 09/819,105. Sub-assembly metering2 is constructed and operates similarly to extract a measured micro-droplet of fluid from a second fluid sample likewise supplied at inlet 2. After the pair of microdroplets are extracted from the inlet ports, DAQ 26 supplies current to heater1 and heater2 to generate gas pressure to propel the two micro-droplets through Y-shaped passage 3 and along passage 4 to the stable position in passage 5 just beyond the junction of the side passage to vent2. During this step, the two microdroplets merge and mix to form a single, larger micro-droplet. Next, DAQ 26 supplies current to valve5 and valve6 to close these valves and isolate the micro-droplet along passage 5. DAQ 26 directs the sub-assembly reaction/detection1 to stimulate a reaction in the trapped micro-droplet by, for example, supplying current to heater 3, which heats the micro-droplet. The DAQ then monitors the results of the stimulated reaction by optically detecting radiation conducted by optical paths o1 and o2. DAQ 26 performs these control functions by selectively supplying electrical (and sometimes optical) signals to the microfluidic substrate via contacts 12, 21, 25. DAO Board Architecture FIG. 3 illustrates a preferred hardware architecture for DAQ board 26. The DAQ board has one or more receptacles, slots, or sockets, where one or more replaceable microfluidic processors may be accommodated in a firmly supporting manner with good contact to its external contacts. As shown, electrical contacts 25(a) on the DAQ mate with corresponding contacts 21(a) of the chip carrier cartridge 20. Thus, leads 39,40 of the DAQ are electrically connected to corresponding leads of the chip carrier cartridge 20. Similarly, contacts 25(b) of the DAQ mate with contacts 21(b) of the chip carrier cartridge, thereby connecting via light pipe, line of sight, or by other suitable means, the DAQ's optical couplings 41,42 to corresponding optical couplings on the chip carrier cartridge. The electrical and optical leads of the chip carrier cartridge are, in turn, connected to the microfluidic substrate 10 via contacts 12. Thus, DAQ 26 can send and receive electrical and optical signals via contacts 12, 21, 25 to and from microfluidic substrate 10 in order to engage and control a variety of components or actuators located thereon. The electrical contacts, which may have many embodiments, are illustrated here as edge contacts that are engaged when the chip carrier and microfluidic substrate are inserted in a DAQ board receptacle. Alternatively, contacts may be suitable for engaging a flexible ribbon cable, or may by multi-pin sockets, for example. The optical contacts may be of types known for connecting fiber-optic cables. The DAQ includes one or more heater drivers 47 for supplying a specified amount of current. The output of each heater driver 47 is connected to an analog multiplexor 48 that routes the current from the driver to a selected I/O contact 25(a). For sensing functions, the DAQ includes one or more temperature sensor drivers 49 which are each connected to an analog multiplexor 50 that multiplexes each temperature sensor driver 49 to a selected one of the plurality of I/O contacts 25(a). The DAQ also includes one or more photodiodes 51 for optical detection. Multiplexor 52 multiplexes these optical detectors to an analog-to digital converter (“ADC”) 55 via a selected one of the plurality of I/O contacts 25(b). Finally, the DAQ is shown including one or more laser diodes 53. Laser enable register 54 enables selected laser diode drivers, thereby emitting light signals on corresponding optical couplings 42 and optical contacts 25 (b). Also shown in FIG. 3, the DAQ also includes a microprocessor and memory 43 for controlling the operation of the drivers 47, sensors 49, photo diodes 51, laser diodes 53 and their associated analog multiplexors 48, 50, 52, as well as laser enable register 54. More specifically, the microprocessor sends control signals to these devices via a bus driver 45 and bus 46, and reads status information from the sensing elements via the same driver 45 and bus 46. Finally, host interface 44 allows the microprocessor 43 to communicate with the general purpose computer 27 (FIG. 1) via leads 38(c) or, as described above, via wireless means. The operation of the DAQ is exemplified by the following description of the control of a simple resistive heater, such as the resistive heater shown in valve 1 of the microfluidic device depicted in FIG. 2. As shown in FIG. 2, valve1 includes a resistive heating element 9 that is connected at its terminals 11, 13 to a pair of I/O contacts 12(a) via leads 8. The DAQ activates this resistive heating element by instructing analog multiplexor 48 to connect the output of heater driver 47 to a pair of I/O contacts 25(a) that are connected to corresponding I/O contacts 21(a) of the chip carrier 20, that are connected to corresponding contacts 12(a) of the substrate. It then instructs heater driver 47 to supply a selected amount of current. The current supplied by driver 47 flows through analog multiplexor 48 and to the resistive heating element 9 via the selected leads 39 and 8. The Relationship Between the Number of I/O Pins and the Number of Control Elements on the Microfluidic Processor For a two terminal device, such as the resistive heater described above, the system must use two I/O contacts to supply the control signals for operation of the device. Thus, if the number of two-terminal devices on the microfluidic process is N, then 2×N I/O contacts are sufficient to allow DAQ 26 to independently control each of the devices. However, for comple7x microfluidic devices the number of I/O contacts can be unreasonably large. In the simple microfluidic device shown in FIG. 2, where only nine different resistive heating elements are shown, only eighteen contacts are required. For increasingly complex microfluidic devices having hundreds of independently controlled components, the number of contacts becomes excessive. Moreover, for discrete droplet fluid processing systems such as described in co-pending application Ser. No. 09/819,105, even relatively simple microfluidic processors may employ a large number of contacts. For example, FIGS. 4A and 4B depict a preferred valve structure for such fluid processing systems that includes three separate resistive heaters for each valve. Referring to FIGS. 4A and 4B, the operation of the preferred valve structure is described in detail below. FIG. 4A depicts the valve in its open position, having a wax plug 76 positioned within side channel 77. To close this valve, DAQ controller supplies current to resistive heater HTR2 via I/O contacts 80, 81. This causes HTR2 to warm, thereby melting plug 76. DAQ 26 then supplies current to HTR1 via I/O contacts 82, 84 to thereby heat gas within chamber 75. As the gas expands, it forces plug 76 to move into channel 78 as shown in FIG. 4B. DAQ 26 then shuts off heater HTR2 and allows the plug to cool, thereby blocking channel 78 and side channel 77. When the plug is cool, DAQ 26 then shuts off HTR1. As HTR1 cools, the pressure in chamber 75 drops, thereby creating a negative pressure which, as will be explained below, may be used to re-open the valve. To open the valve, DAQ 26 supplies current to HTR3 via I/O pins 86, 88 to warm the heater and thereby melt the plug. Once the plug is melted, the negative pressure in chamber 75 draws the plug back into side channel 77, thereby re-opening channel 78. If such bidirectional valves are used to implement the microfluidic device shown in FIG. 2, the number of independently controlled resistive elements nearly triples from nine to twenty-one. However, to accurately control the temperature of each of these resistive elements, even more components maybe used. FIG. 5 depicts a six-terminal resistive heating device. The device includes a two terminal heating element R1 that operates in accordance with heating element 9 of FIG. 2. The device also includes a current flow directional element 70, which allows current to flow substantially only in a single direction between leads 55, 56. As shown in FIG. 5, current flow directional element 70 is a diode configured to allow current to flow from lead 56 to lead 55. Current flow directional element 70 substantially prevents, and preferably excludes, current flow from lead 55 to lead 56. Current flow directional element 70 may be any element that allows current to flow predominately in one direction between points of a circuit. Diodes are preferred current flow directional elements. The device of FIG. 5 also includes a four terminal resistive sensor element R2 in close proximity to R1 so as to be in thermal communication therewith. A current flow directional element 71, which has the generally the same functional characteristics as current flow directional element 70, allows current to flow in substantially one direction between leads 57, 58 and leads 59, 60. In the configuration shown, current flow directional element 71 allows current to flow from leads 59, 60 to leads 57, 58 but substantially prevents, and preferably excludes, current flow from leads 57, 58 to leads 59, 60. Current flow directional elements 70 and 71 may be but are not necessarily formed by microfabrication on a substrate with elements R1 and R2. Rather, current flow directional elements 70 and 71 may be disposed at other positions along current pathways that respectively include R1 and R2. Current flow directional elements 70 and 71 are preferably disposed in series with R1 and R2. The sensor R2 may operate as follows. While DAQ 26 supplies current to R1 (via leads 55,56) it also supplies a relatively low current to R2 via leads 57,60. R2 is a resistive element whose resistance increases with temperature. Accordingly, the voltage across R2 increases with the temperature in the nearby region being heated by heating element R1, and therefore element R2 can be used to measure the temperature in this region. DAQ 26 determines the temperature by measuring the voltage across R2 via leads 58, 59. More specifically, referring now to FIG. 3, DAQ 26 instructs the analog multiplexor to connect temperature sensor 49 to the contact pins 25(a) which are connected to leads 58, 59. Sensor 49 then determines the voltage across R2, thereby providing a measure of the temperature in the vicinity of R1. Thus, if such devices are used in a microfluidic processor, the number of I/O contacts increases even further. For example, one hundred and twenty six contacts are required for the micro-fluid processor shown in FIG. 2. The present invention is directed to techniques for reducing the number of I/O contacts required for an external controller, such as DAQ 26, to independently control a large number of components within microfluidic devices, such as those described above. FIGS. 6A, 6B illustrate a technique for reducing the number of I/O contacts by structuring the leads of the microfluidic device so that each lead serves more than one component, while still allowing DAQ 26 to control each component of the microfluidic device independently of the others. Specifically, FIGS. 6A, 6B depicts a technique for sharing I/O contacts among three of the two-terminal resistors of a bidirectional value structure, such as shown in FIGS. 4A-B discussed above. The valve operates essentially the same as the valve shown in FIGS. 4A, B, except that it uses only four contacts rather than six. In this example, each resistor is connected to a pair of I/O contacts and therefore can be controlled by the DAQ in the same way as described above. Although the other resistors share these I/O contacts, no resistor shares the same pair of contacts with another. Accordingly, the DAQ is able to supply current to any given resistor via the pair of associated contacts, without activating any other resistor. More generally, the number of I/O contacts required for the independent control of a plurality of resistive heaters may be reduced by arranging the contact wiring to each resistor in the form of a logical array. The resulting compression of the number of 110 contacts advantageously simplifies communication with the entire processor. Because each resistor requires two leads to complete an electrical circuit, according to a conventional arrangement of leads and contacts, a device having N resistors requires 2N leads and 2N contacts. By configuring the contact wiring in a shared array, however, the number of required contacts can be reduced to as few as 2{square root}N. For example, in a device comprising 100 resistors, the number of external contacts can be reduced from 200 to 20. FIGS. 7A, 7B depict a DAQ 26 directly connected to a microfluidic substrate 22, without the use of an intermediate chip carrier 20, and show an array of resistive heaters within substrate 22. The leads between contacts 12(a) and resistive heaters 100-109 are shown arranged in columns and rows. However, the actual physical layout of the leads will not necessarily be a physical array. Rather, the leads will be directly routed from the resistive components to contacts 12(a) in any manner that allows each lead to connect to a plurality of resistors while remaining electrically isolated from other leads. According to this arrangement, electrical contacts for N resistors are assigned to R rows and C columns such that the product RC≧N, preferably where R is approximately equal to C, and most preferably where R=C. With this arrangement, resistors assigned to the same row share a common electrical lead and I/O contact 12(a). Similarly, resistors assigned to the same column also share a lead and I/O contact 12(a). However, each resistor has a unique address, corresponding to a unique pair of I/O contacts, (i.e., to its unique row/column combination in the array). Therefore, each resistor is individually actuatable by supplying electric current to the appropriate pair of I/O contacts. As used herein, a “resistor” or “component” that is uniquely associated with a pair of contacts may also refer to a resistive network having a plurality of resistive sub-components components contacted in series and/or parallel) or a component network (having a plurality of sub-components connected in series or parallel). In such embodiments, all sub-components are activated together when the external controller supplies signals across the pair of contacts uniquely associated with those sub-components. As shown in FIG. 7A, the leads are arranged in three rows (Rj, where j=1-3) and three columns (Ci, where i=1-3). For each resistor, one terminal is connected to a row and the other terminal is connected to a column. Although each resistor share these land with other resistors. no two resistors share the same pair of leads. In other words. each resistor is uniquely associated with a particular row/column pair Rj, Ci. FIGS. 7A, &B illustrate the operation of this structure. Heater driver 47 s supplies an output voltage of twenty volts on its terminals for supplying current to heating elements 100-109. The positive output terminal 90 is connected to a first analog multiplexor 49(a). As shown, this terminal can be connected to any one of the rows of the array of leads by individual switching elements within analog multiplexor 48(a). Similarly, the negative output terminal 92 of heater 47 is connected to a second analog multiplexor 48(b). Multiplexer 48(b) allows terminal 92 to connect to any column in the array of leads. In FIG. 7A, the switching elements within analog multiplexors 48(a,b) are all open. Accordingly, none of the heating elements 100-109 as shown are active. FIG. 7B depicts the condition of analog multiplexors 48(a,b) after DAQ 26 has instructed them to close certain internal switches to thereby supply current to a selected on the resistors in the array. In this example, the row switch element 50 is closed, to thereby connect the positive terminal of heater 47 to the top row of the lead array. The column switch element 52 is also closed to connect the negative terminal of heater 47 to the middle columns of the lead array. Thus, the positive terminal 90 of heater 47 is connected to resistors 100, 102, 103 and the negative terminal is connected to resistors 102, 102, 108. However, only one of these resistors, 102, is connected across both terminals of heater 47. Accordingly only resistor 102 receives current and is heated. Resistors heaters 100-109 are disposed in series with respective current flow directional elements 215-223, which allow current to flow in one direction between the positive terminal 90 of a heater driver 47 and a negative or ground terminal 92 of heater driver 47 along a current path that includes one of the resistive elements 100-109. Current flow directional elements 215-223 are preferably configured allow current to flow only from positive terminal 90 to terminal 92. Thus, for example, current may flow from a point 224 to a point 225, through resistive heater 102 to point 226 and then to point 227. The current flow directional elements, however, prevents current from passing through current pathways including resistive heaters other than resistive heater 102. For example, current flow directional element 219 prevents current flow between points 228 and 229. Current flow directional elements 215-223 may be diodes as discussed above for current flow directional elements 70, 71. FIGS. 8A, 8B, 9A, 9B depict similar arrays for the resistive elements used to sense temperature, such as R2 shown in FIG. 5. FIG. 8A depicts one array of leads for supplying current to sensing resistors 110-118. FIG. 8B depicts another set of leads for measuring the voltage across the same resistors. With this structure, leads that are used to stimulate the resistive sensors carry no current from the heater driver 47 because they are electrically isolated from driver 47. Similarly, the leads for sensing the voltage of the resistive sensors 110-18 (FIG. 8B) carry essentially no current because they are isolated from the leads that supply current from drivers 47 and 49(a) (shown in FIGS. 7A, 7B and 8A). This structure provides the most accurate temperature measurement. FIGS. 9A, 9B depict an alternative structure. As with the structure shown in FIGS 8A, 8B, the leads for sensing the voltage across temperature sensing resistors, 110-118, are isolated from both of the current sources (heater driver 47 and RTD driver 49(a)). However, both current sources 47, 49(a) share the same leads for current return, i.e., the leads depicted as columns in the array. This provides greater compression of the number of leads; however, the resistivity in the shared return leads may reduce the accuracy of the temperature measurement. The arrays of FIGS. 8A, 8B, 9A, and 9B include current flow directional elements 215′-223′, which allow current to flow in only direction through sensing resistors 110-118. Thus, current flow directional elements 215′-223′ preferably allow current to flow in only one direction between the positive terminal of RTD drive or RTD sense and the negative or ground terminal of RTD drive or RTD sense along a current path that includes one of sensing resistors 110-118. Preferably, current flow directional elements 215′-223′ allow current to flow from the positive terminal to the negative terminal or ground terminal of either RTD drive or RTD sense but not from the negative or ground terminal to the positive terminal thereof. Current flow directional elements 215′-223′ may be diodes similar to current flow directional elements 70, 71. While the invention has been illustratively described herein with reference to specific aspects, features and embodiments, it will be appreciated that the utility and scope of the invention is not this limited and that the invention may readily embrace other and differing variation, modifications and other embodiments. For example, the same techniques for reducing the number of leads may be-applied to other types of components, not just resistors. The invention therefore is intended to be broadly interpreted and construed, as comprehending all such variations, modifications and alternative embodiments, within the spirit and scope of the ensuing claims. A number of references are cited herein, the entire disclosures of which are incorporated herein in their entirety, by reference for all purposes. Further, none of these references, regardless of how characterized above, is admitted as prior to the invention of the subject matter claimed herein.

<SOH> 2. BACKGROUND OF THE INVENTION <EOH>Micro/nano technology devices are known in the art as devices with components on the scale of 1 μm to 100s of μm that cooperate to perform various desired functions. In particular, microfluidic devices are micro/nano technology devices that perform fluid handling functions which, for example, cooperate to carry out a chemical or biochemical reaction or analysis. Microfluidic devices include a variety of components for manipulating and analyzing the fluid within the devices. Typically, these elements are microfabricated from substrates made of silicon, glass, ceramic, plastic, and/or quartz. These various fluid-processing components are linked by microchannels, etched into the same substrate, through which the fluid flows under the control of a fluid propulsion mechanism. Electronic components may also be fabricated on the substrate, allowing sensors and controlling circuitry to be incorporated in the same device. Because all of the components are made using conventional photolithographic techniques, multi-component devices can be readily assembled into complex, integrated systems. Most microfluidic devices in the prior art are based on fluid flowing through micro-scale passages and chambers, either continuously or in relatively large aliquots. Fluid flow is usually initiated and controlled by electro-osmotic and electrophoretic forces. See, e.g., U.S. Pat. No. 5,632,876, issued Apr. 27, 1997 and entitled “Apparatus and Methods for Controlling Fluid Flow in Microchannels;” U.S. Pat. No. 5,992,820, issued Nov. 30, 1999 and entitled “Flow Control in Microfluidics Devices by Controlled Bubble Formation;” U.S. Pat. No. 5,637,469, issued Jun. 10, 1997 and entitled “Methods and Apparatus for the Detection of an Analyte Utilizing Mesoscale Flow Systems;” U.S. Pat. No. 5,800,690, issued Sep. 1, 1998 and entitled “Variable Control of Electroosmotic and/or Electrophoretic Forces Within a Fluid-Containing Structure Via Electrical Forces;” and U.S. Pat. No. 6,001,231, issued Dec. 14, 1999 and entitled “Methods and Systems for Monitoring and Controlling Fluid Flow Rates in Microfluidic Systems.” See also products from, e.g., Orchid, Inc. (www.orchid.com) and Caliper Technologies, Inc. (www.calipertech.com). Microfluidic devices that manipulate very small aliquots of fluids (known herein as “micro-droplets”) in micro-scale passages rely principally on pressure and other non-electric forces to move the liquid volume. These devices are advantageous because smaller volumes of reagents are required and because non-electric propulsion forces can be generated using relatively small voltages, on the same order of magnitude as voltages required by standard microelectronic components. See, ie. the following patents, the contents of which are incorporated herein in their entirety by reference: U.S. Pat. No. 6,057,149, issued May 2, 2000 and entitled “Microscale Devices And Reactions In Microscale Devices;” U.S. Pat. No. 6,048,734, issued Apr. 11, 2000 and entitled “Thermal Microvalves in a Fluid Flow Method;” and U.S. Pat. No. 6,130,098, issued Oct. 10, 2000. (Citation or identification of any reference in this section or any section of this application shall not be construed that such reference is available as prior art to the present invention). U.S. Pat. No. 6,130,098 (“the '098 patent”), for example, discloses microfluidic devices that include micro-droplet channels for transporting fluid droplets through a fluid processing system. The system includes a variety of micro-scale components for processing the fluid droplets, including micro-reaction chambers, electrophoresis modules, and detectors (such as radiation detectors). In some embodiments, the devices also include air chambers coupled to resistive heaters to internally generate air pressure to automatically withdraw a measured volume of fluid from an input port, and to propel the measured micro-droplet through the microfluidic device. These components are connected to input/output (I/O) pins at the edge of the micro-fluid device which mate with corresponding I/O pins of the external controller. The external controller operates these components by sending and receiving control signals via the input/output pins. For example, a control device, external to the microfluidic device, activates a resistive heater within a microfluidic device by supplying current to the heater through the input/output pins. Microfluidic devices can include a large number of such components which are controlled by external devices. Accordingly, an object of the present invention is to reduce the number of input/output pins required for controlling such microfluidic devices from such external controllers.

<SOH> 3. SUMMARY OF THE INVENTION <EOH>3 . SUMMARY OF THE INVENTION The invention relates generally to techniques for reducing the number of input/output connections required to connect a microfluidic substrate to an external controller for controlling the substrate. In one aspect, the invention involves a microfluidic processing device fabricated on a substrate having a plurality of N independently controllable components, (e.g., resistive heating elements) each having at least two terminals. The substrate includes a plurality of input/output contacts for connecting the substrate to an external controller, and a plurality of leads for connecting the contacts to the terminals of the components. The leads are arranged to allow the external controller to supply control signals to the terminals of the components via the contacts using substantially fewer contacts than the total number of component terminals. For example, in one embodiment, each lead connects a corresponding contact to a plurality of terminals to allow the controller to supply to signals to the terminals without requiring a separate contact for each terminal. The number of contacts may be less than about 50 % of the number of components. However, to assure that the components can each be controlled independently of the others, the leads are also arranged so that each component's terminals are connected to a unique combination of contacts. Thus, the external controller can activate a selected component by supplying control signals to the combination of contacts uniquely associated with that component. The substrate of the microfabricated device preferably includes elements such as valves or pumps, which cooperate to manipulate fluid within channels and chambers of the substrate. For example, the substrate may include a thermally actuated valve. At least one of the N independently controllable components is a heating element in thermal communication with the thermally actuated valve. Actuation of the heating element actuates the valve, whereupon the valve opens or closes. The substrate may include a plurality of thermally actuated valves and a plurality of the N independently controllable components are heating elements in thermal communication with respective thermally actuated valves. The substrate may include a thermally actuated pump comprising a volume of fluid. At least one of the N independently controllable components is a heating element in thermal communication with the volume of fluid, whereby actuation of the heating element heats the fluid and actuates the thermally actuated pump. For example, the fluid may be a gas, whereby expansion of the gas propels a microfluidic sample along a channel of the substrate. The substrate may include a plurality of thermally actuated pumps. Fluid of each pump is in thermal communication with at least one heating element. The substrate may include at least one microfabricated reaction chamber, such as a chamber configured to perform a polymerase chain reaction. At least one of the N independently controllable components is a heating element in thermal communication with the reaction chamber, whereby actuation of the heating element may raise a temperature of material present in the reaction chamber. At least one of the N independently controllable components may be a heat sensor in thermal communication with the reaction chamber, whereby the temperature of the material present in the reaction chamber may be determined.

20050307

20100309

20050714

71230.0

SIEFKE, SAMUEL P

MICROFLUIDIC DEVICES HAVING A REDUCED NUMBER OF INPUT AND OUTPUT CONNECTIONS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Motor controller of deceleration idling-cylinder engine vehicle

A motor control device for a vehicle having a deceleration deactivatable engine which includes at least one deactivatable cylinder which is deactivated during a deceleration traveling of the vehicle, and which is started by a motor when the operation thereof transitions from a deceleration deactivation operation to a normal operation. The motor control device comprises a cylinder deactivation state determining section (S202) for determining whether or not the engine is in a cylinder deactivation state, a cylinder deactivation executing section, a cylinder deactivation operation detecting section (S201) for detecting whether or not the cylinder deactivation executing section is activated, and a starting torque setting section (S201-S204) for setting staring torque for starting the engine by the motor. When it is determined, by the cylinder deactivation state determining section, that the engine is in a cylinder deactivation state, and it is determined, by the cylinder deactivation operation detecting section, that the engine is to return to the fuel supply operation, the starting torque setting section sets a smaller staring torque than in the case of a normal operation. Accordingly, the output of the motor is optimally set when the operation transitions from the cylinder deactivation operation to the normal operation; thus, a smooth drivability and an improved fuel consumption efficiency can be obtained.

1. A motor control device for a vehicle having a deceleration deactivatable engine, wherein, during a deceleration traveling of said vehicle, a fuel cut operation is applied to said engine as well as a deceleration cylinder deactivation operation in which at least one cylinder is deactivated in accordance with a running state of said engine, and said engine is started by a motor when the operation of said engine transitions from the fuel cut operation to a fuel supply operation, said motor control device comprising: a cylinder deactivation state determining section for determining whether or not said engine is in a cylinder deactivation state; a cylinder deactivation executing section for executing the cylinder deactivation operation of said engine; a cylinder deactivation operation detecting section for detecting whether or not said cylinder deactivation executing section is activated; and a starting torque setting section for setting staring torque for starting said engine by said motor, wherein when it is determined, by said cylinder deactivation state determining section, that said engine is in a cylinder deactivation state, and it is determined, by said cylinder deactivation operation detecting section, that said engine is to return to the fuel supply operation, said starting torque setting section sets a smaller staring torque than in the case in which said engine returns to the fuel supply operation from a state in which it is determined, by said cylinder deactivation state determining section, that said engine is not in a cylinder deactivation state. 2. A motor control device for a vehicle having a deceleration deactivatable engine according to claim 1, wherein said starting torque is set in accordance with the running speed of said engine. 3. A motor control device for a vehicle having a deceleration deactivatable engine according to claim 2, wherein said starting torque is set to a fixed value up to a predetermined engine revolution rate, is set so as to decrease as the engine revolution rate increases for the engine revolution rate greater than the predetermined value, and is set to another fixed value for the engine revolution rate greater than an idling revolution. 4. A motor control device for a vehicle having a deceleration deactivatable engine according to claim 1, wherein said vehicle is a hybrid vehicle, and said motor is provided to drive said vehicle.

FIELD OF THE INVENTION The present invention relates to a motor control device for a vehicle having a deceleration deactivatable engine, and in particular, relates to a motor control device for a vehicle in which starting or assisting of the engine by a motor can be smoothly performed when an engine operation transitions from a deceleration deactivation operation to a normal operation in which none of the cylinders of the engine is deactivated. DESCRIPTION OF RELATED ART A hybrid vehicle having not only an engine but also an electric motor as the drive source has been known in the art. As a type of hybrid vehicle, a parallel hybrid vehicle is known that uses an electric motor as an auxiliary drive source for assisting the engine output. In the parallel hybrid vehicle, the power of the engine is assisted by the electric motor during acceleration traveling. On the other hand, during deceleration traveling, the battery or the like is charged via a deceleration regenerating operation while fuel supply to the engine is stopped (generally known as deceleration fuel-cut operation). According to various control operations including the above, the remaining battery charge (remaining electric energy) of the battery is maintained while also satisfying the driver's demands. Because the drive train of the parallel hybrid vehicle comprises the engine and the motor coupled to the engine in series, the whole system is simple in structure, light in weight, and has great flexibility for installation in a vehicle. In one of the above-mentioned parallel hybrid vehicles, a motor-started control process or a motor-assisted control process, in which the engine is started not by a starter motor but by a power assist motor for the engine, is known. Note that the above-mentioned motor-started control process includes not only literally a starting control process conventionally performed by a starter motor in which the engine is started from its stopped state, but also a torque assisting control process in which the power of the engine is assisted when the engine operation transitions from the above-mentioned fuel-cut operation to a self-running operation in which fuel supply is restarted. On the other hand, a deceleration deactivation (cylinder deactivation during deceleration) control process as an engine friction reduction method has been proposed. By using this control process, it is possible to deactivate at least one cylinder during a deceleration fuel-cut operation, and to increase regenerated energy by an amount corresponding to reduction in engine friction as a result of cylinder deactivation so as to increase efficiency in energy recovery. However, because, for example, in the above-mentioned motor-started control process or motor-assisted control process, assisting torque is adjusted so as to be balanced with engine friction at the moment, a drawback is experienced in that when the above-mentioned motor-started control process or motor-assisted control process is applied, without modification, to a vehicle having deceleration deactivatable cylinders, the transition from a deceleration deactivation operation to a normal operation cannot be smoothly performed. In other words, because the engine friction is reduced during the deceleration deactivation operation, a drawback is experienced that if the motor-started control process or motor-assisted control process is performed so as to assist the engine torque as in the normal operation, fuel consumption efficiency may be degraded because the engine may run too fast or the consumed electrical energy may be too great due to an excessively high torque. SUMMARY OF THE INVENTION In view of the above circumstances, the present invention relates to a control process during transitions in engine operation from a deceleration deactivation operation to a normal operation, and in particular, an objective thereof is to provide a motor control device for a vehicle having a deceleration deactivatable engine, with which the output power of the motor may be optimally set when the engine operation transitions from a deceleration deactivation operation to a normal operation so that the fuel consumption efficiency can be improved. In order to achieve the above object, the present invention provides a motor control device for a vehicle having a deceleration deactivatable engine, wherein, during a deceleration traveling of the vehicle, a fuel cut operation is applied to the engine, as well as a deceleration cylinder deactivation operation in which at least one cylinder is deactivated in accordance with a running state of the engine, and the engine is started by a motor when the operation of the engine transitions from the fuel cut operation to a fuel supply operation, the motor control device comprising: a cylinder deactivation state determining section for determining whether or not the engine is in a cylinder deactivation state; a cylinder deactivation executing section for executing the cylinder deactivation operation of the engine; a cylinder deactivation operation detecting section for detecting whether or not the cylinder deactivation executing section is activated; and a starting torque setting section for setting staring torque for starting the engine by the motor, wherein when it is determined, by the cylinder deactivation state determining section, that the engine is in a cylinder deactivation state, and it is determined, by the cylinder deactivation operation detecting section, that the engine is to return to the fuel supply operation, the starting torque setting section sets a smaller staring torque than in the case in which the engine returns to the fuel supply operation from a state in which it is determined, by the cylinder deactivation state determining section, that the engine is not in a cylinder deactivation state. Accordingly, unnatural increase in engine revolution rate can be avoided, which will occur in the case in which the normal starting torque is applied by the motor when the engine does not completely return to the normal operation state, and also an excessive torque is prevented from being applied. The starting torque may be preferably set in accordance with the running speed of the engine. Accordingly, by setting the starting torque in accordance with the engine revolution rate which has a great influence on starting performance of the engine, the minimum starting torque required for starting can be set. Furthermore, the starting torque may be preferably set to a fixed value up to a predetermined engine revolution rate rate, may be set so as to decrease as the engine revolution rate increases for the engine revolution rate greater than the predetermined value, and may be set to another fixed value for the engine revolution rate greater than an idling revolution. Accordingly, the transition from the deceleration cylinder deactivation operation to the normal operation can be smoothly performed. Moreover, the vehicle is preferably a hybrid vehicle, and the motor is preferably provided to drive the vehicle. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram showing the general structure of a hybrid vehicle in an embodiment according to the present invention. FIG. 2 is a flowchart showing the operation for switching into a deceleration deactivation operation in the embodiment of the present invention. FIG. 3 is a flowchart showing the operation for determining whether the conditions permitting the deceleration deactivation operation are satisfied in the embodiment of the present invention. FIG. 4 is a flowchart showing the operation for determining whether the conditions permitting the deceleration deactivation operation are satisfied in the embodiment of the present invention. FIG. 5 is a flowchart showing the operation for determining whether the conditions permitting the deceleration deactivation operation are satisfied in the embodiment of the present invention. FIG. 6 is a flowchart showing the operation for determining the motor-starting power in the embodiment of the present invention. FIG. 7 is a front view showing a variable valve timing mechanism used in the embodiment of the present invention. FIGS. 8A and 8B show the variable valve timing mechanism used in the embodiment of the present invention; in particular, FIG. 8A shows a cross-section of the main part of the variable valve timing mechanism in a cylinder activation state, and FIG. 8B shows a cross-section of the main part of the variable valve timing mechanism in a cylinder deactivation state. FIG. 9 is an enlarged view of the main part in FIG. 1. FIG. 10 is a graph showing a relationship between each of flags and a motor power. FIG. 11 is a graph showing a relationship between a motor-starting torque and engine revolution rates. FIG. 12 is a flowchart showing the operation for determining amount of assist by the motor. DESCRIPTION OF THE PREFERRED EMBODIMENTS The preferred embodiments of the present invention will be explained below with reference to the appended drawings. FIG. 1 is a block diagram schematically illustrating a parallel hybrid vehicle in a first embodiment of the present invention, in which an engine E, an electric motor M, and a transmission T are directly coupled to each other in series. The driving force generated by both the engine E and the electric motor M is transmitted via, for example, a CVT (continuously variable transmission) as the transmission T (the transmission T may be a manual transmission) to front wheels Wf as driving wheels. When the driving force is transmitted from the driving wheels Wf to the electric motor M during deceleration of the hybrid vehicle, the electric motor M functions as a generator for applying a so-called regenerative braking force to the vehicle, i.e., the kinetic energy of the vehicle is recovered and stored as electric energy. Note that elements related to both a vehicle having a manual transmission and a vehicle having a CVT are shown in FIG. 1 for convenience in explanation. The driving of the motor M and the regenerating operation of the motor M are controlled by a power drive unit (PDU) 2 according to control commands from a motor CPU 1M of a motor ECU 1. A high-voltage nickel metal hydride battery 3 for sending and receiving electric energy to and from the motor M is connected to the power drive unit 2. The battery 3 includes a plurality of modules connected in series, and in each module, a plurality of cell units are connected in series. The hybrid vehicle includes a 12-volt auxiliary battery 4 for energizing various accessories. The auxiliary battery 4 is connected to the battery 3 via a downverter 5 or a DC-DC converter. The downverter 5, controlled by an FIECU 11, makes the voltage from the battery 3 step-down and charges the auxiliary battery 4. Note that the motor ECU 1 comprises a battery CPU 1B for protecting the battery 3 and calculating the remaining battery charge thereof. In addition, a CVTECU 21 is connected to the transmission T, which is a CVT, for controlling the same. The FIECU 11 controls, in addition to the motor ECU 1 and the downverter 5, a fuel injection valve (not shown) for controlling the amount of fuel supplied to the engine E, a starter motor, ignition timing, etc. To this end, the FIECU 11 receives various signals such as a signal from a speed sensor S1 for sensing vehicle speed VP, a signal from an engine revolution rate speed sensor S2 for sensing engine revolution rate speed NE, a signal from a shift position sensor S3 for sensing the shift position of the transmission T, a signal from a brake switch S4 for detecting the operation of a brake pedal 8, a signal from a clutch switch S5 for detecting the operation of a clutch pedal 9, a signal from a throttle opening-degree sensor S6 for sensing the degree of throttle opening TH of a throttle valve 32, a signal from an intake negative pressure sensor S7 for sensing negative pressure in the air-intake passage, a signal from a knocking sensor S8, and the like. Reference symbol BS indicates a booster associated with the brake pedal, in which a master vac negative pressure sensor S9 is provided for sensing negative pressure in the brake master vac (hereinafter referred to as master vac negative pressure). The master vac negative pressure sensor S9 is connected to the FIECU 11. Note that the intake negative pressure sensor S7 and the throttle opening-degree sensor S6 are provided in an air-intake passage 30, and the master vac negative pressure sensor S9 is provided in a communication passage 31 connected to the air-intake passage 30. The air-intake passage 30 is provided with a secondary air passage 33 for air communication between the upstream portion with respect to the throttle valve 32 and the downstream portion, and the secondary air passage 33 is provided with a control valve 34. The purpose of providing the secondary air passage 33 is to supply a small amount of air into the cylinders even when the air-intake passage 30 is completely closed by the throttle valve 32. The control valve 34 is controlled by means of the signal from the FIECU 11 in accordance with the intake negative pressure measured by the intake negative pressure sensor S7. A POIL (oil pressure) sensor S10, a solenoid of a spool valve 71, and a TOIL (oil temperature) sensor S11, all of which will be explained below, are also connected to the FIECU 11. The engine E includes three cylinders associated with the variable valve timing mechanism (i.e., a cylinder deactivation section) VT on both an intake side and an exhaust side, and a cylinder associated with a conventional valve mechanism NT which has no relation to the cylinder deactivation operation. In other words, the engine E is a deactivatable engine in which the operation state may be alternated between normal operation in which all four cylinders including three deactivatable cylinders are active and a cylinder deactivation operation in which three deactivatable cylinders are inactive. In the engine E, the operation of the intake valves IV and exhaust valves EV associated with the deactivatable cylinders can be temporarily stopped by means of the variable valve timing mechanism VT. Next, the variable valve timing mechanism VT will be explained in detail with reference to FIGS. 7 to 9. FIG. 7 shows an example of an SOHC engine provided with the variable valve timing mechanism VT which is adapted for a cylinder deactivation operation. The cylinder (not shown) is provided with the intake valve IV and the exhaust valve EV which are biased by valve springs 51 and 51 in a direction which closes the intake port (not shown) and exhaust port (not shown), respectively. Reference symbol 52 indicates a lift cam provided on a camshaft 53. The lift cam 52 is engaged with an intake cam lifting rocker arm 54a for lifting the intake valve and an exhaust cam lifting rocker arm 54b for lifting the exhaust valve, both of which are rockably supported by a rocker arm shaft 62. The rocker arm shaft 62 also supports valve operating rocker arms 55a and 55b in a rockable manner, which are located adjacent to the cam lifting rocker arms 54a and 54b, and whose rocking ends press the top ends of the intake valve IV and the exhaust valve EV, respectively, so that the intake valve IV and the exhaust valve EV open their respective ports. As shown in FIGS. 8A and 8B, the proximal ends (opposite the ends contacting the valves) of the valve operating rocker arms 55a and 55b are adapted so as to be able to engage a circular cam 531 provided on the camshaft 53. FIGS. 8A and 8B show, as an example, the cam lifting rocker arm 54b and the valve operating rocker arm 55b provided in the exhaust valve side. As shown in FIGS. 8A and 8B, a hydraulic chamber 56 is formed in the cam lifting rocker arm 54b and the valve operating rocker arm 55b in a continuous manner, which is located on the opposite side of the rocker arm shaft 62 with respect to the lift cam 52. The hydraulic chamber 56 is provided with a pin 57a and a disengaging pin 57b both of which are slidable and biased toward the cam lifting rocker arm 54b by means of a pin spring 58. The rocker arm shaft 62 is provided with, in its inside, a hydraulic passage 59 which is divided into hydraulic passages 59a and 59b by a partition S. The hydraulic passage 59b is connected to the hydraulic chamber 56 at the position where the disengaging pin 57b is located via an opening 60 of the hydraulic passage 59b and a communication port 61b in the cam lifting rocker arm 54b. The hydraulic passage 59a is connected to the hydraulic chamber 56 at the position where the pin 57a is located via an opening 60 of the hydraulic passage 59a and a communication port 61 a in the valve operating rocker arm 55b, and is adapted to be further connectable to a drain passage (not shown). As shown in FIG. 8A, the pin 57a is positioned by the pin spring 58 so as to bridge the cam lifting rocker arm 54b and the valve operating rocker arm 55b when hydraulic pressure is not applied via the hydraulic passage 59b. On the other hand, when hydraulic pressure is applied via the hydraulic passage 59b in accordance with a cylinder deactivation signal, both of the pin 57a and the disengaging pin 57b slide toward the valve operating rocker arm 55b against the biasing force of the pin spring 58, and the interface between the pin 57a and the disengaging pin 57b corresponds to the interface between the cam lifting rocker arm 54b and the valve operating rocker arm 55b to disconnect these rocker arms 54b and 55b, as shown in FIG. 8B. The intake valve side is also constructed in a similar manner. The hydraulic passages 59a and 59b are connected to an oil pump 70 via the spool valve 71 which is provided for ensuring hydraulic pressure of the variable valve timing mechanism VT. As shown in FIG. 9, a passage for deactivation 72 branching from the spool valve 71 is connected to the hydraulic passage 59b in the rocker arm shaft 62, and a passage for canceling deactivation 73 branching from the spool valve 71 is connected to the hydraulic passage 59a. The POIL sensor S10 is connected to the passage for canceling deactivation 73. The POIL sensor S10 monitors hydraulic pressure in the passage for canceling deactivation 73, which exhibits low values during a deactivation operation and exhibits high values during normal operation. The TOIL sensor S11 (shown in FIG. 1) is connected to an oil supplying passage 74 which branches from a passage connecting the outlet of the oil pump 70 and the spool valve 71 and which supplies operating oil to the engine E so as to monitor the temperature of the operating oil. When the condition for entering into a cylinder deactivation operation, which will be described below, is satisfied, the spool valve 71 is operated in accordance with a. signal from the FIECU 11, and hydraulic pressure is applied to the hydraulic chamber 56 via the oil pump 70 and the hydraulic passage 59b in both the intake valve and exhaust valve sides. Subsequently, the pins 57a, which have been bridging the cam lifting rocker arms 54a, 54b and the valve operating rocker arms 55a and 55b together with the disengaging pin 57b and slide toward the valve operating rocker arms 55a and 55b, and the cam lifting rocker arms 54a and 54b and the valve operating rocker arms 55a and 55b are disconnected. In this state, although the cam lifting rocker arms 54a and 54b are driven by the rotating lift cam 52, the movements are not transmitted to the valve operating rocker arms 55a and 55b which have been disconnected from the cam lifting rocker arms 54a and 54b. As a result, because the valve operating rocker arms 55a and 55b are not driven and the intake valve IV and the respective ports of the exhaust valve EV remain closed, a deceleration deactivation operation of the engine can be performed. Operation for switching into deceleration deactivation operation Now, the operation for switching into a deceleration deactivation operation will be explained with reference to FIG. 2. The term “deceleration deactivation operation” herein means an engine operation state in which both of the intake and exhaust valves remain in their closing positions by means of the variable valve timing mechanism VT under predetermined conditions during regenerated deceleration, and it is performed in order to reduce engine friction and to increase the energy regenerated during deceleration. In the flowchart shown in FIG. 2, a flag (i.e., cylinder deactivation executing flag F_DECCS) used to alternate the engine operation state between a deceleration deactivation operation and an all-cylinder operation (normal operation) in which all cylinders are active is set and reset at a predetermined period. In step S100, it is determined whether the value of a flag F_GDECCS is “1”. The flag F_GDECCS is provided since cancellation of the cylinder deactivation operation is required when the degree of deceleration is relatively great. When the result of the determination in step S100 is “YES”, the operation proceeds to step S111, and when the result is “NO”, the operation proceeds to step S101. In step S101, it is determined whether the value of a flag F_GDECMA (included in the deceleration state determining section) is “1”. The flag F_GDECMA is provided since cancellation of regenerated deceleration is required when the degree of deceleration is relatively great. When the result of the determination in step S101 is “YES”, the operation proceeds to step S111, and when the result is “NO”, the operation proceeds to step S102. The reason for providing the determination in step S101 is that it is better not to execute the cylinder deactivation operation when stopping of the vehicle has the highest priority. When a braking operation of high deceleration is applied, negative pressure in the master vac is greatly reduced (i.e., the absolute pressure is increased), and subsequently, there is a high probability that the engine operation state may return to normal operation from the cylinder deactivation operation; therefore, the cylinder deactivation operation should be cancelled during high deceleration traveling. The reason for providing the determination in step S101 is that it is better not to execute the cylinder deactivation operation in order to prevent wheel skidding by a regenerative braking during high deceleration traveling. In step S102, the operation for judgment whether the conditions permitting the deceleration deactivation operation, which will be explained below, are satisfied is executed, and the operation proceeds to step S103. In step S103, it is determined whether the value of a flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is “1”. When the result of the determination in step S103 is “NO”, which means that the conditions for the deceleration deactivation operation are not satisfied, the operation proceeds to step S111, and when the result is “YES”, which means that the conditions for the deceleration deactivation operation are satisfied, the operation proceeds to step S104. In step S104, it is determined whether the value of a solenoid ON delay timer TDCSDL1, which will be explained below, is “0”. When the result of the determination in step S104 is “YES”, which means that a predetermined period has passed, the operation proceeds to step S105, and when the result is “NO”, which means that a predetermined period has not passed, the operation proceeds to step S113. In step S105, a predetermined value #TMDCS2 is set in a solenoid OFF delay timer TDCSDL2 for the spool valve 71, then the operation proceeds to step S106. This procedure is performed in order to ensure that a certain period of time has passed from completion of the determination in step S103 to completion of the OFF operation of the solenoid for the spool valve 71, when the engine operation is alternated from the deceleration deactivation operation to the normal operation. In step S106, the flag F_CSSOL of the solenoid for the cylinder deactivation operation is set to “1”, i.e., the solenoid for the cylinder deactivation operation in the spool valve 71 is set to be ON, then the operation proceeds to step S107. This flag is set to “1” when the solenoid for the cylinder deactivation operation of the spool valve 71 is set to be ON, and is set to “0” when the solenoid is set to be OFF. In step S107, it is determined by the POIL sensor S10 whether hydraulic pressure is actually produced after the solenoid for the cylinder deactivation operation was set to be ON. Specifically, it is determined whether or not engine oil pressure POIL is equal to or less than cylinder deactivation permissible oil pressure #POILCSH. When the result of the determination in step S107 is “YES”, the operation proceeds to step S108, and when the result is “NO” (there is hysteresis), the operation proceeds to step S115. An oil pressure switch may be provided for the determination instead of the POIL sensor S10. In step S108, it is determined whether the value of a cylinder deactivation execution delay timer TCSDLY1 is “0” in order to ensure that a certain period of time has passed from when the spool valve 71 is switched on to when oil pressure is produced. When the result of the determination in step S 108 is “YES”, the operation proceeds to step S109, and when the result is “NO”, the operation proceeds to step S117. In step S109, a timer value #TMNCSDL2, which is retrieved from a table depending on the engine running speed NE, is set in a cylinder deactivation cancellation delay timer TCSDLY2. The reason for setting the timer value #TMNCSDL2 depending on the engine running speed NE is that the oil pressure response changes depending on the engine running speed NE. Therefore, the lower the engine running speed NE is, the greater the timer value #TMNCSDL2 is. In step S110, the cylinder deactivation executing flag F_DECCS is set to “1”, which means that the deceleration deactivation operation is executed, and the control operation of this flow is terminated. In step S111, it is determined whether the value of the solenoid OFF delay timer TDCSDL2 is “0”. When the result of the determination in step S111 is “YES”, which means that a predetermined period has passed, the operation proceeds to step S112, and when the result is “NO”, which means that a predetermined period has not passed, the operation proceeds to step S106. In step S112, a predetermined value #TMDCS1 is set in the solenoid ON delay timer TDCSDL1 for the spool valve 71, then the operation proceeds to step S113. This procedure is performed in order to ensure that a certain period of time has passed from completion of the determination in step S103 to an ON operation of the solenoid for the spool valve 71 in step S106 when the engine operation is alternated from the deceleration deactivation operation to normal operation. In step S113, the flag F_CSSOL of the solenoid for the cylinder deactivation operation is set to “0”, i.e., the solenoid for the cylinder deactivation operation in the spool valve 71 is set to be OFF, then the operation proceeds to step S114. In step S114, it is determined by the POIL sensor S10 whether hydraulic pressure is actually reduced after the solenoid for the cylinder deactivation operation was set to be OFF. Specifically, it is determined whether or not engine oil pressure POIL is equal to or greater than cylinder deactivation cancellation oil pressure #POILCSL. When the result of the determination in step S117 is “YES”, which means that engine oil pressure POIL is at the high pressure side (there is hysteresis), the operation proceeds to step S115, and when the result is “NO”, the operation proceeds to step S108. An oil pressure switch may be provided for the determination instead of the POIL sensor S10. In step S115, it is determined whether the value of the cylinder deactivation cancellation delay timer TCSDLY2 is “0” in order to ensure that a certain period of time has passed from when the spool valve 71 is switched off to when oil pressure is reduced. When the result of the determination in step S115 is “YES”, the operation proceeds to step S116, and when the result is “NO”, the operation proceeds to step S110. In step S116, a timer value #TMNCSDL1, which is retrieved from a table depending on an engine running speed NE, is set in the cylinder deactivation execution delay timer TCSDLY1, then the operation proceeds to step S117. The reason for setting the timer value #TMNCSDL1 depending on the engine running speed NE is that the oil pressure response changes depending on the engine running speed NE. Therefore, the lower the engine running speed NE is, the greater the timer value #TMNCSDL1 is. In step S117, a timer value #TMCSCEND is set in a cylinder deactivation compulsory cancellation timer TCSCEND, then the operation proceeds to step S118. The cylinder deactivation compulsory cancellation timer TCSCEND is provided to compulsorily cancel the cylinder deactivation operation when a predetermined period has passed since the beginning of the cylinder deactivation operation. In step S118, the cylinder deactivation executing flag F_DECCS is set to “0”, which means that the normal operation is being executed, and the control operation of this flow is terminated. Operation for judgment whether the conditions permitting the deceleration deactivation operation are satisfied Next, the operation for judgment whether the conditions permitting the deceleration deactivation operation are satisfied in step S102 shown in FIG. 2 will be explained with reference to FIGS. 3 to 5. In this operation, the flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is set or reset by continuously monitoring whether or not the conditions for deceleration deactivation operation are satisfied. This operation will be repeated at a predetermined period. In step S151, it is determined whether the value of the cylinder deactivation compulsory cancellation timer TCSCEND is “0”. When the result of the determination in step S151 is “YES”, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, the operation proceeds to step S152, because the cylinder deactivation operation should be cancelled when the value of the cylinder deactivation compulsory cancellation timer TCSCEND is “0”. In step S152, it is determined whether the value of the fuel cut-off flag F_FC is “1”. When the result of the determination in step S152 is “YES”, the operation proceeds to step S153, and when the result is “NO”, the operation proceeds to step S166. This procedure is provided because the purpose of the cylinder deactivation operation is to further obtain regenerated energy corresponding to the reduction in engine friction resulting when the fuel supply is stopped during deceleration traveling. In step S166, a cylinder deactivation ending flag F_DCSCEND is set to “0”, then the operation proceeds to step S184 shown in FIG. 5. In step S153, it is determined whether the value of the cylinder deactivation ending flag F_DCSCEND is “1”. When the result of the determination in step S153 is “YES”, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, the operation proceeds to step S154. In step S154, it is determined whether ambient temperature TA is within a predetermined range, i.e., whether the ambient temperature TA satisfies the following inequality: (lowest permissible ambient temperature for cylinder deactivation #TADCSL)≦TA≦(highest permissible ambient temperature for cylinder deactivation #TADCSH). When it is determined, in step S154, that the ambient temperature TA is within the predetermined range, the operation proceeds to step S155. When it is determined that the ambient temperature TA is out of the predetermined range, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the cylinder deactivation operation may make the engine unstable when ambient temperature TA is below the lowest permissible ambient temperature for cylinder deactivation #TADCSL or when the ambient temperature TA is above the highest permissible ambient temperature for cylinder deactivation #TADCSH. In step S155, it is determined whether cooling water temperature TW is within a predetermined range, i.e., whether cooling water temperature TW satisfies the following inequality: (lowest permissible cooling water temperature for cylinder deactivation #TWDCSL)≦TA≦(highest permissible cooling water temperature for cylinder deactivation #TWDCSH). When it is determined, in step S155, that the cooling water temperature TW is within the predetermined range, the operation proceeds to step S156. When it is determined that the cooling water temperature TW is out of the predetermined range, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the cylinder deactivation operation may make the engine unstable when cooling water temperature TW is below the lowest permissible cooling water temperature for cylinder deactivation #TWDCSL or when the cooling water temperature TW is above the highest permissible cooling water temperature for cylinder deactivation #TWDCSH. In step S156, it is determined whether ambient pressure PA is equal to or greater than a lowest permissible ambient pressure for cylinder deactivation #PADCS. When the result of the determination in step S156 is “YES”, which means that the ambient pressure PA is in higher side, the operation proceeds to step S157, and when the result is “NO”, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because it is undesirable to execute the cylinder deactivation operation when the ambient pressure is relatively low. For example, when the cylinder deactivation operation is executed under such a condition, negative pressure in the master vac for the brake system may not be ensured to be sufficient for the braking operation. In step S157, it is determined whether voltage VB of the 12-volt auxiliary battery 4 is equal to or greater than a lowest permissible voltage for cylinder deactivation #VBDCS. When the result of the determination instep S157 is “YES”, which means that the voltage VB is in greater side, the operation proceeds to step S159, and when the result is “NO”, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the response of the spool valve 71 is degraded when the voltage VB of the 12-volt auxiliary battery 4 is relatively low. In addition, this procedure is provided in order to protect the auxiliary battery 4 when the voltage thereof is decreased under a low ambient temperature or when the auxiliary battery 4 is deteriorated. In step S159, it is determined whether the value of an idling indication flag F_THIDLMG is “1”. When the result of the determination in step S159 is “YES”, which means that the throttle of the engine is not completely closed, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, which means that the throttle of the engine is completely closed, the operation proceeds to step S160. This procedure is provided to cancel the cylinder deactivation operation even when the throttle is slightly opened from a completely closed state so that marketability of the vehicle is enhanced. In step S160, it is determined whether oil temperature TOIL (the temperature of the engine oil) is within a predetermined range, i.e., whether the oil temperature TOIL satisfies the following inequality: (lowest permissible oil temperature for cylinder deactivation #TODCSL)≦TOIL≦(highest permissible oil temperature for cylinder deactivation #TODCSH). When it is determined, in step S160, that the oil temperature TOIL is within the predetermined range, the operation proceeds to step S161. When it is determined that oil temperature TOIL is out of the predetermined range, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the response in alternation between normal operation and the cylinder deactivation operation of the engine may be unstable if the cylinder deactivation operation is executed when the oil temperature TOIL is below the lowest permissible oil temperature for cylinder deactivation #TODCSL or when the oil temperature TOIL is above the highest permissible oil temperature for cylinder deactivation #TODCSH. In step S161, it is determined whether deceleration regeneration is being performed. When the result of the determination in step S161 is “YES”, the operation proceeds to step S162, and when the result is “NO”, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the purpose of the cylinder deactivation operation is to further obtain regenerated energy corresponding to the reduction in engine friction resulting when the fuel supply is stopped during deceleration traveling. In step S162, it is determined whether the value of an MT/CVT indication flag F_AT is “1”. When the result of the determination in step S162 is “NO”, which means that the present vehicle employs an MT (manual transmission), the operation proceeds to step S163, and when the result is “YES”, which means that the present vehicle employs an AT (automatic transmission) or a CVT, the operation proceeds to step S167. In step S167, it is determined whether the value of an in-gear indication flag F_ATNP is “1”. When the result of the determination in step S167 is “NO”, which means that the vehicle is in driving mode, the operation proceeds to step S168, and when the result is “YES”, which means that the transmission is in N (neutral) or P (parking) position, the operation proceeds to step S184 shown in FIG. 5. In step S168, it is determined whether the value of a reverse position indication flag F_ATPR is “1”. When the result of the determination in step S168 is “YES”, which means that the transmission is in reverse position, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, which means that the transmission is in a position other than the reverse position, the operation proceeds to step S165. Through the procedures in steps S167 and S168, the cylinder deactivation operation is cancelled in N/P or reverse position. In step S163, it is determined whether the previous gear position NGR is equal to or higher than a lowest permissible gear position for cylinder deactivation #NGRDCS (e.g., third gear). When the result of the determination in step S163 is “YES”, i.e., higher gear position, the operation proceeds to step S164, and when the result is “NO”, i.e., lower gear position, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the regeneration efficiency is reduced in low gear positions, and to avoid a frequent alternation into the cylinder deactivation operation when the vehicle is in a traffic jam. In step S164, it is determined whether the value of a half-engaged clutch indication flag F_NGRHCL is “1”. When the result of the determination in step S164 is “YES”, which indicates a half-engaged clutch state, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, the operation proceeds to step S165. By providing this procedure, it is possible to avoid undesirable cylinder deactivation operations which may cause an engine stall when the clutch is placed in a half-engaged state to stop the vehicle, or an insufficient acceleration performance when the clutch is placed in a half-engaged state for gear position shifting to accelerate the vehicle. In step S165, it is determined whether an engine revolution rate decrease amount DNE is equal to or smaller than a highest permissible engine revolution rate decrease amount for cylinder deactivation #DNEDCS. When the result of the determination in step S165 is “YES”, which means that the engine revolution rate is considerably decreased, the operation proceeds to step S184 shown in FIG. 5, and when the result is “NO”, the operation proceeds to step S169. This procedure is provided to avoid undesirable cylinder deactivation operations which may cause an engine stall when the engine revolution rate is rapidly decreasing. In step S169 shown in FIG. 4, it is determined whether battery temperature TBAT of the battery 3 is within a predetermined range, i.e., whether the battery temperature TBAT satisfies the following inequality: (lowest permissible battery temperature for cylinder deactivation #TBDCSL)≦TBAT≦(highest permissible battery temperature for cylinder deactivation #TBDCSH). When the result of the determination in step S169 is “YES”, the operation proceeds to step S170, and when the result is “NO”, the operation proceeds to step S184 shown in FIG. 5. This procedure is provided because the cylinder deactivation operation should not be executed when the temperature of the battery 3 is out of the predetermined range in view of protecting the battery. In step S170, it is determined whether a remaining battery charge QBAT is within a predetermined range, i.e., whether the remaining battery charge QBAT satisfies the following inequality: (lowest permissible remaining battery charge for continuation of cylinder deactivation #QBDCSL)<QBAT<(highest permissible remaining battery charge for continuation of cylinder deactivation #QBDCSH). When it is determined, in step S170, that the remaining battery charge QBAT is within the predetermined range, the operation proceeds to step S170A. When it is determined that the remaining battery charge QBAT is out of the predetermined range, the operation proceeds to step S184 shown in FIG. 5. Accordingly, the cylinder deactivation operation is cancelled when the remaining battery charge QBAT is below the lowest permissible remaining battery charge for cylinder deactivation continuation #QBDCSL, or when the remaining battery charge QBAT is above the highest permissible remaining battery charge for cylinder deactivation continuation #QBDCSH. This procedure is provided because electric energy supplied to the motor M for assisting the engine driving cannot be ensured when the remaining battery charge QBAT is too low, and because regenerated energy cannot be drawn when the remaining battery charge QBAT is too high. In step S170A, it is determined whether a vehicle speed VP is equal to or below the highest permissible vehicle speed for continuation of cylinder deactivation #VPDCSH. When the result of the determination in step S170A is “YES”, the operation proceeds to step S170B, and when the result is “NO” (with hysteresis), the operation proceeds to step S184 shown in FIG. 5. In step S170B, it is determined whether a brake switch flag F_BKSW is “1”. When the result of the determination in step S170B is “YES”, which means that the brake of the vehicle is applied, the operation proceeds to step S170D, and when the result is “NO”, which means that the brake of the vehicle is not applied, the operation proceeds to step S170C. Note that a brake fluid pressure or the degree of deceleration of the vehicle (i.e., negative acceleration) may be measured to detect a brake activation instead of using the brake switch flag F_BKSW. In step S170C, it is determined whether the vehicle speed VP is equal to or greater than the lowest permissible vehicle speed for continuation of cylinder deactivation during brake OFF #VPDCSL (e.g., 30 km/h). When the result of the determination in step S170C is “YES”, the operation proceeds to step S171 shown in FIG. 5, and when the result is “NO” (with hysteresis), the operation proceeds to step S184 shown in FIG. 5. In step S170D, it is determined whether the vehicle speed VP is equal to or greater than the lowest permissible vehicle speed for continuation of cylinder deactivation during brake ON #VPDCSBL (e.g., 10 km/h). When the result of the determination in step S170D is “YES”, the operation proceeds to step S171 shown in FIG. 5, and when the result is “NO” (with hysteresis), the operation proceeds to step S184 shown in FIG. 5. The reason of setting the lowest permissible vehicle speed for continuation of cylinder deactivation to be different between when the brake is in the ON state and when the brake is in the OFF state is that the driver of the vehicle may intend to stop the vehicle with high probability when the brake is in the ON state, and the driver may intend to re-accelerate the vehicle when the brake is in the OFF state. Accordingly, the lowest permissible vehicle speed for continuation of cylinder deactivation during brake OFF #VPDCSL is set higher than the lowest permissible vehicle speed for continuation of cylinder deactivation during brake ON #VPDCSBL, whereby the cylinder deactivation operation is more easily executed when the brake is in the ON state than when the brake is in the OFF state, and also the drivability of the vehicle is improved by smoothly reflecting the driver's desire when the driver intends to re-accelerate the vehicle. The above-mentioned lowest permissible vehicle speed for continuation of cylinder deactivation during brake ON #VPDCSBL and lowest permissible vehicle speed for continuation of cylinder deactivation during brake OFF #VPDCSL constitute the reference lowest permissible vehicle speeds. In step S171, it is determined whether the engine running speed NE is equal to or below a predetermined value, i.e., whether the engine running speed NE satisfies the following inequality: NE≦(highest permissible engine running speed for continuation of cylinder deactivation #NDCSH). When it is determined, in step S171, that the engine running speed NE is equal to or below a predetermined value, the operation proceeds to step S172. When it is determined that the engine running speed NE is above the predetermined value (with hysteresis), the operation proceeds to step S184. In step S172, the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL (a reference engine running speed) is retrieved from a #NDCSL table in accordance with the oil temperature TOIL, and the operation proceeds to step S173. The reason for retrieving the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL in such a way, i.e., in accordance with the oil temperature TOIL is that the higher the oil temperature, i.e., the temperature of the engine oil, is, the lower the viscosity of the engine oil is; then, it becomes difficult to apply sufficient pressure, and it is necessary to cancel the deactivation operation earlier, i.e., before the engine running speed becomes too low. By this procedure, an accurate control is realized in accordance with the oil temperature TOIL, i.e., in accordance with the thermal state of the engine. Note that the lowest permissible engine running speed for continuation of cylinder deactivation #NDCSL has hysteresis, and the higher the oil temperature TOIL is, the higher #NDCSL is set. Note that, instead of the oil temperature TOIL as mentioned above, the temperature of cooling water of the engine or the temperature of the engine itself may be used for setting the lowest permissible engine running speed for continuation of cylinder deactivation #NDCSL. In step S173, it is determined whether a brake switch flag F_BKSW is “1”. When the result of the determination in step S173 is “YES”, which means that the brake of the vehicle is applied, the operation proceeds to step S174, and when the result is “NO”, which means that the brake of the vehicle is not applied, the operation proceeds to step S182. Note that, as mentioned above, a brake fluid pressure or the degree of deceleration of the vehicle (i.e., negative acceleration) may be measured to detect a brake activation instead of using the brake switch flag F_BKSW. In step S182, the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL is increased by a predetermined amount of #DNDCSL, and the operation proceeds to step S174. By detecting, to some extent, that the driver intends to stop the vehicle through detecting a brake activation, and by increasing the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL by the predetermined amount of #DNDCSL, the cylinder deactivation operation is more easily executed when the brake is in the ON state than when the brake is in the OFF state, whereby it is possible to smoothly reflect the driver's desire when the driver intends to re-accelerate the vehicle, and thus drivability can be improved. Note that if the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL can be changed, various ways are possible, for example, the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL may be corrected using multiplying coefficients, or a map may be made for the NDCSL, instead of increasing the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL by an amount of #DNDCSL. In step S174, it is determined whether the engine running speed NE is equal to or above the lowest permissible engine running speed for continuation of cylinder deactivation NDCSL. When the result of the determination in step S174 is “YES”, the operation proceeds to step S175, and when the result is “NO”, the operation proceeds to step S184. In step S175, it is determined whether the value of the cylinder deactivation stand-by flag F_DCSSTB is “1”. This flag is set to “1” instep S178 when pre-deactivation conditions are satisfied, and set to “0” in step S185 when the pre-deactivation conditions are not satisfied. When the result of the determination in step S174 is “YES”, the operation proceeds to step S178, and when the result is “NO”, the operation proceeds to step S176. In step S176, it is determined whether intake negative pressure PBGA is higher (i.e., closer to atmospheric pressure) than a permissible negative pressure for cylinder deactivation #PBGDCS. The permissible negative pressure for cylinder deactivation #PBGDCS is retrieved from a table which was defined in accordance with the engine running speed NE such that the greater the engine running speed NE, the less (closer to vacuum) the permissible negative pressure #PBGDCS is. This procedure is provided in order not to immediately execute the cylinder deactivation operation, but to execute the operation after utilizing the intake negative pressure for ensuring negative pressure in the master vac when the load of the engine is considerably great, i.e., the intake negative pressure is lower (closer to vacuum) than the permissible negative pressure #PBGDCS. When the result of the determination in step S176 is “YES” (i.e., low load), the operation proceeds to step S177, and when the result is “NO” (i.e., high load), the operation proceeds to step S183. In step S183, a deceleration intake negative pressure increasing flag F_DECPBUP is set to “1”, then the operation proceeds to step S185. When the value of the flag F_DECPBUP is “1”, the secondary air passage 33 is closed under certain conditions, and when the value of the flag F_DECPBUP is “0”, the secondary air passage 33 is opened under certain conditions. In other words, when it is determined, in step S176, that the engine is under a high load condition, the secondary air passage 33 is closed (step S183) because the negative pressure is insufficient, the cylinder deactivation operation is not started (step S188), and when it is determined, in step S176, that the intake negative pressure PBGA has reached a predetermined value, the control operation is triggered to proceed to steps S177 and S180, then the pre-deactivation conditions are deemed to be satisfied, i.e., the value of the flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is set to “1”. In step S177, the deceleration intake negative pressure increasing flag F_DECPBUP is set to “0”, then the operation proceeds to step S178. In step S178, because the pre-deactivation conditions are satisfied, the cylinder deactivation stand-by flag F_DCSSTB is set to “1”, then the operation proceeds to step S179. In step S179, it is determined whether the master vac negative pressure MPGA is equal to or lower than (closer to vacuum) the permissible negative pressure for continuation of cylinder deactivation #MPDCS. The permissible negative pressure for continuation of cylinder deactivation #MPDCS is retrieved from a table which was defined depending on the vehicle speeds VP such that the greater the vehicle speed VP, the lower (closer to vacuum) the permissible negative pressure #MPDCS is. The permissible negative pressure #MPDCS is preferably determined in accordance with the kinetic energy of the vehicle, i.e., the vehicle speed, because the master vac negative pressure MPGA is used to stop the vehicle. When it is determined, in step S179, that the master vac negative pressure MPGA is lower than the permissible negative pressure for continuation of cylinder deactivation #MPDCS, which means that the master vac negative pressure MPGA is closer to vacuum, the operation proceeds to step S180. When it is determined, in step S179, that the master vac negative pressure MPGA is higher than the permissible negative pressure for continuation of cylinder deactivation #MPDCS, which means that the master vac negative pressure MPGA is closer to atmospheric pressure, the operation proceeds to step S186. This procedure is provided because it is undesirable to continue the cylinder deactivation operation when the master vac negative pressure MPGA is not sufficiently low. In step S180, the flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is set to “1”, then the control operation is terminated. In step S184, the deceleration intake negative pressure increasing flag F_DECPBUP is set to “0”, then the operation proceeds to step S185. In step S185, because the pre-deactivation conditions are not satisfied, the cylinder deactivation stand-by flag F_DCSSTB is set to “0”, then the operation proceeds to step S186. In step S186, it is determined whether the value of the flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is “1”. When the result of the determination is “YES”, the operation proceeds to step S187, and when the result is “NO”, the operation proceeds to step S188. In step S187, a cylinder deactivation ending flag F_DCSCEND is set to “1”, and then the operation proceeds to step S188. In step S188, the flag F_DCSCND, which indicates that the conditions for deceleration deactivation operation are satisfied, is set to “0”, and then the control operation is terminated. Motor Starting Output Determination Operation Next, a motor starting output determination operation will be explained with reference to FIG. 6. In a hybrid vehicle, a mode determination operation, in which it is determined how the motor M should be operated, is executed. This “motor starting output determination operation” is executed in a motor starting mode in order to determine motor starting torque. This operation constitutes the starting torque setting section. A specific embodiment for setting torque is shown in FIG. 11 which will be explained below. Note that this operation is repeated at a predetermined period. In step S201 (the cylinder deactivation operation detecting section), it is determined whether the value of the cylinder deactivation solenoid flag F_CSSOL is “1”. When the result of the determination is “YES”, which means that the engine is not in a starting mode, and the operation is terminated. When the result of the determination is “NO”, which means that the engine is going to be activated, the operation proceeds to step S202. In step S202 (the deactivation state detecting section), it is determined whether the value of the cylinder deactivation executing flag F_DECCS is “1”. When the result of the determination is “YES”, which means that the engine is in the deactivation state, the operation proceeds to step S203, and when the result of the determination is “NO”, the operation proceeds to step S204. In step S203, a small torque is selected as the starting torque, and the operation is terminated. In step S204, a normal torque is selected as the starting torque, and the operation is terminated. More specifically, as shown in FIG. 10, in step S 203, a small torque is set as the starting torque from when cancellation of cylinder deactivation is requested, i.e., the cylinder deactivation solenoid flag F_CSSOL alters from “1” to “0” to when the cylinder deactivation operation is cancelled, i.e., the cylinder deactivation executing flag F_DECCS alters from “1” to “0”, during which the engine E does not completely return to the normal operation due to such as delay in hydraulic operation, and then a normal torque is selected as the starting torque when the engine E completely returns to the normal operation. FIG. 11 shows the relationship between a motor-starting torque and engine revolution rates, which is a specific example used for setting torque. The upper line in FIG. 11 represents motor-starting torque values for the normal operation in which the cylinder deactivation is not executed, and the lower line represents motor-starting torque values which are adjusted taking into consideration the reduced engine friction during the cylinder deactivation operation. In other words, the torque for the cylinder deactivation operation represented by the lower line is smaller than the torque for the normal operation represented by the upper line, and the difference between the two lines means engine friction. As is also shown in FIG. 11, each of the starting torques is set in accordance with the engine revolution rate. For example, in the case of the torque data for the normal operation (represented by the upper line), a fixed torque (e.g., 10 kgm) is set in a range in which the engine revolution rate ranges from 0 to a predetermined value (e.g., 300 rpm), in a range b, torque is gradually decreased in accordance with the engine revolution rate, and again a fixed torque (e.g., 0.5 kgm) is set in a range c in which the engine revolution rate ranges from an idling revolution Q (e.g., 800 rpm) or greater. On the other hand, in the case of the torque data for the cylinder deactivation operation, which are smaller than that for the normal operation, respective torque data are set as a range a′ (e.g., 5 kgm), as a range b′ (e.g., 5 to 0 kgm), and as a range c′ (e.g., 0 kgm). Because engine friction is reduced during the cylinder deactivation operation, if the starting torque for the normal operation is used, the starting torque is excessive by an amount of the reduced engine friction, and the engine revolution rate rises unnaturally, whereby the marketability and the fuel consumption efficiency of the vehicle are degraded. As a solution for this problem, the smaller starting torques (the ranges a′, b′, and c′ shown in FIG. 11) than in the case of normal operation are used for starting until the engine E completely returns to the normal operation from the cylinder deactivation operation. Therefore, as shown by the line representing the motor output in FIG. 10, when the engine revolution rate gradually increases while the cylinder deactivation operation is being executed, the motor output, which has been “0” until cancellation of the cylinder deactivation operation is requested, gradually increases as the engine friction gradually increases because the deactivatable cylinders become activated from request of cancellation of the cylinder deactivation to actual cancellation of the cylinder deactivation, and upon completion of cancellation of the cylinder deactivation, the motor output rapidly increases to transitions to the motor output for the normal operation. Motor Assist Amount Determination Operation Next, a motor assist amount determination operation will be explained, with reference to FIG. 12. In general, in the case of hybrid vehicles, when the acceleration pedal of the vehicle is pressed, which means that the driver of the vehicle intends to accelerate the vehicle, and when the degree of throttle opening exceeds a certain threshold (an assist trigger threshold) which is determined by taking various conditions into consideration, the engine E is assisted by the motor M to accelerate the vehicle. This motor assist amount determination operation is provided for adjusting the amount of motor assist by the motor M when the acceleration pedal of the vehicle is pressed during the deceleration cylinder deactivation operation, so that, as in the case of the starting torque explained above, the assist torque by the motor is not excessive considering the reduced engine friction due to the deceleration cylinder deactivation operation. Note that this operation will be repeated-at a predetermined period. In step S301, assuming that the vehicle transitions into an acceleration mode by taking into consideration the amount of acceleration pedal pressing, i.e., the degree of throttle opening, the state of charge of the battery, vehicle speed, electrical consumption in a 12-volt system, etc., a normal assist torque calculation operation is executed in which the amount of assist is calculated, and then the operation proceeds to step S302. In step S302, it is determined whether the value of the cylinder deactivation solenoid flag F_CSSOL is “1”. When the result of the determination is “YES”, which means that the vehicle is not in an assist mode, the assist torque is set to “0” in step S304, and the operation is terminated. When the result of the determination is “NO”, the operation proceeds to step S303. In step S303, it is determined whether the value of the cylinder deactivation executing flag F_DECCS is “1”. When the result of the determination is “YES”, the operation proceeds to step S305. When the result of the determination is “NO”, the operation proceeds to step S306. In step S306, the normal assist torque calculated in step S301 is selected, and the operation is terminated. In step S305, a corrected value calculated by correcting the normal assist torque calculated in step S301 is selected, and the operation is terminated. Note that the corrected value is a smaller value than the normal assist torque. Because engine friction is reduced during the cylinder deactivation operation, if the normal assist torque is used, the assist torque is excessive by an amount of the reduced engine friction, whereby the marketability and the fuel consumption efficiency of the vehicle are degraded. As a solution for this problem, a smaller assist torque than the normal assist torque is used for assisting until the engine E completely returns to the normal operation from the cylinder deactivation operation. When the assist torque is generated by pressing the acceleration pedal during the deceleration cylinder deactivation operation, a corrected assist torque which is smaller than the normal assist torque by an amount of the reduced engine friction is selected for assisting to avoid applying an excessive torque until the cylinder deactivation operation is cancelled, and when the cylinder deactivation operation is completely cancelled, the normal assist torque is selected for assisting driving power by the normal assist torque. According to the above embodiment, unnatural increase in engine revolution rate can be avoided, which will occur in the case in which the normal starting torque is applied by the motor M when the engine does not completely return to the normal operation state, and the engine friction is relative low; therefore, the marketability of the vehicle may be improved, and also fuel consumption efficiency can be improved because electrical energy is saved by preventing an excessive torque from being applied. In addition, by setting the starting torque in accordance with the engine revolution rate which has a great influence on starting performance of the engine E, the minimum starting torque required for starting can be set, and energy loss and degradation in fuel consumption efficiency can be prevented; thus a preferable energy management can be realized. Furthermore, because the transition from the deceleration cylinder deactivation operation to the normal operation can be smoothly performed, the driver will not experience an unnatural feeling; therefore, the marketability of the vehicle may be improved. Moreover, when the assist torque is generated by pressing the acceleration pedal during the deceleration cylinder deactivation operation, the corrected assist torque which is smaller than the normal assist torque by an amount of the reduced engine friction is selected for assisting to avoid applying an excessive assist torque until the cylinder deactivation operation is cancelled, and when the cylinder deactivation operation is completely cancelled; accordingly, the drivability and marketability of the vehicle can be improved, energy loss may be reduced, and thus the fuel consumption efficiency of the vehicle can also be improved. Industrial Applicability As explained above, according to the present invention, unnatural increase in engine revolution rate can be avoided, which will occur in the case in which the normal starting torque is applied by the motor M when the engine does not completely return to the normal operation state, and the engine friction is relative low; therefore, the marketability of the vehicle may be improved, and also fuel consumption efficiency can be improved by an amount of saved electrical energy due to preventing an excessive torque from being applied. In addition, according to the present invention, by setting the starting torque in accordance with the engine revolution rate which has a great influence on starting performance of the engine E, the minimum starting torque required for starting can be set, and energy loss and degradation in fuel consumption efficiency can be prevented; thus a preferable energy management can be realized. Furthermore, because the transition from the deceleration cylinder deactivation operation to the normal operation can be smoothly performed, the driver will not feel an unnatural feeling; therefore, the marketability of the vehicle may be improved. Furthermore, according to the present invention, because the transition from the deceleration cylinder deactivation operation to the normal operation can be smoothly performed, the driver will not feel an unnatural feeling; therefore, the marketability of the vehicle may be improved.

<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a motor control device for a vehicle having a deceleration deactivatable engine, and in particular, relates to a motor control device for a vehicle in which starting or assisting of the engine by a motor can be smoothly performed when an engine operation transitions from a deceleration deactivation operation to a normal operation in which none of the cylinders of the engine is deactivated.

<SOH> SUMMARY OF THE INVENTION <EOH>In view of the above circumstances, the present invention relates to a control process during transitions in engine operation from a deceleration deactivation operation to a normal operation, and in particular, an objective thereof is to provide a motor control device for a vehicle having a deceleration deactivatable engine, with which the output power of the motor may be optimally set when the engine operation transitions from a deceleration deactivation operation to a normal operation so that the fuel consumption efficiency can be improved. In order to achieve the above object, the present invention provides a motor control device for a vehicle having a deceleration deactivatable engine, wherein, during a deceleration traveling of the vehicle, a fuel cut operation is applied to the engine, as well as a deceleration cylinder deactivation operation in which at least one cylinder is deactivated in accordance with a running state of the engine, and the engine is started by a motor when the operation of the engine transitions from the fuel cut operation to a fuel supply operation, the motor control device comprising: a cylinder deactivation state determining section for determining whether or not the engine is in a cylinder deactivation state; a cylinder deactivation executing section for executing the cylinder deactivation operation of the engine; a cylinder deactivation operation detecting section for detecting whether or not the cylinder deactivation executing section is activated; and a starting torque setting section for setting staring torque for starting the engine by the motor, wherein when it is determined, by the cylinder deactivation state determining section, that the engine is in a cylinder deactivation state, and it is determined, by the cylinder deactivation operation detecting section, that the engine is to return to the fuel supply operation, the starting torque setting section sets a smaller staring torque than in the case in which the engine returns to the fuel supply operation from a state in which it is determined, by the cylinder deactivation state determining section, that the engine is not in a cylinder deactivation state. Accordingly, unnatural increase in engine revolution rate can be avoided, which will occur in the case in which the normal starting torque is applied by the motor when the engine does not completely return to the normal operation state, and also an excessive torque is prevented from being applied. The starting torque may be preferably set in accordance with the running speed of the engine. Accordingly, by setting the starting torque in accordance with the engine revolution rate which has a great influence on starting performance of the engine, the minimum starting torque required for starting can be set. Furthermore, the starting torque may be preferably set to a fixed value up to a predetermined engine revolution rate rate, may be set so as to decrease as the engine revolution rate increases for the engine revolution rate greater than the predetermined value, and may be set to another fixed value for the engine revolution rate greater than an idling revolution. Accordingly, the transition from the deceleration cylinder deactivation operation to the normal operation can be smoothly performed. Moreover, the vehicle is preferably a hybrid vehicle, and the motor is preferably provided to drive the vehicle.

20040914

20050927

20050113

61075.0

HOANG, JOHNNY H

MOTOR CONTROLLER OF DECELERATION IDLING-CYLINDER ENGINE VEHICLE

UNDISCOUNTED

ACCEPTED

ACCEPTED

Advanced power management for satellite positioning system

A power management system for managing power in a wireless device having a SPS receiver, communication device and a power source, the power management is described. The power management system may include a real-time clock, an input/output device, a radio frequency front-end and a SPS engine in signal communication with the real-time clock, input/output device and radio frequency front-end, the SPS engine capable of powering down itself, the input/output device and radio frequency front-end in response to determining a mode of operation.

1. A method for managing power in a wireless device having a SPS receiver, communication device and a power source, the method comprising: obtaining a position of the wireless device with the SPS receiver; determining the mode of operation of the SPS receiver; and adjusting an amount of power supplied by the power source to the SPS receiver in response to the determined mode of operation. 2. The method of claim 1, wherein obtaining a fix of the wireless device includes determining a fix of the wireless device in a cold-start operation. 3. The method of claim 1, wherein determining the mode includes receiving a mode command from the communication device and determining an environment of operation in response to obtaining a position of the wireless device. 4. The method of claim 3, wherein the mode command includes a duty priority mode command and time-between-fixes mode command. 5. The method of claim 4, wherein adjusting an amount of power supplied by the power source includes powering up all components of the SPS receiver in response to determining the mode is a full power sub-mode. 6. The method of claim 4, wherein adjusting an amount of power supplied by the power source includes powering down components of the SPS receiver except a processor and a real-time clock in response to determining the mode is a processor only sub-mode. 7. The method of claim 6, wherein adjusting an amount of power supplied by the power source includes powering down components of the SPS receiver except the real-time clock in response to determining the mode is a tricklestate sub-mode. 8. The method of claim 7, wherein adjusting the amount of power supplied by the power source includes programming the real-time clock with the processor for a wakeup time; powering down radio frequency front-end and input/output device located in the SPS receiver; and powering down the processor. 9. The method of claim 8, wherein programming the real-time clock includes setting a wakeup time for the real-time clock to send a wakeup signal to the processor at the wakeup time. 10. The method of claim 9, further including powering up the processor in response to receiving the wakeup signal from the real-time clock; and powering up the radio frequency front-end of the SPS receiver; obtaining measurement data from the radio frequency front-end; powering down the radio frequency front-end; computing a new fix of wireless device in response to obtaining the measurements; powering up the input/output device of the SPS receiver; sending the computed new fix to the communication device; determining a sleep time and wakeup time for the processor; setting a new wakeup time for the real-time clock; and powering down the processor. 11. A power management system for managing power in a wireless device having a SPS receiver, communication device and a power source, the power management system comprising: a real-time clock; input/output device; an radio frequency front-end; and a SPS engine in signal communication with the real-time clock, input/output device and radio frequency front-end, the SPS engine capable of powering down itself, the input/output device and radio frequency front-end in response to determining a mode of operation. 12. The system of claim 11, wherein the SPS engine receives a mode command from the communication device. 13. The system of claim 12, wherein the mode command includes a duty priority mode command and time-between-fixes mode command. 14. The system of claim 13, wherein the real-time clock includes a backup memory. 15. A power management system for managing power in a wireless device having a SPS receiver, communication device and a power source, the power management system comprising: means for obtaining a position of the wireless device with the SPS receiver; means for determining the mode of operation of the SPS receiver; and means for adjusting an amount of power supplied by the power source to the SPS receiver in response to the determined mode of operation. 16. The system of claim 15, wherein determining means includes means for receiving a mode command from the communication device and means for determining an environment of operation in response to obtaining a position of the wireless device. 17. The system of claim 16, wherein the mode command includes a duty priority mode command and time-between-fixes mode command. 18. The system of claim 17, wherein adjusting means includes means for powering up all components of the SPS receiver in response to determining the mode is a full power sub-mode. 19. The system of claim 17, wherein adjusting means includes means for powering down components of the SPS receiver except a processor and a real-time clock in response to determining the mode is a processor only sub-mode. 20. The system of claim 19, wherein adjusting means includes means for powering down components of the SPS receiver except the real-time clock in response to determining the mode is a tricklestate sub-mode. 21. The system of claim 20, wherein adjusting means includes means for programming the real-time clock with the processor for a wakeup time; means for powering down radio frequency front-end and input/output device located in the SPS receiver; and means for powering down the processor. 22. The system of claim 21, wherein programming means includes means for setting a wakeup time for the real-time clock to send a wakeup signal to the processor at the wakeup time. 23. The system of claim 22, further including means for powering up the processor in response to receiving the wakeup signal from the real-time clock; and means for powering up the radio frequency front-end of the SPS receiver; means for obtaining measurement data from the radio frequency front-end; means for powering down the radio frequency front-end; means for computing a new fix of wireless device in response to obtaining the measurements; means for powering up the input/output device of the SPS receiver; means for sending the computed new fix to the communication device; means for determining a sleep time and wakeup time for the processor; means for setting a new wakeup time for the real-time clock; and means for powering down the processor. 24. A signal-bearing medium having software for managing power in a wireless device having a SPS receiver, communication device and a power source, the signal-bearing medium comprising: logic configured for obtaining a position of the wireless device with the SPS receiver; logic configured for determining the mode of operation of the SPS receiver; and logic configured for adjusting an amount of power supplied by the power source to the SPS receiver in response to the determined mode of operation. 25. The signal-bearing medium of claim 24, wherein determining logic includes logic configured for receiving a mode command from the communication device and logic configured for determining an environment of operation in response to obtaining a position of the wireless device. 26. The signal-bearing medium of claim 25, wherein the mode command includes a duty priority mode command and time-between-fixes mode command. 27. The signal-bearing medium of claim 26, wherein adjusting logic includes logic configured for powering up all components of the SPS receiver in response to determining the mode is a full power sub-mode. 28. The signal-bearing medium of claim 26, wherein adjusting logic includes logic configured for powering down components of the SPS receiver except a processor and a real-time clock in response to determining the mode is a processor only sub-mode. 29. The signal-bearing medium of claim 19, wherein adjusting logic includes logic configured for powering down components of the SPS receiver except the real-time clock in response to determining the mode is a tricklestate sub-mode. 30. The signal-bearing medium of claim 29, wherein adjusting logic includes logic configured for programming the real-time clock with the processor for a wakeup time; logic configured for powering down radio frequency front-end and input/output device located in the SPS receiver; and logic configured for powering down the processor. 32. The signal-bearing medium of claim 30, wherein programming logic includes logic configured for setting a wakeup time for the real-time clock to send a wakeup signal to the processor at the wakeup time. 32. The signal-bearing medium of claim 31, further including logic configured for powering up the processor in response to receiving the wakeup signal from the real-time clock; and logic configured for powering up the radio frequency front-end of the SPS receiver; logic configured for obtaining measurement data from the radio frequency front-end; logic configured for powering down the radio frequency front-end; logic configured for computing a new fix of wireless device in response to obtaining the measurements; logic configured for powering up the input/output device of the SPS receiver; logic configured for sending the computed new fix to the communication device; logic configured for determining a sleep time and wakeup time for the processor; logic configured for setting a new wakeup time for the real-time clock; and logic configured for powering down the processor.

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Provisional Patent Application Ser. No. 60/322,329, filed on Sep. 14, 2001, and entitled “Advanced Power Management For Global Positioning System Receivers,” which is herein incorporated by reference. BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates generally to Satellite Positioning Systems (“SPS”) devices, and in particular to a SPS device capable of providing fast update rates while being power conscious. 2. Related Art The worldwide utilization of wireless devices such as two-way radios, pagers, portable televisions, personal communication system (“PCS”), personal digital assistants (“PDAs”) cellular telephones (also known a “mobile phones”), Bluetooth, satellite radio receivers and Satellite Positioning Systems (“SPS”) such as Global Positioning Systems (“GPS”), also known as NAVSTAR, is growing at a rapid pace. As the number of people employing wireless devices increases, the number of features offered by wireless service providers also increases, as does the integration of these wireless devices in other products. However, wireless devices, in order to operate, receive power from portable power sources such as batteries. As these wireless devices increase in complexity by offering greater features and increased integration of different devices in a single product, the amount of power required to properly operate these wireless devices increases. As an example, there is a need for additional power as SPS devices are integrated into other wireless devices such as two-way radios, pagers, portable televisions, PCS, PDAs, cellular telephones, Bluetooth devices, satellite radio and other similar devices. Unfortunately, energy is expensive and at times in short supply. Generally, portable power sources such as batteries have a limited battery time. Limited battery time results into limited continuous operation time of the wireless device. As an example, if a user (a user may be a person or an application) forgets to power off the wireless device the battery will drain and force the user to re-charge the battery before it can be utilized again. However, for typical SPS applications, SPS devices do not have to operate continuously because a user may not need or desire to obtain the positional information of the SPS device (also known as a “fix” of the SPS device) continuously. This is generally true for applications involving a slow moving wireless device in an “open sky” (i.e., there are no obstructions to prevent the viewing of available satellites) environment. Examples of this situation may include traveling in an automobile on an open road, a marine vehicle (such as a ship or boat) in open waters, or hiking on an open path with a wireless device (such as a cellular telephone) with an integrated SPS receiver. A user may only need fixes at specific times (such as every 20 to 300 seconds) or on demand (such as when the user places an E911 call based on the new Federal Communication Commissions' “FCC” guidelines). As a result, operating the SPS receiver continuously in these situations would be a waste of limited power and result in shorter operation times for the wireless device. Therefore, there is a need in the art for a power management scheme capable of regulating the amount of power consumed by the SPS device based on the needs of wireless device and user. SUMMARY A power management system for managing power in a wireless device having a SPS receiver, communication device and a power source, the power management is disclosed. The power management system may include a real-time clock, an input/output device, an radio frequency front-end and a SPS engine in signal communication with the real-time clock, input/output device and radio frequency front-end, the SPS engine capable of powering down itself the input/output device and radio frequency front-end in response to determining a mode of operation. The power management system typical operates by obtaining a position of the wireless device with the SPS receiver, determining the mode of operation of the SPS receiver and adjusting an amount of power supplied by the power source to the SPS receiver in response to the determined mode of operation. Other systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims. BRIEF DESCRIPTION OF THE FIGURES The invention can be better understood with reference to the following Figures. The components in the Figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Moreover, in the Figures, like reference numerals designate corresponding parts throughout the different views. FIG. 1 is a block diagram illustrating an example implementation of a power management system (“PMS”). FIG. 2 is a signal flow diagram illustrating an example method of operation of the PMS shown in FIG. 1. FIG. 3 is a block diagram illustrating an example implementation of a SPS engine block shown in FIG. 1. FIG. 4 is a graphical plot of SPS signal power level versus time. FIG. 5 is a graphical plot of PMS operational power versus time in a duty priority mode. FIG. 6 is a graphical plot of PMS operational power versus time in a time between fix (“TBF”) priority mode. FIG. 7 is a block diagram illustrating another example implementation of the PMS. DETAILED DESCTIPTION In FIG. 1, a block diagram of an example implementation of a power management system (“PMS”) 100 is illustrated. The PMS may be in signal communication with a communication unit such as a processing (“CP”) unit 102, power source 104 and an antenna 106 via signal paths 108, 110, 112, 114, 116 and 118. The PMS 100 may include a satellite positioning system (“SPS”) engine 120, a radio frequency (“RF”) front-end 122, a real-time clock (“RTC”) 124 and an input/output (“I/O”) device 126. The SPS engine 120 is in signal communication with RF front-end 122, RTC 124, I/O 126, power source 104 and CP unit 102 via signal paths 128, 130, 132, 134, 136, 140, 142 and 116, respectively. The RTC 124 provides the SPS engine with a clock signal 130 and may include a backup memory 144. The power source 104 may be a battery. FIG. 2 is a signal flow diagram 200 illustrating an example operation of the PMS 100. In general, the PMS 100 first obtains satellite measurement data from the RF front-end 122 via signal path 128 (signal 202). The SPS engine 120 then calculates a fix, where a “fix” is the position (i.e., a “fixed position”), of the SPS receiver at a given time. The SPS engine 120 then stores the fix data and the time (“To”) it took the SPS receiver to acquire the fix in a SPS memory (not shown but optionally located within the SPS engine 120). The I/O 126 receives a mode of operation request from the CP 102, via signal path 114, (signal 204) and passes it to the SPS engine 120 via signal path 136 (signal 206). The PMS 100 has two modes of operation. The first mode is a “duty cycle” mode and the second mode is time-between fixes mode (“TBF mode”). In the duty cycle mode, the PMS 100 operates in a manner to maximize the lifetime of the power source 104. In the TBF mode, the PMS 100 is set so that the SPS receiver produces fixes at a specific time. In response to the mode requested by the CP 102, the SPS engine 120 prepares to power down itself and the RF front-end 122 and I/O 126 in order to lower the power consumption of the PMS 100. The SPS engine 120 first programs the RTC 124, via signal path 132 (signal 208), with an alarm signal. The alarm signal contains the information needed by the RTC 124 to wakeup the SPS engine 120 once it is powered down in a sleep mode of operation. The RTC 124 may store the information from the alarm signal in the backup memory 144. The SPS engine 120 then powers down the RF front-end 122, via signal path 146 (signal 210), and I/O 126, via signal path 148 (signal 212), by ordering the RF front-end 122 and I/O 126 to no longer accept power, via signal path 110 and 108, respectively, from the power source 104. The SPS engine 120 then powers itself down, via signal path 142, and no longer accepts power from the power source 104 via signal path 140. The RTC 124 then sends a wake up signal to the SPS engine 120 (signal 214), via signal path 134, based on the information provided by the alarm signal. In response, to receiving the wakeup signal, the SPS engine 120 powers up itself, the I/O 126 (signal 216) and RF front-end 122 (signal 218), via signal paths 148 and 146, respectively. The SPS engine 120 then obtains new satellite measurement data from the RF front-end 122, via signal path 128 (signal 220), and again powers down the RF front-end 122 (signal 222). The SPS engine 120 then calculates a fix for the PMS 100. Once the fix is obtained, it is sent to the CP 102 via the I/O 126. The SPS engine 120 then recalculates the off-time and on-time needed for a power duty cycle that will maintain the power consumption of the PMS 100 to a desired level. The SPS engine 120 then re-programs the RTC 124, via signal path 132 (signal 224), with a new alarm signal and the process repeats. It is appreciated that the CP 102 may wakeup the SPS engine 120 at any time providing an external interrupt message via signal path 116 (signal 226). FIG. 3 shows an example implementation of the SPS engine 120. The SPS engine 120 is a control and processing section of a SPS receiver. Examples of the SPS receiver may include SiRFstarI, SiRFstarII and SiRFstarIII GPS receiver produced by SiRF Technology, Inc. of San Jose, Calif., GPSOne GPS receiver produced by Qualcomm Incorporated of San Diego, Calif., or any other GPS receiver. The SPS engine 120 may include a SPS processor 300, GPS memory 302 and a digital signal processor (“DSP”) 304. The RF front-end 122 may be any general front-end of a receiver for receiving SPS such as global positioning system (“GPS”) signals. Examples of the RF front-end 122 may include GRF2i produced by SiRF Technology, Inc. of San Jose, Calif., MRFIC1505 produced by Motorola, Inc. of Schaumburg, Ill., or any other similar SPS RF front-end. The I/O 126 may be a universal asynchronous receiver/transmitter (“UART”) or similar input/output device or interface. It is appreciated by one skilled in the art that the SPS engine 120, I/O 126 and RTC 124 may be integrated into one unit such as, for example, GSP2e produced by SiRF Technology, Inc. of San Jose, Calif. As an example operation, a user (not shown) interfaces with the CP 102. The user may be a person or an application (not shown) from another system (not shown) such as handset processor in a cellular telephone (not shown) or a network server (not shown) is signal communication with the cellular telephone. As before, the PMS 100 has two modes of operation. In the duty cycle mode, the PMS 100 is set by the user to operate in a manner that maximizes the power source 104 life. The TBF mode is set by the user to assure that the SPS receiver produces fixes at a specific time. If the duty cycle mode (also known as “duty priority”) is selected, the PMS 100 first obtains a fix for the SPS receiver. The PMS 100 determines the time (“T0”) it took the SPS receiver to acquire the fix. Once the PMS 100 determines T0, the PMS 100 attempts to conserve power from the power source 104 by selectively powering down (i.e., placing in sleep mode) the RF front-end 122, I/O 126 and SPS engine 120 for a certain amount of time (“TOff”) and then powering up the RF front-end 122, I/O 126 and SPS engine 120 for another certain amount of time (“TOn”) based on the duty cycle needed to maintain a desired power consumption for the PMS 100. The effect of this is that the time between subsequent fixes (“TTBF”) is a variable number. TTBF is generally stable when the signal conditions are not varying but generally the PMS 100 will not attempt to main TTBF constant. Typically, TOn=T0 and T Off = T On ⁡ ( 1 - duty ⁢ ⁢ cycle duty ⁢ ⁢ cycle ) . It is appreciated that while the PMS 100 will not normally attempt to maintain a constant TTBF, the PMS 100 will attempt to maintain a constant TTBF when the calculated TOff would result in a smaller TTBF than requested by the user. In this case, the TOff will be extended to give the requested TTBF. If the TBF mode (also known as “TBF priority mode”) is selected instead, the PMS 100 first obtains a fix for the SPS receiver then the PMS 100 determines T0. Once the PMS 100 determines T0, the PMS 100 attempts to conserve power from the power source 104 by selectively powering down the RF front-end 122, I/O 126 and SPS engine 120 for TOff and then powering up the RF front-end 122, I/O 126 and SPS engine 120 for another TOn based the desired TTBF. Typically, TTBF is determined by the relation TOff=TTBF−TOn. If the TTBF is to small (i.e., TOn is equal to or greater than TTBF) for the PMS 100 to power down and then up again, the PMS 100 will be set to full power mode. Beyond the user selections, the environment effects the operation of the PMS 100 in both the duty priority and TBF priority modes. In an unobstructed environment (known as “open sky”) the SPS receiver in the PMS 100 will receive relatively high power signals from the available satellites. In FIG. 4, a graphical plot 400 of SPS signal power level 402 versus time 404 is shown. In an open sky environment the received SPS signal power level at the PMS 100 is relatively high 406. However, if the wireless device leaves this open sky environment and enters 408, as an example, an obstructed environment (such as entering a structure or an area with mountains, trees and other types of obstructions) the received SPS signal power level drops to a relatively low level 410. As a result of the environment, the PMS 100 will need more time to acquire the signals and generate a fix. In FIG. 5, a graphical plot 500 of PMS 100 operational power 502 versus time 504 in a duty priority mode is shown. The time values correspond to the time values in FIG. 4. In FIG. 5, TTBF 506, 508, 510 and 512 are shown as variable based on the duty cycle of the PMS 100 powering down to low power 514 (also known as “tricklestate”) and then power back up to full power 516. As the received SPS signal power levels drop 408, the PMS 100 determines that the SPS receiver requires more time in acquiring a fix that it originally needed when the received SPS signal power levels where high 406. The PMS 100, in a duty priority mode, recognizes that in order to get a fix the needed TOn is longer than before so the PMS 100 increases the TOff in order to maintain the same duty cycle. As a result, the PMS 100 changes the TTBF based on the received SPS signal power. In FIG. 6, a graphical plot of PMS 100 operational power 602 versus time 604 in a TBF priority mode is shown. Again, the time values correspond to the time values in FIG. 4. In FIG. 6, TTBF 606, 608, 610, 612, 614, 616 and 618 are shown as variable based on the duty cycle of the PMS 100 powering down to low power 620 to the tricklestate and then power back up to full power 622. Similar to FIG. 5, as the received SPS signal power levels drop 408, the PMS 100 determines that the SPS receiver requires more time in acquiring a fix that it originally needed when the received SPS signal power levels where high 406. The PMS 100, in a TBF priority mode, recognizes that in order to get a fix the needed TOn is longer than before but if the PMS 100 increases the TOff in order to maintain the same duty cycle, the desired TTBF will not be met. As a result, the PMS 100 meets the desired TTBF by powering up all the components and by operating at full power with no duty cycle. Once the received SPS signal power increases (i.e., the environment improves), the PMS 100 will again begin to power down the system as needed. FIG. 7 is a block diagram illustrating another example implementation of the PMS 700 in signal communication with a CP 702 and power supply 704. The PMS 700 may include a SPS engine 706, RF front-end 708, RTC 710, RF section regulator 712, switch 714 and low noise amplifier 716. The PMS 700 has three modes of operation including full power, central processor unit (“CPU”) only mode and trickelestate. In the full power state after initial hard reset, the CP 702 toggles the power control 718 of the power supply 704 that powers both the RF regulator 712 and SPS engine 706 via signal paths 720 and 722, respectively. After an initial hard reset, the PWRCTL/GPIO8 line 724 is set to default high, which ensures that the RF regulator 712 is on and GPSCLK 726 is supplied to the SPS engine 706. Software (optionally located in the SPS engine 706) will subsequently toggle GPIO3 728 high (which has a default value of low) to put the RF front-end 708 into full power mode and power the low noise amplifier (“LNA”) 716. If GPIO3 728 is low, the RF front-end 708 will be in a “clock-only” mode as long as power is being supplied. Therefore, regardless of the GPIO3 728 state, the RF front-end 708 will generate the GPSCLK 726 signal for clocking the SPS engine 706 as long as RF front-end 708 is powered by the RF section regulator 712. To enter the CPU-Only mode, the SPS engine 706 will toggle the GPIO3 728 line low. This will place the RF front-end 708 into a clock only mode and disable the LNA 716. Also at this time, the SPS engine 706 will disable some internal clocks to the SPS DSP side (not shown) of the SPS engine 706. The result is that only the interface (such as an ARM) (not shown) and UARTs (not shown) are still clocked. At this mode, none of the internal timer interrupts are available of the SPS engine 70r are available. To enter the lowest possible power state (“known as the “tricklestate”), the PMS 700 will first enter the CPU-Only state (described above). If the PMS 700 has determined that it is time to shutdown, then the PMS 700 will enable an internal finite-state machine (“FSM”) (not shown) to shut down the PMS 700 after all serial communication has been completed. The FSM is entered from a type of background loop once all pending tasks have been completed. The FSM will stop the clock to the SPS engine 706 interface, wait a certain number of RTC 710 cycles and then toggle the PWRCTL/GPIO8 line 724 low (the default number of cycles is 1 and the maximum number of cycles is 7). This will shutdown the RF section regulator 712 which stops the GPSCLK 726. In the tricklestate, the internal memory (not shown) is maintained through an internal refresh. Once the PMS 700 has entered the tricklestate, only the external interrupt 730, RTC interrupt 732 or a hard power reset from the CP 702 can restart it. If the SPS engine 706 plans on providing another fix after the shutdown, the SPS engine 706 will program the RTC 710 counters (not shown) to wake up the SPS engine 706 in a timely manner. If the required number of fixes has been sent, the SPS engine 706 will enter the tricklestate without setting the RTC 710. The SPS engine 706 will remain essentially dormant until an external interrupt 730 is received from the CP 702 or the SPS engine 706 is reset. If the SPS engine 706 is in the tricklestate, SPS engine 706 may be woken up by an RTC interrupt 732, an external interrupt 730 or a hard-reset. A hard-reset would be similar to the full power state after initial hard reset situation described above. In the hard-reset case, the contents of the SPS engine 706 memory would be lost and any aiding information would need to be provided again. If the SPS engine 706 receives an interrupt, the PWRCTL/GPIO8 line 724 is driven high by SPS engine 706. The result is that the RF section regulator 712 will be turned on. The RF section regulator 712 then powers the RF front-end 708 and the GPSCLK 726 will again be provided to the SPS engine 706 allowing the interfaces and other components to run. In order to ensure that a stable clock is provided to the SPS engine 706, the FSM will wait a certain number of RTC 710 clock cycles after the PWRCTL/GPIO8 line 724 goes high until the FSM enables the clocks in the SPS engine 706. The default number of cycles that the board waits is 48, and the maximum is 63. In this example, the delay between when the PWRCTL/GPIO8 line 724 gets toggled and when the clocks are enabled in the SPS engine 706 may be about 1.5 ms. The software in an interrupt handler (not shown) will toggle GPIO3 728 high to put the PMS 700 into full power. The process in FIG. 2 may be performed by hardware or software. If the process is performed by software, the software may reside in software memory (not shown) in the mobile unit or cellular network server. The software in software memory may include an ordered listing of executable instructions for implementing logical functions (i.e., “logic” that may be implement either in digital form such as digital circuitry or source code or in analog form such as analog circuitry or an analog source such an analog electrical, sound or video signal), may selectively be embodied in any computer-readable (or signal-bearing) medium for use by or in connection with an instruction execution system, apparatus, or device, such as a computer-based system, processor-containing system, or other system that may selectively fetch the instructions from the instruction execution system, apparatus, or device and execute the instructions. In the context of this document, a “computer-readable medium” and/or “signal-bearing medium” is any means that may contain, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The computer readable medium may selectively be, for example but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, device, or propagation medium. More specific examples “a non-exhaustive list” of the computer-readable medium would include the following: an electrical connection “electronic” having one or more wires, a portable computer diskette (magnetic), a RAM (electronic), a read-only memory “ROM” (electronic), an erasable programmable read-only memory (EPROM or Flash memory) (electronic), an optical fiber (optical), and a portable compact disc read-only memory “CDROM” (optical). Note that the computer-readable medium may even be paper or another suitable medium upon which the program is printed, as the program can be electronically captured, via for instance optical scanning of the paper or other medium, then compiled, interpreted or otherwise processed in a suitable manner if necessary, and then stored in a computer memory. While various embodiments of the application have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible that are within the scope of this invention. Accordingly, the invention is not to be restricted except in light of the attached claims and their equivalents.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates generally to Satellite Positioning Systems (“SPS”) devices, and in particular to a SPS device capable of providing fast update rates while being power conscious. 2. Related Art The worldwide utilization of wireless devices such as two-way radios, pagers, portable televisions, personal communication system (“PCS”), personal digital assistants (“PDAs”) cellular telephones (also known a “mobile phones”), Bluetooth, satellite radio receivers and Satellite Positioning Systems (“SPS”) such as Global Positioning Systems (“GPS”), also known as NAVSTAR, is growing at a rapid pace. As the number of people employing wireless devices increases, the number of features offered by wireless service providers also increases, as does the integration of these wireless devices in other products. However, wireless devices, in order to operate, receive power from portable power sources such as batteries. As these wireless devices increase in complexity by offering greater features and increased integration of different devices in a single product, the amount of power required to properly operate these wireless devices increases. As an example, there is a need for additional power as SPS devices are integrated into other wireless devices such as two-way radios, pagers, portable televisions, PCS, PDAs, cellular telephones, Bluetooth devices, satellite radio and other similar devices. Unfortunately, energy is expensive and at times in short supply. Generally, portable power sources such as batteries have a limited battery time. Limited battery time results into limited continuous operation time of the wireless device. As an example, if a user (a user may be a person or an application) forgets to power off the wireless device the battery will drain and force the user to re-charge the battery before it can be utilized again. However, for typical SPS applications, SPS devices do not have to operate continuously because a user may not need or desire to obtain the positional information of the SPS device (also known as a “fix” of the SPS device) continuously. This is generally true for applications involving a slow moving wireless device in an “open sky” (i.e., there are no obstructions to prevent the viewing of available satellites) environment. Examples of this situation may include traveling in an automobile on an open road, a marine vehicle (such as a ship or boat) in open waters, or hiking on an open path with a wireless device (such as a cellular telephone) with an integrated SPS receiver. A user may only need fixes at specific times (such as every 20 to 300 seconds) or on demand (such as when the user places an E911 call based on the new Federal Communication Commissions' “FCC” guidelines). As a result, operating the SPS receiver continuously in these situations would be a waste of limited power and result in shorter operation times for the wireless device. Therefore, there is a need in the art for a power management scheme capable of regulating the amount of power consumed by the SPS device based on the needs of wireless device and user.

<SOH> SUMMARY <EOH>A power management system for managing power in a wireless device having a SPS receiver, communication device and a power source, the power management is disclosed. The power management system may include a real-time clock, an input/output device, an radio frequency front-end and a SPS engine in signal communication with the real-time clock, input/output device and radio frequency front-end, the SPS engine capable of powering down itself the input/output device and radio frequency front-end in response to determining a mode of operation. The power management system typical operates by obtaining a position of the wireless device with the SPS receiver, determining the mode of operation of the SPS receiver and adjusting an amount of power supplied by the power source to the SPS receiver in response to the determined mode of operation. Other systems, methods, features and advantages of the invention will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the invention, and be protected by the accompanying claims.

20040723

20090811

20050421

93003.0

ISSING, GREGORY C

ADVANCED POWER MANAGEMENT FOR SATELLITE POSITIONING SYSTEM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Device for mixing two flows of fluid which are initially guided separate from one another in a two-circuit reaction engine

The invention relates to a device for mixing two fluid flows, initially guided separately from one another, in a two-circuit reaction engine, a mixing tube which encloses a hot core stream being provided, along the outer shaped lateral surface of which a cold bypass flow flows. The mixing tube is designed in the form of a truncated cone narrowing in the direction of flow and has openings arranged at the downstream end in the circumferential direction of the mixing-tube lateral surface in a cross-sectional plane lying perpendicularly to the longitudinal axis of the mixing tube. The hot core stream flowing through the mixing tube penetrates through the openings into the cold bypass flow flowing around the mixing-tube lateral surface. The openings have passage areas of elliptical shape with a major axis and a minor axis, the major axis of the passage areas running on the lateral surface of the mixing tube in the direction of flow of the fluids and the minor axis running perpendicularly thereto.

1. Device for mixing two fluid flows, initially guided separately from one another, in a two-circuit reaction engine, a mixing tube which encloses the first fluid flow—hot core stream being provided, along the outer shaped lateral surface of which the second fluid flow—cold bypass flow flows, characterized in that the mixing tube is designed in the form of a truncated cone narrowing in the direction of flow, and in that the mixing tube has openings arranged at the downstream end in the circumferential direction of the mixing-tube lateral surface in a cross-sectional plane lying perpendicularly to the longitudinal axis of the mixing tube, through which openings the hot core stream flowing through the mixing tube penetrates into the cold bypass flow flowing around the mixing-tube lateral surface. 2. The device as claimed in claim 1, characterized in that the openings have passage areas of elliptical shape with a major axis and a minor axis, and to this end the major axis (of the passage areas runs on the lateral surface of the mixing tube in the direction of flow of the fluids and the minor axis of the passage areas runs perpendicularly thereto. 3. The device as claimed in claim 1, characterized in that the passage areas have a hole collar on the outside of the mixing-tube lateral surface. 4. The device as claimed in claim 3, characterized in that the transition from the outside of the mixing-tube lateral surface to the hole collar of the passage areas is of concave design. 5. The device as claimed in claim 3, characterized in that the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube. 6. The device as claimed in claim 2, characterized in that the passage areas have a hole collar on the outside of the mixing-tube lateral surface. 7. The device as claimed in claim 6, characterized in that the transition from the outside of the mixing-tube lateral surface to the hole collar of the passage areas is of concave design. 8. The device as claimed in claim 4, characterized in that the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube. 9. The device as claimed in claim 6, characterized in that the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube. 10. The device as claimed in claim 7, characterized in that the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube. 11. A mixing tube which in use encloses and guides a hot core stream of a two circuit reaction engine, said mixing tube having a lateral wall with a laterally outward facing surface over which cold bypass flow flows and a laterally inward facing surface over which the hot core stream flows, wherein said mixing tube is configured as a truncated cone which narrows in a direction of flow through the mixing tube, and wherein mixing openings extend laterally through said lateral wall of the mixing tube at its downstream end to accommodate flow therethrough of portions of the hot core stream which then penetrates into the cold bypass flow along the outward facing surface. 12. A mixing tube according to claim 11, wherein the openings have passage areas of elliptical shape with a major axis and a minor axis, and wherein the major axis of the passage areas runs on the lateral surface of the mixing tube in the direction of flow of the fluids and the minor axis of the passage areas runs perpendicularly thereto. 13. A mixing tube according to claim 11, wherein the passage areas have a hole collar on the outside of the mixing-tube lateral surface. 14. A mixing tube according to claim 12, wherein the transition from the outside of the mixing-tube lateral surface to the hole collar of the passage areas is of concave design. 15. A mixing tube according to claim 13, wherein the transition from the outside of the mixing-tube lateral surface to the hole collar of the passage areas is of concave design. 16. A mixing tube according to claim 13, wherein the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube. 17. A two circuit reaction engine comprising a mixing tube which in use encloses and guides a hot core stream of the two circuit reaction engine, said mixing tube having a lateral wall with a laterally outward facing surface over which cold bypass flow flows and a laterally inward facing surface over which the hot core stream flows, wherein said mixing tube is configured as a truncated cone which narrows in a direction of flow through the mixing tube, and wherein mixing openings extend laterally through said lateral wall of the mixing tube at its downstream end to accommodate flow therethrough of portions of the hot core stream which then penetrates into the cold bypass flow along the outward facing surface. 18. A two circuit reaction engine according to claim 17, wherein the openings have passage areas of elliptical shape with a major axis and a minor axis, and wherein the major axis of the passage areas runs on the lateral surface of the mixing tube in the direction of flow of the fluids and the minor axis of the passage areas runs perpendicularly thereto. 19. A two circuit reaction engine according to claim 17, wherein the passage areas have a hole collar on the outside of the mixing-tube lateral surface. 20. A two circuit reaction engine according to claim 18, wherein the passage areas have a hole collar on the outside of the mixing-tube lateral surface. 21. A two circuit reaction engine according to claim 19, wherein the transition from the outside of the mixing-tube lateral surface to the hole collar of the passage areas is of concave design. 22. A two circuit reaction engine according to claim 17, wherein the height of the hole collar with respect to the mixing-tube lateral surface varies in such a way that the maximum height of the hole collar is located at the upstream apex of the major axis of the elliptical passage areas and decreases from there in the direction of flow, the region of the downstream apex of the major axis of the elliptical passage area being without a hole collar or varies in such a way that it becomes “negative” toward the downstream apex of the major axis of the elliptical passage area, i.e. the hole collar at the downstream end projects into the interior of the mixing tube.

BACKGROUND AND SUMMARY OF THE INVENTION Device for mixing two flows of fluid, which are initially guided separate from one another, in a two-circuit reaction engine The invention relates to a device for mixing two fluid flows, which are initially guided separately from one another, in a two-circuit reaction engine. To this end, it is known that “lobe mixers” are used in two-circuit reaction engines in order to mix the hot core stream of the reaction engine and the cold bypass flow before discharge from the reaction engine nozzle. In this case, the hot core stream of the reaction engine is guided through a “mixing tube”, whereas the cold bypass flow flows along the outside of the mixing-tube lateral surface. The mixing of the two fluid flows is forced by the special shaping of the downstream lateral surface of the mixing tube. For this purpose, that lateral surface of the mixing tube which is formed downstream has “lobes” which extend radially outward. In this case, after flow has taken place through or respectively around the downstream section of the mixing tube, these lobes direct said hot core stream into the cold bypass flow, and also direct the cold bypass flow into the hot core stream. With regard to the known prior art, reference is made, for example, to GB 2 160 265 A. A disadvantage with these known lobe mixers is in this case the fact that the lobe mixers, on account of the large radial extent of the lobes at the downstream end, tend to vibrate and in addition deformations occur due to material heating and pressure differences. It has therefore been attempted to remove these disadvantages by “struts” which support the lobe mixer on the outlet cone or the nozzle housing of the reaction engine. However, these struts constitute an additional source of weight. In addition, on account of the large radial extent of the lobes of the lobe mixer, interference may occur in the region of the engine suspension between the lobes of the lobe mixer and the engine suspension. To avoid such interference, the relevant lobes of the lobe mixer, the “pylon lobes”, are designed differently. However, this has the disadvantage that a decrease in the mixing efficiency is associated with the redesign of the “pylon lobes”. The object of the invention is to provide a remedy here by a new design of the device for mixing the hot core stream of the reaction engine with the cold bypass flow. Based on a device of the type mentioned at the beginning, this object is achieved according to the invention in that the mixing tube is designed in the form of a truncated cone narrowing in the direction of flow of core stream and bypass flow, and in that the mixing tube has openings arranged at the downstream end in the circumferential direction of the mixing-tube lateral surface in a cross-sectional plane lying perpendicularly to the longitudinal axis of the mixing tube, through which openings the hot core stream flowing through the mixing tube penetrates into the cold bypass flow flowing around the mixing-tube lateral surface. The mixing tube design according to the invention leads to substantial advantages. By the openings being provided in the mixing-tube lateral surface, lobe mixers with the large radial extent of their lobes are dispensed with. The vibration tendency is thus substantially reduced, so that the hitherto requisite struts are dispensed with. The risk of possible interference with the engine suspension thus does not arise either. In addition, the smaller radial extent has the advantage that the novel mixing tube according to the invention is also suitable for confined installations. Furthermore, the closed annular lateral surface at the downstream end of the mixing tube leads to a robust, low-vibration construction, so that disturbances on account of fluctuations in operating pressure and temperature have less effect on the mixing tube. Since supporting struts are no longer necessary for fixing the mixing tube, this omission of the supporting struts at the same time also entails a lighter construction and thus lower weight of the reaction engine. Furthermore, the simplified form of the mixing tube leads to a more cost-effective production, since the complicated deep-drawing operations required for producing the lobes are dispensed with. According to a further feature of the invention, the openings in the mixing-tube lateral surface have passage areas of elliptical shape with a major axis and a minor axis. In this case, the major axis of the elliptical passage areas runs on the mixing-tube lateral surface in the direction of flow of the hot core stream and of the cold bypass flow, and the minor axis is arranged perpendicularly thereto. Further features of the invention follow from the subclaims. A combination of the novel mixing tube according to the invention with sufficiently well-known conventional lobe mixers is possible. The replacement of existing mixers with mixers according to the invention is conceivable, since the changes of the new mixer regarding mixer efficiency (lower) and overall pressure loss (lower) act in a neutral manner with regard to the gain in thrust. The invention is described below with reference to an exemplary embodiment shown more or less schematically in the drawing. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows a sectional representation of a mixing tube of a two-circuit reaction engine in the form of a truncated cone with openings distributed over the circumference of the truncated cone, and FIG. 2 shows an enlarged representation of an opening from FIG. 1. DETAILED DESCRIPTION OF THE DRAWINGS A mixing tube designated overall by the reference numeral 10 in FIG. 1 and intended for mixing two fluid flows, initially guided separately from one another, in a two-circuit reaction engine comprises a lateral surface 12 and a longitudinal axis 14. The direction of flow of the fluid flows to be mixed, that is to say of a hot core stream 16 and of a cold bypass flow 18, is indicated by the arrows S. In this case, the mixing tube 10 is in the form of a truncated cone narrowing in the direction of flow S. The other components of a reaction engine, apart from the mixing tube 10, are not shown for reasons of clarity. At the downstream end of the mixing tube 10, a plurality of openings 20 are incorporated in the mixing-tube lateral surface 12 in the circumferential direction of the mixing-tube lateral surface 12 in a cross-sectional area lying perpendicularly to the longitudinal axis 14 of the mixing tube 10. An enlarged representation of one of the openings 20 lying at the downstream end of the mixing tube 10 is shown in FIG. 2. In this case, the openings 20 have a passage area 22 of elliptical shape with a major axis 24 and a minor axis 26. Whereas the major axis 24 of the passage areas 22 runs on the mixing-tube lateral surface 12 in the direction of flow S, the minor axis 26 is arranged perpendicularly thereto. In addition, the elliptical passage areas 22 have a hole collar 28 on the outside of the mixing-tube lateral surface 12. As FIG. 2 shows, the height of the hole collar 28 is designed in such a way that the maximum height of the hole collar 28 is located at the upstream apex 30 of the major axis 24 of the elliptical passage areas 22 and decreases from there in the direction of flow S. A region of the downstream apex 32 of the major axis 24 of the elliptical passage areas 22 is formed without a hole collar 28. It may alternatively be bent inward (relative to the mixing-tube lateral surface 12). In the present exemplary embodiment, the transition from the outside of the mixing-tube lateral surface 12 to the hole collar 28 is of concave design; other continuous configurations are also possible. The mode of operation of the device described above is as follows: Whereas the hot core stream 16 coming from the reaction engine flows through the conical mixing tube 10, the cold bypass flow 18 flows around the mixing-tube lateral surface 12. The hot core stream 16 flowing through the mixing tube 10 penetrates through the openings 20 at the downstream end of the mixing tube 10 into the cold bypass flow 18 flowing around the mixing-tube lateral surface 12. As a result of the design of the passage area 22 and of the hole collar 28, good intermixing of the two fluid flows is achieved with low pressure losses, this intermixing corresponding to the greatest possible extent to that of the known lobe mixers.

<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>Device for mixing two flows of fluid, which are initially guided separate from one another, in a two-circuit reaction engine The invention relates to a device for mixing two fluid flows, which are initially guided separately from one another, in a two-circuit reaction engine. To this end, it is known that “lobe mixers” are used in two-circuit reaction engines in order to mix the hot core stream of the reaction engine and the cold bypass flow before discharge from the reaction engine nozzle. In this case, the hot core stream of the reaction engine is guided through a “mixing tube”, whereas the cold bypass flow flows along the outside of the mixing-tube lateral surface. The mixing of the two fluid flows is forced by the special shaping of the downstream lateral surface of the mixing tube. For this purpose, that lateral surface of the mixing tube which is formed downstream has “lobes” which extend radially outward. In this case, after flow has taken place through or respectively around the downstream section of the mixing tube, these lobes direct said hot core stream into the cold bypass flow, and also direct the cold bypass flow into the hot core stream. With regard to the known prior art, reference is made, for example, to GB 2 160 265 A. A disadvantage with these known lobe mixers is in this case the fact that the lobe mixers, on account of the large radial extent of the lobes at the downstream end, tend to vibrate and in addition deformations occur due to material heating and pressure differences. It has therefore been attempted to remove these disadvantages by “struts” which support the lobe mixer on the outlet cone or the nozzle housing of the reaction engine. However, these struts constitute an additional source of weight. In addition, on account of the large radial extent of the lobes of the lobe mixer, interference may occur in the region of the engine suspension between the lobes of the lobe mixer and the engine suspension. To avoid such interference, the relevant lobes of the lobe mixer, the “pylon lobes”, are designed differently. However, this has the disadvantage that a decrease in the mixing efficiency is associated with the redesign of the “pylon lobes”. The object of the invention is to provide a remedy here by a new design of the device for mixing the hot core stream of the reaction engine with the cold bypass flow. Based on a device of the type mentioned at the beginning, this object is achieved according to the invention in that the mixing tube is designed in the form of a truncated cone narrowing in the direction of flow of core stream and bypass flow, and in that the mixing tube has openings arranged at the downstream end in the circumferential direction of the mixing-tube lateral surface in a cross-sectional plane lying perpendicularly to the longitudinal axis of the mixing tube, through which openings the hot core stream flowing through the mixing tube penetrates into the cold bypass flow flowing around the mixing-tube lateral surface. The mixing tube design according to the invention leads to substantial advantages. By the openings being provided in the mixing-tube lateral surface, lobe mixers with the large radial extent of their lobes are dispensed with. The vibration tendency is thus substantially reduced, so that the hitherto requisite struts are dispensed with. The risk of possible interference with the engine suspension thus does not arise either. In addition, the smaller radial extent has the advantage that the novel mixing tube according to the invention is also suitable for confined installations. Furthermore, the closed annular lateral surface at the downstream end of the mixing tube leads to a robust, low-vibration construction, so that disturbances on account of fluctuations in operating pressure and temperature have less effect on the mixing tube. Since supporting struts are no longer necessary for fixing the mixing tube, this omission of the supporting struts at the same time also entails a lighter construction and thus lower weight of the reaction engine. Furthermore, the simplified form of the mixing tube leads to a more cost-effective production, since the complicated deep-drawing operations required for producing the lobes are dispensed with. According to a further feature of the invention, the openings in the mixing-tube lateral surface have passage areas of elliptical shape with a major axis and a minor axis. In this case, the major axis of the elliptical passage areas runs on the mixing-tube lateral surface in the direction of flow of the hot core stream and of the cold bypass flow, and the minor axis is arranged perpendicularly thereto. Further features of the invention follow from the subclaims. A combination of the novel mixing tube according to the invention with sufficiently well-known conventional lobe mixers is possible. The replacement of existing mixers with mixers according to the invention is conceivable, since the changes of the new mixer regarding mixer efficiency (lower) and overall pressure loss (lower) act in a neutral manner with regard to the gain in thrust. The invention is described below with reference to an exemplary embodiment shown more or less schematically in the drawing.

<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>Device for mixing two flows of fluid, which are initially guided separate from one another, in a two-circuit reaction engine The invention relates to a device for mixing two fluid flows, which are initially guided separately from one another, in a two-circuit reaction engine. To this end, it is known that “lobe mixers” are used in two-circuit reaction engines in order to mix the hot core stream of the reaction engine and the cold bypass flow before discharge from the reaction engine nozzle. In this case, the hot core stream of the reaction engine is guided through a “mixing tube”, whereas the cold bypass flow flows along the outside of the mixing-tube lateral surface. The mixing of the two fluid flows is forced by the special shaping of the downstream lateral surface of the mixing tube. For this purpose, that lateral surface of the mixing tube which is formed downstream has “lobes” which extend radially outward. In this case, after flow has taken place through or respectively around the downstream section of the mixing tube, these lobes direct said hot core stream into the cold bypass flow, and also direct the cold bypass flow into the hot core stream. With regard to the known prior art, reference is made, for example, to GB 2 160 265 A. A disadvantage with these known lobe mixers is in this case the fact that the lobe mixers, on account of the large radial extent of the lobes at the downstream end, tend to vibrate and in addition deformations occur due to material heating and pressure differences. It has therefore been attempted to remove these disadvantages by “struts” which support the lobe mixer on the outlet cone or the nozzle housing of the reaction engine. However, these struts constitute an additional source of weight. In addition, on account of the large radial extent of the lobes of the lobe mixer, interference may occur in the region of the engine suspension between the lobes of the lobe mixer and the engine suspension. To avoid such interference, the relevant lobes of the lobe mixer, the “pylon lobes”, are designed differently. However, this has the disadvantage that a decrease in the mixing efficiency is associated with the redesign of the “pylon lobes”. The object of the invention is to provide a remedy here by a new design of the device for mixing the hot core stream of the reaction engine with the cold bypass flow. Based on a device of the type mentioned at the beginning, this object is achieved according to the invention in that the mixing tube is designed in the form of a truncated cone narrowing in the direction of flow of core stream and bypass flow, and in that the mixing tube has openings arranged at the downstream end in the circumferential direction of the mixing-tube lateral surface in a cross-sectional plane lying perpendicularly to the longitudinal axis of the mixing tube, through which openings the hot core stream flowing through the mixing tube penetrates into the cold bypass flow flowing around the mixing-tube lateral surface. The mixing tube design according to the invention leads to substantial advantages. By the openings being provided in the mixing-tube lateral surface, lobe mixers with the large radial extent of their lobes are dispensed with. The vibration tendency is thus substantially reduced, so that the hitherto requisite struts are dispensed with. The risk of possible interference with the engine suspension thus does not arise either. In addition, the smaller radial extent has the advantage that the novel mixing tube according to the invention is also suitable for confined installations. Furthermore, the closed annular lateral surface at the downstream end of the mixing tube leads to a robust, low-vibration construction, so that disturbances on account of fluctuations in operating pressure and temperature have less effect on the mixing tube. Since supporting struts are no longer necessary for fixing the mixing tube, this omission of the supporting struts at the same time also entails a lighter construction and thus lower weight of the reaction engine. Furthermore, the simplified form of the mixing tube leads to a more cost-effective production, since the complicated deep-drawing operations required for producing the lobes are dispensed with. According to a further feature of the invention, the openings in the mixing-tube lateral surface have passage areas of elliptical shape with a major axis and a minor axis. In this case, the major axis of the elliptical passage areas runs on the mixing-tube lateral surface in the direction of flow of the hot core stream and of the cold bypass flow, and the minor axis is arranged perpendicularly thereto. Further features of the invention follow from the subclaims. A combination of the novel mixing tube according to the invention with sufficiently well-known conventional lobe mixers is possible. The replacement of existing mixers with mixers according to the invention is conceivable, since the changes of the new mixer regarding mixer efficiency (lower) and overall pressure loss (lower) act in a neutral manner with regard to the gain in thrust. The invention is described below with reference to an exemplary embodiment shown more or less schematically in the drawing.

20040922

20071127

20050203

63696.0

RODRIGUEZ, WILLIAM H

DEVICE FOR MIXING TWO FLOWS OF FLUID WHICH ARE INITIALLY GUIDED SEPARATE FROM ONE ANOTHER IN A BYPASS JET ENGINE

UNDISCOUNTED

ACCEPTED

ACCEPTED

Wireless communication system

An RFID tag (200) and similar control/sensing unit (300) for a communications system are described. The control/sensing unit has a control element (301) having one or more states, and include an antenna (207) as well as an electrical circuit (201-206) generating a pulse control signal for controlling transmission from the antenna and varying a parameter of the pulse control signal in dependence on the state of the control element (301). Also disclosed is a receiving communication unit in the form of a base unit or system controller for such a communications system, the unit including a receiver (100) for receiving a pulsed RF signal and an electrical circuit (105-106) for detecting a parameter of the pulsed RF signal. An output circuit (107) then produces an output control signal dependent on the detected parameter of the pulsed RF signal.

1. A communication unit for a communications system, the unit including a control element having one or more states; an antenna; and an electrical circuit generating a pulse control signal for controlling transmission from the antenna and varying a parameter of the pulse control signal in dependence on the state of the control element. 2. A communication unit according to claim 1, wherein the antenna is a backscatter antenna for reflecting RF radiation impinging thereon; and the electrical circuit further includes a modulation element receiving the pulse control signal and modulating the radiation reflected by the backscatter antenna dependent on the control signal and hence the state of the control element. 3. A unit according to claim 1 or claim 2, wherein the control element comprises a manually operable switch. 4. A unit according to claim 1 or claim 2, wherein the control element includes a sensor for sensing one or more physical conditions. 5. A unit according to claim 3 or claim 4, wherein the control element has two operative positions. 6. A unit according to claim 3 or claim 4, wherein the control element has a continuously variable output. 7. A unit according to claim 4, wherein the sensor includes one or more of a movement detector, a light level detector; a gas detector; a smoke detector; a temperature detector; a sound level detector; an electromagnetic radiation detector; a humidity detector; pressure detector; and a fluid level detector. 8. A unit according to any of claims 1 to 7, wherein the electrical circuit is also able to vary the length of the repeating signal. 9. A unit according to any of claims 1 to 8, wherein the repeating signal is modulated to transmit binary data from the control unit. 10. A unit according to any of claims 1 to 8, wherein a second repeating output signal is output by the electrical circuit at the same period as the first signal and the time between the first and second signals is adjustable dependent on the state of the control element. 11. A unit according to any of claims 1 to 10, wherein the control signal comprises an output signal output through the antenna. 12. A unit according to any of claims 2 to 10, including a backscatter antenna; a modulation element for modulating the radiation reflected by the backscatter antenna; and wherein the control signal comprises an input to the modulation element. 13. A unit according to claim 1, wherein the unit comprises an RFID tag. 14. A unit according to any of claims 1 to 13, wherein the unit includes a battery for powering the unit. 15. A unit according to any of claims 1 to 13, wherein the unit includes an electromagnetic sensor adapted to receive electromagnetic radiation, and a power supply circuit for converting said radiation into electrical power for powering the unit. 16. A unit according to claim 15, wherein the electromagnetic sensor is an RF sensor adapted to receive RF radiation. 17. A unit according to claim 15, wherein the electromagnetic sensor is a light sensor adapted to receive light radiation. 18. A unit according to any of claims 1 to 13, wherein the unit includes a heat sensor adapted to receive heat, and a power supply circuit for converting the heat into electrical power for powering the unit. 19. A receiving communication unit for a communications system, the unit including a receiver for receiving a pulsed RF signal; an electrical circuit for detecting a parameter of the pulsed RF signal; and an output circuit for producing an output control signal dependent on the detected parameter of the pulsed RF signal. 20. A receiving communication unit according to claim 19, wherein the parameter is the period between pulses of the pulsed signal. 21. A receiving communication unit according to claim 19, wherein the parameter is the length of the pulses of the pulsed RF signal. 22. A receiving communication unit according to claim 19, wherein the parameter is the amplitude of the pulsed RF signal. 23. A receiving communication unit according to claim 19, wherein the parameter is the frequency of the pulsed RF signal. 24. A unit according to any of claims 19 to 23, including means for demodulating binary data also transmitted by said RF signal. 25. A unit according to any of claims 19 to 23, wherein the output circuit includes a radio transmitter for transmitting the control signal. 26. A unit according to any of claims 19 to 23, wherein the output circuit includes an infra-red transmitter for transmitting the control signal. 27. A unit according to any of claims 19 to 23, wherein the output control signal is a digital control signal. 28. A communications system including one or more communications units according to any of claims 1 to 18. 29. A communications system according to claim 28, including a base unit having transmitter comprising an RF loop antenna. 30. A communications system according to claim 28, including a base unit having transmitter comprising a discrete RF antenna. 31. A communications system according to claim 29 or claim 30, wherein said transmitter includes an electrical circuit for modulating the frequency of the transmitted RF radiation. 32. A communications system according to any of claims 29 to 31, wherein the base unit includes an RF receiver for receiving RF radiation and producing an electrical current to power the base unit. 33. A communications system according to any of claims 29 to 32, wherein said transmitter includes an electrical circuit for transmitting digital data from the base unit. 34. A communications system according to any of claims 29 to 33, and further including a receiving communication unit according to any of claims 19 to 27, said receiving communication unit communicating with an environmental control system to control at least one parameter of said environmental control system. 35. A communications system according to claim 34, wherein said parameter is one of a lighting circuit control parameter; an air conditioning circuit control parameter; a heating circuit control parameter; a ventilation circuit control parameter; a humidity circuit control parameter; an access circuit control parameter; and a security circuit control parameter. 36. A communications system having a transmitter arranged to transmit bursts of RF energy at a regular period; a communications unit having an antenna through which RF energy is received from the transmitter, storage means for storing the energy, an electrical circuit for generating output responses at a period dependent on the amount of energy stored and transmitting the output responses; and a receiving communications unit having an electrical circuit for receiving the output responses from the communications unit and for detecting the time of receipt of the output responses, determining if a change in the period of receipt of the responses occurs and, if so, generating an output. 37. A system according to claim 36, including plural communications units. 38. A system according to claim 37, wherein each communications unit includes a sensitivity switch for modifying the rate at which RF energy is stored. 39. A system according to any of claims 36 to 38, wherein the communications unit electrical circuit has means for discharging the stored energy and the output responses of the communications unit are generated when the stored energy reaches a given value, whereby the period at which the output responses of the communications unit are generated is determined by the time taken for the stored energy to reduce from its maximum value to the given value. 40. A system according to claim 39, wherein the or each communications unit includes a sensitivity switch for modifying the rate at which RF energy is stored. 41. A system according to claim 39, wherein the or each communications unit includes a sensitivity switch for modifying the rate at which RF energy is discharged. 42. A system according to any of claims 36 to 41, wherein the communications unit electrical circuit includes means for transmitting a coded output signal. 43. A system according to any of claims 36 to 42, wherein the transmitter is arranged to transmit RF energy at a relatively low frequency, the communications unit is arranged to transmit output responses at a relatively high RF frequency, and the receiving communications unit electrical circuit is arranged to detect changes in the strength of the received output responses. 44. A communication unit according to any of claims 1 to 14, wherein the antenna is embedded in or attached to a pad or mat. 45. A communication unit according to any of claims 1 to 14, wherein the antenna is embedded in or attached to an item or furniture, for example a shelf.

The present invention relates to a wireless communications system, particularly for use in building or asset security monitoring, and to the various components of such a system. Applications of a system of this type include home, building and car security as well as domestic control applications. In our earlier PCT patent application (WO-A-00/19235) we describe and claim a system for monitoring the position of one or more RFID tags, the system comprising one or more detectors incorporating means for receiving signals from the RFID tag for detecting changes in the range of an RFID tag from the detector or detectors; and control means comparing the signals received from the RFID tag at different times to detect a change in range of the RFID tag and triggering an alarm if a detected change in range exceeds a predetermined threshold. Such a system may include tags which have circuitry arranged to emit short bursts of RF energy at periodic intervals, and the or each detector including circuitry for detecting changes in the periodic interval at which energy is transmitted by the or each tag. The or each detector preferably includes circuitry for predicting the time of receipt of a burst of energy from a tag and for triggering an alarm if the time of actual receipt varies from the predicted time of receipt by more than a predetermined interval and/or if the rate of change in the periodic interval at which energy is transmitted by a tag is outside a predetermined range. Alternatively, or additionally, the detector(s) may include circuitry for analysing changes in the rate of receipt of bursts of energy from a tag and for triggering an alarm if the rate of change is more than a predetermined level. A system of this type may be utilised, for example in the home, for ensuring the security of components such as valuable equipment such as televisions, personal computers and the like, or other valuable items such as paintings, furniture and the like which may be relatively easily stolen by removal from their normal location, movement of a detector being recognised by the central controller and an appropriate alarm signal given. The equipment senses a change in distance between a transmitter- receiver and an RFID tag which can be used to initiate an alarm or some other function. Placing a controller and antenna within the vehicle or building and then fitting tags to each door can provide a very effective alarm system. Opening any door could set off the alarm. Installation is simple with none of the additional wiring that can be a major cost for manufacturers. Furthermore, a system of this type can be used for personal security in that a small portable system could easily be attached to hotel room doors and windows, and indeed to any valuable items it is desired to protect within the room. According to a first aspect of the present invention there is provided a communication unit for a communications system, the unit including a control element having one or more states; an antenna; and an electrical circuit generating a pulse control signal for controlling transmission from the antenna and varying a parameter of the pulse control signal in dependence on the state of the control element. Preferably, the antenna is a backscatter antenna for reflecting RF radiation impinging thereon, and the electrical circuit further includes a modulation element receiving the pulse control signal and modulating the radiation reflected by the backscatter antenna dependent on the control signal and hence the state of the control element. The control signal may comprises an input to the modulation element. The control element may comprise a manually operable switch or a sensor for sensing one or more physical conditions. The control element may have two or more operative positions or a continuously variable output. The sensor may include one or more of a movement detector; a light level detector; a gas detector; a smoke detector; a temperature detector; a sound level detector; an electromagnetic radiation detector; a humidity detector; pressure detector; and a fluid level detector. The electrical circuit may also be able to vary the length of the repeating signal. The repeating signal may be modulated to transmit binary data from the control unit. A second repeating output signal may be output by the electrical circuit at the same period as the first signal and the time between the first and second signals may be adjustable dependent on the state of the control element. This could be achieved by generating the first pulse by a clock oscillator circuit with a divider chain to generate a repeating signal say once per second. The second pulse could be timed from the first pulse and so the design of the tag would be much the same as before but with the charging of the storage capacitor inhibited until the first pulse has finished. Once the first pulse has finished the capacitor is allowed to charge and when it gets to a threshold it can produce the second pulse. The time delay between the two pulses would then represent the inductive field strength. The unit may comprise an RFID tag. The unit may include an electromagnetic sensor adapted to receive electromagnetic radiation, and a power supply circuit for converting said radiation into electrical power for powering the unit. According to a second aspect of the invention, there is provided a receiving communication unit for a communications system, the unit including a receiver for receiving a pulsed RF signal; an electrical circuit for detecting a parameter of the pulsed RF signal; and an output circuit for producing an output control signal dependent on the detected parameter of the pulsed RF signal. The parameter is preferably the period between pulses of the pulsed signal or the length of the pulses of the pulsed RF signal. To achieve the latter, the receiving unit may contain a radio receiver which is able to detect the radio transmissions from the tag, demodulate these and convert them back to a baseband signal. Hence the output of the radio receiver would be a pulsed signal identical to that produced by the tag. The receiving communication unit would contain a microprocessor that is able to monitor the timing of the pulsed signals it is receiving and perform an operation based on the timing of these signals. Alternatively, the parameter may the amplitude of the pulsed RF signal, in which case the demodulator would be an AM (Amplitude Modulation) demodulator which in its simplest form is a diode feeding a capacitor with a slow discharge path introduced across the capacitor. The output of this would be fed to a threshold detector and then to the microprocessor. A third aspect of the invention provides a communications system having a transmitter arranged to transmit bursts of RF energy at a regular period; a communications unit having an antenna through which RF energy is received from the transmitter, storage means for storing the energy, an electrical circuit for generating output responses at a period dependent on the amount of energy stored and transmitting the output responses; and a receiving communications unit having an electrical circuit for receiving the output responses from the communications unit and for detecting the time of receipt of the output responses, determining if a change in the period of receipt of the responses occurs and, if so, generating an output. A signal received by the receiving unit from the RFID control/sensing units will have time and amplitude characteristics that are a function of the relative positions of the receiving units and the RFID control/sensing units. The receiving unit creates a time-amplitude “picture” of the returned signal. The process is repeated and successive time-amplitude “pictures” are compared. Any variations are the result of changes in the relative positions of the receiving unit and RFID control/sensing units. The system can thus sense a change in distance between the receiving unit and two or more RFID control/sensing units which can be used to initiate an alarm or for some other purpose. The system described may operate using time ‘frames’ which considerably simplifies and hence reduces the cost of implementing a detection system. The system controller simply has to measure a time delay before response of each tag which can be implemented with relatively simple circuitry. If two tags transmit simultaneously then there will be a clash. To avoid this, the tags preferably contain a sensitivity switch that can either be manually set on the tag or automatically set by the system controller possibly during registration. The sensitivity switch can either switch in a different value of storage capacitor J, modify the charge/discharge rate to alter the delay time t2. During registration tags in a given system are individually registered to the system controller. If the tags are programmed with a code during manufacture then this allows the system controller to read and store the tag code or ID. Alternatively, the system controller may program the tags giving each subsequent tag a different code or ID. This reduces problems caused by clashes and interference from an identical system operated in the adjoining room or area as the system controller can distinguish tags in its system (which have been registered to it) from other tags. The registration process may be carried out using radio or other wireless communication between tag and system controller, or the tag may have electrical contacts on it so that the registration can occur by direct connection between tag and system controller. The system controller may have a registration slot or similar designed into the caseworks with a microswitch or other means at the bottom of the slot for confirming the presence of the tag in the correct position, such that process of pushing a tag into the slot initiates registration. Movement detection and choice of frequencies. As with the existing patent application the proposed system can detect changes of range or orientation of the tags. To reduce the effect of people and animals influencing the RF field around the tags, the frequency chosen for the transmission from system controller to tag is a relatively low frequency field currently (but not limited to) 125 KHz. Low frequency RF fields are relatively unaffected by people and animals and so the field strength at any given point in the detection zone is fairly constant despite the movement of people and animals. The frequency chosen for transmission from tag to system controller is a relatively high frequency currently (but not limited to) 868 MHz which propagates easily with small antennas and low power available in the tag. An additional advantage is that high RF frequencies are influenced by people and animals and so it is potentially possible for the system controller to detect motion of people and animals in the room by monitoring the received signal strength generated by each tag, A sudden change in received signal strength indicates that a person or animal has moved in the detection zone. Variations in signal strength from a particular tag could give approximate location information about that person or object as this indicates that the person or object has moved into the area between a tag and the system controller. Other forms of transmission from a tag or control/sensing unit back to the system controller, such as sound, light, infra-red etc. may be utilised. In WO-A-00/19235 we describe (see page 3, lines 20 et seq) how an RFID tag may be moved in a circular arc (ie without changing the distance between the transmitter-receiver and the RFID tag). This may result, depending on the orientation of the tag, in there being no change in the electromagnetic flux linking the antenna (coil) on the tag. In order to overcome this problem, and to ensure that any change in position or orientation of the tag can be detected, a number of options exist. The key to this is the recognition that in a field generated from a single coil in a base unit, there will be lines of flux that radiate out from the coil forming continuous loops. Perpendicular to the lines of flux will be lines of constant field amplitude conceptually similar to the “isobars” on a weather map. Theoretically a tag could be moved along one of these “isobars” without a change in field or flux amplitude linking with the coil in the tag. If the tag is able to sense the field in two or more directions however, then it would be extremely difficult to move the tag along an “isobar” without changing the coupling into one or more of the multiple pick-up coils. Another advantage of having two or more base unit energising coils is that if they are energised sequentially and are physically separate then the ‘isobars’ will be in different directions and then it really would be impossible to move the tag without changing the coupling in one or more of the pick up coils in the tag. In one use of a system according to the invention, the presence of an RFID tag within a chosen zone may be used to disable security monitoring of tagged items disposed in or adjacent that zone. This may be used, for example, in retail stores to allow items on display for sale to be removed from a display location by a sales assistant with a particular coded tag to be shown to a potential customer without triggering an alarm. Preferably, the items are protected by an RFID tag or similar according to the invention. Another use of a system according to the invention is in the field of car park monitoring. By disposing a communications unit according to the invention at each bay and particularly by arranging for each tag to transmit signals with different parameters, the presence or absence of a vehicle in a bay may be readily determined without the need for hard-wiring of each bay, by means of a receiving communication according to the invention. A number of examples of systems according to the present invention will now be described with reference to the accompanying drawings, in which: FIG. 1 is a block diagram of a first example of a system controller; FIG. 2 is a block diagram of an example of an RFID tag for use in a system; FIG. 3 is a timing diagram indicating the timing of various signals in the system shown in FIGS. 1 & 2; FIG. 4 is a further timing diagram indicating the timing of various signals in a system of the type shown in FIGS. 1 & 2, when multiple tags are present; FIG. 5 illustrates a system having multiple tags and which may be used, additionally, to detect movement of a person within the area covered by the system; FIG. 6 is a block diagram of an example of a control and sensing unit; FIG. 7 is a block diagram of a tag incorporating a backscatter antenna; FIG. 8 is circuit diagram of a system controller adapted to use the backscatter technique; FIG. 9 shows a modified form of tag which may be used for enabling the tag to be ‘registered’ to a given system controller on installation; FIG. 10 is a timing diagram illustrating a method of carrying out an anti-collision scheme; and FIG. 11 is a diagrammatic representation of a further embodiment which can be used to detect movement of metallic objects towards or away from a specific location. A system falling within the terms of the present invention may have control/sensing units, tags, a system controller and associated components. Various examples of these will now be described. FIG. 1 shows a system controller 100 having a power amplifier 101 which may be a Class A, B, C or D amplifier and additionally could be an amplifier where the supply voltage is varied in order to control the output power and feeds a resonating capacitor 102 which is used to drive an inductive transmitter coil antenna 103 in resonance (to generate sufficient current). The inductive transmitter coil antenna 103 consists of an inductive winding which may be air-cored or may contain a ferrite or other high permeability material core. However, the antenna could be any other form of antenna such as dipole, monopole, slot, patch, room-loop etc. The system controller 100 also has a receive antenna 104 which is used to receive radio frequency (RF) transmissions from plural tags 200 (see FIG. 2) and which, in some forms of the system, could be the same antenna as the antenna 103. However, in one form of the system the antenna 104 could be replaced by an infra-red or light detection device. A controller radio receiver 105 receives the tag transmissions from the antenna 104 and converts the transmissions from RF into baseband signals and passes them to an optional decoder 106. The resulting baseband signal may contain codes transmitted by the tag(s) and the decoder 106 translates the codes into a form that can be used by a microprocessor 107. The microprocessor 107 processes the timing of received codes from the tags and in some implementations may perform the decoding of the tag transmission and/or clock recovery. It also controls a user interface 108 which may be a display, LED's, or keyboard and interfacing to other equipment. The system is capable of communicating with a number of RFID tags, the component parts of which are shown in FIG. 2. Each tag 200 has an inductive pick-up coil or ferrite antenna 201 tuned to be resonant (at, for example, 125 KHz), and a rectifier 202, (which may be half-wave but could be full-wave or a diode charge-pump or an active rectifier circuit) and which receives energy from the antenna 201. The rectifier 202 may contain a biassing circuit to overcome the forward voltage drop of its diode or diodes. A storage capacitor 203 stores the resulting energy which is used to power the tag 200 if it is passive, and/or used to trigger a detector 204 if it is active (containing a battery), or hybrid where some of the tag power is provided by the battery and some is provided by the transmissions from the system controller. The detector 204 triggers other circuitry dependent on the voltage/current experienced by the storage capacitor 203. In the this example, the detector 204 is capable of decoding/demodulating data transmitted by the system controller. A code generator 205 stores a code either stored at manufacture or when later programmed into the tag 200 during registration of the tag to a given system controller 100; The code generator can reproduce this code when it is enabled by the detector 204 and generates a modulating signal to an. RF transmitter 206. The code stored, could in some instances, be a rolling/cyclic code to improve detection and/or security of the system. The transmitter 206 is an RF transmitter in this example, but could be an ultra-sound, infra-red, or light transmitter circuit transmitter. It responds to modulation from the code generator 205 to generate amplitude modulation (AM), ON/OFF modulation (OOK), amplitude-shift keying (ASK), frequency modulation (FM), frequency shift keying (FSK), phase modulation or other form of standard modulation scheme. Its output is passed to a transmission device or antenna 207 which could be an RF antenna, infra-red emitter, ultra-sound emitter or other propagating wave generator. In one form of the system the device 207 is an RF antenna used to produce ‘RF backscatter’ of an RF transmission from the system controller as described above. The tag 200 may also (in some implementations) have a battery, solar cell, or storage capacitor 208. If the tag is ‘active’ it is powered by this device, but in other implementations of the system, the tag is powered by the transmissions from the system controller 100 and is a ‘passive tag’. A third variant is a hybrid tag. The tag 200 has a clock generator 209 which may be a crystal oscillator circuit or may be another form of electronic oscillator circuit or alternatively the clock generator may use an aspect of the controller transmissions to lock-on or regenerate a clock signal produced by the system controller. To prevent excessive voltages appearing across the storage capacitor 203 a shunt regulator device 210 is provided. In operation, (see FIG. 3) a tag 200 receives energy from the system controller 100 (in the form of a pulse shown in waveform 1 of FIG. 3) and uses this to charge the storage capacitor 203 using the rectifier 202 to convert from AC to DC. This is the tag charging phase and lasts for a time t1 during which time the storage capacitor 203 is charged (see waveform 2 in FIG. 3). The RF transmission from the base unit/system controller 100 then stops (or reduces in amplitude in a modification not shown) and the voltage on the tag storage capacitor 203 leaks away either naturally or via a dedicated discharge device on the tag 200. Once the capacitor voltage reaches a threshold Vt (see waveform 2 in FIG. 3) the detector 204 triggers and enables the code generator 205 and transmitter 206. The code generator 205 and transmitter 206 then produce (see waveform 3 in FIG. 3) a burst of RF or other radiation (possibly backscatter) that contains (in this example) a code—as shown by the waveform 4 of FIG. 3, which is an enlarged and expanded view of the waveform 3. The time between the system controller 100 switching off its transmission and the tag 200 responding back is shown as t2 (in waveform 4 of FIG. 3). The length of this time t2 gives an indication of the tag range (subject to orientation and polar co-ordinates with respect to the controller transmitter coil). If the time t2 for a particular tag changes and the field strength in the interrogation zone is reasonably constant from one burst or frame to another, the system controller is able to detect that the tag has moved with respect to the controller transmitter. In a modification, the power source 208 could be say a Peltier charge pump device. If the Peltier device were subjected to a thermal gradient it would generate a small amount of current which could potentially power the electronics of the tag without the need for a battery (or could charge a battery if fitted). Alternatively, the powering device could also be a solar cell on its own or a solar cell that charges a high value capacitor or battery. If a battery is fitted it could be a primary, non-rechargeable cell or a secondary, rechargeable cell. The interrogation zone may include a number of tags 200.1-200.5 as illustrated in FIGS. 4 & 5. In this case the response time of each tag 200 can be identified. If each tag contains a unique code then the movement of a particular tag can be detected. In one form of the system the tags do not have an ID and the system controller can still detect if one of the tags has moved by looking at successive time frames or pictures and detecting a change in timing of one of the responses. FIG. 4 illustrates, in waveform 1, an energising pulse from the system controller 100 and waveform 2 shows the charging of the storage capacitors in three tags 200.1, 200.2 & 200.3, the charging rate for each of which is different depending on the tags' positions and orientation which affect the electromagnetic field at each tag. As a result, each of the tag capacitors is charged to a different voltage as shown and the time each takes to decay to the voltage Vt is also different therefore as shown in waveform 3. The system controller 100 transmits another burst of RF energy again after a time T (see waveform 1 in FIG. 4) at which point the process repeats. The system controller 100 may vary the power of the transmission burst, the frequency, or the repetition interval T in order to improve the detection algorithms implemented in the microprocessor 107 (or provide some other performance benefit). The charging/discharging waveforms are shown as linear for simplicity, but these may be exponential or other. Movement detection is also possible using systems according to the invention and this is also illustrated in FIG. 5. To reduce the effect of people and animals influencing the RF field around the tags and supplying energy to the tags, the frequency chosen for the transmission from system controller to tag is preferably a relatively low frequency field currently (but not limited to) 125 KHz. Low frequency RF fields are relatively unaffected by people and animals and so the field strength at any given point in the detection zone is fairly constant despite the movement of people and animals. The frequency chosen for transmission from tag to system controller is a relatively high frequency currently (but not limited to) 868 MHz which propagates easily with small antennas and low power available in the tag. An additional advantage is that high RF frequencies are influenced by people and animals and so it is potentially possible for the system controller to detect motion of people and animals in the room by monitoring the received signal strength generated by each tag. A sudden change in received signal strength indicates that a person or animal has moved in the detection zone. Variations in signal strength from a particular tag could give approximate location information about that person or object as this indicates that the person or object has moved into the area between a tag and the system controller. As shown in FIG. 5, the RF signal from tag 200.4 is attenuated by a person P standing between tag 200.4 and the system controller 100. This attenuates the RF transmission, reducing the received signal strength at the system controller 100 and gives approximate location information for the person. In a security system, this proposed technique could remove the need for passive infra-red (PIR) (or other types of motion detectors) in the room in addition to the present system. The system is also capable of being used for home automation, environmental control etc. and a control/sensing unit 300 for such a purpose is illustrated in FIG. 6. The control/sensing unit 300 has components substantially the same as the tag 200 illustrated above in FIG. 2, but additionally includes a desired sensor 301 (eg. a light, temperature, air flow, pressure, humidity, radiation, sound or other ambient condition sensor or a simple on-off or variable position switch). In this case all the control/sensing units 300 are charged to the same nominal voltage, then the system controller transmission ceases. The sensor (or switch) 301 then modifies the discharge rate or trip threshold Vt in order to modify the delay time t2. FIG. 7 illustrates a tag utilising a backscatter communication technique. In the Figure is shown a tag similar to that of FIG. 2, but includes a frequency modulator or divider 211 in place of the transmitter 206 and also a backscatter modulation transistor 212 and a backscatter antenna 213 in the form (as shown) of a dipole antenna. As described above, a short burst, or ‘chirp’, of RF energy is produced at periodic intervals and when the voltage on the capacitor 203 reaches a preset threshold, after a time dependent on the RF field, the detector 204 senses this and enables the frequency modulator 211 which divides the inductive input frequency by two (or by some other constant) and produces an output that drives the backscatter modulation transistor 212. When the voltage on the capacitor 3 falls to a lower threshold the detector 204 disables the frequency divider 211, thus disabling the output to the backscatter modulation transistor 212. The process then repeats. The result is that the backscatter transistor 212 is driven with bursts of modulation at 62.5 kHz every time the tag “chirps”. Of course, the same principle can be used with a control/sensing unit 300. The inductive energising system 101-103 of the system controller shown in FIG. 8 operates in exactly the same as that of the system controller described previously. The backscatter receiver operates as follows: An RF source 109 generates an unmodulated RF carrier. Some of this RF signal is fed to an RF buffer amplifier 110 and some of the signal is fed to the receiver circuit 105. The RF buffer amplifier 110 amplifies and buffers the RF signal and then feeds this to a directional coupler 111 which allows the RF power to be passed to the antenna II. This unmodulated RF carrier is emitted by the antenna 104 as a continuous wave RF signal which then propagates into the area around the system controller 100. The tag's backscatter modulating antenna 213 modulates this continuous wave signal in coded or uncoded bursts when it transmits. The bursts of modulation at the tag 200 generate modulation sidebands caused by the reflected energy from the tag which can be received by the antenna 104. This received RF power is channelled by the directional coupler 111 into the receiver 105. The antenna 104 thus operates as a transmit and receive antenna simultaneously. The receiver 105 takes the received RF signal containing the modulation sidebands and mixes this with the raw unmodulated RF carrier generated by the RF source 109. The mixing process (a well known RF technique) translates the RF signal containing the sidebands to a low-frequency baseband signal containing the tag data transmissions in modulated form. This signal is fed to a demodulator/decoder 106 which outputs the unmodulated tag data. This data is fed to the microprocessor circuit 107 which performs all the decoding algorithms needed to process the tag transmissions. The microprocessor circuit also controls the user interface 108 which is used for configuring the system, displaying alarm conditions and communicating alarm conditions to other equipment. As the chirp rate of each control/sensing unit 300 in a system is dependent upon the incident electromagnetic field, control/sensing units at different distances will chirp at different rates and they can therefore be differentiated from one another. The circuitry of the control/sensing units 300 and the tags 200 may also be configured to allow changes to be made to the length and shape of the chirp waveform and also allow changes to be made to the nature of the variation of the output signal. The system may also include a process for registration of tags 200 (and/or control/sensing units 300) on installation. During registration the tags in a given system are individually registered to the system controller. If the tags or control/sensing units are programmed with a code during manufacture then this allows the system controller to read and store the tag code or control/sensing unit ID. Alternatively, the system controller may program the tags giving each subsequent tag a different code or ID. This reduces problems caused by clashes and interference from an identical system operated in the adjoining room or area as the system controller can distinguish tags in its system (which have been registered to it) from other tags. The registration process may be carried out using radio or other wireless communication between tag and system controller, or the tag may have electrical contacts on it so that the registration can occur by direct connection between the tag and the system controller. Additionally, the system controller may have a registration slot designed into the caseworks with a microswitch at the bottom of the slot such that process of pushing a tag into the slot initiates registration. One method by which registration can be carried out is illustrated by reference to FIG. 9, which shows a modified tag 200 which has an electronic memory 214. Registration is started, for example, by a tag or control/sensing unit entering the operating zone of a system controller, by operating a switch on the tag or control/sensing unit or by slotting the tag into a ‘registration slot’ on the system controller. Once the registration process has started, the system controller can read the tag ID (if it has one programmed at manufacture) or program a unique ID onto the tag if it is not pre-programmed. The ID code is stored on the tag using a suitable form of electronic memory 214, eg an electrically erasable programmable read only memory (EEPROM). The ID code stored in memory is used by the code generator 205 to transmit a modulation sequence using the transmitter 206 and antenna 207. When the tags have been mounted to the items to be protected there is a finite probability that the delay time t2 happens to be the same as another tag. In this instance the system controller will receive corrupted data transmissions from two or more tags whose data bursts ‘collide’. The system controller 100 will indicate an error to the user who will take the last placed tag back to the system controller to be re-registered. This time during registration the system controller will store a different discharge constant on the memory 214 which together with a programmable discharge device 215 (for example in the form of a resistor network or current sink) will ensure a different discharge slope for that tag and so avoid collisions. Alternatively, the constant stored in the memory 214 will influence the voltage threshold VT in order to modify the response time and avoid collision. The definition of the threshold or the discharge rate could also be controlled directly by the tag ID to reduce data storage on the tag. Other methods of modifying the discharge rate or threshold include having a mechanical switch on the tag or tear-off strip to modify the capacitance J by the user and so modify the response time of the tag. Again referring to FIG. 9, the electrical circuit may also be able to vary the length of the repeating signal, which length could be used to convey information about the identity of the tag or to convey information about the field strength back to the system controller. The method of doing this would be modify the decay rate of the storage capacitor 203. This can be controlled by the discharge device 215. If one were to modify the discharge rate this would have the effect of varying the pulse width when the tag ‘chirps’. An alternative scheme to avoid data collisions following registration uses a variation of the system already described but this time the tag is used to measure the delay time. The tag has a counter on board which is used to measure the time delay between the tag being energised and the capacitor voltage reaching a preset threshold. The count value is latched into a register on the tag. Once 125 KHz transmission burst from the system controller ceases, the tag transmits back to the system controller a packet of data containing the tag ID code and count value. In order to avoid collisions, the tag transmissions are allocated to time slots which are synchronised with the controller bursts. During registration, each tag is allocated a different ID code and time slot for transmission back to the system controller so even if all the tags have the same delay time they can transmit back to the system controller without collisions. In detail and with reference to FIG. 10, the tag itself measures the delay time t1, which is the time delay between the capacitor voltage on capacitor 203 charging between two voltage thresholds V1 and V2. The tag's on-board oscillator circuit 209 can be used in conjunction with a counter circuit to measure the time t1. The tag latches this count value into a register on the tag. During the registration process with the system controller, the system controller allocates an ID code to the tag which is stored on the tag in a memory element such as an EEPROM. In addition to allocating an ID code to the tag during registration, the system controller also allocates the tag a unique “time-slot” for it to respond back to the system controller as illustrated in the diagram below (as time slots 1-16). In the diagram the tag has been allocated to timeslot 6 and this is also stored in the on-board memory of the tag. An advantage of this proposed system is that each tag is allocated to a unique time-slot and the maximum number of tags is purely limited by the total number of timeslots available. If a new tag is registered the system controller simply allocates it the next consecutive time slot to respond in. Each data packet sent back to the system controller contains the ID code and the time measurement t1 (which represents the field strength) along with formatting data and error checking. FIG. 11 illustrates how the same principle can be applied to detecting movement of metallic articles (or articles which have a metallic component or attachment). The presence of metal in the electric field around a tag produces a different tag response (chirp rate) to that produced when no metal is present and this operational feature can be used, in much the same way as described with reference to FIG. 5 (for detecting movement) to provide an alarm function. FIG. 11 shows a pad or mat 400 which incorporates electronics 401 identical to the electronics of a tag 100 as described above (a pad-tag), but with an extended inductive loop pick-up or antenna 402. Metallic articles 403 are shown adjacent the mat. Pad-tags such as this could be used in the home or retail environment and a modified version could be incorporated into a supermarket shelf or the like. A field modifying component in the form, say, of a small coil or loop tuned to the energising frequency (currently 125 KHz), a patch of foil, a piece of ferrite, or some other material that influences the RF field can then be attached to articles which it is desired to monitor. As long as the material influences the field strength in some way it should be possible to detect an item being placed on or removed from the pad-tag. The tag-pad is identical electrically to the other variants of tags already. described. However in this instance the tag is kept stationary with respect to the energising coil 103 of the system controller 100. The system controller monitors the pulsing signal in any of the methods described previously and so is able to detect that the item to be protected from theft has moved.

20041015

20080805

20050310

64713.0

NGUYEN, PHUNG

WIRELESS COMMUNICATION SYSTEM

SMALL

ACCEPTED

ACCEPTED

Formation of self-organized stacked islands for self-aligned contacts of low dimensional structures

Method for making a semiconductor structure is proposed. It comprises the steps: -providing a base layer (10) having a first lattice constant, -forming buried islands on the base layer (10) having a second lattice constant that is smaller or larger than the first lattice constant, -at least partially covering the base layer (10) and the buried islands with a cover layer (14), whereby the cover layer (14) has a locally increased or reduced lattice constant in areas above the buried islands, -growing small islands (15) on the areas of the cover layer (14) with locally increased or reduced lattice constant, -depositing a thin layer (16) at least partially covering the cover layer (14) and the small islands (15), -at least partially removing the small islands (15) to provide for an opening (17) being positioned exactly above the buried islands.

1. Method for making a semiconductor structure, comprising the steps: providing a base layer comprising a first material having a first lattice constant, forming buried islands on the base layer comprising a second material having a second lattice constant that is smaller or larger than the first lattice constant, at least partially covering the base layer and the buried islands with a cover layer comprising a third material, whereby the cover layer has a locally increased or reduced lattice constant in areas above the buried islands, growing small islands comprising a fourth material on the areas of the cover layer with locally increased or reduced lattice constant, depositing a thin layer at least partially covering the cover layer and the small islands, at least partially removing the small islands to provide for an opening being positioned exactly above the buried islands. 2. The method of claim 1, whereby the first material and the third material are the same material, preferably silicon. 3. The method of claim 1, whereby the second material and the fourth material are the same material, preferably germanium or a silicon-germanium composition. 4. The method of claim 1, whereby the thin layer comprises a dielectricum. 5. The method of claim 1, whereby the small islands (15) are removed by a selective etch step. 6. The method of one of the claims 1, whereby the small islands are removed by a lift-off process 7. The method of claim 1, comprising the step: depositing gate materials in order to form a gate electrode being laterally aligned relative to the buried islands. 8. The method of claim 1, wherein the buried islands comprise a few monolayers. 9. Semiconductor device being made using the process in accordance with claim 1. 10. Semiconductor device according to claim 9, whereby the device is a n-type transistor or a p-type transistor, preferably a n-type field-effect transistor or a p-type field-effect transistor. 11. Semiconductor device according to claim 9, whereby the device is a CMOS. 12. The method of claim 2, whereby the second material and the fourth material are the same material, preferably germanium or a silicon-germanium composition. 13. The method of claim 3, whereby the thin layer comprises a dielectricum. 14. The method of claim 3, whereby the small islands are removed by a selective etch step. 15. The method of one of the claim 3, whereby the small islands are removed by a lift-off process. 16. The method of claim 3, comprising the step: depositing gate materials n order to form a gate electrode being laterally aligned relative to the buried islands. 17. The method of claim 3, wherein the buried islands comprise a few monolayers. 18. Semiconductor device being made using the process in accordance with claim 2. 19. Semiconductor device being made using the process in accordance with claim 3. 20. Semiconductor device according to claim 10, whereby the device is a CMOS.

The present invention concerns self-organized stacked islands, methods for making self-organized stacked islands, and devices based thereon. The invention is well suited for forming self-aligned contacts of low dimensional structures. BACKGROUND OF THE INVENTION More and more transistors are being integrated in integrated circuits (ICs) allowing to realize devices that satisfy the demand for powerful and flexible applications. The next generation of ICs is going to comprise transistors having a gate length (L) and a gate width (W) of 50 nm and below. In addition to the ongoing miniaturization of the integrated active—known as scaling—and passive elements, new materials and material compositions are being employed in order to increase the processing speed of the ICs and to Improve performance. A typical example is the deployment of Silicon-Germanium (SiGe) on Silicon. One concept that was recently announced by IBM is based on strained silicon layers in relaxed SiGe layers. Called strained silicon, this concept stretches the materials, speeding the flow of electrons through transistors to increase the performance and decrease the power consumption in ICs. Fabrication of such devices is difficult. First, the growth of the relaxed buffer layer is, due to the required thickness in the range of a few microns, time consuming. This growth process may generate high defect densities and unfavorably low thermal conductance. Second, the high-quality oxide formation requires elevated temperatures, which in turn cause undesirable plastic strain relaxation and dislocation propagation into the active channel. Furthermore, the integration of p-type and n-type transistors on one common substrate is difficult. A concept that avoids certain disadvantages of the strained silicon approach is described by O. G. Schmidt and K. Eberl in the paper ,,Self-Assembled Ge/Si Dots for Faster Field Effect Transistors,, Max-Planck-Institut fur Festkbrperforschung, Stuttgart, Germany. The researchers propose to employ so-called buried islands. Nanostructured Ge-dots on silicon can serve as buried islands, for example. When the Ge-dots are grown in the Stranski-Krastanow mode with 3-5 monolayers of Ge, there is a strong misfit induced strain around such Ge-dots in the silicon. The position of the Ge-dots can be influenced by pre-structuring the silicon substrate, n-type and p-type transistors are described that have an increased charge flow. A yet unsolved problem is the alignment of the gate electrode with respect to a buried island. For a transistor having a gate length and gate width of less than 50 nm, the overlay accuracy has to be in the range of 20 nm or below. Certain aspects of the work reported in the paper by O. G. Schmidt and K. Eberl are also covered by the German patent application DE 100 25 264. This patent application is an earlier patent document that was published after the filing date of the present application. It is an object of the present invention to provide a method for making improved active devices, such a n-type or p-type transistors. It is an object of the present invention to provide improved active devices, such as n-type or p-type transistors. It is an object of the present invention to provide a method for contacting small transistors or other devices and to provide devices based on this method. SUMMARY OF THE PRESENT INVENTION The present invention relies of a self assembly or self formation of islands above pre-fabricated buried islands. Lattice misfits introduced by the pre-fabricated buried islands are advantageously used for the formation of islands being stacked vertically above the buried ones. When growing a suitable layer, small islands nucleate exactly on top of the pre-fabricated buried islands. This nucleation is enforced by the misfits introduced by the pre-fabricated buried islands. According to the present invention, a method for making a semiconductor structure is proposed. It comprises the steps: providing a base layer having a first lattice constant, forming first islands on the base layer having a second lattice constant that is smaller or larger than the first lattice constant, burying the first islands (for sake of simplicity herein called buried islands) at least partially covering the base layer and the buried islands with a cover layer, whereby the cover layer has a locally increased or reduced lattice constant in areas above the buried islands, growing second islands (for sake of simplicity herein called small islands) on the areas of the cover layer with locally increased or reduced lattice constant, depositing a thin layer at least partially covering the cover layer and the small islands, at least partially removing the small islands to provide for an opening being positioned exactly above the buried islands. Various advantageous methods are claimed in the dependent claims 2 through 8. According to the present invention, a semiconductor device is proposed that is being made using the process in accordance with one of the claims 1 through 8. It is an advantage of the invention presented herein, that the obstacles and disadvantages of known approaches can be circumvented or even avoided. BRIEF DESCRIPTION OF THE DRAWINGS For a more complete description of the present invention and for further objects and advantages thereof, reference is made to the following description, taken in conjunction with the accompanying drawings, in which: FIG. 1A-1H is a sequence of schematic cross-sections used to describe certain steps of a method for making a semiconductor device, according to the present invention. FIG. 2 is a schematic cross-section used to describe an intermediate step of another method, according to the present invention. FIG. 3A-3B is a sequence of two schematic cross-sections used to describe the steps of oxidizing the silicon surface and germanium islands. DETAILED DESCRIPTION The present invention takes advantage of the tendency for atoms inside compounds to align with one another. When silicon, for example, is deposited on top of a substrate with atoms spaced farther apart, the silicon atoms stretch to line up with the atoms underneath, stretching or straining the silicon. In the strained silicon, for example, the electrons experience less resistance and flow up to 70 percent faster. This effect can be used to realize ICs that are up to 35 percent faster without even having to shrink the size of the individual transistors. The silicon has slightly smaller spaces between the atoms than germanium's crystalline lattice. Germanium forms islands on a silicon surface due to this lattice mismatch between silicon and germanium. In the germanium islands the lattice is released towards the apex of the island. A subsequent layer of silicon grown on top of the islands is strained above the islands, since the germanium atoms tug at their silicon neighbors trying to get them to line up with the same spacing. This leads to stress or strain, depending on the combination and/or arrangement of layers. According to the present invention, a substrate or base layer can be pre-structured or pre-patterned by forming buried islands. A method for making a semiconductor structure, in accordance with the present invention, is described in connection with FIGS. 1A-1H. In a first step, a base layer or substrate 10 is provided. This base layer or substrate 10 comprises a material, e.g. silicon, having a first lattice constant. A 4″ silicon wafer (001 oriented) can be used as substrate, for example. In a next step, this base layer or substrate 10 is structured in order to form nucleation grooves or trenches 11. The position, shape and size of the grooves or trenches 11 can be defined by a lithographic process followed by an etch step. Well suited is a dry-etch step. In the present example, the grooves 11 are formed that have a depth between 5 nm and 10 nm. In a subsequent step, a first layer 12 is formed. This layer may comprise silicon, for example. On top of the first layer 12, a thin layer 13 is grown. This layer has to have a lattice constant that is different than the lattice constant of the layer 12. Well suited is a germanium layer formed on silicon. In regions above the nucleation grooves 11, the germanium grows more rapidly, thus resulting in a germanium layer 13 where the thickness is slightly increased above the nucleation grooves 11. The size of these so-called buried islands can be influenced by controlling the concentration of the germanium during the growth process. In a subsequent step, the germanium layer 13 is at least partially covered by a cover layer 14 comprising a third material, such as silicon, for example. Due to the fact that there are buried germanium islands underneath the cover layer 14 which show a lattice mismatch with respect to silicon, strain fields exist around the buried islands. In other words, the cover layer 14 has a locally increased or reduced lattice constant in areas above the buried islands. Now, small islands 15 are formed by growing a fourth material, e.g., germanium, on top of the cover layer 14. The size of these so-called small islands 15 can be influenced by controlling the concentration of the germanium during this growth process. The small islands 15 can be smaller, larger or equal in lateral size as the buried islands underneath. Due to the fact that the fourth material tends to grow where there is a strain field on the cover layer 14, the small islands 15 are automatically aligned with respect to the buried islands. In other words, the small islands 15 are stacked on top of the buried islands. In order to be able to form a device, such as a transistor or the like, the small islands 15 are removed to provide for openings 17 being positioned exactly above the buried islands. In the FIG. 1E through 1H, exemplary steps are shown that allow to provide for the openings 17. As Indicated in FIG. 1E, a thin layer 16 (e.g., SiNx or any other material is suited that is not selectively etched against the material of the small islands), is deposited. If this deposition is carried out under a certain angle, the thin layer 16 shows an uneven distribution close to the small islands 15 due to the so-called shadowing effect. In a subsequent step, the small islands 15 can be removed using an appropriate etchant (lift-off process). Preferably, a selective etchant is employed that mainly attacks the small germanium islands 15 rather than the thin layer 16 and the cover layer 14. In the openings 17, the upper surface of the cover layer 14 is exposed. The different rates on the side walls on the small islands may be sufficient to reach a lift-off process. The process can be continued by depositing a thin dielectric layer 18 (e.g., a high-k material or an HT-CVD oxide serving as gate dielectricum) and a thicker layer 19 (e.g., polysilicon), as shown in FIG. 1G. Using photolithographic steps, the layers 18 and 19 can be structured according to the current needs. As shown in FIG. 1H, the layers 18 and 19 can be structured so that a gate dielectricum 21 and a gate electrode 20 is provided above the buried islands. The gate dielectricum 21 and the gate electrode 20 are automatically aligned with respect to the buried islands. However, for the proposed transistor (DotFET), it is best to deposit an insulating layer 18 (e.g., SiNx, SiO2, or CaF2) or a layer 18 comprising a high dielectric constant (k) material, such as TiO2, HfOx, Al2O3 etc. This can be easily seen in FIG. 1H, where the layer 18 restricts the gate area and relaxing therefor the overlay accuracy of the gate contact considerably. Note that in connection with FIG. 1A-1H a process Is described that begins with a structured substrate or base layer 10. The structures on the substrate or base layer 10 are used to define the position of the buried islands. This approach allows the devices to be formed to be precisely positioned with respect to other devices on a chip, for example. According to another embodiment of the present invention, an unstructured base layer or substrate is employed and randomly buried islands are formed. The position of these randomly distributed buried islands Is unknown since one or more layer(s) cover the buried islands. When forming the small islands, these small islands automatically grow in regions where there is a compressive or tensile strain. Due to this, one can form randomly distributed devices. This approach Is suited for making optic or electro-optic devices, for example. The manufacturing is much simpler and less costly. Instead of depositing a thin layer 16, one may oxidize the surface of a silicon layer 43 and the small Ge islands 44, as schematically depicted in FIGS. 3A and 3B. In the embodiment of FIG. 3A and 3B, there is a burried island 45 on a silicon layer 42. After the oxidization step, the surface of the silicon layer 43 comprises an oxide layer 47 and the Ge island 44 is covered by an oxide layer. Depending on the duration of the oxidization step, the Ge islands 44 might be completely transformed into an oxide 46. After the oxidization, the Ge island 44 can be selectively etched. In principle, all materials can be deposited as a thin layer on an island, which show a different chemical reaction with silicon and germanium. Examples are materials that form silicides. Preferably, the size of the buried island is similar to or larger than the gate length of the transistor to be formed. Lateral sizes of buried islands between 0.01 microns and 0.5 microns are feasible. This lateral size is perfectly suited for the desired gate lengths in transistors. Each of the two structures shown in FIG. 1H can be used to form a transistor (e.g., a Dot field-effect transistor also called DotFET), for example. Standard CMOS processes can be used for this purpose, as outlined in the following sections. Implant regions can be formed in a subsequent step. When forming transistors, n+ and/or p+ implant regions can be formed on the left hand side and on the right hands side of the gate electrode 10, for example. After the formation of the implant regions, a side passivation layer can be formed at the gate electrode 20 and the necessary metallization can be provided by a sputter process, for example. According to another embodiment, the buried islands comprise an alternating stack of germanium layers 32, 34, 36, 38, and 40 (each a few monolayers thick), and silicon layers 31, 33, 35, 37 and 39, as depicted in FIG. 2. On top of this stack of layers, there is a cover layer 41, e.g. comprising silicon. The small islands, according to the process described in connection with FIGS. 1D-1E can be formed on top of the cover layer 41. Devices can be realized by process steps similar to the ones described in connection with FIGS. 1E-1H. According to yet another embodiment of the present invention, the pre-fabricated substrate comprises clusters of several buried islands. These islands are formed so that the strain field of each individual island overlaps with the strain fields of the other islands. I.e., in a layer above, the individual strain fields can no longer be resolved. According to the present invention, one can form an island on top of the cluster. This island is well aligned with the cluster underneath. The cluster of buried islands produce a stronger strain than a single buried island. It is an advantage of the technology presented herein that it can be easily combined with current and future standard semiconductor processes, such as complementary metal-oxide-semiconductor (CMOS) processes. The invention allows a precise alignment of a gate contact with respect to a buried island formed in or on a substrate, wherein there exists tensile stress or strain in the substrate close to the island. The expression “island” is in the present context used as a synonym for quantum dots, buried nanocrystals, Ge-island in Si-substrate (also called Ge/Si dots), aggregation of islands, and so forth. The islands as used in connection with the present invention typically have a size of a few nanometers. The strain field introduced by the buried islands extends far into the matrix of the surrounding substrate and/or the layer(s) above. Preferably, the islands are smaller than the buried islands. The inventive method is advantageous, since it allows to position a small island exactly above the middle of the buried island. This allows to form a gate structure that itself is exactly aligned above the middle of the buried island. This is advantageous, since the strain field is the strongest in the region just above the middle (apex) of a buried island. It is to be noted that the present invention is not limited to germanium and silicon. The same principle applies to III-V semiconductors such as GaAs/GaAIAs, GaInN/GaN/GaAIN/GaInAsN or InP/InGaAs and related compositions, II/VI semiconductors, and IV/VI semiconductors. Due to the present invention the mobility can be enhanced and thus the speed of devices improved. The inventive concept is well suited for use In transistors, sensors, spectroscopy, quantum computers, and other devices/systems. Various methods can be used for the formation of the different layers. Well suited are molecular beam epitaxy (MBE), chemical vapor deposition (CVD), or ultra-high vacuum-chemical vapor deposition (UHV-CVD).

<SOH> BACKGROUND OF THE INVENTION <EOH>More and more transistors are being integrated in integrated circuits (ICs) allowing to realize devices that satisfy the demand for powerful and flexible applications. The next generation of ICs is going to comprise transistors having a gate length (L) and a gate width (W) of 50 nm and below. In addition to the ongoing miniaturization of the integrated active—known as scaling—and passive elements, new materials and material compositions are being employed in order to increase the processing speed of the ICs and to Improve performance. A typical example is the deployment of Silicon-Germanium (SiGe) on Silicon. One concept that was recently announced by IBM is based on strained silicon layers in relaxed SiGe layers. Called strained silicon, this concept stretches the materials, speeding the flow of electrons through transistors to increase the performance and decrease the power consumption in ICs. Fabrication of such devices is difficult. First, the growth of the relaxed buffer layer is, due to the required thickness in the range of a few microns, time consuming. This growth process may generate high defect densities and unfavorably low thermal conductance. Second, the high-quality oxide formation requires elevated temperatures, which in turn cause undesirable plastic strain relaxation and dislocation propagation into the active channel. Furthermore, the integration of p-type and n-type transistors on one common substrate is difficult. A concept that avoids certain disadvantages of the strained silicon approach is described by O. G. Schmidt and K. Eberl in the paper ,,Self-Assembled Ge/Si Dots for Faster Field Effect Transistors,, Max-Planck-Institut fur Festkbrperforschung, Stuttgart, Germany. The researchers propose to employ so-called buried islands. Nanostructured Ge-dots on silicon can serve as buried islands, for example. When the Ge-dots are grown in the Stranski-Krastanow mode with 3-5 monolayers of Ge, there is a strong misfit induced strain around such Ge-dots in the silicon. The position of the Ge-dots can be influenced by pre-structuring the silicon substrate, n-type and p-type transistors are described that have an increased charge flow. A yet unsolved problem is the alignment of the gate electrode with respect to a buried island. For a transistor having a gate length and gate width of less than 50 nm, the overlay accuracy has to be in the range of 20 nm or below. Certain aspects of the work reported in the paper by O. G. Schmidt and K. Eberl are also covered by the German patent application DE 100 25 264. This patent application is an earlier patent document that was published after the filing date of the present application. It is an object of the present invention to provide a method for making improved active devices, such a n-type or p-type transistors. It is an object of the present invention to provide improved active devices, such as n-type or p-type transistors. It is an object of the present invention to provide a method for contacting small transistors or other devices and to provide devices based on this method.

<SOH> SUMMARY OF THE PRESENT INVENTION <EOH>The present invention relies of a self assembly or self formation of islands above pre-fabricated buried islands. Lattice misfits introduced by the pre-fabricated buried islands are advantageously used for the formation of islands being stacked vertically above the buried ones. When growing a suitable layer, small islands nucleate exactly on top of the pre-fabricated buried islands. This nucleation is enforced by the misfits introduced by the pre-fabricated buried islands. According to the present invention, a method for making a semiconductor structure is proposed. It comprises the steps: providing a base layer having a first lattice constant, forming first islands on the base layer having a second lattice constant that is smaller or larger than the first lattice constant, burying the first islands (for sake of simplicity herein called buried islands) at least partially covering the base layer and the buried islands with a cover layer, whereby the cover layer has a locally increased or reduced lattice constant in areas above the buried islands, growing second islands (for sake of simplicity herein called small islands) on the areas of the cover layer with locally increased or reduced lattice constant, depositing a thin layer at least partially covering the cover layer and the small islands, at least partially removing the small islands to provide for an opening being positioned exactly above the buried islands. Various advantageous methods are claimed in the dependent claims 2 through 8 . According to the present invention, a semiconductor device is proposed that is being made using the process in accordance with one of the claims 1 through 8 . It is an advantage of the invention presented herein, that the obstacles and disadvantages of known approaches can be circumvented or even avoided.

20040917

20060718

20050217

57520.0

LE, THAO P

FORMATION OF SELF-ORGANIZED STACKED ISLANDS FOR SELF-ALIGNED CONTACTS OF LOW DIMENSIONAL STRUCTURES

SMALL

ACCEPTED

ACCEPTED

Variable capacity store for objects

A variable-capacity store (1) for objects (2), wherein an endless conveyor (8) defines a conveying branch (11) for conveying a mass of elongated elements (2), and a return branch (14), the conveying branch and the return branch respectively forming a first and at least a second coil (51, 57), each extending about two respective guide drums (26, 27) (43, 44) movable transversely with respect to each other to adjust the length of the respective coil (51) (57); and wherein the conveying surface (10) positioned on edge with respect to the guide drums (26, 27) of the first coil (51), and positioned flat against the guide drums (43, 44) of the second coil (57).

1) A variable-capacity store for objects, the store (1) comprising an input station (3) and an output station (4) arranged in series along a feed path (P) of the objects (2); an endless conveyor (8) comprising a conveying branch (11) for conveying said objects (2) along said path (P) and forming a first coil (51) of a first given length about a pair of first guide drums (26, 27), and a return branch (14) forming at least a second coil (57) of a second given length about a pair of second guide drums (43, 44); and adjusting means (15) for adjusting said lengths in complementary manner; said conveyor (8) comprising a conveyor belt (9) having a flat conveying surface (10), which is positioned on edge with respect to the first guide drums (26, 27) and along the first coil (51); characterized in that the flat conveying surface (10) of the conveyor belt (9) is positioned flat against the second guide drums (43, 44) and along the second coil (57). 2) A store as claimed in claim 1, wherein the diameter of said second guide drums (43, 44) is smaller than the diameter of said first guide drums (26, 27). 3) A store as claimed in claim 1, wherein the diameter of said second guide drums (43, 44) is one third to one fifth of the diameter of said first guide drums (26, 27). 4) A store as claimed in claim 1, wherein said first guide drums (26, 27) are perpendicular to said second guide drums (43, 44). 5) A store as claimed in claim 1, wherein said first guide drums (26, 27) have respective vertical first axes (26a, 27a), and said second guide drums (43, 44) have respective horizontal second axes (43a, 44a). 6) A store as claimed in claim 1, wherein said second guide drums (43, 44) are located beneath said first guide drums (26, 27). 7) A store as claimed in claim 1, wherein said first guide drums (26, 27) are located a first distance apart, and said second guide drums (43, 44) are located a second distance apart; said adjusting means (15) comprising an adjusting device (16) for adjusting said first distance and, therefore, said first length, said adjusting device (16) comprising said first guide drums (26, 27); and a compensating device (17) for adjusting said second distance and, therefore, said second length in complementary manner with respect to said first length, said compensating device (17) comprising said second guide drums (43, 44). 8) A store as claimed in claim 7, wherein said adjusting device (16) comprises a frame (18, 68) supporting said first guide drums (26, 27); and said compensating device (17) is suspended from said frame (18, 68) and located beneath the frame (18, 68). 9) A store as claimed in claim 7, wherein said compensating device (17) comprises first and second supporting means (41, 42) movable with respect to each other in a direction (39) crosswise to said second guide drums (43, 44), and each supporting a respective said second guide drum (43) (44) in said pair of second guide drums (43, 44). 10) A store as claimed in claim 9, wherein said first supporting means (41) are integral with said frame (18, 68), and said second supporting means (42) are connected to said frame (18, 68) to move with respect to the frame (18, 68) in said direction (39). 11) A store as claimed in claim 1, wherein said compensating device (17) is located beneath a central portion of said frame (18, 68), and defines, beneath the frame (18, 68), two recesses (66, 67) located on opposite sides of the compensating device (17) and for respectively receiving, at least partly, supply means (A) supplying said objects (2) to the store (1), and receiving means (B) receiving said objects (2) from the store (1). 12) A store as claimed in claim 1, wherein said direction (39) is a vertical direction. 13) A store as claimed in claim 12, wherein said second supporting means (42) are located beneath said first supporting means (41), and are moved from and to said first supporting means (41) at least partly by and, respectively, in opposition to the force of gravity. 14) A store as claimed in claim 1, and also comprising elastic means (40) compressed between said first (41) and second (42) supporting means. 15) A store as claimed in claim 1, wherein said direction (39) is a horizontal direction. 16) A store as claimed in claim 15, wherein a fixed first guide drum (26) and a fixed second guide drum (43) are carried in a fixed position by a frame (68); a straight guide (19) being connected to the frame (68) to support in sliding manner a movable first guide drum (27) and a movable second guide drum (44). 17) A store as claimed in claim 16, wherein a first slide (21) supporting the movable first guide drum (27) runs along a top portion of the. guide (19), and a second slide (37) supporting the movable second guide drum (44) runs along a bottom portion of the guide (19). 18) A store as claimed in claim 1, wherein two pairs of second guide drums (43, 44) are located on opposite sides of said guide (19). 19) A store as claimed in claim 18, wherein said second slide (37) supports a transition pulley (69) fitted idly astride the guide (19) and rotating freely about a vertical axis to permit passage of the conveyor belt (9) from the pair of second guide drums (43, 44) on one side of the guide (19) to the pair of second guide drums (43, 44) on the other side of the guide (19); the flat conveying surface (10) of the conveyor belt (9) being positioned on edge with respect to said transition pulley (69). 20) A store as claimed in claim 1, wherein the conveyor (8) is moved by a powered input pulley (12) located at the input station (3), and by a powered output pulley (13) located at the output station (4); the movable first guide drum (27) and the movable second guide drum (44) being mounted to slide freely along the straight guide (19); and a connecting device (71) being provided, which is so designed that any displacement of the movable first guide drum (27) corresponds to an identical displacement of the movable second guide drum (44) in the opposite direction. 21) A store as claimed in claim 20, wherein the connecting device (71) comprises an endless belt (72) looped about two idle end pulleys (73) and connected mechanically to both the movable first guide drum (27)and the movable second guide drum (44). 22) A store as claimed in claim 1, wherein the frame (68) is defined by a parallelepiped-shaped box body housing the pair of second guide drums (43, 44) and the second coil (57). 23) A store as claimed in claim 22, wherein said frame (68) has a top surface (74); cleaning means being provided to clean the top surface (74) of the frame (68). 24) A store as claimed in claim 23, wherein the cleaning means comprise a movable head connected to a movable first guide drum (27). 25) A store as claimed in claim 24, wherein the movable head comprises a brush. 26) A store as claimed in claim 1, wherein each guide drum (26, 27; 43, 44) in each pair of guide drums (26, 27; 43, 44) comprises a respective number of pulleys (29; 47) fitted to a corresponding central shaft (28; 46); the pulleys (29; 47) of each guide drum (26, 27; 43, 44) in each pair of guide drums (26, 27; 43, 44) being fitted to the corresponding central shaft (28; 46) on a tilt differing from that of the pulleys (29 ; 47) of the other guide drum (27, 26 ; 44, 43). 27) A store as claimed in claim 1, and comprising a number of said second coils (57) arranged in series along said return branch (14) and supported by respective said pairs of second guide drums (43, 44). 28) A store as claimed in claim 1, wherein said first guide drums (26, 27) are perpendicular to said second guide drums (43, 44); said first guide drums (26, 27) have respective vertical first axes (26a, 27a), and said second guide drums (43, 44) have respective horizontal second axes (43a, 44a) and are located beneath said first guide drums (26, 27). 29) A store as claimed in claim 28, wherein the diameter of said second guide drums (43, 44) is smaller than the diameter of said first guide drums (26, 27). 30) A store as claimed in claim 1, and comprising a number of said second coils arranged in series along said return branch (14) and supported by respective said pairs of second guide drums (43, 44). 31) A store as claimed in claim 1, for containing objects defined by elongated elements (2), in particular cigarettes.

TECHNICAL FIELD The present invention relates to a variable-capacity store for objects. In particular, the present invention relates to a variable-capacity store for objects defined by elongated elements, the store comprising an input station and an output station arranged in series along a feed path of the elongated elements; an endless conveyor comprising a conveying branch for conveying said elongated elements along said path and forming a first coil of a first given length about a pair of first guide drums, and a return branch forming at least a second coil of a second given length about a pair of second guide drums; and adjusting means for adjusting said lengths in complementary manner. The present invention may be used to advantage for storing cigarettes, to which the following description refers purely by way of example. BACKGROUND ART For storing cigarettes, a store of the above type—as described, for example, in EP-0738478 or WO-9944446—is interposed between a cigarette manufacturing machine and a packing machine to compensate for any difference in the number of cigarettes produced and the number packed, by lengthening or shortening said first or conveying coil, and shortening or lengthening said second or return coil in complementary manner. U.S. Pat. No. 5,361,888 discloses a reversible reservoir for cigarettes or filters including relatively small and relatively large capacity sections arranged in series with a drive for driving these sections at different rates. The small section is preferably arranged adjacent the reservoir inlet and is capable of buffering the main part of the reservoir so that the latter is not required to undergo high accelerations; the reservoir may be in the form of an elongated helix with an endless conveyor passing around spaced columns of wheels, one of the lowermost wheels being bodily movable so as to be capable of imposing an additional velocity on the section of conveyor adjacent the reservoir inlet. The movable wheel is carried on a which also carries a pulley for the conveyer return run; tensioning for the conveyor is provided by arranging for the position of the pulley to be adjustable relative to the beam. FR2510527 discloses a feed for stocking articles between work positions; the feed is for stocking parts between two work positions and has an endless chain, along which are parts at even distances to hold the parts to be stocked. The chain has a vertical section of variable length; on this are loading supports for the stock, passing over a toothed wheel carried on a slide, which moves vertically and is permanently urged upwards. A second chain section is also of variable length and has unloaders for the stocked parts; a drive operates the chain upwards and another operates the chain downwards. The conveyor of known stores of the above type is normally defined by a belt, the conveying surface of which is maintained, along the two coils, substantially parallel to itself and substantially on edge, i.e. perpendicular to the axes of the relative guide drums, and is transversely flexible to wind on edge about all the guide drums. Consequently, known stores are relatively bulky by employing fairly large-radius guide drums along both the conveying and return branch, to prevent excessive tensile stress along the curved portions of the on-edge belt, and, at least as regards the conveying branch, instability of the conveyed mass of cigarettes due to excessively small radii of the curved portions. DISCLOSURE OF INVENTION It is an object of the present invention to provide a store of the above type, which, for a given capacity, is smaller in overall size as compared with known stores of the same type. According to the present invention, there is provided a variable-capacity store for objects as recited by claim 1. BRIEF DESCRIPTION OF THE DRAWINGS A non-limiting embodiment of the present invention will be described by way of example with reference to the accompanying drawings, in which: FIG. 1 shows a view in perspective, with parts removed for clarity, of a preferred embodiment of a store in accordance with the present invention; FIG. 2 shows a larger-scale view in perspective of a first detail of FIG. 1; FIG. 3 shows a larger-scale view in perspective of a second detail of FIG. 1; FIG. 4 shows a schematic view in perspective, with parts removed for clarity, of an alternative embodiment of a store in accordance with the present invention; FIG. 5 shows a view in perspective, with further parts removed for clarity, of the FIG. 4 store; FIG. 6 shows a larger-scale plan view of a detail of the FIG. 4 store; FIG. 7 shows a larger-scale front section of the FIG. 4 store; FIG. 8 shows a side view, with further parts removed for clarity, of the FIG. 4 store. BEST MODE FOR CARRYING OUT THE INVENTION Number 1 in FIG. 1 indicates as a whole a variable-capacity store for objects defined, for example, by elongated elements 2, in particular cigarettes, and comprising, for elongated elements 2, an input station 3 and an output station 4 arranged in series along a feed path P of elongated elements 2. More specifically, store 1 provides for storing a quantity of elements 2 varying as required within a given range, and for supplying station 4 with the elements 2 fed first, in use, to store 1 at station 3. Store 1 receives a number of elements 2, arranged in bulk in a continuous stream 6, from a conveyor 5 located at input station 3 and connected to the output of a manufacturing machine A, and feeds elements 2 to a conveyor 7 located at output station 4 and terminating at the input of a packing machine B. Store 1 comprises an endless conveyor 8 defined by an endless belt 9 having a substantially rectangular section and two opposite major lateral surfaces, one of which is a conveying surface 10 for supporting elongated elements 2 as they are fed through store 1. Conveyor 8 comprises a conveying branch 11, which, together with conveyors 5 and 7, defines the feed path between manufacturing machine A and packing machine B, extends from an input pulley 12 at input station 3 to an output pulley 13 at output station 4, and provides for feeding elongated elements 2 from input station 3 to output station 4. Conveyor 8 also comprises a return branch 14 extending from output pulley 13 to input pulley 12. Store 1 comprises an adjusting assembly 15 for adjusting the length of conveying branch 11 and the length of return branch 14 in complementary manner, so as to adjust the capacity of store 1, and which comprises an adjusting device 16 associated with conveying branch 11, and a compensating device 17 associated with return branch 14. Adjusting device 16 comprises a fixed frame defined by a substantially horizontal plate 18 having, on its top surface, a straight guide 19 extending between input station 3 and output station 4 and fitted with two blocks: a first block 20 fitted in a fixed position at the end of guide 19 facing input station 3; and a second block defined by a slide 21 run along guide 19 by an actuating device 22 comprising, in the example shown, a reversible motor 23 supported by plate 18, a screw 24 extending parallel to guide 19 and rotated about its axis by motor 23, and a nut screw 25 carried by slide 21 and engaged by screw 24. Slide 21 may, obviously, be operated differently. For example, in a variation not shown, motor 23 is mounted on slide 21 and drives a pinion meshing with a rack formed along guide 19. Block 20 and slide 21 support respective guide or transmission drums 26 and 27, the respective axes 26a and 27a of which extend vertically upwards with respect to plate 18. As shown in FIG. 2, each guide drum 26, 27 comprises a central, vertical, angularly fixed shaft 28, on which are equally spaced a number of pulleys 29, each of which comprises a central hub 30 fitted idly and in an axially fixed position to shaft 28; and an outer rim 31 coaxial with shaft 28 and relative hub 30, and connected integrally to hub 30 by a number of spokes 32. Rim 31 has an L-shaped section, and comprises a tubular body 33 coaxial with shaft 28; and an annular flange 34 coaxial with shaft 28, projecting outwards from the bottom end of relative tubular body 33, and of a width substantially equal to the width of belt 9 and relative conveying surface 10. Compensating device 17 comprises two brackets 35 projecting vertically downwards from a central portion of plate 18, and having respective vertical guides 36, along each of which runs a relative slide 37. Compensating device 17 also comprises a counterweight in turn comprising, in addition to slides 37, a plate 38, which is parallel to plate 18, is located directly beneath said central portion of plate 18, is connected integrally to slides 37, and is moved, with slides 37 and with respect to plate 18, in a vertical direction 39 by a spring 40 compressed between each slide 37 and plate 18. In a variation not shown, springs 40 are dispensed with, and slides 37 slide downwards along guides 36 solely under their own weight and the weight of plate 38. Two flat supports 41 and 42 extend respectively vertically downwards from plate 18 and vertically upwards from plate 38, are coplanar with each other, and respectively support a number of guide or transmission drums 43 and a number of guide or transmission drums 44. Guide drums 43 and 44 have respective horizontal axes 43aand 44a crosswise to guide 19 and to axes 26a and 27a. More specifically, axes 43a are located side by side along support 41 and are equally spaced in the same plane parallel and adjacent to plate 18; and axes 44a are located side by side along support 42 and are equally spaced in the same plane parallel and adjacent to plate 38. As shown in FIG. 1, guide drums 43 are equal in number to guide drums 44, and each guide drum 43 forms, with a corresponding guide drum 44, a pair 45 of superimposed guide drums interposed between plates 18 and 38. In the example shown, pairs 45 of guide drums are four in number, but, in other embodiments not shown, may vary from one to over four. As shown in FIG. 3, each guide drum 43, 44 comprises a shaft 46 integral with relative support 41, 42 and coaxial with relative axis 43a, 44a; and a number of pulleys 47 equally spaced along and fitted idly to shaft 46, and having respective outer grooves 48 of a width approximately equal to but no smaller than the width of belt 9 and relative conveying surface 10. Conveying branch 11 of conveyor 8 extends, as stated, from input pulley 12, which has a horizontal axis and is located, at input station 3, adjacent to an output pulley 49 of output conveyor 5 of manufacturing machine A; and belt 9 extends, downstream from input pulley 12, along a straight, substantially horizontal portion 50 up to the periphery of drum 27, and winds, clockwise in FIG. 1 and downwards, about both guide drums 26 and 27 to form a vertical coil 51, each turn 52 of which is supported by two corresponding pulleys 29. Conveying branch 11 is completed by a straight portion 53 extending from the lowest pulley 29 on drum 27 to output pulley 13, which is powered by a reversible motor 54 to rotate (anticlockwise in FIG. 1) about its own horizontal axis parallel to the axis of input pulley 12, and is located, at output station 4, adjacent to an input pulley 55 of input conveyor 7 of packing machine B. Along conveying branch 11, belt 9 is positioned with conveying surface 10 facing upwards, and, along coil 51, is positioned on edge with respect to guide drums 26 and 27 and resting flat on annular flanges 34 of pulleys 29. Along return branch 14 of conveyor 8, belt 9 extends downwards from output pulley 13, and is guided, by a series of horizontal-axis pulleys 56 carried by plate 18, towards guide drums 43 and 44 to form, about pairs 45, a succession of horizontal coils 57 arranged in series along return branch 14. Each horizontal coil 57 extends about a relative pair 45 of guide drums 43 and 44 to form a succession of turns 58, each supported by a respective pair of pulleys 47. Along each horizontal coil 57, belt 9 is laid flat with respect to relative guide drums 43 and 44, and rests flat on relative pulleys 47, with conveying surface 10 contacting the bottom surface of relative grooves 48. By virtue of belt 9 resting flat on guide drums 43 and 44, the diameter of pulleys 47 of guide drums 43 and 44 may be more or less the same as that of pulleys 12, 13 and 56, and decidedly smaller than, e.g. a third to a fifth of, the diameter of tubular body 33 of pulleys 29. At the end of the last horizontal coil 57, belt 9 is guided upwards to input pulley 12 by a series of pulleys 59 carried by plate 18 and similar to pulleys 56. Pulleys 13 and 55 at output station 4 are connected on top by a plate 60 for supporting the elongated elements 2 leaving store 1, and are powered respectively by motor 54 and a motor (not shown) of packing machine B to operate belt 9 and conveyor 7 at the same linear speed and in the same direction at output station 4. Pulleys 12 and 49 at input station 3 are connected on top by a plate 61 for supporting the elongated elements 2 entering store 1, and have respective encoders 62 and 63 for measuring their angular operating speeds, and which are connected to respective inputs of a comparing circuit 64, which receives a known signal from each encoder 62, 63, and supplies a central control unit 65, controlling motor 23, with an error signal proportional to the difference between the angular speeds of pulleys 12 and 49, so as to regulate displacement of guide drum 27 with respect to guide drum 26. In actual use, elongated elements 2 are fed continuously by conveyor 5 over plate 61 to the straight input portion 50 of conveying branch 11, and are fed by conveying branch 11 to output station 4, where the first elongated elements 2 to enter store 1 are fed over plate 60 on to conveyor 7. In normal operating conditions, the number of elongated elements 2 fed by conveyor 5 to input station 3 equals the number of elements 2 absorbed by conveyor 7 at output station 4, and the linear speed of straight portion 50 of conveying branch 11 equals that of conveyor 5. Comparing circuit 64 supplies a zero error signal to central control unit 65, which leaves motor 23 idle and therefore makes no change in the distance between guide drums 26 and 27. In other words, in the above situation, the lengths of conveying branch 11 and return branch 14 remain unchanged. Conversely, in the event the number of elements 2 fed to input station 3 is greater than the number of elements 2 absorbed at output station 4, comparing circuit 64 supplies an error signal to central control unit 65, which activates motor 23, and therefore the screw-nut screw transmission 24-25, so as to move guide drum 27 away from guide drum 26 and so increase the length of conveying branch 11 and the capacity of store 1. Obviously, the increase in conveying branch 11 is made at the expense of return branch 14 by moving plate 38 towards plate 18, and therefore guide drums 44 towards relative guide drums 43, in opposition to springs 40. Conversely, in the event the number of elements 2 fed to input station 3 is smaller than the number of elements 2 absorbed at output station 4, comparing circuit 64 supplies an error signal to central control unit 65, which activates motor 23, and therefore the screw-nut screw transmission 24-25, so as to move guide drum 27 towards guide drum 26 and so reduce the length of conveying branch 11 and accordingly increase the length of return branch 14. In connection with store 1 described above, it should be pointed out that the relatively small diameter of guide drums 43 and 44, permitted by winding belt 9 flat about pairs 45 of guide drums 43 and 44, provides for housing the whole of return branch 14 in a relatively small space. If, as in the example shown, compensating device 17 is located beneath adjusting device 16, the small volume of compensating device 17 not only enables adjusting device 16 to be located over manufacturing machine A and packing machine B, and in line with conveyors 5 and 7, but also provides for obtaining a T-shaped store 1, and for forming, on either side of compensating device 17, two recesses 66 and 67 for housing at least part of manufacturing machine A and packing machine B respectively, thus greatly reducing the overall size of the line defined by store 1 and machines A and B. FIGS. 4-8 show a further embodiment of store 1 comprising input station 3 and output station 4 for elements 2 (not shown), located in series along feed path P of elements 2; and endless conveyor 8 defined by endless belt 9 and in turn comprising conveying branch 11 extending from input pulley 12 to output pulley 13, and return branch 14 extending from output pulley 13 to input pulley 12. Store 1 also comprises adjusting assembly 15 for adjusting the length of conveying branch 11 and the length of return branch 14 in complementary manner to adjust the capacity of store 1, and which in turn comprises adjusting device 16 associated with conveying branch 11, and compensating device 17 associated with return branch 14. Adjusting device 16 comprises a fixed frame defined by a parallelepiped-shaped box body 68, which supports drum 26 in a fixed position and in turn comprises straight guide 19, along which runs slide 21 supporting drum 27. More specifically, straight guide 19 is defined by a square section (shown more clearly in FIGS. 6 and 7), a top portion of which supports drum 26 and, by means of slide 21, drum 27, and a bottom portion of which supports a pair of guide drums 43 in a fixed position, and a pair of guide drums 44 by means of slide 37. The two guide drums 43, 44 in each pair of guide drums 43, 44 are located on opposite sides of guide 19, with their respective axes 43a, 44a perpendicular to guide 19; and each guide drum 43, 44 comprises a shaft 46, and a number of pulleys 47 fitted idly to and equally spaced along shaft 46, and having respective outer grooves 48 of a width approximately equal to but no smaller than the width of belt 9. In addition to the two guide drums 44, slide 37 also supports a pulley 69, which is fitted idly astride guide 19 to rotate freely about a vertical axis, and allows belt 9 to pass from the guide drum 43 on one side of guide 19 to the guide drum 43 on the other side of guide 19. More specifically, the passage of belt 9 from the guide drum 43 on one side of guide 19 to the guide drum 43 on the other side of guide 19 is made possible by belt 19 winding on edge about pulley 69. Return branch 14 is therefore housed entirely inside box body 68, and drums 44 carried by slide 37 move with respect to fixed guide drums 43 along a horizontal plane defined by guide 19. Output pulley 13 is powered by reversible motor 54 to rotate about its horizontal axis; while input pulley 12 is powered to rotate about its horizontal axis by a reversible motor 70. As shown in FIG. 8, slide 21 supporting drum 27, and slide 37 supporting guide drums 44 are connected mechanically to each other by a connecting device 71 designed so that any displacement of slide 21 corresponds to an identical displacement of slide 37 in the opposite direction. More specifically, connecting device 71 comprises an endless belt 72 looped about two end pulleys 73, which are fitted idly to box body 68 to rotate freely about respective horizontal axis; and slides 21 and 37 are connected mechanically to belt 72 so that any displacement of slide 21 corresponds to an identical displacement of slide 37 in the opposite direction. Store 1 in FIGS. 4-8 operates in substantially the same way as store 1 in FIGS. 1-4, the only difference being that the length of conveying branch 11 and return branch 14 is adjusted, not by drive means and/or force of gravity, but solely by tensioning belt 9 by means of motor 70 fitted to input pulley 12, and motor 54 fitted to output pulley 13. When the number of elements 2 fed to input station 3 equals the number of elements 2 absorbed at output station 4, input pulley 12 and output pulley 13 operate belt 9 at the same speed, and the length of conveying branch 11 and return branch 14 remains unchanged. When the number of elements 2 fed to input station 3 is smaller than the number of elements 2 absorbed at output station 4, input pulley 12 operates belt 9 at a slower speed than output pulley 13, so that drum 27 fitted to slide 21 is drawn towards fixed drum 26, thus shortening conveying branch 11; and, by virtue of connecting device 71, the displacement of slide 21 corresponds to an equal displacement of slide 37 in the opposite direction, thus increasing the distance between guide drums 43 and 44, and so increasing the length of return branch 14 to compensate for the reduction in the length of conveying branch 11. Conversely, when the number of elements 2 fed to input station 3 is greater than the number of elements 2 absorbed at output station 4, input pulley 12 operates belt 9 at a higher speed than output pulley 13, so that guide drums 44 fitted to slide 37 are drawn towards fixed guide drum 43, thus shortening return branch 14; and, by virtue of connecting device 71, the displacement of slide 37 corresponds to an equal displacement of slide 21 in the opposite direction, thus increasing the distance between drums 27 and 26, and so increasing the length of conveying branch 11 to compensate for the reduction in the length of return branch 14. In the preferred embodiment shown in FIGS. 4-8, pulleys 29 on drum 26 are tilted, i.e. not perpendicular to relative shaft 28, and pulleys 29 on drum 27 are tilted the opposite way on relative shaft 28, so as to assist the passage of belt 9 from one pulley 29 on drum 26 to the corresponding pulley 29 on drum 27 and vice versa. Similarly, pulleys 47 on each guide drum 43 are tilted, i.e. not perpendicular to relative shaft 46, and pulleys 47 on each guide drum 44 are tilted the opposite way on relative shaft 46, so as to assist the passage of belt 9 from a pulley 47 on a guide drum 43 to the corresponding pulley 47 on guide drum 44 and vice versa. In an embodiment not shown, a cleaning member is provided to clean the top surface 74 of box body 68, on which powdered tobacco from elements 2 on conveying branch 11 of store 1 tends to deposit. The cleaning member preferably comprises a movable head having a brush and/or suction member, and which is fitted to slide 21 and moved along the whole of top surface 74 during normal operation of store 1.

<SOH> BACKGROUND ART <EOH>For storing cigarettes, a store of the above type—as described, for example, in EP-0738478 or WO-9944446—is interposed between a cigarette manufacturing machine and a packing machine to compensate for any difference in the number of cigarettes produced and the number packed, by lengthening or shortening said first or conveying coil, and shortening or lengthening said second or return coil in complementary manner. U.S. Pat. No. 5,361,888 discloses a reversible reservoir for cigarettes or filters including relatively small and relatively large capacity sections arranged in series with a drive for driving these sections at different rates. The small section is preferably arranged adjacent the reservoir inlet and is capable of buffering the main part of the reservoir so that the latter is not required to undergo high accelerations; the reservoir may be in the form of an elongated helix with an endless conveyor passing around spaced columns of wheels, one of the lowermost wheels being bodily movable so as to be capable of imposing an additional velocity on the section of conveyor adjacent the reservoir inlet. The movable wheel is carried on a which also carries a pulley for the conveyer return run; tensioning for the conveyor is provided by arranging for the position of the pulley to be adjustable relative to the beam. FR2510527 discloses a feed for stocking articles between work positions; the feed is for stocking parts between two work positions and has an endless chain, along which are parts at even distances to hold the parts to be stocked. The chain has a vertical section of variable length; on this are loading supports for the stock, passing over a toothed wheel carried on a slide, which moves vertically and is permanently urged upwards. A second chain section is also of variable length and has unloaders for the stocked parts; a drive operates the chain upwards and another operates the chain downwards. The conveyor of known stores of the above type is normally defined by a belt, the conveying surface of which is maintained, along the two coils, substantially parallel to itself and substantially on edge, i.e. perpendicular to the axes of the relative guide drums, and is transversely flexible to wind on edge about all the guide drums. Consequently, known stores are relatively bulky by employing fairly large-radius guide drums along both the conveying and return branch, to prevent excessive tensile stress along the curved portions of the on-edge belt, and, at least as regards the conveying branch, instability of the conveyed mass of cigarettes due to excessively small radii of the curved portions.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>A non-limiting embodiment of the present invention will be described by way of example with reference to the accompanying drawings, in which: FIG. 1 shows a view in perspective, with parts removed for clarity, of a preferred embodiment of a store in accordance with the present invention; FIG. 2 shows a larger-scale view in perspective of a first detail of FIG. 1 ; FIG. 3 shows a larger-scale view in perspective of a second detail of FIG. 1 ; FIG. 4 shows a schematic view in perspective, with parts removed for clarity, of an alternative embodiment of a store in accordance with the present invention; FIG. 5 shows a view in perspective, with further parts removed for clarity, of the FIG. 4 store; FIG. 6 shows a larger-scale plan view of a detail of the FIG. 4 store; FIG. 7 shows a larger-scale front section of the FIG. 4 store; FIG. 8 shows a side view, with further parts removed for clarity, of the FIG. 4 store. detailed-description description="Detailed Description" end="lead"?

20040917

20060314

20050127

60100.0

DEUBLE, MARK A

VARIABLE CAPACITY STORE FOR OBJECTS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Semiconductor device and its manufacturing method

A semiconductor device includes a first insulating layer, a semiconductor layer formed on the first insulating layer, a second insulating layer on a part of the semiconductor layer, and a gate electrode formed on the semiconductor layer through the second insulating layer. The semiconductor layer includes a low concentration region formed under the gate electrode through the second insulating layer, two high concentration regions which are formed in at least upper regions on outer sides of the low concentration region under the gate electrode through the second insulating layer, and have an impurity concentration higher than an impurity concentration of the low concentration region, respectively, and two source/drain regions which are formed in side portions of the high concentration regions to have low concentration region side end portions, respectively. A width of the high concentration region is equal to or less than 30 nm.

1. A semiconductor device comprising: a first insulating layer; a semiconductor layer formed on said first insulating layer; a second insulating layer on a part of said semiconductor layer; and a gate electrode formed on said semiconductor layer through said second insulating layer, wherein said semiconductor layer comprises: a low concentration region formed under said gate electrode through said second insulating layer; two high concentration regions formed in at least two upper regions on outer sides of said low concentration region under said gate electrode through said second insulating layer, and have an impurity concentration higher than that of said low concentration region, respectively; and two source/drain regions formed in side portions outside said high concentration regions to have low concentration region side end portions, respectively, and a width of said high concentration region is equal to or less than 30 nm. 2. The semiconductor device according to claim 1, wherein said semiconductor layer further comprises: two diffusion barrier regions formed between said high concentration regions and said low concentration region, respectively, to prevent diffusion of impurity in said high concentration regions into said low concentration region. 3. The semiconductor device according to claim 1, wherein said impurity concentration gradually decreases in a direction from said low concentration region side end portions of said source/drain regions to a center portion of said low concentration region. 4. The semiconductor device according to claim 1, wherein said impurity concentration of said high concentration region is lower than {fraction (1/10)} of said impurity concentration at said low concentration region side end portion of each of said source/drain regions at a position apart from said low concentration region side end portions of said source/drain regions by 30 nm. 5. The semiconductor device according to claim 1, wherein a horizontal gradient of said impurity concentration of said high concentration region is higher than 1×1024 cm-4 at a position apart from said low concentration region side end portions of said source/drain regions into a direction of said low concentration region by 20 nm. 6. The semiconductor device according to claim 1, wherein said low concentration region is an intrinsic region, said high concentration regions are of a first conductive type, and said source/drain regions are of a second conductive type which is different from said first conductive type. 7. The semiconductor device according to claim 1, wherein said low concentration region and said high concentration regions are of a first conductive type, and said source/drain regions are of a second conductive type which is different from said first conductive type. 8. The semiconductor device according to claim 7, wherein said low concentration region comprises: a first conductive type upper region; and a low concentration region diffusion barrier region formed under said first conductive type upper region to prevent downward diffusion of an impurity of said first conductive type upper region. 9. The semiconductor device according to claim 7, further comprising: a second conductive type region which is formed under said low concentration region and said high concentration region not to contact said source/drain regions. 10. The semiconductor device according to claim 1, wherein said impurity concentration of said low concentration region is high in an upper region on a side of said second insulating layer and is low in a lower region on a side of said first insulating layer. 11. The semiconductor device according to claim 1, wherein said impurity concentration of said low concentration region is high in an upper region on a side of said second insulating layer becomes low once in a lower region on a side of said first insulating layer and increases with approaching a boundary with said first insulating layer. 12. The semiconductor device according to claim 10, wherein a peak value of said impurity concentration of said upper region is larger three times than a peak value of said impurity concentration of said lower region. 13. A manufacturing method of a semiconductor device comprising: (a) forming a low concentration region in a semiconductor layer which is formed on a first insulating film; (b) forming a second insulating layer on said semiconductor layer; (c) forming a gate electrode on said low concentration region through said second insulating film; (d) forming high concentration regions on outer sides of said low concentration region in said semiconductor layer under said gate electrode to have a width equal to or less than 30 nm in a surface direction; and (e) forming source/drain electrodes in said semiconductor layer outside said high concentration regions. 14. The manufacturing method of the semiconductor device according to claim 13, further comprising: (f) forming diffusion prevention regions between said high concentration region and said low concentration region to prevent diffusion of impurity from said high concentration region into said low concentration region. 15. The manufacturing method of the semiconductor device according to claim 13, wherein said (d) forming comprises: forming said high concentration region such that said impurity concentration of each of said high concentration regions decreases gradually in a direction from a low concentration region side end portions of said source/drain region to a center portion of said low concentration region. 16. The manufacturing method of the semiconductor device according to claim 13, wherein said impurity concentration of said high concentration region is lower than {fraction (1/10)} of an impurity concentration at end portions of said source/drain regions at a position apart from said low concentration region side end portions of said source/drain regions by 30 nm. 17. The manufacturing method of the semiconductor device according to claim 13, wherein a horizontal gradient of said impurity concentration of said high concentration region is higher than 1×1024 cm−4 at a position apart from said low concentration region side end portions of said source/drain regions by 20 nm. 18. The manufacturing method of the semiconductor device according to claim 13, wherein said low concentration region and said high concentration region are of a first conductive type, and said source/drain regions are of a second conductive type which is different from said first conductive type. 19. The manufacturing method of the semiconductor device according to claim 18, wherein said low concentration region has an upper region and a lower region, and said (a) forming comprises: forming a diffusion barrier region to prevent downward diffusion of a first conductive type impurity implanted into said upper region in said lower region of said low concentration region; and implanting said first conductive type impurity in said upper region of said low concentration region. 20. The manufacturing method of the semiconductor device according to claim 18, further comprising: forming a second conductive type region under said low concentration region and said high concentration region not to contact said source/drain regions. 21. The manufacturing method of the semiconductor device according to claim 13, wherein said (a) forming comprises: forming said low concentration region such that said impurity concentration of said low concentration region is high in an upper region on a side of said second insulating layer, and becomes low in a lower region on a side of said first insulating layer. 22. The manufacturing method of the semiconductor device according to claim 13, wherein said (a) forming comprises: forming said low concentration region such that said impurity concentration of said low concentration region is high in an upper region on a side of said second insulating layer, becomes low once in a lower region on a side of said first insulating layer, and increases with approaching a boundary with said first insulating film. 23. The manufacturing method of the semiconductor device according to claim 21, wherein a peak value of said impurity concentration of said upper region is higher three times than a peak value of said impurity concentration of said lower region. 24. A semiconductor device comprising: a first insulating layer; a semiconductor layer formed on said first insulating layer; a second insulating layer formed on said semiconductor layer; and a gate electrode formed on said semiconductor layer through said second insulating film, wherein said semiconductor layer comprises: a channel region formed under said gate electrode through said second insulating film; and two source/drain regions formed outside said channel region in said semiconductor layer, an impurity concentration of said channel region is lower than ¼ of an impurity concentration of said channel region at end portions of said source/drain regions at a position apart from said end portions of said source/drain regions by 20 nm. 25. A semiconductor device comprising: a first insulating layer; a semiconductor layer formed on said first insulating layer; a second insulating layer formed on a part of said semiconductor layer; and a gate electrode formed on said semiconductor layer through said second insulating film, wherein said semiconductor layer comprises: a low concentration region formed under said gate electrode through said second insulating film; two high concentration regions formed under said gate electrode through said second insulating film in upper regions of outer sides of said low concentration region not to contact said first insulating film and to have an impurity concentration higher than that of said low concentration region; and two source/drain regions formed on outer sides of said high concentration regions to have low concentration region side end portions, respectively. 26. A semiconductor device comprising: a first insulating layer; a semiconductor layer formed on said first insulating layer; a second insulating layer formed on a part of said semiconductor layer; and a gate electrode formed on said semiconductor layer through said second insulating film, wherein said semiconductor layer comprises: a low concentration region formed under said gate electrode through said second insulating film; two first high concentration regions formed under said gate electrode through said second insulating film in upper regions of outer sides of said low concentration region not to contact said first insulating film and to have an impurity concentration higher than that of said low concentration region; two second high concentration regions formed under said first high concentration regions not to contact said first insulating film and to have an impurity concentration higher than that of a region of said low concentration region which contacts said first insulating layer; and two source/drain regions formed on outer sides of said high concentration regions to have low concentration region side end portions, respectively. 27. A semiconductor device comprising: a first insulating layer; a semiconductor layer formed on said first insulating layer; a second insulating layer formed on a part of said semiconductor layer; and a gate electrode formed on said semiconductor layer through said second insulating film. wherein said semiconductor layer comprises: a low concentration region formed under said gate electrode through said second insulating film; two high concentration regions formed under said gate electrode through said second insulating film in upper regions of outer sides of said low concentration region not to contact said first insulating film and to have an impurity concentration higher than that of said low concentration region; an embedded implantation region formed under said high concentration regions and said low concentration region to contact said first insulating film and to have a conductive type opposite to those of said high concentration regions and said low concentration region; and two source/drain regions formed on outer sides of said high concentration regions to have low concentration region side end portions, respectively.

TECHNICAL FIELD The present invention relates to a semiconductor device and a manufacturing method of the same, and more particularly to a semiconductor device such as a MOSFET formed on an SOI (silicon-on-insulator) substrate which has an SOI layer and a manufacturing method for the same. BACKGROUND ART An SOI substrate is known as a semiconductor substrate in which an insulating film (an oxide film in many cases) is formed on a substrate and a semiconductor layer (a silicon layer) is formed on it. In a MOSFET to which such an SOI substrate is applied, because the insulating film is formed under a source region and a drain region, a parasitic capacitance can be made smaller compared with a case of a usual bulk substrate in which the SOI layer is not used. As a result, the SOI substrate is superior in high speed operation of the device and it has been widely used. Generally, the MOSFETs using the SOI substrate is grouped into a fully depleted SOI-MOSFET in which the SOI layer below the gate is depleted and a partially depleted SOI-MOSFET in which the SOI layer is not fully depleted so that a neutral region is left. The partially depleted SOI-MOSFET has an advantage that it can be manufactured by a manufacturing method in which a process for a bulk substrate is used. However, because the neutral region which is electrically separated from the substrate is left, the potential of the neutral region changes depending on an operation condition and operation current changes, namely, so-called floating body effect is caused. For this reason, circuit design becomes difficult. On the other hand, because there is not an neutral region in the fully depleted SOI-MOSFET, the potential under the channel does not change and there is an advantage that the circuit operation is stable.. However, in the full depleted transistor, unless the SOI layer is made extremely thin, the characteristic degradation of the device is easy to be caused due to punch-through and short channel effects, compared with the partially depleted SOI transistor. A measure to the characteristic degradation is proposed in which Halo regions where a channel impurity concentration is high are formed on both sides of the channel region. Such a conventional technique is known in Japanese Laid Open Patent Application (JP-A-Heisei 9-293871). FIGS. 1 and 2 show such a semiconductor device. Referring to FIG. 1, SD (source and drain) regions 103 are formed in the SOI substrate in which a buried insulating film 102 of an oxide film is formed on a base substrate 101 of silicon and a semiconductor layer is formed on the buried insulating film 102. A low concentration region 104 for a channel region and the Halo implantation regions 105 are formed in the region, and a gate insulating film 106, a gate electrode 107, side wall insulating films 108 are formed. Especially, the Halo implantation region 105 has an impurity density profile of the shape shown in FIG. 2 in a lateral direction. The setting of the Halo region with such a high impurity density profile is excellent to restrain the floating body effect. The profile N(x) of the Halo region 105 of such a conventional semiconductor device in the lateral direction is expressed by the following equation. N(x)+N0+Nb0·|exp(−[η·(x−L/2]g)+exp(−[η·(x+L/2]g)| When η is in a range from 8 to 20 or the concentration inclination in the lateral direction is in 3−8×1022 cm−4, the current gain hfe of a parasitic bipolar transistor formed by the SD regions 103 and the low concentration region 104 can be reduced. In addition to the restraint of the short channel effect, the fine and stable operation becomes possible. However, in the above-mentioned conventional example, the spreading of the impurity distribution from the peak into the lateral direction is about 0.1 μm. When a device is formed to have a gate length of a sub half micron range, the tails of the impurity profiles from both sides overlap and the Halo structure cannot be formed to have high concentration regions on both sides. If the tails of the impurity profiles from both sides overlap, the impurity concentration in the center portion of the channel region rises, so that the partially depleted SOI-MOSFET operation is easy to be carried out. That is, the fully depleted MOSFET operation becomes difficult. It is demanded that the technique which restrains the floating body effect is established and the technique is different from the conventional method of setting a concentration inclination (a range of η from 8 to 20 or the concentration inclination in the lateral direction is 3−8×1022 cm−4) in accordance with the principle of the conventional example. Conventionally, the SOI-MOSFETs having various Halo regions are proposed. However, they does not described the effective knowledge to form ideal impurity distribution nor suggests what impurity distribution is proper. Because the gate oxide film becomes thin if the miniaturization of the transistor proceeds, the channel impurity concentration increases to get a necessary threshold voltage. With the increase, the minimum potential decreases so that it is easy to carry out the partially depleted SOI-MOSFET operation. In case of the N-channel transistor, the minimum potential decreases, in case of the P-channel transistor, the maximum potential increases. Thus, the same problem is caused in the N-channel transistor and the P-channel transistor. Hereinafter, the N-channel transistor will be described in this description as long as special notation is necessary. However, it could be understood to the person in the art that the same thing can be applied to the P-channel transistor. In the channel concentration in which the fully depleted MOSFET operation is carried out, it is known that the threshold voltage decreases, and a measure to it is needed. In conjunction with the above description, an SOI transistor is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 9-45919). In this conventional example, the transistor is composed of a semiconductor substrate, a buried insulating layer formed on the semiconductor substrate, a semiconductor layer section, a gate insulating film, a gate electrode layer, and a channel region. The semiconductor layer section is arranged on the buried insulating layer and is composed of a top surface, a bottom surface contacting the buried insulating layer, a source region and a drain region. The gate insulating layer is arranged on the top surface of the semiconductor layer section between the source region and the drain region. The gate electrode layer is arranged on the gate insulating layer. The channel region is arranged on the buried insulating layer under the gate insulating layer and is arranged at the semiconductor layer section between the source region and the drain region. The channel region has a top dopant concentration in correspondence to the top surface of the semiconductor layer section, and a bottom dopant concentration in correspondence to the bottom surface of the semiconductor layer section. Here, the top dopant concentration is higher than the bottom dopant concentration. Also, a silicon semiconductor transistor having a Halo implantation region is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 10-4198). In this conventional example, the transistor is composed of an insulating layer, and a semiconductor mesa which includes a first surface in contact with the insulating layer and a second surface opposite to the first surface. The semiconductor mesa is composed of a first source/drain region of a first conductive type, a second source/drain region of the first conductive type, a body region, and an implantation region. The body region has a first dopant level of a second conductive type, contacts the insulating layer, extends to the second surface of the mesa and is arranged between the first source/drain region and the second source/drain region. The implantation region is arranged between the first source/drain region and the body region to separate the first source/drain region from the body region. Also, the implantation region is of a second conductive type and has a dopant level which is substantively equal to or higher than the first dopant level. Also, a semiconductor device is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 11-204783. In this conventional example, in the semiconductor device includes a MIS-type electric field effect-type transistor. A region where halogen elements or halogen ions such as fluorine and chlorine exist is provided in at least one of a surface region and an inside region of the active region of the MIS-type electric field effect-type transistor of the semiconductor substrate. Also, a field effect transistor is disclosed in Japanese Laid Open Patent Application (JP-P 2000-349295). In this conventional example, the field effect transistor is composed of a semiconductor layer, a gate electrode, a source region and a drain region of a first conductive type. An element formation semiconductor layer is covered with an insulator at the bottom at least. A gate electrode is provided on the gate insulating film which is formed on the semiconductor layer. The source region and the drain region of the first conductive type are formed in the semiconductor layer on both sides of the gate electrode. A position where the second conductive type impurity concentration is maximum in the semiconductor layer under the gate electrode is nearer to the semiconductor layer surface than a maximum depth of an inverted layer in the neighborhood of the semiconductor layer surface when the gate electrode is supplied with a voltage larger than a threshold voltage. Also, the second conductive type impurity concentration is monotonously decreased from the maximum depth of the inverted layer toward a boundary between the semiconductor layer and the insulator. DISCLOSURE OF INVENTION An object of the present invention is to provide a semiconductor device and a manufacturing method of the same, in which a fully depleted MOSFET operation can be achieved and decrease of a threshold voltage can be restrained. Another object of the present invention is to provide a semiconductor device and a manufacturing method of the same, in which a fully depleted MOSFET operation can be achieved and decrease of a threshold voltage can be restrained, by optimizing an impurity distribution of a Halo region. In an aspect of the present invention, a semiconductor device includes a first insulating layer; a semiconductor layer formed on the first insulating layer; a second insulating layer on a part of the semiconductor layer; and a gate electrode formed on the semiconductor layer through the second insulating layer. The semiconductor layer includes a low concentration region formed under the gate electrode through the second insulating layer; two high concentration regions and two source/drain regions. The high concentration regions are formed in at least two upper regions on outer sides of the low concentration region under the gate electrode through the second insulating layer, and have an impurity concentration higher than that of the low concentration region, respectively. The source/drain regions are formed in side portions outside the high concentration regions to have low concentration region side end portions, respectively. The width of the high concentration region is equal to or less than 30 nm. Here, the semiconductor layer may further include two diffusion barrier regions formed between the high concentration regions and the low concentration region, respectively, to prevent diffusion of impurity in the high concentration regions into the low concentration region. Also, it is desirable that the impurity concentration gradually decreases in a direction from the low concentration region side end portions of the source/drain regions to a center portion of the low concentration region. Also, the impurity concentration of the high concentration region is desirably lower than {fraction (1/10)} of the impurity concentration at the low concentration region side end portion of each of the source/drain regions at a position apart from the low concentration region side end portions of the source/drain regions by 30 nm. Also, a horizontal gradient of the impurity concentration of the high concentration region is desirably higher than 1×24 cm−4 at a position apart from the low concentration region side end portions of the source/drain regions into a direction of the low concentration region by 20 nm. Also, the low concentration region may be an intrinsic region, the high concentration regions may be of a first conductive type, and the source/drain regions may be of a second conductive type which is different from the first conductive type. Otherwise, the low concentration region and the high concentration regions may be of a first conductive type, and the source/drain regions may be of a second conductive type which is different from the first conductive type. In this case, the low concentration region may include a first conductive type upper region; and a low concentration region diffusion barrier region formed under the first conductive type upper region to prevent downward diffusion of an impurity of the first conductive type upper region. Also, the semiconductor device may further include a second conductive type region which is formed under the low concentration region and the high concentration region not to contact the source/drain regions. Also, it is desirable that the impurity concentration of the low concentration region is high in an upper region on a side of the second insulating layer and is low in a lower region on a side of the first insulating layer. Also, the impurity concentration of the low concentration region may be high in an upper region on a side of the second insulating layer, may become low once in a lower region on a side of the first insulating layer, and may increase with approaching a boundary with the first insulating layer. Also, it is desirable that a peak value of the impurity concentration of the upper region is larger three times than a peak value of the impurity concentration of the lower region. In another aspect of the present invention, a manufacturing method of a semiconductor device is achieved by (a) forming a semiconductor layer on a first insulating layer; by (b) forming a low concentration region; by (c) forming a second insulating layer on the semiconductor layer; by (d) forming a gate electrode on the low concentration region through the second insulating film; by (e) forming high concentration regions on outer sides of the low concentration region in the semiconductor layer under the gate electrode to have a width equal to or less than 30 nm in a surface direction; and by (f) forming source/drain electrodes in the semiconductor layer outside the high concentration regions. Here, the manufacturing method may further include (g) forming diffusion prevention regions between the high concentration region and the low concentration region to prevent diffusion of impurity from the high concentration region into the low concentration region. Also, the (e) forming is desirably achieved by forming the high concentration region such that the impurity concentration of each of the high concentration regions decreases gradually in a direction from a low concentration region side end portions of the source/drain region to a center portion of the low concentration region. Also, it is desirable that the impurity concentration of the high concentration region is lower than {fraction (1/10)} of an impurity concentration at end portions of the source/drain regions at a position apart from the low concentration region side end portions of the source/drain regions by 30 nm. Also, it is desirable that a horizontal gradient of the impurity concentration of the high concentration region is higher than 1×1024 cm−4 at a position apart from the low concentration region side end portions of the source/drain regions by 20 nm. Also, the low concentration region and the high concentration region may be of a first conductive type, and the source/drain regions may be of a second conductive type which is different from the first conductive type. In this case, when the low concentration region has an upper region and a lower region, the (b) forming may be achieved by forming a diffusion barrier region to prevent downward diffusion of a first conductive type impurity implanted into the upper region in the lower region of the low concentration region; and by implanting the first conductive type impurity in the upper region of the low concentration region. Also, the manufacturing method may further include forming a second conductive type region under the low concentration region and the high concentration region not to contact the source/drain regions. Also, it is desirable that in the (b) forming, the low concentration region is formed such that the impurity concentration of the low concentration region is high in an upper region on a side of the second insulating layer, and becomes low in a lower region on a side of the first insulating layer. Also, the (b) forming may be achieved by forming the low concentration region such that the impurity concentration of the low concentration region is high in an upper region on a side of the second insulating layer, becomes low once in a lower region on a side of the first insulating layer, and increases with approaching a boundary with the first insulating film. Also, it is desirable that a peak value of the impurity concentration of the upper region is higher three times than a peak value of the impurity concentration of the lower region. In another aspect of the present invention, a semiconductor device includes a first insulating layer; a semiconductor layer formed on the first insulating layer; a second insulating layer formed on the semiconductor layer; and a gate electrode formed on the semiconductor layer through the second insulating film. The semiconductor layer includes a channel region formed under the gate electrode through the second insulating film; two source/drain regions formed outside the channel region in the semiconductor layer. The impurity concentration of the channel region is lower than ¼ of an impurity concentration of the channel region at end portions of the source/drain regions at a position apart from the end portions of the source/drain regions by 20 nm. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a cross section view showing the structure of a conventional semiconductor device; FIG. 2 is a graph showing an impurity density profile in the semiconductor device shown in FIG. 1; FIG. 3 is a cross section view showing the structure of a semiconductor device according to a first embodiment of the present invention; FIG. 4 is a graph showing an impurity density profile in a lateral direction in the semiconductor device according to the first embodiment of the present invention; FIGS. 5A to 5H are cross sectional views showing a manufacturing method of the semiconductor device according to the first embodiment of the present invention; FIG. 6 is a cross section view showing the structure of the semiconductor device according to a second embodiment of the present invention; FIG. 7 is a diagram showing an impurity density profile in the semiconductor device according to the second embodiment of the present invention; FIGS. 8A to 8I are cross sectional views showing a manufacturing method of the semiconductor device according to the second embodiment of the present invention; FIG. 9 is a cross section view showing the structure of the semiconductor device according to a third embodiment of the present invention; FIG. 10 is a diagram showing an impurity density profile in the semiconductor device according to the third embodiment of the present invention; FIG. 11 is a cross section view showing the structure of the semiconductor device according to a fourth embodiment of the present invention; FIG. 12 is a diagram showing an impurity density profile in the semiconductor device according to the fourth embodiment of the present invention; FIGS. 13A to 13H are cross sectional views showing a manufacturing method of the semiconductor device according to the fourth embodiment of the present invention; FIG. 14 is a cross section view showing the structure of the semiconductor device according to a fifth embodiment of the present invention; FIG. 15 is a diagram showing an impurity density profile in the semiconductor device according to the fifth embodiment of the present invention; FIG. 16 is a cross section view showing the structure of the semiconductor device according to a sixth embodiment of the present invention; FIG. 17 is a cross section view showing the structure of the semiconductor device according to a seventh embodiment of the present invention; FIG. 18 is a cross section view showing the structure of the semiconductor device according to an eighth embodiment of the present invention; FIG. 19 is a diagram showing an impurity density profile in the semiconductor device according to the eighth embodiment of the present invention; FIG. 20 is a diagram showing a relationship of threshold voltage and minimum potential; FIG. 21 is a diagram showing a relationship of implantation width and minimum potential; FIG. 22 is a diagram showing a relationship of position and impurity concentration; and FIG. 23 is a diagram showing another relationship of threshold voltage and minimum potential. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a semiconductor device and a manufacturing method of the same of the present invention will be described in detail with reference to the attached drawings. FIG. 3 is a cross sectional view showing the structure of the semiconductor device according to the first embodiment of the present invention. Referring to FIG. 3, in the semiconductor device according to the first embodiment of the present invention, a buried insulating film 2 is formed on a semiconductor substrate 1. A silicon substrate exemplifies the substrate, and an oxide film exemplifies the buried insulating film 2. The semiconductor layer of silicon is laminated on the buried insulating film 2. N-type SD regions 3 are formed in the semiconductor layer on an SOI substrate having such a laminated structure. N-type SD extension regions 4 are formed to be connected to the respective SD regions. A P-type low concentration region 5 is formed as a channel region on the central region between the SD extension regions 4. A P-type Halo implantation region 6 is formed between each of the SD extension regions 4 and the low concentration region 5. A gate insulating film 7 is formed on the SD extension regions 4, the low concentration region 5 and the Halo implantation regions 6. A gate electrode 8 is formed on the gate insulating film 7. A side wall insulating film 9 is formed on either side of the gate electrode 8. A field insulator 11 is formed at an outer end of the SD region 3 for device isolation. As shown in FIG. 4, it is essentially important that the width of the Halo implantation region 6 in a lateral direction is equal to or less than 30 nm. When the Halo implantation region width is equal to or less than 30 nm, the short channel effect can be restrained without changing the threshold voltage in an FET which has a small gate length of equal to or less than 0.1 μm. FIGS. 5A to 5H show a manufacturing method of the semiconductor device according to the first embodiment of the present invention. As shown in FIG. 5A, the buried insulating film 2 as the oxide film is formed on the substrate 1 formed of silicon or semiconductor insulation material such as sapphire to have a proper thickness, e.g. 100 nm. Next, the semiconductor layer 3′ of silicon is deposited on the buried insulating film 2 to have a proper thickness in a range of 5 nm to 2 μm. The SOI substrate having such a laminate structure can be formed by the SIMOX method through an ion implantation of oxygen in the silicon substrate or be formed as the laminate structure. Next, as shown in FIG. 5B, the field insulator 11 as a device isolation region is formed on the either outer end of the semiconductor layer 3 by a LOCOS method or a trench separation method. Subsequently, an oxide film 12 with the thickness of 10 nm is formed on the semiconductor layer 3 by a thermal oxidation. Subsequently, impurities are added into the semiconductor layer 3 by the ion implantation method to form the low concentration region 5. Next, as shown in FIG. 5C, the oxide film 12 is removed and the gate insulating film 7 is formed as the oxide film with the thickness of about 2 nm by the thermal oxidation technique. Subsequently, a polysilicon film is deposited on the gate insulating film 7 to have the thickness of 200 nm. The polysilicon film is selectively etched to form the gate electrode 8. The gate insulating film 7 is limited to the oxide film and may be formed of a nitride film and a film of other insulation material. Next, as shown in the FIG. 5D, the gate electrode 8 is used as a mask to form the Halo implantation region 6 having the impurity density higher than the impurity density of the low concentration region 5. In this implantation process, ions are implanted from a diagonal or oblique direction into a region below the gate electrode 8 via the gate insulating film so that the low concentration region 5 can be defined. In this way, by changing the implantation angle in the diagonal implantation, the width of the Halo implantation region 6 in the lateral direction can be adjusted. Next, as shown in FIG. 5E, the SD extension regions 4 having a conductive type opposite to the conductive type of the low concentration region 5 and the Halo implantation region 6 are formed by the implantation method. The SD extension regions 4 are formed on the outside of the Halo implantation regions 6 and the ion implantation direction is perpendicular direction to the surface of the SOI substrate. Through such an ion implantation method, the Halo implantation region 6 is formed on the inside of the SD extension region 4. The width of the Halo implantation region 6 can be changed by adjusting a geometrical condition such as the implantation angle and a thermal diffusion process condition. In the present invention, the width of the Halo implantation region 6 is set to be an equal to or less than 30 nm. Next, as shown in FIG. 5F, an insulating film, e.g. an oxide film is deposited by the CVD method to have the thickness of about 150 nm. Anisotropic etching is carried out such that the insulating film is left on the side walls of the gate electrode 8. Thus, side wall insulating films 9 are formed through the etching. At the same time, the gate insulating film 7 is etched. Next, as shown in FIG. 5G, impurity atoms are added into the SD extension regions 4 to form the SD regions 3 by the ion implantation method using the gate electrode 8 and the side wall insulating films 9 as a mask. Next, as shown in FIG. 5H, an insulating film 14 is formed over the whole surface, and contact regions are opened in the insulating film 14. A metal film is deposited by the CVD method to form an embedded metal plug in the opening for the contact region and then the metal film is removed by the CMP method. As a result a FET is produced. In order to reduce a resistance of the SD region, it is desirable that a cobalt silicide film is formed on the SD regions 3 and the gate electrode 8 by sputtering atoms such as Co and carrying out a thermal treatment, after the process of FIG. 5G. Also, in the above, the threshold voltage is controlled by adding the impurity in the low concentration region 5 by the technique such as the ion implantation. However, the low concentration region 5 may be substituted to a so-called intrinsic semiconductor region in which no impurity atom is added. In this case, the gate electrode is formed as a metal gate having a different work function from polysilicon. Thus, it is possible to achieve control of the threshold voltage by the metal gate and high mobility in the channel of the intrinsic semiconductor. In case of the intrinsic semiconductor, it is possible to prevent degradation of the semiconductor device characteristics due to punch-through and formation of a channel on the side of the buried insulating film, by forming the Halo implantation regions. Moreover, it is possible to form a device with a small gate length equal to or less than 0.1 μm by controlling the width of the Halo implantation region 6. The width of the Halo implantation region 6 is finally determined based on the implantation angle of the ion implantation in the formation of the Halo implantation region, an implantation energy, diffusion of implanted ions in the lateral direction, an ion implantation condition for formation of the SD extension regions in the later process, and diffusion of implanted ions into the lateral direction. The technique for the formation of the Halo implantation region is not limited to the ion implantation method, and another technique such as solid diffusion to add impurity may be applied. In the above, though the low concentration region is formed by the technique to add impurity through the ion implantation, it is not limited to this. An intrinsic semiconductor may be used. In this case, the mobility of carriers is higher than in case that the impurity is added. Thus, a merit of improvement of device character in operation speed is achieved. A fully depleted MOSFET operation can be carried out by setting the width of the Halo implantation region equal to or less than 30 nm, more desirably 20 nm. In case that the width of the Halo implantation region is larger than 40 nm, it becomes easy for a partially depleted SOI-MOSFET operation to be caused, as the gate length is made finer. FIG. 6 shows a semiconductor device according to the second embodiment of the present invention. Referring to FIG. 6, a buried insulating film 2 as an oxide film is formed on a substrate 1 to have the thickness from 10 nm to 500 nm. A semiconductor layer of silicon is laminated on the buried insulating film 2 to have the thickness from 10 nm to 500 nm. In this way, a SOI substrate of the laminated structure is formed. SD regions 3, SD extension regions 4, Halo implantation regions 6 and a low concentration region 5 are formed on the SOI substrate in the same way as the first embodiment of the present invention. Moreover in the same way of the first embodiment, a gate insulating film 7, a gate electrode 8 and side wall insulating films 9 are formed. Especially in the second embodiment of the present invention, a diffusion barrier region 17 is formed on each side end of the low concentration region 5 in the directions of the Halo implantation regions 6, that is, the diffusion barrier regions 17 are formed between the low concentration region 5 and each of the Halo implantation regions 6. The diffusion barrier region 17 can be formed by an adding technique such as an ion implantation method to add atoms such as fluorine or carbon. FIG. 7 shows an impurity concentration profile in the lateral direction between the SD regions 4 in a semiconductor device according to the second embodiment of the present invention. As shown in FIG. 7, the Halo implantation regions 6 are formed on the both sides of the low concentration region 5 put between the SD extension regions 4. The diffusion barrier regions 17 are respectively formed between the low concentration region 5 and the Halo implantation regions 6. Especially, the diffusion barrier region 17 in which fluorine or the like is added in this way has an effect to reduce a boron diffusion rate and can restrain the spread of the width of the Halo implantation region 6. Through such a restraint effect, an element with a finer gate length is provided. FIGS. 8A to 8I show a manufacturing method of the semiconductor device according to the second embodiment of the present invention. As shown in FIG. 8A, a buried insulating film 2 with the thickness of 100 nm is formed as the oxide film on the substrate 1 formed of silicon or an insulation material such as sapphire. Moreover, a semiconductor layer 13 of silicon is laminated on the buried insulating film 2 to have the thickness from 5 nm to 2 μm. Thus, a SOI substrate is formed. Next, as shown in FIG. 8B, field insulator 11 are formed as device isolation regions by a LOCOS method or a trench separation method. An oxide film 12 of 10 nm in thick is formed on the semiconductor layer 13 by a thermal oxidation. Subsequently, impurity is added to the semiconductor layer 13 so that the low concentration region 5 is formed. Next, as shown in FIG. 8C, the oxide film 5 is removed and the gate insulating film 7 is formed by the thermal oxidation as the oxide film with the thickness of about 2 nm. Subsequently, a polysilicon film is deposited in the thickness of 200 nm, and is selectively etched to form the gate electrode 8. Next, as shown in FIG. 8D, the gate electrode 8 is used as a mask to add fluorine or carbon in a dose quantity from 1012 cm−2 to 1016 cm−2 from a diagonal or oblique direction by the ion implantation method. Next, as shown in FIG. 8E, ions are implanted from the diagonal or oblique direction. That is, boron is implanted in NMOS, arsenic is implanted in PMOS, from the diagonal direction as the impurities. Here, the Halo implantation regions 6 can be formed on the outer side of each of the diffusion barrier regions 17 by the ion implantation in which the implantation angle is smaller than that in the formation of the diffusion barrier regions 17 in the previous process, or by implantation energy which leads the shallow implantation. Next, as shown in FIG. 8F, the impurities of a conductive type opposite to that of the low concentration region 5 and the Halo implantation region 6, for example, boron in the NMOS and arsenic in PMOS, are added by the ion implantation method to form the SD extension regions 4. In this case, the impurity is implanted from the perpendicular direction. Thus, the Halo implantation regions 6 are formed on the inside of the SD extension regions 4. In this way, the Halo implantation region 6 is formed between the SD extension region 4 and the diffusion barrier region 17. By controlling a thermal treatment condition after this process, the width of the Halo implantation region 6 can be varied and especially, can be controlled to be equal to or less than 30 nm. Because the diffusion rate of the impurity implanted into the Halo implantation region 6 in the diffusion barrier region 17 is slow, it is hard for the impurity of the Halo implantation region 6 to diffuse toward the low concentration region 5 at the thermal treatment process. As a result, the characteristics of the transistor never degrade even if the gate length is made finer and the low concentration region 5 is made narrower. Next, as shown in FIG. 8G, an insulating film as the oxide film is deposited by the CVD method to have the thickness of about 150 nm, and the insulating film is etched by anisotropic etching. In this-way, the side wall insulating films 9 remain on the sides of the gate electrode 8 and the gate insulating film 7 is etched at the same time. Next, as shown in FIG. 8H, the gate electrode 8 and the side wall insulating films 9 are used as a mask, and the impurity is added by the ion implantation method. Thus, the SD regions 3 are formed. Next, as shown in FIG. 8I, an insulating film 14 is formed over the whole surface and openings for contact regions are produced in the insulating film 14. A metal film is deposited and embedded metal plugs 15 are formed in the contact regions. Then, wiring line layers 16 are selectively formed on the contact region, and an FET is produced. As mentioned above, according to the second embodiment, it is possible to restrain that the impurity in the Halo implantation region 6 diffuses toward the low concentration region, even if the thermal treatment is carried out after the formation of the Halo implantation region. Also, the Halo implantation region can be formed even in a finer gate length with a good controllability. The technique for forming the diffusion barrier region 17 is not limited to the technique for forming it through the implantation from the diagonal or oblique direction using the gate electrode as a mask. A technique may be also adopted in which the diffusion barrier region is previously formed fully on the semiconductor layer surface before the formation of the gate electrode. In the second embodiment as mentioned above, a concentration profile of the Halo implantation region 6 in the lateral direction is shown as the structure that the Halo implantation region 6 is formed to have a trapezoidal shape where a concentration is constant in the lateral direction. However, the present invention is not limited to this. It is in practical that the Halo implantation region 6 is formed to have a concentration profile in which the impurity density gradually decreases in a direction from the both edges of the SD extension regions 4 to the low concentration region 5. In this case, a neutral region is difficult to be formed compared with the case of the trapezoidal shape, and a fully depleted MOSFET operation can be achieved. Moreover, because the width on the side of the buried insulating film is made larger, it is possible to suppress the back channel effect. FIG. 9 shows a semiconductor device according to the third embodiment of the present invention. Referring to FIG. 9, a buried insulating film 2 in thickness from 100 nm to 500 nm is formed on a substrate 1. Moreover, a semiconductor layer in a thickness from about 100 nm to 500 nm is laminated to form a SOI substrate of a laminated structure. On the SOI substrate, SD regions 3, SD extension regions 4, a low concentration region 5 as a channel region, and a Halo implantation region 6 formed between the low concentration region 5 and each of the SD extension regions 4 are formed. Moreover, a gate insulating film 7, a gate electrode 8, side wall insulating films 9 are formed in the same way as the above mentioned first and second embodiments. FIG. 10 shows an impurity concentration profile in the deep direction in the low concentration region 5 of the semiconductor device according to the third embodiment of the present invention. As shown in FIG. 10, the low concentration region 5 as the channel region has a nonuniform concentration profile, in which the concentration is high on the side near to the gate electrode 8, and is low on the side near to the buried insulating film 2. In this way, by localizing the impurity atoms on the side of the surface, and by setting the impurity concentration on the side of the buried insulating film to be low, a depletion layer spreads largely on the side of the buried insulating film. For this reason, it is possible to realize the same fully depleted MOSFET operation as in case of an SOI structure which has the film thickness corresponding to the depth of high concentration region of the low concentration region 5, even if the film thickness of the SOI structure is thick. It is desirable for realizing the fully depleted MOSFET operation that the depth of the region with a high concentration is equal to or less than about ¼ length of the gate length. FIG. 11 shows a semiconductor device according to the forth embodiment of the present invention. A buried insulating film 2 in a thickness from 10 nm to 500 nm is formed on a substrate 1. A substrate of the laminate structure is formed, in which a semiconductor layer in a thickness about 10 nm to 500 nm film is laminated on the buried insulating film 2. On an SOI substrate are formed SD regions 3, SD extension regions 4, a low concentration region 5, a Halo implantation region 6 formed between the low concentration region 5 and each of the SD extension regions 4 and a buried diffusion barrier region 17 under the low concentration region 5 on the side of the buried oxide film 2. Moreover, a gate insulating film 7, a gate electrode 8, side wall insulating films 9 are formed in the same way as the above mentioned first to third embodiments. FIG. 12 shows an impurity concentration profile in the deep direction in the low concentration region 5 and the diffusion barrier region 17 below the gate insulating film 7 in the semiconductor device according to the forth embodiment of the present invention. As shown in FIG. 12, the low concentration region 5 as a channel region has a nonuniform concentration profile, in which the concentration is high on the side near to the gate electrode 8, and is low on the side near to the buried insulating film 2. Moreover, the buried diffusion barrier region 17 is formed on a deeper side region on the side of the buried oxide film 2. Here, in case of an NMOS FET, the impurity of the low concentration region 5 is an element such as boron, and the impurity in the buried diffusion barrier region 17 is an element such as fluorine, carbon, and indium. Moreover, it is desirable that the impurity atoms in the low concentration region 5 are implanted in a depth region from 10 nm to 30 nm from the gate insulating film 7. By forming the buried diffusion barrier region 17 in this way, it is possible to effectively prevent that the impurity atoms in the high concentration region diffuse in the depth direction. Thus, it is possible to form a shallower impurity distribution precisely. FIG. 13A to 13H show a manufacturing method of the semiconductor device according to the forth embodiment of the present invention. As shown in FIG. 13A, a buried insulating film 2 with the thickness of 100 nm is formed on the substrate 1. A semiconductor layer 3 in a thickness from 5 nm to 2 μm is laminated on the buried insulating film 2. Next, as shown in FIG. 13B, an oxide film 12 with the thickness of about 10 nm is formed on the semiconductor layer 3. An impurity such as fluorine is added into the semiconductor layer 3 by the ion implantation method to form a buried diffusion barrier region 17. Then, a low concentration region 5 is formed by the ion implantation method. Here, in case of NMOS, the low concentration region 5 is formed in a dose quantity from 1012 cm−2 to 1016 cm−2 through the ion implantation of the low energy of 0.5 KeV to 1 Kev. As a result, a concentration profile is formed to decrease gradually from the surface of the semiconductor layer 3. Next, as shown in FIG. 13C, the oxide film 12 is removed and a gate insulating film 7 with the thickness of about 2 nm is formed. The, a polysilicon film is deposited in the thickness of 200 nm and is selectively etched to form a gate electrode 8. Next, as shown in FIG. 13D, the ions are implanted from the diagonal or oblique direction, that is, boron is implanted in case of NMOS, and arsenic is implanted in case of PMOS. Here, by selecting angle and energy in the ion implantation, the Halo implantation region 6 can be defined outside the diffusion barrier region 17. Next, as shown in FIG. 13E, the impurities of a conductive type opposite to that of the low concentration region 5 and the Halo implantation region 6, for example, arsenic in the case of NMOS and boron in the case of the PMOS, are added through the ion implantation to form the SD extension regions 4. The direction of the ion implantation is perpendicular so that a Halo implantation region 6 is formed on the inside of the SD extension region 4. Next, as shown in FIG. 13F, an insulating film is deposited in the thickness of about 150 nm by the CVD method and then the insulating film is removed through the anisotropic etching to form side wall insulating films 9 on side walls of the gate electrode 8. At the same time, the gate insulating film 7 is removed. Next, as shown in FIG. 13G, the gate electrode 8 and the side wall insulating films 9 are used as a mask, and the impurity is added by the ion implantation method to form the SD regions 3. Next, as shown in FIG. 13G, the insulating film 14 is formed over the whole surface and openings for contact regions are produced in the insulating film 14. A buried metal 15 is deposited to fill the contact regions. Subsequently, wiring line layers 16 are selectively formed on the contact region. Thus, the FET is produced. According to the forth embodiment, the diffusion barrier region 17 is previously formed before the ion implantation process of the low concentration region. Thus, it is possible to restrain the deep diffusion of the impurities of the low concentration region spreads forming. In this way, the impurity density of the low concentration region 5 near to the gate insulating film 7 can be kept high so that the fully depleted MOSFET operation can be carried out. Moreover, the threshold voltage can be set high. FIG. 14 shows a semiconductor device according to the fifth embodiment of the present invention. A buried insulating film 2 in a thickness from 10 nm to 500 nm is formed on a substrate 1. A semiconductor layer in a thickness from about 10 nm to 500 nm is laminated to form a SOI substrate of a laminated structure. On the SOI substrate are formed SD regions 3, SD extension regions 4, a low concentration region 5 as a channel region, and Halo implantation regions 6 which are respectively formed between the low concentration region 5 and the SD extension regions 4. Moreover, a gate insulating film 7, a gate electrode 8, side wall insulating films 9 are formed in the same way as the first and second embodiments. FIG. 15 shows an impurity concentration profile the Halo implantation region 6 in the depth direction in the semiconductor device according to the forth embodiment of the present invention. As shown in FIG. 15, the low concentration region 5 as the channel region has a nonuniform concentration profile, in which the concentration is high on the side near to the gate electrode 8, and is low on the side of the buried insulating film 2, and is high again at the phase boundary of the buried insulating film 2. In this way, by localizing the impurity ions on the side of the surface, and by setting the impurity density on the side of the buried insulating film to be low, a depletion layer largely spreads on the side of the buried insulating film 2. Therefore, though a thickness of the SOI film is thick, a fully depleted MOSFET operation can be carried out in the same way as a transistor which has the film thickness corresponding to the depth of the high concentration region in the low concentration region 5 on the surface side. Moreover, by setting the concentration near to the buried insulating film 2 to be high, it is possible to restrain so-called back channel operation, in which a channel is formed on the side of the buried insulating film 2. In order to set the concentration of the low concentration region near to the buried insulating film 2 to be high, the ion implantation with high energy is preferable. Besides, methods are applicable such as a method of adding the impurity into the buried insulating film 2 previously and a method of segregating ions in a surface. FIG. 16 shows the semiconductor device according to the sixth embodiment of the present invention. A buried insulating film 2 in a thickness from 10 nm to 500 nm is formed on a substrate 1. A semiconductor layer in a thickness from 10 nm to 500 nm is laminated on the buried insulating film 2 to form a SOI substrate of a laminated structure. On the SOI substrate of the laminated structure are formed SD regions 3, SD extension regions 4, a low concentration region 5 as a channel region, and a Halo implantation region 6 formed between the low concentration region 5 and each of the SD extension regions 4. Moreover, a gate insulating film 7, a gate electrode 8, and side wall insulating films 9 are formed. An impurity density profile of the low concentration region 5 in the depth direction is the same as the profiles shown in FIG. 10, FIG. 12, and FIG. 15. As shown in FIG. 16, the Halo implantation regions 6 are formed on the surface side of the SOI layer, but are not formed on the side near to the insulating film 1. In the first embodiment, the concentration of a lower portion of the Halo implantation region 6 near to the buried insulating film 2 is set higher than that of a lower portion of the low concentration region 5 near to the buried insulating film 2. Therefore, a neutral region is formed in the Halo implantation region 6, and there is a case that a partially depleted SOI-MOSFET operation is easy to be carried out. However, the Halo implantation region 6 is formed only on the surface side of a channel region in the sixth embodiment and thereby it is possible to restrain the generation of the partially depleted SOI-MOSFET operation in the Halo region 6. FIG. 17 shows a semiconductor device according to the seventh embodiment of the present invention. A buried insulating film 2 in a thickness from 10 nm to 500 nm is formed on a substrate 1. A semiconductor layer in a thickness from about 10 nm to 500 nm is laminated on the buried insulating film 2 to form a SOI substrate of a laminated structure. On the SOI substrate are formed SD regions 3, SD extension regions 4, a low concentration region 5 as a channel region, and a Halo implantation region 6a with a high concentration and a Halo implantation region 6b with a low concentration formed between the low concentration region 5 and each of the SD extension regions 4. Moreover, a gate insulating film 7, a gate electrode 8, and side wall insulating films 9 are formed so that forming a FET is completed. An impurity density profile of the low concentration region 5 in the depth direction is as same as the profiles shown in FIG. 10, FIG. 12, and FIG. 15. As shown in FIG. 17, the Halo implantation region 6a is formed on the surface side of the SOI layer, and the Halo implantation region 6b is formed on the side of the buried insulating film 2. Here, the impurity densities of the Halo implantation regions are set to be higher than the concentration of the low concentration region 5 on the near side of the buried insulating film 2 to restrain the generation of a punch-through. Moreover, the density of the Halo implantation region 6b is set lower than a density in which a short channel effect in the Halo implantation region 6a can be restrained. Thus, a partially depleted SOI-MOSFET operation can be further restrained. FIG. 18 shows a semiconductor device according to the eighth embodiment of the present invention. A buried insulating film 2 in a thickness from 10 nm to 500 nm is formed on a substrate 1. A semiconductor layer in a thickness from 10 nm to 60 nm is laminated on the buried insulating film 2 to form a SOI substrate. On the SOI substrate of the laminated structure are formed SD regions 3, SD extension regions 4, a low concentration region 5, and a Halo implantation region 6 formed between the low concentration region 5 and each of the SD extension regions 4. A buried implantation region 18 is formed under the Halo implantation regions 6 and the low concentration regions 5 and on the buried insulating film 2. Moreover, a gate insulating film 7, a gate electrode 8, and side wall insulating films 9 are formed. The impurity of a conductive type opposite to that of the Halo implantation region 6 and the low concentration region 5 is implanted into the buried implantation region 18. In the semiconductor device according to the eighth embodiment of the present invention, an impurity density profile of the low concentration region 5 in the depth direction is the same as FIG. 10 or FIG. 12 or is uniform. FIG. 19 shows an example of detail of the impurity density profile in a portion A of FIG. 18. The impurity, e.g., boron is implanted and added to the low concentration region 5 in the energy of about 0.5 Kev and in a dose quantity from 1×1013 cm−3 to 5×1013 cm−3, especially 1×1013 cm−3 to 3×1013 cm−3. Moreover, another impurity, e.g., arsenic is implanted and added to the low concentration region 5 in the energy of about 50 Kev and in a dose quantity from 0.5×1013 cm−3 to 5×1013 cm−3, especially 0.5×1013 cm−3 to 2×1013 cm−3. After the gate electrode 8 is formed, the impurity ions BF2 are implanted in the energy of about 20 Kev and in a dose quantity of approximately 3.5×1013 cm−3 from a proper diagonal or oblique angle, for example, at 30 degrees from a perpendicular direction to a wafer surface to form the Hallo implantation region. By forming the buried implantation region 18 of the conductive type opposite to those of the Halo implantation region 6 and the low concentration region 5, a carrier concentration under the Halo implantation regions 6 and the low concentration regions 5 is cancelled based on the degrees of depths of P-type impurity and N-type impurity. As a result, the Halo implantation region 6 and the low concentration region 5 substantively decrease in concentration under these regions and have the conductive type of an N-type. As shown in FIG. 19, the concentration of the Halo implantation region 6 decreases sharply in the depth direction while the Halo implantation region 6 keeps the P-type, and the low concentration region 5 decreases further sharply in a region deeper than the decrease region and changes into the N-type by a PN junction 19. FIG. 19 shows a case that the Halo implantation region 6 keeps a P-type, and the Halo implantation region 6 has changed into the N-type. However, it is possible to implant the impurity such that the concentrations of the Halo implantation region 6 and the low concentration region 5 decrease sharply while the Halo implantation region 6 and the low concentration region 5 keep the P-type. It is also possible to set the density distribution proper effectively by the multi-layer structure as in the seventh embodiment. It is effective in achievement of the objects of the present invention to change a lower region of each of the Halo implantation regions 6 and the low concentration region 5 into the N-type. In this case, it is essentially important to restrain the concentration in a low concentration of the N-type to the extent that a punch-through is not caused. By forming the buried impurity region 18 in which the impurity concentration continuously or rapidly increases in the depth direction, the impurity density profiles of the Halo implantation region 6 and the low concentration region 5 have shapes such that the impurity effectively exists in the surface region on the side of the gate to restrain decrease in the minimum potential of the SOI layer and to restrain the partially depleted SOI-MOSFET operation. The buried impurity region 18 can provide the conspicuous restraint effect by a simple manufacturing process without the precise control of the impurity density profiles of the Halo implantation region 6 and the low concentration region 5. FIG. 20 shows a relation between threshold voltage and the minimum potential in the SOI layer using the width of the Halo implantation region as a parameter. In the MOSFET using the SOI substrate with the Halo implantation region width less than or equal to 30 nm, especially, less than or equal to 20 nm, a problem of the decrease of the minimum potential in the SOI layer is caused. The problem can be prevented by implanting the impurity in a region of the SOI layer apart from the source/drain (SD) region by 20 nm to 30 nm, especially, in a lower portion of the region of the SOI layer. This principle is clearly shown in FIG. 21. According to such principle, the Halo implantation region 6 functions effectively in the semiconductor device designed to have a narrow lateral direction width and a very small gate length. Thus, as shown in FIG. 20, the decrease in the minimum potential can be achieved while the Halo implantation region 6 has a width equal to or less than 30 nm, preferably, equal to or less than 20 nm and the threshold voltage in the fully depleted MOSFET operation is kept high. FIG. 21 shows a relation with the width of the Halo implantation region 6 and the minimum potential of the semiconductor device. The rise of the minimum potential of the semiconductor device is steeper when the width of the Halo implantation region becomes narrower than 30 nm, compared with the case that the width of the Halo implantation region is equal to or more than 30 nm. If the width of the Halo implantation region becomes narrower than 20 nm, the rise of the minimum potential of the semiconductor device is further steeper compared with the case that the width of the Halo implantation region is equal to or more than 30 nm. FIG. 22 shows the impurity concentration inclination in the lateral direction. The horizontal axis indicates a relative position in the lateral direction, containing the 30-nm width of the Halo implantation region 6. The vertical axis indicates the impurity concentration. The impurity concentration in a certain reference position, for example, a source junction position is approximately 3.5×1018 cm−3. A graph under a condition 1 shows a concentration inclination in the present invention in which impurities is implanted under the condition mentioned in the graph. A graph under a condition 2 shows a concentration inclination in the conventional semiconductor device in which the impurity is implanted under the condition mentioned in the graph. The inclination under the condition 2 is gentle and is approximately 3×1023 cm−4 on the average in case of the width of 30 nm. On the other hand, the inclination under the condition 1 of the present invention is approximately 1×1024 cm−4 on the average in case of the width of 30 nm. FIG. 22 shows the inclination between a distance from the source junction plane and the concentration decrease. The concentration decrease by {fraction (1/10)} is equivalent to the width of 30 nm, and the concentration decrease by ¼ is equivalent to the width of 20 nm. FIG. 23 shows a relation between the threshold voltage and the minimum potential and shows comparison between the above-mentioned condition 1 and condition 2. It is obvious that the minimum potential in the SOI layer is high in the state of high threshold voltage, as shown by the graph of the condition 1 according to the present invention. As shown in FIG. 22, in case that the impurity concentration in the Halo implantation region in the lateral direction has inclination, it could be understood that the minimum potential decrease becomes small when the impurity is implanted into the width of the 30 nm or 20 nm in the Halo implantation region 6, especially the impurity is implanted into a region lower than the Halo implantation region 6, by setting the concentration at a position apart from the source/drain end by 30 nm to {fraction (1/10)} of the concentration at the source/drain end, by setting the concentration at a position apart from the source/drain end by 20 nm to ¼ of the concentration at the source/drain end, or by setting the concentration inclination at a position apart from the source/drain end by 20 nm to 1×1024 cm−4. As a result, it is possible to restrain the decrease in the minimum potential, to keep a fully depleted MOSFET operation, and to restrain a floating body effect. FIG. 20 indicates that it is possible to restrain the potential decrease in the lower region of the Halo implantation region, to keep the fully depleted MOSFET operation, and to restrain the floating body effect, by limiting a region of the Halo implantation region where the impurity is implanted to a high concentration, to the surface region on the side of the gate insulating film, or by setting the concentration in the surface region to three times higher than a peak value of the concentration in the lower region. It is possible to stabilize the fully depleted MOSFET operation, by applying the concentration inclination in the depth direction and the concentration inclination in the lateral direction to the Halo implantation region. Further, it is possible to keep the fully depleted MOSFET operation in the state in which the threshold voltage is held high in the semiconductor device with a smaller gate length, by forming the impurity region for the effective channel region shallowly in the surface region of the Halo implantation region on the side of the gate insulating film. Also, it is possible to restrain a short channel effect. In this way, a smaller fully depleted MOSFET device can be formed in the state that the SOI film is thick. Moreover, it is possible to prevent the spreading of the Halo implantation region through a thermal treatment process by forming a diffusion barrier region on the channel side of the Halo implantation region. Additionally, in a CMOS device, it is possible to match a diffusion rate of boron with a fast diffusion rate with a diffusion rate of arsenic with a slow diffusion rate boron, by forming the diffusion barrier region in which the boron as the impurity of the Halo implantation region is added and by forming no diffusion barrier region in which the arsenic as the impurity of the Halo implantation region is added. Moreover, it is possible to carry out the fully depleted MOSFET operation of the semiconductor device with the comparative thick SOI film under the condition that the decrease of the threshold voltage is restrained, forming the buried diffusion barrier region on the side of the buried oxide film below the channel region and by forming the Halo implantation region on the surface side to have a ununiform impurity distribution in the depth direction. Furthermore, by adding the impurity atoms for the conductive type opposite to that of the channel region to a lower region of the channel region, the impurity concentration is high in the channel region and the impurity concentration is low in the lower region or the lower region has the opposite conductive type. In this way, it is possible to form a laminated structure by which the partially depleted SOI-MOSFET operation is hard to be caused. According to the semiconductor device and the manufacturing method of the semiconductor device of the present invention, the width of the Halo implantation region is equal to or less than 30 nm, preferably equal to or less than 20 nm, the decrease of the minimum potential in the SOI layer is

<SOH> BACKGROUND ART <EOH>An SOI substrate is known as a semiconductor substrate in which an insulating film (an oxide film in many cases) is formed on a substrate and a semiconductor layer (a silicon layer) is formed on it. In a MOSFET to which such an SOI substrate is applied, because the insulating film is formed under a source region and a drain region, a parasitic capacitance can be made smaller compared with a case of a usual bulk substrate in which the SOI layer is not used. As a result, the SOI substrate is superior in high speed operation of the device and it has been widely used. Generally, the MOSFETs using the SOI substrate is grouped into a fully depleted SOI-MOSFET in which the SOI layer below the gate is depleted and a partially depleted SOI-MOSFET in which the SOI layer is not fully depleted so that a neutral region is left. The partially depleted SOI-MOSFET has an advantage that it can be manufactured by a manufacturing method in which a process for a bulk substrate is used. However, because the neutral region which is electrically separated from the substrate is left, the potential of the neutral region changes depending on an operation condition and operation current changes, namely, so-called floating body effect is caused. For this reason, circuit design becomes difficult. On the other hand, because there is not an neutral region in the fully depleted SOI-MOSFET, the potential under the channel does not change and there is an advantage that the circuit operation is stable.. However, in the full depleted transistor, unless the SOI layer is made extremely thin, the characteristic degradation of the device is easy to be caused due to punch-through and short channel effects, compared with the partially depleted SOI transistor. A measure to the characteristic degradation is proposed in which Halo regions where a channel impurity concentration is high are formed on both sides of the channel region. Such a conventional technique is known in Japanese Laid Open Patent Application (JP-A-Heisei 9-293871). FIGS. 1 and 2 show such a semiconductor device. Referring to FIG. 1 , SD (source and drain) regions 103 are formed in the SOI substrate in which a buried insulating film 102 of an oxide film is formed on a base substrate 101 of silicon and a semiconductor layer is formed on the buried insulating film 102 . A low concentration region 104 for a channel region and the Halo implantation regions 105 are formed in the region, and a gate insulating film 106 , a gate electrode 107 , side wall insulating films 108 are formed. Especially, the Halo implantation region 105 has an impurity density profile of the shape shown in FIG. 2 in a lateral direction. The setting of the Halo region with such a high impurity density profile is excellent to restrain the floating body effect. The profile N(x) of the Halo region 105 of such a conventional semiconductor device in the lateral direction is expressed by the following equation. in-line-formulae description="In-line Formulae" end="lead"? N ( x )+N 0 +N b0 ·|exp(−[η·( x−L /2] g )+exp(−[η·( x+L/ 2] g )| in-line-formulae description="In-line Formulae" end="tail"? When η is in a range from 8 to 20 or the concentration inclination in the lateral direction is in 3−8×10 22 cm −4 , the current gain h fe of a parasitic bipolar transistor formed by the SD regions 103 and the low concentration region 104 can be reduced. In addition to the restraint of the short channel effect, the fine and stable operation becomes possible. However, in the above-mentioned conventional example, the spreading of the impurity distribution from the peak into the lateral direction is about 0.1 μm. When a device is formed to have a gate length of a sub half micron range, the tails of the impurity profiles from both sides overlap and the Halo structure cannot be formed to have high concentration regions on both sides. If the tails of the impurity profiles from both sides overlap, the impurity concentration in the center portion of the channel region rises, so that the partially depleted SOI-MOSFET operation is easy to be carried out. That is, the fully depleted MOSFET operation becomes difficult. It is demanded that the technique which restrains the floating body effect is established and the technique is different from the conventional method of setting a concentration inclination (a range of η from 8 to 20 or the concentration inclination in the lateral direction is 3−8×10 22 cm −4 ) in accordance with the principle of the conventional example. Conventionally, the SOI-MOSFETs having various Halo regions are proposed. However, they does not described the effective knowledge to form ideal impurity distribution nor suggests what impurity distribution is proper. Because the gate oxide film becomes thin if the miniaturization of the transistor proceeds, the channel impurity concentration increases to get a necessary threshold voltage. With the increase, the minimum potential decreases so that it is easy to carry out the partially depleted SOI-MOSFET operation. In case of the N-channel transistor, the minimum potential decreases, in case of the P-channel transistor, the maximum potential increases. Thus, the same problem is caused in the N-channel transistor and the P-channel transistor. Hereinafter, the N-channel transistor will be described in this description as long as special notation is necessary. However, it could be understood to the person in the art that the same thing can be applied to the P-channel transistor. In the channel concentration in which the fully depleted MOSFET operation is carried out, it is known that the threshold voltage decreases, and a measure to it is needed. In conjunction with the above description, an SOI transistor is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 9-45919). In this conventional example, the transistor is composed of a semiconductor substrate, a buried insulating layer formed on the semiconductor substrate, a semiconductor layer section, a gate insulating film, a gate electrode layer, and a channel region. The semiconductor layer section is arranged on the buried insulating layer and is composed of a top surface, a bottom surface contacting the buried insulating layer, a source region and a drain region. The gate insulating layer is arranged on the top surface of the semiconductor layer section between the source region and the drain region. The gate electrode layer is arranged on the gate insulating layer. The channel region is arranged on the buried insulating layer under the gate insulating layer and is arranged at the semiconductor layer section between the source region and the drain region. The channel region has a top dopant concentration in correspondence to the top surface of the semiconductor layer section, and a bottom dopant concentration in correspondence to the bottom surface of the semiconductor layer section. Here, the top dopant concentration is higher than the bottom dopant concentration. Also, a silicon semiconductor transistor having a Halo implantation region is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 10-4198). In this conventional example, the transistor is composed of an insulating layer, and a semiconductor mesa which includes a first surface in contact with the insulating layer and a second surface opposite to the first surface. The semiconductor mesa is composed of a first source/drain region of a first conductive type, a second source/drain region of the first conductive type, a body region, and an implantation region. The body region has a first dopant level of a second conductive type, contacts the insulating layer, extends to the second surface of the mesa and is arranged between the first source/drain region and the second source/drain region. The implantation region is arranged between the first source/drain region and the body region to separate the first source/drain region from the body region. Also, the implantation region is of a second conductive type and has a dopant level which is substantively equal to or higher than the first dopant level. Also, a semiconductor device is disclosed in Japanese Laid Open Patent Application (JP-A-Heisei 11-204783. In this conventional example, in the semiconductor device includes a MIS-type electric field effect-type transistor. A region where halogen elements or halogen ions such as fluorine and chlorine exist is provided in at least one of a surface region and an inside region of the active region of the MIS-type electric field effect-type transistor of the semiconductor substrate. Also, a field effect transistor is disclosed in Japanese Laid Open Patent Application (JP-P 2000-349295). In this conventional example, the field effect transistor is composed of a semiconductor layer, a gate electrode, a source region and a drain region of a first conductive type. An element formation semiconductor layer is covered with an insulator at the bottom at least. A gate electrode is provided on the gate insulating film which is formed on the semiconductor layer. The source region and the drain region of the first conductive type are formed in the semiconductor layer on both sides of the gate electrode. A position where the second conductive type impurity concentration is maximum in the semiconductor layer under the gate electrode is nearer to the semiconductor layer surface than a maximum depth of an inverted layer in the neighborhood of the semiconductor layer surface when the gate electrode is supplied with a voltage larger than a threshold voltage. Also, the second conductive type impurity concentration is monotonously decreased from the maximum depth of the inverted layer toward a boundary between the semiconductor layer and the insulator.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a cross section view showing the structure of a conventional semiconductor device; FIG. 2 is a graph showing an impurity density profile in the semiconductor device shown in FIG. 1 ; FIG. 3 is a cross section view showing the structure of a semiconductor device according to a first embodiment of the present invention; FIG. 4 is a graph showing an impurity density profile in a lateral direction in the semiconductor device according to the first embodiment of the present invention; FIGS. 5A to 5 H are cross sectional views showing a manufacturing method of the semiconductor device according to the first embodiment of the present invention; FIG. 6 is a cross section view showing the structure of the semiconductor device according to a second embodiment of the present invention; FIG. 7 is a diagram showing an impurity density profile in the semiconductor device according to the second embodiment of the present invention; FIGS. 8A to 8 I are cross sectional views showing a manufacturing method of the semiconductor device according to the second embodiment of the present invention; FIG. 9 is a cross section view showing the structure of the semiconductor device according to a third embodiment of the present invention; FIG. 10 is a diagram showing an impurity density profile in the semiconductor device according to the third embodiment of the present invention; FIG. 11 is a cross section view showing the structure of the semiconductor device according to a fourth embodiment of the present invention; FIG. 12 is a diagram showing an impurity density profile in the semiconductor device according to the fourth embodiment of the present invention; FIGS. 13A to 13 H are cross sectional views showing a manufacturing method of the semiconductor device according to the fourth embodiment of the present invention; FIG. 14 is a cross section view showing the structure of the semiconductor device according to a fifth embodiment of the present invention; FIG. 15 is a diagram showing an impurity density profile in the semiconductor device according to the fifth embodiment of the present invention; FIG. 16 is a cross section view showing the structure of the semiconductor device according to a sixth embodiment of the present invention; FIG. 17 is a cross section view showing the structure of the semiconductor device according to a seventh embodiment of the present invention; FIG. 18 is a cross section view showing the structure of the semiconductor device according to an eighth embodiment of the present invention; FIG. 19 is a diagram showing an impurity density profile in the semiconductor device according to the eighth embodiment of the present invention; FIG. 20 is a diagram showing a relationship of threshold voltage and minimum potential; FIG. 21 is a diagram showing a relationship of implantation width and minimum potential; FIG. 22 is a diagram showing a relationship of position and impurity concentration; and FIG. 23 is a diagram showing another relationship of threshold voltage and minimum potential. detailed-description description="Detailed Description" end="lead"?

20040325

20090203

20050714

67210.0

KALAM, ABUL

SOI SEMICONDUCTOR DEVICE WITH IMPROVED HALO REGION AND MANUFACTURING METHOD OF THE SAME

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method and nework for ensuring secure forwarding of messages

The method and network ensure secure forwarding of a message in a telecommunication network that has at least one first terminal and another terminal. The first terminal moves from a first address to a second address. A secure connection between the first address of the first terminal and the other terminal defining at least the addresses of the two terminals is established. When the first terminal moves from the first address to a second address, the connection is changed to be between the second address and to the other terminal by means of a request from the first terminal and preferably a reply back to the first terminal.

1. A method for ensuring secure forwarding of a message in a telecommunication network, having at least one mobile terminal and another terminal, the method comprising: a) establishing a secure connection between a first address of the mobile terminal and the other terminal, the secure connection defined by at least the addresses of the two terminals, b) the mobile terminal moving from the first address to a second address, and c) changing the connection to be defined between the second address and the other terminal by means of a request message from the mobile terminal to the other terminal to change the address in the definition of the secure connection to the second address. 2. The method of claim 1, characterized in that, the secure connection is established in step a) by forming a Security Association (SA) using the IPSec protocols. 3. The method of claim 1, characterized in that in step c) a reply back to the mobile terminal is sent from the other terminal after the request from the mobile terminal to change the address. 4. The method of claim 1, characterized in that the registration request and/or the reply message is encrypted and/or authenticated by using the same SA already established. 5. The method of claim 1, characterized in that the change of addresses in the secure connection as a result of the request message is performed by means of a central register of current address of the terminals belonging to the network. 6. The method of claim 1 wherein the method further comprises providing a telecommunication network that has at least one mobile terminal and another terminal and a secure connection defined between a first address of the mobile terminal and the other terminal, characterized by means for changing the connection to be defined between a second address of the mobile terminal and the other terminal. 7. The method of claim 6, characterized in that the mobile terminal and the other terminal forms an end-to-end connection whereby the secure connection is an IPSec transport connection or IPSec tunnel connection. 8. The method of claim 6, characterized in that one of or both of the mobile terminal and the other terminal is a security gateway protecting one or more computers, whereby IPSec tunnel mode or IPSec together with a tunneling protocol is used for the secure connection between the mobile terminal and the other terminal. 9. The method of claim 6, characterized in that both terminals are mobile terminals. 10. The method of claim 9, wherein the method further comprises providing a central register of current locations of the terminals belonging to the network.

TECHNICAL FIELD The method and network of the invention is intended to secure mobile connections in telecommunication networks. Especially, it is meant for IPSec connections. The invention provides a method for ensuring secure forwarding of a message in a telecommunication network comprising at least one mobile terminal and another terminal, when the mobile terminal moves from a first address to a second address and there is a secure connection established between the first address of the mobile terminal and the other terminal, which secure connection defines at least the addresses of the two terminals. The invention also provides a network for performing such a method. TECHNICAL BACKGROUND An internetwork is a collection of individual networks connected with intermediate networking devices and functions as a single large network. Different networks can be interconnected by routers and other networking devices to create an internetwork. A local area network (LAN) is a data network that covers a relatively small geographic area. It typically connects workstations, personal computers, printers and other devices A wide area network (WAN) is a data communication network that covers a relatively broad geographic area. Wide area networks (WANs) interconnect U-Ns across normal telephone lines and, for instance, optical networks; thereby interconnecting geographically disposed users. There is a need to protect data and resources from disclosure, to guarantee the authenticity of data, and to protect systems from network based attacks. More in detail, there is a need for confidentiality (protecting the contents of data from being read), integrity (protecting the data from being modified, which is a property that is independent of confidentiality), authentication (obtaining assurance about the actual sender of data), replay protection (guaranteeing that data is fresh, and not a copy of previously sent data), identity protection (keeping the identities of parties exchanging data secret from outsiders), high availability, i.e. denial-of-service protection (ensuring that the system functions even when under attack) and access control. IPSec is a technology providing most of these, but not all of them. (In particular, identity protection is not completely handled by IPSec, and neither is denial-of-service protection.) The IP security protocols (IPSec) provides the capability to secure communications between arbitrary hosts, e.g. across a LAN, across private and public wide area networks (WANs) and across the internet IPSec can be used in different ways, such as for building secure virtual private networks, to gain a secure access to a company network, or to secure communication with other organisations, ensuring authentication and confidentiality and providing a key exchange mechanism. IPSec ensures confidentiality integrity, authentication, replay protection, limited traffic flow confidentiality, limited identity protection, and access control based on authenticated identities. Even if some applications already have built in security protocols, the use of IPSec further enhances the security. IPSec can encrypt and/or authenticate traffic at IP level. Traffic going in to a WAN is typically compressed and encrypted and traffic coming from a WAN is decrypted and decompressed. IPSec is defined by certain documents, which contain rules for the IPSec architecture. The documents that define IPSec, are, for the time being, the Request For Comments (RFC) series of the Internet Engineering Task Force (IETF), in particular, RFCs 2401-2412. Two protocols are used to provide security at the IP layer; an authentication protocol designated by the header of the protocol, Authentication Header (AH), and a combined encryption/authentication protocol designated by the format of the packet for that protocol, Encapsulating Security Payload (ESP). AH and ESP are however similar protocols, both operating by adding a protocol header. Both AH and ESP are vehicles for access control based on the distribution of cryptographic keys and the management of traffic flows related to these security protocols. Security association (SA) is a key concept in the authentication and the confidentiality mechanisms for IP. A security association is a one-way relationship between a sender and a receiver that offers security services to the traffic carried on it if a secure two way relationship is needed, then two security associations are required. If ESP and AH are combined, or if ESP and/or AH are applied more than once, the term SA bundle is used, meaning that two or more SAs are used. Thus, SA bundle refers to one or more SAs applied in sequence, e.g. by first performing an ESP protection, and then an AH protection. The SA bundle is the combination of all SAs used to secure a packet. The term IPsec connection is used in what follows in place of an IPSec bundle of one or more security associations, or a pair of IPSec bundles—one bundle for each direction—of one or more security associations. This term thus covers both unidirectional and bidirectional traffic protection. There is no implication of symmetry of the directions, i.e., the algorithms and IPSec transforms used for each direction may be different. A security association is uniquely identified by three parameters. The first one, the Security Parameters Index (SPI), is a bit string assigned to this St The SPI is carried in AH and ESP headers to enable the receiving system to select the SA under which a received packet will be processed. IP destination address is the second parameter, which is the address of the destination end point of the SA, which may be an end user system or a network system such as a firewall or a router. The third parameter, the security protocol identifier indicates whether the association is an AH or ESP security association. In each IPSec implementation, there is a nominal security association data base (SADB) that defines the parameters associated with each SA. A security association is normally defined by the following parameters. The Sequence Number Counter is a 32-bit value used to generate the sequence number field in AH or ESP-headers. The Sequence Counter Overflow is a flag indicating whether overflow of the sequence number counter should generate an auditable event and prevent further transmission of packets on this SA. An Anti-Replay Window is used to determine whether an inbound AH or ESP packet is a replay. AH information involves information about the authentication algorithm, keys and related parameters being used with AH. ESP information involves information of encryption and authentication algorithms, keys, initialisation vectors, and related parameters being used with IPSec. The sixth parameter, Lifetime of this Security Association, is a time-interval and/or byte-count after which a SA must be replaced with a new SA (and: new SPI) or terminated plus an indication of which of these actions should occur. IPSec Protocol Mode is either tunnel or transport mode. Path MTU, which is an optional feature, defines the maximum size of a packet that can be transmitted without fragmentation. Both AH and ESP support two modes used, transport and tunnel mode. Transport mode provides protection primarily for upper layer protocols and extends to the payload of an IP packet. Typically, transport mode is used for end-to-end communication between two hosts. Transport mode may be used in conjunction with a tunnelling protocol (other that IPSec tunnelling). Tunnel mode provides protection to the entire IP packet and is generally used for sending messages through more than two components, although tunnel mode may also be used for end-to-end communication between two hosts. Tunnel mode is often used when one or both ends of a SA is a security gateway, such as a firewall or a router that implements IPSec. With tunnel mode, a number of hosts on networks behind firewalls may engage in secure communications without implementing IPSec. The unprotected packets generated by such hosts are tunnelled through external networks by tunnel mode SAs set up by the IPSec software in the firewall or secure router at boundary of the local network. To achieve this, after the AH or ESP fields are added to the IP packet, the entire packet plus security fields are treated as the payload of a new outer IP packet with a new outer IP header. The entire original, or inner, packet travels through a tunnel from one point of an IP network to another no routers along the way are able to examine the inner IP packet. Because the original packet is encapsulated, the new larger packet may have totally different source and destination addresses, adding to the security. In other words, the first step in protecting the packet using tunnel mode is to add a new IP header to the packet; thus the “IP|payload” packet becomes “IP|IP|payload”. The next step is to secure the packet using ESP and/or AH. In case of ESP, the resulting packet is “IP|ESP|IP|payload”. The whole inner packet is covered by the ESP and/or AH protection. AH also protects parts of the outer header, in addition to the whole inner packet. The IPSec tunnel mode operates e.g. in such a way that if a host on a network generates an IP packet with a destination address of another host on another network, the packet is routed from the originating host to a security gateway (SGW), firewall or other secure router at the boundary of the first network. The SGW or the like filters all outgoing packets to determine the need for IPSec processing. If this packet from the first host to another host requires IPSec, the firewall performs IPSec processing and encapsulates the packet in an outer IP header. The source IP address of this outer IP header is this firewall and the destination address may be a firewall that forms the boundary to the other local network. This packet is now routed to the other hosts firewall with intermediate routers examining only the outer IP header. At the other host firewall, the outer IP header is stripped off and the inner packet is delivered to the other host. ESP in tunnel mode encrypts and optionally authenticates the entire inner IP packet, including the inner IP header. AH in tunnel mode authenticates the entire inner IP packet including the inner IP header, and selected portions of the outer IP header. The key management portion of IPSec involves the determination and distribution of secret keys. The default automated key management protocol for IPSec is referred to as ISAKMP/Oakley and consists of the Oakley key determination protocol and Internet Security Association and Key Management Protocol (ISAKMP). Internet key exchange (IKE) is a newer name for the ISAKMP/Oakley protocol. IKE is based on the Diffie-Hellman algorithm and supports RSA signature authentication among other modes. IKE is an extensible protocol, and allows future and vendor-specific features to be added without compromising functionality. IPSec has been designed to provide confidentiality, integrity, and replay protection for IP packets. However, IPSec is intended to work with static network topology, where hosts are fixed to certain subnetworks. For instance, when an IPSec tunnel has been formed by using Internet Key Exchange (IKE) protocol, the tunnel endpoints are fixed and remain constant If IPSec is used with a mobile host the IKE key exchange will have to be redone from every new visited network. This is problematic, because IKE key exchanges involve computationally expensive Diffie-Hellman key exchange algorithm calculations and possibly RSA calculations. Furthermore, the key exchange requires at least three round trips (six messages) if using the IKE aggressive mode followed, by IKE quick mode, and nine messages if using IKE main mode followed by IKE quick mode. This may be a big problem in high latency networks, such as General Packet Radio Service (GPRS) regardless of the computational expenses. In this text, the term mobility and mobile terminal does not only mean physical mobility, instead the term mobility is in the first hand meant moving from one network to another, which can be performed by a physically fixed terminal as well. The problem with standard IPSec tunnel end points are that they are fixed. A SA is bound to a certain IP address, and if it is changed, the existing IPSec SA becomes useless because it has been established by using different endpoint addresses. The problem has been discussed in the IETF standardisation forum, www.IETF.org, wherein an idea to support mobility for IPSec ESP tunnels by means of signalling to update the address of one end after a movement was mentioned by Francis Dupont. No solutions have however been presented until this date. The standard Mobile IP protocol provides a mobile terminal with a mobile connection, and defines mechanisms for performing efficient handovers from one network to another. However, Mobile IP has several disadvantages. The security of Mobile IP is very limited. The mobility signalling messages are authenticated, but not encrypted, and user data traffic is completely unprotected. Also, there is no key, exchange mechanism for establishing the cryptographic keys required for authenticating the mobility signalling. Such keys need to be typically distributed manually. Finally, the current Mobile IP protocol does not define a method for working through Network Address Translation (NAT) devices. A way to solve this problem is to use e.g. Mobile IP to handle the mobility of the host, and use IPSec on top of the static IP address provided by the Mobile IP. Thus, the IPSec SAs are bound to static addresses, and the IPSec SAs can survive mobility of the host. However, this approach suffers from packet size overhead of both Mobile IP and IPSec tunnels, which can affect performance considerably when using links with small throughput. The documents that define IP in general are the RFC standards RFC 768, RFC 791, RFC 7933, RFC 826 and RFC 2460. RFC 2002, RFC 2003, RFC 2131, RFC 3115, MOBILE Ipv4 and IPv6, and DHCPV6 define Mobile IP, IP-IP and DHCP. Prior art solutions in this technical area are presented in WO 01 39538, WO 00 41427, WO 01 24560, US 2001/009025 and EP 1 24 397. In WO 01 39538, WO 00 41427, WO 01 24560 and EP 1 24 397, a secure connection, which in the two first emntioned ones is an IPSec SA connection, is transferred from one access point to another in a hand-over situation of a mobile terminal. US 2001/009025 generally presents a secure communication method by means of an IP Sec SA connection. REFERENCES The following is a list of useful references of standards mentioned. IP in general, TCP and UDP: [RFC768] J. Postel, User Datagram Protocol, RFC 768, August 1980. ftp://ftp.isi.edu/in-notes/rfc7688.txt [RFC791] J. Postel, Internet Protocol, RFC 791, September 1981. ftp://ftp.isi.edu/in-notes/rfc791.text [RFC792] J. Postel, Internet Control Message Protocol, RFC 792, September 1981. ftp://ftp.isi.edu/in-notes/rfc792.txt [RFC793] J. Postel, Transmission Control Protocol, RFC 793, September 1981. ftp://ftp.isi.edu/in-notes/rfc793.txt [RFC826] D. C. Plummer, An Ethernet Address Resoluffon Protocol, RFC 826, November 1982. ftp://ftp.isi.edu/in-notes/rfc826.txt [RFC2460] S. Deering, R. Hinden, Internet Protocol, Version 6 (IPv6) Specification, RFC 2460, December 1998. [RFC2002] C. Perkins, IP Mobility Support, RFC 2002, October 1996. ftp://ftp.isi.edu/in-notes/rfc2002.txt [RFC2003] C. Perkins, IP Encapsulation Within IP, RFC 2003, October 1996. ftp://ftp.isi.edu/in-notes/rfc2003.txt [RFC2131] R. Droms, Dynamic Host Configuration Protocol, RFC 2131, March 1997. ftp://ftp.isi.edu/in-notes/rfc2131.txt [RFC3115] G. Dommety, and K. Leung, Mobile IP Vendor/Organization-specific Extensions, RFC 3115, April 2001. ftp://ftp.isi.edu/in-notes/rfc3115.txt [MOBILEIPv6] D. B. Johnson, C. Perkins, Mobility Support in IPv6, Work in progress (Internet-Draft is available), July 2000. [DHCPV6] J. Bound, M. Carney, C. Perking, R. Droms, Dynamic Host Configuration Protocol for IPv6 (DHCPv6), Work in progress (Internet-Draft is available), June 2001. IPsec Standards: [RFC2401] S. Kent, and R. Atkinson, Security Architecture for the Internet Protocol, RFC 2401, November 1998. ftp://ftp.isi.edu/in-notes/rfc2401.txt [RFC2402] S. Kent, and R. Atkinson, IP Authentication Header, RFC 2402, November. 1998. ftp://ftp.isi.edu/in-notes/rfc2402.txt [RFC2403] C. Madson, R. Glenn, The Use of HMAC-MD596 within ESP and AH, RFC 2403, November 1998. [RFC2404] C. Madson, R. Glenn, The Use of HMAC-SHA-1-96 win ESP and AH, RFC 2404, November 1998. [RFC2405] C. Madson, N. Doraswamy, The ESP DES-CBC Cipher Algorithm With Explicit IV, RFC 2405, November 1998. [RFC2406] S. Kent, and R. Atkinson, IP Encapsulating Security Payload (ESP), RFC 2406, November 1998. ftp://ftp.isi.edu/in-notes/rfc2406.txt [RFC2407] D. Piper, The internet IP Security Domain of Interpretation for ISAKMP, RFC 2407, November 1998. ftp://ftp.isi.edu/in-notes/rfc2407.txt [RFC2408] D. Maughan, M. Schneider, M. Scheater, and J. Turner, Internet Security Association and Key Management Protocol (ISAKMP), RFC 2408, November 1998. ftp://ftp.isi.edu/in-notes/rfc2408.txt [RFC2409] D. Harkins, and D. Carrel, The Internet Key Exchange (IKE), RFC 2409, November 1998. ftp://ftp.isi.edu/in-notes/rfc2409.txt [RFC2410] R. Glenn, S. Kent, The NULL Encryption Algorithm and Its Use With IPsec, RFC 2410, November 1998. [RFC2411] R. Thayer, N. Doraswamy, R. Glenn, IP Security Document Roadmap, RFC 2411, November 1998. [RFC2412] H. Orman, The OAKLEY Key Determination Protocol, RFC 2412, November 1998. NAT: [RFC2694] P. Srisuresh, G. Tsirtsis, P. Akkiraju, and A Heffeman, DNS Extensions to Network Address Translators (DNS—ALG), RFC 2694, September 1999. [RFC3022] P. Shisuresh, K. Egevang, Traditional IP Network Address Translator (Traditional NAT), RFC 3022, January 2001 ftp://ftp.isi.edu/in-notes/rfc3022.txt THE OBJECT OF THE INVENTION The object of the invention is to ensure secure forwarding of messages from and to mobile terminals by avoiding the problems of prior art. SUMMARY OF THE INVENTION The method and network of the invention is to ensure secure forwarding of a message in a telecommunication network, comprising at least one first terminal and another terminal. In the method, the first terminal moves from a first address to a second address. A secure connection between the first address of the first terminal and the other terminal defining at least the addresses of the two terminals is established. The first terminal moves from the first address to a second address. The connection is changed to be between the second address and the other terminal by means of a request from the first terminal and preferably, a reply back to the first terminal. In the invention, the first terminal is movable from one network to another. Such a terminal can physically be a mobile terminal or a fixed terminal. The secure connection is an IPSec connection established by forming one or more Security Associations (SAs) using the IPSec protocols. The request and/or the reply message can be protected e.g. by IPSec encryption and/or authentication, possibly using the same IPSec SA that is used for traffic protection purposes. In general, registration request and registration reply are Mobile IP terms while the invention is not bound to Mobile IP. In the invention, the terms request and reply are used in the generic sense, and may or may not be related to Mobile IP. The method of the invention can be used in different kinds of networks. If the first terminal and the other terminal form an end-to-end connection, the secure connection may be an IPSec tunnel mode or transport mode connection. Furthermore, one of or both of the first terminal and the other terminal can be a security gateway protecting one or more computers, whereby IPSec tunnel mode, or IPSec transport mode together with a tunnelling protocol (such as Layer 2 Tunnelling Protocol, L2TP), is used for the secure connection between the first terminal and the other terminal. If both terminals are mobile, a special solution is required for the situation when both terminals move simultaneously in case of a so called “double jump” situation. This solution can be implemented e.g. by using a centralised registry of current locations of hosts, although other solutions exist for the problem. However, the “changeable” IPSec tunnel or transport mode SAs of the invention could be used in that case, too. The applicant has solved the above problems of prior art by defining a signalling mechanism that allows an existing IPSec security association, that is, the symmetric encryption and authentication algorithms used for packet processing, along with their keys and other parameters, to be moved from one network to another. To be more precise, an existing IPSec tunnel endpoint can be moved in the invention from one point of attachment to another. For instance, an IPSec tunnel established between addresses A and X tunnel can be changed by using the defined signalling to be between addresses B and X using only a single round trip for signalling (2 messages), or half a round trip (1 message, if a reply message is not used) for signalling. The solution requires minimal computational overhead compared to Diffie-Helman or strong authentication calculations. The signalling mechanism is preferably similar to the one in Mobile IP, i.e. a registration request (RREQ) is sent to the other end of the SA followed by a registration reply (RREP) back to the sender of the RREQ message, both of which are extensible for future features and optional attributes. The RREQ/RREP message pair is sent from the new network, and once properly authenticated, the sender IPSec tunnel endpoint is updated from the old network to the now network. In case the security association used for protecting user traffic is also used for signalling purposes, the reception of the RREQ message by the other end of the SA requires a change in a normal IPSec implementation to accept a packet that appears to belong to a certain IPSec tunnel, but comes from a wrong address (i.e. the tunnel is currently between A and X, and the RREQ comes from address B). This is only necessary for the RREQ message. Such an implementation is provided by the invention; it is necessary to modify IPSec if IPSec is used for the RREQ/RREP signalling. In that case, it is required specifically for processing of the RREQ and RREP messages, if the reply message is to be used. The request message may-update a set of security associations, for instance, a single security association, a security association bundle, an IPSec connection, a group of IPSec connections, or any combinations of these. In practice, it is useful to update either a single IPSec connection or a group of IPSec connections. The latter may be important if separate IPSec connections are used for different kinds of traffic. A single request message can then update all (or a certain set) of such connections to a new address, instead of requiring separate requests for each IPSec connection. In the following, the case of updating a single IPSec connection is discussed, without limiting the invention to this behaviour. Another method of performing the signalling is to use a separate protocol. The protocol should preferably provide encryption and/or authentication of the signalling messages. The IKE protocol already has messages defined for e.g. deleting IPSec SAs. One method of providing the necessary signalling would be by adding a new IKE notification message type that requests a change in an existing IPSec SA Such a message should provide its own encryption and/or authentication to avoid requiring an IKE connection set up from the new address, which would require extra messaging. IP version 4 (IPv4) is the currently widely deployed Internet Protocol version. Its major disadvantage is the small number of unique, public IP addresses. IP version 6 (IPv6) has a much larger address space, which fixes the most important IPv4 problem known today. IPv6 also changes some other things in the Internet Protocol, for example, how fragmentation of packets is done, but these changes are quite small. Most protocols have separate definitions on how they are used within the IPv4 and the IPv6 context. For instance, there are separate versions of IPSec and Mobile IP for use with IPv4 and IPv6. However, such modifications to protocols are quite small, and do not usually change the essentials of the protocols significantly. The invention can be applied to both IPv4 and IPv6. In the following, the invention is further described by means of figures and some examples. The intention is not to restrict the invention to the details of the following description or to the details of protocols such as the IPSec and IKE protocols which might be changed in the future. FIGURES FIG. 1 illustrates an example of a telecommunication network to be used in the invention. FIG. 2 illustrates a second example of a telecommunication network to be used in the invention. FIG. 3 illustrates a third example of a telecommunication network to be used in the invention. FIG. 4 describes the prior art solution to enable mobility for IPSec connections. FIG. 5 describes the method of the invention to enable mobility for IPSec connections. DETAILED DESCRIPTION FIG. 1 illustrates an example of a telecommunication network to be used in the invention. Thus, in FIG. 1, computer 1 may be a client computer and computer 2 a destination computer, to which the secure messages are sent in the invention by means of an IPSec tunnel established between computer 1 and computer 2. Computer 2 might be a security gateway for a third computer 3. Then, the messages sent from computer 2 to computer 3 are sent in plaintext. The security gateway can be a common security gateway for e.g. a company LAN, whereby there are several computers in the LAN protected by computer 2. The other protected computers are not shown in FIG. 1, but naturally, the invention covers also such networks. The network of FIG. 2 otherwise corresponds to that of FIG. 1, but in FIG. 2 also computer 1 is a security gateway, e.g. for computer 4. Also here, the security gateway 1 can be a common security gateway for e.g. a company LAN, whereby there are several computers in the LAN protected by computer 1. The other protected computers are not shown in FIG. 2 But naturally, the invention covers also such networks. The messages between security gateway 1 and the computers it protects are sent in plaintext as the IPSec tunnel only exist between computers 1 and 2. The network of FIG. 3 is a network wherein the IPSec messages are sent between an end-to-end connection between two computers 1, 2 only whereby IPSec transport mode can be used instead of tunnel mode. FIG. 4 describes the prior art solution to enable mobility for IPSec connections. As a diagram, this is the standard IPSec procedure when establishing a tunnel between addresses A and X, and then B and X. The protocol begins with the IKE main mode requiring 6 messages in total, see steps 1a-6a in FIG. 4. The protocol involves strong user authentication, policy negotiation and the use of the Diffie-Hellman algorithm. Any other IKE phase 1 mode might of course be used as an alternative. Another approach to minimise the number of message exchanges would be to avoid IKE phase 1 and perform only the IKE quick mode (3 messages). However, IKE phase 1 is associated with IP addresses (along with other identifying information). A modified implementation might ignore IP addresses when processing IKE messages, and thus be able to maintain IKE phase 1 state between connection points. The protocol then continues with IKE quick mode requiring 3 messages in total (steps 7a-9a in FIG. 4). Quick mode includes IPSec policy negotiation and optionally the use of the Diffie-Helman algorithm. An alternative IKE phase 2 exchange could of course be used instead of quick mode. At this point the tunnel has been established between addresses A and X. 9 messages have been used along with the computational expense (each Diffie-Hellman computation may take hundreds of milliseconds, for instance, depending on the host), also the roundtrip times being considerable (9/2=4.5 roundtrips, with a roundtrip time of 500 ms this is 2.25 seconds for latency alone). The movement of the mobile terminal to address B causes full re-negotiation and again IKE main mode requires 6 messages in total (steps 1b-6b in FIG. 4), strong user authentication, policy negotiation, and optionally the use of the Diffie-Helman algorithm. The use of the protocol continues with IKE quick mode requiring 3 messages total (steps 7b-9b). The tunnel between addresses B and X is now complete. FIG. 5 describes the method of the invention. To establish the tunnel been address A and host X, IKE main mode is again used requiring 6 messages in total (steps 1a-6a in FIG. 5) as in FIG. 4 including strong user authentication, policy negotiation and the use of the Diffie-Hellman algorithm. Then IKE quick mode is again used requiring 3 messages in total (steps 7a-9 in FIG. 5). The quick mode includes IPSec policy negotiation, and optionally the use of the Diffie-Hellman algorithm. Again, IKE main mode may be replaced by any other IKE phase I mode, and IKE quick mode by any other IKE phase 2 mode. At this point the tunnel has been established between addresses A and X. 9 messages have been used along with the computational expense. In the invention, movement to address B requires only a single round trip, when using registration request messages to be sent from the mobile terminal, when it moves from address A to address B. In signal 10a of FIG. 5, which is sent from the mobile terminal to the other end of the established IPSec tunnel when it has moved to address B, a request for registration (RREQ) of the new address is sent. Preferably, a reply message (RREP) is sent (step 11a) from the host to confirm the address change. Both signals 10a and 11a can be encrypted and/or authenticated. The encryption and/or authentication is preferably performed by using IPSec, in which case it is preferable to use the same IPSec SA for protecting both data and registration traffic. 11a is optional in the invention. The preferable encryption method is IPSec, preferably with the modified reception processing described previously. However, the exact method of signalling is not important, the essence is to carry over the IPSec SA to the new connection point. The SA that existed between addresses A and X has now been changed to be between addresses B and X and is now complete. The next time the mobile terminal sends a message, host 2 in FIG. 1-3 is able to properly handle IPSec packets that come from address B and vice versa. Traffic can now flow inside the tunnel as normal with IPSec. Any further movement from network to another can be accomplished with a similar exchange of signalling message(s). The IPSec SA does not need to be re-established until the lifetime of the SA has been exhausted. The invention requires half a roundtrip if only a request message is used without a reply, and one roundtrip of the reply message is used. The example describes the tunnel mode of IPSec, but transport mode can also be used. IPSec transport mode connections in examples can be replaced with IPSec tunnel mode connections and vice versa. IPSec transport mode combined with an external tunnelling protocol, such as the Layer 2 Tunnelling Protocol (L2TP), is a replacement for IPSec tunnel mode with regards to functionality. The implementation may optimise the start of traffic flows with regard to message 10a (and optionally 11a); e.g. after sending 10a, the client may directly send IPSec-protected traffic. This essentially makes the handover latency zero, although it requires more complicated processing if the message 10a is lost while being delivered. However, the essential part of the invention is that it is possible to make the invention provide essentially zero-latency handover for client-to-server traffic, and half a roundtrip latency for server-to client traffic. Different network topologies can, of course, be used in the invention. For instance in FIG. 1, the connection between hosts 2 and 3 may use IPSec transport or tunnel mode, instead of being plaintext, etc.

<SOH> TECHNICAL BACKGROUND <EOH>An internetwork is a collection of individual networks connected with intermediate networking devices and functions as a single large network. Different networks can be interconnected by routers and other networking devices to create an internetwork. A local area network (LAN) is a data network that covers a relatively small geographic area. It typically connects workstations, personal computers, printers and other devices A wide area network (WAN) is a data communication network that covers a relatively broad geographic area. Wide area networks (WANs) interconnect U-Ns across normal telephone lines and, for instance, optical networks; thereby interconnecting geographically disposed users. There is a need to protect data and resources from disclosure, to guarantee the authenticity of data, and to protect systems from network based attacks. More in detail, there is a need for confidentiality (protecting the contents of data from being read), integrity (protecting the data from being modified, which is a property that is independent of confidentiality), authentication (obtaining assurance about the actual sender of data), replay protection (guaranteeing that data is fresh, and not a copy of previously sent data), identity protection (keeping the identities of parties exchanging data secret from outsiders), high availability, i.e. denial-of-service protection (ensuring that the system functions even when under attack) and access control. IPSec is a technology providing most of these, but not all of them. (In particular, identity protection is not completely handled by IPSec, and neither is denial-of-service protection.) The IP security protocols (IPSec) provides the capability to secure communications between arbitrary hosts, e.g. across a LAN, across private and public wide area networks (WANs) and across the internet IPSec can be used in different ways, such as for building secure virtual private networks, to gain a secure access to a company network, or to secure communication with other organisations, ensuring authentication and confidentiality and providing a key exchange mechanism. IPSec ensures confidentiality integrity, authentication, replay protection, limited traffic flow confidentiality, limited identity protection, and access control based on authenticated identities. Even if some applications already have built in security protocols, the use of IPSec further enhances the security. IPSec can encrypt and/or authenticate traffic at IP level. Traffic going in to a WAN is typically compressed and encrypted and traffic coming from a WAN is decrypted and decompressed. IPSec is defined by certain documents, which contain rules for the IPSec architecture. The documents that define IPSec, are, for the time being, the Request For Comments (RFC) series of the Internet Engineering Task Force (IETF), in particular, RFCs 2401-2412. Two protocols are used to provide security at the IP layer; an authentication protocol designated by the header of the protocol, Authentication Header (AH), and a combined encryption/authentication protocol designated by the format of the packet for that protocol, Encapsulating Security Payload (ESP). AH and ESP are however similar protocols, both operating by adding a protocol header. Both AH and ESP are vehicles for access control based on the distribution of cryptographic keys and the management of traffic flows related to these security protocols. Security association (SA) is a key concept in the authentication and the confidentiality mechanisms for IP. A security association is a one-way relationship between a sender and a receiver that offers security services to the traffic carried on it if a secure two way relationship is needed, then two security associations are required. If ESP and AH are combined, or if ESP and/or AH are applied more than once, the term SA bundle is used, meaning that two or more SAs are used. Thus, SA bundle refers to one or more SAs applied in sequence, e.g. by first performing an ESP protection, and then an AH protection. The SA bundle is the combination of all SAs used to secure a packet. The term IPsec connection is used in what follows in place of an IPSec bundle of one or more security associations, or a pair of IPSec bundles—one bundle for each direction—of one or more security associations. This term thus covers both unidirectional and bidirectional traffic protection. There is no implication of symmetry of the directions, i.e., the algorithms and IPSec transforms used for each direction may be different. A security association is uniquely identified by three parameters. The first one, the Security Parameters Index (SPI), is a bit string assigned to this St The SPI is carried in AH and ESP headers to enable the receiving system to select the SA under which a received packet will be processed. IP destination address is the second parameter, which is the address of the destination end point of the SA, which may be an end user system or a network system such as a firewall or a router. The third parameter, the security protocol identifier indicates whether the association is an AH or ESP security association. In each IPSec implementation, there is a nominal security association data base (SADB) that defines the parameters associated with each SA. A security association is normally defined by the following parameters. The Sequence Number Counter is a 32-bit value used to generate the sequence number field in AH or ESP-headers. The Sequence Counter Overflow is a flag indicating whether overflow of the sequence number counter should generate an auditable event and prevent further transmission of packets on this SA. An Anti-Replay Window is used to determine whether an inbound AH or ESP packet is a replay. AH information involves information about the authentication algorithm, keys and related parameters being used with AH. ESP information involves information of encryption and authentication algorithms, keys, initialisation vectors, and related parameters being used with IPSec. The sixth parameter, Lifetime of this Security Association, is a time-interval and/or byte-count after which a SA must be replaced with a new SA (and: new SPI) or terminated plus an indication of which of these actions should occur. IPSec Protocol Mode is either tunnel or transport mode. Path MTU, which is an optional feature, defines the maximum size of a packet that can be transmitted without fragmentation. Both AH and ESP support two modes used, transport and tunnel mode. Transport mode provides protection primarily for upper layer protocols and extends to the payload of an IP packet. Typically, transport mode is used for end-to-end communication between two hosts. Transport mode may be used in conjunction with a tunnelling protocol (other that IPSec tunnelling). Tunnel mode provides protection to the entire IP packet and is generally used for sending messages through more than two components, although tunnel mode may also be used for end-to-end communication between two hosts. Tunnel mode is often used when one or both ends of a SA is a security gateway, such as a firewall or a router that implements IPSec. With tunnel mode, a number of hosts on networks behind firewalls may engage in secure communications without implementing IPSec. The unprotected packets generated by such hosts are tunnelled through external networks by tunnel mode SAs set up by the IPSec software in the firewall or secure router at boundary of the local network. To achieve this, after the AH or ESP fields are added to the IP packet, the entire packet plus security fields are treated as the payload of a new outer IP packet with a new outer IP header. The entire original, or inner, packet travels through a tunnel from one point of an IP network to another no routers along the way are able to examine the inner IP packet. Because the original packet is encapsulated, the new larger packet may have totally different source and destination addresses, adding to the security. In other words, the first step in protecting the packet using tunnel mode is to add a new IP header to the packet; thus the “IP|payload” packet becomes “IP|IP|payload”. The next step is to secure the packet using ESP and/or AH. In case of ESP, the resulting packet is “IP|ESP|IP|payload”. The whole inner packet is covered by the ESP and/or AH protection. AH also protects parts of the outer header, in addition to the whole inner packet. The IPSec tunnel mode operates e.g. in such a way that if a host on a network generates an IP packet with a destination address of another host on another network, the packet is routed from the originating host to a security gateway (SGW), firewall or other secure router at the boundary of the first network. The SGW or the like filters all outgoing packets to determine the need for IPSec processing. If this packet from the first host to another host requires IPSec, the firewall performs IPSec processing and encapsulates the packet in an outer IP header. The source IP address of this outer IP header is this firewall and the destination address may be a firewall that forms the boundary to the other local network. This packet is now routed to the other hosts firewall with intermediate routers examining only the outer IP header. At the other host firewall, the outer IP header is stripped off and the inner packet is delivered to the other host. ESP in tunnel mode encrypts and optionally authenticates the entire inner IP packet, including the inner IP header. AH in tunnel mode authenticates the entire inner IP packet including the inner IP header, and selected portions of the outer IP header. The key management portion of IPSec involves the determination and distribution of secret keys. The default automated key management protocol for IPSec is referred to as ISAKMP/Oakley and consists of the Oakley key determination protocol and Internet Security Association and Key Management Protocol (ISAKMP). Internet key exchange (IKE) is a newer name for the ISAKMP/Oakley protocol. IKE is based on the Diffie-Hellman algorithm and supports RSA signature authentication among other modes. IKE is an extensible protocol, and allows future and vendor-specific features to be added without compromising functionality. IPSec has been designed to provide confidentiality, integrity, and replay protection for IP packets. However, IPSec is intended to work with static network topology, where hosts are fixed to certain subnetworks. For instance, when an IPSec tunnel has been formed by using Internet Key Exchange (IKE) protocol, the tunnel endpoints are fixed and remain constant If IPSec is used with a mobile host the IKE key exchange will have to be redone from every new visited network. This is problematic, because IKE key exchanges involve computationally expensive Diffie-Hellman key exchange algorithm calculations and possibly RSA calculations. Furthermore, the key exchange requires at least three round trips (six messages) if using the IKE aggressive mode followed, by IKE quick mode, and nine messages if using IKE main mode followed by IKE quick mode. This may be a big problem in high latency networks, such as General Packet Radio Service (GPRS) regardless of the computational expenses. In this text, the term mobility and mobile terminal does not only mean physical mobility, instead the term mobility is in the first hand meant moving from one network to another, which can be performed by a physically fixed terminal as well. The problem with standard IPSec tunnel end points are that they are fixed. A SA is bound to a certain IP address, and if it is changed, the existing IPSec SA becomes useless because it has been established by using different endpoint addresses. The problem has been discussed in the IETF standardisation forum, www.IETF.org, wherein an idea to support mobility for IPSec ESP tunnels by means of signalling to update the address of one end after a movement was mentioned by Francis Dupont. No solutions have however been presented until this date. The standard Mobile IP protocol provides a mobile terminal with a mobile connection, and defines mechanisms for performing efficient handovers from one network to another. However, Mobile IP has several disadvantages. The security of Mobile IP is very limited. The mobility signalling messages are authenticated, but not encrypted, and user data traffic is completely unprotected. Also, there is no key, exchange mechanism for establishing the cryptographic keys required for authenticating the mobility signalling. Such keys need to be typically distributed manually. Finally, the current Mobile IP protocol does not define a method for working through Network Address Translation (NAT) devices. A way to solve this problem is to use e.g. Mobile IP to handle the mobility of the host, and use IPSec on top of the static IP address provided by the Mobile IP. Thus, the IPSec SAs are bound to static addresses, and the IPSec SAs can survive mobility of the host. However, this approach suffers from packet size overhead of both Mobile IP and IPSec tunnels, which can affect performance considerably when using links with small throughput. The documents that define IP in general are the RFC standards RFC 768, RFC 791, RFC 7933, RFC 826 and RFC 2460. RFC 2002, RFC 2003, RFC 2131, RFC 3115, MOBILE Ipv4 and IPv6, and DHCPV6 define Mobile IP, IP-IP and DHCP. Prior art solutions in this technical area are presented in WO 01 39538, WO 00 41427, WO 01 24560, US 2001/009025 and EP 1 24 397. In WO 01 39538, WO 00 41427, WO 01 24560 and EP 1 24 397, a secure connection, which in the two first emntioned ones is an IPSec SA connection, is transferred from one access point to another in a hand-over situation of a mobile terminal. US 2001/009025 generally presents a secure communication method by means of an IP Sec SA connection.

<SOH> SUMMARY OF THE INVENTION <EOH>The method and network of the invention is to ensure secure forwarding of a message in a telecommunication network, comprising at least one first terminal and another terminal. In the method, the first terminal moves from a first address to a second address. A secure connection between the first address of the first terminal and the other terminal defining at least the addresses of the two terminals is established. The first terminal moves from the first address to a second address. The connection is changed to be between the second address and the other terminal by means of a request from the first terminal and preferably, a reply back to the first terminal. In the invention, the first terminal is movable from one network to another. Such a terminal can physically be a mobile terminal or a fixed terminal. The secure connection is an IPSec connection established by forming one or more Security Associations (SAs) using the IPSec protocols. The request and/or the reply message can be protected e.g. by IPSec encryption and/or authentication, possibly using the same IPSec SA that is used for traffic protection purposes. In general, registration request and registration reply are Mobile IP terms while the invention is not bound to Mobile IP. In the invention, the terms request and reply are used in the generic sense, and may or may not be related to Mobile IP. The method of the invention can be used in different kinds of networks. If the first terminal and the other terminal form an end-to-end connection, the secure connection may be an IPSec tunnel mode or transport mode connection. Furthermore, one of or both of the first terminal and the other terminal can be a security gateway protecting one or more computers, whereby IPSec tunnel mode, or IPSec transport mode together with a tunnelling protocol (such as Layer 2 Tunnelling Protocol, L2TP), is used for the secure connection between the first terminal and the other terminal. If both terminals are mobile, a special solution is required for the situation when both terminals move simultaneously in case of a so called “double jump” situation. This solution can be implemented e.g. by using a centralised registry of current locations of hosts, although other solutions exist for the problem. However, the “changeable” IPSec tunnel or transport mode SAs of the invention could be used in that case, too. The applicant has solved the above problems of prior art by defining a signalling mechanism that allows an existing IPSec security association, that is, the symmetric encryption and authentication algorithms used for packet processing, along with their keys and other parameters, to be moved from one network to another. To be more precise, an existing IPSec tunnel endpoint can be moved in the invention from one point of attachment to another. For instance, an IPSec tunnel established between addresses A and X tunnel can be changed by using the defined signalling to be between addresses B and X using only a single round trip for signalling (2 messages), or half a round trip (1 message, if a reply message is not used) for signalling. The solution requires minimal computational overhead compared to Diffie-Helman or strong authentication calculations. The signalling mechanism is preferably similar to the one in Mobile IP, i.e. a registration request (RREQ) is sent to the other end of the SA followed by a registration reply (RREP) back to the sender of the RREQ message, both of which are extensible for future features and optional attributes. The RREQ/RREP message pair is sent from the new network, and once properly authenticated, the sender IPSec tunnel endpoint is updated from the old network to the now network. In case the security association used for protecting user traffic is also used for signalling purposes, the reception of the RREQ message by the other end of the SA requires a change in a normal IPSec implementation to accept a packet that appears to belong to a certain IPSec tunnel, but comes from a wrong address (i.e. the tunnel is currently between A and X, and the RREQ comes from address B). This is only necessary for the RREQ message. Such an implementation is provided by the invention; it is necessary to modify IPSec if IPSec is used for the RREQ/RREP signalling. In that case, it is required specifically for processing of the RREQ and RREP messages, if the reply message is to be used. The request message may-update a set of security associations, for instance, a single security association, a security association bundle, an IPSec connection, a group of IPSec connections, or any combinations of these. In practice, it is useful to update either a single IPSec connection or a group of IPSec connections. The latter may be important if separate IPSec connections are used for different kinds of traffic. A single request message can then update all (or a certain set) of such connections to a new address, instead of requiring separate requests for each IPSec connection. In the following, the case of updating a single IPSec connection is discussed, without limiting the invention to this behaviour. Another method of performing the signalling is to use a separate protocol. The protocol should preferably provide encryption and/or authentication of the signalling messages. The IKE protocol already has messages defined for e.g. deleting IPSec SAs. One method of providing the necessary signalling would be by adding a new IKE notification message type that requests a change in an existing IPSec SA Such a message should provide its own encryption and/or authentication to avoid requiring an IKE connection set up from the new address, which would require extra messaging. IP version 4 (IPv4) is the currently widely deployed Internet Protocol version. Its major disadvantage is the small number of unique, public IP addresses. IP version 6 (IPv6) has a much larger address space, which fixes the most important IPv4 problem known today. IPv6 also changes some other things in the Internet Protocol, for example, how fragmentation of packets is done, but these changes are quite small. Most protocols have separate definitions on how they are used within the IPv4 and the IPv6 context. For instance, there are separate versions of IPSec and Mobile IP for use with IPv4 and IPv6. However, such modifications to protocols are quite small, and do not usually change the essentials of the protocols significantly. The invention can be applied to both IPv4 and IPv6. In the following, the invention is further described by means of figures and some examples. The intention is not to restrict the invention to the details of the following description or to the details of protocols such as the IPSec and IKE protocols which might be changed in the future.

20041122

20091117

20050421

57423.0

YALEW, FIKREMARIAM A

METHOD AND NEWORK FOR ENSURING SECURE FORWARDING OF MESSAGES

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for performing a transmission diffraction analysis

The present invention relates to a method for performing a transmission diffraction analysis of an analyte on a support surface, wherein the method comprises: irradiating said analyte with a radiation beam generated by a source of radiation, and detecting said radiation after passing through the analyte. The method is characterised in that irradiation is performed such that the radiation beam strikes the analyte in a substantially vertical and substantially perpendicular direction. Further the present invention relates to an apparatus for performing a transmission diffraction analysis.

1-24. (canceled) 25. An improved method for performing a transmission of diffraction analysis of one or more analytes on a support having a support surface, wherein the method comprises: irradiating each of said analytes with a radiation beam generated by a source of radiation, said radiation beam being directed onto said analyte, thereby creating a pattern of diffracted radiation, and detecting said diffracted radiation after passing through the analyte, and determining the diffraction pattern of the analyte, wherein the improvement is that said irradiation is performed such that the radiation beam strikes the analyte in a substantially vertical and substantially perpendicular direction in relation to the support surface. 26. The method according to claim 25, wherein the support surface is essentially horizontal. 27. The method according to claim 25, wherein a plurality of analytes is placed on the support. 28. The method according to claim 25, wherein a plurality of analytes is placed on the support, and wherein during the analysis the support is moved with respect to the beam automatically so that successively each of the analytes is radiated by said beam. 29. The method according to claim 25, wherein a plurality of analytes is placed on the support, and wherein the plurality of analytes is placed in an array. 30. The method according to claim 25, wherein a plurality of analytes is placed on the support, and wherein the plurality of analytes is placed in a 2-dimensional array. 31. The method according to claim 25, wherein the one or more analytes are placed on the support in the absence of any additional attachment. 32. The method according to claim 25, wherein the support comprises for each analyte a container containing the analytes, and wherein each container is translucent for the radiation. 33. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the radiation, and wherein multiple containers are provided in said support. 34. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the container is filled with a different analyte. 35. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the radiation, and wherein the container is open at the top during the analysis. 36. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the radiation, and wherein the containers are arranged in an array. 37. The method according to claim 25, wherein the support comprises for each analyte a container continuing the analyte, and wherein each container is translucent for the radiation, and wherein the analyte is crystallised in said container prior to the diffraction analysis. 38. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the radiation, and wherein the support is a plate having a plurality of wells each forming a container for receiving an analyte. 39. The method according to claim 25, wherein the support comprises for each analyte a container containing the analyte, and wherein each container is translucent for the radiation, and wherein the one or more containers are sealed during the analysis. 40. The method according to claim 25, wherein the support is translucent for the radiation. 41. The method according to claim 25, wherein the support is translucent for visual light. 42. The method according to claim 25, wherein the method includes the step of determining the background diffraction pattern of the support and the step of correcting the measured pattern for this background diffraction pattern. 43. The method according to claim 25, wherein the atmospheric conditions are controlled. 44. The method according to claim 25, wherein heat transfer means are used for controlling the temperature of the analyte, e.g. for effecting phase change of the analyte or drying of the analyte during the transmission diffraction analysis. 45. The method according to claim 25, wherein powder diffraction patterns of the one or more analytes are detected and recorded. 46. The method according to claim 25, wherein phase behaviour of the one or more analytes is screened. 47. The method according to claim 25, wherein polymorphism of the one or more analytes is detected. 48. An apparatus for performing a transmission diffraction analysis of an analyte, wherein the apparatus comprises: a source of radiation being adapted to direct a radiation beam to the analyte; a support for supporting the analyte, which support is translucent to the radiation; and a detector for detection of the radiation passed through the analyte, wherein the source of radiation, the support for the analyte and the detector are positioned such that the radiation beam generated by the source of radiation can strike the analyte in a substantially vertical and substantially perpendicular direction. 49. The apparatus according to claim 48, wherein the support is designed for supporting a plurality of analytes.

The present invention relates to a method for performing a transmission diffraction analysis of one or more analytes on a support surface, wherein the method comprises: irradiating said analyte with a radiation beam generated by a source of radiation, and detecting said radiation after passing through the analyte. WO-A-00/36405 discloses an apparatus and method for characterising libraries of different materials using X-ray scattering. The apparatus includes an X-ray beam directed at the library, which library contains an array of elements each containing a different material, a chamber which houses the library and a beam line for directing the X-ray beam onto the library in the chamber. During the characterisation, the X-ray beam scatters off of the element and a detector detects the scattered X-ray beam in order to generate characterisation data for the element. U.S. Pat. No. 6,111,930 discloses an X-ray diffractometer suitable for detection in reflection mode as well as transmission mode. In the reflection mode the support for an analyte is in horizontal position. In order to perform an analysis in transmission mode the support is rotated about a horizontal axis of the goniometer, so that the support is in an essentially vertical position. Scattering of incident radiation such as X-rays, gamma gays, cathode rays, etc. from a sample of material can yield information about the atomic structure of the material. When such a beam of radiation strikes a sample, a pattern of diffracted radiation is created, which has a spatial intensity distribution that depends on the wavelength of the incident radiation and the atomic structure of the material and that can be recorded on a suitable detector. Diffraction analysis is the method of choice for studying crystalline materials, crystallisation behaviour and liquid, gel or solid phase, or phase transitions of materials. Crystallisation is in general considered as the separation or precipitation out of a liquid environment or the settling into the solid phase of a melt. The basic approach to crystallisation of substance from a solution is usually fairly simple. The molecule(s) to be crystallised is (are) dissolved or suspended and subsequently subjected to conditions that affect the solubility of the molecule or molecular complex in solution. This can be achieved by removal of the solvent or by the addition of other compounds that reduce the solubility, optionally in combination with variation of other factors such as temperature, pressure or gravitational forces. When the conditions are right, small nuclei will form from which crystals will grow. However, the relations between the crystallisation conditions and the crystal packing or even the occurrence of crystallisation is generally not well understood. The optimisation of the crystallisation conditions and the identification of conditions that lead to one specific type of molecular packing in the crystal are largely based on trial and error. The determination of the optimal crystallisation conditions can therefore be a laborious and time-consuming process. When many different samples have to be submitted to diffraction analysis, the efficiency of the analysis is of the utmost importance. By far the most efficient way of analysis in terms of amount of sample required, measuring time and signal-to-noise ratio is the transmission geometry of diffraction. In the transmission diffraction mode, the entire fan of forwardly diffracted radiation is measured by a position sensitive radiation detector, unlike in the reflection mode, where only a small section of the fan of diffracted radiation is measured. However the transmission geometry of powder diffraction is hardly ever used, since it can be compromised by strong absorption in the case of very electron dense samples. Also, very thin analyte films have to be used to obtain a suitable resolution. Nevertheless, many organic samples, like drugs or drug candidates, are sufficiently transparent not to compromise the quality of the powder diffraction data. In these and many other cases, applying the transmission geometry to such samples will substantially reduce the measuring time required to obtain a signal-to-noise ratio that is sufficient for further characterisation. To increase throughput, an automated array, allowing for fast measuring of many analytes without human interference, is highly desirable. To this end, a convenient way of mounting all samples simultaneously in an array format, and automatically translating said array during the analysis from one sample to the next can be employed. In all set-ups for diffraction in the transmission geometry that have been used up till now, as is also the case in WO-A-00/36405, the radiation beam is horizontal and the analyte support mounted substantially vertical, implying that any sample either needs to be bonded by some physical means to a (semi-)translucent substrate, or enclosed in a container, e.g. a thin-walled glass or quartz capillary. In this “horizontal” set-up the analytes that are formed during a certain experiment have to be removed to another container for transmission diffraction analysis. This can be inconvenient, because it is time-consuming, and it involves an extra processing step. Removal of an analyte further involves risks of the crystallised structure of the analyte being disrupted, or the analyte being contaminated. Furthermore, it is not convenient to study phase transitions of the analyte using the known apparatus, when one of the phases is liquid as the analyte may drop off or shift relative to the radiation beam. Furthermore, until presently, for successful crystallisation to take place, a large amount of analyte is required. The above problems are particularly pertinent in the case of e.g. the early development of new substances or in high throughput experimentation wherein often only a very small amount of analyte is available. High throughput experimentation is known in the art and is used for simultaneously conducting a large number of experiments using a plurality of vessels, optionally with different reaction conditions. High throughput experimentation is used for instance in the pharmaceutical industry for discovery and development of new and useful drugs and in the field of catalysts for the development of new catalysts. Therefore it is an object of the present invention to provide a new and alternative way of performing a transmission diffraction analysis of an analyte, having a high signal-to-noise ratio, especially when the amount of analyte available is very small. The above and other objects can be achieved by a method for performing a transmission diffraction analysis of an analyte, wherein the method comprises: irradiating said analyte with a radiation beam generated by a source of radiation, and detecting said radiation after passing through the analyte, characterised in that irradiation is performed such that the radiation beam strikes the analyte in a substantially vertical and substantially perpendicular direction in relation to the support surface. Using the method according to the present invention a surprisingly simple, very quick and efficient way of simultaneously analysing a plurality of analytes has become possible. Also, the method according to the present invention provides for a surprisingly elegant and convenient way to study phase transitions of analytes, when one of the phases is liquid. Further the method allows easy automation. According to the present invention, with “substantially vertical and substantial perpendicular direction” is meant any direction which meets a horizontal plane (i.e. a plane substantially parallel to the earth's surface) at such an angle that no additional attachment of the analytes to a support on which (or a container in which) the analyte is placed is required. Preferably this angle is about 90 degrees. However, the person skilled in the art will readily understand that also other angles between the horizontal plane and the direction of the beam of radiation used in the method according to the invention may be used. Suitably, this angle is at least 75 degrees. The person skilled in the art will understand that the source of radiation may provide itself a substantial vertical direction of the beam of radiation. Alternatively, the direction of the beam of radiation, provided by a source of radiation of the invention, may be changed before performance of a transmission diffraction analysis, for instance by using at least one mirror. According to the present invention, with “radiation” any radiation is meant which can be used for performing a transmission diffraction analysis of an analyte, such as X-rays, gamma rays, cathode rays. In use, the source of radiation may be located above the analyte, pointing downwards; alternatively said source of radiation may be located underneath the analyte, pointing upwards. An “analyte” is defined herein as a sample or a compound of which the diffraction or crystallisation behaviour is to be determined. Such an analyte may be a chemical substance, or a mixture of different substances. Also, at least one crystal form of the substance may be known or expected to exist. An analyte of the invention may comprise an organic or organo-metallic molecular compound, such as a pharmaceutically active molecule or catalyst-ligand complex or a dimer, salt, ester, solvate or functional part thereof. An analyte of the present invention may also comprise a biomolecule, for instance a nucleic acid (such as DNA, RNA and PNA), a polypeptide, peptides, glycoprotein and other proteinaceous substances, a lipoprotein, protein-nucleic acid complex, carbohydrate, biomimetic or a functional part, derivative and/or analogue thereof. The present invention allows for the simultaneous screening of a plurality of analytes, e.g. placed in arrays, without having to physically remove the analytes from the container in which said analytes are prepared, as long as said containers are translucent to the radiation which is used. Thus, preferably, said analyte is not removed to another container or support. The alignment such that the direction of the radiation beam is substantially vertical, is a prerequisite for achieving a transmission geometry for diffraction of an analyte in an open container or resting on a support, without having to physically or otherwise attach said analyte to said container or support. It is now possible with the method of the invention to analyse said analyte in a 2-dimensional array, for instance a microtiter plate. Therefore, according to a preferred embodiment of the method according to the present invention, the analyte is placed on a support, without any additional attachment. This means that the analyte may be bonded to a support by no other means than the force of gravity. Herewith contamination of the analyte can be prevented, or at least minimised. The present invention is especially useful in powder diffraction analysis, especially when a plurality of small amounts of analytes in arrays are to be analysed simultaneously. The method of the invention is ideally suited for detecting both wide and small angle scattering from said analytes, when formed in situ in a translucent container. In this particular embodiment, the samples are crystallised in said container and analysed without having to harvest the samples onto a suitable carrier. The plurality of containers can subsequently be presented for diffraction analysis, which also increases the potential for further automation of sample analysis in general. The analyte may be provided in a specially designed substrate similar to a microtiter plate, fabricated from material that is translucent to X-rays. Said substrate is preferably chemically inert to the substances and solvents employed and is preferably transparent to the detection technique used, e.g. X-ray transparent in case of X-ray diffraction technique. The substrate is preferably also transparent to visual light (ca 200 nm to 1000 nm) to allow visual or optical inspection. The substrate is preferably also capable of transferring heat, thereby allowing for temperature variations. Examples of arrays are 8 by 12 mm up to 32 by 48 mm, with orthogonal centre to centre distance varying from 2 to 10 mm between the containers or wells of the substrate. Of course, the substrate may be provided with means for controlling and/or adjusting the atmosphere conditions in or directly above the cells. For this purpose the support medium is for instance fitted with sealing devices or sealing substances which seal off individual cells or groups of cells. Balls, plates, caps, inert liquids like paraffin oil, silicon oil, etc. can be provided for said sealing purposes. In this respect it is noted that the sealing devices and/or sealing substances do not necessarily (and preferably do not) attach the analyte to the support, but are provided for controlling the atmosphere in or directly above an individual cell or a group of cells. With the method of the invention, determination of diffraction characteristics of a crystallised analyte can conveniently be carried out in a provided array in which the crystallisation method has been carried out (in situ). In transmission diffraction geometry this requires that the array itself is transparent to diffraction or that the background diffraction pattern from the array is determined and the obtained diffraction data from the crystal in the array are corrected for this background pattern. The advantage of using a transmission geometry over more conventional reflection geometry of this diffraction experiments, is that substantially more signal is measured per mass unit of analyte. It is thus possible to use milligram, preferably microgram, nanogram or picogram amounts of material and still achieve an improved throughput. Although the art generally teaches that large quantities of material are required for successful crystallisation it has been shown that sub-microgram quantities can be used for small molecules (molecular weight in the order of less than 500 grams per mole) and even down to 1 nanogram quantities for proteins (molecular weight in the order of more than 5000 grams per mole). Because of the small volumes that can be used in the methods according to the invention, availability of analytes is less of a problem and rapid testing of numerous conditions and easy adjustment of relevant conditions is easily obtained. A method of the invention is thus advantageously used when only minute quantities of the analyte are available, for instance in an early stage of the research. Thus, one embodiment of the invention provides a method according to the invention, wherein the amount of said analyte is less than 1 microgram. Major advantages of the method according to the invention are that automated set-up of the experiments is generally quicker for small volumes, the automated detection of crystals in an array of conditions is quicker as more samples can be tested simultaneously, less material is required thereby reducing wastage, more tests can be performed given the amount of material available, the chance that the conditions under which crystallisation is achieved are identified significantly increases and the chances of identification of different polymorphic forms increases likewise. In a further aspect the present invention provides an apparatus for performing a transmission diffraction analysis of an analyte, wherein the apparatus comprises: a source of radiation being adapted to direct a radiation beam to the analyte; a support for supporting the analyte, which support is translucent to the radiation; and a detector for detection of the radiation passed through the analyte, wherein the source of radiation, the support for the analyte and the detector are positioned such that the radiation beam generated by the source of radiation can strike the analyte in a substantially vertical and substantially perpendicular direction. As support e.g. an open container or a small plate of translucent material may be used. As has been described above, a source of radiation may provide an essentially vertical beam of radiation which can be used directly. However, alternatively, the direction of a beam of radiation of an apparatus of the invention may artificially be made substantially vertical for performance of a transmission diffraction analysis, for instance by use of at least one mirror. The apparatus according to the present invention is very suitable for high throughput experimentation, and to this end the support of the apparatus is designed for supporting a plurality of analytes. The support may be in the form of an array of translucent containers as mentioned above. Further the present invention relates to the use of the method or the apparatus according to the invention for detection and recording powder diffraction patterns of the analyte. Herewith a powder diffraction pattern can easily be obtained. Further the present invention relates to the use of the method or the apparatus according to the invention for screening phase behaviour of the analyte, more in particular crystallisation behaviour in liquid, gel or solid phase of an analyte. Said analyte may be an organic molecule, for instance a pharmaceutically interesting compound or complex, oligomer, salt, ester or solvate thereof, or an organo-metallic molecule such as a catalyst for homogeneous catalysis, etc. Preferably the method for screening the phase behaviour of an analyte is carried out in an array of separate cells, whereby each cell contains a different composition. When a change in phase behaviour occurs, this is detected and can be correlated to the specific composition and conditions under which the screening is taking place. Using the method or apparatus according to the invention, the analyte will not drop off from the substrate when a change in phase behaviour occurs, or shift relative to the beam. According to another aspect of the present invention it relates to the use of the method or apparatus of the invention for detecting polymorphism of the analyte. Herewith the present invention provides an easy way of determination of crystallisation conditions that allow for the growth of different crystal forms of the analyte, thus enabling the identification of polymorphic forms of the analyte. This is valuable information, for instance in the case of a pharmaceutical compound of interest whereby polymorphs of said pharmaceutical compound can each have different physical properties or different properties in terms of biological activity. Official approval such as from the United States' Food and Drug Administration of a specific and well defined drug cannot be transferred to another polymorph of the sample, although the chemical nature of the constituting molecules is identical. It is therefore very important that the various polymorphs are discovered and identified in order to gain an understanding of their biological properties. Hereinafter the present invention will be illustrated in more detail by a drawing. Herein shows: FIG. 1 a diagram of a transmission mode X-ray diffraction analysing apparatus in accordance with the present invention., FIG. 2 schematically a preferred embodiment of a transmission diffraction analysis apparatus according to the invention, FIG. 3 schematically an alternative preferred embodiment of a transmission diffraction analysis apparatus according to the invention. FIG. 1 shows a diagram of an exemplary transmission mode X-ray diffraction analysing apparatus 1 in accordance with the present invention. The apparatus 1 comprises a source 2 of intense X-ray radiation 6 such as a conventional X-ray tube, an array 3 such as a translucent microtiter plate for supporting a plurality of analytes 4, and a detector 5 for detection of the radiation passed through the analyte 4. In the shown embodiment the source 2 of X-ray radiation 6 is located above the analyte 4. The detector 5 for the radiation is in the shown embodiment located on the opposite end of the analyte 4 from the source of radiation 2, such that the radiation 6 is detected and recorded after passing through the analyte 4. The detector 5 may be any suitable detector, such as a stimulable phosphor image plate detector. Preferably the detector 5 is a position sensitive 2D radiation detector. In use a beam of X-rays 6 is generated by the radiation source 2, and directed to one of the analytes 4 positioned in the array 3. The beam of X-rays 6 strikes the analyte 4 positioned on the array 3 in a substantially vertical and substantially perpendicular direction, and the diffracted radiation scatters from the analyte 4 in a pattern which is recorded in the detector 5. Subsequently, a further analyte 4 is analysed. The person skilled in the art will understand that many modifications may be made. For instance, the detector 5 may be located above the array 3 of analytes 4, while the X-ray source 2 is placed beneath the analytes 4. FIG. 2 schematically shows a transmission diffraction analysis apparatus 20 comprising a source 22 of radiation generating a radiation beam 26, which is oriented vertically and downwards onto a common support 23 for multiple analytes 24. The support 23 is held in horizontal orientation and the analytes 24 are placed in a two-dimensional array on said support 23. The beam 26 is directed onto one of said analytes 24 and passes through focussing means 27. The beam 26 passes through the analyte and thereby a pattern of diffracted radiation 28. A suitable detector 25 for the diffracted radiation is placed vertically below said support 23. The detector 25 is coupled to a recorder (not shown) for recording the pattern of each specific analyte. In order to analyse each of the analytes 24 in the support 23 a displacement device 39 is provided, in this example a device 29 allowing movement of the support 23 in a horizontal plane, so that each of the analytes 24 can be brought into the beam 26 for analysis of said analyte 24. The device 29 preferably allows for an automatic displacement of the support 23 so that all the analytes 24 on the support 23 are analysed successively. FIG. 3 shows the transmission diffraction analysis apparatus 30, which apparatus 30 basically includes the same components as the apparatus 20. In the apparatus 30 however the radiation source 22 is placed below the support 23 and generates a vertically upward directed beam 26, which strikes an analyte 24 from below. The detector 25 is now arranged above the support 23 for receiving the upward directed pattern of diffracted radiation. The support 23 preferably has a container for each analyte, which container is translucent for the radiation, at least the part of the container forming the support surface for the analyte. In a preferred embodiment the container is open at the top during the analysis, however it is also envisaged that the containers are closed. In a preferred embodiment the analytes are crystallised in their containers prior to the diffraction analysis, so that the analytes do not need to be transferred between the step of crystallisation and transmission diffraction analysis. In a practical embodiment the support 23 is a plate having a plurality of wells each forming a container for receiving an analyte. It is also preferred that the support is translucent for visual light. It is envisaged that the method includes the step of determining the background diffraction pattern of the support and the step of correcting the measured pattern for this background diffraction pattern. In an embodiment not show in the drawings means are provided for controlling the atmospheric conditions. Also it is possible to provide heat transfer means for controlling the temperature of the analyte, e.g. for effecting phase change of the analyte or drying of the analyte during the transmission diffraction analysis.

20040329

20060718

20050331

97030.0

YUN, JURIE

VERTICAL TRANSMISSION DIFFRACTON ANALYSIS

UNDISCOUNTED

ACCEPTED

ACCEPTED

4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives for treating an excess of metal in the body

The present invention provides new 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives which can be used in the treatment of diseases which cause an excess of metal in the human or animal body or are caused by it.

1. A compound of the formula I wherein one of the radicals R1, R2, R3 and R4 is hydroxy and the remaining radicals are each independently of the others hydrogen or hydroxy; or a salt thereof. 2. A compound of the formula I according to claim 1, which is 4-[3-(2,3-dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, or a salt thereof. 3. A compound of the formula I according to claim 1, which is 4-[3-(2,5-dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, or a salt thereof. 4. A compound of the formula I according to claim 1, which is 4-[5-(2,5-dihydroxy-phenyl)-3-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, or a salt thereof. 5. A compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for use in the treatment of diseases which cause an excess of metal in the human or animal body or are caused by it. 6. A compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for use in the treatment of diseases which cause an excess of iron in the human or animal body or are caused by it. 7. A pharmaceutical preparation comprising at least one compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 together with at least one pharmaceutically acceptable carrier. 8. Use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for the production of a pharmaceutical preparation for the treatment of an excess of metal in the human or animal body. 9. Use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, according to claim 1 for the production of a pharmaceutical preparation for the treatment of an excess of iron in the human or animal body.

Various disorders of warm-blooded animals are linked with an excess of metals, in particular trivalent metals, in the body tissues. For example aluminium in dialysis encephalopathy and osteomalacia, as well as in Alzheimer's disease. In other illnesses, in particular of man, an excess of iron occurs in the various tissues. This is designated as iron overload (formerly haemosiderosis). It occurs, for example, after parenteral administration of iron (especially repeated blood transfusions) or after increased uptake of iron from the gastrointestinal tract. Repeated transfusions are necessary in serious anaemias, especially in thalassaemia major, the severe form of β-thalassaemia, but also in other anaemias. Increased iron absorption from the gastrointestinal tract either takes place primarily, e.g. on account of a genetic defect (so-called haemochromatosis), or secondarily, such as after anaemias in which blood transfusions are not necessary, for example thalassaemia intermedia, a milder form of β-thalassaemia. Untreated iron overload can cause severe organ damage, in particular of the liver, the heart and the endocrine organs, and can lead to death. Iron chelators are able to mobilize and excrete the iron deposited in the organs and thus lower the iron-related morbidity and mortality. A reduction in the iron(III) concentration is also of interest for the treatment of disorders due to iron(III)-dependent microorganisms and parasites, which is of key importance not only in human medicine, such as in particular in malaria, but also in veterinary medicine. Complexing of other metals, in partcular trivalent metals, can also be used for excretion thereof from the organism. A number of further applications are also described in the literature, e.g. by G. Kontoghiorghes, Toxicology Lett. 80, 1-18 (1995). Desferrioxamine B has already been known for a long time and used therapeutically for these purposes (H. Bickel, H. Keberle and E. Vischer, Helv. Chim. Acta 46, 1385-9 [1963]). A disadvantage of this preparation, however, turns out to be the fact that desferrioxamine and its salts only have a low, inadequate activity on oral administration and require a parenteral administration form in all of the abovementioned application possibilities. It is thus recommended, for example, as a particularly effective method to administer the active substance by means of a slow (8- to 12-hour) subcutaneous infusion, which, however, demands the use of a portable mechanical device, such as an infusion syringe actuated by an electrical drive. Apart from their awkwardness, such solutions are affected by a high treatment cost, which severely restricts their use; in particular a comprehensive treatment of the thalassaemias in the countries of the Mediterranean region, of the Middle East, India and South-East Asia, of malaria worldwide and of sickle-cell anaemia in African countries is made impossible. These widespread diseases are furthermore a serious problem for the health service in these countries and make the search for a simpler and more inexpensive therapy, preferably by means of an orally active preparation, the urgent object in this area. The present invention provides new 4-[3,5-bis-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid derivatives which can be used in the treatment of diseases which cause an excess of metal in the human or animal body or are caused by it. The present invention relates to compounds of the formula I wherein one of the radicals R1, R2, R3 and R4 is hydroxy and the remaining radicals are each independently of the others hydrogen or hydroxy; and salts thereof. Salts are especially the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines. In the presence of a basic group and an acid group in the same molecule, a compound of formula I may also form internal salts. For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. Only the pharmaceutically acceptable salts or free compounds (if the occasion arises, in the form of pharmaceutical compositions) attain therapeutic use, and these are therefore preferred. In view of the close relationship between the novel compounds in free form and in the form of their salts, including those salts that can be used as intermediates, for example in the purification or identification of the novel compounds, hereinbefore and hereinafter any reference to the free compounds is to be understood as referring also to the corresponding salts, as appropriate and expedient. The compounds of formula I have valuable pharmacological properties when used in the treatment of disorders which cause an excess of metal in the human or animal body or are caused by it, primarily a marked binding of trivalent metal ions, in particular those of iron (A. E. Martell and R. J. Motekaitis, “Determination and Use of Stability Constants”, VCH Publishers, New York 1992). They are able, for example in an animal model using the non-iron overloaded cholodocostomized rat (R. J. Bergeron et al., J. Med. Chem. 34, 2072-2078 (1991)) or the iron-overloaded monkey (R. J. Bergeron et al., Blood 81, 2166-2173 (1993)) in doses from approximately 5 μmol/kg, inter alia, to prevent the deposition of iron-containing pigments and in the case of existing iron deposits in the body cause excretion of the iron. Very special preference is given to a compound of the formula I which is selected from the group consisting of 4-[3-(2,3-dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, [3-(2,5-dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, 4-[5-(2,5-dihydroxy-phenyl)-3-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid, and salts thereof. A compound of the invention may be prepared by processes known per se for other compounds. In particular, they can be prepared by the processes described in e.g. WO 97/49395. In the preferred embodiment, a compound of the formula I is prepared according to the processes and process steps defined in the Examples below. Pharmaceutical Compositions, Methods, and Uses In particular, the invention relates to the use of a compound of formula I for the treatment of diseases which cause an excess of iron in the human or animal body or are caused by it, preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the human body, and to a treatment method of this type. In addition, the invention relates to novel preparations, comprising at least one compound of the formula I and salts thereof; and at least one pharmaceutically acceptable carrier; and to methods for their preparation. These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being contained on its own or together with customary pharmaceutical adjuncts. The pharmaceutical preparations contain (in percentages by weight), for example, from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 100%, of the active ingredient. Pharmaceutical preparations for enteral or parenteral administration are, for example, those in unit dose forms, such as sugar-coated tablets, tablets, dispersible tablets, effervescent tablets, capsules, suspendable powders, suspensions or suppositories, or ampoules. These are prepared in a manner known per se, e.g. by means of conventional pan-coating, mixing, granulation or lyophilization processes. Pharmaceutical preparations for oral administration can thus be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained and processing the mixture or granules, if desired or necessary, after addition of suitable adjuncts to give tablets or sugar-coated tablet cores. Suitable carriers are, in particular, fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch pastes, using, for example, maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are primarily flow-regulating and lubricating agents, e.g. salicylic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Sugar-coated tablet cores are provided with suitable, if desired enteric, coatings, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, e.g. for the identification or the marking of various doses of active ingredient, can be added to the tablets or sugar-coated tablet coatings. Dispersible tablets are tablets which rapidly disintegrate in a comparatively small amount of liquid, e.g. water, and which, if desired, contain flavourings or substances for masking the taste of the active ingredient. They can advantageously be employed for the oral administration of large individual doses, in which the amount of active ingredient to be administered is so large that on administration as a tablet which is to be swallowed in undivided form or without chewing that it can no longer be conveniently ingested, in particular by children. Further orally administrable pharmaceutical preparations are hard gelatin capsules and also soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The hard gelatin capsules can contain the active ingredient in the form of granules, e.g. as a mixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilizers. Moreover, suspendable powders, e.g. those which are described as “powder in bottle”, abbreviated “PIB”, or ready-to-drink suspensions, are suitable for an oral administration form. For this form, the active ingredient is mixed, for example, with pharmaceutically acceptable surface-active substances, for example, sodium lauryl sulfate or polysorbate, suspending auxiliaries, e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose or another known from the prior art and previously described, for example, in “Handbook of Pharmaceutical Ecipients”, pH regulators, such as citric or tartaric acid and their salts or a USP buffer and, if desired, fillers, e.g. lactose, and further auxiliaries, and dispensed into suitable vessels, advantageously single-dose bottles or ampoules. Immediately before use, a specific amount of water is added and the suspension is prepared by shaking. Alternatively, the water can also be added even before dispensing. Rectally administrable pharmaceutical preparations are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. A suitable suppository base is, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Gelatin rectal capsules can also be used which contain a combination of the active ingredient with a base substance. Possible base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons. For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. of a water-soluble salt, are primarily suitable; furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, being used, or aqueous injection suspensions which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, also stabilizers. The dosage of the active ingredient can depend on various factors, such as activity and duration of action of the active ingredient, severity of the illness to be treated or its symptoms, manner of administration, warm-blooded animal species, sex, age, weight and/or individual condition of the warm-blooded animal. The doses to be administered daily in the case of oral administration are between 10 and approximately 120 mg/kg, in particular 20 and approximately 80 mg/kg, and for a warm-blooded animal having a body weight of approximately 40 kg, preferably between approximately 400 mg and approximately 4,800 mg, in particular approximately 800 mg to 3,200 mg, which is expediently divided into 2 to 12 individual doses. Preferably, the invention relates to novel preparations comprising at least one compound of the formula I and salts thereof; and at least one pharmaceutically acceptable carrier, and to methods for their preparation. These pharmaceutical preparations are those for enteral, in particular oral, and furthermore rectal, administration, and those for parenteral administration to warm-blooded animals, especially to man, the pharmacological active ingredient being present on its own or together with customary pharmaceutical adjuncts. The pharmaceutical preparations contain (in percentages by weight), for example, from approximately 0.001% to 100%, preferably from approximately 0.1% to approximately 50%, of the active ingredient. EXAMPLES The following Examples serve to illustrate the invention without limiting its scope. Temperatures are measured in degrees Celsius. Unless otherwise indicated, the reactions take place at room temperature. The Rf values which indicate the ratio of the distance moved by each substance to the distance moved by the eluent front are determined on silica gel thin-layer plates (Merck, Darmstadt, Germany) by thin-layer chromatography using the respective named solvent systems. The analytical HPLC conditions are as follows: Instrument: HP-1100 System with G1311A quaternery pump (0.8 ml dead volume), G1313A autosampler, G1316A column compartment (35° C.), G1315A diode array detector and G1946A mass spectrometer. Column: Waters Symmetry C8, 50 × 2.1 mm 3.5 μm mean particle size. Detection by UV absorption at 210-250 nm. The retention times (tR) are given in minutes. Flow rate: 0.5 ml/ min. Gradient: 5% → 95% b) in a) within 6.5 min. a): water + 5% acetonitrite + 0.1% TFA b): Acetonitrile + 0.1% TFA. The short forms and abbreviations used have the following definitions: h hour(s) MS-ES mass spectroscopy (electron spray) min minute(s) m.p. melting point MS-APCI+ mass spectroscopy (atomic pressure chemical ionisation) tR retention times. Example 1 4-[3-(2,3-Dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]benzoic Acid (M2) A mixture of 5.5 g of 2-(2,3-dihydroxy-phenyl)benzo[e][1,3]oxazin-4-one with 8-hydroxy-2-(2-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one and 3.3 g 4-hydrazino-benzoic acid in 50 ml of ethanol is heated to reflux for 2. The mixture is evaporated to dryness and the product is isolated by preparative HPLC; HPLC tR=5.15 min, MS-APCI+: (M+H)+=390, m.p.: 223-226° C. Step 1.1: Mixture of 2-(2,3-Dihydroxy-phenyl)-benzo[e][1,3]oxazin-4-one with 8-Hydroxy-2-(2-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one A mixture of 10 g 2,3-dihydroxy-benzoic acid, 7.5 g 2-hydroxy-benzamide and 0.5 ml pyridine in 50 ml toluene is heated under reflux. 8.8 ml of thionylchloride is added over a period of 1 h. The mixture is kept under reflux for another hour, cooled to 40° C. and 100 ml ethanol are added. After cooling to 5° C. the precipitated product is filtered off and washed with cold ethanol; HPLC tR=4.63 min, MS-APCI+: (M+H)+=256. Example 2 4-[3-(2,5-Dihydroxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic Acid (M1) and 4-[5-(2,5-Dihydroxy-phenyl)-3-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic Acid (M4) A mixture of 5 g of 4-[3-(2-hydroxy-5-methoxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid with 4-[5-(2-hydroxy-5-methoxy-phenyl)-3-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic acid is dissolved in 40 ml acetic acid and 40 ml aqueous hydrogen bromide (45%) and heated under reflux for 3 h. The solvents are evaporated and the residue is suspended in hot water and filtered. The two isomeric products are separated by preparative HPLC: M1: HPLC tR=4.95 min, MS-APCI+: (M+H)+=390, m.p.: 297-299° C.; M4: HPLC tR=5.25 min, MS-APCI+: (M+H)+=390, m.p.: 312-315° C. Step 2.1: Mixture of 2-(2-Hydroxy-phenyl)-6-methoxy-benzo[e][1,3]oxazin-4-one with 2-(2-hydroxy-5-methoxy-phenyl)benzo[e][1,3]oxazin-4-one A mixture of 11 g 2-hydroxy-5-methoxy-benzoic acid, 7.5 g 2-hydroxy-benzamide and 0.5 ml pyridine in 50 ml xylene is heated under reflux. 8.8 ml of thionylchloride is added over a period of 1 h. The mixture is kept under reflux for another hour, cooled to 40° C. and 100 ml ethanol are added. After cooling to 5° C. the precipitated product is filtered off and washed with cold ethanol; HPLC tR=5.23 & 5.41 min, MS-APCI+: (M+H)+=270. Step 2.2: Mixture of 4-[3-(2-Hydroxy-5-methoxy-phenyl)-5-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic Acid with 4-[5-(2-Hydroxy-5-methoxy-phenyl)-3-(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-benzoic Acid A mixture of 7 g of 2-(2-hydroxy-phenyl)6-methoxy-benzo[e][1,3]oxazin-4-one with 2-(2-hydroxy-5-methoxy-phenyl)-benzo[e][1,3]oxazin-4-one and 4 g 4-hydrazino-benzoic acid in 70 ml of ethanol are heated to reflux for 1 h. The mixture is evaporated to dryness; HPLC tR=5.56 & 5.67 min, MS-APCI+: (M+H)+=404.

20040329

20060711

20050414

93950.0

CHUNG, SUSANNAH LEE

4-[3,5-BIS-(2-HYDROXY-PHENYL)-[1,2,4]TRIAZOL-1-YL]-BENZOIC ACID DERIVATIVES FOR TREATING AN EXCESS OF METAL IN THE BODY

UNDISCOUNTED

ACCEPTED

ACCEPTED

Transmission of data within a communications network

The invention relates to methods for providing a network element 5 of a communications network with data, in particular HSDPA related data. In order to enable the transmission of user data, it is proposed that a controller 4 of the network uses a dedicated frame structure for assembling frames with said user data. The frames can then be transmitted from the controller 4 via an interface to the network element 5. In order to enable the transmission of control parameters, it is further proposed that an interface application protocol is employed which allows the controller 4 to add control parameters to control messages transmitted from the controller 4 to a network element 5 via the interface.

1. A method for transmitting user data within a communications network from a controller (4) to a network element (5) over an interface, wherein said controller (4) uses at least one dedicated frame structure for assembling data frames with said user data, which data frames are transmitted via said interface to said network element (5), wherein said frame structure includes at least a header section for receiving information required in said network element (5) for processing said user data. 2. A method according to claim 1, wherein said frame structure further includes a payload section for receiving at least one SDU to which HSDPA related user data was distributed by said controller. 3. A method according to claim 1, wherein said user data is HSDPA (High speed downlink packet access) related user data, wherein said communications network is a UTRAN (Universal mobile telecommunication services terrestrial radio access network), wherein said controller is an RNC (radio network controller), wherein said network element is a Node B, wherein said interface is an Iub interface, and wherein said at least one frame structure is at least one dedicated HSDPA FP (frame protocol) frame structure. 4. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least one cyclic redundancy check information for data inserted into said header section of said data frame (“header CRC”). 5. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of a frame type of said data frame (“FT”). 6. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the number of SDUs included in said payload section of said data frame (“NumOfSDUs”). 7. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the status of a buffer assigned to a user equipment in RNC buffers (“User_Buffer_size”), which assigned buffer is employed for buffering user data of said user equipment in said RNC (4) before transmitting it to a Node B (5). 8. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of a relative priority of said data frame and of said SDUs included in said payload section of said data frame (“CMCH-PI”). 9. A method according to claim 3, wherein in a frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the kind of user equipment identification, if any, a receiving Node B (5) should include in a header for said SDUs, which header might already have been added by said RNC (4) to said SDUs (“UE_Id type”). 10. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure, said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the number of RNC buffers from which user data has been inserted into said payload section of said data frame (“NumOfBuff”). 11. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the number of SDUs in said data frame which include user data originating from a single RNC buffer (9,11) (“NumOfSDUs”). 12. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the size of the SDUs in said data frame (“Size_of_MAC SDU”). 13. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the status of a buffer assigned to a respective user equipment in RNC buffers (9,11) (“User_Buffer_size”), which assigned buffer is employed for buffering user data for said user equipment in said RNC (4) before transmitting it to a Node B (5). 14. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of a relative priority of the frame and/or of said SDUs included in said data frame (“CMCH-PI”) 15. A method according to claim 3, wherein said RNC (4) is allowed to multiplex HSDPA related user data intended for several user equipments to frames of a single Iub transmission connection, which multiplexed data is demultiplexed by said Node B (5), and wherein for a data frame assembled by said RNC (4) according to one of said at least one dedicated HSDPA FP frame structure said header section comprises for receiving HSDPA relevant information a dedicated field for at least an indication of the kind of user equipment identification, if any, a receiving Node B (5) should include in a header added to said SDUs, which headers might already have been added by said RNC (4) to said SDUs (“UE_ID type”). 16. A method according to claim 3, wherein an identification of user equipments, for which said HSDPA related user data distributed to said SDUs is intended, is required in said Node B (5), and wherein for one of said at least one dedicated HSDPA FP frame structure said header section comprises at least one dedicated field for including a user equipment identification information (“UE-id”). 17. A method according to claim 3, wherein an identification of user equipments, for which said HSDPA related user data distributed to said SDUs is intended, is required in said Node B (5), and wherein for one of said at least one dedicated HSDPA FP frame structure a user equipment identification information is added to said SDUs included in said payload section. 18. A method according to claim 16, wherein an RNTI (radio network temporary identity) assigned to a user equipment is used as respective user equipment identification information. 19. A method according to claim 2, wherein said SDUs are MAC−d and/or MAC−c/sh SDUs. 20. A communications network comprising at least one controller (4) and at least one network element (5), which controller (4) and which network element (5) are connected to each other via an interface, and in which communications network at least one frame structure is defined for transmission of information required at said network element (5) for processing user data from said controller (4) to said network element (5) over said interface according to claim 1, wherein said controller (4) comprises means for using said at least one frame structure for assembling frames with said information for transmission of said information via said interface to said network element (5), and wherein said network element (5) comprises means for extracting said information from received frames having said at least one frame structure. 21. A communications network according to claim 20, wherein said communications network is a UTRAN (Universal mobile telecommunication services terrestrial radio access network), wherein said controller is an RNC (radio network controller) (4), wherein said network element is a Node B (5), wherein said interface is an Iub interface. 22. A communications network according to claim 21, wherein said means of said RNC (4) is a MAC −c/sh (2) and/or a MAC −d (3) and wherein said means of said Node B (5) is a MAC −hs (1). 23. A controller for a communications network comprising means for using a frame structure for assembling frames with information required by a network element (5) of said communications network for processing user data for transmission of said information via an interface to said network element (5) according to claim 20. 24. A network element (5) for a communications network comprising means for extracting information required in said network element (5) for processing user data from frames received via an interface from a controller (4) of said communications network, which frames have a frame structure, according to claim 20. 25. A network element (5) according to claim 24, wherein said network element is a Node B of a UTRAN (Universal mobile telecommunication services terrestrial radio access network). 26. A method for providing a network element (5) of a communications network with control parameters available at a controller (4) of said communications network, which controller (4) is connected to said network element (5) via an interface, wherein said method comprises employing an interface application protocol which enables an insertion of at least one control parameter into at least one kind of control message transmitted from said controller (4) to said network element (5) over said interface. 27. A method according to claim 26, wherein said communications network is a UTRAN (Universal mobile telecommunication services terrestrial radio access network), wherein said network element is a Node B, wherein said controller is an RNC (radio network controller) and wherein said interface is an Iub interface. 28. A method according to claim 27, wherein the content of said at least one HSDPA related control parameter is a fixed value, a limiting value or a sequence of allowed values to be used by said Node B (5). 29. A method according to claim 27, wherein said at least one HSDPA related control parameter is comprised in at least one information element (IE) and is inserted into a control message by adding said information element to a control message of said at least one kind of control message transmitted from said RNC (4) of said UTRAN to said Node B (5) over said Iub-interface. 30. A method according to claim 27, wherein at least one of said at least one HSDPA related control parameter is a cell specific control parameter required by said Node B (5) for a setup of a cell and/or for a reconfiguration of a cell. 31. A method according to claim 30, wherein said at least one cell specific control parameter comprises for insertion into at least one kind of control message at least one of the following parameters: sets of a modulation and coding schemes (MCS) from which said Node B (5) can choose every TTI (transmission time interval) for HSDPA transmissions; a power level to be used by said Node B (5) for HS-DSCHs (high speed downlink shared channel) in HSDPA; the number of code channels which will be assigned to HS-DSCHs used by said Node B (5); an indication of a TTI length to be used by said Node B (5); and one or more parameters to be used by said Node B (5) to configure a HARQ (hybrid automatic repeat request) implemented in said Node B (5). 32. A method according to claim 31, wherein said one or more parameters to be used by said Node B (5) to configure HARQ includes at least one of the number of channels to be used for HARQ, the maximum number of attempts for HARQ, and restrictions of redundancy versions from which said Node B (5) can choose. 33. A method according to claim 30, wherein said at least one kind of control message is a CELL SETUP REQUEST message and/or a CELL RECONFIGURATION REQUEST message. 34. A method according to claim 27, wherein at least one of said at least one HSDPA related control parameter is a radio link specific control parameter required for a setup of a radio link and/or for a reconfiguration of a radio link. 35. A method according to claim 34, wherein said at least one radio link specific control parameter comprises for insertion into at least one kind of control message at least the identity of an HS DSCH (high speed downlink shared channel) currently to be used by said Node B (5) for HSDPA. 36. A method according to claim 34, wherein said at least one radio link specific control parameter comprises for insertion into at least one kind of control message at least one of the following parameters: the identity of an HS DSCH (high speed downlink shared channel) currently to be used by said Node B (5) for HSDPA; a binding identity identifying the user data stream which is currently to be transmitted by said Node B (5); and a transport layer address defining the current transport address of said Node B (5). 37. A method according to claim 34, wherein said at least one radio link specific control parameter comprises for insertion into at least one kind of control message at least one of the following parameters: the identity of an HS DSCH (high speed downlink shared channel) currently to be used by said Node B (5) for HSDPA. the identity of a user equipment to which user data is to be transmitted by said Node B (5) with HSDPA; a transport format set currently to be used by said Node B (5); an allocation and/or retention priority indicating a priority level in the allocation and/or retention of internal resources of said Node B (5); a frame handling priority indicating a priority level to be used by said Node B (5) during the lifetime of a HS-DSCH for temporary restrictions of allocated resources due overload reason; a time of arrival of a window startpoint (ToAWS) after which downlink data frames are expected to be received at said Node B (5); a time of arrival of a window endpoint (ToAWE) before which downlink data frames are expected to be received at said Node B (5); the number of code channels which are currently assigned to a HS DSCH used by said Node B (5); a buffer status (BufferStatus) indicating a current status of buffers of said RNC (4); and one or more parameters currently to be used by said Node B (5) to configure HARQ (hybrid automatic repeat request) implemented in said Node B (5). 38. A method according to claim 37, wherein said one or more parameters to be used by said Node B (5) to configure HARQ includes at least one of the number of channels to be used for HARQ, a maximum allowed number of attempts for HARQ, and restrictions of redundancy versions from which said Node B (5) can choose. 39. A method according to claim 34, wherein said at least one kind of control message is at least one of a RADIO LINK SETUP REQUEST message, a RADIO LINK SETUP RESPONSE message, a RADIO LINK RECONFIGURATION PREPARE message and a RADIO LINK RECONFIGURATION READY message. 40. A communications network comprising at least one controller (4) and at least one network element (5), which controller (4) and which network element (5) are connected to each other via an interface, wherein said communications network further comprises an implementation of an interface application protocol enabling said controller (4) to provide said network element (5) with at least one control parameter by inserting said at least one control parameter into at least one kind of control message transmitted from said controller (4) to said network element (5) over said interface according to claim 34. 41. A communications network according to claim 40, is a UTRAN (Universal mobile telecommunication services terrestrial radio access network), wherein said controller is an RNC (radio network controller) (4), wherein said network element is a Node B (5) and wherein said interface is an Iub interface. 42. A controller (4) for a communications network, which controller (4) comprises means for providing a network element (5) of said communications network via an interface in accordance with an interface application protocol with at least one control parameter by inserting said at least one control parameter into a control message transmitted from said controller (4) to said network element (5) over said interface according to claim 40. 43. A network element (5) for a communications network comprising means for receiving control messages from a controller (4) of said communications network via an interface, and for extracting at least one control parameter from at least one kind of received messages into which at least one control parameter was inserted by said controller (4) according to claim 40. 44. A network element (5) according to claim 43, wherein said network element is a Node B of a UTRAN (Universal mobile telecommunication services terrestrial radio access network). 45. A controller (4) according to claim 23, wherein said controller is an RNC (radio network controller) of a UTRAN. 46. A method according to claim 27, wherein said control parameters are HSDPA (High speed downlink packet access) related control parameters. 47. A controller (4) according to claim 42, wherein said controller is an RNC (radio network controller) of a UTRAN.

FIELD OF THE INVENTION The invention relates to methods for providing a network element, e.g. a Node B, of a communications network, e.g. an UTRAN (Universal mobile telecommunication services terrestrial radio access network) with data, e.g. HSDPA (High speed downlink packet access) related data, required at said network element. On the one hand, the invention relates more specifically to a method for transmitting within a communications network user data, e.g. HSDPA related user data, from a controller to a network element over an interface, e.g. an Iub interface. On the other hand, the invention relates more specifically to a method for providing a network element, e.g. a Node B, of a communications network, e.g. an UTRAN, with control parameters, e.g. HSDPA related control parameters, available at a controller of said communications network, e.g. an RNC, which controller is connected to said network element via an interface, e.g. an Iub interface. The invention equally relates to corresponding communications networks, network elements and controllers. BACKGROUND OF THE INVENTION HSDPA is a concept that was introduced for UTRAN architectures as an enhancement to the shared channel concept in 3GPP (3rd generation partnership project). In UMTS, the UTRAN handles all radio-related functionality. To this end, an UTRAN comprises one or more RNCs, and connected to each RNC one or more Node Bs. The RNCs of the UTRAN are connected to a core network via an Iu interface. RNCs of one UTRAN may be interconnected in addition by an Iur interface. In downlink transmissions, an RNC receives user data from the core network, possibly via another RNC, and forwards it via an Iub interface to a Node B. The Node B then transmits the data to the addressed user equipment UE via a Uu interface. The RNCs of an UTRAN might take different roles. A controlling RNC (CRNC) may be defined, for example, with respect to a specific set of Node Bs. There is only one CRNC for any Node B. The CRNC has an overall control over the logical resources of its Node Bs. A serving RNC (SRNC) may be defined with respect to a specific connection between an UE and an UTRAN. There is one SRNC for each UE that has a connection to UTRAN. The SRNC is in charge of the radio resource control (RRC) connection between a UE and the UTRAN. The Serving RNC also terminates the Iu for this UE. In the shared channel concept in UTRAN for FDD mode, a DSCH (downlink shared channel) is defined as a downlink transport channel which is shared dynamically between several UEs. The DSCH is assembled in a CRNC and transmitted via a Node B to a UE, as described for instance in the technical specification 3GPP TS 25.301 V3.6.0 (2000-09): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; Radio Interface Protocol Architecture (Release 1999)”. The basic idea of HSDPA is to offer for downlink transmissions shared high speed channels with a higher data rate and a quicker retransmission mechanism already from Node B. The shared high speed channels are to comprise a HS-DSCH (high speed downlink shared channel) as transport channel and a DPCH (dedicated physical channel), combined with a separate shared physical control channel in combination with a HS-PDSCH (high speed physical downlink shared channel). The fast retransmission mechanism to be implemented in the Node B is HARQ (hybrid automatic repeat request). The currently used DSCH may also support high data rates, but retransmission is always provided by a RLC (radio link control) layer in the RNC, which slows the transaction down. In order to support the new capabilities, especially HARQ, a new MAC (medium access control) entity was introduced in the technical report 3GPP TR 25.855 V1.0.0 (2001-06): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; High Speed Downlink Packet Access; Overall UTRAN Description (Release 5)”, which is incorporated by reference herein. The new MAC entity is called MAC −hs and is always located in the Node B. In the preceding releases of 3GPP, all UTRAN MAC entities capable of handling also user plane data were always located exclusively in the RNCs. The MAC −hs exists only when the cell is configured to support the HSDPA concept, and it is connected to a MAC −c/sh located in an RNC through the Iub interface. A MAC layer is used for mapping logical channels to transport channels. A logical channel is a channel type which is defined between the radio link control (RLC) in an RNC and the MAC layer. Each logical channel defines what kind of data is going to be transmitted through it. In the case of HSDPA, the logical channels always locate in the SRNC. A transport channel is a channel type which is defined between the MAC layer and L1 (layer 1). It describes how data is to be transmitted through the radio link. In the DSCH concept, the transport channel is seen on the Iub interface, whereas in the HSDPA concept the transport channel is an internal channel in Node B. The connection of different MACs of an UTRAN for HSDPA is illustrated in FIG. 1, which was taken from the above cited technical report TR 25.855. FIG. 1 depicts a MAC −hs 1 located in a Node B, and in addition a MAC −c/sh 2 and a MAC −d 3 located in one or more RNCs. The MAC −hs 1 is connected to the MAC −c/sh 2 via the Iub interface, while the MAC −c/sh 2 is connected to the MAC −d 3 via an Iur interface in case they are located in different RNC, otherwise these MACs 2, 3 are interconnected locally. A MAC control has access to each of the MACs 1-3. Such logical channels as PCCH (Paging channel) and BCCH (broadcast control channel) are directly mapped to the MAC −c/sh 2 without intervening of MAC −d 3. However such logical channels as DCCH (Dedicated control channel) and DTCH (dedicated traffic channel) are always connected to MAC −d 3, which forwards the received data packets to the MAC −c/sh 2, if the UE has access right either to the common channel(s) or to the shared channel(s). MAC −c/sh 2 and MAC −d 3 map different kinds of logical channels onto transport channels, like PCH (paging channel), FACH (forward access channel), DCH (dedicated channel) etc., for transmission to a UE via a Node B. Received HSDPA related data is provided by MAC −d 3 via MAC −c/sh 2 without mapping to the MAC −hs 1 of the Node B for transmission in HS DSCHs to a UE. For the details of FIG. 1 it is referred to the technical report TR 25.855. Alternatively, the MAC −hs could be connected directly to a MAC −d. Since functionalities previously implemented only in the RNCs have now to be provided also in Node Bs, like TFC (transport format combination) selection, the functional split between Node B and RNC has been reorganized. The new distribution of functionalities is shown in FIGS. 2 and 3, which were equally taken from technical report TR 25.855, and which presents in more detail some of the functions provided by MAC −c/sh 2 and MAC −hs 1 respectively. Upon the reorganization, scheduling/priority handling and TFC selection functions have been removed from the MAC −c/sh 2 of the RNC in FIG. 2 for HSDPA related downlink transmissions and added to the MAC −hs 1 of the Node B in FIG. 3. Thus, the final scheduling and the real time traffic control not under RNC control any more for HSDPA. Accordingly, in the MAC −c/sh 2 in FIG. 2, HSDPA related data received from a MAC −d are passed on to the MAC −hs 1 of FIG. 3 without any scheduling, priority handling or TFC selection etc. being performed as for other downlink data. Previously, these functions were always taken care of either in a SRNC when Node B was connected directly to an SRNC, or in a CRNC when the Node B was connected to an CRNC. In addition, HARQ is implemented in the new MAC −hs 1 of FIG. 3. For the details of FIGS. 2 and 3 it is referred to the above cited technical report TR 25.855. The reorganization of functionalities implies that the known transmissions of downlink user data and of required control information from an RNC to a Node B has to be adapted. For the transmission of downlink user data, it was proposed that the RLC layer is not changed. This means that the RLC buffers as before RLC PDUs (protocol data units) in RNC buffers, and that the RLC submits data to the lower layer only upon request of the MAC layer which locates on the RNC, i.e. MAC −d 3. Therefore the transactions to support data transmission between a MAC entity in an RNC and a MAC −hs 1 in a Node B are currently defined only on high level, but details are still missing. By these high level definitions, a flow control functionality is defined between MAC −c/sh 2 and MAC −hs 1 as a new feature, as indicated in FIG. 3, in order to control the data flow from the RNC to the Node B. To support actual data transmissions on the Iub-interface, moreover a HS-DSCH Frame protocol layer (HS-DSCH FP) was included under the MAC −c/sh and above the MAC −hs. This layer is indicated in FIG. 4, which was again taken from technical report TR 25.855. FIG. 4 shows a radio interface protocol architecture of HSDPA, and more specifically layers of network elements which network elements are, from left to right, a user equipment UE connected via a Uu interface to a Node B, which is further connected via an Iub interface to a first RNC, which is finally connected via an Iur interface to a second RNC. Each of the Node B, the first and the second RNC comprises in addition to the respective MAC entity a HS-DSCH FP. This HS-DSCH FP is intended to transmit not only data packets from the RNC to the Node B, but also related control information. Such an FP protocol is proposed without any details for data transmissions in downlink on both, Iub and Iur interfaces, which transmissions are using the service of L2 (layer 2) of MAC and RLC. For the details of FIG. 4, it is referred to the above cited technical report TR 25.855. None of the current FP frame structures defined for the Iub interface, however, is applicable for HSDPA. In particular the FP frame structure used for DSCHs, from which DSCHs the proposal for HSDPA proceeds, is not suited for HSDPA data transmissions, since a DSCH FP frame contains fields of which the values can only be defined when the scheduling or TFC selection has already been made. As mentioned above, these functions were shifted for HSDPA related transmissions to the Node B. Moreover, a DSCH FP frame does not contain all of the information which is required for HSDPA to support flow control between an RNC and a Node B. In addition to HSDPA related user data, also control information has to be available at the Node B so that the Node B can set up and re-configure HS-DSCH channels for transmissions. Due to the functional reorganization, the current application protocol procedures on Iub for DSCH setup and reconfiguration, described e.g. in the technical specification 3GPP TS 25.433 V3.4.1 (2000-12): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; UTRAN Iub Interface NBAP Signalling (Release 1999)”, cannot be used for HS-DSCH. For example, in the case of HSDPA it is not necessary to provide channel coding parameters during a radio link (RL) setup as for DSCH, since these channel coding parameters are decided upon in the Node B. On the other hand, some parameters that are not required by a Node B for DSCH should be provided to a Node B for HSDPA during a cell setup procedure so the Node B can configure HS-DSCH attributes in a cell. It should moreover be possible to modify these parameters cell-based, preferably in a semi-static manner. SUMMARY OF THE INVENTION It is an object of the invention to enable the transmission of data within a communications network, which data is required at a network element of said communications network. It is also an object of the invention to enable the use of HSDPA by an UTRAN, and more specifically to enable the RNC of an UTRAN to provide a Node B of the UTRAN with HSDPA related data. It is in particular an object of the invention to enable an RNC to provide a Node B in a suitable way with HSDPA related user data and with HSDPA relevant control parameters on NBAP (Node B Application Part). A first aspect of the invention is directed at the transmission user data, while a second aspect of the invention is directed at the transmission of control parameters. For the first aspect of the invention, a method is proposed for transmitting user data within a communications network from a controller to a network element over an interface. The communications network can be in particular an UTRAN, the controller an RNC, the network element a Node B and the interface an Iub interface. The controller uses at least one dedicated frame structure, in particular a dedicated HSDPA FP frame structure, for assembling data frames with the user data. The data frames are then transmitted via the interface to the network element. The frame structure includes at least a header section for receiving information required in said network element for processing the user data. For the first aspect of the invention, in addition a communications network, in particular an UTRAN, a controller, in particular an RNC, and a network element, in particular a Node B, are proposed which comprise means for realizing the proposed method. Concerning the first aspect, the invention proceeds from the idea that the transmission of information required for the processing of HSDPA related user data should be similar to the solutions used for other shared channels, but still be optimized for the requirements of HSDPA. The proposed dedicated frame structure allows to remove all fields employed in the structures for DSCH which are no longer necessary for HSDPA, and to insert fields for the information required additionally for HSDPA. Thus, an optimized transmission of information required for HSDPA related user data via the Iub interface is enabled. The same considerations may apply for other communications networks, network elements and situations. For the second aspect of the invention, a method is proposed for providing a network element of a communications network with control parameters available at a controller of the communications network, which controller is connected to said network element via an interface. The communications network can be in particular an UTRAN, the controller an RNC, the network element a Node B and the interface an Iub interface. The method comprises employing an interface application protocol which enables an insertion of at least one control parameter, in particular an HSDPA related control parameter, into at least one kind of control message transmitted from said controller to said network element over said interface. Also for the second aspect of the invention, in addition a communications network, in particular an UTRAN, a controller, in particular an RNC, and a network element, in particular a Node B, are proposed which comprise means for realizing the proposed method. Concerning the second aspect, the invention proceeds from the idea that the most efficient way to provide a Node B with control parameters required for setting up an re-configuring HS DSCH channels is to include the parameters in control messages transmitted from an RNC to the Node B. Since RNC and Node B are connected to each other via an Iub interface, it is thus proposed to modify the Iub application protocol accordingly. As a result, the Node B is for example able to setup and re-configure HS-DSCH channels based on received control parameters. The Node B can therefore be configured by the RNC to support HSDPA related data to user equipment in the cell. The same considerations may apply for other communications networks, network elements and situations. Both aspects of the invention have in common that they comprise an HSDPA specific implementation of general specifications used for transmitting data from RNC to Node B via the Iub interface, i.e. on the one hand an implementation of dedicated frame structures and on the other hand an implementation of an Iub application protocol with HSDPA specific procedures. Preferred embodiments of the invention become apparent from the subclaims. In a preferred embodiment of the first aspect of the invention, the frame structure further includes a payload section for receiving at least one SDU to which HSDPA related user data was distributed by said controller, wherein the header section receives information required in the network element for processing HSDPA related user data. Thus, information required at Node B for processing HSDPA related user data can be transmitted in an advantageous way in a single frame together with said user data. The SDUs are in particular MAC −d SDUs and/or MAC −c/sh SDUs. For the first aspect of the invention it is to be noted that the proposed HSDPA FP frame structure can be designed to receive any number of information, which information can be predetermined arbitrarily according to the requirements. Further, it should not be obligatory that the payload section contains any data in a frame assembled according to the dedicated frame structure so that the same structure may be used for transmitting information only in the header section, e.g. information for an HSDPA flow control. In particular, different FP frame structures can be provided for the cases that MAC/FP UE-ID multiplexing is or is not allowed in the RNC. UE-ID multiplexing is a multiplexing type in which different UEs are multiplexed onto the same transport channel and can be performed either in the MAC layer or the FP layer of an RNC. In the case of FP UE-ID multiplexing, the header of the FP frame should always contain the UE-ID identification. This identification can be e.g. RNTI, or it can be a new identification defined for this purpose only and thus be shorter than the current RNTI. In a case of MAC UE-ID multiplexing, the UE-ID field is used in the MAC header, i.e. RNTI is added into MAC header, no identification is necessarily required in FP frame. The Node B can fetch the UE-ID information by reading the MAC header. Then again if it is wanted that the FP frame should contain the UE-ID field despite the addition of the RNTI into the MAC header, the used UE-ID can be e.g. RNTI, or it can be a new identification defined for this purpose only and thus be shorter than the current RNTI. There are moreover different alternatives how multiplexing can be carried out, and the used multiplexing method may have to be considered when determining the most suitable structure of the FP frame. The kind of multiplexing used can in particular have an impact on the number of fields of the same kind provided in one FP frame. One alternative for multiplexing is time division base multiplexing, which means that one FP data frame can carry data, which belongs to one UE only. In another alternative it is possible to carry data belonging to different UEs in one FP frame. Further, multiplexing could be taken care of by allowing an FP entity to send only one FP frame within one TTI, and this frame could be devoted to only one UE or it could transmit data for a number of UEs. Multiplexing could also mean that an FP entity could send more than one FP frame within one TTI which all are assigned to one UE, or each FP frame could carry data which is meant for different UEs. Equally, different FP frame structures can be provided for the cases that a user equipment identification has or has not to be transmitted from the RNC to the Node B. The size of frames based on one predetermined frame structure can be made variable, by allowing for some information in the header section a dedicated field for each user equipment or for each RNC buffer from which data was taken etc. A field structure can moreover be generalized by making the insertion of some of the information optional. Some information that is taken into account by a specific frame structure may be related to RNC buffers or buffering employed in HSDPA data transmission for buffering user data in an RNC. It is to be noted that the term RNC buffering or RNC buffers is used to indicate the buffering capability in the RNC without identifying the exact location of the buffer. Therefore, the buffering may be provided for instance on the RLC layer and/or on the MAC layer. In the first aspect of the invention, some user equipment specific information can moreover be either included in the header section of the proposed frame structure, or in a header section of a respective SDU inserted in the payload section of the proposed frame structure. In the second aspect of the invention, also the Iub application protocol can permit to include any suitable kind and number of parameters into any suitable kinds of message according to the requirements. There are two classes of control parameters that might have to be provided from an RNC to a Node B according to the second aspect of the invention. Either the RNC decides on an exact value of a parameter and the Node B has to follow this decision, or the RNC provides a bound of possible choices. In the latter case, the Node B can decide on the value according to its own conditions within the provided bound. Thus, the content of each control parameter is either a fixed value, an indication of a range for the value, or a set of allowed values to be used by said Node B. The control parameters of the second aspect of the invention can be in particular cell specific parameters required in the Node B e.g. for the setup and/or the reconfiguration of a cell, or a radio link specific parameter required in the Node B e.g. for the setup and/or the reconfiguration of a radio link. It can then be determined by the Iub application protocol that the parameters are to be included in control messages relating to a cell setup or reconfiguration or in a control message relating to an RL setup or reconfiguration respectively. Both, cell specific parameters and RL specific parameters can be provided either as specific value or as bound of choices. In order to include the control parameters of the second aspect of the invention in a control message, preferably one or more information elements (IE) or group of IEs are defined. Each IE can then comprise a field for each parameter required for a specific situation. The IEs can be added to a control message which has to be transmitted in this specific situation. In addition, IEs defined for DSCH or corresponding IEs might be used, as far as the required parameters are the same for some situations. It is also possible to define sets of IEs and/or groups of IEs for specific situations which are to be added to some control message for the respective situation. BRIEF DESCRIPTION OF THE FIGURES In the following, the invention is explained in more detail with reference to drawings, of which FIG. 1 shows a known UTRAN-side overall MAC architecture defined for HSDPA; FIG. 2 shows details of a known MAC −c/sh of an RNC; FIG. 3 shows details of a known MAC −hs of a Node B; FIG. 4 shows a known radio interface protocol architecture defined for HSDPA; FIG. 5 shows a model for the Iub, when no MAC level multiplexing is allowed in RNC; FIG. 6 shows a model for the Iub, when MAC level multiplexing is allowed in RNC; FIG. 7 shows a known DSCH FP frame structure; FIG. 8 shows a first embodiment of an HDSPA FP frame structure according to the invention; FIG. 9 shows second embodiment of an HDSPA FP frame structure according to the invention; FIG. 10 shows third embodiment of an HDSPA FP frame structure according to the invention; FIG. 11 illustrates a MAC PDU structure; FIG. 12 shows a first example of possible FP frame header field values for the embodiment of FIG. 10; FIG. 13 shows a second example of possible FP frame header field values for the embodiment of FIG. 10; FIG. 14 is a table presenting a set of cell specific IEs for an embodiment of the second aspect of the invention; FIG. 15 is a table presenting an RL cell specific IE for an embodiment of the second aspect of the invention; FIG. 16 is a table presenting a first set of RL cell specific IEs for an embodiment of the second aspect of the invention; FIG. 17 is a table presenting a second set of RL cell specific IEs for an embodiment of the second aspect of the invention; and FIG. 18 is a table illustrating a modification of a known TFS for an embodiment of the second aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION First, three embodiments of an HSDPA FP frame structure according to the first aspect of the invention will be presented. The respective frame structures are to be used for transmitting HSDPA related user data within an UTRAN from a MAC −c/sh of an RNC via a Iub interface to a MAC −hs of a Node B. A UE to which the user data is addressed is connected to this Node B. When determining a suitable frame structure, the requirements and capabilities of the network elements, i.e. RNC and Node B, should be considered. One factor that should be considered for example is MAC/FP UE-ID multiplexing which can be allowed in the RNC or not, as will be explained in the following. In a first model, which is illustrated in FIG. 5, the RNC is not allowed to perform MAC/FP UE-ID level multiplexing. FIG. 5 schematically shows an RNC 4 and a Node B 5 interconnected by an Iub interface. The RNC 4 comprises an RLC 6, a MAC −d and MAC −c/sh 2,3 and an FP entity 7. The Node B 5 equally comprises an FP entity 8, and a MAC −hs 1. In a current situation, three radio bearers RB w, z and v are assigned to a first user equipment UEx, while two further radio bearers RB m and n are assigned to a second user equipment UEy. The RBs of UEy and equally RB v of UEx are passed on without multiplexing from the RLC 6 in logical channels via MAC −d and MAC −c/sh 2,3 and the FP entity 7, the Iub interface and the FP entity 8 of the Node B 5 to the MAC −hs 1. The RBs w and z of UEx are C/T multiplexed in the MAC layer of the RNC 4 and transmitted on a single transport connection via the same entities to Node B 5. C/T multiplexing means the multiplexing of different RBs, i.e. which are using different logical channels, which all are assigned for the same UE on the same transport channel. The MAC −hs 1 then maps the received logical channels onto transport channels. If C/T multiplexing is allowed to be performed between radio bearers (RB), which all are assigned to the same UE, the minimum number of required Iub transmission connections is equal to the number of UEs having access to the HS-DSCH. C/T multiplexing can be used by an RNC e.g. only for some RBs of some UEs, as in FIG. 5, or for all RBs of all UEs. Alternatively, a C/T multiplexing of different radio bearers RB into the same Iub transmission connection might not be allowed at the RNC 4 of FIG. 5. C/T multiplexing might not even allowed to provide, e.g. due to different priority levels, if all radio bearers are assigned for the same UE. In this case, the number of transport connections on the Iub interface is equal to the number of radio bearers which are using the HSDPA type transport method. In a second model, which is illustrated in FIG. 6, the RNC 4 is allowed in contrast to perform MAC level UE-ID multiplexing. FIG. 6 schematically shows the same structure of an RNC 4 and a Node B 5 interconnected by an Iub interface as FIG. 5. Only in this case, a separate MAC −d 3 and MAC −c/sh 2 are depicted. Moreover, the same radio bearers RB w, z, v, m and n are assigned to the same user equipments UEx, UEy as in FIG. 5. Radio bearers RB w and RB z are again C/T multiplexed in the MAC layer, more specifically by the MAC −d 3. In addition, the output of the C/T multiplexing and the three other radio bearers RB v, m and n are UE-ID multiplexed by the MAC −c/sh 2 to a single transport connection for transmission to the MAC −hs 1 via the FP layer 7 of the RNC 4, the Iub interface and the FP layer 8 of Node B 5. The MAC −hs 1 first performs a demultiplexing, and then a mapping of the logical channels onto transport channels. In the Node B 5, the MAC layer correspondingly demuliplexes the received information, before mapping it to the HS-DSCHs and further on to the HS-PDSCH as in FIG. 5. There could also be more than one transport connection used in multiplexing. The general idea in multiplexing is that it is possible that all UEs which fulfill the same criteria can use the same transport resources. The multiplexing can be based for example on the number of cells in the Node B. That means, if the Node B supports more than one cell, one transport connection is provided per cell. Alternatively, the multiplexing could be based on priority levels assigned to the logical channels, i.e. one transport connection is provided per priority. Further, only a single transport connection could be provided for one Node-B. Multiplexing could also be based on the number of HSDPA related physical channels on the Radio interface. In the second model, MAC/FP UE-ID multiplexing is not restricted in any way, which means that it is possible that all UEs are allowed to use the same transport connection on the Iub interface. The second model can be provided also by placing the UE-ID multiplexing to the FP layer. In both case, if RNTI is used in the MAC header, no UE-ID is mandatory in the FP frame, and if no identification is included into the MAC header but multiplexing is allowed, then the FP header should contain also the UE-ID field(s). When MAC/FP UE-ID multiplexing is allowed, the frame structure should be defined in a way that the receiver is able to extract the information belonging to different UEs correctly from a received HSDPA frame. FIGS. 7 to 10 now show a conventional DSCH FP frame structure defined for the Iub interface presented for comparison, a first embodiment of an HSDPA FP frame structure for the case when no UE-ID mulitplexing is allowed and a second and third embodiment of an HSDPA FP frame structure for the case when UE-ID mulitplexing is allowed. The DSCH FP frame structure of FIG. 7 was taken from the technical specification 3GPP TS 25.435, V3.5.0 (2000-12): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; UTRAN Iub Interface User Plane Protocols for Common Transport Channel Data Streams (Release 1999)”. It is composed of a payload section and a header section, each divided into rows of 8 bits 0-7. The payload section comprises first to last TBs (transport blocks), a “Spare Extension”, and a “Payload CRC” (cyclic redundancy check). The header section comprises the fields “Header CRC”, “FT”, “CFN”, “TFI”, “Power Offset”, “Code number”, “SF” and “MC Info”. The “CFN” field is used to indicate the connection frame number (CFN), in which the data of a frame should be transmitted through the radio interface. In the HSDPA concept, the value of this field is only known by the Node B after a scheduling of the corresponding data to the radio interface, and therefore the RNC cannot provide this field to the Node B. The “TFI” field is used to indicate the valid transport format (TF) for the data in the frame. In the HSDPA concept, the TFC selection is carried out in the Node B, and therefore the RNC can not submit such information to the Node B. The “Power Offset” field is used to indicate the power level requested for the transmission of the data of the corresponding FP frame. This field is needed in the case of DSCH, because for the DSCH a closed loop power control is provided. In the case of HSDPA, no close loop power control is provided, and therefore no power control information is required from the RNC. The “Code number” field indicates the used code for the DSCH. In the case of HSDPA, the code selection is made in the Node B, and therefore no such information is required from the RNC. The “SF” field identifies the to be used spreading factor (SF) in a PDSCH for the corresponding data packets in the frame. In the HSDPA concept, the SF is defined in the Node B, and therefore no such information is required from the RNC. The “MC Info” field is used to indicate the number of parallel PDSCH codes on which the DSCH data will be carried. In the HSDPA concept, this kind of information is defined in the Node B, and therefore no such information is required from the RNC. Thus, non of the fields of the header section except the “Header CRC” field and the “FT” (frame type) field is required for HSDPA, and these fields can be removed when designing an HSDPA FP frame structure. But on the other hand, if the fields are simply removed, the Node B does not receive enough information for extracting the received FP frame. Therefore, new fields are required in order to guarantee that the flow control mechanisms work as the new MAC entity MAC −hs is located in the Node B. FIG. 8 presents an HSDPA frame structure which comprises such new fields for the case that no MAC/FP UE-ID multiplexing is allowed. It is composed again of a payload section and a header section, each divided into rows of 8 bits. Similar to the DSCH frame structure, the payload section comprises first to last MAC −c/sh SDUs (service data units), a “Spare Extension”, and a “Payload CRC”. The structure of a MAC SDU with a variable header is known from the state of the art as MAC PDU, and will be described below with reference to FIG. 11. The header section now comprises fields referred to by “Header CRC”, “FT”, “NumOfSDUs”, “User Buffer size”, “UE-ID type”, and “CMCH-PI”. In particular an introduction of the last two fields is optional. The “NumOfSDUs” field is used to indicated the number of the MAC −c/hs SDUs in the frame. The length of the field can be selected suitably. The “User Buffer size” field is used to indicate the status of the buffer assigned to the respective UE in the RNC buffers (e.g. in bytes). This field informs the Node B how much data belonging to the same data flow is still left in the RNC. A data amount carried in the corresponding FP data frame can be either excluded or included into the user buffer size information field. The Node B may use this information for instance in scheduling so that a data flow which has the highest priority and most data in the RNC buffers gets access to the HSDPA channel earlier than a data flow which has a lower priority and a smaller amount of data in the RNC buffers. Different possible significations of the term RNC buffers will be explained below with reference to FIGS. 12 and 13. The length of the field can be selected suitably. The “UE Id type” field is used, to indicate what kind of RNTI, i.e. c-RNTI or U-RNTI, the MAC −hs of the Node B should add to the MAC header. The type U-RNTI (UTRAN radio network temporary identity) may be used in a MAC header of the MAC PDU, which payload part contains specific L3 (RRC) signaling messages when the use of the U-RNTI is mandatory. This kind of situation is reported by RRC by sending a command to L2 (MAC layer via RLC layer) to use U-RNTI instead of C-RNTI in a MAC header. The type C-RNTI (Cell radio network temporary identity) is used on DTCH and DSCH in FDD (frequency division duplex) mode, and may be used in a MAC header, when no request to use U-RNTI is received from upper layers (RRC). The UE ID type field is required only if the RNTI is specified to be added in the Node B. If the RNTI is specified to be added in an SRNC or if no RNTI at all is used for HSDPA data transmissions, such a field is not required in the HSDPA FP data frame. The length of the field is one bit. The common transport channel priority indicator (“CMCH-PI”) field is used to indicate the relative priority of the data frame and/or of the SDUs included. For HSDPA data transmissions the use of this field can be introduced, but the priority of the RB when no multiplexing is provided could be introduced upon time when the corresponding transport connection over the Iub is configured. In this first embodiment of an HSDPA FP frame structure, it is not necessary that a field for a MAC SDU size information is included, because for HSDPA it has been defined that semi-static TB sizes will be used, wherein the MAC SDU is of a fixed size in case no multiplexing is allowed. FIG. 9 presents an HSDPA frame structure which comprises new fields for the case that MAC/FP UE-ID multiplexing is allowed. It is composed again of a payload section and a header section, each divided into rows of 8 bits. Similar to the DSCH FP frame structure and the first embodiment of an HSDPA FP frame structure, the payload section comprises first to last MAC −c/sh SDUs (service data units), a “Spare Extension”, and a “Payload CRC”. The header section now comprises fields referred to by “Header CRC”, “FT”, “NumOfSDUs”, “NumOfBuff”, “Size of MAC SDU”, “User Buffer size” 1-N, “UE-ID type”, and “CMCH-PI”. Also for “NumOfSDUs”, “NumOfBuff2, “Size of MAC SDU”, and “CMCH-PI” there may be several fields, even though only one field for each parameter is indicated in the figure. The “NumOfSDUs” field is used to identify the number of the MAC −c/sh SDUs which have been taken from one RNC buffer. The length of the field can be set suitably. The number of this kind of fields is equal to the number of “NumOfBuff” fields. The “NumOfBuff” field indicates from how many RNC buffers data has been supplied to this FP frame. It is to be noted that this field does not describe the number of RNC buffers from which data could be supplied. The length of the field can be set suitably. The “Size of MAC SDU”, field is introduced because the MAC multiplexing is not a mandatory feature, i.e. it is possible that even if MAC/FP UE-ID multiplexing is allowed, some operators do not want to use it. Therefore, to support the multivendor case when MAC/FP UE-ID multiplexing is allowed, the size of MAC SDU field defines the size of the SDUs in the respective frame. In principle, a TB has always a fixed size in HSDPA, but since the MAC header is of variable length depending on whether MAC/FP UE-ID multiplexing is supported or not, the size of the MAC SDU can vary depending on the content or existence of the MAC header. This information is required at the receiver side in order to extract SDUs from the HSDPA data frame correctly. The length of the field can be set suitably. The “User Buffer size” field is used to indicate the status of the buffer assigned to one UE in the RNC buffers in bytes. The length of the field can be set suitably. The number of fields of this kind in a frame is equal to the number of “NumOfBuff” fields. The “CMCH-PI” field could be used to provide an information about the priority of the data when MAC/FP UE-ID multiplexing is allowed. If it is allowed to multiplex data with different priority levels, then the number of fields of this kind must be equal to the number of the “NumOfBuffer” fields, but if no such multiplexing is allowed, it is sufficient to provide one “CMCH-PI” field per frame. It is to be noted that even if MAC/FP UE-ID multiplexing is allowed, the number of the respective multiplexing related fields “NumOfSDUs”, “User Buffer size”, “Size of MAC SDUs” and “CMCH-PI” can be decreased, if a restriction is identified that one HSDPA FP frame can contain only data which belongs to one UE or RB. In this case the MAC/FP UE-ID multiplexing is made based on a time division method. A further modification of the HSDPA FP frame structure presented as third embodiment relates to an identification of user equipment in HSDPA related data transmissions. If no UE identification is required in the Node B, and thus no MAC/FP UE-ID multiplexing is allowed in the RNC, an identification of the UE is neither included in the RNC nor in the Node B. The data is rather identified by using other methods. However, if a UE identification is required, the places where this information can be coupled with the data is either the MAC −c/sh in a CRNC or the MAC −hs in a Node B. In the first case, the used UE identification could be either the currently used RNTI or it can be a new UE identification which is defined only for the transmission of data over the Iub interface. If RNTI is used, the UE identification information can be included either in the MAC −c/sh SDU headers, which already have fields for this purpose, or in the header section of the respective HSDPA FP data frame. If it is included in the MAC −c/sh SDU header, the Node B has to extract this header part in order to find out the identity of the UE. If the UE identity is included into the header section of a HSDPA FP data frame, no extraction is required. For the frame structure of FIG. 9 it was assumed that if UE identification is required, the identification is RNTI and is include into the MAC SDU header either in the CRNC or in the Node B. For the case that no RNTI is desired on the air interface, but that still a UE identification is desired on the Iub, a third embodiment of a frame structure is presented, which is illustrated in FIG. 10. The frame structure of FIG. 10 again supports MAC/FP UE-ID multiplexing and comprises all fields present in the frame structure of FIG. 9. It comprises additional fields “UE-id 1” to “UE-id N” for identifying UEs for which data is included in MAC −c/sh SDUs in the payload section. In this figure, there are also N different fields “NumOfBuff”, “NumOfSDUs”, “Size of MAC SDU”, and “CMCH-PI”, respectively, explicitly indicated. The content of the UE identification fields “UE-id” can be the RNTI, but in order to save transmission capacity on the Iub interface, also a new shorter identification could be defined. The length of this field thus depends on the selected kind of identification. The number of the “UE-id” fields depends on whether one HSDPA frame can contain data for different UEs. If this is allowed, the number of the fields must be equal to the number of the “NumOfBuff” fields. However, if MAC/FP UE-ID multiplexing is allowed, i.e. more than one UE is using the same transport connection on the Iub interface, but one HSDPA FP frame can contain data only from one RNC buffer, the number of required UE identification fields is 1. FIG. 11 presents the MAC PDU structure when DTCH or DCCH are mapped to DSCH and when DTCH or DCCH are the only logical channels, and which can be employed also for HSDPA. The figure was taken from the technical specification 3GPP TS 25.321 V3.6.0 (2000-12): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; MAC protocol specification (Release 1999)”. The MAC PDU in FIG. 11 is composed of a MAC SDU and a MAC header. The header comprises a “UE-Id type” field, a “UE-Id” field and a “C/T” field. The “UE-Id type” and the “UE-Id” fields are included in the MAC header for FDD only. The “UE-Id” field provides an identifier of the UE on common transport channels. The “UE-Id Type” field is needed to ensure a correct decoding of the UE-Id field in MAC Headers. The “C/T” field is included in the MAC header if C/T multiplexing on MAC is applied. The “C/T” field provides an identification of the logical channel instance when multiple logical channels are carried on the same transport channel. The “C/T” field is also used to provide an identification of the logical channel type on dedicated transport channels and on FACH (forward access channel) and RACH (random access channel) when used for user data transmission. The size of the “C/T” field is fixed to 4 bits for both, common transport channels and dedicated transport channels. For the first aspect of the invention, finally an example is presented of how the FP frame header field values in a frame according to the frame structure in FIG. 10 can be set for two different models for the RNC buffers. The first buffering model is illustrated in FIG. 12. In this alternative, the last RNC buffers before the Node B buffers are located on the RLC layer in the RNC. FIG. 12 shows five of such RNC buffers 9, RLC buffer z, h, k y and u. RLC buffer z is assigned to the data for a user equipment UEx, more specifically to a radio bearer RBz used for this UE. It outputs data with a priority level r for use in one RLC PDU. RLC buffers h and k are assigned to radio bearer RBh and RBk respectively, which are both used for user equipment UEy. Only buffer k, however, outputs data for distribution to RLC PDUS. More specifically two logical channels are provided from the RLC layer by buffer k. To the data a priority level m is assigned, and the data is distributed to two RLC PDUs. RLC buffers y and u are assigned to radio bearer RBy and RBu respectively, which are both used for user equipment UEz. Buffer v outputs data with a priority level r for use in one RLC PDU. Buffer u outputs data with a priority level of m, which data is distributed to three RLC PDUs. Each RLC PDU will be used in the MAC layer as basis for one MAC −c/sh SDU in an assembled HSDPA FP frame. In the model of FIG. 12, the value of the field “NumOfBuff” can be defined based on RBs. That means, the value of the field “NumOfBuff” is equal to the number of RBs, and thus the number of RLC buffers 9, which provide data for the HSDPA FP frame. Thus, in the presented example, the value of the field “NumOfBuff” of a data frame based on the frame structure of FIG. 10 is set to 4, since the data is extracted from four of the RNC buffers, i.e. RLC buffers z, k, y and u. The value of the field “NumOfSDUs” for RLC buffer z is set to 1, since only data for one RLC PDU was extracted from this buffer for the current frame. For RLC buffer k, the value of the field “NumOfSDUs” is set to 2, since data for two RLC PDUs was extracted from this buffer for the current frame. For RLC buffer v, the value of the field “NumOfSDUs” is set again to 1, since only data for one RLC PDU was extracted from this buffer for the current frame. For RLC buffer u, the value of the field “NumOfSDUs” is set to 3, since data for three RLC PDUs was extracted from this buffer for the current frame. The value of the fields “SizeOfSDUs” and “User Buffer size” are set to the respectivly applicable values. In the depicted example, user equipment UEy has an RLC entity from which two different logical channels are provided to the MAC layer, as indicated in the figure. Such a configuration is possible in an acknowledged RLC mode. Even if data has been received from two logical channels, the buffer size information needs to be combined, which means that the “User Buffer size” field contains information about the status of RLC buffer k. The value of the field “UE-id” for RLC buffer z is set to x, since the data in this buffer is meant for UE x. The value of the field “UE-id” for RLC buffer k is set to y, since the data in this buffer is meant for UE y. The value of the field “UE-id” for RLC buffers y and u is set to z, since the data in these buffer is meant for UE z. The value of the field “CMCH-PI” for RLC buffer z and RLC buffer v respectively is set to r, since the priority level for the data extracted from these two buffers was set to r. The value of the field “CMCH-PI” for RLC buffer k and RLC buffer u respectively is set to m, since the priority level for the data extracted from these two buffers was set to m. Another way to realize the RNC buffers is to locate the last buffers before the Node B buffers to the MAC layer of the RNC, e.g. to the MAC −c/sh, which is illustrated in FIG. 13. FIG. 13 shows again five RLC layer buffers 10 of an RNC, RLC buffer z, h, k, v and u. In this case, however, in addition four MAC layer buffers 11 are present, MAC buffer z, h, k, and uv. RLC buffer z is assigned again to a radio bearer RBz used for user equipment UEx. RLC buffer z outputs data with a priority level p to MAC buffer z, which MAC buffer outputs data for use in one MAC SDU. RLC buffers h and k are assigned again to radio bearer RBh and RBk respectively, which are both used by user equipment UEy. RLC buffer h is connected to MAC buffer h and RLC buffer k to MAC buffer k, but only RLC buffer k forwards data to MAC buffer k with an assigned priority level of m. MAC buffer k outputs data that is to be distributed to two MAC SDUs. RLC buffers v and u are assigned again to radio bearer RBy and RBu respectively, which are both used for user equipment UEz. Both, RLC buffer v and RLC buffer u, forward received data with the same priority level r to MAC buffer uv. MAC buffer uv outputs data that is to be distributed to four MAC SDUs. In the buffering model according FIG. 13, the value of the “NumOfBuff” field defines the number of MAC level buffers 11 from which data is supplied to the corresponding HSDPA FP data frame. Thus, in the presented example, the value of the field “NumOfBuff” of a data frame based on the frame structure of FIG. 10 is set to 3, since the data is extracted from three MAC buffers, i.e. MAC buffers z, k, and vu. The value of the field “NumOfSDUs” for MAC buffer z is set to 1, since only data for one MAC SDU was extracted from this buffer for the current frame. For MAC buffer k, the value of the field “NumOfSDUs” is set to 2, since data for two MAC SDUs was extracted from this buffer for the current frame. For MAC buffer uv, the value of the field “NumOfSDUs” is set to 4, since data for four MAC SDUs was extracted from this buffer for the current frame. The values of the fields “SizeOfSDUs” and “User Buffer size” are set to the respectively applicable values. The value of the field “UE-id” for MAC buffer z is set to x, since the data in this buffer is meant for UE x. The value of the field “UE-id” for MAC buffer k is set to y, since the data in this buffer is meant for UE y. The value of the field “UE-id” for MAC buffer uv is set to z, since the data in this buffer is meant for UE z. The value of the field “CMCH-PI” for MAC buffer z is set to p, since the priority level for data provided to this buffer was set to p. The value of the field “CMCH-PI” for MAC buffer k is set to m, since the priority level for data provided to this buffer was set to m. The value of the field “CMCH-PI” for MAC buffer uv is set to r, since the priority level for data provided to this buffer was set to r. In the example of FIG. 13, several RBs assigned to the same UE may use a common MAC buffer 11, if they have for example a common priority value. It would also be possible to use a common MAC buffer 11 for all RBs having a common priority value for the transmitted UE information, regardless of the UE to which the RBs are assigned. This would make the flow control much more complex, though. In the whole, different HSDPA FP frame structures according to the first aspect of the invention were presented which can be employed advantageously for different situations for transmitting HSDPA related user data together with required additional information from an RNC to a Node B of an UTRAN. The presented frame structures can be modified in any suitable way in order to provide an optimal adaptation to specific requirements. Now, an embodiment of the second aspect of the invention will be presented for an HSDPA capable UTRAN comprising an RNC and a Node B interconnected by an Iub interface. In this embodiment, an Iub application protocol is provided, which defines several IEs that can be added by the RNC to selected control messages transmitted via the Iub interface to the Node B, in order to enable the Node B to configure the HSDPA. FIG. 14 shows a table with a set of new semi-static “HS_DSCH Information” IEs comprising cell related parameters with HS-DSCH related information which can be used by a Node B for configuring HSDPA in a cell and the characteristics of the implemented HARQ. The table has the format of tables used by 3GPP for defining IEs, e.g. in the above cited technical specification TS 25.433. These tables comprise a respective column for an IE/Group Name, the requirements on the presence of the IE, a range, an IE type and a reference, a semantic description, a criticality, and an assigned criticality. In FIG. 14 only the column “IE/Group Name” is used. The other columns can be completed according to the respective requirements. A first IE in the set of the table of FIG. 14 is called “MCS Sets”. It comprises the sets of modulation and coding schemes (MCS) from which Node B can choose every TTI for transmissions. A second IE in this set is called “HS_DSCH Power Level”. This IE defines the relationship between the HS-DSCH and the CPICH (common pilot channel) code power level in case of NQAM (n-symbol quadrature amplitude modulation). A third IE in this set is called “NumOfCodes”, which defines the number of code channels which will be assigned to HS-DSCHs. The RNC can assign the number of code channels for a cell to enable the configuration of HS-DSCH characteristics. A fourth IE in this set is called “TTI Selection”. The “TTI Selection” includes an information about the TTI length which the Node B shall use. Further included in the table is the “HARQ Information”, which is an IE group that might include several HARQ specific IEs, which IEs depend on the selected HARQ implementation. The “HARQ Information” group defines information to configure HARQ in Node B. The parameters of this group allow the RNC to restrict the capacity of the Node B. In FIG. 14, the IE group “HARQ information” includes the IEs “NumOfChannel”, “MaxAttempt” and “RedudancyVer”. In case an n-channnel SAW-HARQ is used, the IE “NumOfChannel” can be included to enable the RNC to configure the number of channels. Assuming moreover that the Node B can reject a UE retransmission request after a certain amount of trials, the inclusion of the IE “MaxAttempt” enables the RNC to provide the Node B with a maximum number of trials, and the Node B can then decide to reject or not to reject a request under this limitation according to its own conditions. Finally, in case that an incremental redundancy method is used instead of a soft/chaise combining method, the IE “Redundancyver” can define the restriction of redundancy versions from which the Node B can choose. Especially the IE “NumOfCodes” and the IEs belonging to the IE group “HARQ Information” are providing limits to the Node B, which Node B can select the proper value dynamically from within the set bound. It would also be possible to classify these parameters alternatively as fixed value and/or as RL specific values. The described cell specific IEs can be added to the CELL SETUP procedure and the CELL RECONFIGURATION procedure and be included by the RNC in HSDPA related CELL SETUP REQUEST messages and CELL RECONFIGURATION REQUEST messages transmitted by the RNC to the Node B. FIGS. 15 to 17 each show a table with a set of IEs comprising RL related parameters that can be used by the Node B to setup and reconfigure HS-DSCH channels. The IEs can be added in the RADIO LINK SETUP procedure and the SYNCHRONIZED RADIO LINK RECONFIGURATION PREPARATION procedure. The tables have the same format as the table of FIG. 14. The table of FIG. 15 only contains one IE “HS_DSCH ID”. This IE uniquely identifies a HS-DSCH within a Node B Communication Context. The table of FIG. 16 comprises “HS_DSCH Information Response” IEs, which provide information for HS-DSCHs that have been established or modified. The range of entries for each IE is from 1 to the maximum numbers of HS-DSCHS for one UE. A first IE in this set is again the already mentioned IE “HS_DSCH ID”, which should be included mandatorily. A second IE in this set is called “Binding ID”, and can be included optionally. The “Binding ID” is the identifier of a user data stream. It is allocated at the Node B and it is unique for each transport bearer under establishment to or from the Node B. The meaning is thus the same as for DSCH. A third IE in this set is called “Transport Layer Address” and can also be included optionally. This IE defines the transport address of the Node B. The meaning is thus the same as for DSCH. The IEs of the table of FIG. 16 can be included in RADIO SETUP RESPONSE messages and RADIO LINK RECONFIGURATION READY messages. The table of FIG. 17 comprises “HS_DSCH FDD Information” IEs, which provide information for HS-DSCHs that are to be established. The range of entries for each IE is again from 1 to the maximum numbers of HS-DSCHS for one UE. A first IE in this set is again the above mentioned IE “HS_DSCH ID”. A second IE in this set is called “UE_ID” and is employed to enable the Node B to distinguish between different UEs. This IE will be used to fill up the MAC header. It can be RNTI or something else, e.g. a new kind of user equipment identity indication, which could be transparent for the UE. A third IE in this set is called “Transport Format Set”. The “Transport Format Set” is defined as the set of transport formats associated to a Transport Channel, e.g. HS-DSCH. A fourth IE in this set is called “Allocation/Retention Priority”. This parameter indicates the priority level in the allocation and retention of the internal resources of the Node B. The meaning is thus the same as for DSCH. A fifth IE of this set is called “Frame Handling Priority”. This parameter indicates the priority level to be used during the lifetime of the HS-DSCH for temporary restrictions of the allocated resources due overload reason. The meaning is the thus same as for DSCH. A sixth IE of this set is called “ToAWE”. The parameter “ToAWE” is the time of arrival of the window endpoint. Downlink data frames are expected to be received before this window endpoint. The meaning is thus the same as for DSCH. A seventh IE of this set is called “ToAWS”. The parameter “ToAWS” is the time of arrival of the window startpoint. Downlink data frames are expected to be received after this window startpoint. The meaning is thus the same as for DSCH. An eighth IE of this set is called “NumOfCodes” and was already mentioned as possible cell based parameter. The RNC could select the value for this parameter according to the respective UE capability. A ninth IE of this set is called “BufferStatus” and indicates the current status of RNC buffers. This parameter can be used at the beginning of the connection for the flow control. Further included in the set is the “HARQ Capacity”, which is an IE group that might include several HARQ specific IEs identical to those of the “HARQ Information” group in the table of FIG. 14. But even though the names of IEs are identical in both cell-specific and RL-specific case, the meanings are slightly different, since in the cell-specific case the “HARQ Information” restricts the cell capacity, while in the RL-specific case the “HARQ Capacity” reflects the QoS (Quality of Service) of the radio link or the UE capability. The IEs of this table can be included in RADIO LINK SETUP REQUEST messages and RADIO LINK RECONFIGURATION PREPARE messages. A further HSDPA specific set of IEs is defined for HS-DSCH Information that is to be modified. This set comprises a subset of the set for “HS-DSCH FDD information”. More specifically, it includes the IEs “HS-DSCH ID”, “Transport Format Set”, “Allocation/Retention Priority”, “Frame Handling Priority”, “ToAWS”, “ToAWE”, and “NumOfCodes”, and possibly the IEs of the “HARQ Capacity” group. The IEs of this set can also be included in RADIO LINK RECONFIGURATION PREPARE messages. Many of the RL related IEs have a corresponding meaning as DSCH related IEs presented e.g. in the above cited technical specification TS 25.433, which is incorporated by reference herein and to which is referred for further details. Not known for DSCH is the IE group “HARQ Capacity”, which denotes HARQ characteristics of a RL, and which could also reflect the UE capabilities and/or the QoS of the RL. Moreover, the IE “UE_ID” was added as a new parameter, in order to help completing the MAC header in the Node B. If no ID is included or needed in the MAC header, this parameter can be used alternatively on the FP layer for the same purpose. The IE “Transport Format Set” is very similar to the corresponding IE for DSCH, but for some IEs new values shall be defined to support HS-DSCH. This is indicated in FIG. 18, which shows a table for the DSCH transport format set taken from the above cited specification TS 25.433 with some underlined modifications. More specifically, some more possible values are added for the “Transmission time interval” IE, namely “1slot”, “3slot”, “5slot” and “15slot”. These values are to be used for HS-DSCH only and no other values are to be applicable to HS-DSCH. In addition, the “Convolutional” value should not be used in the “Type of channel coding” IE for HSDPA. Thus, in the presented embodiment of the second aspect of the invention, basic IEs are defined which can be provided during cell setup and reconfiguration and RL setup and reconfiguration to support HSDPA. The described sets of IEs and the IEs themselves can be modified in any suitable way in order to be adapted to specific requirements. Equally, further sets of IEs can be defined in the Iub application protocol in order to enable any required transfer of HSDPA related control information.

<SOH> BACKGROUND OF THE INVENTION <EOH>HSDPA is a concept that was introduced for UTRAN architectures as an enhancement to the shared channel concept in 3GPP (3rd generation partnership project). In UMTS, the UTRAN handles all radio-related functionality. To this end, an UTRAN comprises one or more RNCs, and connected to each RNC one or more Node Bs. The RNCs of the UTRAN are connected to a core network via an Iu interface. RNCs of one UTRAN may be interconnected in addition by an Iur interface. In downlink transmissions, an RNC receives user data from the core network, possibly via another RNC, and forwards it via an Iub interface to a Node B. The Node B then transmits the data to the addressed user equipment UE via a Uu interface. The RNCs of an UTRAN might take different roles. A controlling RNC (CRNC) may be defined, for example, with respect to a specific set of Node Bs. There is only one CRNC for any Node B. The CRNC has an overall control over the logical resources of its Node Bs. A serving RNC (SRNC) may be defined with respect to a specific connection between an UE and an UTRAN. There is one SRNC for each UE that has a connection to UTRAN. The SRNC is in charge of the radio resource control (RRC) connection between a UE and the UTRAN. The Serving RNC also terminates the Iu for this UE. In the shared channel concept in UTRAN for FDD mode, a DSCH (downlink shared channel) is defined as a downlink transport channel which is shared dynamically between several UEs. The DSCH is assembled in a CRNC and transmitted via a Node B to a UE, as described for instance in the technical specification 3GPP TS 25.301 V3.6.0 (2000-09): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; Radio Interface Protocol Architecture (Release 1999)”. The basic idea of HSDPA is to offer for downlink transmissions shared high speed channels with a higher data rate and a quicker retransmission mechanism already from Node B. The shared high speed channels are to comprise a HS-DSCH (high speed downlink shared channel) as transport channel and a DPCH (dedicated physical channel), combined with a separate shared physical control channel in combination with a HS-PDSCH (high speed physical downlink shared channel). The fast retransmission mechanism to be implemented in the Node B is HARQ (hybrid automatic repeat request). The currently used DSCH may also support high data rates, but retransmission is always provided by a RLC (radio link control) layer in the RNC, which slows the transaction down. In order to support the new capabilities, especially HARQ, a new MAC (medium access control) entity was introduced in the technical report 3GPP TR 25.855 V1.0.0 (2001-06): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; High Speed Downlink Packet Access; Overall UTRAN Description (Release 5)”, which is incorporated by reference herein. The new MAC entity is called MAC −hs and is always located in the Node B. In the preceding releases of 3GPP, all UTRAN MAC entities capable of handling also user plane data were always located exclusively in the RNCs. The MAC −hs exists only when the cell is configured to support the HSDPA concept, and it is connected to a MAC −c/sh located in an RNC through the Iub interface. A MAC layer is used for mapping logical channels to transport channels. A logical channel is a channel type which is defined between the radio link control (RLC) in an RNC and the MAC layer. Each logical channel defines what kind of data is going to be transmitted through it. In the case of HSDPA, the logical channels always locate in the SRNC. A transport channel is a channel type which is defined between the MAC layer and L 1 (layer 1 ). It describes how data is to be transmitted through the radio link. In the DSCH concept, the transport channel is seen on the Iub interface, whereas in the HSDPA concept the transport channel is an internal channel in Node B. The connection of different MACs of an UTRAN for HSDPA is illustrated in FIG. 1 , which was taken from the above cited technical report TR 25.855. FIG. 1 depicts a MAC −hs 1 located in a Node B, and in addition a MAC −c/sh 2 and a MAC −d 3 located in one or more RNCs. The MAC −hs 1 is connected to the MAC −c/sh 2 via the Iub interface, while the MAC −c/sh 2 is connected to the MAC −d 3 via an Iur interface in case they are located in different RNC, otherwise these MACs 2 , 3 are interconnected locally. A MAC control has access to each of the MACs 1 - 3 . Such logical channels as PCCH (Paging channel) and BCCH (broadcast control channel) are directly mapped to the MAC −c/sh 2 without intervening of MAC −d 3 . However such logical channels as DCCH (Dedicated control channel) and DTCH (dedicated traffic channel) are always connected to MAC −d 3 , which forwards the received data packets to the MAC −c/sh 2 , if the UE has access right either to the common channel(s) or to the shared channel(s). MAC −c/sh 2 and MAC −d 3 map different kinds of logical channels onto transport channels, like PCH (paging channel), FACH (forward access channel), DCH (dedicated channel) etc., for transmission to a UE via a Node B. Received HSDPA related data is provided by MAC −d 3 via MAC −c/sh 2 without mapping to the MAC −hs 1 of the Node B for transmission in HS DSCHs to a UE. For the details of FIG. 1 it is referred to the technical report TR 25.855. Alternatively, the MAC −hs could be connected directly to a MAC −d. Since functionalities previously implemented only in the RNCs have now to be provided also in Node Bs, like TFC (transport format combination) selection, the functional split between Node B and RNC has been reorganized. The new distribution of functionalities is shown in FIGS. 2 and 3 , which were equally taken from technical report TR 25.855, and which presents in more detail some of the functions provided by MAC −c/sh 2 and MAC −hs 1 respectively. Upon the reorganization, scheduling/priority handling and TFC selection functions have been removed from the MAC −c/sh 2 of the RNC in FIG. 2 for HSDPA related downlink transmissions and added to the MAC −hs 1 of the Node B in FIG. 3 . Thus, the final scheduling and the real time traffic control not under RNC control any more for HSDPA. Accordingly, in the MAC −c/sh 2 in FIG. 2 , HSDPA related data received from a MAC −d are passed on to the MAC −hs 1 of FIG. 3 without any scheduling, priority handling or TFC selection etc. being performed as for other downlink data. Previously, these functions were always taken care of either in a SRNC when Node B was connected directly to an SRNC, or in a CRNC when the Node B was connected to an CRNC. In addition, HARQ is implemented in the new MAC −hs 1 of FIG. 3 . For the details of FIGS. 2 and 3 it is referred to the above cited technical report TR 25.855. The reorganization of functionalities implies that the known transmissions of downlink user data and of required control information from an RNC to a Node B has to be adapted. For the transmission of downlink user data, it was proposed that the RLC layer is not changed. This means that the RLC buffers as before RLC PDUs (protocol data units) in RNC buffers, and that the RLC submits data to the lower layer only upon request of the MAC layer which locates on the RNC, i.e. MAC −d 3 . Therefore the transactions to support data transmission between a MAC entity in an RNC and a MAC −hs 1 in a Node B are currently defined only on high level, but details are still missing. By these high level definitions, a flow control functionality is defined between MAC −c/sh 2 and MAC −hs 1 as a new feature, as indicated in FIG. 3 , in order to control the data flow from the RNC to the Node B. To support actual data transmissions on the Iub-interface, moreover a HS-DSCH Frame protocol layer (HS-DSCH FP) was included under the MAC −c/sh and above the MAC −hs. This layer is indicated in FIG. 4 , which was again taken from technical report TR 25.855. FIG. 4 shows a radio interface protocol architecture of HSDPA, and more specifically layers of network elements which network elements are, from left to right, a user equipment UE connected via a Uu interface to a Node B, which is further connected via an Iub interface to a first RNC, which is finally connected via an Iur interface to a second RNC. Each of the Node B, the first and the second RNC comprises in addition to the respective MAC entity a HS-DSCH FP. This HS-DSCH FP is intended to transmit not only data packets from the RNC to the Node B, but also related control information. Such an FP protocol is proposed without any details for data transmissions in downlink on both, Iub and Iur interfaces, which transmissions are using the service of L 2 (layer 2 ) of MAC and RLC. For the details of FIG. 4 , it is referred to the above cited technical report TR 25.855. None of the current FP frame structures defined for the Iub interface, however, is applicable for HSDPA. In particular the FP frame structure used for DSCHs, from which DSCHs the proposal for HSDPA proceeds, is not suited for HSDPA data transmissions, since a DSCH FP frame contains fields of which the values can only be defined when the scheduling or TFC selection has already been made. As mentioned above, these functions were shifted for HSDPA related transmissions to the Node B. Moreover, a DSCH FP frame does not contain all of the information which is required for HSDPA to support flow control between an RNC and a Node B. In addition to HSDPA related user data, also control information has to be available at the Node B so that the Node B can set up and re-configure HS-DSCH channels for transmissions. Due to the functional reorganization, the current application protocol procedures on Iub for DSCH setup and reconfiguration, described e.g. in the technical specification 3GPP TS 25.433 V3.4.1 (2000-12): “3rd Generation Partnership Project; Technical Specification Group Radio Access Network; UTRAN Iub Interface NBAP Signalling (Release 1999)”, cannot be used for HS-DSCH. For example, in the case of HSDPA it is not necessary to provide channel coding parameters during a radio link (RL) setup as for DSCH, since these channel coding parameters are decided upon in the Node B. On the other hand, some parameters that are not required by a Node B for DSCH should be provided to a Node B for HSDPA during a cell setup procedure so the Node B can configure HS-DSCH attributes in a cell. It should moreover be possible to modify these parameters cell-based, preferably in a semi-static manner.

<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the invention to enable the transmission of data within a communications network, which data is required at a network element of said communications network. It is also an object of the invention to enable the use of HSDPA by an UTRAN, and more specifically to enable the RNC of an UTRAN to provide a Node B of the UTRAN with HSDPA related data. It is in particular an object of the invention to enable an RNC to provide a Node B in a suitable way with HSDPA related user data and with HSDPA relevant control parameters on NBAP (Node B Application Part). A first aspect of the invention is directed at the transmission user data, while a second aspect of the invention is directed at the transmission of control parameters. For the first aspect of the invention, a method is proposed for transmitting user data within a communications network from a controller to a network element over an interface. The communications network can be in particular an UTRAN, the controller an RNC, the network element a Node B and the interface an Iub interface. The controller uses at least one dedicated frame structure, in particular a dedicated HSDPA FP frame structure, for assembling data frames with the user data. The data frames are then transmitted via the interface to the network element. The frame structure includes at least a header section for receiving information required in said network element for processing the user data. For the first aspect of the invention, in addition a communications network, in particular an UTRAN, a controller, in particular an RNC, and a network element, in particular a Node B, are proposed which comprise means for realizing the proposed method. Concerning the first aspect, the invention proceeds from the idea that the transmission of information required for the processing of HSDPA related user data should be similar to the solutions used for other shared channels, but still be optimized for the requirements of HSDPA. The proposed dedicated frame structure allows to remove all fields employed in the structures for DSCH which are no longer necessary for HSDPA, and to insert fields for the information required additionally for HSDPA. Thus, an optimized transmission of information required for HSDPA related user data via the Iub interface is enabled. The same considerations may apply for other communications networks, network elements and situations. For the second aspect of the invention, a method is proposed for providing a network element of a communications network with control parameters available at a controller of the communications network, which controller is connected to said network element via an interface. The communications network can be in particular an UTRAN, the controller an RNC, the network element a Node B and the interface an Iub interface. The method comprises employing an interface application protocol which enables an insertion of at least one control parameter, in particular an HSDPA related control parameter, into at least one kind of control message transmitted from said controller to said network element over said interface. Also for the second aspect of the invention, in addition a communications network, in particular an UTRAN, a controller, in particular an RNC, and a network element, in particular a Node B, are proposed which comprise means for realizing the proposed method. Concerning the second aspect, the invention proceeds from the idea that the most efficient way to provide a Node B with control parameters required for setting up an re-configuring HS DSCH channels is to include the parameters in control messages transmitted from an RNC to the Node B. Since RNC and Node B are connected to each other via an Iub interface, it is thus proposed to modify the Iub application protocol accordingly. As a result, the Node B is for example able to setup and re-configure HS-DSCH channels based on received control parameters. The Node B can therefore be configured by the RNC to support HSDPA related data to user equipment in the cell. The same considerations may apply for other communications networks, network elements and situations. Both aspects of the invention have in common that they comprise an HSDPA specific implementation of general specifications used for transmitting data from RNC to Node B via the Iub interface, i.e. on the one hand an implementation of dedicated frame structures and on the other hand an implementation of an Iub application protocol with HSDPA specific procedures. Preferred embodiments of the invention become apparent from the subclaims. In a preferred embodiment of the first aspect of the invention, the frame structure further includes a payload section for receiving at least one SDU to which HSDPA related user data was distributed by said controller, wherein the header section receives information required in the network element for processing HSDPA related user data. Thus, information required at Node B for processing HSDPA related user data can be transmitted in an advantageous way in a single frame together with said user data. The SDUs are in particular MAC −d SDUs and/or MAC −c/sh SDUs. For the first aspect of the invention it is to be noted that the proposed HSDPA FP frame structure can be designed to receive any number of information, which information can be predetermined arbitrarily according to the requirements. Further, it should not be obligatory that the payload section contains any data in a frame assembled according to the dedicated frame structure so that the same structure may be used for transmitting information only in the header section, e.g. information for an HSDPA flow control. In particular, different FP frame structures can be provided for the cases that MAC/FP UE-ID multiplexing is or is not allowed in the RNC. UE-ID multiplexing is a multiplexing type in which different UEs are multiplexed onto the same transport channel and can be performed either in the MAC layer or the FP layer of an RNC. In the case of FP UE-ID multiplexing, the header of the FP frame should always contain the UE-ID identification. This identification can be e.g. RNTI, or it can be a new identification defined for this purpose only and thus be shorter than the current RNTI. In a case of MAC UE-ID multiplexing, the UE-ID field is used in the MAC header, i.e. RNTI is added into MAC header, no identification is necessarily required in FP frame. The Node B can fetch the UE-ID information by reading the MAC header. Then again if it is wanted that the FP frame should contain the UE-ID field despite the addition of the RNTI into the MAC header, the used UE-ID can be e.g. RNTI, or it can be a new identification defined for this purpose only and thus be shorter than the current RNTI. There are moreover different alternatives how multiplexing can be carried out, and the used multiplexing method may have to be considered when determining the most suitable structure of the FP frame. The kind of multiplexing used can in particular have an impact on the number of fields of the same kind provided in one FP frame. One alternative for multiplexing is time division base multiplexing, which means that one FP data frame can carry data, which belongs to one UE only. In another alternative it is possible to carry data belonging to different UEs in one FP frame. Further, multiplexing could be taken care of by allowing an FP entity to send only one FP frame within one TTI, and this frame could be devoted to only one UE or it could transmit data for a number of UEs. Multiplexing could also mean that an FP entity could send more than one FP frame within one TTI which all are assigned to one UE, or each FP frame could carry data which is meant for different UEs. Equally, different FP frame structures can be provided for the cases that a user equipment identification has or has not to be transmitted from the RNC to the Node B. The size of frames based on one predetermined frame structure can be made variable, by allowing for some information in the header section a dedicated field for each user equipment or for each RNC buffer from which data was taken etc. A field structure can moreover be generalized by making the insertion of some of the information optional. Some information that is taken into account by a specific frame structure may be related to RNC buffers or buffering employed in HSDPA data transmission for buffering user data in an RNC. It is to be noted that the term RNC buffering or RNC buffers is used to indicate the buffering capability in the RNC without identifying the exact location of the buffer. Therefore, the buffering may be provided for instance on the RLC layer and/or on the MAC layer. In the first aspect of the invention, some user equipment specific information can moreover be either included in the header section of the proposed frame structure, or in a header section of a respective SDU inserted in the payload section of the proposed frame structure. In the second aspect of the invention, also the Iub application protocol can permit to include any suitable kind and number of parameters into any suitable kinds of message according to the requirements. There are two classes of control parameters that might have to be provided from an RNC to a Node B according to the second aspect of the invention. Either the RNC decides on an exact value of a parameter and the Node B has to follow this decision, or the RNC provides a bound of possible choices. In the latter case, the Node B can decide on the value according to its own conditions within the provided bound. Thus, the content of each control parameter is either a fixed value, an indication of a range for the value, or a set of allowed values to be used by said Node B. The control parameters of the second aspect of the invention can be in particular cell specific parameters required in the Node B e.g. for the setup and/or the reconfiguration of a cell, or a radio link specific parameter required in the Node B e.g. for the setup and/or the reconfiguration of a radio link. It can then be determined by the Iub application protocol that the parameters are to be included in control messages relating to a cell setup or reconfiguration or in a control message relating to an RL setup or reconfiguration respectively. Both, cell specific parameters and RL specific parameters can be provided either as specific value or as bound of choices. In order to include the control parameters of the second aspect of the invention in a control message, preferably one or more information elements (IE) or group of IEs are defined. Each IE can then comprise a field for each parameter required for a specific situation. The IEs can be added to a control message which has to be transmitted in this specific situation. In addition, IEs defined for DSCH or corresponding IEs might be used, as far as the required parameters are the same for some situations. It is also possible to define sets of IEs and/or groups of IEs for specific situations which are to be added to some control message for the respective situation.

20041018

20121002

20050324

95042.0

MIZRAHI, DIANE D

TRANSMISSION OF DATA WITHIN A COMMUNICATIONS NETWORK

UNDISCOUNTED

ACCEPTED

ACCEPTED

Composite materials comprising a reinforcing material and a star polyamide as a thermoplastic matrix, the precursor compound article of said materials and the products obtained using same

The invention relates to a precursor article of a composite material comprising a polymer matrix and at least one reinforcing wire and/or fibres, said article comprising at least one reinforcing wire and/or fibres and at least one polymer matrix wire and/or fibres. The invention is characterised in that: said reinforcing wire and/or fibres are made from a reinforcing material and may comprise a thermoplastic polyamide part; said polymer matrix wire and/or fibres are made from thermoplastic polyamide; and the thermoplastic polyamide of said reinforcing wire and/or fibres and/or said polymer matrix wire and/or fibres comprise at least one polyamide with a star structure which contains: star macromolecular chains comprising one or more cores and at least three branches or three polyamide segments which are linked to the core; if necessary, linear polyamide macromolecular chains

1-24. (canceled) 25. A precursor article of a composite material comprising a polymeric matrix and at least one reinforcing yarn and/or reinforcing fibers, said article comprising at least one reinforcing yarn and/or reinforcing fibers and at least one polymeric matrix yarn and/or polymeric matrix fibers, wherein: said reinforcing yarn and/or said reinforcing fibers are made of reinforcing material and optionally comprise a part made of thermoplastic polyamide, said polymeric matrix yarn and/or said polymeric matrix fibers are made of thermoplastic polyamide, and wherein: said thermoplastic polyamide of said reinforcing yarn and/or of said reinforcing fibers and/or of said polymeric matrix yarn and/or of said polymeric matrix fibers comprises at least one polyamide possessing a star structure comprising: star macromolecular chains comprising one or more cores and at least three polyamide branches or three polyamide segments bonded to a core, and optionally, linear polyamide macromolecular chains. 26. The article as claimed in claim 25, wherein the ratio by weight of the star macromolecular chains to the sum of the star macromolecular chains and linear chains in the polyamide possessing a star structure is between 0.1 and 1. 27. The article as claimed in claim 24, wherein said polyamide possessing a star structure is obtained by copolymerization of a mixture of monomers comprising at least: a) monomers of following general formula (1): b) monomers of following general formulae (IIa) and (IIb): c) and, optionally, monomers of following general formula (III): Z-R3-Z (III) wherein: R1 is an aliphatic or aromatic, cyclic or linear, hydrocarbonaceous radical comprising at least 2 carbon atoms which can comprise heteroatoms, A is a covalent bond or an aliphatic hydrocarbonaceous radical which can comprise heteroatoms and which comprises from 1 to 20 carbon atoms, Z represents a primary amine functional group or a carboxylic acid functional group, and Y is a primary amine functional group when X represents a carboxylic acid functional group, or Y is a carboxylic acid functional group when X represents a primary amine functional group, R2 and R3, which are identical or different, represent substituted or unsubstituted, aromatic, cycloaliphatic or aliphatic hydrocarbonaceous radicals comprising from 2 to 20 carbon atoms which can comprise heteroatoms, and m represents an integer between 3 and 8. 28. The article as claimed in claim 24, wherein said polyamide possessing a star structure is obtained by extrusion of a polyamide obtained by polymerization of lactams and/or amino acids with the compound of formula (I). 29. The article as claimed in claim 27, wherein A represents a methylene, polymethylene or polyoxyalkylene radical. 30. The article as claimed in claim 27, wherein the compound of formula (I) is 2,2,6,6-tetra(β-carboxyethyl)cyclohexanone, trimesic acid, 2,4,6-tri(aminocaproic acid)-1,3,5-triazine or 4-aminoethyl-1,8-octanediamine. 31. The article as claimed in claim 25, wherein the polyamide possessing a star structure has a number-average molecular mass of at least equal to 15 000. 32. The article as claimed in claim 25, wherein the matrix yarn and/or matrix fibers are obtained from a blend of the polyamide possessing a star structure and of a linear polyamide. 33. The article as claimed in claim 25, further comprising at least one matrix yarn and/or matrix fibers made of linear polyamide. 34. The article as claimed in claim 32, wherein the linear polyamide is an aliphatic and/or semicrystalline polyamide or copolyamide is PA-4,6, PA-6, PA-6,6, PA-6,9, PA-6,10, PA-6,12, PA-6,36, PA-11, PA-12, a semicrystalline semiaromatic polyamide or a semicrystalline semiaromatic copolyamide chosen from the group consisting of polyphthalamides, and the blends of these polymers and of their copolymers. 35. The article as claimed in claim 25, wherein the polyamide possessing a star structure has a ratio by weight in the matrix yarn and/or matrix fibers of between 0.4 and 1. 36. The article as claimed in claim 35, wherein the ratio by weight is at least equal to 0.6. 37. The article as claimed in claim 25, wherein the matrix yarn and/or matrix fibers further comprise additives, selected from the group consisting of flame-retardants, plasticizers, heat and light stabilizers, waxes, pigments, nucleating agents, antioxidants, and impact-strength modifiers. 38. The article as claimed in claim 25, wherein the reinforcing yarn and/or reinforcing fibers are carbon, glass, aramid or polyimide yarns and/or fibers. 39. The article as claimed in claim 25, wherein the reinforcing yarn and/or reinforcing fibers are sisal, hemp or flax yarns and/or fibers. 40. The article as claimed in claim 25, further comprising a powdered material which is the matrix precursor. 41. The article as claimed in claim 40, wherein said powdered material is a polyamide. 42. The article as claimed in claim 25, being in the form of continuous or cut yarns, slivers, mats, braids, woven fabrics, knitted fabrics, sheets, multiaxials or nonwovens. 43. A composite material, obtained from an article as claimed in claim 25, by at least partial melting of the matrix yarn and/or matrix fibers of said article. 44. The composite material as claimed in claim 43, wherein exhibiting a level of reinforcing material by weight of between 25 and 80%. 45. A semi-finished product, obtained by the process comprising the steps of thermoforming or of calendering the article as claimed in claim 25, during which the matrix yarn and/or matrix fibers is/are at least partially melted in order to impregnate the reinforcing yarn and/or reinforcing fibers. 46. The semi-finished product as claimed in claim 45, being in the form of panels or of tapes. 47. A finished product, obtained by the process comprising the step of thermoforming the article as claimed in claim 25 to a final form, wherein the matrix yarn and/or matrix fibers is/are at least partially melted in order to impregnate the reinforcing yarn and/or reinforcing fibers.

The field of the invention is that of composite materials and of the processes for their manufacture. More specifically, the invention relates to the use of a polyamide possessing a star structure which is employed for the impregnation of reinforcing materials, particularly in the form of yarns and/or of fibers, which are intended to act as thermoplastic matrix, in composite materials. The term “yarn” is understood to mean a monofilament, a continuous multifilament yarn or a strand of fibers obtained from a single type of fiber or from several types of fibers in an intimate mixture. The continuous yarn can also be obtained by combining several multifilament yarns. The term “fiber” is understood to mean a filament or a combination of cut, split or converted filaments. In the field of high performance materials, composites have assumed a dominating position because of their performance and the savings in weight which they allow; The currently most well known high performance composites are obtained from thermosetting resins, the use of which is limited to small-scale applications, mainly in aeronautics or motor sports, and, in the best cases, which exhibit manufacturing times in the region of approximately fifteen minutes, such as, for example, during the manufacture of skis. The cost of these materials and/or the manufacturing times render them incompatible with use in mass production. One reply, in regard to the manufacturing times, is given by composites comprising a thermoplastic matrix. Thermoplastic resins are generally known for their high viscosity, which constitutes a check as regards the impregnation of the reinforced materials, generally composed of very dense multifilament bundles. The use of the thermoplastic matrices available on the market, in particular polyamide matrices, results in a difficulty in impregnation, requiring either prolonged impregnation times or significant processing pressures. In most cases, the composite materials obtained from these matrices may exhibit microspaces and unimpregnated regions. These microspaces bring about declines in mechanical properties, premature aging of the material and problems of delamination when the material is composed of several reinforcing layers. Several routes have been explored to improve the impregnation of the reinforcing yarns by the matrix and the adhesion between the reinforcing yarns and the matrix. The first of these routes has consisted in using linear polyamides with a reduced molecular weight as matrix. Thus, the document FR-2 158 422 discloses a composite sheet composed of a polyamide matrix and of reinforcing fibers of glass fiber type. The polyamide is obtained by polycondensation of ε-caprolactam, the molecular weight of which is between 3000 and 25 000, having the ability, by virtue of its low viscosity and therefore its low surface tension, to suitably impregnate the reinforcing fibers and thus to limit the appearance of microspaces in the finished product. This document also discloses a process for forming this composite sheet. Generally, the use of polyamides of low molecular weights in the matrix exhibits the major disadvantage of detrimentally affecting the mechanical properties of the composite, in particular as regards the ultimate strength, the yield strength and the fatigue behavior. This is because, during the use of high performance composites reinforced by long fibers, the mechanical properties of these composites depend on the plasticity of the matrix, which transmits the stresses to the reinforcing material, and on the mechanical properties of the matrix. Another route which makes it possible to improve the impregnation of the reinforcing fibers by the matrix consists in employing a matrix which is provided in the form of an oligomer or of a prepolymer of low molecular weight which can be polymerized by polycondensation in situ. Thus, the document FR-A-2 603 891 relates to a process for the manufacture of a composite material composed of a polyamide matrix reinforced by long reinforcing fibers. These fibers are impregnated with a polyamide prepolymer or oligomer which comprises, at each end of the molecular chain, a reactive functional group capable of reacting with another oligomer or prepolymer molecule under the effect of heating, resulting in the elongation of the polymer chain to produce a polyamide of high molecular weight. The oligomer or prepolymer of low molecular mass has the characteristic of being fluid in the molten state. The polyamides used are preferably polyamide-6, polyamide-6,6, polyamide-6,10, polyamide-6,12, polyamide-11 and polyamide-12. The impregnated fibers are subsequently pultruded through a shaping die at high temperature in order to form profiles. This process remains similar to conventional polymerization processes and thus exhibits cycle times incompatible with a rapid production rate. If the cycle times are adjusted so as to render them compatible with mass production, the molecular weight of the polyamide obtained and constituting the matrix is too low to confer, on the matrix, a satisfactory level of mechanical properties. The document EP-B-0 133 825 discloses a flexible composite material mainly composed of a reinforced material in the form of a lock of parallel continuous fibers which are impregnated with thermoplastic powder, preferably with polyamide powder, and of a thermoplastic matrix in the form of a sheath around the lock of continuous fibers, it being possible for this sheath also to be made of polyamide. This material is characterized in that the polymer constituting the thermoplastic matrix has a melting point lower than or equal to that of the polymer constituting the thermoplastic powder, so that the sheathing of the fibers covered with powder is achieved by melting the thermoplastic matrix, but without melting the powder, so that the latter isolates the fibers from the sheath. A disadvantage of the use of a thermoplastic polymer in the form of a powder is the need to use complex equipment which limits the amount of composite obtained. It is therefore clearly apparent that this process is not very compatible with mass production. The document U.S. Pat. No. 5,464,684 discloses a hybrid yarn comprising a core of an intimate mixture of reinforcing filaments and of filaments of polyamides of low viscosity, forming the matrix. This nucleus is covered with a continuous yarn of polyamide, preferably of the same type as that used for the nucleus. The polyamide used is of the nylon-6 or nylon-6,6 type but can also be composed of nylon-6,6T, nylon-6,10, nylon-10 or a polyamide of adipic acid and of 1,3-xylylenediamine. The reinforcing fibers are carbon fibers or glass fibers. The technique used to manufacture such a hybrid yarn is certainly suitable for small-scale applications, such as the manufacture of tennis racquets. However, it is difficult to conceive of the use of such a method on a larger scale. The analysis of the state of the art shows that the improvement in the performance of composite materials, centered on the improvement in the impregnation of the matrix into the reinforcing material, does not meet the requirements either of mechanical properties or of processing time of the mass production applications targeted by the thermoplastic composite materials. The object of the present invention is thus to overcome these disadvantages by providing a precursor article of a composite material comprising different types of yarns and/or of fibers and in particular at least one reinforcing yarn and/or reinforcing fibers and at least one yarn and/or fibers which generate(s) a thermoplastic matrix exhibiting a high fluidity in the molten state, making possible very good impregnation of the reinforcing yarns and/or reinforcing fibers during the formation of the composite material. Such an article makes it possible to obtain a composite material by a simple and rapid thermoforming technique. Another object of the invention is to provide a composite material obtained from this article and exhibiting good mechanical properties. Finally, a last object of the invention is to provide a composite material exhibiting an advantage in reducing manufacturing costs by the use of machinery employing low pressures and shortened cycle times. To this end, the invention relates to a precursor article of a composite material comprising a polymeric matrix and at least one reinforcing yarn and/or reinforcing fibers, said article comprising at least one reinforcing yarn and/or reinforcing fibers and at least one polymeric matrix yarn and/or polymeric matrix fibers, characterized in that: said reinforcing yarn and/or said reinforcing fibers are made of reinforcing material and optionally comprise a part made of thermoplastic polyamide, said polymeric matrix yarn and/or said polymeric matrix fibers are made of thermoplastic polyamide, and in that said thermoplastic polyamide of said reinforcing yarn and/or of said reinforcing fibers and/or of said polymeric matrix yarn and/or of said polymeric matrix fibers comprises at least one polyamide possessing a star structure comprising: star macromolecular chains comprising one or more cores and at least three polyamide branches or three polyamide segments bonded to a core, if appropriate, linear polyamide macromolecular chains. The polyamide possessing a star structure is a polymer comprising star macromolecular chains and, if appropriate, linear macromolecular chains. The polymers comprising such star macromolecular chains are, for example, disclosed in the documents FR 2 743 077, FR 2 779 730, EP 0 682 057 and EP 0 832 149. These compounds are known to exhibit an improved fluidity with respect to linear polyamides. The star macromolecular chains comprise a core and at least three polyamide branches. The branches are bonded to the core by a covalent bond, via an amide group or a group of another nature. The core is an organic or organometallic chemical compound, preferably a hydrocarbonaceous compound optionally comprising heteroatoms and to which the branches are connected. The branches are polyamide chains. The polyamide chains constituting the branches are preferably of the type of those obtained by polymerization of lactams or amino acids, for example of polyamide-6 type. The polyamide possessing a star structure according to the invention optionally comprises, in addition to the star chains, linear polyamide chains. In this case, the ratio by weight of the amount of star chains to the sum of the amounts of star chains and of linear chains is between 0.1 and 1, limits included. It is preferably between 0.5 and 1. According to a preferred embodiment of the invention, the polyamide possessing a star structure, that is to say comprising star macromolecular chains, is obtained by copolymerization of a mixture of monomers comprising at least: a) monomers of following general formula (I): b) monomers of following general formulae (IIa) and (IIb): c) optionally monomers of following general formula (III): Z-R3-Z (III) in which: R1 is an aliphatic or aromatic, cyclic or linear, hydrocarbonaceous radical comprising at least 2 carbon atoms which can comprise heteroatoms, A is a covalent, bond or an aliphatic hydrocarbonaceous radical which can comprise heteroatoms and which comprises from 1 to 20 carbon atoms, Z represents a primary amine functional group or a carboxylic acid functional group, Y is a primary amine functional group when X represents a carboxylic acid functional group or Y is a carboxylic acid functional group when X represents a primary amine functional group, R2 and R3, which are identical or different, represent substituted or unsubstituted, aromatic, cycloaliphatic or aliphatic hydrocarbonaceous radicals comprising from 2 to 20 carbon atoms which can comprise heteroatoms, m represents an integer between 3 and 8. The term “carboxylic acid” is understood to mean carboxylic acids and their derivatives, such as acid anhydrides, acid chlorides, esters, and the like. Processes for producing these star polyamides are disclosed in the documents FR 2 743 077 and FR 2 779 730. These processes result in the formation of star macromolecular chains, as a mixture with optionally linear macromolecular chains. If a comonomer of formula (III) is used, the polymerization (polycondensation) reaction is advantageously carried out until thermodynamic equilibrium is reached. The monomer of formula (I) can also be blended with a molten polymer during an extrusion operation. Thus, according to another embodiment of the invention, the polyamide possessing a star structure is obtained by melt blending, for example using an extrusion device, a polyamide of the type of those obtained by polymerization of lactams and/or amino acids and a monomer of formula (I). Such preparation processes are disclosed in patents EP 0 682 070 and EP 0 672 703. According to a specific characteristic of the invention, the R1 radical is either a cycloaliphatic radical, such as the tetravalent cyclohexanonyl radical, or a 1,1,1-propanetriyl or 1,2,3-propanetriyl radical. Mention may be made, as other R1 radicals suitable for the invention, by way of example, of substituted or unsubstituted trivalent phenyl and cyclohexanyl radicals, tetravalent diaminopolymethylene radicals with a number of methylene groups advantageously of between 2 and 12, such as the radical originating from EDTA (ethylenediaminetetraacetic acid), octavalent cyclohexanonyl or cyclohexadinonyl radicals, and the radicals originating from compounds resulting from the reaction of polyols, such as glycol, pentaerythritol, sorbitol or mannitol, with acrylonitrile. Advantageously, at least two different R2 radicals can be employed in the monomers of formula (II). The A radical is preferably a methylene or polymethylene radical, such as the ethyl, propyl or butyl radicals, or a polyoxyalkylene radical, such as the polyoxyethylene radical. According to a specific embodiment of the invention, the number m is greater than or equal to 3 and advantageously equal to 3 or 4. The reactive functional group of the multifunctional compound represented by the symbol Z is a functional group capable of forming an amide functional group. Preferably, the compound of formula (I) are chosen from 2,2,6,6-tetra(β-carboxyethyl)cyclohexanone, trimesic acid, 2,4,6-tri(aminocaproic acid)-1,3,5-triazine and 4-aminoethyl-1,8-octanediamine. The mixture of monomers which is the source of the star macromolecular chains can comprise other compounds, such as chain-limiting agents, catalysts or additives, such as light stabilizers or heat stabilizers. The polyamide yarn and/or polyamide fibers intended to act as matrix will be referred to hereinafter as “matrix yarn and/or matrix fibers”. Advantageously, the polyamide possessing a star structure exhibits a number-average molecular mass at least equal to 15 000. Advantageously, when the reinforcing yarn and/or reinforcing fibers comprise a polyamide possessing a star structure, the latter is preferably provided in the form of a sheath of polyamide which covers the reinforcing yarn and/or reinforcing fibers. According to an alternative form of the invention, the matrix yarn and/or matrix fibers are obtained from a blend of the polyamide possessing a star structure and of a linear polyamide. According to another alternative form, the precursor article of the composite material also comprises at least one matrix yarn and/or matrix fibers made of linear polyamide. According to a preferred characteristic, this linear polyamide is an aliphatic and/or semicrystalline polyamide or copolyamide chosen from the group consisting of PA-4,6, PA-6, PA-6,6, PA-6,9, PA-6,10, PA-6,12, PA-6,36, PA-11 and PA-12, or a semicrystalline semiaromatic polyamide or copolyamide chosen from the group consisting of polyphthalamides, and the blends of these polymers and of their copolymers. It is then advantageous for the ratio by weight of polyamide possessing a star structure in the matrix yarn and/or matrix fibers to be between 0.4 and 1 and preferably at least equal to 0.6. The matrix yarn and/or matrix fibers can also comprise all the conventional additives, such as flame-retardants, plasticizers, heat and light stabilizers, waxes, pigments, nucleating agents, antioxidants, impact-strength modifiers or analogous compounds which are known to a person skilled in the art. Advantageously, the reinforcing yarn and/or reinforcing fibers are chosen from carbon, glass, aramid and polyimide yarns and/or fibers. According to an alternative form of this characteristic, the reinforcing yarn and/or reinforcing fibers are a natural yarn and/or natural fibers chosen from sisal, hemp or flax yarns and/or fibers. Advantageously, the article according to the invention also comprises a powdered material, the matrix precursor, which can, for example, be a polyamide. Use will preferably be made of a powder exhibiting a particle size of between 1 and 100 microns. Preferably, the article according to the invention is the form of continuous or cut yarns, slivers, mats, braids, woven fabrics, knitted fabrics, sheets, multiaxials, nonwovens and/or complex forms comprising several of the abovementioned forms. By way of examples, a complex form can be a sheet combined with a nonwoven or with continuous yarns. Another subject matter of the invention is a composite material obtained from an article as defined above by at least partial melting of the matrix yarn and/or matrix fibers. This composite material comprises a polymeric matrix and reinforcing yarns and/or reinforcing fibers. The term “partial melting” is understood to mean the melting of at least a part of at least one matrix yarn and/or one matrix fiber. This melting can be carried out by thermoforming at a temperature more or less equal to the melting point of the polymeric matrix and under pressure. This melting makes it possible to obtain homogeneous impregnation of the reinforcing yarns and/or reinforcing fibers by the matrix. According to a preferred characteristic, the composite material thus obtained exhibits a level of reinforcing material by weight of between 25 and 80%. Yet another subject matter of the invention is a semi-finished product obtained by a process of thermoforming or of calendering the abovementioned article, during which the matrix yarn and/or matrix fibers is/are at least partially melted in order to impregnate the reinforcing yarn and/or reinforcing fibers. More advantageously, this semi-finished product is provided in the form of panels or of tapes. The semi-finished product consists of an intermediate product, in which the reinforcing yarns and/or reinforcing fibers have been impregnated by the polymeric matrix, which is found in the form of a continuous phase. This product is not yet in its definitive form. The semi-finished product has to be subjected to a final stage of forming by a forming or thermoforming process which are known to a person skilled in the art, at temperatures greater than the glass transition point and less than their melting point, making it possible to obtain a finished product. Yet another subject matter of the invention is a finished product obtained by a process of thermoforming the abovementioned article to the definitive form, during which the matrix yarn and/or matrix fibers is/are at least partially melted in order to impregnate the reinforcing yarn and/or reinforcing fibers. Generally, the thermoforming processes used employ low pressures (less than 20 bar), temperatures of less than 270° C. and short times (less than 5 minutes). Other details and advantages of the invention will become more clearly apparent in the light of the examples given below, solely by way of indication and by way of illustration. Matrix used: star polyamide-6, obtained by copolymerization from caprolactam in the presence of 0.5 mol % of 2,2,6,6-tetra(β-carboxyethyl)cyclohexanone according to a process disclosed in the document FR 2 743 077, comprising approximately 80% of star macromolecular chains and 20% of linear macromolecular chains, with a melt flow index, measured at 275° C. under 100 g, of 55 g/10 minutes. EXAMPLE 1 Semi-Finished Panel Produced from Star Polyamide-6 and Reinforcing Yarns A series of tests was carried out starting from a multifilament yarn of star polyamide-6 exhibiting a count per strand of between 3 and 8 dTex and a tenacity in the region of 15-20 cN/Tex. Such a multifilament is combined, during a multiaxial weaving operation, with a continuous reinforcing yarn of high performance carbon, comprising 12 000 filaments, or with a reinforcing yarn of glass, exhibiting a count of 600 Tex. In order to validate the high fluidity of the matrix in the molten state, multiaxial fabrics are produced from individual layers, defined as follows: Individual Layer Ply No. 1: reinforcing yarn—orientation: −45° Ply No. 2: reinforcing yarn—orientation: +45° Ply No. 3: star polyamide-6 yarn (matrix)—orientation: 90° A laminated composite is subsequently prepared by placing several individual layers (between 2 and 10) of the fabric obtained in a mold exhibiting a panel form, under a heating plate press, for a period of time of 1 to 3 minutes, under a pressure of between 1 and 20 bar and a temperature greater than the melting point of the star polyamide-6 (230-260° C.). After cooling to a temperature of 50-60° C., the composite is removed from the mold. The level by weight of reinforcing material is then between 60-70%. The high fluidity of the star polymer makes it possible to obtain good impregnation of the reinforcing material by the matrix without bringing about either the declines in mechanical properties or the problems of fatigue strength observed with polymers of low molecular weight. The bending mechanical properties are compared with those of a thermosetting composite obtained from the same reinforcing material and from an epoxy resin in tables Nos. 1.1 and 1.2. TABLE 1.1 Carbon fiber composites Breaking Flexural Elongation stress modulus at break Carbon fibers (MPa) (MPa) (%) Epoxy matrix 796.0 52 000 1.72 Star PA-6 matrix 536.0 54 350 1.05 TABLE 1.2 Glass fiber composites Breaking Flexural Elongation stress modulus at break Glass fibers (MPa) (MPa) (%) Epoxy matrix 630.0 21 000 3.53 Star PA-6 matrix 580.7 21 160 3.26 The use of a reinforcing material in the form of a continuous yarn makes it possible to retain 10 superior mechanical properties in the direction of the unidirectional sheets of reinforcing material. The influence of the temperature on the bending mechanical properties is given in table No. 2. Finally, the fact of using the matrix in the form of a yarn makes possible, in addition to an economic advantage with respect to the conventional dusting or preimpregnation solutions, easy handling and very good control of the level of reinforcement of the final composite material. A summarization of the mechanical properties obtained is given in table No. 3. TABLE 3 Summarization of the mechanical properties obtained Star Star PA-6/carbon PA-6/glass multiaxial multiaxial Units Standard fabric fabric Level of % 59 65 impregnation (w/w) Density 1.4 1.8 Simple tension Tensile strength MPa ISO 527 1090 545 Young's modulus GPa ISO 527 64 21.3 Elongation % ISO 527 1.7 2.76 3-Point bending Breaking stress MPa ISO 14125 536 580 Flexural modulus GPa ISO 14125 54.3 21.1 Compression Breaking stress MPa ISO 604 210 195 EXAMPLE 2 Composite Braids In order to confirm the advantage of the invention for composites with a circular cross section, braids were produced from different star polyamide-6 yarns and from reinforcing materials chosen from those known to a person skilled in the art, such as carbon or glass yarns. To this end, a mixture was produced during braiding by inserting, on the braiding machine, reinforcing yarns and polyamide yarns. The braid thus obtained is subsequently placed in a hollow mold, the braid being maintained by an internal bladder expanded after closing the mold. Optimum impregnation was thus obtained by virtue of the high fluidity of the star polyamide in the molten state, despite low processing pressures [1-5 bar]. The temperatures employed varying between 230° C. and 260° C., the impregnation time is less than 30 seconds. The composite is subsequently removed from the mold after having been cooled to below the crystallization point of the matrix. It then exhibits a level of reinforcing material by weight which can vary from 65 to 75%. The surface condition of the component is improved by virtue of the fluidity of the polymer.

20041006

20080129

20061019

59036.0

D04H1300

EDWARDS, NEWTON O

COMPOSITE MATERIALS COMPRISING A REINFORCING MATERIAL AND A STAR POLYAMIDE AS A THERMOPLASTIC MATRIX, THE PRECURSOR COMPOUND ARTICLE OF SAID MATERIALS AND THE PRODUCTS OBTAINED USING SAME

UNDISCOUNTED

ACCEPTED

D04H

ACCEPTED

Mixing bag or vessel having a receiver for a fluid-agitating element

A vessel in which a fluid is received and agitated using an internal fluidagitating element driven by an external motive device is disclosed. In one aspect, the vessel is a bag including a first receiver for receiving and holding a fluid-agitating element at a home location. The first receiver may be in the form of an inwardly projecting post having an oversized portion for capturing the fluid-agitating element, but various other forms are disclosed. Use of this feature in completely rigid vessels where the fluid-agitating element is free of direct attachment from a first receiver having an oversized portion is also disclosed. In another aspect, the vessel or bag further includes a second receiver for receiving a portion of an external structure, such as a motive device, and aligning the vessel relative thereto. Related methods are also disclosed.

1. A vessel intended for receiving a fluid and a fluid-agitating element, comprising: a bag capable of receiving and holding the fluid, the bag having a rigid portion including a first receiver for receiving and holding the fluid-agitating element at a home location when positioned in the vessel. 2. The vessel according to claim 1, wherein the first receiver is a first inwardly-projecting post. 3. The vessel according to claim 2, wherein the first post includes an oversized portion for capturing the fluid-agitating element. 4. The vessel according to claim 3, wherein the oversized portion is the head of the post and is T-shaped, cross-shaped, Y-shaped, L-shaped, spherical, cubic, or otherwise formed having a shape that confines the fluid-agitating element to adjacent the post. 5. The vessel according to claim 1, further including a second receiver projecting outwardly from the bag, wherein the second receiver facilitates aligning the fluid-agitating element with a motive device for the fluid-agitating element. 6. The vessel according to claim 5, wherein the first receiver is a first, inwardly-projecting post and the second receiver is a second, outwardly-projecting post coaxial with the first inwardly-projecting post. 7. The vessel according to claim 1, wherein the first receiver includes a peripheral flange mating with a portion of the bag to create an interface along which a seal is formed. 8. The vessel according to claim 1, wherein the first receiver is cap-shaped and includes a cavity facing the interior of the bag. 9. The vessel according to claim 1, wherein first receiver includes an generally upstanding peripheral sidewall over which the fluid-agitating element is received and a cavity adapted for receiving a portion of an external structure for rotating the fluid-agitating element. 10. The vessel according to claim 1, wherein the first receiver directly engages and supports the fluid-agitating element in a non-levitating fashion. 11. A vessel intended for use in receiving a fluid and a fluid-agitating element, such as a magnetic impeller, positioned adjacent to an external structure, such as a housing of a motive device for levitating and/or rotating the fluid-agitating element, comprising: a bag capable of receiving and holding the fluid, the bag including a first inwardly-projecting post for receiving and holding the fluid-agitating element at a home location when positioned in the bag and a receiver adapted for receiving at least a portion of the external structure and aligning the fluid-agitating element relative thereto. 12. The vessel according to claim 11, wherein the body comprises a flexible portion and a rigid portion in which the first post and the receiver are formed. 13. The vessel according to claim 11, wherein the receiver is a second outwardly projecting post. 14. The vessel according to claim 13, wherein the first and second posts are coaxial. 15. The vessel according to claim 11, wherein the body comprises a flexible portion and the receiver is defined by a rigid, cap-shaped portion having a cavity and a peripheral flange connected to the flexible portion, the cavity facing an interior of the body for receiving the fluid-agitating element when positioned therein. 16. The vessel according to claim 15, wherein the first inwardly directed post is positioned at least partially in the cavity of the receiver. 17. The vessel according to claim 11, wherein the first inwardly-directed post includes a bearing for directly supporting the fluid-agitating element. 18. In combination, a vessel comprising a flexible portion and a rigid portion including a receiver for receiving and holding an at least partially magnetic fluid-agitating element at a home location or expected position within the vessel. 19. The combination of claim 18, further including a motive device for at least rotating the fluid-agitating element in the vessel. 20. The combination of claim 18, wherein the fluid-agitating element includes at least one blade or vane. 21. The combination of claim 18, wherein the vessel is at least initially hermetically sealed with the fluid-agitating element positioned therein. 22. In combination, a vessel and a fluid-agitating element, the vessel comprising a first receiver for receiving the fluid-agitating element, the first receiver including a portion for capturing the fluid-agitating element, wherein the fluid-agitating element is free of direct attachment to the receiver. 23. The combination according to claim 22, wherein the vessel further includes a second receiver for receiving a portion of an external structure to assist in aligning the fluid-agitating element relative thereto. 24. The combination according to claim 22, wherein the first receiver is a post and the portion is an oversized head end of the post. 25. The combination according to claim 24, wherein the head end of the post is T-shaped. 26. A vessel for receiving a fluid and a fluid-agitating element, such as an impeller, comprising: a bag capable of receiving and holding the fluid; and a rigid receiver connected to the bag, the receiver receiving and holding the fluid-agitating element at a home location when positioned in the bag. 27. The vessel according to claim 26, wherein the rigid receiver is cap-shaped and includes a peripheral flange connected to the bag to form a seal. 28. The vessel according to claim 26, wherein the rigid receiver is positioned in contact with an interior surface of the bag. 29. The vessel according to claim 26, wherein the rigid receiver is positioned in contact with an exterior surface of the bag. 30. A system for agitating a fluid, comprising: an at least partially magnetic fluid-agitating element; a vessel for receiving the fluid, the vessel including a flexible portion and a rigid portion including a receiver for receiving and holding the fluid-agitating element at a home location in the vessel; and a motive device for at least rotating the fluid-agitating element. 31. The system according to claim 30, wherein the motive device also levitates the fluid-agitating element in the vessel. 32. The system according to claim 30, wherein the motive device includes a rotatable drive magnet structure for forming a magnetic coupling with the fluid-agitating element. 33. A method of positioning a fluid-agitating element in a bag intended for receiving a fluid in need of agitation, comprising: providing the bag with a rigid portion including a receiver having a peripheral sidewall and a cavity for receiving and holding the fluid-agitating element at a home location when positioned in the bag. 34. The method according to claim 33, wherein the receiver includes a post projecting toward an interior of the bag, the fluid-agitating element includes an opening, and the providing step comprises inserting the post through the opening. 35. The method according to claim 33, wherein the cavity faces an interior of the bag and the providing step comprises positioning the fluid-agitating element in the cavity. 36. The method according to claim 33, wherein the cavity faces an exterior of the bag, the fluid agitating element includes an opening or recess, and the providing step comprises positioning the peripheral sidewall of the receiver in the opening or recess. 37. A method of agitating a fluid, comprising: providing a bag with a receiver for receiving and holding an at least partially magnetic fluid-agitating element at a home location within the bag; placing a fluid in the bag; and rotating the fluid-agitating element. 38. The method according to claim 37, wherein the bag comprises a flexible portion and a rigid portion including the receiver, wherein the providing step includes connecting the rigid portion to the flexible portion. 39. The method according to claim 37, wherein the step of placing a fluid in the bag is completed after the fluid-agitating element is received in the receiver. 40. The method according to claim 37, wherein the step of rotating includes forming a non-contact coupling with a motive device external to the bag. 41. The method according to claim 37, wherein the providing step includes providing a bearing on the receiver for directly engaging and supporting the fluid-agitating element. 42. The method according to claim 41, further including the steps of folding the bag for storage or shipping with the fluid-agitating element in the receiver and unfolding the bag before the placing step. 43. The method according to claim 37, further including the step of hermetically sealing the bag after the providing step. 44. The method according to claim 43, wherein the placing step comprises introducing the fluid through a sterile fitting provided in the bag. 45. A vessel intended for receiving a fluid and a fluid-agitating element capable of rotating, comprising: a bag capable of receiving and holding the fluid, the bag having an imperforate receiver for receiving and confining the fluid-agitating element to a particular location within the bag. 46. The vessel according to claim 45, wherein the rigid receiver includes a cavity having a surface for engaging the fluid-agitating element during rotation. 47. A vessel intended for receiving a fluid and a magnetic fluid-agitating element capable of rotating without direct attachment to a shaft, comprising: a bag capable of receiving and holding the fluid, the bag having means for capturing the magnetic fluid-agitating element while permitting the magnetic fluid-agitating element to rotate freely. 48. The vessel according to claim 47, wherein the capturing means comprises a rigid receiver having a peripheral flange attached to a flexible portion of the bag and defining a cavity for the magnetic fluid-agitating element. 49. A vessel intended for receiving a fluid and an at least partially magnetic fluid-agitating element capable of rotating, comprising: a bag capable of receiving and holding the fluid, the bag having a rigid, imperforate receiver encircling the fluid-agitating element while permitting the fluid-agitating element to rotate freely. 50. The vessel according to claim 49, wherein the rigid receiver includes a cavity with sidewalls adjacent at least three sides of the fluid agitating element. 51. In combination, a magnetic fluid-agitating element and a bag capable of receiving and holding a fluid, the bag having a rigid receiver for receiving and confining the magnetic fluid-agitating element to a home location while permitting the magnetic fluid-agitating element to rotate. 52. The combination according to claim 51, wherein the fluid-agitating element is a magnetic stir bar. 53. The combination according to claim 51, wherein an upper surface of the rigid receiver is adjacent a lower surface of the fluid agitating element. 54 The combination according to claim 51, wherein the receiver is welded to the bag to form a seal. 55. In combination, a magnetic stir bar and a bag capable of receiving and holding a fluid, the bag having a rigid receiver for encircling and confining the stir bar while permitting the stir bar to rotate freely. 56. A combination comprising a bag including a flexible portion with an aperture and a post inserted through the aperture and having an end adapted for receiving a fluid-agitating element, wherein a fluid-impervious seal is formed at the post/bag interface. 57. The combination of claim 56, wherein the aperture is in a lower portion of the bag and the post is upstanding. 58. The combination of claim 56, wherein the seal is formed using a clamp. 59. The vessel according to claim 1, wherein the fluid-agitating element is at least partially magnetic and the receiver mechanically captures the fluid-agitating element. 60. A vessel intended for receiving a fluid and a fluid-agitating element, comprising: a bag capable of receiving and holding the fluid, the bag having an inside a bag capable of receiving and holding the fluid, the bag having an inside bottom surface including a rigid portion for receiving and holding the fluid-agitating element. 61. The vessel according to claim 60, wherein the rigid portion is imperforate. 62. The vessel according to claim 60, wherein the rigid portion is cup-shaped. 63. The combination of claim 18, further including a rigid container for receiving the vessel, said container including an opening through which at least part of the rigid portion passes. 64. The combination of claim 22, further including a rigid container for receiving the vessel, said container including an opening through which the portion of the first receiver at least partially passes. 65. The vessel of claim 26, further including a rigid container for receiving the bag, said container including an opening through which at least part of the rigid receiver passes. 66. The system of claim 30, further including a rigid container for receiving the vessel, said container including an opening through which at least part of the rigid portion passes.

This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/326,833, filed Oct. 3, 2001, the disclosure of which is incorporated herein by reference. TECHNICAL FIELD The present invention relates generally to vessels in which fluids are agitated and, more particularly, to a vessel or bag including at least one receiver for receiving and holding a fluid-agitating element at a home location. BACKGROUND OF THE INVENTION Most pharmaceutical solutions and suspensions manufactured on an industrial scale require highly controlled, thorough mixing to achieve a satisfactory yield and ensure a uniform distribution of ingredients in the final product. Agitator tanks are frequently used to complete the mixing process, but a better degree of mixing is normally achieved by using a mechanical stirrer or impeller (e.g., a set of mixing blades attached to a metal rod). Typically, the mechanical stirrer or impeller is simply lowered into the fluid through an opening in the top of the vessel and rotated by an external motor to create the desired mixing action. One significant limitation or shortcoming of such an arrangement is the danger of contamination or leakage during mixing. The rod carrying the mixing blades or impeller is typically introduced into the vessel through a dynamic seal or bearing. This opening provides an opportunity for bacteria or other contaminants to enter, which of course can lead to the degradation of the product. A corresponding danger of environmental contamination exists in applications involving hazardous or toxic fluids, or suspensions of pathogenic organisms, since dynamic seals or bearings are prone to leakage. Cleanup and sterilization are also made difficult by the dynamic bearings or seals, since these structures typically include folds and crevices that are difficult to reach. Since these problems are faced by all manufacturers of sterile solutions, pharmaceuticals, or the like, the U.S. Food and Drug Administration (FDA) has consequently promulgated strict processing requirements for such fluids, and especially those slated for intravenous use. In an effort to overcome these problems, others have proposed alternative mixing technologies. Perhaps the most common proposal for stirring a fluid under sterile conditions is to use a rotating, permanent magnet bar covered by an inert layer of TEFLON, glass, or the like. The magnetic “stirrer” bar is placed on the bottom of the agitator vessel and rotated by a driving magnet positioned external to the vessel. An example of such an arrangement where the vessel is a flexible bag is shown in U.S. Pat. No. 5,947,703 to Nojiri et al., the disclosure of which is incorporated herein by reference. Of course, the use of such an externally driven magnetic bar avoids the need for a dynamic bearing, seal or other opening in the vessel to transfer the rotational force from the driving magnet to the stirring magnet. Therefore, a completely enclosed system is provided. This of course prevents leakage and the potential for contamination created by hazardous materials (e.g., cytotoxic agents, solvents with low flash points, blood products, etc.), eases clean up, and allows for the desirable sterile interior environment to be maintained, all of which are considered significant advantages. Despite the advantages of this type of mixing systems and others where the need for a shaft penetrating into the vessel or dynamic seal is eliminated, a substantial, but heretofore unsolved problem with such systems is the difficulty in coupling a fluid-agitating element with an external motive device providing the rotation and/or levitation force. For example, when a vessel in the form of a flexible bag containing an unconfined fluid-agitating element is positioned in proximity to the motive device, the relative location of the fluid-agitating element is generally unknown. In the case of a small (10 liter or less) transparent bag, it is possible to manipulate the bag relative to the motive device in an effort to ensure that the fluid-agitating element is “picked up” and the desired coupling is formed. However, this is considered inconvenient and time consuming, especially if fluid is already present in the bag. Moreover, in the case where the bag is relatively large (e.g., capable of holding 100 liters or more) or formed of an opaque material (e.g., black), achieving the proper positioning of the fluid-agitating element relative to the external motive device is at a minimum difficult, and in many cases, impossible. In the absence of fortuity, a significant amount of time and effort is required to lift and blindly reposition the bag relative to the motive device, without ever truly knowing that the coupling is properly formed. Also, even if the coupling is initially formed, the fluid-agitating element may become accidentally decoupled or disconnected from the motive device during the mixing operation. In view of the semi-chaotic nature of such an event, the ultimate resting place of the fluid-agitating element is unknown and, in cases where the fluid is opaque (e.g., blood) or cloudy (e.g. cell suspensions), not easily determined. If the coupling ultimately cannot be established in the proper fashion, the desired fluid agitation cannot be achieved in a satisfactory manner, which essentially renders the set up useless. These shortcomings may significantly detract from the attractiveness of such fluid agitation systems from a practical standpoint. In many past mixing arrangements, a rigid vessel is used with a fluid-agitating element directly supported by a post carrying a roller bearing, with the rotational force being supplied by an external device (see, e.g., U.S. Pat. No. 4,209,259 to Rains et al., the disclosure of which is incorporated herein by reference). While this direct support arrangement prevents the fluid-agitating element from being lost in the event of an accidental decoupling, the use of such post or like structure in a bag for receiving and holding a fluid-agitating element has not been proposed. The primary reason for this is that, in a typical flexible bag, neither the sidewalls nor any other structure is capable of providing the direct support for the fluid-agitating element or a corresponding bearing. Thus, a need is identified for an improved manner of ensuring that the desired coupling may be reliably achieved between a fluid-agitating element in a vessel such as a bag and an external motive device, such as one supplying the rotational force that causes the element to agitate the fluid, even in large, industrial scale mixing bags or vessels (greater than 100 liters), opaque bags or vessels, or where the fluid to be agitated is not sufficiently clear, and even after an accidental decoupling occurs. The improvement provided by the invention would be easy to implement using existing manufacturing techniques and without significant additional expense. Overall, a substantial gain in efficiency and ease of use would be realized as a result of the improvement, and would greatly expand the potential applications for which advanced mixing systems may be used. SUMMARY OF THE INVENTION In accordance with a first aspect of the invention, a vessel intended for receiving a fluid and a fluid-agitating element is provided. The vessel comprises a bag capable of receiving and holding the fluid. The bag includes a rigid portion having a first receiver for receiving and holding the fluid-agitating element at a home location when positioned in the vessel. In one embodiment, the first receiver is a first inwardly-projecting post for positioning in an opening or recess in the fluid-agitating element. The first post may include an oversized portion for capturing the fluid-agitating element. The oversized portion is preferably the head of the first post and is T-shaped, cross-shaped, Y-shaped, L-shaped, spherical, cubic, or otherwise formed having a shape that confines the fluid-agitating element to adjacent the post. The bag may further include a second receiver projecting outwardly from the bag. The second receiver facilitates aligning the fluid-agitating element with an external structure, such as a motive device for levitating or rotating the fluid-agitating element. In one particularly preferred embodiment, the first receiver is a first, inwardly-projecting post and the second receiver is a second, outwardly-projecting post coaxial with the first inwardly-projecting post. The first receiver may include a peripheral flange mating with a portion of the bag to create an interface along which a seal is formed. Instead of comprising a post, the first receiver may be cap-shaped and include a cavity facing the interior of the bag. Still another option is for the first receiver to include an generally upstanding peripheral sidewall over which the fluid-agitating element is received and a cavity adapted for receiving a portion of an external structure for rotating the fluid-agitating element. The first receiver may also include a bearing for directly engaging and supporting the fluid-agitating element in a non-levitating fashion. In accordance with a second aspect of the invention, a vessel intended for use in receiving a fluid and a fluid-agitating element, such as a magnetic impeller, positioned adjacent to an external structure, such as a housing of a motive device for levitating and/or rotating the fluid-agitating element, is disclosed. The vessel comprises a bag capable of receiving and holding the fluid. The bag includes a first inwardly-projecting post for receiving and holding the fluid-agitating element at a home location when positioned in the bag and a receiver adapted for receiving at least a portion of the external structure and aligning the fluid-agitating element relative thereto. In one embodiment, the body comprises a flexible portion and a rigid portion in which the first post and the receiver are formed. The receiver may take the form of a second outwardly projecting post, with the first and second posts being coaxial. Alternatively, the receiver may be defined by a rigid, cap-shaped portion having a cavity and a peripheral flange connected to the flexible portion, with the cavity facing an interior of the body for receiving the fluid-agitating element when positioned therein. The first inwardly directed post may be positioned at least partially in the cavity of the receiver or may include a bearing for directly supporting the fluid-agitating element. In accordance with a third aspect of the invention, the combination of a vessel and a fluid-agitating element is disclosed. The vessel comprises a flexible portion and a rigid portion including a receiver for receiving and holding a fluid-agitating element at a home location or expected position within the vessel. The combination may further include a motive device for at least rotating the fluid-agitating element in the vessel. The fluid-agitating element used in the combination may be at least partially magnetic and may also include at least one blade or vane. The vessel may be at least initially hermetically sealed with the fluid-agitating element positioned therein. In accordance with a fourth aspect of the invention, the combination of a vessel and a fluid-agitating element is disclosed, with the vessel comprising a first receiver for receiving the fluid-agitating element. The first receiver includes an oversized portion for capturing the fluid-agitating element on the receiver, but the fluid-agitating element is free of direct attachment to the receiver. The vessel may further include a second receiver for receiving a portion of an external structure to assist in aligning the fluid-agitating element relative thereto. The first receiver is preferably a post and the oversized portion is a head end of the post that is T-shaped. In accordance with a fifth aspect of the invention, a vessel for receiving a fluid and a fluid-agitating element, such as an impeller, is disclosed. The vessel comprises a bag capable of receiving and holding the fluid and a rigid receiver connected to the bag. The receiver receives and holds the fluid-agitating element at a home location when positioned in the bag. In one embodiment, the rigid receiver is cap-shaped and includes a peripheral flange connected to the bag to form a seal. Alternatively, the rigid receiver is positioned in contact with an interior surface of the bag. Still another alternative is to position the rigid receiver in contact with an exterior surface of the bag. In accordance with a sixth aspect of the invention, a system for agitating a fluid is disclosed. The system comprises a fluid-agitating element and a vessel for receiving the fluid, the vessel including a flexible portion and a rigid portion. The rigid portion includes a receiver for receiving and holding the fluid-agitating element at a home location in the vessel. A motive device for at least rotating the fluid-agitating element may also form part of the system. In one embodiment, the motive device also levitates the fluid-agitating element in the vessel. The fluid-agitating element is at least partially magnetic or ferromagnetic and the motive device includes a rotating drive magnet structure for forming a magnetic coupling with the fluid-agitating element, an electromagnetic structure for rotating and levitating the fluid-agitating element, or a superconducting element for both levitating and rotating the fluid-agitating element. In accordance with a seventh aspect of the invention, a method of positioning a fluid-agitating element in a bag intended for receiving a fluid in need of agitation is disclosed. The method comprises the step of providing the bag with a rigid portion including a receiver for receiving and holding the fluid-agitating element at a home location when positioned in the bag. Preferably, the receiver includes a post projecting toward an interior of the bag, the fluid-agitating element includes an opening, and the providing step comprises inserting the post through the opening. Alternatively, the receiver may include a peripheral sidewall and a cavity facing an interior of the bag, in which case the providing step comprises positioning the fluid-agitating element in the cavity. Still another alternative is for the receiver to include a peripheral sidewall and a cavity facing an exterior of the bag, in which case the fluid agitating element includes an opening or recess and the providing step comprises positioning the peripheral sidewall of the receiver in the opening or recess. In accordance with a seventh aspect of the invention, a method of agitating a fluid is disclosed. The method comprises providing a bag with a receiver for receiving and holding a fluid-agitating element at a home location within the bag, placing a fluid in the bag, and rotating the fluid-agitating element. In one embodiment, the bag comprises a flexible portion and a rigid portion including the receiver, and the providing step includes connecting the rigid portion to the flexible portion. The step of placing a fluid in the bag is completed after the fluid-agitating element is received in the receiver. The fluid-agitating element may be at least partially magnetic or ferromagnetic, and the step of rotating may include forming a non-contact coupling with a motive device external to the bag. The providing step may include providing a bearing on the receiver for directly engaging and supporting the fluid-agitating element. The method may further include the steps of folding the bag for storage or shipping with the fluid-agitating element in the receiver and unfolding the bag before the placing step, or hermetically sealing the bag after the providing step. The placing step may also comprise introducing the fluid through a sterile fitting provided in the bag. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a partially schematic, partially cross-sectional side view of one embodiment of the present invention including a vessel in the form of a bag having a flexible portion and a rigid portion; FIG. 1a is a partially schematic, partially cross-sectional, enlarged cutaway side view of the rigid portion of the vessel in the embodiment of FIG. 1; FIG. 1b is a partially schematic, partially cross-sectional, enlarged cutaway side view of the fluid-agitating element in the embodiment of FIG. 1; FIG. 1c is an enlarged partially cutaway side view showing one possible manner of attaching a first receiver in the form of a post to the rigid portion of the vessel; FIG. 2 is a partially schematic, partially cross-sectional side view showing the vessel of FIG. 1 positioned in a rigid vessel, with the fluid-agitating element aligned with and levitated/rotated by an adjacent motive device; FIG. 3a is partially schematic, partially cross-sectional side view showing another embodiment of the vessel, including a hat or cap-shaped rigid portion having a cavity facing inwardly, FIG. 3b is a side view similar to FIG. 3a; FIG. 4a is partially schematic, partially cross-sectional side view showing another embodiment of the vessel, including a hat or cap-shaped rigid portion having a cavity facing outwardly; FIG. 4b is a side view similar to FIG. 4a; FIGS. 5a, 5b, 6a, 6b, and 7a, 7b are each partially schematic, partially cross-sectional side views of a vessel with a rigid portion for aligning a fluid-agitating element with a external structure, wherein the fluid-agitating element is directly supported by a slide bearing; FIGS. 8a and 8b are enlarged, partially cross-sectional, partially cutaway side views of yet another embodiment of the vessel of the present invention; FIG. 9 is an enlarged, partially cross-sectional, partially cutaway side view of yet another embodiment of the vessel of the present invention; FIGS. 9a and 9b are cutaway bottom views of the vessel of FIG. 9a showing two different embodiments; FIG. 10 is an enlarged, partially cross-sectional, partially cutaway side view of still another embodiment of the vessel of the present invention; FIGS. 10a and 10b are cutaway bottom views of the vessel of FIG. 10 showing two different embodiments; FIG. 11 is an enlarged, partially cross-sectional, partially cutaway side view of another embodiment of the vessel of the present invention; FIGS. 11a and 11b are cutaway bottom views of the vessel of FIG. 11 showing two different embodiments; FIG. 12 is an enlarged, partially cross-sectional, partially cutaway side view of still another embodiment of the vessel of the present invention; FIG. 13 is an enlarged, partially cross-sectional, partially cutaway side view of still another embodiment of the vessel of the present invention; FIGS. 13a and 13b are cutaway bottom views of the vessel of FIG. 13 showing two different embodiments; FIG. 14 is an enlarged, partially cross-sectional, partially cutaway side view of yet another embodiment of the vessel of the present invention; FIG. 15 is an enlarged, partially cross-sectional, partially cutaway side view of a further embodiment of the vessel of the present invention; FIG. 15a is a bottom view of the vessel of FIG. 15 showing two different embodiments; and FIGS. 16a and 16b are enlarged, cross-sectional cutaway side views showing two different ways in which the rigid receiver may be connected to the bag forming the vessel. DETAILED DESCRIPTION OF THE INVENTION Reference is now made to FIG. 1, which discloses one embodiment of the vessel of the present invention in the form of a bag 10. In this embodiment, the bag 10 includes a body having a flexible or non-rigid portion 12, which is illustrated schematically, and a rigid or stiff portion 14, which is shown in cross-section. However, as outlined further in the description that follows, the use of the many of the present inventive concepts disclosed herein with vessels that are completely rigid is also possible. The bag 10 may be hermetically sealed and may have one or more openings or fittings (not shown) for introducing or recovering a fluid. Alternatively, the bag 10 may be unsealed or open-ended. The particular geometry of the bag 10 employed normally depends on the application and is not considered critical to the invention. For example, in the case of a sterile fluid, a hermetically sealed, pre-sterilized bag with an aseptic fitting might be desirable; whereas, in the case where sterility is not important, an open-ended or unsealed bag might be suitable. The main important point is that the bag 10 is capable of receiving and at least temporarily holding a fluid (which is used herein to denote any substance capable of flowing, as may include liquids, liquid suspensions, gases, gaseous suspensions, or the like, without limitation). The rigid portion 14 includes a first receiver 16 for receiving and holding a fluid-agitating element 18 at a home location (or expected position), when positioned in the bag 10. It is noted that “holding” as used herein defines both the case where the fluid-agitating element 18 is directly held and supported by the first receiver 16 (see below) against any significant side-to-side movement (save tolerances), as well as where the first receiver 16 merely limits the fluid-agitating element to a certain degree of side-to-side movement within the bag 10. In this embodiment, an opening 18a is provided in the fluid-agitating element 18 and the first receiver 16 is a post 20 projecting toward the interior of the bag 10 (see FIGS. 1a and 1b). The post 20 is sized for receiving the fluid-agitating element 18 by extending through the opening 18a formed in the body 18b thereof (which is depicted as being annular, but not necessarily circular in cross-section). As illustrated in FIG. 1, it is preferable that the size of the opening 18a is such that the fluid-agitating element 18 may freely rotate and move in the axial direction along the post 20 without contacting the outer surface thereof. Despite this freedom of movement, the post 20 serving as the first receiver 16 is still considered to hold, confine, or keep the fluid-agitating element 18 at a home location or expected position within the vessel 20 by contacting the surface adjacent to the opening 18a as a result of any side-to-side movement (the boundaries of which are defined by the dimensions of the opening). The flexible portion 12 of the bag 10 may be made of thin (e.g., having a thickness of between 0.1 and 0.2 millimeters) polyethylene film. The film is preferably clear or translucent, although the use of opaque or colored films is also possible. The rigid portion 14 including the post 20 may be formed of plastic materials, such as high density polyethylene (HDPE), ultrahigh molecular weight (UHMW) polyethylene, or like materials. Of course, these materials do have some inherent flexibility when used to form relatively thin components or when a moderate amount of bending force is applied thereto. Despite this flexibility, the rigid portion 14 is distinguished from the flexible portion 12, in that it generally maintains its shape under the weight of any fluid introduced in the bag 10. Optionally, the post 20 may include a portion 20a for capturing the fluid-agitating element 18 and assisting in holding it thereon. The portion 20a is preferably oversized and forms the head or end of the post 20. By “oversized,” it is meant that at least one dimension (length, width, diameter) of this portion 20a of the post 20 is greater than the corresponding dimension of the opening 18a in the fluid-agitating element 18. For example, the portion 20a is shown in FIG. 1 as being disc-shaped, such that it provides the head end of the post 20 with a generally T-shaped cross section. To prevent interference with the levitation and rotation of the fluid-agitating element 18, the oversized portion 20a is strategically positioned at a certain distance along the post 20. In the case where it is oversized, the post 20 may be removably attached to the rigid portion 14 through the opening 18a in the fluid-agitating element 18 (such as by providing a threaded bore in the rigid portion for receiving a threaded end of the post, or as shown in FIG. 1c, a bore 14a having a groove 14b for establishing a snap-fit engagement with a corresponding projection 20b on a tapered end portion 20c of the post). In the case where the post 20 is unitarily formed with the rigid portion 14 and includes an oversized head portion 20a, this portion should be sufficiently thin such that it flexes or temporarily deforms to allow the fluid-agitating element 18 to pass initially (see FIG. 1b and note action arrow A, which demonstrates the direction of force for deforming the oversized head 20a such that it passes through the opening 18a). Alternatively, this portion 20a of the post 20 need not be oversized, as defined above, but instead may simply be sufficiently close in size to that of the opening 18a such that the fluid-agitating element 18 must be precisely aligned and register with the post 20 in order to be received or removed. In any case, it is again important to note that the fluid-agitating element 18 is held in place in the vicinity of the post 20, but remains free of direct attachment. In other words, while the first receiver 16 (post 20) confines or holds the fluid-agitating element 18 at a home location or expected position within the bag 10, it is still free to move side-to-side to some degree (which in this case is defined by the size of the opening 18a), and to move along the first receiver 16 in the axial direction (vertical, in the embodiment shown in FIG. 1), as is necessary for levitation. As perhaps best shown in FIG. 1a, the rigid portion 14 in this embodiment further includes a substantially planar peripheral flange 22. The flange 22 may be any shape or size, and is preferably attached or connected directly to the bag 10 at the interface I between the two structures (which may be created by overlapping the material forming the flexible portion 12 of the bag on an inside or outside surface of the flange 22 to form an overlapping joint, or possibly in some cases by forming a butt joint). In the case where the bag 10 and flange 22 are fabricated of compatible plastic materials, the connection may be made using well-known techniques, such as ultrasonic or thermal welding (heat or laser) at the interface to form a seal (which is at least liquid-impervious and preferably hermetic). Alternatively, other means of connection (e.g., adhesives), may be used at the interface I, although this is obviously less preferred in view of the desirability in most cases for the more reliable, leak-proof seal afforded using welding techniques. In either case, the judicious use of inert sealants may be made along the joint thus formed to ensure that a leak-proof, hermetic seal results. As discussed further below, the need for such an interface may be altogether eliminated by simply affixing the rigid portion 14 to an inside or outside surface of the bag 10 (see FIGS. 16a and 16b). As should be appreciated, the bag 10 shown in FIG. 1 maybe manufactured as described above, with the fluid-agitating element 18 received on the post 20 (which may be accomplished using the techniques shown in FIGS. 1b and 1c). The empty bag 10 may then be sealed and folded for shipping, with the fluid-agitating element 18 held at the home location by the post 20. Holding in the axial direction (i.e., the vertical direction in FIG. 1) may be accomplished by folding the bag 10 over the post 20, or by providing the portion 20a that is oversized or very close in size to the opening 18a in the fluid-agitating element 18. When ready for use, the bag 10 is then unfolded. It may then be placed in a rigid or semi-rigid support structure, such as a container C, partially open along at least one end such that at least the rigid portion 14 remains exposed (see FIG. 2). Fluid F may then be introduced into the bag 10, such as through an opening or fitting (which may be a sterile or aseptic fitting, in the case where the bag 10 is pre-sterilized or otherwise used in a sterile environment). As should be appreciated, in view of the flexible or non-rigid nature of the bag 10, it will generally occupy any adjacent space provided in an adjacent support structure or container C when a fluid F (liquid or gas under pressure) is introduced therein (see FIG. 2). An external motive device 24 is then used to cause the fluid-agitating element 18 (which is at least partially magnetic or ferromagnetic) to at least rotate to agitate any fluid F in the bag 10. In the embodiment of FIG. 2, the fluid-agitating element 18 is at least partially magnetic and is shown as being levitated by the motive device 24, which is optional but desirable. As described in my co-pending U.S. patent application Ser. No. 09/724,815 (now U.S. Pat. No. ______), the disclosure of which is incorporated herein by reference, the levitation may be provided by a field-cooled, thermally isolated superconducting element SE (shown in phantom in FIG. 2) positioned within the motive device 24 and thermally linked to a cooling source (not shown). As also described therein, the fluid-agitating element 18 may then be rotated by rotating the superconducting element SE (in which case the fluid-agitating element 18 should produce an asymmetric magnetic field, such as by using at least two spaced magnets having alternating polarities). Another option is to use a separate drive structure (e.g., an electromagnetic coil) to form a coupling capable of transmitting torque to the particular fluid-agitating element (which may be “levitated” by a hydrodynamic bearing; see, e.g., U.S. Pat. No. 5,141,327 to Shiobara). While it is of course desirable to eliminate the need for a dynamic seal or opening in the bag through which a drive structure (such as a shaft) extends, the particular means used to levitate and/or rotate the fluid-agitating element 18 is not considered critical to practicing the inventions disclosed herein. The fluid-agitating element 18 is also depicted as including a plurality of vanes or blades B to improve the degree of fluid agitation. If present, the vanes or blades B preferably project in a direction opposite the corresponding surface of the rigid portion 14. The particular number, type, and form of the vanes or blades B is not considered important, as long as the desired degree of fluid agitation for the particular application is provided. Indeed, in applications where only gentle agitation is required, such as to prevent damage to delicate suspensions or to merely prevent stagnation of the fluid F in the bag 10, the vanes or blades B need not be provided, as a rotating smooth-walled annular element 18 still provides some degree of agitation. As explained above, it is important to not only know the general location or position of the fluid-agitating element 18 within the bag 10, but also to assure its position relative to the motive device 24. To do so, and in accordance with a second aspect of the invention, the rigid portion 14 maybe provided with a second receiver 26 to facilitate the correct positioning of the motive device 24 relative to the fluid-agitating element 18 when held at the home location. In the embodiment shown in FIGS. 1a and 1b, the second receiver 26 takes the form of a second post 28 projecting in a direction opposite the first post 20. Preferably, the second post 28 is essentially coaxial with the first post 20 (although the post 20 may be a separate component that fits into a receiver 14a defined by the second post 28; see FIG. 1c) and is adapted to receive an opening 24a, such as a bore, in the adjacent end face 24b forming a part of the housing for the motive device 24. Consequently, the second post 28 helps to assure that the alignment between the fluid-agitating element 18 (which is generally held in the vicinity of the first receiver 16/post 20, which is the home location) and the motive device 14 is proper such that the desired coupling for transmitting the levitation or rotational force may be formed. Preferably, the second receiver 26, such as second post 28, has a cross-sectional shape corresponding to the shape of the opening 24a. For example, the second post 28 maybe square in cross-section for fitting in a correspondingly-shaped opening 24a or locator bore. Likewise, the second post 28 could have a triangular cross-sectional shape, in which case the opening 28 would be triangular. Myriad other shapes could also be used, as long as the shape of the second receiver 26 compliments that of the opening 24a such that it may be freely received therein. In this regard, it is noted that a system of matching receivers and openings may be used to ensure that the fluid-agitating element 18 in the bag 10 corresponds to a particular motive device 24. For example, in the case where the fluid-agitating element 18 includes a particular arrangement of magnets producing a magnetic field that corresponds to a particular superconducting element or drive structure, the second receiver 26 maybe provided with a certain shape that corresponds only to the opening 24 in the motive device 24 having that type of superconducting element or drive structure. A similar result could also be achieved using the relative sizes of the second receiver 26 and the opening 24a, as well as by making the size of the opening 18a in the fluid-agitating element 18 such that it only fits on a first receiver 16 having a smaller width or diameter, and then making the second receiver 26 correspond only to an opening 24a in a motive device 24 corresponding to that fluid-agitating element 18. In many past arrangements where a rigid vessel is used with a fluid-agitating element directly supported by a bearing, an external structure is provided to which a motive device could be directly or indirectly attached and held in a suspended fashion (see, e.g., U.S. Pat. No. 4,209,259 to Rains et al., the disclosure of which is incorporated herein by reference). This structure serves to automatically align the motive device with the fluid-agitating element supported therein. However, a bag 10 per se is generally incapable of providing reliable support for the motive device 24, which can weigh as much as twenty kilograms. Thus, the motive device 24 in the embodiments disclosed herein for use with a vessel in the form of a bag 10 is generally supported from a stable support structure (not shown), such as the floor, a wheeled, height adjustable platform, or the like. Since there is thus no direct attachment with the bag 10, the function performed by the second receiver 26 in aligning this device with the fluid-agitating element 18 is an important one. Another embodiment of the vessel forming one aspect of the present invention is shown in FIGS. 3a and 3b. In this embodiment, the vessel is again a bag 10 including a flexible portion 12 and a rigid portion 14. The rigid portion 14 is cap or hat-shaped with a peripheral flange 22 for attachment to the flexible portion 12 of the bag 10. The connection between the two structures may be formed using the various techniques described above, and preferably results in a fluid-impervious, hermetic seal. The rigid portion 14 includes a first receiver 16 in the form of a recess or cavity 30 facing the interior of the bag (see action arrow B) for receiving a correspondingly-shaped portion of the fluid-agitating element 18 in the bag 10 and holding it at a home location, at least when oriented as shown in FIG. 3a. The portion of the fluid-agitating element 18 received in the cavity 30 is preferably the body 18b, which as described above is at least partially magnetic or ferromagnetic and may optionally support a plurality of vanes or blades B. Preferably, the body 18b of the fluid-agitating element 18 is circular in cross-section and the cavity 30 is sized and shaped such that the body (which need not include opening 18a in view of the absence of post 20) may freely be inserted, rotate, and levitate therein. However, as with the first embodiment, the fluid-agitating element 18 could also be in the form of a conventional magnetic stirrer (which of course would not be levitated), such as a bar having a major dimension less than the corresponding dimension (e.g., the diameter) of the cavity 30. In any case, the fluid-agitating element 18 in this embodiment is again free of direct attachment from the first receiver 16, but is held at a home location, even in the event of accidental decoupling. Thus, in the manner similar to that described above with respect to the first embodiment, the fluid-agitating element 18 may be positioned in the first receiver 16 in the bag 10. The bag 10 may then be sealed, folded for storage or shipping, stored or shipped, and ultimately unfolded for use. The folding is preferably completed such that the fluid-agitating element 18 is captured in the cavity 30 and remains held in place during shipping by an adjacent portion of the bag 10. Consequently, upon unfolding the bag 10, the fluid-agitating element 18 is at the expected or home location, but remains free of direct attachment and ready to be rotated (and possibly levitated). If levitated, the levitation height established by the superconducting bearing or hydrodynamic bearing is preferably such that at least a portion of the body 18b of the fluid-agitating element 18 remains within the confines of the cavity 30. This helps to assure that the fluid-agitating element 18 remains held at the home location (that is, in the vicinity of the first receiver 16), even in the case of accidental decoupling from the motive device 24. In other words, in the event of an accidental decoupling, the fluid-agitating element 18 will engage the sidewall of the cavity 30 and simply come to rest therein, which defines the home location. This not only improves the chance of an automatic recoupling, but also makes the task of manually reforming the coupling an easy one. An option to assure that a magnetic fluid-agitating element 18 remains associated with the first receiver 16, even if inverted, is to attach an attractive structure, such as a magnet 32 (shown in phantom in FIG. 3a), to the exterior of the rigid portion 14. The non-contact coupling thus established helps ensure that the fluid-agitating element 18 remains in the home location prior to being coupled to an external motive device. The magnet 32 is removed once the bag 10 is positioned on or in a support structure, such as a container C (see FIG. 2). Such a magnet 32 may also be used with the embodiment of FIG. 1, which eliminates the need for providing the post 20 with portion 20a. The magnet 32 is preferably annular with an opening that is received by the second receiver 26, which advantageously helps to ensure that the alignment is proper for forming the coupling. Yet another option is to provide a frangible adhesive on the fluid-agitating element 18 to hold it in place temporarily in the first receiver 16 prior to use. The strength of any adhesive used is preferably such that the bond is easily broken when the fluid-agitating element 18 is levitated in the first receiver 16. Of course, the use of such an adhesive might not be possible in situations where strict regulations govern the purity of the fluid being mixed. With reference to FIG. 3b, the first receiver 16 in this embodiment also serves the dual function of helping to align the fluid-agitating element 18 relative to an external motive device 24. Specifically, the periphery of the sidewall 34 and the end wall 36 defining the cavity 30 in the rigid portion 14 define a second receiver 26 adapted to receive an opening 24a formed in an adjacent face of a motive device 24. As described above, the opening 24a is preferably sized and shaped for being received by the second receiver 26, and may even help to ensure that the bag 10 is used only with a motive device 24 having the correct superconducting element or magnetic structure(s) for levitating and/or rotating the fluid-agitating element 18. For example, in the case where the sidewall 34 and end wall 36 provide the second receiver 26 with a generally cylindrical shape, the opening 24a is also cylindrical. Preferably, the opening 24a also has a depth such that the end wall 36 rests on the corresponding face 24c of the motive device 24. This feature may be important to ensure that the gap between the superconducting element and/or drive structure in the motive device 24 and the at least partially magnetic or ferromagnetic body 18b of the fluid-agitating element 18 is minimized, which helps to ensure that the strongest possible coupling is established and that the maximum amount of driving torque is transferred. The gaps are shown as being oversized in FIG. 3b merely to provide a clear depiction of the relative interaction of the structures shown. However, in the case where the entire housing of the motive device 24 is rotated, it may be desirable to provide a certain amount of spacing between the sidewall 34, the end wall 36, and the corresponding surfaces defining the opening 24a to avoid creating any interference. FIGS. 4a and 4b show an embodiment similar in some respects to the one shown in FIGS. 3a and 3b. For example, the rigid portion 14 includes a peripheral flange 22 connected to the flexible portion 12 of the bag 10 to form a seal. Also, the rigid portion 14 includes a sidewall 34 and end wall 26 that together define a cavity 30. However, a major difference is that the cavity 30 of the rigid portion 14 essentially faces outwardly, or toward the exterior of the bag 10 (e.g., in a direction opposite action arrow B). Consequently, the sidewall 34 and end wall 36 define the first receiver 16 for receiving the fluid-agitating element 18, which is shown having an annular body 18b that is at least partially magnetic or ferromagnetic and may support a plurality of vanes or blades B. As should be appreciated, the first receiver 16 in the form of the periphery of the sidewall 34 provides a similar receiving function as both the post 20 and the cavity 30 of the other embodiments, since it is capable of maintaining, holding, or confining the fluid-agitating element 18 substantially in a home or expected position within the bag 10. The maximum amount of side-to-side movement is of course dependent on the size of the opening 18a in the fluid-agitating element. Additionally, the outwardly-facing cavity 30 is adapted to serve as the second receiver 26 for receiving a portion of a motive device 24 used to levitate and rotate the fluid-agitating element 18 and serving to align the two. Specifically, the motive device 24 may include a head end 24d adapted for insertion in the cavity 30 to form the desired coupling with the fluid-agitating element 18 positioned adjacent thereto. As with the embodiments described above, the spacing between the head end 24d and at least the sidewall 34 is preferably minimized to maximize the strength of the coupling between the motive device 24 and the fluid-agitating element 18. Moreover, in view of the rigid nature of the rigid portion 14, the end face 24b of the head end 24d may rest against and assist in supporting the bag 10 (which, as described above, maybe positioned in a separate, semi-rigid container (not shown)). In each of the above-referenced embodiments, the possible use of a levitating fluid-agitating element 18 with a superconducting bearing or a hydrodynamic bearing is described. In such systems, a real possibility exists that the fluid-agitating element 18 might accidentally decouple or disconnect from the motive device 24, such as if the fluid is viscous or the amount of torque transmitted exceeds the strength of the coupling. In a conventional bag, the process of reestablishing the coupling is extraordinarily difficult, since the location of the fluid-agitating element 18 within the bag 10 is unknown. In a sterile environment, opening the bag 10 and using an implement to reposition or “fish” out the fluid-agitating element 18 is simply not an option. Thus, an added advantage of the use of the first receiver 16 in each of the above-referenced embodiments is that, despite being free from direct attachment, it still serves the function of holding the fluid-agitating element 18 at the home location in instances where accidental decoupling occurs. This significantly reduces the downtime associated with such an event, since the general position of the fluid-agitating element 18 is known. The use of a first receiver in the bag 10 also improves the chances of automatic recoupling, since the fluid-agitating element 18 remains generally centered relative to the motive device 14 and held generally at the home location, even when decoupling occurs. A related advantage is provided by forming the first receiver 16 in or on a rigid portion 14 of the bag 10. Specifically, in the case where a fluid-agitating element rests on a surface of a bag, the contact over time could result in damage and could even lead to an accidental perforation, which is deleterious for obvious reasons. The possibility for such damage or perforation also exists when a levitating fluid-agitating element 18 accidentally decouples. Advantageously, the potential for such damage or perforation is substantially eliminated in the foregoing embodiments, since the first receiver 16 helps to keep the fluid-agitating element 18 adjacent to the flange 22 of the rigid portion 14, which is generally thicker and less susceptible to being damaged or perforated. In other words, if the fluid-agitating element 18 becomes decoupled, it only engages or contacts the rigid portion 14 of the bag 10. Thus, it is preferable for the flange 22 to be oversized relative to the fluid-agitating element 18 While the embodiments of FIGS. 1-4 are described as bags 10 including both a flexible portion 12 and a rigid portion 14, it should be appreciated that the present invention extends to a completely rigid vessel (that is, one made of metal, glass, rigid plastics, or the like). In the case of a rigid vessel, the post 20 preferably includes a portion 20a for capturing the fluid-agitating element 18 thereon, but without any other means of direct attachment or bearing. Up to this point, the focus has been on a fluid-agitating element 18 capable of levitating in the vessel. However, as briefly noted above, the inventions described herein may also be applied to a bag 10 in combination with a fluid-agitating element 18 directly supported by one or more bearings. For example, as shown in FIGS. 5a and 5b, the first receiver 16 associated with the rigid portion 14 of the bag 10 may be in the form of an inwardly-projecting post 20 including a slide bearing 40 for providing direct support for the fluid-agitating element 18. The bearing 40 is preferably sized and shaped such that it fits into an opening 18a forming in the fluid-agitating element 18, which may rest on the adjacent surface of the post 20 or may be elevated slightly above it. In either case, it should be appreciated that the first receiver 16 receives and holds the fluid-agitating element 18 in a home location, both during shipping and later use. In view of the direct nature of the support, the material forming the slide bearing 40 is preferably highly wear-resistant with good tribological characteristics. The use of a slide bearing 40 is preferred in applications where the bag 10 is disposable and is merely discarded, since it is less expensive than a corresponding type of mechanical roller bearing (and is actually preferred even in the case where the bag 10 is reused, since it is easier to clean). However, it is within the broadest aspects of the invention to provide the first receiver 16 with a conventional roller bearing for providing direct, low-friction, rolling support for the rotating fluid-agitating element 18, although this increases the manufacturing expense and may not be acceptable in certain applications. The rigid portion 14 of the bag 10 in this embodiment may further include a second receiver 26 in the form of a second post 28 coextensive and coaxial with the first post 20. The second post 28 is received in an opening 24a formed in an end face 24b of a motive device 24. In view of the direct support provided for the fluid-agitating element 18 by the bearing 40, the motive device 24 in this case includes only a drive structure DS (shown in phantom in FIG. 5b) for forming a coupling with the body 18b, which is magnetic or ferromagnetic (iron, magnetic steel, etc.). The drive structure DS may be a permanent magnet or may be ferromagnetic, as necessary for forming the coupling with the fluid-agitating element 18, which may be disc-shaped, cross-shaped, an elongated bar, or have any other suitable shape. The drive structure DS may be rotated by a direct connection with a motor (not shown), such as a variable speed electric motor, to induce rotation in the fluid-agitating element 18. Alternatively, the drive structure DS may be an electromagnet with windings to which current is supplied to cause the magnetic fluid-agitating element 18 rotate and possibly levitate slightly to create a hydrodynamic bearing (see, e.g., U.S. Pat. No. 5,141,327, the disclosure of which is incorporated herein by reference). Again, it is reiterated that the particular type of motive device 24 employed is not considered critical to the present invention. FIGS. 6a and 6b show an embodiment of the bag 10 in which the first receiver 16 is in the form of a cavity 30 formed in the rigid portion 14 and facing inwardly. A bearing 40 is provided in the cavity 30 for providing direct support for a fluid-agitating element 18 positioned therein. As with the embodiment described immediately above, the bearing 40 may be a slide bearing adapted for insertion in the opening 18a of the fluid-agitating element 18 formed on the head end of a post 42. The post 42 may be supported by or unitarily formed with the end wall 36. Despite the depiction of a slide bearing 40, it is reiterated that the particular type of bearing used is not considered critical, as long as rotational support is provided for the fluid-agitating element 18 and the other needs of the particular fluid-agitating operation are met (e.g., low friction, reduced expense, easy clean-up, etc.). The body 18b of the fluid-agitating element 18, which is at least partially magnetic or ferromagnetic, is sized to fit within the sidewall 34 defining the cavity 30 and, thus, is capable of rotating therein as the result of an externally-applied, non-contact motive force. The periphery of the sidewall 34 also defines a second receiver 26 for receiving a corresponding opening 24a in a motive device 24, which in view of the direct support provided by bearing 40 need only provide the force necessary to rotate the fluid-agitating element 18 in a non-contact fashion. As should be appreciated, the embodiment shown in FIGS. 7a and 7b is the direct support counterpart for the embodiment shown in FIGS. 4a and 4b. The rigid portion 14 again includes a cavity 30 facing outwardly or toward the exterior of the bag 10 and a first receiver 16 for receiving and defining a home location for a fluid-agitating element 18. The first receiver 16 includes a bearing 40 for supporting the fluid-agitating element 18, which again is at least partially magnetic or ferromagnetic. The bearing 40 may be a slide bearing formed on the head end of a post 44 integral with the end wall 36 of the rigid portion 14 and adapted for fitting into an opening or recess 18a in the fluid-agitating element 18, or may be a different type of bearing for providing support therefor. The motive device 24 includes a head end 24d adapted for insertion in a second receiver 26 defined by the cavity 30. This head end 24d preferably includes the drive structure DS that provides the force for causing the at least partially magnetic or ferromagnetic fluid-agitating element 18 to rotate about bearing 40. In FIGS. 7a and 7b, it is noted that the fluid-agitating element 18 includes an optional depending portion 18b that extends over the sidewall 34. As should be appreciated, this portion may also be magnetized or ferromagnetic such that a coupling is formed with the drive structure DS. A similar type of fluid-agitating element 18 could also be used in the levitation scheme of FIGS. 4a and 4b. Various other modifications may be made based on the foregoing teachings. For example, FIGS. 8a and 8b show another possible embodiment of a vessel of the present invention for use in a fluid-agitating or mixing system. The vessel for holding the fluid is shown as being a bag 110 having a flexible portion 112, generally cylindrical in shape, and substantially or hermetically sealed from the ambient environment. In this embodiment, the bag 110 includes a first receiver 116 for receiving and holding the fluid-agitating element 118 at a home location. The first receiver 116 is in the form of a post 120 adapted to receive the fluid-agitating element 118, which has a corresponding opening 118a. The post 120 preferably includes an oversized head portion 120a that captures the fluid-agitating element 118, both before and after a fluid is introduced into the bag 110. Thus, the bag 110 may be manufactured, sealed (if desired), shipped, or stored prior to use with the fluid-agitating element 118 held in place on the post 120. The vessel 110 may also be sterilized as necessary for a particular application, and in the case of a flexible bag, may even be folded for compact storage. As should be appreciated, the post 120 also serves the advantageous function of keeping, holding, maintaining, or confining the fluid-agitating element 118 substantially at a home location or “centered,” should it accidentally become decoupled from the adjacent motive device, which as described above may include a rotating superconducting element SE for not only providing the rotational force, but also a levitation force. In this particular embodiment, the post 120 is shown as being defined by an elongated, rigid or semi-rigid, rod-like structure inserted through an opening typically found in the flexible plastic bags frequently used in the bioprocessing industry (pharmaceuticals, food products, cell cultures, etc.), such as a rigid or semi-rigid fitting or nipple 134. Despite the general rigidity of the post 120, the oversized portion 120a, which is shown as being T-shaped in cross-section, is preferably sufficiently thin and/or formed of a material that may flex or deform to easily pass through the opening in the nipple 134, as well as through the opening 118a in the fluid-agitating element 118. A conventional clamp 136, such as a cable tie, may be used to form a fluid-impervious seal between the nipple 134 and the post 120. Any other nipples or fittings present may be used for introducing the fluid F prior to mixing, retrieving a fluid during mixing or after mixing is complete, or circulating the fluid. Advantageously, the use of the rod/nipple combination allows for easy retrofitting. The oversized head portion 120a may be cross-shaped, L-shaped, Y-shaped, spherical, cubic, or may have any other shape, as long as the corresponding function of capturing the fluid-agitating element 118 is provided. The head portion 120a maybe integrally formed, or maybe provided as a separate component clamped or fastened to the post 120. In accordance with another aspect of this embodiment of the invention, the bag 110 may also include a second receiver 126 that helps to ensure that proper alignment is achieved between the fluid-agitating element 118 and an adjacent structure, such as a support structure or a device for rotating and/or levitating the element. In the embodiment of FIGS. 8a and 8b, this second receiver 126 is shown as the opposite end 128 of the rod forming post 120. This end 128 of the rod may be inserted in a bore or opening 124a in an adjacent surface of a motive device 124 to assure proper alignment with the fluid-agitating element 118. In other words, as a result of the use of first and second receivers 116, 126, assurance is thus provided that the fluid-agitating element 118 is in the desired home or expected position for forming a coupling with an adjacent motive device 124. FIG. 8a also shows the post 120 forming the first receiver 116 as projecting upwardly from a bottom wall of the vessel 110, but as should be appreciated, it could extend from any wall or other portion thereof. For example, as illustrated in FIG. 8b, the rod serving as both the first and second receivers 116, 126 may be positioned substantially perpendicular to a vertical plane. Specifically, in the particular embodiment shown, the bag 110 is positioned in a rigid or semi-rigid support container C having an opening O. Once the bag 110 is inserted in the container C, but preferably prior to introducing a fluid, the end 128 of the rod is positioned in the opening O such that it projects therefrom and maybe inserted in the opening 124a formed in the motive device 124, which includes a superconducting element SE and may still levitate, and possibly rotate the at least partially magnetic fluid-agitating element 118 in this position. This ensures that the fluid-agitating element 118 is in the desired position to form the coupling necessary for levitation and/or rotation. Preferably, the portion of the rod extending outside the bag 110 and forming the second receiver 126 is greater in length than that in the embodiment shown in FIG. 1, and the depth of the opening 124a in the motive device 124 corresponds to this length. This in combination with the rigid or semi-rigid nature of the nipple 134 helps to ensure that the other end of the rod forming post 120 is properly aligned with the fluid-agitating element 118 when the magnetic coupling is formed. Other possible embodiments are shown in FIGS. 9-15. In FIG. 9, a first receiver 216 in the form of a post 220 includes an oversized spherical head 220a that serves to mechanically capture an adjacent fluid-agitating element 218 (shown in phantom). The post 220 is integrally formed with the vessel, which is preferably a bag 210 but may be partially or completely rigid. On the outer surface of the vessel 210, a low-profile second receiver 226 in the form of an outwardly-directed projection 228 is provided for receiving a corresponding portion 224a of the adjacent motive device 224. The projection 228 may have any shape desired, including square, circular, or the like (see FIGS. 9a and 9b), with the portion 224a having a corresponding shape. Once the projection 228 is aligns with and receives the corresponding portion 224a, the captive fluid-agitating element 218 is properly aligned with the adjacent motive device 224. Another embodiment is shown in FIG. 10 in which the vessel 310 may be rigid or at least partially flexible. In this embodiment, the first receiver 316 is a post 320, which is shown merely for purposes of illustration as having an L-shaped head portion 320a for mechanically capturing an adjacent fluid-agitating element 318 (shown in phantom). The second receiver 326 is in the form of at least one projection 328 substantially concentric with the post 320. The projection 328 may be square, circular, or may have any other desired shape. The projection may also be continuous, as shown in FIG. 10a, or interrupted to form segments 328a, 328b . . . 328n, as shown in FIG. 10b. Although a plurality of segments are shown, it should be appreciated that the number of segments provided maybe as few as one, regardless of the shape of the projection 328 (and could even be a single stub offset from the post 320). The corresponding portion 324a of the motive device 324 that is received by the second receiver 326 is similarly shaped and preferably continuous, but could also have one or more segments matching the segments in the vessel 310 (including a single offset bore). In the embodiment of FIG. 11, the vessel 410 includes a first receiver 416 in the form of a post 420, again shown with an oversized T-shaped head 420a The second receiver 426 includes at least one channel, recess, or groove 428 formed in the vessel 410. A corresponding projection 425 is provided in the motive device 424 for engaging the channel, recess or groove 428 to provide the desired alignment function, such as between driving magnets and driven magnets, between driven magnets and a rotating superconducting element, or between any other driver and a driven structure associated with a fluid-agitating element. The channel, groove, or recess 428 is preferably continuous (see FIG. 11a, with the projection 425 shown in phantom), but may be segmented as well (see FIG. 11b). Yet another embodiment is shown in FIG. 12. In this embodiment, the vessel 510 again includes a first receiver 516 in the form of a post 520, which is shown for purposes of illustration as having a frusto-conical head to create a Y-shaped cross-section. The second receiver 526 is in the form of a low-profile recessed portion 528 formed in the vessel 510. This recessed portion 528 is sized and shaped for receiving a portion of the motive device 510, and thus ensures that the proper alignment is achieved between a fluid-agitating element 518 concentric with the post 520 and any structure for levitating and/or rotating the element. As with the embodiments described above, the recessed portion 528 may have any shape desired, including square, circular, triangular, rectangular, polygonal, or the like. FIG. 13 illustrates an embodiment wherein the vessel 610 is provided with a first receiver 616 in the form of a post 620 having a head 620a (shown as disc-shaped), as well as a plurality of structures 628 defining second receivers 626 adapted for receiving a portion of an external structure, such as a projection 625 formed on an end face of a motive device 624. The second receivers 626 may be in the form of concentric ring-shaped recesses 628, as illustrated in FIG. 13a, but could also comprise concentric squares or even arrays of straight lines, as shown in FIG. 13b. Three second receivers 626 are shown in FIGS. 13 and 13a, but it should be appreciated that more or fewer maybe provided as desired. Indeed, the number of structures provided may be used as an indicator of the size, shape, or other characteristic of the fluid-agitating element 618 in the vessel 610, which thus allows the user to select a suitable motive device (such as one having a superconducting element having a particular characteristic). FIG. 14 shows an embodiment wherein the vessel 710, which again may be rigid or partially flexible, includes a first receiver 716 in the form of a post 720 having an oversized head portion 720a and a second receiver 726 in the form of a hat or cup-shaped projection 728 (which may be integrally formed or a separate rigid portion). The second receiver 726 receives a portion of an intermediate support structure T including a first recess R1 on one side and a second recess R2 on the opposite side. The second recess R2 is adapted for receiving at least a portion of the motive device 724, which is shown as a cryostat including a rotating, thermally isolated superconducting element SE for coupling with at least two alternating polarity magnets M (or alternatively, the head of the cryostat may be attached to a bearing positioned in recess R2 and rotated). This particular embodiment dispenses with the need for forming a locator bore in the motive device 724 to align the fluid-agitating element 718 therewith (although it remains possible to provide such a bore for receiving a projection on the support structure T to achieve the alignment function). Generally, it is of course desirable to form the wall 764 between the recesses R1, R2 as thin as possible to enhance the stiffness of the coupling used to rotate and/or levitate the adjacent fluid-agitating element 718 (which includes vanes V). FIG. 15 shows an embodiment where a second receiver 826 in the form of a slightly raised projection 828 is provided in the vessel 810 that corresponds to a dimple 825 formed in an external structure, such as the end face of the motive device 824. As should be appreciated, the opposite arrangement could also be used, with the dimple formed in the vessel 810 and serving as a second receiver 826. Optionally, or instead of the projection 828/dimple 825 combination, at least one indicia may be provided to allow an observer to determine the proper location of the structure such as motive device 824 relative to the vessel 810. The indicia is shown as a darkened ring 866 formed in the outer wall of the vessel 810, which could be a bag or a rigid or semi-rigid container. However, it should be appreciated that the indicia could be in the form of one or more marks placed on or formed in the outer surface of the vessel 810 (including even possibly a weld or seal line), or even marks placed on the opposite sides of an intermediate support surface (not shown). In any case, the indicia 866 is preferably designed such that it helps to align the motive device 824 relative to a first receiver 816 in the vessel 810 for receiving and defining a home location for a fluid agitating element, such as the post 820 (which is shown having a cross-shaped head 820a). The indicia 866 thus helps to ensure that the fluid-agitating element is aligned with any driving or levitating structure held therein. Obvious modifications or variations are possible in light of the above teachings. For example, instead of forming the rigid portion 14 as part of the bag 10 by forming a seal at an interface between the two, it could also be positioned in contact to an inner or outer surface of the bag and attached using vacuum-forming techniques, adhesives, or the like. For example, in the cap-shaped embodiment of FIG. 3a, the bag 10 would essentially line the inside surfaces of the sidewall 34 and end wall 36 (see FIG. 16a). Likewise, in the embodiment of FIG. 4a, the bag 10 would cover the sidewall 34 and end wall 36 (see FIG. 16b). In both cases, the need for the flange 22 may be eliminated. It is also possible to provide any of the first receivers with a tapered or frusto-conical engagement surface that mates with a corresponding surface on the fluid-agitating element, as disclosed in my co-pending patent application Ser. No. PCT/US01/31459, the disclosure of which is incorporated herein by reference. The foregoing descriptions of various embodiments of the present inventions have been presented for purposes of illustration and description. These descriptions are not intended to be exhaustive or to limit the invention to the precise forms disclosed. The embodiments described provide the best illustration of the principles of the invention and its practical applications to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally and equitably entitled.

<SOH> BACKGROUND OF THE INVENTION <EOH>Most pharmaceutical solutions and suspensions manufactured on an industrial scale require highly controlled, thorough mixing to achieve a satisfactory yield and ensure a uniform distribution of ingredients in the final product. Agitator tanks are frequently used to complete the mixing process, but a better degree of mixing is normally achieved by using a mechanical stirrer or impeller (e.g., a set of mixing blades attached to a metal rod). Typically, the mechanical stirrer or impeller is simply lowered into the fluid through an opening in the top of the vessel and rotated by an external motor to create the desired mixing action. One significant limitation or shortcoming of such an arrangement is the danger of contamination or leakage during mixing. The rod carrying the mixing blades or impeller is typically introduced into the vessel through a dynamic seal or bearing. This opening provides an opportunity for bacteria or other contaminants to enter, which of course can lead to the degradation of the product. A corresponding danger of environmental contamination exists in applications involving hazardous or toxic fluids, or suspensions of pathogenic organisms, since dynamic seals or bearings are prone to leakage. Cleanup and sterilization are also made difficult by the dynamic bearings or seals, since these structures typically include folds and crevices that are difficult to reach. Since these problems are faced by all manufacturers of sterile solutions, pharmaceuticals, or the like, the U.S. Food and Drug Administration (FDA) has consequently promulgated strict processing requirements for such fluids, and especially those slated for intravenous use. In an effort to overcome these problems, others have proposed alternative mixing technologies. Perhaps the most common proposal for stirring a fluid under sterile conditions is to use a rotating, permanent magnet bar covered by an inert layer of TEFLON, glass, or the like. The magnetic “stirrer” bar is placed on the bottom of the agitator vessel and rotated by a driving magnet positioned external to the vessel. An example of such an arrangement where the vessel is a flexible bag is shown in U.S. Pat. No. 5,947,703 to Nojiri et al., the disclosure of which is incorporated herein by reference. Of course, the use of such an externally driven magnetic bar avoids the need for a dynamic bearing, seal or other opening in the vessel to transfer the rotational force from the driving magnet to the stirring magnet. Therefore, a completely enclosed system is provided. This of course prevents leakage and the potential for contamination created by hazardous materials (e.g., cytotoxic agents, solvents with low flash points, blood products, etc.), eases clean up, and allows for the desirable sterile interior environment to be maintained, all of which are considered significant advantages. Despite the advantages of this type of mixing systems and others where the need for a shaft penetrating into the vessel or dynamic seal is eliminated, a substantial, but heretofore unsolved problem with such systems is the difficulty in coupling a fluid-agitating element with an external motive device providing the rotation and/or levitation force. For example, when a vessel in the form of a flexible bag containing an unconfined fluid-agitating element is positioned in proximity to the motive device, the relative location of the fluid-agitating element is generally unknown. In the case of a small (10 liter or less) transparent bag, it is possible to manipulate the bag relative to the motive device in an effort to ensure that the fluid-agitating element is “picked up” and the desired coupling is formed. However, this is considered inconvenient and time consuming, especially if fluid is already present in the bag. Moreover, in the case where the bag is relatively large (e.g., capable of holding 100 liters or more) or formed of an opaque material (e.g., black), achieving the proper positioning of the fluid-agitating element relative to the external motive device is at a minimum difficult, and in many cases, impossible. In the absence of fortuity, a significant amount of time and effort is required to lift and blindly reposition the bag relative to the motive device, without ever truly knowing that the coupling is properly formed. Also, even if the coupling is initially formed, the fluid-agitating element may become accidentally decoupled or disconnected from the motive device during the mixing operation. In view of the semi-chaotic nature of such an event, the ultimate resting place of the fluid-agitating element is unknown and, in cases where the fluid is opaque (e.g., blood) or cloudy (e.g. cell suspensions), not easily determined. If the coupling ultimately cannot be established in the proper fashion, the desired fluid agitation cannot be achieved in a satisfactory manner, which essentially renders the set up useless. These shortcomings may significantly detract from the attractiveness of such fluid agitation systems from a practical standpoint. In many past mixing arrangements, a rigid vessel is used with a fluid-agitating element directly supported by a post carrying a roller bearing, with the rotational force being supplied by an external device (see, e.g., U.S. Pat. No. 4,209,259 to Rains et al., the disclosure of which is incorporated herein by reference). While this direct support arrangement prevents the fluid-agitating element from being lost in the event of an accidental decoupling, the use of such post or like structure in a bag for receiving and holding a fluid-agitating element has not been proposed. The primary reason for this is that, in a typical flexible bag, neither the sidewalls nor any other structure is capable of providing the direct support for the fluid-agitating element or a corresponding bearing. Thus, a need is identified for an improved manner of ensuring that the desired coupling may be reliably achieved between a fluid-agitating element in a vessel such as a bag and an external motive device, such as one supplying the rotational force that causes the element to agitate the fluid, even in large, industrial scale mixing bags or vessels (greater than 100 liters), opaque bags or vessels, or where the fluid to be agitated is not sufficiently clear, and even after an accidental decoupling occurs. The improvement provided by the invention would be easy to implement using existing manufacturing techniques and without significant additional expense. Overall, a substantial gain in efficiency and ease of use would be realized as a result of the improvement, and would greatly expand the potential applications for which advanced mixing systems may be used.

<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with a first aspect of the invention, a vessel intended for receiving a fluid and a fluid-agitating element is provided. The vessel comprises a bag capable of receiving and holding the fluid. The bag includes a rigid portion having a first receiver for receiving and holding the fluid-agitating element at a home location when positioned in the vessel. In one embodiment, the first receiver is a first inwardly-projecting post for positioning in an opening or recess in the fluid-agitating element. The first post may include an oversized portion for capturing the fluid-agitating element. The oversized portion is preferably the head of the first post and is T-shaped, cross-shaped, Y-shaped, L-shaped, spherical, cubic, or otherwise formed having a shape that confines the fluid-agitating element to adjacent the post. The bag may further include a second receiver projecting outwardly from the bag. The second receiver facilitates aligning the fluid-agitating element with an external structure, such as a motive device for levitating or rotating the fluid-agitating element. In one particularly preferred embodiment, the first receiver is a first, inwardly-projecting post and the second receiver is a second, outwardly-projecting post coaxial with the first inwardly-projecting post. The first receiver may include a peripheral flange mating with a portion of the bag to create an interface along which a seal is formed. Instead of comprising a post, the first receiver may be cap-shaped and include a cavity facing the interior of the bag. Still another option is for the first receiver to include an generally upstanding peripheral sidewall over which the fluid-agitating element is received and a cavity adapted for receiving a portion of an external structure for rotating the fluid-agitating element. The first receiver may also include a bearing for directly engaging and supporting the fluid-agitating element in a non-levitating fashion. In accordance with a second aspect of the invention, a vessel intended for use in receiving a fluid and a fluid-agitating element, such as a magnetic impeller, positioned adjacent to an external structure, such as a housing of a motive device for levitating and/or rotating the fluid-agitating element, is disclosed. The vessel comprises a bag capable of receiving and holding the fluid. The bag includes a first inwardly-projecting post for receiving and holding the fluid-agitating element at a home location when positioned in the bag and a receiver adapted for receiving at least a portion of the external structure and aligning the fluid-agitating element relative thereto. In one embodiment, the body comprises a flexible portion and a rigid portion in which the first post and the receiver are formed. The receiver may take the form of a second outwardly projecting post, with the first and second posts being coaxial. Alternatively, the receiver may be defined by a rigid, cap-shaped portion having a cavity and a peripheral flange connected to the flexible portion, with the cavity facing an interior of the body for receiving the fluid-agitating element when positioned therein. The first inwardly directed post may be positioned at least partially in the cavity of the receiver or may include a bearing for directly supporting the fluid-agitating element. In accordance with a third aspect of the invention, the combination of a vessel and a fluid-agitating element is disclosed. The vessel comprises a flexible portion and a rigid portion including a receiver for receiving and holding a fluid-agitating element at a home location or expected position within the vessel. The combination may further include a motive device for at least rotating the fluid-agitating element in the vessel. The fluid-agitating element used in the combination may be at least partially magnetic and may also include at least one blade or vane. The vessel may be at least initially hermetically sealed with the fluid-agitating element positioned therein. In accordance with a fourth aspect of the invention, the combination of a vessel and a fluid-agitating element is disclosed, with the vessel comprising a first receiver for receiving the fluid-agitating element. The first receiver includes an oversized portion for capturing the fluid-agitating element on the receiver, but the fluid-agitating element is free of direct attachment to the receiver. The vessel may further include a second receiver for receiving a portion of an external structure to assist in aligning the fluid-agitating element relative thereto. The first receiver is preferably a post and the oversized portion is a head end of the post that is T-shaped. In accordance with a fifth aspect of the invention, a vessel for receiving a fluid and a fluid-agitating element, such as an impeller, is disclosed. The vessel comprises a bag capable of receiving and holding the fluid and a rigid receiver connected to the bag. The receiver receives and holds the fluid-agitating element at a home location when positioned in the bag. In one embodiment, the rigid receiver is cap-shaped and includes a peripheral flange connected to the bag to form a seal. Alternatively, the rigid receiver is positioned in contact with an interior surface of the bag. Still another alternative is to position the rigid receiver in contact with an exterior surface of the bag. In accordance with a sixth aspect of the invention, a system for agitating a fluid is disclosed. The system comprises a fluid-agitating element and a vessel for receiving the fluid, the vessel including a flexible portion and a rigid portion. The rigid portion includes a receiver for receiving and holding the fluid-agitating element at a home location in the vessel. A motive device for at least rotating the fluid-agitating element may also form part of the system. In one embodiment, the motive device also levitates the fluid-agitating element in the vessel. The fluid-agitating element is at least partially magnetic or ferromagnetic and the motive device includes a rotating drive magnet structure for forming a magnetic coupling with the fluid-agitating element, an electromagnetic structure for rotating and levitating the fluid-agitating element, or a superconducting element for both levitating and rotating the fluid-agitating element. In accordance with a seventh aspect of the invention, a method of positioning a fluid-agitating element in a bag intended for receiving a fluid in need of agitation is disclosed. The method comprises the step of providing the bag with a rigid portion including a receiver for receiving and holding the fluid-agitating element at a home location when positioned in the bag. Preferably, the receiver includes a post projecting toward an interior of the bag, the fluid-agitating element includes an opening, and the providing step comprises inserting the post through the opening. Alternatively, the receiver may include a peripheral sidewall and a cavity facing an interior of the bag, in which case the providing step comprises positioning the fluid-agitating element in the cavity. Still another alternative is for the receiver to include a peripheral sidewall and a cavity facing an exterior of the bag, in which case the fluid agitating element includes an opening or recess and the providing step comprises positioning the peripheral sidewall of the receiver in the opening or recess. In accordance with a seventh aspect of the invention, a method of agitating a fluid is disclosed. The method comprises providing a bag with a receiver for receiving and holding a fluid-agitating element at a home location within the bag, placing a fluid in the bag, and rotating the fluid-agitating element. In one embodiment, the bag comprises a flexible portion and a rigid portion including the receiver, and the providing step includes connecting the rigid portion to the flexible portion. The step of placing a fluid in the bag is completed after the fluid-agitating element is received in the receiver. The fluid-agitating element may be at least partially magnetic or ferromagnetic, and the step of rotating may include forming a non-contact coupling with a motive device external to the bag. The providing step may include providing a bearing on the receiver for directly engaging and supporting the fluid-agitating element. The method may further include the steps of folding the bag for storage or shipping with the fluid-agitating element in the receiver and unfolding the bag before the placing step, or hermetically sealing the bag after the providing step. The placing step may also comprise introducing the fluid through a sterile fitting provided in the bag.

20040401

20090127

20050106

92575.0

SOOHOO, TONY GLEN

MIXING BAG OR VESSEL HAVING A RECEIVER FOR A FLUID-AGITATING ELEMENT

UNDISCOUNTED

ACCEPTED

ACCEPTED

Dispersant compositions

Dispersant compositions are described which contain: (a) a carrier medium comprising glycerol carbonate, the carrier medium present in an amount of from 10 to 80% by weight based on the composition; and (b) one or more polyester dispersants present in an amount of from 20 to 90% by weight based on the composition.

1-4. (Canceled) 5. A dispersant composition comprising: (a) a carrier medium comprising glycerol carbonate, the carrier medium present in an amount of from 10 to 80% by weight based on the composition; and (b) one or more polyester dispersants present in an amount of from 20 to 90% by weight based on the composition. 6. The dispersant composition according to claim 5, wherein the one or more polyester dispersants comprises a carboxyl-containing polyester, wherein at least 5% by weight of the carboxyl-containing polyester is water-soluble in the neutralized state, and wherein at least 20% by weight of the carboxyl-containing polyester is soluble in glycerol carbonate in the acidic state. 7. The dispersant composition according to claim 5, wherein the one or more polyester dispersants comprises a polyester having ethylene oxide oligomer structural elements. 8. The dispersant composition according to claim 6, wherein the carboxyl-containing polyester further comprises ethylene oxide oligomer structural elements. 9. The dispersant composition according to claim 5, wherein the composition is substantially free from VOC's. 10. The dispersant composition according to claim 6, wherein the composition is substantially free from VOC's. 11. The dispersant composition according to claim 7, wherein the composition is substantially free from VOC's. 12. The dispersant composition according to claim 8, wherein the composition is substantially free from VOC's. 13. The dispersant composition according to claim 5, wherein the composition is liquid and pourable at 25° C. 14. The dispersant composition according to claim 6, wherein the composition is liquid and pourable at 25° C. 15. The dispersant composition according to claim 7, wherein the composition is liquid and pourable at 25° C. 16. The dispersant composition according to claim 8, wherein the composition is liquid and pourable at 25° C. 17. The dispersant composition according to claim 9, wherein the composition is liquid and pourable at 25° C. 18. The dispersant composition according to claim 12, wherein the composition is liquid and pourable at 25° C. 19. A dispersant composition comprising: (a) a carrier medium comprising glycerol carbonate, the carrier medium present in an amount of from 10 to 80% by weight based on the composition; and (b) one or more polyester dispersants present in an amount of from 20 to 90% by weight based on the composition, wherein the one or more polyester dispersants comprises a carboxyl-containing polyester, wherein at least 5% by weight of the carboxyl-containing polyester is water-soluble in the neutralized state, and wherein at least 20% by weight of the carboxyl-containing polyester is soluble in glycerol carbonate in the acidic state; wherein the composition is liquid and pourable at 25° C, and wherein the composition is substantially free from VOC's. 20. The dispersant composition according to claim 19, wherein the one or more polyester dispersants comprises a polyester having ethylene oxide oligomer structural elements. 21. The dispersant composition according to claim 19, wherein the carboxyl-containing polyester further comprises ethylene oxide oligomer structural elements. 22. A paint formulation comprising a dispersant composition according to claim 5. 23. A paint formulation comprising a dispersant composition according to claim 19.

FIELD OF THE INVENTION This invention relates to dispersant compositions for paint formulations, these dispersant compositions being liquid and pourable at 25° C. and being based on a special carrier medium and a polyester-based dispersant. PRIOR ART Dispersants are used in paint manufacture largely for the following reasons: a) to disperse the film former, b) to disperse pigments and fillers and c) to disperse other additives which may be present in paint formulations, for example hardening accelerators, thickeners, flow controllers, flatting agents, preservatives. As the expert is aware, paint manufacturers generally seek to have the components used for the production of paint formulations available in a form which allows for easy handling. A major advantage in this regard is if a component is present in liquid rather than solid form and can be poured at room temperature (room temperature in the context of the present invention is understood to be a temperature of 25° C. This is routinely achieved by the use of solvents. In principle, suitable solvents are on the one hand water and, on the other hand, organic solvents. However, there are instances where, on the one hand, water is not suitable because it is unable satisfactorily to dissolve the dispersant or because the dispersant is not permanently stable in water and where, on the other hand, organic solvents are not suitable. The latter point is of increasing importance because organic solvents have become increasingly unattractive for environmental reasons so that substantial freedom from VOCs (volatile organic compounds) is desirable. Accordingly, there is a constant demand for dispersants to be presented in a form which is not attended by any of the above-mentioned disadvantages. DESCRIPTION OF THE INVENTION The problem addressed by the present invention was to provide dispersant compositions which would consist of a carrier medium and one or more dispersants and which would satisfy the following conditions: the compositions would be liquid at 25° C., homogeneous, concentrated, pourable, stable in storage and substantially free from VOCs. By “homogeneous” is meant that the dispersant is homogeneously dispersed in the carrier medium. By “concentrated” is meant that the composition contains at least 20% by weight of the dispersant, based on the composition as a whole. “Pourable” means that the Brookfield viscosity of the composition, as measured at 25° C./25 r.p.m., is below 50,000 mPas. “Stable in storage” is understood to mean that, even in the event of prolonged storage, the composition remains stable both chemically (no decomposition of the components) and in regard to consistency (no loss of homogeneity). “Substantially free from VOCs” is understood to mean that the composition contains hardly any volatile substances. This means in particular that the carrier medium of the composition is of low volatility. In addition, the composition of the carrier medium should be such that no adverse interactions occur when the combination of carrier medium and dispersant is used for the production of a paint formulation where it inevitably comes into contact with film formers, pigments, fillers and/or paint additives. The present invention relates to dispersant compositions for paint formulations which are liquid and pourable at 25° C. and which consist of a) 10 to 80% by weight of a carrier medium in the form of glycerol carbonate and b) 20 to 90% by weight of one or more polyester-based dispersants for paint formulations. It has surprisingly been found that the compositions according to the invention solve the problem stated above excellently in every respect. The compositions are liquid, homogeneous, pourable and stable in storage. They are also distinguished by substantial freedom from VOCs. The VOC content of a composition can be determined by methods known to the relevant expert. In the context of the present invention, substantial freedom from VOCs is understood to mean a VOC value of less than 0.5% and preferably less than 0.2%, based on the composition as a whole. In the context of the present invention, the VOC content of a sample is determined in accordance with DIN 75201 (“Determination of the Fogging Behavior of Materials Used for the Interior Trim of Motor Vehicles”) using the following procedure: the sample is placed on the bottom of a lip-free glass beaker with fixed graduations. The beaker is covered with an aluminium foil on which volatile constituents from the test specimen or the sample are able to condense. The aluminium foil is cooled. The beaker thus prepared is placed for 16 hours in a bath thermostat set to a test temperature of 100±0.3° C. The effect of the fogging deposit on the aluminium foil is quantitatively determined by weighing the foil before and after the fogging test. The VOC value is calculated in accordance with the following equation: VOC value (%)=(A/B)*100 where A is the weight of the fogging deposit (in g) and B is the weight of the sample used (in g). In addition, the compositions according to the invention are compatible with film formers, pigments, fillers and paint additives which are normally used in the production of paint formulations. The carrier medium a) is glycerol carbonate of which the rational name is 4-hydroxymethyl-1,3-dioxolan-2-one. The compound carries the Chemical Abstracts Registry Number (CAS Registry Number) 931-40-8 and is characterized by formula (I) below: The dispersant b) is a polyester. Particularly preferred polyesters are carboxyl-containing polyesters of which at least 5% by weight is water-soluble in the neutralized or partly neutralized state and of which at least 20% by weight is soluble in glycerol carbonate in the acidic state. The dispersants suitable for the purposes of the invention may be used individually or in admixture with one another. Suitable polyesters are in particular those which, besides hydrophobic chains and carboxyl groups, also contain ethylene oxide oligomers as structural elements. The present invention also relates to the use of the above-described dispersant compositions in the production of paint formulations. EXAMPLES Substances Used Hydropalat 3275: pigment dispersant for water-based paint systems (37.5% aqueous solution of a polyester neutralized with dimethyl ethanolamine; a product of Cognis Deutschland GmbH). Dispersant Compositions Example 1 100 g Hydropalat 3275 were freed from water and diethanolamine in a rotary evaporator at 80° C./20 mbar. 38 g of a viscous wax solid at room temperature were obtained. The wax was melted with the same quantity of glycerol carbonate in a water bath at 70° C. and homogenized by stirring. A solution liquid at room temperature with a Brookfield viscosity of 19 Pas (as measured at 20 r.p.m., 25° C., spindle 5) was obtained. The mixture was stored for three months at room temperature and was found to be stable in storage.

<SOH> FIELD OF THE INVENTION <EOH>This invention relates to dispersant compositions for paint formulations, these dispersant compositions being liquid and pourable at 25° C. and being based on a special carrier medium and a polyester-based dispersant.

20040406

20070508

20050106

75327.0

CAIN, EDWARD J

DISPERSANT COMPOSITIONS CONTAINING GLYCEROL CARBONATE AND POLYESTER-BASED DISPERSANTS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for establishing a foundation in particular for a tower of a wind energy plant

The invention relates to a method for building a foundation for a structure comprising a plurality of segments, in particular for a wind turbine tower, a foundation segment for use in such method, and a wind turbine. In order to create a stable foundation, a method comprising the following steps is proposed on the basis of experience gained:_excavating a foundation bed,_building a stable, substantially level and horizontal subbase in a foundation bed, setting down a foundation segment of the structure on the subbase, wherein at least three vertically adjustable support poles are fixedly attached to said foundation segment by means of a supporting bracket mounted at the end of the support poles in such a way that only the support poles are placed onto predetermined points of support on the subbase,_producing a reinforcement on the subbase,_filling the remainder of the foundation bed with foundation mass, in particular concrete, to a level above the bottom rim of the foundation segment.

1. A method for building a foundation for a structure comprising a plurality of segments, in particular for a tower of a wind turbine, with the following steps: a) excavating a foundation bed, b) building a stable, substantially level and horizontal subbase (in a foundation bed, c) setting down a foundation segment of the structure on the subbase, wherein at least three vertically adjustable support poles are fixedly attached to said foundation segment by means of a supporting bracket mounted at the end of the support poles in such a way that only the support poles are set down onto predetermined points of support on the subbase, d) producing a reinforcement on the subbase, e) casting the remainder of the foundation bed with foundation mass, in particular concrete, to a level above the bottom rim of the foundation segment. 2. The method according to claim 1, characterized in that the support poles are each attached by means of support plates to a flange on the underside of the foundation segment. 3. The method according to claim 1, characterized in that the support poles, each having an internal threaded pole, are vertically adjusted by means of a vertical adjustment device disposed at the lower end of the support poles facing the subbase. 4. The method according to claim 1, characterized in that the support poles are each mounted on a flange at the upper rim of the foundation segment. 5. The method according to claim 4, characterized in that the support poles are passed through eyes on the lower rim of the foundation segment and extend into the foundation segment. 6. The method according to claim 1, characterized in that the remaining foundation bed is filled with foundation mass by firstly casting in foundation mass until approximately the lower rim of the foundation segment is reached, after which any vertical alignment of the foundation segment is performed and that the remaining foundation bed is subsequently filled with foundation mass. 7. The method according to claim 1, characterized in that the points of support on the subbase are mechanically reinforced. 8. The method according to claim 1, characterized in that reinforcement is braided through the holes provided in the side walls of the foundation segment, and that the remainder of the foundation bed is filled mit foundation mass to such a height that the holes are covered over by foundation mass. 9. The method according to claim 1, characterized in that the currently adjusted height of the separate supporting brackets is measured by suitable measurement means, in particular optical measurement means, in order to adjust the height of said supporting brackets. 10. The method according to claim 9, characterized in that, for the purpose of adjusting the height of the supporting brackets a height measurement signal, in particular a bundled light beam is transmitted in a horizontal direction from a transmitter disposed inside the foundation segment, in particular from a light source, to the supporting brackets fitted with a corresponding sensor, in particular an optical sensor, that a sensor signal is generated by the sensors, each signal containing information about the adjusted height of the respective supporting bracket, and that the associated supporting bracket is vertically adjusted in response to the sensor signal generated. 11. The method according to claim 10, characterized in that the supporting brackets are vertically adjusted by means of a controlled drive means, wherein the sensor signals generated by the sensors analyzed in order to control said drive means. 12. A support pole, in particular for use in the method according to claim 1,_characterized by an outer pipe, a threaded pole disposed therein and a supporting bracket, in particular in the form of a support plate, at one end of said outer pipe. 13. The support pole according to claim 12,_characterized by a nut screwed onto the end of the threaded pole facing away from the supporting bracket and supporting itself against the outer pipe. 14. A support pole, in particular for use in the method according to claim 1,_characterized by an outer pipe and a supporting bracket at one end of the support pole, wherein the supporting bracket has a pole displaceable inside the outer pipe, a first plate mounted on the outer pipe and a second plate mounted on the pole, said plates being connected by means of at least one threaded pole for changing the gap between the two plates, and wherein the second plate is configured for fixed attachment to an element to be supported. 15. The support pole according to claim 12, characterized by a base plate at the opposite end support pole from the supporting bracket. 16. The support pole according to claim 12,_characterized by drive means, in particular hydraulic or pneumatic drive means, for vertical adjustment of the supporting brackets. 17. The support pole according to claim 12,_characterized by a sensor*, in particular an optical sensor, disposed on the supporting bracket for receiving a signal from the sensor and for generating a sensor signal containing information about the adjusted height of the supporting bracket. 18. The support pole according to claim 17,_characterized in that the sensor has a plurality of sensor elements arranged along the longitudinal direction of the support pole. 19. A foundation segment for a structure comprising a plurality of segments, in particular for a wind turbine tower, characterized in that least three vertically adjustable support poles are fixedly attached to the foundation segment by means of a support plate mounted at the end of the support poles for setting the foundation segment down on supporting points of a subbase in a foundation bed. 20. The foundation segment according to claim 19,_characterized in that holes are provided in the side walls of the foundation segment, in particular a circumferential row of holes, through which reinforcement steel is passed in order to establish a mechanical connection between the reinforcement and the foundation segment. 21. A wind turbine with a tower comprised of a plurality of segments, wherein the lowermost segment is a foundation segment according to claim 19. 22. The wind turbine with a tower comprising a plurality of segments, wherein the foundation of the tower is manufactured in accordance with claim 1.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to a method for building a foundation for a structure comprising a plurality of segments, in particular for a wind turbine tower. The invention also relates to a support pole, a foundation segment for such a structure and a wind turbine. 2. Description of the Related Art Constructing a permanently stable and level foundation is of enormous importance for larger structures. Particularly in the case of a wind turbine tower, which can be more than 100 m in height and be exposed in operation to enormous forces, the foundation must conform to exacting specifications. Wind turbine foundations are currently constructed by firstly making a so-called subbase in a foundation bed, in other words a cement or concrete base layer that is as level and horizontal as possible. Support poles for setting down the foundation segment on the subbase are then mounted on the foundation segment, i.e., the lowermost segment of a tower comprised of several segments. In order to compensate for any unevenness in the subbase and to align the foundation segment as horizontally as possible, the support poles can be screwed varying depths into the underside of the foundation segment, the support poles being configured for this purpose as threaded poles in at least the upper section facing the underside of the foundation segment. There have been cases in which support poles have either penetrated into the subbase or broken off from the underside of the foundation segment as a result of the enormous lateral loads exerted on the support poles by the foundation segment, which can currently weigh between 10 and 14 metric tonnes. This has resulted in the foundation segment overturning. In addition to the dangers to which persons engaged in constructing the foundation were exposed, this has led not only to delays but also to additional costs for remedying the damage caused. BRIEF SUMMARY OF THE INVENTION One object of the invention is therefore to provide a method for building a foundation for a structure comprising a plurality of segments, in particular, for a wind turbine tower; an improved support pole; a suitable foundation segment and a wind turbine in which the aforementioned problems are avoided. This object is accomplished pursuant to the invention by a method according to claim 1, said method comprising the following steps: a) excavating a foundation bed, b) building a stable, substantially level and horizontal subbase in a foundation bed, c) setting down a foundation segment of the structure onto the subbase, wherein at least three vertically adjustable support poles are fixedly attached to said foundation segment by means of a supporting bracket mounted at the end of the support poles in such a way that only the support poles are placed onto predetermined points of support on the subbase, d) producing a reinforcement on the subbase, e) filling the remainder of the foundation bed with foundation mass, in particular concrete, to a level above the bottom rim of the foundation segment. The invention is based on the realization that the problems occurring with methods to date can be avoided if the support poles are not screwed directly into the underside of the foundation segment, but instead are fixedly attached to distributed points on the foundation segment by means of supporting brackets, e.g., in the form of a support plate, before the foundation segment is set down on the subbase. The vertical adjustment means are still provided on the support poles, but elsewhere than hitherto, and the height of the segment is adjusted by screwing the support poles by different amounts into the underside of the foundation segment. The supporting brackets provide the foundation segment with a significantly larger supporting surface on the support poles, and hence a significantly improved distribution of load. This means that buckling of a threaded pole at the underside of the foundation segment will no longer occur. In order to prevent the support pole from penetrating the subbase, the invention also provides for reinforcement of those points where the support poles bearing the foundation segment are set down on the subbase. These points may be reinforced over a larger area by installing (additional) reinforcement mats and/or by providing local reinforcement, for example by making the subbase higher at predefined positions. An alternative or additional means is to use base plates. These can be laid at predefined positions on the subbase so that the support poles can be set down on them, or they are mounted on the support pole at the opposite end from the supporting bracket. After the foundation segment with the support poles has been set down on these points of support or base plates and been vertically adjusted to compensate for differences in height, the rest of the foundation bed is filled with foundation mass, for example with concrete, in one or more filling steps, the foundation mass being poured in until it reaches a level that is above the lower rim of the foundation segment, thus achieving a stable foundation. Owing to this stable support for the foundation segment, problems that are known to occur during this final casting process when prior art methods are used, particularly changes in the position of the foundation segment when it is being filled with foundation mass, no longer occur. In one preferred configuration, the support poles are each attached by means of support plates to a flange mounted on the underside of the foundation. The support plates are preferably bolted to the flange. This enables particularly good positioning and support of the foundation segment on the support poles to be achieved. In an alternative configuration, the support poles are each attached to a flange around the upper rim of the foundation segment. To this end, it is preferred that the supporting bracket at the upper end of the support pole be configured in such a way that it can be firmly attached to the flange, for example by bolting together the flange and the bracket. To ensure that the foundation segment is securely supported, it is also preferred in such a configuration that the support poles pass through eyes attached to the lower rim of the foundation segment and extend inside the foundation segment. In the final step of the method, the foundation bed can be filled with foundation mass in a single casting. In a preferred version, particularly when the support poles are configured as just described, the rest of the foundation bed can also be filled in two steps. In a first step, the foundation bed is filled with foundation mass to a level approximately equal to that of the lower rim of the foundation segment. Any vertical alignment of the foundation segment that is necessary can then be carried out in order to compensate for any shifts in the position of the foundation segment during the first casting step, and a position achieved that is as horizontal as possible. To this end, the support poles have the vertical adjustment means in a section that of course has not yet been filled with foundation mass at this time. Finally, once the foundation segment has been vertically aligned, the rest of the foundation bed can then be filled until the desired level of foundation mass is reached. In another configuration according to the invention, the rest of the foundation bed is filled with foundation mass to such a height that holes provided in the side walls of the foundation segment are covered, the foundation mass being poured into the hollow interior of the foundation segment as well. In a preferred embodiment, a row of holes is provided around the circumference of the foundation segment and equidistant from the underside of the foundation segment. Reinforcement wires are braided through said holes to form a mechanical connection between the foundation and the foundation section. In other words, the foundation mass is poured into the foundation bed not only in the area around the foundation segment, but also into the interior of the hollow foundation segment, in order that said foundation segment is not exposed to lateral forces resulting from the foundation mass being poured into the outer area, which could lead in turn to the foundation segment changing its position when the foundation mass is being poured. Due to the fact that foundation mass is also poured into the interior of the foundation segment, the latter is stabilized in its position and cannot be tilted or changed in its position by foundation mass poured into the outer area. It is preferred that the vertical adjustment for the support poles be provided on the lower end of the support poles facing the subbase. This could be accomplished with an adjuster nut, for example. Preferably, the support pole itself has an internal threaded rod for performing such vertical adjustment. In one advantageous configuration of the method according to the invention, there is a means for measuring the current vertical adjustment of the separate supporting brackets. This is preferably achieved with optical measurement means, such as a measurement means that transmits a focused laser beam in a horizontal direction, with matching sensors mounted on the supporting brackets. Said sensors generate a sensor signal containing information about the current height of the supporting bracket, thus permitting vertical adjustment so that the foundation segment is horizontally aligned. Furthermore, controlled drive means for vertical adjustment of the supporting brackets can also be provided that automatically adjust the height of the supporting brackets in response to the sensor signals that are detected. Support poles according to the invention and of the kind preferably used in the inventive method are defined in claims 12 to 18. A foundation segment according to the invention and with the described features is defined in claims 19 and 20. The invention also relates to a wind turbine with a tower comprising a plurality of segments, the lowermost segment being a foundation segment of the kind described and the foundation of the tower being made by the method described. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS The invention shall now be explained in greater detail with reference to the drawings. These show: FIG. 1 shows a wind turbine according to the invention, with a tower comprised of a plurality of segments; FIG. 2 shows a first configuration of a foundation segment according to the invention; FIG. 3 shows a section of the inventive foundation segment in FIG. 2, with a support pole; FIG. 4 showsa second configuration of a foundation segment according to the invention; FIG. 5 shows a cross-section of the foundation segment in FIG. 4, with a support pole; FIG. 6 shows a section of the inventive foundation segment in FIG. 5; FIG. 7 shows a further section of the inventive foundation segment in FIG. 5; FIG. 8 shows a supporting bracket of a support pole shown in FIG. 5; FIG. 9 shows a front view of a further configuration of a support pole according to the invention; FIG. 10 shows a side elevation view of the support pole in FIG. 9; FIG. 11 shows a side elevation view of a further configuration of an inventive support pole, with a drive means; FIG. 12 shows a front view of a further configuration of an inventive support pole, with a sensor for vertical adjustment; FIG. 13 shows a plan view of a foundation segment according to the invention, illustrating the generation of sensor signals for vertical adjustment; and FIG. 14 shows a block diagram of a vertical adjustment sensor as provided in one configuration of the support poles. DETAILED DESCRIPTION OF THE INVENTION The wind turbine 1 shown schematically in FIG. 1 has a tower 2 comprising a plurality of segments 3, wherein the lowermost segment 4, the so-called foundation segment, is embedded in a foundation 5. A nacelle 6 is rotatably mounted at the top of the tower 2, and a rotor 7 with a plurality of blades 8 is attached to said nacelle. Disposed inside nacelle 6 is an electrical generator that is made to rotate by the wind forces acting on the rotor blades 8, thus generating electrical energy. The segments 3, including foundation segment 4 of tower 2, are preferably steel elements, but generally can also be prestressed concrete elements into which prestressing steel elements or braces, for example, are cast. Foundation segment 4 is cast into a foundation block 9 that preferably consists of concrete. Said foundation block 9 may extend above the surrounding ground 10 or end level with the ground, but in any case covers the lower rim of the foundation segment 4 as well as the support poles 11 attached to the underside of said foundation segment 4. By means of said support poles 11, the foundation segment is propped on a subbase 12, which is a cement or concrete bed made as level and horizontal as possible and cast in the foundation bed before foundation segment 4 with support poles 11 is erected. FIG. 2 shows the main element of foundation 5 prior to casting of the foundation mass to form foundation block 9. To make the foundation, a foundation bed 13 is excavated from the ground 10. A subbase 12, the upper surface of which should be as level and horizontal as possible, is then made on the floor of the foundation bed. Before foundation segment 4 is placed on subbase 12, three support poles 11 are first attached fixedly to the underside 41 of foundation segment 4. In order to achieve maximum uniformity of load distribution and optimal support of the foundation segment on the support poles 11, said support poles each have a support plate 110 fixedly attached as a support to the upper end facing the underside of foundation segment 4, by means of which the support poles 11 are attached, preferably tightly bolted, to a flange 42 of the foundation segment. Support poles 11 are also uniformly spaced apart or arranged at predefined positions around the circumference of the cylindrical foundation segment 4. Before foundation segment 4 is set down, points of support 14 are marked on subbase 12 and reinforced with base plates in order to prevent the support poles 11 from penetrating the subbase 12. Once foundation segment 4 has been set down on base plates 14, it can be adjusted in height by means of support poles 11 so that foundation segment 4 is as horizontal as possible. For this purpose, support poles 11 have vertical adjustment means 111 that may be configured as an internal threaded rod with an adjuster nut. After foundation segment 4 has been vertically adjusted, it is then reinforced. This is done by braiding reinforcement wires through the holes in the row of holes 43 provided in the side walls of foundation segment 4. In a final step, foundation bed 13 is completely filled with foundation mass, preferably concrete. The foundation mass is poured not only into the outer cavity of foundation segment 4 but also into the interior space 44 of foundation segment 4, to ensure that the position of the foundation segment is not changed, for example as a result of lateral forces exerted externally on the foundation segment by the foundation mass when it is being poured. Owing to the fact that foundation reinforcement wires are fed through the holes in the row of holes 43, tensile forces can also be safely conducted from the tower into the foundation. Once foundation segment 4 has been firmly encast, the remainder of the tower can be assembled. FIG. 3 shows a more detailed section of foundation segment 4 with a support pole 11. It can be seen how support pole 11 is bolted to flange 42 of foundation segment 4 by means of support plate 110 fixedly attached to support pole 11. In at least the lower portion of support pole 11, an internal threaded rod 114 is provided to which an adjuster nut 112 is fitted in order to adjust the height, i.e., to change the length of support pole 11. Adjuster nut 112 supports itself against the outer jacket of support pole 11, thus permitting lengthwise adjustment of the threaded rod 114. The fixed nut 113 enables the threaded pole 114 to be securely held such that it cannot turn at the same time as nut 112 is turned. FIG. 4 shows an alternative configuration of a foundation segment according to the invention, in which other support poles 21 are used. What is shown is again foundation segment 4 supported on three support poles 21. Between the subbase 12 and the support poles 21, support plates 14 for distributing the weight are provided in order to prevent the support poles 21 from penetrating the subbase 12. In this particular configuration, the support poles 21 extend inside the interior 44 of foundation segment 4 as far as its upper rim, as can be clearly seen in FIG. 5. The latter Figure shows a foundation segment 4 with a single support pole 21 in cross-section. The support pole 21 is comprised of several parts and has a supporting bracket 210, a middle section 211 and an end member 212 with a base plate 213. Supporting leg 210 is for attaching support pole 21 to the upper flange 45 of foundation segment 4. The middle section 211 is attached to the supporting bracket 210, on the one hand, and also to end member 212, for example by screwing it into end member 212 by means of a threaded portion in a transition section 214. Transition section 214 is positioned above the row of holes 43 at a height where it is not covered with foundation mass after the foundation bed has been completely filled. Only the end member 212 of each support pole 21 is covered by the foundation mass, whereas the middle section 211 and the supporting bracket 210 can each be re-used. To provide better support for the foundation segment, support pole 21 is passed through an eye 46 attached to the lower flange 42, as can seen in detail in FIG. 6. FIG. 7 shows the upper portion of the support pole, i.e., part of the middle section 211 and the supporting bracket 210. Supporting leg 210 comprises several parts for attaching the support pole 21 to the upper flange 45 of foundation segment 4 and for adjusting or aligning the height of the foundation segment when making the foundation. Plates 22, 23 are located above and below the circumferential flange 45. The lower plate 22 partially conceals a screw 27 that grips through the pattern of holes 47 in the upper flange 45 and attaches the upper plate 23 of the supporting bracket 210 to foundation segment 4. Inside foundation segment 4, there are also two threaded poles 24 running between the two plates 22, 23, said threaded poles permitting the position of the upper plate 23 to be adjusted relative to the rest of supporting bracket 210 by means of nuts 25. A rod 26 attached to the upper plate 23 slides inside the middle section 211, the latter serving as an outer pipe. Since foundation segment 4 is connected to upper plate 23, any change in the position of upper plate 23 also causes the entire foundation segment 4 to move relative to the subbase 12. The upper plate 23 can be adjusted, by raising the foundation segment 4 with suitable lifting equipment, for example, such as a crane. Nuts 25 visible underneath the upper plate 23 (see also FIG. 8) can thus be adjusted until the desired position is reached. After such adjustment, foundation segment 4 can be lowered again until it is located in the desired position. This makes it easy to vertically adjust or align the foundation segment when the foundation is being constructed. Another configuration of a support pole according to the invention is shown in a front view and a side elevation view in FIGS. 9 and 10, respectively. The end member 212, as shown in FIG. 5, is again passed through an eye on the lower rim of the foundation section. What is also unchanged is that said end member is encast inside the foundation and is not used again. The foundation is filled to a height indicated in said Figures by line 217. In order to prevent moisture penetration, caps 215 are provided that can be used, after removing the re-usable part of the support pole from the end member,212, to cover what are then open ends. The upper portion of said support pole is also largely identical to the support pole previously described. There are two plates 22, 23 between which threaded poles 24 with nuts are disposed. In the front view in FIG. 9, two threaded poles 24 with nuts 25 can be seen; in the side elevation view in FIG. 10, these are aligned one behind the other, which is why only one threaded pole 24 with nut 25 can be identified. In FIG. 10, a part of the upper plate 23 is broken open to show a through hole 28. Plate 23 and hence the support pole can be connected to the upper flange of the foundation segment through said through hole 28. To simplify vertical adjustment and further reduce the proportion of manual work, an arrangement comprising a telescopic cylinder 29 and a telescopic pole 26 is provided between the two plates 22, 23. Said cylinder can be operated pneumatically or hydraulically, for example, and thus permit easy adjustment of the foundation section joined to the support pole. In this embodiment, threaded pole 24 and nut 25 serve, on the one hand, to fixate the position that is initially set by hydraulic or pneumatic means, and on the other hand as an “emergency actuation” means for manually adjusting the foundation section in the event that the hydraulic or pneumatic system fails. In FIG. 11, to provide a better overview, only the upper portion of a support pole according to the invention is shown as far as the transition to the end member 212. Said Figure also includes part of foundation section 4. The latter is joined to the upper plate 23. Rod 26 can be in the form of a threaded rod that is rotatably mounted at its lower end and turned by a drive means 216 such that plate 23 can be vertically moved with a matching thread, depending on the direction of rotation. This also changes the vertical position of foundation segment 4 attached to the upper plate. The control systems for drive means such as electric motors, as well as the control systems for the cylinders 26, 29 shown in FIGS. 9 and 10 are well known, so they are not described her in further detail. FIG. 12 shows a further embodiment of a support pole according to the invention that permits the supporting bracket to move automatically into a pre-definable position. The same Figure shows only the upper potion of the support pole according to the invention, again for a better overview. This structure is substantially the same as that of the variant shown in FIGS. 9 and 10. However, a sensor 30 is provided here in addition to the elements shown in FIGS. 9 and 10. Said sensor comprises a plurality of light-sensitive elements 32 arranged in a housing 31, such as phototransistors, photoresistors or the like. Filters may also be provided, or the light-sensitive elements 32 can be configured in such a way that they respond only to a predefined spectral range in order to minimize or completely eliminate the influence of stray light and daylight. Thus, if a light source is provided in a predefined horizontal position, the light from said light source will strike the light-sensitive elements 32 regardless of the alignment of said light source, on the one hand, and the adjusted position of the supporting bracket, on the other hand. If said light is now sufficiently focused, only some of the light-sensitive elements 32 are struck by the light. This makes it possible to derive the vertically adjusted position of the respective supporting bracket relative to the light source. Thus, if sensor 30 is in a clearly defined position and the light source is also in a clearly defined position, it is possible to derive a correcting variable, for example from the deviation of the incident beam of light from a from a predefined position in sensor 30, e.g., its centre, that can be used to change the vertical adjustment of the supporting bracket. In this way, it is possible for the foundation section to be automatically adjusted. An example of this arrangement is shown in FIG. 13. The latter shows a plan view of a foundation section 4, on the inner side of which three support poles according to the invention are arranged at 120° to each other. The important aspect of this arrangement is that the alignment of this foundation section is oriented to the upper flange, because said flange must be exactly horizontal in its alignment, whereas the alignment of the lower flange of the foundation section is irrelevant for easily understandable reasons. A light source 35 is installed in the centre of foundation section 4, for example on a tripod 36, and aligned so that it is perfectly horizontal. Said light source 35 can transmit a laser beam 37, for example, the light from which is still sufficiently bundled, even at a considerable distance, and which moves in a 360° circle inside the foundation, section. Each of the three supporting brackets is shown with its upper plate 23, which is fixedly attached to the foundation section 4. Also shown are the threaded rods 24, the drive means 216 and the sensor 30. If laser beam 37 now rotates with perfect horizontal alignment, a signal is generated at each sensor 30, said signal providing an indication as to whether the supporting bracket at that point is in the desired position, or must be adjusted by actuating the drive means 216, or manually adjusted. In practice, vertical adjustment of the supporting brackets is preferably performed in such a way that one of the supporting brackets is first brought into a predefined position, that this supporting bracket is then left unchanged, and the alignment of foundation section 4 is then performed on the two other supporting brackets. Sensor 30 can, of course, exercise a direct influence on drive means 216 with its output signal. On the other hand, a centralized control system can be provided that analyses the sensor signal and outputs corresponding signals for actuating the associated drive means 216. FIG. 14 shows, in simplified form, an example of a sensor 30. In said sensor 30, light-sensitive sensor elements 32 are arranged beside and/or above each other. By way of illustration, these sensor elements are shown here as phototransistors. The external circuitry of the transistors has been left out for the sake of a better overview, but are common knowledge to the person skilled in the art. The collectors of these phototransistors 32 are connected in parallel to the power supply at a connector 51. Depending on the position of the transistor in this sensor, the emitters of the transistors are connected to gates, or form a signal output. The emitters of the upper nine transistors shown in this Figure are connected to the input terminals of an OR-gate 50. The output from this gate 50 is available as an output signal 52. The emitters of the lower nine phototransistors shown in this figure are similarly connected to input terminals of an OR-gate, the output 53 from which is similarly available as an output signal. The output of the middle phototransistor is directly available as output signal 54. All outputs may also be conducted through amplifier stages, of course. If sensor 30 is installed in such a way that the desired horizontal position is reached when the middle transistor is illuminated, it is easy to conclude from this that, whenever light shine on one of the phototransistors above this middle transistor, the sensor and hence the supporting bracket are positioned too low. Gate 50 causes a signal to appear at output 52 that triggers an upward adjustment of the supporting bracket and hence of the sensor. If the light falls on a phototransistor below the middle phototransistor, it can be concluded from this that the supporting bracket must be adjusted to a lower position. As soon as the middle phototransistor output a signal at terminal 54, this can be used as a “Stop” signal for terminating adjustment of the supporting bracket. Since the absolute height, e.g., above mean sea level, is not strictly defined for the upper flange of the foundation section, there is an alternative procedure for aligning the foundation section that can also be considered. In this procedure, one of the supporting brackets is first set to a desired height. The rotating beam of light will therefore strike one of the light-sensitive elements 32. This sensor outputs a sensor signal that permits the light-sensitive element 32 struck by the rotating light beam to be inferred, and that therefore represents the adjusted height of the supporting bracket. Such a signal can be an analog signal, or a digital signal, e.g., a binary-coded signal. This signal can be fed to a central controller, for example. When the two supporting brackets still to be adjusted are moved until each of the assigned sensors outputs the same signal to the central controller, i.e., until the same sensor element is struck by the light beam, the foundation section has again been horizontally aligned. Other configurations of the sensors and a different way of adjusting the supporting brackets are also possible, of course. For example, one configuration provides for a reflecting element that reflects an incident beam of light to be disposed at the same vertical position on each supporting bracket. Not only the light source but also a matching receiver is then disposed at the centre of the foundation section. Only when the light beam hits the reflector element is a reflected beam of light received by the receiver, thus signaling the correct vertical position. All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. The invention is not limited to use in wind turbines, but can essentially be applied in any kind of structure comprising at least two segments in order to make a stable foundation. The number, arrangement and specific configuration of the elements shown in the Figures, in particular the support poles, can be varied. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention relates to a method for building a foundation for a structure comprising a plurality of segments, in particular for a wind turbine tower. The invention also relates to a support pole, a foundation segment for such a structure and a wind turbine. 2. Description of the Related Art Constructing a permanently stable and level foundation is of enormous importance for larger structures. Particularly in the case of a wind turbine tower, which can be more than 100 m in height and be exposed in operation to enormous forces, the foundation must conform to exacting specifications. Wind turbine foundations are currently constructed by firstly making a so-called subbase in a foundation bed, in other words a cement or concrete base layer that is as level and horizontal as possible. Support poles for setting down the foundation segment on the subbase are then mounted on the foundation segment, i.e., the lowermost segment of a tower comprised of several segments. In order to compensate for any unevenness in the subbase and to align the foundation segment as horizontally as possible, the support poles can be screwed varying depths into the underside of the foundation segment, the support poles being configured for this purpose as threaded poles in at least the upper section facing the underside of the foundation segment. There have been cases in which support poles have either penetrated into the subbase or broken off from the underside of the foundation segment as a result of the enormous lateral loads exerted on the support poles by the foundation segment, which can currently weigh between 10 and 14 metric tonnes. This has resulted in the foundation segment overturning. In addition to the dangers to which persons engaged in constructing the foundation were exposed, this has led not only to delays but also to additional costs for remedying the damage caused.

<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>One object of the invention is therefore to provide a method for building a foundation for a structure comprising a plurality of segments, in particular, for a wind turbine tower; an improved support pole; a suitable foundation segment and a wind turbine in which the aforementioned problems are avoided. This object is accomplished pursuant to the invention by a method according to claim 1 , said method comprising the following steps: a) excavating a foundation bed, b) building a stable, substantially level and horizontal subbase in a foundation bed, c) setting down a foundation segment of the structure onto the subbase, wherein at least three vertically adjustable support poles are fixedly attached to said foundation segment by means of a supporting bracket mounted at the end of the support poles in such a way that only the support poles are placed onto predetermined points of support on the subbase, d) producing a reinforcement on the subbase, e) filling the remainder of the foundation bed with foundation mass, in particular concrete, to a level above the bottom rim of the foundation segment. The invention is based on the realization that the problems occurring with methods to date can be avoided if the support poles are not screwed directly into the underside of the foundation segment, but instead are fixedly attached to distributed points on the foundation segment by means of supporting brackets, e.g., in the form of a support plate, before the foundation segment is set down on the subbase. The vertical adjustment means are still provided on the support poles, but elsewhere than hitherto, and the height of the segment is adjusted by screwing the support poles by different amounts into the underside of the foundation segment. The supporting brackets provide the foundation segment with a significantly larger supporting surface on the support poles, and hence a significantly improved distribution of load. This means that buckling of a threaded pole at the underside of the foundation segment will no longer occur. In order to prevent the support pole from penetrating the subbase, the invention also provides for reinforcement of those points where the support poles bearing the foundation segment are set down on the subbase. These points may be reinforced over a larger area by installing (additional) reinforcement mats and/or by providing local reinforcement, for example by making the subbase higher at predefined positions. An alternative or additional means is to use base plates. These can be laid at predefined positions on the subbase so that the support poles can be set down on them, or they are mounted on the support pole at the opposite end from the supporting bracket. After the foundation segment with the support poles has been set down on these points of support or base plates and been vertically adjusted to compensate for differences in height, the rest of the foundation bed is filled with foundation mass, for example with concrete, in one or more filling steps, the foundation mass being poured in until it reaches a level that is above the lower rim of the foundation segment, thus achieving a stable foundation. Owing to this stable support for the foundation segment, problems that are known to occur during this final casting process when prior art methods are used, particularly changes in the position of the foundation segment when it is being filled with foundation mass, no longer occur. In one preferred configuration, the support poles are each attached by means of support plates to a flange mounted on the underside of the foundation. The support plates are preferably bolted to the flange. This enables particularly good positioning and support of the foundation segment on the support poles to be achieved. In an alternative configuration, the support poles are each attached to a flange around the upper rim of the foundation segment. To this end, it is preferred that the supporting bracket at the upper end of the support pole be configured in such a way that it can be firmly attached to the flange, for example by bolting together the flange and the bracket. To ensure that the foundation segment is securely supported, it is also preferred in such a configuration that the support poles pass through eyes attached to the lower rim of the foundation segment and extend inside the foundation segment. In the final step of the method, the foundation bed can be filled with foundation mass in a single casting. In a preferred version, particularly when the support poles are configured as just described, the rest of the foundation bed can also be filled in two steps. In a first step, the foundation bed is filled with foundation mass to a level approximately equal to that of the lower rim of the foundation segment. Any vertical alignment of the foundation segment that is necessary can then be carried out in order to compensate for any shifts in the position of the foundation segment during the first casting step, and a position achieved that is as horizontal as possible. To this end, the support poles have the vertical adjustment means in a section that of course has not yet been filled with foundation mass at this time. Finally, once the foundation segment has been vertically aligned, the rest of the foundation bed can then be filled until the desired level of foundation mass is reached. In another configuration according to the invention, the rest of the foundation bed is filled with foundation mass to such a height that holes provided in the side walls of the foundation segment are covered, the foundation mass being poured into the hollow interior of the foundation segment as well. In a preferred embodiment, a row of holes is provided around the circumference of the foundation segment and equidistant from the underside of the foundation segment. Reinforcement wires are braided through said holes to form a mechanical connection between the foundation and the foundation section. In other words, the foundation mass is poured into the foundation bed not only in the area around the foundation segment, but also into the interior of the hollow foundation segment, in order that said foundation segment is not exposed to lateral forces resulting from the foundation mass being poured into the outer area, which could lead in turn to the foundation segment changing its position when the foundation mass is being poured. Due to the fact that foundation mass is also poured into the interior of the foundation segment, the latter is stabilized in its position and cannot be tilted or changed in its position by foundation mass poured into the outer area. It is preferred that the vertical adjustment for the support poles be provided on the lower end of the support poles facing the subbase. This could be accomplished with an adjuster nut, for example. Preferably, the support pole itself has an internal threaded rod for performing such vertical adjustment. In one advantageous configuration of the method according to the invention, there is a means for measuring the current vertical adjustment of the separate supporting brackets. This is preferably achieved with optical measurement means, such as a measurement means that transmits a focused laser beam in a horizontal direction, with matching sensors mounted on the supporting brackets. Said sensors generate a sensor signal containing information about the current height of the supporting bracket, thus permitting vertical adjustment so that the foundation segment is horizontally aligned. Furthermore, controlled drive means for vertical adjustment of the supporting brackets can also be provided that automatically adjust the height of the supporting brackets in response to the sensor signals that are detected. Support poles according to the invention and of the kind preferably used in the inventive method are defined in claims 12 to 18 . A foundation segment according to the invention and with the described features is defined in claims 19 and 20 . The invention also relates to a wind turbine with a tower comprising a plurality of segments, the lowermost segment being a foundation segment of the kind described and the foundation of the tower being made by the method described.

20041018

20091110

20050407

94463.0

HERRING, BRENT W

METHOD FOR BUILDING A FOUNDATION, IN PARTICULAR A FOUNDATION FOR A WIND TURBINE TOWER

UNDISCOUNTED

ACCEPTED

ACCEPTED

Object distribution

A method of locating objects in a distributed electronic environment comprising defining a plurality of object-types, which object-types are assigned a plurality of attributes, one attribute being an object-precedence attribute. A plurality of home locations for objects are defined. When a new object is instantiated, which object has associations with other objects, the new object is located at the home location of the existing object which has the highest precedence value of all the associated objects.

1. A method of locating objects in distributed electronic environment comprising defining a plurality of object-types, which object-types are assigned a plurality of attributes, characterized in that one attribute is an object-precedence attribute, where in a plurality of home locations for objects are defined, and in that when a new object is instantiated, which object has associations with other object, the new object is located at the home location of the existing object which has the highest precedence value of all the associated objects. 2. A method according to claim 1, wherein the value of the object-type-precedence is unique for each object type. 3. A device according to claim 1, wherein the precedence value is determined such that objects having a relationship with other objects are located in proximity to one another.

The invention relates to a method of locating objects in a distributed electronic system. In certain distributed systems, in which system components may also be geographically distributed, the problem of deciding where to locate, or home, objects within the system arises. These objects may have geographic dependencies themselves, as may further objects which relate to the first set. Generally the problem of identifying where an object should be homed and what the optimum configuration with respect to network and processor efficiency is a challenging one. This problem is further compounded when this object relates (with processing dependencies) to a number of further objects within the system, which further objects are diversely located across the system themselves. U.S. Pat. No. 5,787,284 discloses a method in which programs are grouped together based on the weights of connections, i.e. the execution count between procedures, between the objects and their costs. System-imposed constraints on memory size can be taken into account to avoid creating groupings that overload system capacity. Such a method is generally applicable only in a processor environment and does not deal adequately with the restrictions imposed by operation in a distributed environment. The present invention seeks to provide a method of distributing objects in an efficient manner with respect to one another. According to the invention there is provided a method of locating objects in a distributed electronic environment comprising defining a plurality of object-types, which object-types are assigned a plurality of attributes, one attribute being an object-precedence attribute, defining a plurality of home locations for objects, wherein when a new object is instantiated, which object has associations with other objects, the new object is located at the home location of the existing object which has the highest precedence value of all the associated objects. Preferably, the value of the object-precedence is unique for each object-type. Preferably, the precedence value is determined such that objects having a relationship with other objects are located in proximity to one another. In the method of the invention objects which are related to each other are advantageously arranged in proximity to each other such that overheads associated with processes which reference these objects are minimised. This approach improves the efficiency of processing throughout a system of disparate processors in comparison to the conventional techniques of not organising these relationships, such as a random placing of object through the distributed system or the organised homing of all objects of a given type at a single home. An exemplary embodiment of the invention will now be described in greater detail with reference to the examples. In a conventional object oriented environment, each object within the system is of a particular class. Following a standard object oriented approach, each object within the system is an instance of such a class. This means that a base description, or template of an object is provided as a class definition, and from this template, an object has been created or instantiated. This object then takes on the properties of this template or object-type. As part of the object-type definition, an attribute known as object-type precedence is defined. The object-type precedence is defined as having a integer value, which should be unique. Therefore, each and every object within the electronic system is assigned a predetermined object-type precedence value based upon what object-type they are instantiated from. The value of the object-type precedence attribute is that assigned to the object-type precedence attribute within that class. The method of assigning values to the object-type precedence attribute may be manually determined by entering specific values, or may be automated by means of a unique number generator. The respective values of the pre-determined object-type precedent values are determined by the location of an initial number of objects within the system. These objects may not have any relationship to one another. Once these initial objects have been ‘homed’, they provide the basis for assigning ‘homes’ to newly defined objects which relate to them within the system. The intention of this is to reduce inter-process communication and associated overheads, thus increasing efficiency compared to a simple pooling of objects of the same type together at the same processing location. In an electronic system, it is known to use a policy based management system. A policy is an administrator-specified directive that manages certain aspects of the desired outcome of interactions within a given system. This system may provide an environment for users, applications, services, and infrastructure or any other quantifiable object. A policy provides guidelines for how these different entities within such an environment should be managed in response to interactions within the system. In the following example, it is assumed for sake of clarity that only one object per object-type may be associated with another object. It makes sense to ‘home’ Policy 1 with at least one of the objects which already exist in the system which Policy 1 has associations with (processing dependencies). This is not association through existing ‘homes’, but is association through precedence value, i.e. it is the precedence value which determines which existing object the new object should be homed with. The home is determined by looking at where that existing object currently resides. An object ‘Policy1’ might be associated with the following objects: Policy1: ObjectA, ObjectB, ObjectC Each of these objects is of the following object-types: ObjectA: Object-typeXX ObjectB: Object-typeYY ObjectC: Object-typeZZ Where each object-type has the following object-type precedence values assigned to them: Object-typeXX: 1 Object-typeYY: 3 Object-typeZZ: 2 Also, the objects have already been assigned ‘homes’ at the following locations: ObjectA: located at HomeN ObjectB: located at HomeO ObjectC: located at HomeP As a result of this, Policy 1 is homed at Home N, if another object is instantiated and is associated with Policy 1, then it will also be homed at HomeN even if the new object has a higher precedence value itself. This is determined by the precedence value of the existing object with which the new object is associated with rather than the precedence value of the new object. The object Policy1 is will be ‘homed’ or located at HomeN since, of the objects which are associated with Policy1, Object-type has the highest precedence. Therefore since ObjectA is of Object-type and is located at HomeN, therefore Policy1 will be also located at HomeN. The example assumes that ‘1’ is the highest precedence value—it need not be, it alternatively could be that the higher the value, the higher the precedence. It is not a problem to associate more than one object of the same type with another specific object. This simply results in both of the new objects of the same type being homed at the same server.

20040412

20100629

20050519

63607.0

DAFTUAR, SAKET K

OBJECT DISTRIBUTION

UNDISCOUNTED

ACCEPTED

ACCEPTED

Color display devices and methods with enhanced attributes

A color display device for displaying an n-primary color image wherein n is greater than three, the device including an array of sub-pixel (801) configured to have at least one repeating unit having one sub-pixel representing each of the n primary colors, wherein repeating unit (906) is configured to optimize at least one of the n-primary color image.

1-36. (canceled) 37. A color display device for displaying an n-primary color image, wherein n is greater than four, the device comprising an array of sub-pixels configured to have at least one repeating unit comprising one sub-pixel representing each of said n primary colors, wherein the repeating unit is configured to optimize at least one attribute of the n-primary color image. 38. A device according to claim 37 comprising a controller able to receive an input corresponding to said color image and to selectively activate at least some of said sub-pixels to produce one or more attenuation patterns corresponding to a gray-level representation of said color image. 39. A device according to claims 37, wherein said sub-pixels are arranged according to a hue order of said n primary colors. 40. A device according to claim 37, wherein said sub-pixels are arranged in sub-sets, each sub-set comprising neighboring sub-pixels, wherein each one of said sub-sets has a relatively neutral white-balance. 41. A device according to claim 40, wherein one or more of said sub-sets comprises three neighboring color sub-pixels. 42. A device according to claim 41, wherein said three neighboring color sub-pixels are located on one row or column. 43. A device according to claim 40, wherein one or more of said sub-sets comprises sub-pixels of five primary colors arranged in the order red, green, blue, yellow and cyan. 44. A device according to claim 40, wherein one or more of said sub-sets comprises two neighboring color sub-pixels. 45. A device according to claim 44, wherein said two neighboring color-sub-pixels are located on one row or column. 46. A device according to claim 38, wherein said controller is able to activate at least one of said sub-pixels in accordance with an adjusted coverage value. 47. A device according to claim 46, wherein said controller is able to determine said adjusted coverage value by applying a smoothing function to initial coverage values of a group of less than n different primary color sub-pixels containing the activated sub-pixel. 48. A device according to claim 47, wherein said group of sub-pixels comprises two sub-pixels neighboring said activated sub-pixel. 49. A device according to claim 48, wherein the two sub-pixels neighboring said activated sub-pixel are located on one row or column. 50. A device according to claims 46, wherein said controller is able to determine said adjusted coverage value by applying first and second smoothing functions to initial coverage values of first and second groups of sub-pixels, respectively, wherein each of said first and second groups of sub-pixels contains the activated sub-pixel and comprises less than n different primary color sub-pixels. 51. A device according to claim 50, wherein said first group comprises two sub-pixels in a single row or column including said activated sub-pixel. 52. A device according to claim 50, wherein said second group comprises at least one neighboring sub-pixel on the same column or row as said activated sub-pixel. 53. A device according to claims 37, wherein sub-pixels of said repeating unit are arranged in a one-dimensional array. 54. A device according to claims 37, wherein sub-pixels of said repeating unit are arranged in a two-dimensional array comprising a plurality of rows and columns. 55. A device according to claim 54 comprising six primary color sub-pixels arranged in first and second rows, said first row comprising color sub-pixels in the order red, green, blue, cyan, magenta and yellow, and said second row comprising color sub-pixels in the order cyan, magenta, yellow, red, green and blue. 56. A device according to claim 37, wherein said n primary colors comprise red, green, blue and yellow. 57. A device according to claim 37, wherein said n primary colors comprise at least five different primary colors. 58. A device according to claim 57, wherein said at least five different primary colors comprise red, green, blue, yellow and cyan. 59. A device according to claim 57, wherein said at least five different primary colors comprise at least six different primary colors. 60. A device according to claim 59, wherein said at least six different primary colors comprise red, green, blue, yellow, cyan and magenta. 61. A device according to claim 37, wherein said repeating unit comprises an arrangement of said sub-pixels that optimizes at least one property of said displayed image. 62. A device according to claim 61, wherein the arrangement of said sub-pixels is selected based on minimizing a harmonic of a transformation function applied to luminance values of a group of possible sub-pixel arrangements. 63. A device according to claim 62, wherein said transformation function comprises a Fourier Transform and wherein said harmonic comprises a first harmonic of said Fourier Transform. 64. A device according to claim 37, wherein said at least one attribute comprises a gray-level range of said repeating unit. 65. A device according to claim 37, wherein said at least one attribute comprises color saturation. 66. A device according to claim 37, wherein said at least one attribute comprises luminance uniformity. 67. A device according to claim 37, wherein said at least one attribute comprises image resolution. 68. A device according to claim 37, wherein said at least one attribute comprises a property related to a color fringes effect. 69. A device according to claim 37 comprising an n-primary color Liquid Crystal Display (LCD) device, wherein said array of sub-pixels comprises an array of sub-pixel filters, each sub-pixel filter transmitting light of one of said n primary colors. 70. A color display device for displaying an n-primary color image, wherein n is greater than three, the device comprising: an array of sub-pixels configured to have at least one repeating unit comprising one sub-pixel representing each of said n primary colors, wherein the repeating unit is configured to optimize at least one attribute of the n-primary color image; and a controller able to receive an input corresponding to said color image and to selectively activate at least some of said sub-pixels to produce one or more attenuation patterns corresponding to a gray-level representation of said color image. 71. A device according to claim 70, wherein said sub-pixels are arranged according to a hue order of said n primary colors. 72. A device according to claim 70, wherein said sub-pixels are arranged in sub-sets, each sub-set comprising at least two neighboring sub-pixels, wherein each one of said sub-sets has a relatively neutral white-balance. 73. A device according to claim 72, wherein said at least two neighboring sub-pixels are located on one row or column. 74. A device according to claim 70, wherein said controller is able to activate at least one of said sub-pixels in accordance with an adjusted coverage value. 75. A device according to claim 74, wherein said controller is able to determine said adjusted coverage value by applying a smoothing function to initial coverage values of a group of less than n different primary color sub-pixels containing the activated sub-pixel. 76. A device according to claim 75, wherein said group of sub-pixels comprises two sub-pixels neighboring said activated sub-pixel. 77. A device according to claims 74, wherein said controller is able to determine said adjusted coverage value by applying first and second smoothing functions to initial coverage values of first and second groups of sub-pixels, respectively, wherein each of said first and second groups of sub-pixels contains the activated sub-pixel and comprises less than n different primary color sub-pixels. 78. A device according to claim 77, wherein said first group comprises two sub-pixels in a single row or column including said activated sub-pixel. 79. A device according to claim 78, wherein said second group comprises at least one neighboring sub-pixel on the same column or row as said activated sub-pixel. 80. A device according to claim 70, wherein sub-pixels of said repeating unit are arranged in a one-dimensional array. 81. A device according to claim 70, wherein sub-pixels of said repeating unit are arranged in a two-dimensional array comprising a plurality of rows and columns. 82. A device according to claim 70, wherein said n primary colors comprise red, green, blue and yellow. 83. A device according to claim 70, wherein said repeating unit comprises an arrangement of said sub-pixels that optimizes at least one property of said displayed image. 84. A device according to claim 83, wherein the arrangement of said sub-pixels is selected based on minimizing a harmonic of a transformation function applied to luminance values of a group of possible sub-pixel arrangements 85. A device according to claim 84, wherein said transformation function comprises a Fourier Transform and wherein said harmonic comprises a first harmonic of said Fourier Transform. 86. A device according to claim 70, wherein said at least one attribute comprises a gray-level range of said repeating unit. 87. A device according to claim 70, wherein said at least one attribute comprises color saturation. 88. A device according to claim 70, wherein said at least one attribute comprises luminance uniformity. 89. A device according to claim 70, wherein said at least one attribute comprises image resolution. 90. A device according to claim 70, wherein said at least one attribute comprises a property related to a color fringes effect. 91. A device according to claim 70 comprising an n-primary color Liquid Crystal Display (LCD) device, wherein said array of sub-pixels comprises an array of sub-pixel filters, each sub-pixel filter transmitting light of one of said n primary colors. 92. A method of displaying a color image on a color display comprising an array of sub-pixels configured in a plurality of repeating units of at least one type, each repeating unit including a sub-pixel of each of n different primary colors, wherein n is greater than three, the method comprising producing a color combination by at least one of said repeating units without activating a sub-set of sub-pixels capable of producing substantially white light in the repeating unit producing said color combination. 93. A method of displaying a color image on a color display comprising an array of sub-pixels including a plurality of sub-pixels of each of n different primary colors, wherein n is greater than three, the method comprising: activating at least one of said sub-pixels in accordance with an adjusted coverage value. 94. A method according to claim 93 comprising determining said adjusted coverage value by applying a smoothing function to initial coverage values of a group of less than n different primary color sub-pixels containing said activated sub-pixel. 95. A method according to claim 94 comprising determining said adjusted coverage value by applying first and second smoothing functions to initial coverage values of first and second groups of sub-pixels respectively, wherein each of said first and second groups contains the activated sub-pixel and comprises less than n different primary color sub-pixels. 96. A method according to claim 94 comprising determining one or more of said initial coverage values.

FIELD OF THE INVENTION The invention relates generally to color display devices, systems and methods and, more particularly, to display devices, systems and methods having improved color image reproduction capability. BACKGROUND OF THE INVENTION Standard computer monitors and TV displays are typically based on reproduction of three, additive, primary colors (“primaries”), for example, red, green, and blue, collectively referred to as RGB. Unfortunately, these monitors cannot display many colors perceived by humans, since they are limited in the range of color they are capable of displaying. FIG. 1A schematically illustrates a chromaticity diagram as is known in the art. The closed area in the shape of a horseshoe represents the chromaticity range of colors that can be seen by humans. However, chromaticity alone does not filly represent all visible color variations. For example, each chromaticity value on the two-dimensional chromaticity plane of FIG. 1A may be reproduced at various different brightness levels. Thus, a fill representation of the visible color space requires a three dimensional space including, for example, two coordinates representing chromaticity and EL third coordinate representing brightness. Other three dimensional space representations may also be defined. The points at the border of the horseshoe diagram in FIG. 1A, commonly referred to as “spectrum locus”, correspond to monochromatic excitations at wavelengths ranging, for example, from 400 nm to 780 nm. The straight in “closing” the bottom of the horseshoe, between the extreme monochromatic excitation at the longest and shortest wavelengths, is commonly referred to as “the purple line”. The range of colors discernible by the human eye, represented by the area of the horseshoe diagram above the purple line, at varying brightness levels, is commonly referred to as the color gamut of the eye. The dotted triangular area of FIG. 1A represents the range of colors that are reproducible by a standard RGB monitor. There are many known types of RGB monitors, using various display technologies, including but not limited to CRT, LED, plasma, projection displays, LCD devices and others. Over the past few years, the use of color LCD devices has been increasing steadily. A typical color LCD device is schematically illustrated in FIG. 2A. Such a device includes a light source 202, an array of liquid crystal (LC) elements (cells) 204, for example, an LC array using Thin Film Transistor (TFT) active-matrix technology, as is known in the art. The device further includes electronic circuits 210 for driving the LC array cells, e.g., by active-matrix addressing, as is known in the art, and a tri-color filter array, e.g., a RGB filter array 206, juxtaposed the LC array. In existing LCD devices, each full-color pixel of the displayed image is reproduced by three sub-pixels, each sub-pixel corresponding to a different primary color, e.g., each pixel is reproduced by driving a respective set of R, G and B sub-pixels. For each sub-pixel there is a corresponding cell in the LC array. Back-illumination source 202 provides the light needed to produce the color images. The transmittance of each of the sub-pixels is controlled by the voltage applied to the corresponding LC cell, based on the RGB data input for the corresponding pixel. A controller 208 receives the input RGB data, scales it to the required size and resolution, and transmits data representing the magnitude of the signal to be delivered by the different drivers based on the input data for each pixel. The intensity of white light provided by the back-illumination source is spatially modulated by the LC array, selectively attenuating the light for each sub pixel according to the desired intensity of the sub-pixel. The selectively attenuated light passes through the RGB color filter array, wherein each LC cell is in registry with a corresponding color sub-pixel, producing the desired color sub-pixel combinations. The human vision system spatially integrates the light filtered through the different color sub-pixels to perceive a color image. U.S. Pat. No. 4,800,375 (“the '375 patent”), the disclosure of which is incorporated herein by reference in its entirety, describes an LCD device including an array of LC elements juxtaposed in registry with an array of color filters. The filter array includes the three primary color sub-pixel filters, e.g., RGB color filters, which are interlaced with a fourth type of color filter to form predetermined repetitive sequences. The various repetitive pixel arrangements described by the '375 patent, e.g., repetitive 16-pixel sequences, are intended to simplify pixel arrangement and to improve the ability of the display device to reproduce certain image patterns, e.g., more symmetrical line patterns. Other than controlling the geometric arrangement of pixels, the '375 patent does not describe or suggest any visual interaction between the three primary colors and the fourth color in the repetitive sequences. LCDs are used in various applications. LCDs are particularly common in portable devices, for example, the small size displays of PDA devices, game consoles and mobile telephones, and the medium size displays of laptop “notebook”) computers. These applications require thin and miniaturized designs and low power consumption. However, LCD technology is also used in non-portable devices, generally requiring larger display sizes, for example, desktop computer displays and TV sets. Different LCD applications may require different LCD designs to achieve optimal results. The more “traditional” markets for LCD devices, e.g., the markets of battery-operated devices (e.g., PDA, cellular phones and laptop computers) require LCDs with high brightness efficiency, which leads to reduced power consumption In desktop computer displays, high resolution, image quality and color richness are the primary considerations, and low power consumption is only a secondary consideration. Laptop computer displays require both high resolution and low power consumption; however, picture quality and color richness are compromised in many such devices. In TV display applications, picture quality and color richness are generally the most important considerations; power consumption and high resolution are secondary considerations in such devices. Typically, the light source providing back-illumination to LCD devices is a Cold Cathode Fluorescent Light (CCFL). FIG. 3 schematically illustrates typical spectra of a CCFL, as is known in the art. As illustrated in FIG. 3, the light source spectra include three, relatively narrow, dominant wavelength ranges, corresponding to red, green and blue light, respectively. Other suitable light sources, as are known in the art, may alternatively be used The RGB filters in the filter sub-pixel array are typically designed to reproduce a sufficiently wide color gamut (e.g., as close as possible to the color gamut of a corresponding CRT monitor), but also to maximize the display efficiency, e.g., by selecting filters whose transmission curves generally overlap the CCFL spectra peaks in FIG. 3. In general, for a given source brightness, filters with narrower transmission spectra provide a wider color gamut but a reduced display brightness, and vice versa For example, in applications where power efficiency is a critical consideration, color gamut width may often be sacrificed. In certain TV applications, brightness is an important consideration; however, dull colors are not acceptable. FIG. 4A schematically illustrates typical RGB filter spectra of existing laptop computer displays. FIG. 4B schematically illustrates a chromaticity diagram representing the reproducible color gamut of the typical laptop spectra (dashed-triangular area in FIG. 4B), as compared with an ideal NTSC color gamut (dotted triangular area in FIG. 4B). As shown in FIG. 4B, the NTSC color gamut is significantly wider than the color gamut of the typical laptop computer display and therefore, many color combinations included in the NTSC gamut are not reproducible by the typical color laptop computer display. SUMMARY OF THE INVENTION Many colors seen by humans are not discernible on standard red-green-blue (RGB) monitors. By using a display device with more than three primary colors, the reproducible color gamut of the display is expanded Additionally or alternatively, the brightness level produced by the display may be significantly increased. Embodiments of the present invention provide systems and methods of displaying color images on a display device, for example, a thin profile display device, such as a liquid crystal display CCD) device, using more than three primary colors. Exemplary embodiments of an aspect of the invention provide improved multi-primary display devices using more than three sub-pixels of different colors to create each pixel. In embodiments of this aspect of the invention, the use of four or more different color sub-pixels, per pixel, allows for a wider color gamut and higher luminous efficiency. In some embodiments, the number of sub-pixels per pixel and the color spectra of the different sub-pixels may be optimized to obtain a desired combination of a sufficiently wide color gamut, sufficiently high brightness, and sufficiently high contrast. In some embodiments of the invention, the use of more than three primary colors may expand the reproducible color gamut of the display by enabling the use of relatively narrow wavelength ranges for some of the primary colors, e.g., red, green and blue, thus increasing the saturation of those primary colors. To compensate for a potentially reduced brightness level from such narrower ranges, in some embodiments of the invention, broad wavelength range privy colors, e.g., specifically designed yellow and/or cyan, may be used in addition to the narrow wavelength range colors, thus increasing the overall brightness of the display. In further embodiments of the invention, additional primary colors (e.g., magenta) and/or different primary color spectra may be used to improve various other aspects of the displayed image. In accordance with embodiments of the invention, an optimal combination of color gamut width and over-all display brightness can be achieved, to meet the requirements of a given system, by designing specific primary colors and sub-pixel arrangements. The color gamut and other attributes of a more-than-three primary color LCD device in accordance with embodiments of the invention may be controlled by controlling the spectral transmission characteristics of the different primary color sub-pixel filter elements used by the device. According to an aspect the invention, four or more different primary color sub-pixel filters are used, to produce four or more, respective, primary colors, for example, RGB and yellow (Y). In further embodiments of the invention, at least five different primary color sub-pixel filters are used, for example, RGB, Y and cyan (C) filters. In additional embodiments of the invention, at least six different primary color sub-pixel filters are used, for example, RGB, Y, C and magenta (M) filters. The primary color sub-pixel filters for a more-than-three primary color LCD device in accordance with the invention may be selected in accordance with various criteria, for example, to establish sufficient coverage of a desired color gamut, to maximize the brightness level that can be produced by the display, and/or to adjust the relative intensities of the primary colors according to a desired chromaticity standard. In accordance with embodiments of the invention, a multi-primary display with n primary colors may include an array of pixels, each pixel including n sub-pixels, wherein each sub-pixel has a predetermined aspect ratio, for example, n:1, which yields a desired aspect ratio, for example, 1:1, for each pixel. According to farther embodiments of the invention attributes of a multi-primary LCD display may be controlled and/or affected by specific arrangements of the n sub-pixels forming each pixel and/or specific arrangements of the pixels. Such attributes may include picture resolution, color gamut wideness, luminance uniformity and/or any other display attribute that may depend on the arrangement of the pixels d/or sub-pixels. According to one exemplary embodiment of the invention, color saturation may be improved by arranging the n primary colors in the n sub-pixels forming each pixel based on a hue order of the n primary colors. According to another exemplary embodiment of the invention, optimal viewed image uniformity, e.g., optimally uniform luminance across the viewed image may be achieved by arranging the n primary color sub-pixels forming each pixel to yield a minimal variance in luminance between neighboring groups of sub-pixels. In some embodiments of the invention, the sub-pixel arrangement may be determined by mapping a plurality of sub-pixel arrangements, determining a luminance value of each mapped arrangement, transforming the luminance values from spatial coordinates to spatial frequencies, e.g., harmonics, for example, by applying a Fourier Transform to the calculated luminance values, and minimizing the amplitude of a harmonic, e.g., the first harmonic, of the transformation. According to a further embodiment of the invention, the n primary sub-pixels are arranged within each pixel such that sub-sets of neighboring sub-pixels within the pixels have a relatively neutral white-balance. According to exemplary embodiments of another aspect of the invention, there is provided a system and method for n-primary subpixel rendering of a displayed graphic object, for example, a character having a certain font The method may enable modification of the viewed contour and/or edges of the displayed graphic, for example, to reduce a color fringes effect of the viewed object. The method may include sampling the graphic image, assigning each sub-pixel an initial coverage value, applying to each sub-pixel a smoothing function, for example, calculating a weighted average of a neighboring group of sub-pixels, and assigning an adjusted coverage value to each sub-pixel in the group based on the values calculated by the smoothing function. According to exemplary embodiments of yet another aspect of the invention, the reproducible bit-depth of a more-than-three primary color display may be expanded, i.e., a wider span of gray-levels may be obtained, compared to the bit-depth of three primary color displays, by reproducing at least some colors Bring combinations of only some of the primary color sub-pixels. This aspect of the invention may be advantageous in producing low gray-level pixels, because the variety of gray-levels may be particularly significant for the lower gray-levels. In some embodiments of this aspect of the invention, the gray-level of a pixel may be adjusted by adjusting the intensity of a sub-set of the n sub-pixels forming the pixel, for example, a sub-set capable of producing a substantially neutral white-balance. BRIEF DESCRIPTION OF THE DRAWINGS The invention will be understood and appreciated more filly from the following detailed description of embodiments of the invention; taken in conjunction with the accompanying drawings in which: FIG. 1A is a schematic illustration of a chromaticity diagram representing a prior art RGB color gamut, superimposed with a chromaticity diagram of the color gamut of a human vision system, as is known in the art; FIG. 1B is a schematic illustration of a chromaticity diagram representing a wide color gamut in accordance with an exemplary embodiment of the invention superimposed with the chromaticity diagram of FIG. 1A; FIG. 2A is a schematic block diagram illustrating a prior art 3-primary LCD system; FIG. 2B is a schematic block diagram illustrating an n-primary LCD system in accordance with an embodiment of the invention; FIG. 3 is a schematic graph illustrating typical spectra of a prior art Cold Cathode Fluorescent Light (CCFL) source; FIG. 4A is a schematic graph illustrating typical RGB filter spectra of a prior art laptop computer display; FIG. 4B is a schematic illustration of a chromaticity diagram representing the color gamut reproduced by the prior art RGB filter spectra of FIG. 4A, superimposed with an ideal prior art NTSC color gamut, FIG. 5A is a schematic graph illustrating transmission curves of an exemplary, filter design for a five-primary display device in accordance with an embodiment of the invention; FIG. 5B is a schematic illustration of a chromaticity diagram representing the color gamut of the filter design of FIG. 5A, superimposed with two exemplary prior art color gamut representations; FIG. 5C is a schematic graph illustrating transmission curves of another, exemplary, filter design for a five-primary display device in accordance with an embodiment of the invention; FIG. 5D is a schematic illustration of a chromaticity diagram representing the color gamut of the filter design of FIG. 5C, superimposed with two exemplary prior art color gamut representations; FIG. 6 is a schematic illustration of a chromaticity diagram of a human vision color gamut divided into a plurality of color sub-gamut regions; FIGS. 7A, 7B and 7C are schematic illustrations of one-dimensional configurations of sub-pixels of an n-primary LCD display in accordance with exemplary embodiments of the invention; FIGS. 7D and 7E are schematic illustrations of two-dimensional configurations of sub-pixels of an n-primary LCD display in accordance with exemplary embodiments of the invention; FIGS. 8A and 8B are schematic illustrations of arrangements of primary colors in groups of sub-pixels based on hue order of the n primary colors, for a one-dimensional 5-primary display and for a two-dimensional 4-primary display, respectively, in accordance with exemplary embodiments of the invention; FIGS. 9A and 9B are schematic illustrations of prior art arrangements of sub-pixels in a ROB display; FIG. 9C is a schematic illustration of an arrangement of sub-pixels including a basic repeating unit having a one-dimensional 5-primary configuration in accordance with an exemplary embodiment of the invention; FIG. 10 is a schematic block-diagram illustration of a method for arranging n primary colors in groups of n sub-pixels of a LCD display in accordance with exemplary embodiments of the invention; FIG. 11A is a schematic illustration of an arrangement of primary colors in sub-pixels for a one-dimensional 5-primary display, in accordance with an exemplary embodiment of the invention; FIG. 11B is a schematic illustration of an arrangement of primary colors in sub-pixels for a two-dimensional 6-primary display, in accordance with an exemplary embodiment of the invention; FIG. 11C is a schematic illustration of a chromaticity diagram representing the color gamut of a 5-primary display in accordance with an exemplary embodiment of the invention; FIG. 12A is a schematic illustration of an enlarged character rastered to black and white pixels according to prior art methods; FIG. 12B is a schematic illustration of an enlarged character rastered to gray-scale pixels according to prior art methods; FIG. 12C is a schematic illustration of an enlarged character rastered to RGB sub-pixels according to prior art methods; FIG. 12D is a schematic illustration of a character enlarged by an initial stage of n-primary sub-pixel rendering according to exemplary embodiments of the invention; FIG. 12E is a schematic illustration of a table showing initial coverage values that may be assigned to sub-pixels of the image of FIG. 12D based on an assignment method according to exemplary embodiments of the invention; FIG. 12F is a schematic illustration of a character enlarged and adjusted by sub-pixel rendering according to exemplary embodiments of the invention; FIG. 12G is a schematic illustration of a table showing adjusted coverage values that may be assigned to sub-pixels of the image of FIG. 12F based on an assignment method according to exemplary embodiments of the invention; FIG. 13A is a schematic block illustration of a method for multi-primary sub-pixel rendering in accordance with exemplary embodiments of the invention; FIG. 13B is a schematic block illusion of data flow in a system of multi-primary sub-pixel rendering of a multi-primary display in accordance with exemplary embodiments of the invention; FIG. 14 is a schematic diagram of the flow of data in a LCD display system incorporating a method for increasing bit depth, in accordance with exemplary embodiments of the invention; and FIG. 15 is a schematic illustration of EL chromaticity diagram representing a color gamut of a 6-primary display in accordance with an exemplary embodiment of the invention. DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION In the following description, various aspects of the invention are described, with reference to specific embodiments that provide a thorough understanding of the invention; however, it will be apparent to one skilled in the art that the present invention is not limited to the specific embodiments and examples described herein. Further, to the extent that certain details of the devices, systems and methods described herein are related to known aspects of color display devices, systems and methods, such details may have been omitted or simplified for clarity. FIG. 1B schematically illustrates a color gamut of a more-than-three-primary display in accordance with an embodiment of the invention, enclosed by a horseshoe diagram representing the perceivable color gamut of the human eye, on a chromaticity plane. The six-sided shape in FIG. 1B represents the color gamut of a six-primary display in accordance with an exemplary embodiment of the invention. This color gamut is significantly wider than a typical RGB color gamut, which is represented by the dotted triangular shape in FIG. 1B. Embodiments of monitors and display devices with more than three primaries, in accordance with exemplary embodiments of the invention, are described in U.S. patent application Ser. No. 09/710,895, entitled “Device, System And Method For Electronic True Color Display”, filed Nov. 14, 2000, in International Application PCT/IL01/00527, filed Jun. 7, 2001, entitled “Device, System and Method For Electronic True Color Display” and published Dec. 13, 2001 as PCT Publication WO 01/95544, in U.S. patent application Ser. No. 10/017,546, filed Dec. 18, 2001, entitled “Spectrally Matched Digital Print Proofer” and published Oct. 17, 2002 as U.S. Publication US-2002-014954, in International Application PCT/IL02/00410, filed May 23, 2002, entitled “System and method of data conversion for wide gamut displays” and published Dec. 12, 2002 as PCT Publication WO 02/99557, and in International Application PCT/IL02/00452, filed Jun. 11, 2002, entitled “Device, System and Method For Color Display” and published Dec. 19, 2002 as PCT Publication WO02/101644, the disclosures of all of which applications and publications are incorporated herein by reference. While, in embodiments of the present invention, methods and systems disclosed in the above referenced patent applications may be used, for example, methods of converting source data to primary data, or methods of creating primary color materials or filters; in alternate embodiments, the system and method of the present invention may be used with any other suitable r-primary display technology, wherein n is greater than three. Certain embodiments described in these applications are based on rear or front projection devices, CRT devices, or other types of display devices. While the following description focuses mainly on n-primaries flat panel display devices in accordance with exemplary embodiments of the invention, wherein n is greater than three, preferably using LCDs, it should be appreciated that, in alternate embodiments, the systems, methods and devices of the present invention may also be used in conjunction with other types of display and other types of light sources and modulation techniques. For example, it will be appreciated by persons skilled in the art that the principles of the n-primary color display device of the invention may be readily implemented, with appropriate changes, in CRT displays, Plasma display, Light Emitting Diode (LED) displays, Organic LED (OLED) displays and Field Emissions Display (FED) devices, or any hybrid combinations of such display devices, as are known in the art. FIG. 2B schematically illustrates a more-than-three primary color display system in accordance with an embodiment of the invention The system includes a light source 212, an array of liquid crystal (LC) elements (cells) 214, for example, an LC array using Thin Film Transistor (TFT) active-matrix technology, as is known in the art. The device further includes electronic circuits 220 for driving the LC array cells, e.g., by active-matrix addressing, as is known in the art, and an n-primary-color filter array 216, wherein n is greater than three, juxtaposed the LC array. In embodiments of the LCD devices according to embodiments of the invention, each full-color pixel of the displayed image is reproduced by more than three sub-pixels, each sub-pixel corresponding to a different primary color, e.g., each pixel is reproduced by driving a corresponding set of four or more sub-pixels. For each sub-pixel there is a corresponding cell in LC array 214. Back-illumination source 212 provides the light needed to produce the color images. The transmittance of each of the sub-pixels is controlled by the voltage applied to a corresponding LC cell of array 214, based on the image data input for the corresponding pixel. An n-primaries controller 218 receives the input data, e.g., in RGB or YCC format, optionally scales the data to a desired size and resolution, and transmits data representing the magnitude of the signals to be delivered by the different drivers based on the input data for each pixel. The intensity of white light provided by back-illumination source 212 is spatially modulated by elements of the LC array, selectively controlling the illumination of each sub-pixel according to the image data for the sub-pixel. The selectively attenuated light of each sub-pixel passes through a corresponding color filter of color filter array 216, thereby producing desired color sub-pixel combinations. The human vision system spatially integrates the light filtered through the different color sub-pixels to perceive a color image. The color gamut and other attributes of LCD devices in accordance wit embodiments of the invention may be controlled by a number of parameters. These parameters include: the spectra of the back illumination element (light source), for example a Cold Cathode Fluorescent Light (CCFL); the spectral transmission of the LC cells in the LC array; and the spectral transmission of the color filters. In a 3-primaries display, the first two parameters, namely, the spectra of the light source and the spectral transmission of the LC cell are typically dictated by system constraints and, therefore, the colors for the filters may be selected straightforwardly to provide the required colorimetric values at the “corners” of the desired RGB triangle, as shown in FIG. 1A. To maximize the efficiency of 3-primaries LCD devices, the spectral transmissions of the filters are designed to substantially overlap, to the extent possible, with the wavelength peaks of the light source. The filters selection in 3-primary LCD devices may be based primarily on maximizing the overall brightness efficiency. In this context it should be noted that selecting filters having narrower spectral transmission curves, which result in more saturated prinary colors, generally decreases the over-all brightness level of the display. For a multi-primary display with more than three primary colors, in accordance, with embodiments of the invention, an infinite number of filter combinations can be selected to substantially overlap a required color gamut The filter selection method of the invention may include optimizing the filter selection according to the following requirements: establishing sufficient coverage of a desired two-dimensional color gamut, for example, the NTSC standard gamut for wide-gamut applications and a “conventional” 3-color LCD gamut for higher brightness applications; maximizing the brightness level of a balanced white point that can be obtained from combining all the primary colors; and adjusting the relative intensities of the primary colors in accordance with a desired illumination standard, e.g., the D65 white point chromaticity standard of High Definition TV (HDTV) systems. Embodiments of the present invention provide systems and methods of displaying color images on a display device, for example, a thin profile display device, such as a liquid crystal display (LCD) device, using more than three colors. A number of embodiments of the invention are described herein in the context of an LCD device with more than three primary colors; wherein the number of color filters used per pixel is greater than three. This arrangement has several advantages in comparison to conventional RGB display devices. First, the n-primary display device in accordance with the invention enables expansion of the color gamut covered by the display. Second, the device in accordance with the invention enables a significant increase in the luminous efficiency of the display; in some cases, an increase of about 50 percent or higher may be achieved, as discussed below. This feature of the invention is particularly advantageous for portable (e.g., battery-operated) display devices, because increased luminous efficiency may extend the usable time of a battery after each recharging and/or reduce the overall weight of the device by using a lighter battery. Third, a device in accordance with the invention enables improved graphics resolution by efficient utilization of a technique for arranging primary colors in sub-pixels, as described in detail below with reference to specific embodiments of the invention. In some multi-primary display devices in accordance with embodiments of the invention, more than three sub-pixels of different colors are used to create each pixel. In embodiments of the invention, the use of four or more different color sub-pixels, per pixel allows for a wider color gamut and higher luminous efficiency. In some embodiments, the number of sub-pixels per pixel and the transmittance spectrum of the different sub-pixel filters may be optimized to obtain a desired combination of a sufficiently wide color gamut sufficiently high brightess, and sufficiently high contast. For example, the use of more than three primaries in accordance with an embodiment of the invention may enable expansion of the reproducible color gamut by enabling the use of filters with narrower transmission curves (e.g., narrower effective transmission ranges) for the R, G and B color filters and, thus, increasing the saturation of the F G and B sub-pixels. To compensate for such narrower ranges, in some embodiments of the invention, broader band sub-pixel filters may be used in addition to the RGB saturated colors, thus increasing the overall brightness of the display. In accordance with embodiments of the invention, an optimal combination of color gamut width and over-all picture brightness can be achieved, to meet the requirements of a given system, by appropriately designing the sub-pixel filters of the n-primary display and the filter arrangement. FIG. 5A and 5C schematically illustrate transmission curves for two, respective, alternative designs of a five-primary display device in accordance with embodiments of the invention, wherein the five primary colors used are red (R), green (G), blue (B), cyan (C) and yellow (Y), denoted collectively RGBCY. FIGS. 5B and 5D schematically illustrate the resulting color gamut of the filter designs of FIGS. 5A and SC, respectively. It will be appreciated that both designs produce wider gamut coverage and/or higher brightness levels than corresponding conventional three-color LCD devices, as discussed in details below. As known in the ark the normalized over-all brightness level of a conventional 3-color LCD may be calculated as follows: Y(3-colors)=(Y(color1)+Y(color2)+Y(color3))/3 In an analogous manner, the normalized brightness level of a 5-color LCD device in accordance with an embodiment of the present invention may be calculated as follows: Y(5-colors)=(Y(color1)+Y(color2)+Y(color3)+Y(color4)+Y(color5))/5 wherein Y(color1) denotes the brightness level of the i'th primary color and Y(n-colors) denotes the over-all, normalized, brightness level of the n-primaries display. Although the color gamut illustrated in FIG. 5B is comparable with that of a corresponding 3-color LCD device (FIG. 4B), the brightness level that can be obtained using the filter design of FIG. 5A is about 50% higher than that of the corresponding 3-color LCD. The higher brightness levels achieved in this embodiment are attributed to the addition of yellow (Y) and cyan (C) color sub-pixels, which are specifically designed to have broad transmission regions and, thus, transmit more of the back-illumination than the RGB filters. This new filter selection criterion is conceptually different from the conventional selection criteria of primary color filters, which are typically designed to have narrow transmission ranges. The white point chromaticity coordinates for this embodiment, as calculated from the transmission spectra and the back-illumination spectra using methods known in the known art are x=0.318; y=0.352. As shown in FIG. 5D, the color gamut for the filter design of FIG. 5C is considerably wider than that of the corresponding conventional 3-color LCD (FIG. 4B), even wider than a corresponding NTSC gamut, which may be the reference gamut for color CRT devices, with brightness levels roughly equal to those of a 3-color LCD. In this embodiment, the over-all brightness level of the 5-color LCD device may be similar to that of a 3-color LCD device having a much narrower color gamut. The white point coordinates for this embodiment, as calculated from the transmission spectra and the back-illumination spectra using methods known in the known art, are x=0.310; y=0.343. Other designs may be used in embodiments of the invention, including the use of different primaries and/or additional primaries (e.g., 6 color displays), to produce higher or lower brightness levels, a wider or narrower color gamut, or any desired combination of brightness level and color gamut, as maybe suitable for specific applications. FIG. 6 schematically illustrates a chromaticity diagram of the color gamut discernable by humans, divided into six sub-gamut regions, namely red (R), green (G), blue (B), yellow (Y), magenta (M) and cyan (C) color sub-gamut regions, that may be used for selecting effective color filters spectra in accordance with embodiments of the invention. In some embodiments, more than three primary color filters, for example, five color filters as in the embodiments of FIG. 5A may be selected to produce chromaticity values within respective sub-gamut regions in FIG. 6. The exact chromaticity position selected for a given primary color within a respective subgamut region may be determined in accordance with specific system requirements, for example, the desired width of the color gamut in the chromaticity plane and the desired image brightness. As discussed in detail above, the system requirements depend on the specific device application, e.g., certain applications give preference to gamut size, while other applications give preference to image brightness. The sub-gamut regions in FIG. 6 represent approximated boundaries from which primary colors may be selected to provide large gamut coverage and/or high brightness levels, while maintaining a desired white point balance, in accordance with embodiments of the invention. The positions of the primary chromaticity values within the sub-gamut regions of FIG. 6, for given filter spectra selections and known back-illumination spectra, can be calculated using straightforward mathematical calculations, as are known in the art, to determine whether a desired color gamut is obtained for the given filter spectra selections. In accordance with embodiments of the invention, a multi-primary display with n primary colors may include an array of pixels, each pixel including n sub-pixels, wherein each sub-pixel has a predetermined aspect ratio, for example, n:1, which yields a desired aspect ratio, for example, 1:1, for each pixel. The sub-pixels in each pixel may be configured in a one dimensional or a two-dimensional array. FIGS. 7A, 7B and 7C illustrate one-dimensional configurations of sub-pixels in a pixel of an n-primary LCD display in accordance with exemplary embodiments of the invention. The configurations illustrated in FIGS. 7A, 7B and 7C are one dimensional in the sense Eat all the sub-pixels of each pixel are configured in a single linear sequence. If n is not a prime number, ie., if n=1*k wherein k≠1 and 1≠1 are integers, it is possible to configure the sub-pixels in two-dimensional configurations, e.g., in 1 rows and k columns. FIGS. 7D and 7E schematically illustrate two-dimensional configurations of sub-pixels in a pixel of an n-primary LCD display, in accordance with exemplary embodiments of the invention. For example, as shown in FIGS. 7A-7E, sub-pixels of a 5-primary display may have a one-dimensional configuration 702, whereas sub pixels of 4-primary or 6-primary displays may be configured either in one-dimensional configurations, e.g., 701 and 704, respectively, or in two-dimensional configurations, eg., 703 and 705, respectively. According to embodiments of the invention, some of the attributes of an n-primary LCD display may be related to the arrangement of the n sub-pixels forming each pixel as described hereinafter. Such attributes may include, for example, image resolution, color saturation, viewed luminance uniformity, and/or any display attribute that may be affected by sub-pixel arrangements described herein. According to an exemplary embodiment of the invention, desired color saturation may be achieved by arranging the I primary colors forming each pixel based on a hue order of the individual a primary colors. In this context, the hue order may be based on the circumferential sequence of the individual n primary colors on a chromaticity diagram, for example, the horseshoe diagram illustrated in FIG. 1B. Light of each display sub-pixel may be transmitted through a corresponding color filter. However, due to light scattering and reflection effects, the light may also “leak” through the color filters of neighboring sub-pixels. This may result in distortion or reduction of the desired color saturation. For example, if neighboring sub-pixels reproduce complementary primary colors, light leakage between the sub-pixels may reduce the effective color saturation of the sub-pixels due to a certain degree of neutral color viewed from the combination of complementary colors. It should be noted that the effect of light leakage from one sub-pixel to another may depend on the length of the border between the sub-pixels as well as the distance between the sub-pixels, e.g., the leakage of light may be reduced as the distance between the centers of neighboring sub-pixels is increased For example, vertically or horizontally neighboring sub-pixels, e.g., on the same row or on the same column, may be more susceptible to leakage than two diagonally neighboring sub-pixels. Furthermore, neighboring pixels on rows and columns may produce different leakage effects depending on the aspect ratio of the sub-pixels. In order to avoid the viewed leakage effect described above, arrangements of sub-pixels according to exemplary embodiments of the invention may be designed to maximize the distance between sub-pixels of complementary primary colors and/or partly complementary sub-pixels. An arrangement of sub-pixels according to hue order in accordance with exemplary embodiments of the invention may minimize the effect of light leakage from one sub-pixel to another and, thus, increase the color saturation and minimize distortion of entire pixels. FIGS. 8A and 8B schematically illustrate arrangements 801 and 802, respectively, of primary colors in sub-pixels based on the hue order of primary colors, for a one-dimensional 5-primary display and for a two-dimensional 4-primary display, respectively, in accordance with exemplary embodiments of the invention. The 5 sub-pixels in arrangement 801 of the 5-primary display are arranged according to hue order, e.g., RYGCB. This arrangement implies that potential leakage of light from each sub-pixel to a neighboring sub-pixel may only slightly shift the hue of the color represented by the entire pixel without significantly affecting the color saturation of the pixel. It will be appreciated that, in contast to arrangements 801 and 802, for example, if the yellow and blue colors were to be arranged in neighboring sub-pixels, such as in a RYBC arrangement, even a small light leakage from one sub-pixel to a neighboring sub-pixel would have caused a large reduction in saturation of he entire pixel. In the exemplary case of the two-dimensional arrangement 802 of the 4-primary display, the blue and yellow sub pixels are located on one diagonal and the red and green sub-pixels are located on another diagonal, thus creating an arrangement wherein each color sub-pixel directly neighbors only sub-pixels with relatively close hues, e.g., the yellow color sub-pixel may directly neighbor the red and green color sub-pixels. It should be noted that the exemplary arrangements shown and described herein are demonstrative only. It will be appreciated by persons skilled in the art that other suitable arrangements of the sub-pixels, wherein each sub-pixel neighbors other sub-pixels based on hue values, are also within the scope of the invention. According to another exemplary embodiment of the invention, to improve the viewed spatial uniformity of an image, viewed variations in the brightness of a spatially uniform image may be reduced by appropriately arranging the n primary color sub-pixels internally within each pixel, as follows. According to exemplary embodiments of the invention, an array of pixels forming the LCD display may be broken-down into a plurality of identical basic repeating units. A basic repeating unit may contain a configuration and/or arrangement of one or more pixels, or a predefined combination of sub-pixels, which is repeated throughout the array of sub-pixels forming display. FIGS. 9A and 9B illustrate arrangements of sub-pixels including a basic repeating unit in a PGB LCD display, in accordance with exemplary embodiments of the invention. In a conventional arrangement 901 of pixels of a RGB LCD display, for example, a red sub-pixel may occupy the same position in different rows, such that the order of sub-pixels in each row may be R-G-B. The basic repeating unit in this exemplary arrangement represents one RGB pixel 902. In another exemplary RGB arrangement 903, a first row of the display may include R-G-B sub-pixel arrangements, a second row may include B-R-G sub-pixel arrangements, a third row may include G-B-R sub-pixel arrangements, and a forth row may again include the R-G-B sub-pixel arrangements. In this case, a basic repeating unit 904 may include three pixels, one directly below the other. A similar approach may be used for a more-than-three primary display wherein the sub-pixels are configured in one-dimensional or two-dimensional configurations as described above. For a two dimensional sub-pixel configuration, the relationships between sub-pixel colors in neighboring pixels on different rows as well as the relationships between sub-pixel colors in neighboring pixels of the same row may be analyzed in an analogous manner. FIG. 9C schematically illustrates an arrangement 905 of sub-pixels including a basic repeating unit 906 having a one-dimensional 5-primary configuration in accordance with an exemplary embodiment of the invention. Luminance values of the primary colors may depend on a set of primary color filters and the type of backlight used by the display. Different filters and light sources may provide different primary color luminance values; therefore, the methods described herein for arranging the sub-pixels may yield sub-pixel arrangements for achieving optimal luminance uniformity for a given combination of backlight and filters. According to an exemplary embodiment of the invention, a 5-primary display may include a set of five primary colors, denoted P1, P2, P3, P4 and P5, having luminance values of for example, 0.06, 0.13, 0.18, 0.29 and 0.34, respectively. According to this exemplary embodiment of the invention, there may be 24 different one dimensional arrangements of the primary colors. To determine an optimal arrangement of the sub-pixels, in an embodiment of the invention, a function transforming spatial coordinates to spatial frequencies, e.g., harmonics, for example, a Fourier Transform, may be applied to each arrangement, and the amplitude of the first harmonic of the transformation may be analyzed as a criterion for choosing an optimal arrangement. For example, a Fourier Transform analysis as described with reference to FIG. 10 below indicates that a relatively low first harmonic amplitude may be obtained for an arrangement of the 5 primary colors in unit 906 in the order P2-P3-P4-P1-P5, as shown schematically in FIG. 9C, as well as for an arrangement of the primary colors in the order P2-P5-P1-P4-P3 (not shown). According to this exemplary embodiment of the invention, either one of the optimal arrangements, namely, P2-P3-P4-P1-P5 or P2-P5-P1-P4-P3, may be chosen to optimize further required display attributes, e.g., image brightness, color saturation, image resolution, or any other relevant display attribute. FIG. 10 is a schematic block-diagram illustrating a method for arranging n primary color sub-pixels within a pixel of a LCD display in accordance with exemplary embodiments of the invention. The method may include mapping all possible arrangements of the n primary colors to the n sub-pixels for a selected sub-pixel configuration, as indicated at block 1001. As indicated at block 1002, the known luminance values of each of the primary colors are used to calculate a set of luminance values as a function of sub-pixel position for each of the mapped sub-pixel arrangements of block 1001. As indicated at block 1003, a transformation function, for example, a Fourier Transform of the position-dependent luminance values calculated at block 1002, may be calculated. Since the eye is more sensitive to contrast variations at low spatial frequencies, the amplitude of the first harmonic of the transform may be analyzed for all arrangements, to select arrangements with a relatively small amplitude of the first harmonic, as indicated at block 1004. According to alternative embodiments of the invention, block 1004 may include further operation techniques, for example, since the sensitivity of the eye may be different in different directions, the selection of an optimal arrangement may also be based on the direction of variation of the first harmonic. According to exemplary embodiments of the invention, a computer running suitable software, or any other suitable combination of hardware and/or software, may be used to perform the method described above. According to a further embodiment of the invention, the primary colors may be arranged in sub-pixels in a combination wherein each su-set of neighboring sub-pixels within a pixel may have a substantially neutral white-balance, i.e., each sub-set may be capable of producing light as close as possible to white light An advantage of this arrangement is that it may enable high-resolution rendering of black-and-white images, for example, images of characters, e.g., black text over white background. FIGS. 11A and 11B illustrate an assignment of primary colors to sub-pixels, wherein each sub-set of neighboring sub-pixels win a pixel may have a relatively neutral white-balance, in accordance with an exemplary embodiment of the invention. In the 5-primary one-dimensional configuration illustrated in FIG. 11A, the primary color subpixels are arranged in a RGBYC arrangement 1101, including RGB, GBY, BYC, YCR and CRC tiad sub-sets. FIG. 11C is a schematic illustration of a chromaticity diagram representing a color gamut of a 5-primary display in accordance with an exemplary embodiment of the invention. It will be appreciated that the color gamut produced by each of the triads listed above includes an area 1104, which contains a D65 white point 1103, and thus may produce light very close to white light Therefore, the arrangement of sub-pixels according to arrangement 1101 may increase the effective luminance resolution of the display by a factor of 5/3 compared to the luminance resolution that may be achieved by a 5-primary display without the specific sub-pixel arrangement described herein. In the 6-primary two-dimensional configuration illustrated in FIG. 11B, arrangement 1102 of the primary colors is preformed for two neighboring pixels, wherein the first row may include the combination RGBCMY and the second row may include the combination CMYRGB. Each combination includes the triads RGB and CMY, which may each produce substantially white light. This arrangement farther creates in each one of the columns desirable sub-combinations, e.g., sub-pixel pairs RC, GM and YB. These sub-combinations may include pairs of complementary colors, which may each produce substantially white light It will be appreciated that the arrangement of FIG. 11B may increase the resolution of the display by a factor of about 3 in the horizontal direction and by a factor of about two in the vertical direction compared to a luminance resolution achieved by a 6-primary display without the sub-pixel arrangements described herein. Another embodiment of the invention relates to a method of -primary sub-pixel rendering of a displayed graphic object, for example, a character of a text font. When displaying a graphic object on a screen, resolution may be an important factor, especially when extrapolation or interpolation methods are used to resize graphic objects to a given screen resolution. For example, when a relatively &mall graphic object is enlarged, using up-scaling methods as are known in the art, to display a relatively large image of the graphic object, the clarity of the enlarged image may be impaired because of inaccurate extrapolation of data to create new pixels. This problem may be particularly apparent at or near the edges of a displayed graphic object, e.g., along the contour of the graphic object. FIG. 12A illustrates an enlargement of the letter “A” when rastered to be displayed using black and white pixels. The letter illustrated in FIG. 12A may not be easily readable because of its low resolution. FIG. 12B illustrates an enlargement of the letter “A” using gray-scale pixel rendering. In order to improve the resolution and readability of monochromatic, high-contrast images, e.g., a black graphic image on white background, a gray-scale pixel rendering method may be used. A gray-scale pixel rendering method may include sampling each pixel of a pixel-matrix representation of the image to determine a percentage of the pixel-area covered by the graphic object for each partly-covered pixel and reproducing the pixel with a gray-level responsive, e.g., proportional, to the percentage of the pixel area covered by the graphic object. A drawback of this method may be a fuzziness of the object as shown in FIG. 12B. An improvement of graphic object rendering may include sub-pixel rendering. Sub-pixel rendering for a LCD display may utilize a subpixel matrix instead of a full-pixel matrix. FIG. 12C illustrates an enlargement of the letter “A” as produced by RGB sub-pixel rendering techniques. As shown in FIG. 12C, each pixel is composed of 3 sub-pixels, whereby the rendering may be carried out separately for each sub-pixel. This method may allow improved readability compared to the full-pixel rendering methods. However, this method has a drawback of color fringes effects, which may result from luminance variation between neighboring sub-pixels, e.g., a sub-pixel covered by the graphic object may have a luminance level different from a neighboring sub-pixel not covered by the object This problem may be particularly apparent at or near the edges of a displayed graphic object, e.g., along the contour of the graphic object. According to an exemplary embodiment of the invention, a method for minimizing color fringes may be applied to a given sub-pixel configuration, for example, five-primary one dimensional arrangement 1101 (FIG. 11A), or to any other one-dimensional or two-dimensional configuration, as described in detail below. Reference is made to FIG. 12D, which schematically illustrates an enlargement of an upper part of the letter “A” using n-primary sub-pixel rendering according to exemplary embodiments of the invention, and to FIG. 12E, which schematically illustrates a table showing initial coverage values that may be assigned to sub-pixels of the image of FIG. 12D using an assignment method according to exemplary embodiments of the invention. According to exemplary embodiments of the sub-pixel rendering method of the invention, each sub-pixel may be assigned with an initial coverage value, which may be related, e.g., proportional, to the percentage of the sub-pixel area covered by the graphic object, as illustrated schematically in FIGS. 12D and 12E. Reference is also made to FIG. 12F, which schematically illustrates an enlargement of an upper part of the letter “A” using sub-pixel rendering according exemplary embodiments of the invention, and to FIG. 12G, which schematically illustrates a table showing adjusted coverage values that may be assigned to sub-pixels of the image of FIG. 12F based on an assignment method according to exemplary embodiments of the invention. According to exemplary embodiments of the sub-pixel rendering method of the invention, an adjusted coverage value may be assigned to each of three subpixels, composing a pre-defined triad, based on a predetermined smoothing function, for example, a weighted average. The smoothing function may be used to reduce or eliminate variations in the initial coverage values of the different sub-pixels composing each sub-pixel triad. By adjusting the brightess of the sub-pixel in accordance wit the adjusted coverage values, a substantially color-neutral luminance, e.g., a gray color, may be viewed throughout the image, and particularly along the contour of the graphic object, as described below. According to an exemplary embodiment of the invention, the smoothing function may include a weighted average, wherein predetermined weights are assigned to the sub-pixels of the triad, for example, a weight of 1 may be assigned to each subpixel in the triad. According to one exemplary embodiment of the invention, an adjusted coverage value 1210 assigned to sub-pixel 1201 may be determined by averaging initial coverage value 1204 of subpixel 1201 and initial coverage values 1202 and 1206 of neighboring sub-pixels 1205 and 1203, respectively. According to this exemplary embodiment, sub-pixel 1201 may be assigned an adjusted coverage value of 1/6, which corresponds to a weighted average of a set of initial coverage values of the triad containing sub-pixel 1201, for example, initial coverage values (0, 0, 0.5). According to another exemplary embodiment of the invention, sub-pixel 1203 may be assigned an adjusted coverage value 1212 corresponding to a weighted average of initial coverage values 1204, 1206 and 1208 of sub-pixels 1201 and 1203 and 1207, respectively. According to this exemplary embodiment, sub-pixel 1203 may be assigned an effective coverage value of 1/3, which corresponds to a weighted avenge of a set of initial coverage values of the triad containing sub-pixel 1203, for example, coverage values (0, 0.5, 0.5). According to further embodiments of the invention, the weighted average may include assigning a different weight to each sub-pixel. According to exemplary embodiments of the invention, there may be n different triad arrangements for a one dimensional n-primary configuration. Thus, according to an exemplary embodiment of the invention, n different weighting functions may be defined to allow calculating an adjusted coverage value for each sub-pixel of the arrangement, e.g., arrangement 1101 (FIG. 11A). According to another embodiment of the invention, a method forming color fringes may be applied to a six primary, two dimensional arrangement, e.g., arrangement 1102 (FIG. 11B), or to any other two-dimensional configuration The method may include using a smoothing function for assigning an adjusted coverage value to each sub-pixel of the triads composing a row and to each sub-pixel of the pairs composing a column as described above. According to exemplary embodiments of the invention, there may be 2 n different arrangements available in a two-dimensional n-primary display. Thus, according to an exemplary embodiment of the invention, 2 n different smoothing functions may be pre-defined to allow calculating an adjusted coverage value for each sub-pixel of the two-dimensional arrangement. FIG. 13A is a schematic block illustration of a method for multi-primary sub-pixel rendering in accordance with exemplary embodiments of the invention The method of FIG. 13A may allow sub-pixel rendering with enhanced resolution and enhanced readability, while minimizing color fringe effects. This may be achieved by monitoring the contour and/or edges of a viewed graphic object As indicated at block 1301, the method may include, according to embodiments of the invention, sampling a two-dimensional graphic object at sub-pixel resolution and assigning an initial coverage value to each sub-pixel according to the corresponding relative coverage of the graphic object. For example, if the graphic object covers 50% of a certain sub-pixel, then the sub-pixel maybe assigned an initial coverage value of 0.5. As indicated at block 1302, the method according to embodiments of the invention may include calculating a smoothing function, for example, a running weighted average, i.e., a continual re-calculation, of the initial coverage values of sub-pixel triads. As indicated at block 1303, an adjusted coverage value may be assigned to each sub-pixel according to the result of the smoothing function applied at block 1302. FIG. 13B is a schematic block diagram illustrating the flow of data in a system for sub-pixel rendering in accordance with exemplary embodiments of the invention. According to embodiments of the invention, the sub-pixel rendering system may include receiving an input corresponding to a graphic object from a suitable application software 1310, for example, a word-processing software. The system may further include a graphic interpreter 1320, a sub-pixel rendering unit 1330, a video card Same buffer 1340, and an n-primary display 1350, which may include any type of more-than-three pry color display, for example, an n-primary color LCD display according to embodiments of the invention. Application software 1310 may be used to define graphic objects, e.g., text characters, and their size and position. Graphic interpreter 1320 may be used to translate the text and/or other graphic objects defined by application software 1310 into continuous two-dimensional objects, the contours of which may be defined by simple curves. The two-dimensional graphic objects may be processed by sub-pixel rendering unit 1330, which may sample the graphic objects at the sub-pixel resolution of the display, to obtain a relative coverage at each sub-pixel, and may apply a smoothing function, as discussed above, to provide a smooth bitmap defining the image to be displayed. The bitmap provided by sub-pixel rendering unit 1330 may be temporarily stored in graphic card frame buffer 1340 and may be further transferred and displayed on n-primary display 1350. In TV applications, text and graphic information may appear in the form of sub-titles, closed captioning, or TELETEXT signals. In digital TV application, this information may be included in a broadcast MPEG format, and may be decoded by a MPEG decoder, for example, by a set-off box or a DVD player. According to embodiments of the invention, a data flow system supporting sub-pixel rendering as described herein may be used to support fee applications of digital TV, for example, interactive text and graphics presentations. According to another embodiment of the invention, the n-primary color arrangements described above may be used to display a wider range of gray levels compared to a RCGB LCD display. A pre-defined bit depth of size bd may yield a range of 2bd gray levels for each one of the primary colors used in a display, e.g., an 8-bit depth may yield 256 gray-levels for each primary color. In conventional RGB LCD displays, a combination of all 3 primary colors is used in order to display most colors, or to adjust the gray-level of a given color. Therefore, the maximum number of gray-levels for each displayed color depends on the bit-depth, e.g., 256 gray levels, numbered 0 to 255, for an 8-bit depth, wherein levels 0 and 255 correspond to black and white, respectively. In such a display, the brightest displayable white may be obtained using level 255 for all three primaries. In a similar manner, the darkest displayable gray is obtained when all three primary-color sub-pixels are activated at level 1. Since the pixels of an input image may include a wider range of gray-levels, i.e., a larger bitmap, for example, a 10-bit depth, many gray-levels may not be reproducible by existing displays. This problem may be particularly significant at low gray levels. Embodiments of the present invention may expand the reproducible bit-depth of a displayed image in a more-than-three primary display, for example, to a bitdepth of more than 8 bits, by reproducing additional gray-levels using combinations of only some of the sub-pixels in certain pixels or repeating units. This aspect of he invention may be advantageous in producing low gray-level pixels, because the variety of gray-levels may be particularly significant for the lower gray-levels. According to exemplary embodiments of the invention, a more-than-three primary color sub-pixel arrangement, for example, 6-primary RGBMCY sub-pixel arrangement 1102 (FIG. 11A), wherein each sub-pixel has an 8-bit depth, may enable reproduction of an expanded gray-level range, e.g., arrange of more than 256 gray levels. For example, several different sub-pixel combinations of arrangement 1102 may be used to display a substantially white color using sets of sub-pixel pairs or triads as described in detail above. Thus, sub-pixel arrangements in accordance with the invention, for example, arrangement 1102, may enable displaying a substantially white color without using all primary color subpixels, e.g., using only part of the sub-pixels of a displayed pixel or repeating unit For example, in a display using arrangement 1102, the brightest white may be provided by setting the value of each sub-pixel to 255. The darkest gray achievable by a full pixel, corresponding to 8-bit color depth, may be obtained by setting the luminance value of each sub-pixel to 1. However, darker grays may be achieved according to embodiments of the invention, for example, by setting the values of the RGB sub-pixels to 1 while concurrently setting the luminance values of the CMY sub-pixels to 0. Since, according to an exemplary embodiment of the invention, the RGB triad may have only about a third or less of the total brightness of RGBMCY arrangement 1102, the darkest gray created by the RGB triad of arrangement 1102 may be darker than the darkest level of gray obtained by exciting all sub-pixels. Thus, by use of different triad combinations, according to exemplary embodiments of the invention, the displayable gray level range may be widened, e.g., by a factor of about 4, yielding an increase in bit-depth from about 8 to about 10. Although the above exemplary embodiments have been described for gray-level display, it will be appreciated by persons sided in the art that the n-primary arrangements described above may also be used to produce an expanded bit depth, i.e., a wider range of gray-levels, for colors of different tints and hues. FIG. 14 is a schematic diagram of the flow of data in a LCD display system incorporating a method for expanding bit depth in accordance with exemplary embodiments of the invention. Reference is also made to FIG. 15, which schematically illustrates a chromaticity diagram representing the color gamut of a 6-primary display in accordance with an exemplary embodiment of the invention. The method of FIG. 14 may include receiving input data, as indicated at block 1401. A first channel may be used to process the input data and to create an n-primary output as indicated at block 1402. For the 6 primary colors illustrated in FIG. 15, a selection of a triad of primary colors may define an effective field, e.g., effective field 1502 may be defined by a YMR triad. According to embodiments of the invention, in order to provide an expanded gray-level range for a desired color gamut, a triad of primary colors may be selected such that an effective field defined by the selected triad may include the desired color gamut, as explained in detail above. Referring again to FIG. 14, the input data may further be used to select a set of three primary colors corresponding to the effective field required to produce a desired gray level range and color gamut, as indicated at block 1403. An effective field may be defined by different color triads, e.g., effective field 1504 may be defined by the RGB and YCMY Selection of the three primary colors from a set of available triads debug a required effective field may include optimization of display attributes, for example, luminance uniformity, smoothness, or any other objective, subjective or relative display attribute. As indicated at block 1404, a second channel may be used to process the input data based on the three-primary colors selected at block 1403. The Input data may be further used to calculate a combination parameter as indicated at block 1405. The combination parameter calculation may be based on providing a smooth display, a required level of brightness or any other related display attribute. For example, for a high luminance input, combining the channels may provide an output including substantially the multi-primary output of the first channel. For a low-luminance input, combining the channels may provide an output including substantially the 3-prinary output of the second channel. For a substantially medium luminance input, the output may include a combination of both channels. The first and second channels may be smoothly combined as indicated at block 1406, as a function of the combination parameter calculated at block 1405. While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as the within the true spirit of the invention.

<SOH> BACKGROUND OF THE INVENTION <EOH>Standard computer monitors and TV displays are typically based on reproduction of three, additive, primary colors (“primaries”), for example, red, green, and blue, collectively referred to as RGB. Unfortunately, these monitors cannot display many colors perceived by humans, since they are limited in the range of color they are capable of displaying. FIG. 1A schematically illustrates a chromaticity diagram as is known in the art. The closed area in the shape of a horseshoe represents the chromaticity range of colors that can be seen by humans. However, chromaticity alone does not filly represent all visible color variations. For example, each chromaticity value on the two-dimensional chromaticity plane of FIG. 1A may be reproduced at various different brightness levels. Thus, a fill representation of the visible color space requires a three dimensional space including, for example, two coordinates representing chromaticity and EL third coordinate representing brightness. Other three dimensional space representations may also be defined. The points at the border of the horseshoe diagram in FIG. 1A , commonly referred to as “spectrum locus”, correspond to monochromatic excitations at wavelengths ranging, for example, from 400 nm to 780 nm. The straight in “closing” the bottom of the horseshoe, between the extreme monochromatic excitation at the longest and shortest wavelengths, is commonly referred to as “the purple line”. The range of colors discernible by the human eye, represented by the area of the horseshoe diagram above the purple line, at varying brightness levels, is commonly referred to as the color gamut of the eye. The dotted triangular area of FIG. 1A represents the range of colors that are reproducible by a standard RGB monitor. There are many known types of RGB monitors, using various display technologies, including but not limited to CRT, LED, plasma, projection displays, LCD devices and others. Over the past few years, the use of color LCD devices has been increasing steadily. A typical color LCD device is schematically illustrated in FIG. 2A . Such a device includes a light source 202 , an array of liquid crystal (LC) elements (cells) 204 , for example, an LC array using Thin Film Transistor (TFT) active-matrix technology, as is known in the art. The device further includes electronic circuits 210 for driving the LC array cells, e.g., by active-matrix addressing, as is known in the art, and a tri-color filter array, e.g., a RGB filter array 206 , juxtaposed the LC array. In existing LCD devices, each full-color pixel of the displayed image is reproduced by three sub-pixels, each sub-pixel corresponding to a different primary color, e.g., each pixel is reproduced by driving a respective set of R, G and B sub-pixels. For each sub-pixel there is a corresponding cell in the LC array. Back-illumination source 202 provides the light needed to produce the color images. The transmittance of each of the sub-pixels is controlled by the voltage applied to the corresponding LC cell, based on the RGB data input for the corresponding pixel. A controller 208 receives the input RGB data, scales it to the required size and resolution, and transmits data representing the magnitude of the signal to be delivered by the different drivers based on the input data for each pixel. The intensity of white light provided by the back-illumination source is spatially modulated by the LC array, selectively attenuating the light for each sub pixel according to the desired intensity of the sub-pixel. The selectively attenuated light passes through the RGB color filter array, wherein each LC cell is in registry with a corresponding color sub-pixel, producing the desired color sub-pixel combinations. The human vision system spatially integrates the light filtered through the different color sub-pixels to perceive a color image. U.S. Pat. No. 4,800,375 (“the '375 patent”), the disclosure of which is incorporated herein by reference in its entirety, describes an LCD device including an array of LC elements juxtaposed in registry with an array of color filters. The filter array includes the three primary color sub-pixel filters, e.g., RGB color filters, which are interlaced with a fourth type of color filter to form predetermined repetitive sequences. The various repetitive pixel arrangements described by the '375 patent, e.g., repetitive 16-pixel sequences, are intended to simplify pixel arrangement and to improve the ability of the display device to reproduce certain image patterns, e.g., more symmetrical line patterns. Other than controlling the geometric arrangement of pixels, the '375 patent does not describe or suggest any visual interaction between the three primary colors and the fourth color in the repetitive sequences. LCDs are used in various applications. LCDs are particularly common in portable devices, for example, the small size displays of PDA devices, game consoles and mobile telephones, and the medium size displays of laptop “notebook”) computers. These applications require thin and miniaturized designs and low power consumption. However, LCD technology is also used in non-portable devices, generally requiring larger display sizes, for example, desktop computer displays and TV sets. Different LCD applications may require different LCD designs to achieve optimal results. The more “traditional” markets for LCD devices, e.g., the markets of battery-operated devices (e.g., PDA, cellular phones and laptop computers) require LCDs with high brightness efficiency, which leads to reduced power consumption In desktop computer displays, high resolution, image quality and color richness are the primary considerations, and low power consumption is only a secondary consideration. Laptop computer displays require both high resolution and low power consumption; however, picture quality and color richness are compromised in many such devices. In TV display applications, picture quality and color richness are generally the most important considerations; power consumption and high resolution are secondary considerations in such devices. Typically, the light source providing back-illumination to LCD devices is a Cold Cathode Fluorescent Light (CCFL). FIG. 3 schematically illustrates typical spectra of a CCFL, as is known in the art. As illustrated in FIG. 3 , the light source spectra include three, relatively narrow, dominant wavelength ranges, corresponding to red, green and blue light, respectively. Other suitable light sources, as are known in the art, may alternatively be used The RGB filters in the filter sub-pixel array are typically designed to reproduce a sufficiently wide color gamut (e.g., as close as possible to the color gamut of a corresponding CRT monitor), but also to maximize the display efficiency, e.g., by selecting filters whose transmission curves generally overlap the CCFL spectra peaks in FIG. 3 . In general, for a given source brightness, filters with narrower transmission spectra provide a wider color gamut but a reduced display brightness, and vice versa For example, in applications where power efficiency is a critical consideration, color gamut width may often be sacrificed. In certain TV applications, brightness is an important consideration; however, dull colors are not acceptable. FIG. 4A schematically illustrates typical RGB filter spectra of existing laptop computer displays. FIG. 4B schematically illustrates a chromaticity diagram representing the reproducible color gamut of the typical laptop spectra (dashed-triangular area in FIG. 4B ), as compared with an ideal NTSC color gamut (dotted triangular area in FIG. 4B ). As shown in FIG. 4B , the NTSC color gamut is significantly wider than the color gamut of the typical laptop computer display and therefore, many color combinations included in the NTSC gamut are not reproducible by the typical color laptop computer display.

<SOH> SUMMARY OF THE INVENTION <EOH>Many colors seen by humans are not discernible on standard red-green-blue (RGB) monitors. By using a display device with more than three primary colors, the reproducible color gamut of the display is expanded Additionally or alternatively, the brightness level produced by the display may be significantly increased. Embodiments of the present invention provide systems and methods of displaying color images on a display device, for example, a thin profile display device, such as a liquid crystal display CCD) device, using more than three primary colors. Exemplary embodiments of an aspect of the invention provide improved multi-primary display devices using more than three sub-pixels of different colors to create each pixel. In embodiments of this aspect of the invention, the use of four or more different color sub-pixels, per pixel, allows for a wider color gamut and higher luminous efficiency. In some embodiments, the number of sub-pixels per pixel and the color spectra of the different sub-pixels may be optimized to obtain a desired combination of a sufficiently wide color gamut, sufficiently high brightness, and sufficiently high contrast. In some embodiments of the invention, the use of more than three primary colors may expand the reproducible color gamut of the display by enabling the use of relatively narrow wavelength ranges for some of the primary colors, e.g., red, green and blue, thus increasing the saturation of those primary colors. To compensate for a potentially reduced brightness level from such narrower ranges, in some embodiments of the invention, broad wavelength range privy colors, e.g., specifically designed yellow and/or cyan, may be used in addition to the narrow wavelength range colors, thus increasing the overall brightness of the display. In further embodiments of the invention, additional primary colors (e.g., magenta) and/or different primary color spectra may be used to improve various other aspects of the displayed image. In accordance with embodiments of the invention, an optimal combination of color gamut width and over-all display brightness can be achieved, to meet the requirements of a given system, by designing specific primary colors and sub-pixel arrangements. The color gamut and other attributes of a more-than-three primary color LCD device in accordance with embodiments of the invention may be controlled by controlling the spectral transmission characteristics of the different primary color sub-pixel filter elements used by the device. According to an aspect the invention, four or more different primary color sub-pixel filters are used, to produce four or more, respective, primary colors, for example, RGB and yellow (Y). In further embodiments of the invention, at least five different primary color sub-pixel filters are used, for example, RGB, Y and cyan (C) filters. In additional embodiments of the invention, at least six different primary color sub-pixel filters are used, for example, RGB, Y, C and magenta (M) filters. The primary color sub-pixel filters for a more-than-three primary color LCD device in accordance with the invention may be selected in accordance with various criteria, for example, to establish sufficient coverage of a desired color gamut, to maximize the brightness level that can be produced by the display, and/or to adjust the relative intensities of the primary colors according to a desired chromaticity standard. In accordance with embodiments of the invention, a multi-primary display with n primary colors may include an array of pixels, each pixel including n sub-pixels, wherein each sub-pixel has a predetermined aspect ratio, for example, n:1, which yields a desired aspect ratio, for example, 1:1, for each pixel. According to farther embodiments of the invention attributes of a multi-primary LCD display may be controlled and/or affected by specific arrangements of the n sub-pixels forming each pixel and/or specific arrangements of the pixels. Such attributes may include picture resolution, color gamut wideness, luminance uniformity and/or any other display attribute that may depend on the arrangement of the pixels d/or sub-pixels. According to one exemplary embodiment of the invention, color saturation may be improved by arranging the n primary colors in the n sub-pixels forming each pixel based on a hue order of the n primary colors. According to another exemplary embodiment of the invention, optimal viewed image uniformity, e.g., optimally uniform luminance across the viewed image may be achieved by arranging the n primary color sub-pixels forming each pixel to yield a minimal variance in luminance between neighboring groups of sub-pixels. In some embodiments of the invention, the sub-pixel arrangement may be determined by mapping a plurality of sub-pixel arrangements, determining a luminance value of each mapped arrangement, transforming the luminance values from spatial coordinates to spatial frequencies, e.g., harmonics, for example, by applying a Fourier Transform to the calculated luminance values, and minimizing the amplitude of a harmonic, e.g., the first harmonic, of the transformation. According to a further embodiment of the invention, the n primary sub-pixels are arranged within each pixel such that sub-sets of neighboring sub-pixels within the pixels have a relatively neutral white-balance. According to exemplary embodiments of another aspect of the invention, there is provided a system and method for n-primary subpixel rendering of a displayed graphic object, for example, a character having a certain font The method may enable modification of the viewed contour and/or edges of the displayed graphic, for example, to reduce a color fringes effect of the viewed object. The method may include sampling the graphic image, assigning each sub-pixel an initial coverage value, applying to each sub-pixel a smoothing function, for example, calculating a weighted average of a neighboring group of sub-pixels, and assigning an adjusted coverage value to each sub-pixel in the group based on the values calculated by the smoothing function. According to exemplary embodiments of yet another aspect of the invention, the reproducible bit-depth of a more-than-three primary color display may be expanded, i.e., a wider span of gray-levels may be obtained, compared to the bit-depth of three primary color displays, by reproducing at least some colors Bring combinations of only some of the primary color sub-pixels. This aspect of the invention may be advantageous in producing low gray-level pixels, because the variety of gray-levels may be particularly significant for the lower gray-levels. In some embodiments of this aspect of the invention, the gray-level of a pixel may be adjusted by adjusting the intensity of a sub-set of the n sub-pixels forming the pixel, for example, a sub-set capable of producing a substantially neutral white-balance.

20050202

20180424

20050609

75126.0

KARIMI, PEGEMAN

Color display devices and methods with enhanced attributes

UNDISCOUNTED

ACCEPTED

ACCEPTED

Sand catcher

The invention relates to a sand catcher comprising a deposition chamber (1) that is configured as a steel container with a cylindrical cross-section, traversed in a longitudinal direction. Said deposition chamber comprises air-supply nozzles (4) on one longitudinal side for generating a circulatory motion or the water transversally to the longitudinal direction of the deposition chamber (1) and a sand collection channel (3), located in the lower section, that runs in a longitudinal direction. A waste water inlet (6) for generating the circulatory motion of the water leads into the upper section of the deposition chamber (1), running transversally to said chamber. The air-supply nozzles (4) are provided on the side of the waste water inlet (6) below the latter (6).

1. A sand catcher comprising a longitudinal deposition chamber, a wastewater inlet at one end portion thereof, a water outlet at the other end portion thereof, air supply nozzles at one side for generating a transverse circulatory motion of the water, and a sand collection channel longitudinally disposed in the lower section of the chamber, wherein the wastewater inlet leads transversely to the deposition chamber into the upper section of said deposition chamber; and the air supply nozzles are disposed on the side of the wastewater inlet below the wastewater inlet. 2. A sand catcher as claimed in claim 1, wherein the air supply nozzles are provided incrementally at intervals from the wastewater inlet that increase in the longitudinal direction of the deposition chamber. 3. A sand catcher as claimed in claim 1, wherein the outlet end portion of the deposition chamber comprises a flotation section, which has air nozzles with a small cross section in order to generate fine air bubbles. 4. A sand catcher as claimed in claim 1, wherein the deposition chamber comprises a cylindrical steel container. 5. A sand catcher as claimed in claim 1, wherein the wastewater inlet has a screening grate from which a rake removes the screenings. 6. A sand catcher as claimed in claim 6, wherein the screening grate runs at least partially below the filling height of the deposition chamber. 7. A sand catcher as claimed in claim 1, wherein the outlet end of the deposition chamber is higher than the wastewater inlet end. 8. A sand catcher as claimed in claim 7, wherein the sand collection channel has a sand conveyor screw which conveys the sand to a discharge end, and the sand discharge point lies above the water level in the deposition chamber owing to the inclination of the deposition chamber. 9. A sand catcher as claimed in claim 1, wherein the water outlet is formed by a transversely running channel on the side of the deposition chamber opposite the wastewater inlet. 10. A sand catcher as claimed in claim 9, wherein the channel has, on the side facing the wastewater inlet, a side wall that extends higher than the maximum water level in the deposition chamber, and on its side facing away from the wastewater inlet a side wall which forms an overflow edge over which the water runs into the channel. 11. A sand catcher as claimed in claim 9, wherein the side walls of the channel have the same height and in front of the side facing the wastewater inlet a downflow wall projects from the top into the deposition chamber. 12. A sand catcher as claimed in at least claim 10, wherein, in front of the higher side wall or the downflow wall there is a scum intake, which extends as far as just below the normal water level in the deposition chamber. 13. A sand catcher as claimed in claim 1, further comprising a bypass line running from the wastewater inlet behind an overflow edge to the water outlet. 14. A sand catcher as claimed in claim 13, wherein the bypass line has a device for coarse purification and/or a scum catcher that can overflow. 15. A sand catcher as claimed in claim 5, wherein the sand collection channel is displaced with respect to a perpendicular central axis of the deposition chamber in the direction of the side of the screening grate. 16. A sand catcher as claimed in claim 1, wherein, on the side of the deposition chamber opposite the wastewater inlet, the water outlet is formed by an overflow pipe which empties into an overflow channel attached externally to the deposition chamber. 17. A sand catcher, as claimed in claim 16, wherein the deposition chamber has a cylindrical cross section and the overflow pipe empties into the deposition chamber in the area of its longitudinal axis. 18. A sand catcher as claimed in claim 1, further comprising a baffle arranged below the wastewater inlet.

The invention relates to a sand catcher, comprising a deposition chamber, which is traversed in the longitudinal direction, has a wastewater inlet and a water outlet, has air supply nozzles on one longitudinal side for generating a circulatory motion of the water transversely to the longitudinal direction of the deposition chamber, and has a sand collection channel, which runs in the longitudinal direction, in the lower section. A sand catcher of the aforementioned type is described in the journal “gwf”, volume 99, issue 22, May 30, 1958, pages 535-539. The special feature of the sand catcher, which is explained in this document and is made of concrete, lies in the fact that its deposition chamber has an oval cross section and that a circulatory motion of the water is generated by lateral air nozzles. The wastewater flows axially to the deposition chamber, destroying the kinetic energy of the oncoming water by means of an impact wall, provided at the inlet, with vortex chamber, so that the air nozzles can produce undisturbed the desired circulatory motion. The drawback with this prior sand catcher is that the desired circulatory motion can be realized only partially and that relatively large quantities of compressed air must be introduced. Furthermore, in the ideal case the quantity of air has to be regulated as a function of the quantity of wastewater flowing in, because the energy requirement for generating the circulatory motion increases as the quantity of wastewater increases. The invention is based on the problem of designing a sand catcher of the class described in the introductory part in such a manner that the requisite circulatory motion can be generated as reliably as possible and with a minimum air requirement. The invention solves this problem in that the wastewater inlet for generating the circulatory motion of the water leads transversely to the deposition chamber, into the upper section of said deposition chamber; and the air supply nozzles are provided on the side of the wastewater inlet below the wastewater inlet. Due to this inventive orientation of the wastewater inlet the kinetic energy of the water flowing in does not have to be destroyed, as explained in the publication cited in the introductory part, by means of an impact wall and vortex chamber. Rather, as in the case of a cyclone, this kinetic energy can be used to generate the circulatory motion. Therefore, the circulatory motion is generated independently of the compressed air that is fed in. The only function that the introduced compressed air still has is to assist the circulatory motion and to maintain it over the length of the deposition chamber. Therefore, the inventive sand catcher needs a significantly smaller quantity of air, so that hardly any more compressed air is necessary than what is already present to remove grease and organic substances from the sand. Under some circumstances, one can also work with pressurized water, instead of compressed air, so that the water issues under pressure from the air supply nozzles, provided according to the invention, a feature that also induces the water to circulate in the deposition chamber. It is especially advantageous to provide incrementally the air supply nozzles at intervals from the wastewater inlet that increase in the longitudinal direction of the deposition chamber. In such an arrangement optimal consideration is given to the fact that the circulatory motion is generated then primarily by the energy of the wastewater flowing in transversely and that the friction-induced flow losses do not have to be balanced by the energy of the compressed air until the distance from the wastewater inlet increases. If it is important that more grease be removed—for example in the food industry, it is advantageous to provide a flotation section on the outlet side of the deposition chamber. To generate fine air bubbles, the flotation section has air nozzles with a small cross section. The sand catcher of the invention can be manufactured especially economically and can be delivered as a functional unit, if the deposition chamber is designed as a cylindrical steel container. Such steel containers are commercially available at a good price as standardized components with outwardly rounded heads. The sand catcher can perform at the same time additional functions and hence be designed as a compact system, if, according to another further development of the invention, the wastewater inlet has a screening grate, from which a rake removes the screenings. Such a rake can be designed, for example, as described in the DE 195 09 738 A1, so that a fully automatic operation is possible and the screenings can be thrown to the side of the deposition chamber. The water in the deposition chamber flows around the bottom side of the screening grate, so that the risk of clogging is low, if, according to another further development of the invention, the screening grate runs at least partially below the filling height of the deposition chamber. Fatty substances, which have detached themselves from the sand in the deposition chamber or float freely in the wastewater, move due to buoyancy automatically to one end of the deposition chamber, from where they can be readily extracted, when the deposition chamber rises, seen from the direction of the wastewater inlet. In this respect it is especially advantageous for the sand collection channel to have a sand conveyor screw, which conveys the sand to a discharge side, and for the sand discharge point to lie above the water level in the deposition chamber owing to the inclination of the deposition chamber. In this manner the sand conveyor screw can convey the sand as far as the discharge point, so that no additional transport mechanism for ejecting the sand is necessary. The water outlet is designed optimally, if it is formed by a transversely running channel on the side of the deposition chamber opposite the wastewater inlet. The water leaves the deposition chamber without generating any turbulence in said deposition chamber and without taking any floating matter with it, when, according to another further development of the invention, the channel exhibits on its side facing the wastewater inlet a side wall that extends higher than the maximum water level in the deposition chamber, and on its side, facing away from the wastewater inlet, a side wall, which forms an overflow edge, over which the water runs into the channel. However, it is also possible as an alternative that the side walls of the channel have the same height and that in front of the side facing the wastewater inlet a downflow wall projects from the top into the deposition chamber. In this manner the channel has two overflow edges. Grease and other floating matter can be removed separately, if in front of the higher side wall or the downflow wall there is a scum intake, which extends as far as just below the normal water level in the deposition chamber. In the event of malfunctions in the sand catcher, the wastewater can bypass easily said sand catcher, if a bypass line, which is provided preferably with a device for coarse purification of the water, runs from the wastewater inlet behind an overflow edge to the water outlet. In this case it involves, for example, a screening grate, which is to be cleaned manually and has a slit width of approximately 20 to 30 mm. Furthermore, there can also be a scum catcher that can overflow. In place of the overflow edge, there can also be a slide valve, which is opened when the water accumulates in front of the wastewater inlet. The water rotating in the deposition chamber flows first through an equalizing stretch before it passes with the sand to be removed to the sand collection channel, when, according to another further development of the invention, the sand collection channel is displaced with respect to a perpendicular central axis of the deposition chamber in the direction of the side of the screening grate. As an alternative to the aforementioned water outlet with a channel running transversely to the deposition chamber, there can also be an overflow pipe, which empties into an overflow channel, attached externally to the deposition chamber. It has the advantage that the rotation of the water in the cylindrical deposition chamber extends over its entire length so that its solids removal efficiency is increased. Preferably the overflow pipe empties into the deposition chamber in the area of its longitudinal axis. There the still remaining sand concentration is minimal, so that almost sandless water is removed from the deposition chamber. The arrangement of a baffle below the wastewater inlet also forces the circulation of the water that is generated by the air bubbles flowing in. The invention permits various embodiments. To further explain its basic principle, two embodiments are depicted as schematic drawings and are described below. FIG. 1 is a cross section of a sand catcher, according to the invention. FIG. 2 is a top view of the sand catcher. FIG. 3 is a side view of a second embodiment of the inventive sand catcher. FIG. 4 is a longitudinal view of a modified, rear section of a sand catcher. FIG. 5 is a top view of the section, according to FIG. 4. FIG. 6 is a longitudinal view of a modified embodiment of the sand catcher. FIG. 7 is a cross section of the embodiment, according to FIG. 6. FIG. 8 is a cross section of an alternative embodiment, according to FIG. 4. The sand catcher, depicted in FIG. 1, has a deposition chamber 1 with a cylindrical cross section. In the lower section, seen in the drawing shifted to the left, this deposition chamber 1 has a sand collection channel 2, which runs in the longitudinal direction of the deposition chamber 1 and in which there is a sand conveyor screw 3. On the side of the sand collection channel 2, air supply nozzles 4, from which air bubbles 5 rise to the top owing to the supply of compressed air, are arranged in succession over the entire length of the deposition chamber 1. Similarly on the side of the sand collection channel 2 a wastewater inlet 6 is arranged on the upper side of the deposition chamber 1. This wastewater inlet contains an inclined screening grate 7, over the top side of which a rake 8 can move so that the screenings pass into an ejector (not illustrated). Below the screening grate there is a baffle 6a, which assists air bubbles-induced circulation, by introducing the water flowing in through the wastewater inlet 6 tangentially into the deposition chamber 1. FIG. 2 shows that the deposition chamber 1 is designed as a steel container with outwardly rounded heads 10. Shown as a schematic drawing is the sand collection channel 2 with the sand conveyor screw 3, which conveys the sand that has settled out to a sand discharge point 11. Furthermore, FIG. 2 shows the wastewater inlet 6 on the left side of the deposition chamber 1 and a water outlet 12, through which the purified water leaves the deposition chamber 1. On the side of the water outlet 12 the deposition chamber 1 has a flotation section 13, which differs from the rest of the section in that, in place of the air supply nozzles 4, there are relatively fine air nozzles 14 in an air hose 15. Through these air nozzles 14 air flows in the form of fine air bubbles into the water with the result that more grease is removed in the flotation section 13. In the embodiment, according to FIG. 3, the deposition chamber 1 rises from the wastewater inlet 6 to the water outlet 12. Thus, the sand discharge point 11 can be arranged so high that it lies above the water level in the deposition chamber 1 and that the sand conveyor screw 3 can convey the sand that is removed directly to the sand discharge point 11. FIG. 4 shows the outlet-sided end of the deposition chamber 1. In this embodiment the water outlet 12 is formed by a transversely running channel 16 on the side of the deposition chamber 1 that is opposite the wastewater inlet 6. This channel has two side walls 17, 18, of which the side wall 17, facing the wastewater inlet 6, is higher than the maximum water level in the deposition chamber 1. The side wall 18 on the side, facing away from the wastewater inlet 6, is lower and forms an overflow edge 19, over which the water runs into the channel 16. Thus, the water always flows from the rear side into the channel, after it had to flow beforehand below the channel. In front of the higher side wall 17 there is a scum intake 20, which extends as far as just below the normal water level and by means of which the especially fatty and other floating matter can be extracted. FIG. 5 illustrates the design shown in FIG. 4. One can see the channel 16 as a part of the water outlet 12 and an outlet connecting pipe 21, through which the water leaves the deposition chamber 1. Furthermore, FIG. 5 shows a bypass line 22, which leads to the outlet connecting pipe 21, and the significance of which is explained by means of FIGS. 6 and 7. FIG. 6 shows that the bypass line 22 leads from the wastewater inlet 6 to the water outlet 12. If the deposition chamber 1 is fed too much wastewater, it does not flow through an inlet channel 24 and the screening grate 7 into the deposition chamber 1, but rather over an overflow edge 23 into the bypass line 22 and from there directly to the water outlet 12. FIG. 7 shows the inlet channel 24, which leads to the screening grate 7, and the bypass line 22 behind the overflow edge 23. A coarse purification and optionally a scum catcher that can overflow is installed in the bypass line 22, which is not illustrated here in detail. FIG. 8 shows a water outlet, which constitutes an alternative to the water outlet, depicted in FIG. 4. An overflow pipe 25, which is bent upwardly and the mouth 26 of which lies below the water level 27 in the deposition chamber 1, attaches axially at a central point on the outlet-sided head 10 of the deposition chamber 1. The overflowing water is collected in an overflow channel 28, attached externally to the outlet-sided head 10 and continues from there. The overflow pipe 25 can be designed in such a manner that one part of pipe wall is formed by the outlet-sided head 10. List of Reference Numerals 1 deposition chamber 2 sand collection channel 3 sand conveyor screw 4 air supply nozzle 5 air bubble 6 wastewater inlet 6a baffle 7 screening grate 8 rake 10 head 11 sand discharge point 12 water outlet 13 flotation section 14 air nozzle 15 air hose 16 channel 17 side wall 18 side wall 19 overflow edge 20 scum intake 21 water outlet connecting pipe 22 bypass line 23 overflow edge 24 inlet channel 25 overflow pipe 26 mouth 27 water level 28 overflow channel

20041112

20081021

20050303

99019.0

LITHGOW, THOMAS M

SAND CATCHER

SMALL

ACCEPTED

ACCEPTED

Flow control mechanism for a downhole tool

There is disclosed a flow control mechanism for a downhole tool and a downhole tool incorporating the flow control mechanism. In one embodiment, a flow control mechanism (202) is disclosed for controlling a centralizer (200). The flow control mechanism (202) comprises a body (212) defining a fluid chamber (234); an inlet flow path (292) for fluid flow into the chamber (234); at least one tool flow path (294) for fluid flow between the chamber (234) and at least part of the downhole tool (200); an exhaust flow path (297) for fluid flow from the chamber (234) to a fluid exhaust (240); and control means including a control member (218) mounted for movement within the chamber (234) for controlling flow into and out of the chamber (234) along the inlet flow path (292), the at least one tool flow path (294), and the exhaust flow path (297). The mechanism (202) controls flow to a piston (214) of the centralizer (200) for centralizing the centralizer (200) within, for example, a tubular (211) in the bore hole.

1. A flow control mechanism for a downhole tool, the downhole tool comprising a downhole tool for generating a fluid pressure pulse, the mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow of fluid into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path, and wherein the fluid is a wellbore fluid, and the control mechanism is activatable in response to applied fluid pressure from the wellbore. 2. A flow control mechanism for a downhole tool, the mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow of fluid into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path, and wherein the fluid is a wellbore fluid, and the control mechanism is activatable in response to applied fluid pressure from the wellbore. 3. A flow control mechanism as claimed in claim 2, wherein the mechanism is for controlling flow between the chamber and a fluid activated member of the downhole tool. 4. A flow control mechanism as claimed in claim 3, wherein the mechanism is activatable in response to a static well fluid pressure. 5. A flow control mechanism as claimed in claim 3, wherein the mechanism is activatable in response to hydrostatic well fluid pressure. 6. A flow control mechanism as claimed in claim 2, wherein the mechanism is activatable in response to well fluid flow. 7. A flow control mechanism as claimed in claim 2, wherein the mechanism is provided as an integral part of a downhole tool. 8. A flow control mechanism as claimed in claim 2, wherein the mechanism is adapted to be coupled to a downhole tool. 9. A flow control mechanism as claimed in claim 2, wherein the control member is movable in a direction along a length of the body for opening flow between the inlet flow path, the chamber and the at least part of the downhole tool. 10. A flow control mechanism as claimed in claim 9, wherein the control member is also movable for opening fluid flow between the downhole tool, the chamber and the exhaust flow path. 11. A flow control mechanism as claimed in claim 2, including a plurality of tool flow paths for flow between the chamber and separate parts of the downhole tool. 12. A flow control mechanism as claimed in claim 2, including a plurality of tool flow paths for flow between the chamber and parts of a plurality of downhole tools. 13. A flow control mechanism as claimed in claim 2, further comprising a plurality of seal elements which, together with the control member, are adapted to control flow into the chamber along the inlet flow path, flow between the chamber and the downhole tool, and flow out of the chamber along the exhaust flow path. 14. A flow control mechanism as claimed in claim 13, wherein the seal elements are provided in the chamber and are adapted to seal with a surface of the control member. 15. A flow control mechanism as claimed in claim 2, wherein the tool flow path defines a flow path for flow from the chamber to the downhole tool and vice-versa. 16. A flow control mechanism as claimed in claim 2, wherein the control member is locatable in a first position where flow between the inlet flow path and the chamber, the chamber and the downhole tool and the chamber and the exhaust, respectively, is prevented. 17. A flow control mechanism as claimed in claim 16, wherein the control member is movable to a second position allowing fluid flow between the inlet flow path and the chamber and between the chamber and the downhole tool, and to a third position allowing fluid flow between the downhole tool, the chamber and the exhaust. 18. A flow control mechanism as claimed in claim 16, wherein in the first position the control member is in sealing engagement with first and second seal elements. 19. A flow control mechanism as claimed in claim 18, wherein in the second position the control member is out of sealing engagement with a first seal for allowing flow into the chamber along the inlet flow path and flow between the chamber and the downhole tool. 20. A flow control mechanism as claimed in claim 19, wherein in the third position the control member is out of sealing engagement with the first seal and a second seal for allowing flow between the downhole tool and the chamber and between the chamber and the exhaust. 21. A flow control mechanism as claimed in claim 20, wherein the inlet flow path is closed before the control member is located in the third position. 22. A flow control mechanism as claimed in claim 20, further comprising an inlet flow path entrance port for supply of fluid into the inlet flow path, the entrance port being closed before the control member is located in the third position. 23. A flow control mechanism as claimed in claim 22, including a movable plug for closing the entrance port. 24. A flow control mechanism as claimed in claim 2, further comprising a filter for filtering fluid entering the inlet flow path. 25. A flow control mechanism as claimed in claim 2, comprising at least two tool flow paths, each tool flow path for fluid flow between the chamber and a respective separate part of the downhole tool. 26. A flow control mechanism as claimed in claim 2, comprising at least two tool flow paths, each tool flow path for fluid flow between the chamber and a separate downhole tool. 27. A flow control mechanism as claimed in claim 25, wherein each tool flow path defines a flow path for flow from the chamber to part of a downhole tool and vice-versa. 28. A flow control mechanism as claimed in claim 2, wherein the control member is movable between a first position allowing flow into the chamber along a first tool flow path and from the chamber to the downhole tool; and a second position allowing flow into the chamber and from the chamber to the downhole tool along a second tool flow path. 29. A flow control mechanism as claimed in claim 28, wherein in the first position, the control member also allows flow from the downhole tool to the chamber along the second tool flow path. 30. A flow control mechanism as claimed in claim 28, wherein in the second position, the control member also allows flow from the downhole tool to the chamber along the first tool flow path. 31. A flow control mechanism as claimed in claim 28, wherein in the first position of the control member, the member is in sealing engagement with selected seal elements for allowing flow between the chamber and the downhole tool along a selected tool flow path. 32. A flow control mechanism as claimed in claim 31, wherein in the second position of the control member, the member is in sealing engagement with selected other seal elements for allowing flow between the chamber and the downhole tool along a selected tool flow path. 33. A flow control mechanism as claimed in claim 2, wherein the chamber is subdivided into a number of secondary chambers which are adapted to be selectively fluidly isolated by the control member. 34. A flow control mechanism as claimed in claim 33, wherein seal elements in the chamber, together with the control member, define the secondary chambers. 35. A flow control mechanism as claimed in claim 31, wherein the control member includes reduced dimension portions adapted to straddle a seal element to allow fluid flow. 36. A flow control mechanism as claimed in claim 2, wherein the control member comprises a needle valve rod. 37. A flow control mechanism as claimed in claim 2, wherein the mechanism is adapted to be activated mechanically by application of a force to the control member for moving the control member within the chamber. 38. A flow control mechanism as claimed in claim 2, including a release mechanism coupled to the control member, in a restraint position the release mechanism restraining the control member against movement and in a release position the control member being movable within the chamber. 39. A flow control mechanism as claimed in claim 38, wherein the release mechanism is adapted to be moved between the restraint and release positions by a wireline coupled to the assembly. 40. A flow control mechanism as claimed in claim 38, wherein the release mechanism is adapted to be moved between the restraint and release positions by application of fluid pressure. 41. A flow control mechanism as claimed in claim 2, wherein the fluid exhaust comprises an exhaust chamber isolated from the hydrostatic pressure of fluid outside the mechanism. 42. A flow control mechanism as claimed in claim 41, wherein the exhaust chamber is initially at surface atmospheric pressure. 43. A downhole tool assembly having at least one flow control mechanism according to claim 2. 44. A downhole tool assembly as claimed in claim 43, wherein the downhole tool includes at least one fluid activated member; and the flow control mechanism controls at least part of the downhole tool comprising the at least one fluid activated member. 45. A downhole tool assembly as claimed in downhole tool assembly as claimed in claim 43, wherein the downhole tool comprises a downhole tool for generating a fluid pressure pulse. 46. A downhole tool assembly as claimed in claim 45, wherein the assembly comprises a measurement-while-drilling apparatus. 47. A downhole tool assembly as claimed in claim 45, further comprising flow restriction means mounted for movement between a first position and a second position where fluid flow is restricted with respect to the first position to generate a fluid pressure pulse. 48. A downhole tool assembly as claimed in claim 47, including a fluid activated member in the form of a piston defining the flow restriction means. 49. A downhole tool assembly as claimed in claim 47, including a fluid activated member in the form of a piston coupled to the flow restriction means. 50. A downhole tool assembly as claimed in claim 48, wherein the piston is movable in a direction along a length of the tool. 51. A downhole tool as claimed in claim 47, wherein the flow restriction means comprises a first part which is movable in response to movement of the control member, and a second part for restricting the flow of fluid through the body. 52. A downhole tool as claimed in claim 47, wherein the flow restriction means comprises a piston assembly which is movable in response to applied fluid pressure. 53. A downhole tool as claimed in claim 52, wherein at least part of the piston assembly is hollow to selectively allow fluid to pass therethrough. 54. A downhole tool as claimed in claim 52, wherein the piston assembly includes a first piston part which is movable in response to applied fluid pressure and a second piston part for restricting flow. 55. A downhole tool as claimed in claim 47, wherein a body of the tool includes a first fluid inlet through which fluid enters the tool body, and wherein the flow restriction means closes the first fluid inlet when the flow restriction means is in the second position. 56. A downhole tool as claimed in claim 47, wherein the fluid exhaust comprises an exhaust chamber dimensioned to contain fluid discharged from multiple cycles of movement of the flow restriction means between the first and second positions. 57. A downhole tool as claimed in claim 45, wherein the tool further comprises pressure isolation means for isolating at least part of the flow restriction means from the pressure of fluid outside the tool. 58. A downhole tool as claimed in claim 57, wherein the pressure isolation means includes an isolation chamber at least partly containing a gas. 59. A downhole tool as claimed in claim 45, wherein the tool further comprises drive means for moving the control member, the drive means operative in response to an applied fluid pressure. 60. A downhole tool assembly as claimed in claim 44, comprising a plurality of fluid activated members. 61. A downhole tool assembly as claimed in claim 60, wherein the fluid activated members are spaced along a length of the downhole tool and are rotationally spaced around the tool. 62. A downhole tool assembly as claimed in claim 44, wherein the fluid activated member is mounted in a tool/body for movement substantially radially with respect to the tool/body. 63. A downhole tool assembly as claimed in claim 44, wherein the downhole tool comprises a centraliser and the fluid activated member comprises a piston of the centraliser. 64. A downhole tool assembly as claimed in claim 63, wherein the centraliser comprises a plurality of pistons for centralising the tool within a tubular in a borehole. 65. A downhole tool assembly as claimed in claim 63, comprising at least three pistons spaced around a circumference of the centraliser, the pistons being activatable to move outwardly and engage the borehole wall. 66. A downhole tool assembly as claimed in claim 63, wherein the piston is mounted in a cylinder coupled to the chamber, the cylinder containing a gas at a pressure less than the hydrostatic pressure of fluid outside the tool. 67. A downhole tool assembly as claimed in claim 63, wherein the piston defines a first inner piston area greater than a second, outer piston area, the second piston area being open to well pressure. 68. A downhole tool assembly as claimed in claim 67, wherein the piston extends through a sealed opening in the cylinder. 69. A centraliser comprising a flow control mechanism and a fluid activated member movable outwardly for centralising the centraliser in a borehole, the flow control mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and the fluid activated member; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. 70. A downhole tool for generating a fluid pressure pulse, the downhole tool comprising a flow control mechanism and a flow restriction means, the flow restriction means including a fluid activated member movable between a first position and a second position where fluid flow is restricted compared to the first position, the flow control mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and the fluid activated member; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. 71. A method of controlling the operation of a downhole tool, the method comprising the steps of: coupling a control mechanism to the downhole tool to define: an inlet flow path for fluid flow into a chamber of the mechanism; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; and an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and moving a control member of the mechanism within the chamber to control flow into and out of the chamber along the inlet flow path, the at least one tool flow path and the exhaust flow path. 72. A downhole tool comprising: a body defining a fluid flow path; flow restriction means movably mounted in the body, for movement between a first position and a second position where fluid flow is restricted compared to the first position; and activating means including a member movable in a direction along a length of the body to cause the flow restriction means to move between the first and second positions. 73. A downhole tool comprising: a housing defining a fluid flow path; flow restriction means movably mounted in a first chamber in the housing, for movement in response to applied fluid pressure between a first position and a second position where fluid flow is restricted compared to the first position; and activating means including a member movable to cause the flow restriction means to move between the first and second positions, whereby movement of the flow restriction means between the first and second positions displaces fluid from the first chamber into a second, storage chamber defined in the housing. 74. A downhole tool comprising: a body defining a fluid flow path; flow restriction means movably mounted in the body, for movement between a first position and a second position where fluid flow is restricted compared to the first position; activating means including a member movable to cause the flow restriction means to move between the first and second positions; and pressure isolation means for isolating at least part of the flow restriction means from the exterior of the tool. 75. A method of generating a fluid pressure pulse in a borehole, the method comprising the steps of: locating a body in the borehole to define a fluid flow path through the body; providing a movable flow restriction means in the body, movable between a first position and a second position where fluid flow through the body is restricted compared to the first position; and moving a flow restriction means activating member in a direction along a length of the body, to cause the flow restriction means to move to the second position, to restrict the flow of fluid through the body, generating a fluid pressure pulse. 76. A method as claimed in claim 75, further comprising a method of transmitting data indicating the value of a desired parameter. 77. A flow control mechanism for a downhole tool, the mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. 78. A downhole tool assembly as claimed in claim 43, wherein the downhole tool comprises one of: a fluid pressure pulse generator, a centraliser, a downhole packer, a downhole valve, a sliding sleeve, a downhole shutting tool, a temporary positioning tool or a trigger.

The present invention relates to a flow control mechanism for a downhole tool. The present invention also relates to a downhole tool assembly including a downhole tool and a flow control mechanism. In the oil and gas exploration and production industry, a wide range of downhole tools are used for performing specific functions in the downhole environment. Many of these tools are fluid pressure activated and include relatively complex flow control mechanisms for controlling activation of the tool. Frequently these tools require a positive fluid flow for activation, for example, flow past the tool when located in a borehole. Other tools, such as centralisers which are used for centralising a secondary tool in tubing in a well borehole, are mechanical and may include, for example, fins such as rubber fins or sprung arms. Where rubber fins are used, the fins are dimensioned to be a close fit within a tubular in which the centraliser is located whilst sprung arms are compressed inwardly on location of the centraliser within the tubular. In both cases, this acts to centralise a body of the centraliser and thus a tool coupled to the centraliser, such as a drill bit, within the tubular. However, fixed dimension centralisers such as these create potential problems when subsequently removed from the borehole, as a tool such as a packer, valve or jar may have been located in the borehole above the centraliser, these tools restricting the diameter of the borehole and making it difficult to withdraw the centraliser. Also, to comply with safety regulations and to monitor the inclination of well boreholes, among other reasons, the hole may be surveyed periodically during drilling. It is important, for example, that the location of the drill bit relative to the mouth of the hole is known so that a relief well can be drilled in the event of a blow-out. It is presently known to measure the inclination of a drilled hole using one of four types of devices. The first type of device is a drift indicator, the second is a magnetic single shot device, the third is a mechanical measuring-while drilling device (MMWD), and the fourth is a directional measuring-while-drilling device (DMWD). The first two types of device (the drift indicator and emagnetic single shot device) have been used for more than 50 years. They require a person drilling a well to lower the device into the hole, wait for the device to perform a reading, raise the device from the hole, and then check the measurement taken by the device. Frequently, a second measurement is required to confirm the accuracy of the first measurement. These devices are very expensive to use because the drilling procedure is halted while the device is being used to survey the hole. The third type of device (the MMWD) has been used for more than 40 years. It is located above the drill bit in a purpose-built collar. This device uses a swinging mechanical pendulum to measure the inclination of the device with reference to the vertical plane. This inclination reading is linked to a mechanically activated plunger which, when activated, produces a pulse which is transferred to the surface. Each pulse represents 0.5 degrees of inclination. This provides a measurement of the verticality (the downhole inclination) of the hole. The fourth type of device (the DMWD) is similar to the MMWD but conveys information about the inclination of the hole by means of binary code rather than by mechanically activated pressure pulses. At the drilling console, the code is received, decoded and the results are displayed to the drill operators. The DMWD has a number of disadvantages associated with it. For example, it usually needs at least one trained engineer to operate it correctly and it is more expensive than the other devices. Presently, the most commonly used device is the MMWD device. It is relatively inexpensive to run and does not require an additional trained engineer to operate it. However, these devices are not very accurate or reliable. They are also very expensive to make because they are housed in collars which can cost more than the combined cost of the component parts inside them. A further disadvantage of these devices is that they are sometimes lost downhole, that is, they have to be abandoned, for example in situations where the bottom hole assembly becomes stuck. It is amongst the objects of embodiments of the present invention to obviate or mitigate at least one of the foregoing disadvantages. According to a first aspect of the present invention, there is provided a flow control mechanism for a downhole tool, the mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. The invention therefore provides a control mechanism for controlling fluid flow within a downhole tool by movement of a control member of the mechanism. Thus the mechanism may be used to control exposure of the downhole tool to fluid pressure. The mechanism may be for controlling flow between(the chamber and a fluid activated member of the downhole tool, such as a piston, valve or sliding sleeve. The control mechanism may be activatable in response to applied fluid pressure, and may be activatable in response to a static fluid pressure, for example, the hydrostatic pressure of a fluid in which the control mechanism is located, such as the well pressure of fluid in a borehole of an oil or gas well. Accordingly, the mechanism may be adapted to be activated by hydrostatic well pressure and does not require fluid flow for activation, in contrast to prior assemblies. The mechanism may also be activatable in response to fluid flow, and may therefore be activatable in response to applied pressure of a flowing fluid. The mechanism may therefore function in a fluid flow environment, for example, where there is fluid flow past the downhole tool, or by supplying hydraulic fluid to the mechanism through control lines or the like. The mechanism may be adapted to be provided as an integral part of a downhole tool, or as a separate mechanism adapted to be coupled to a downhole tool. The mechanism may comprise a control mechanism for a plurality of downhole tools and the control member may be movable for controlling flow between the chamber and parts of a plurality of downhole tools. The body may comprise a body of a downhole tool, or may comprise a separate body adapted to be coupled to a downhole tool. The control member may be movable in a direction along a length of the body and may define an activating member. The control member may be movable for opening flow between the inlet flow path, the chamber and the part of the downhole tool, for supplying fluid to the downhole tool. The control member may also be movable for opening fluid flow between the downhole tool, the chamber and the exhaust flow path. The mechanism may comprise an inlet flow port for flow into the chamber along the inlet flow path, a tool flow port for flow between the chamber and the downhole tool along the tool flow path and an exhaust flow port for flow between the chamber and the exhaust along the exhaust flow path. The mechanism may include a plurality of tool flow ports and associated tool flow paths for flow between the chamber and separate parts of the downhole tool, or between the chamber and parts of a plurality of downhole tools. The control means may further comprise a plurality of seal elements which, together with the control member, are adapted to control flow into the chamber along the inlet flow path, flow between the chamber and the downhole tool, and flow out of the chamber along the exhaust flow path. The seal elements may be provided in the chamber and may be adapted to seal with a surface of the control member. The control member may be movable out of sealing abutment with the seals for opening fluid flow. The control member may be movable between a position allowing fluid flow between the inlet flow path and the chamber and between the chamber and the downhole tool, and a further position allowing fluid flow between the downhole tool, the chamber and the exhaust. Thus simple, relatively small movements of the control member may control flow of fluid through the mechanism. The tool flow path may define a flow path for flow between the chamber and the downhole tool and vice-versa. This allows flow both to and from the downhole tool along a single tool flow path. The control member may be locatable in a position where flow between the inlet flow path and the chamber, the chamber and the downhole tool and the chamber and the exhaust, respectively, is prevented or closed, which may comprise a first, running-in position of the control member. This may allow the downhole tool to be run-in to a well without inadvertently activating the mechanism. The control member may be movable to second and third positions where flow is allowed, as described above. In the first position of the control member, the member may be in sealing engagement with first and second seal elements for closing flow. In the second position, the control member may be out of sealing engagement with a first seal, for allowing flow into the chamber along the inlet flow path and flow between the chamber and the downhole tool; and in the third position, the control member may be out of sealing engagement with a second seal for allowing flow between the downhole tool and the chamber and between the chamber and the exhaust. Flow into the chamber along the inlet flow path may be adapted to be closed before or during movement of the control member to the third position. This allows the chamber to exhaust without further flow into the chamber along the inlet flow path. The mechanism may further comprise an inlet flow path entrance port for supply of fluid into the inlet flow path. The entrance port may be adapted to be closed before or during movement of the control member to the third position. The mechanism may include a movable plug such as a sleeve or collar movable for closing the entrance port. The mechanism may further comprise a filter for filtering fluid entering the inlet flow path. This allows the mechanism to be activated using well fluids or other fluids typically found in a well borehole. The movable plug may define the filter, and may define a passage between an inner surface of the plug and the body for flow of fluid into the inlet flow path, the passage dimensioned to prevent solids entering the passage. In an alternative embodiment, the mechanism may comprise at least two tool flow paths, each tool flow path for fluid flow between the chamber and a respective separate part of the downhole tool, or separate downhole tools. Each flow path may be adapted for flow from the chamber to separate parts of the downhole tool, or from the chamber to respective parts of separate downhole tools, as well as for flow from separate parts of the downhole tool to the chamber, or respective parts of separate downhole tools and the chamber. Thus fluid may be supplied to and exhausted from the downhole tool. The control member may be movable between a first position allowing flow into the chamber along a first tool flow path and from the chamber to the downhole tool; and a second position allowing flow into the chamber and from the chamber to the downhole tool along a second tool flow path. In the first position, the control member may also allow flow from the downhole tool to the chamber along the second tool flow path. This may facilitate movement of a fluid activated member such as a piston of the downhole tool coupled in a closed loop to the chamber, for example, by fluid flow to one end of the fluid activated member and fluid exhaust from the other end of the fluid activated member. In the second position, the control member may also allow flow from the downhole tool to the chamber along the first tool flow path. In the first position of the control member, the member may be in sealing engagement with selected seal elements for allowing flow between the chamber and the downhole tool along tool flow paths. In the second position of the control member, the member may be in sealing engagement with selected other seal elements for allowing flow between the chamber and the downhole tool along tool flow paths. The chamber may be subdivided into a number of secondary chambers which are adapted to be selectively fluidly isolated by the control member. The seal elements, together with the control member, may define the secondary chambers. The control member may include reduced dimension portions which are adapted to straddle a seal element to allow fluid flow. The control member may comprise a needle valve which may be generally rod shaped. The mechanism may be adapted to be activated mechanically by application of a force to the control member for moving the control member within the chamber. The control mechanism may be adapted to be activated mechanically. For example, the assembly may include a release mechanism coupled to the control member, in a restraint position the release mechanism restraining the control member against movement and in a release position, the control member being movable within the chamber. The release mechanism may be moved between the restraint and release positions by a wireline coupled to the assembly. Alternatively, the release mechanism may be movable by applied fluid pressure, for example, by application of a pressure above a predetermined threshold, or by flow sequencing, for example, by application of fluid pressures in a determined sequence. In further alternatives, the release mechanism may be movable remotely and independently using electronic programming, for example, by electronic wireline coupled to the assembly, or by a combination of any of the foregoing. It will be understood that following activation in this fashion, the control mechanism may be subsequently activated by applied fluid pressure as described above. The exhaust may comprise an exhaust chamber isolated from the hydrostatic pressure of fluid outside the mechanism. This allows flow to the exhaust chamber from the fluid chamber when required. The exhaust chamber may initially be at surface atmospheric pressure. According to a second aspect of the present inventions there is provided a downhole tool assembly comprising: a downhole tool including a fluid activated member; and a flow control mechanism for controlling operation of the fluid activated member, the flow control mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and the fluid activated member; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. Further features of the flow control mechanism are defined above. The downhole tool may comprise a plurality of fluid activated members. The fluid activated members may be spaced along a length of the downhole tool, and may be rotationally spaced around the tool. The fluid activated member may be mounted in the body for movement substantially radially with respect to the body. The downhole tool may comprise a centraliser and the fluid activated member may comprise a piston of the centraliser. Preferably, the centraliser comprises a plurality of pistons which are adapted to centralise the tool within a borehole of an oil or gas well, such as within a tubular such as casing, liner, production tubing or any other tubular. The centraliser may be adapted to centralise a downhole tool within a borehole. Thus the centraliser may be adapted to be coupled to a downhole tool for centralising the downhole tool and the tool may therefore be hydraulically self-centring within a borehole. Most preferably, the centraliser comprises at least three pistons spaced around a circumference of the centraliser, the pistons being activatable to move outwardly and engage the borehole wall. The piston may be retractable from a radially extended position, allowing the tool assembly to pass through a bore restriction. The piston may be retractable when the control member is in the second position, allowing flow to the exhaust. The pistons may be equally rotationally spaced and where there are three pistons, may be spaced at 120° intervals for centralising the tool when the pistons are moved outwardly. The pistons may act as clamps for clamping a wall of a borehole. The piston may be mounted in a cylinder coupled to the chamber, the cylinder initially containing a gas at a pressure less than the pressure of fluid supplied to the chamber. The piston may also define a first inner piston area greater than a second, outer piston area, the second piston area being open to well pressure. In this fashion, the piston experiences a force when fluid is supplied from the chamber to the piston cylinder, to move the piston radially outwardly. The piston may extend through a sealed opening in the cylinder and may include an abutment surface which may comprise a protective cover coupled to the piston, for exerting a force on a borehole to centralise the tool within the borehole. Alternatively, the downhole tool may comprise a downhole tool for generating a fluid pressure pulse, such as a borehole inclination measuring (drift) tool, the tool including a fluid activated member in the form of a piston, the piston coupled to or defining flow restriction means mounted for movement between a first position and a second position where fluid flow is restricted compared to the first position. The piston may be movable in a direction along a length of the tool. The flow restriction means may include the fluid activated member such that movement of the flow restriction means depends upon movement of the fluid activated member, which movement is controlled by the control mechanism. Further features of the downhole tool for generating a fluid pressure pulse will be defined below. In alternative embodiments, other downhole tools may be provided incorporating the control mechanism or the control mechanism may be provided as part of a tool used to control other downhole tools; for example a downhole packer; a downhole valve such as an open/shut valve; a sliding sleeve; a downhole shutting tool (for shutting off a well); or a tool for providing temporary positioning of tools, such as cutting or patching tools, in tubing; or as a trigger for other devices such as sampling tools, perforating tools or any other downhole tool requiring positioning and/or activating. The fluid activated member may comprise a piston coupled to a sliding sleeve, a valve element such as a ball valve or flapper valve or to any other fluid activated member of a downhole tool. According to a third aspect of the present invention, there is provided a centraliser comprising a flow control mechanism and a fluid activated member movable outwardly for centralising the centraliser in a borehole, the flow control mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and the fluid activated member; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. The fluid activated member may be movable radially outwardly for centralising the centraliser in the borehole. It will be understood that the term centralising within a borehole is intended to include centralising within a tubular within a borehole, for example, casing, liner or production tubing, as well as in an open (unlined) borehole. Further features of the centraliser are defined above. According to a fourth aspect of the present invention, there is provided a downhole tool for generating a fluid pressure pulse, the downhole tool comprising a flow control mechanism and a flow restriction means, the flow restriction means including a fluid activated member movable between a first position and a second position where fluid flow is restricted compared to the first position, the flow control mechanism comprising: a body defining a fluid chamber; an inlet flow path for fluid flow into the chamber; at least one tool flow path for fluid flow between the chamber and the fluid activated member; an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and control means including a control member mounted for movement within the chamber for controlling flow into and out of the chamber along the inlet flow path, the at least one tool flow path, and the exhaust flow path. The downhole tool may comprise a borehole inclination measuring (drift) tool. Further features of the tool for generating a fluid pressure pulse are defined above. According to a fifth aspect of the present invention, there is provided a method of controlling the operation of a downhole tool, the method comprising the steps of: coupling a control mechanism to the downhole tool to define: an inlet flow path for fluid flow into a chamber of the mechanism; at least one tool flow path for fluid flow between the chamber and at least part of the downhole tool; and an exhaust flow path for fluid flow from the chamber to a fluid exhaust; and moving a control member of the mechanism within the chamber to control flow into and out of the chamber along the inlet flow path, the at least one tool flow path and the exhaust flow path. According to a further aspect of the present invention, there is provided a downhole tool comprising: a body defining a fluid flow path; flow restriction means movably mounted in the body, for movement between a first position and a second position where fluid flow is restricted compared to the first position; and activating means including a member movable in a direction along a length of the body to cause the flow restriction means to move between the first and second positions. Preferably, the downhole tool is for generating a fluid pressure pulse. The flow restriction means may be movable between the first and second positions to generate a fluid pressure pulse. Advantageously, movement of the activating member controls fluid communication between, for example, the exterior of the tool and the flow restriction means, for moving the flow restriction means between the first and second positions. The flow restriction means may comprise a first or upper part which is movable in response to movement of the activating member, and a second or lower part which restricts the flow of fluid through the body when the flow restriction means is in the second position. The flow restriction means may be generally in the form of a piston. Preferably, the flow restriction means comprises a piston assembly which is movable in a direction along a length of the body in response to applied fluid pressure. At least part of the piston assembly may be hollow to selectively allow fluid to pass therethrough, and at least part of the piston assembly may be mounted in a cylinder defined by the body. The piston assembly may include a first or upper piston part which is movable in response to applied fluid pressure and a second or lower piston part. The first piston part may be hollow. A piston rod may couple the first and second piston parts. The body may comprise a generally tubular outer housing of the tool and may include a first fluid inlet through which fluid may enter the body. It will be understood that, when the tool is located in, for example, a drill string, fluid may partly flow around the tool, but that the major part of the fluid flow is through the first fluid inlet into the body, passing through the body and exhausting into the string at a downstream location. The flow restriction means, preferably the second piston part may close the first fluid inlet when the flow restriction means is in the second position. The body may include a separate, second fluid inlet through which fluid may enter the body for moving the flow restriction means between the first and second positions. The activating means may include a bore in the body and the activating member may be movably mounted in the bore. Preferably, the activating means further comprises a hollow control body mounted in the tool body, the control body defining the bore. The control body may include a sleeve in which part of the piston assembly, preferably the upper piston part, is mounted, and one or more housing rings coupled to the sleeve. The sleeve may define a cylinder, and the one or more housing rings may define the activating member bore. The activating means, in particular the control body, may include a control flow port for allowing selective supply of fluid to the bore. In use, fluid may be supplied from the body second fluid inlet and to the control flow port. Preferably, the activating means, in particular the control body, includes four control flow ports opening on to the bore and associated with respective first, second, third and fourth control fluid flow channels, which channels may be defined by the control body. The first fluid flow channel may be for supplying fluid to the bore through the first control fluid port, and the second, third and fourth fluid flow channels may be for allowing fluid communication between the bore and the flow restriction means through the second, third and fourth flow ports, respectively. The second fluid flow channel may couple a first end of the upper piston part to the bore and the third fluid flow channel may couple a second end of the upper piston part to the bore. Advantageously therefore, when fluid is supplied from the bore to one end of the upper piston part, fluid is returned from the other end to the bore, and vice versa. Thus it will be understood that by controlling the flow of fluid to and from the flow restriction means, the movement of the flow restriction means and thus the generation of a fluid pressure pulse may be controlled. The tool may further comprise a chamber for storing fluid evacuated from the bore. In particular, the chamber may be for storing fluid returned to the bore through the second and third channels. The fourth fluid flow channel may couple the bore and the chamber. Conveniently, the fourth fluid flow channel couples the bore with the hollow interior of the upper piston part, for exhausting fluid through the upper piston part into the chamber. The chamber may be dimensioned to contain fluid discharged from multiple, for example, at least one hundred and fifty cycles of movement of the flow restriction means between the first and second positions. The bore may comprise a number of secondary chambers, which chambers may be selectively fluidly isolated by the activating member. A number of seals may be provided in the bore, said seals, together with the activating member, defining the secondary chambers. The activating member may be movable with respect to the seals, and may define fluid flow paths which are selectively isolated by the seals. In particular, the activating member may comprise a generally cylindrical rod, the rod including cut-away or reduced dimension portions, which may straddle a seal to define a flow path and allow fluid communication therethrough depending upon the position of the activating member. Preferably also, the tool further comprises pressure isolation means for isolating the part of the piston assembly from the pressure of fluid outside the tool. The pressure isolation means may include an isolation chamber at least partly containing a gas, which may be at surface atmospheric pressure. The upper piston part and/or an end of the piston rod may be mounted partly in the isolation chamber. The lower piston part may experience equal fluid pressure on opposite piston faces thereof. This may prevent hydraulic lock of the piston assembly. The tool may further comprise drive means for moving the activating member, which drive means may include a drive motor. The motor is conveniently battery powered, and may be operative in response to an applied fluid pressure. This is particularly advantageous in that a drive means is provided which does not require, for example, control lines or power lines extending to surface, with the associated disadvantages which will be appreciated by the skilled person. The activating member may be in the form of a partly screw threaded rod, which may be rotated by the drive means to move in the direction along a length of the housing. According to a still further aspect of the present invention, there is provided a downhole tool comprising: a housing defining a fluid flow path; flow restriction means movably mounted in a first chamber in the housing, for movement in response to applied fluid pressure between a first position and a second position where fluid flow is restricted compared to the first position; and activating means including a member movable to cause the flow restriction means to move between the first and second positions, whereby movement of the flow restriction means between the first and second positions displaces fluid from the first chamber into a second, storage chamber defined in the housing. According to a yet further aspect of the present invention, there is provided a downhole tool comprising: a body defining a fluid flow path; flow restriction means movably mounted in the body, for movement between a first position and a second position where fluid flow is restricted compared to the first position; activating means including a member movable to cause the flow restriction means to move between the first and second positions; and pressure isolation means for isolating at least part of the flow restriction means from the exterior of the tool. Preferably, the downhole tool is for generating a fluid pressure pulse. The flow restriction means may be movable between the first and second positions to generate a fluid pressure pulse. By this arrangement, the pressure isolation means advantageously prevents hydraulic lock of the flow restriction means, in use. According to a yet further aspect of the present invention, there is provided a method of generating a fluid pressure pulse in a borehole, the method comprising the steps of: locating a body in the borehole to define a fluid flow path through the body; providing a movable flow restriction means in the body, movable between a first position and a second position where fluid flow through the body is restricted compared to the first position; and moving a flow restriction means activating member in a direction along a length of the body, to cause the flow restriction means to move to the second position, to restrict the flow of fluid through the body, generating a fluid pressure pulse. The step of providing a movable flow restriction means may further comprise mounting a piston in the housing and selectively coupling the piston to a fluid pressure source. The step of moving the flow restriction means activating member may further comprise the step of coupling drive means to the activating member and activating the drive means to move the member. The fluid pressure pulse may provide an indication that the measurement of a desired parameter is to be transmitted, the magnitude of said measurement depending upon the length of time between pressure pulses. Thus the method may further comprise a method of transmitting data indicating the value of a desired parameter. The step of moving the flow restriction member may further comprise the step of selectively supplying fluid to a first part of the flow restriction means whilst exhausting fluid from a second part of the flow restriction means. It will be understood that one or more features of the above described aspects of the present invention may be provided singly or in combination. Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which: FIG. 1 is a schematic illustration of a downhole tool incorporating a flow control mechanism, in accordance with an embodiment of the present invention, the tool shown located in a drill string in a borehole; FIG. 1A is an enlarged, longitudinal partial cross-sectional view of the downhole tool of FIG. 1, shown in an open position; FIG. 1B is a schematic cross-sectional view of part of the downhole tool of FIG. 1A, taken along line A-A of FIG. 1A; FIG. 1C is an enlarged view of part of the downhole tool of FIG. 1A, taken along line D-D indicated in FIG. 1B; FIGS. 1D and 1E are further enlarged views of part of the tool of FIG. 1, taken along lines B-B and C-C of FIG. 1B, respectively; FIG. 2 is a view of the downhole tool of FIG. 1, similar to the view of FIG. 1A but showing the tool in a closed position; FIG. 2A is a graphical illustration of generation of fluid pressure pulses using the tool of FIG. 1; FIGS. 3A and 3B are enlarged views of part of the downhole tool shown in the open position of FIG. 1A; FIGS. 4A and 4B are enlarged views of part of the downhole tool shown in the closed position of FIG. 2; FIG. 5 is a schematic illustration of a downhole tool including a flow control mechanism, in accordance with an alternative embodiment of the present invention, the tool shown located in a drill string in a borehole in a deactivated position; FIG. 6 is a view of the downhole tool of FIG. 5 in an activated position; FIG. 7 is an enlarged view of the downhole tool of FIG. 5; FIG. 8 is a top view of the downhole tool shown in FIG. 7; FIG. 9 is a partially sectioned exploded view of the downhole tool shown in FIG. 7; FIG. 10 is a schematic illustration of part of the flow control mechanism of the downhole tool shown in FIG. 7; and FIGS. 11, 12 and 13 are schematic views of parts of the downhole tool of FIG. 7 shown at various stages in a procedure of operating the tool. Referring initially to FIG. 1, there is shown somewhat schematically a view of a downhole tool in accordance with an embodiment of the present invention, the tool indicated generally by reference numeral 10. The tool 10 takes the form of an Electronic Drift Tool (EDT) for use in MWD techniques. The tool 10 is shown located within a string of tubing, typically a drill string 11, by a baffle 13 of a type similar to that disclosed in United Kingdom Patent Publication No. 2334732 the content of which is incorporated herein by reference. Drilling fluid (not shown) is pumped through the string 11 to a drill bit 15 in the direction of-the arrow A′, before returning to surface through annulus 19, in the direction of the arrows B′, carrying entrained drill cuttings. Supply of the drilling fluid is controlled by a pump 21, whose operation is governed manually by the drill operator 23. A pressure sensor 25 measures the pressure of the fluid in the annulus 19, to detect a pressure pulse, and the measurements are recorded by a processor 27. The tool 10 includes an electronics package 29, which includes a pressure sensor, inclinometer, accelerometer and a processor (not shown), together with a drive means in the form of a motor 22, shown in FIG. 1A and which will be described in more detail below. The baffle 13 both locates the tool 10 in the drill string, and constrains flow through the string 11 to be directed through ports 17 in the baffle 13 and, selectively, through the tool 10. In fact, as will be described below, a major part of the fluid flow through the drill string is directed through the tool 10, when the tool 10 is in an open position. Referring now to FIG. 1A, there is shown a longitudinal cross-sectional view of the downhole tool 10 of FIG. 1 in more detail. A control mechanism 2 in accordance with an embodiment of the present invention is provided as part of the tool 10. The control mechanism 2 includes a body in the form of an outer housing 12 of the tool 10, the body defining a chamber or inner bore 34; an inlet flow path 92 for fluid flow into the chamber 34; at least one tool flow path 94, 96 for fluid flow between the chamber 34 and part of the tool 10; an exhaust flow path 97, 112 for fluid flow from the chamber to a fluid exhaust 40; and control or activating means, indicated generally by reference numeral 16, which includes a control or activating member 18. The control member 18 is mounted for movement within the chamber 34 for controlling flow into and out of the chamber 34 along the inlet flow path 92, the at least one tool flow path 94, 96, and the exhaust flow path 97, 112, as will be described in more detail below. The control member 18 is movable along a length of the housing 12 to cause the flow restriction means of the tool 10, comprising a piston assembly 14, to move between first and second positions. The tool 10 is shown in FIG. 1A in an open position, where the piston assembly 14 is in a first position and fluid flows through the housing 12. In FIG. 2, the piston assembly 14 is shown in the second position where the piston assembly 14 has moved to close the tool 10, to prevent fluid flow therethrough and thereby generate a fluid pressure pulse. The structure of the tool will now be described in more detail, viewing FIGS. 1A and 2 top to bottom. At an upper end of the tool 10, drive means 20 are provided for moving the control member 18. The drive means 20 includes a fluid activated electric motor 22 powered by a battery in the tool (not shown), and a bearing and gearing assembly 24. The control member 18 takes the form of a needle valve or activating rod, which is threaded at 19 and extends through an internally threaded upper guide housing 26. When the motor 22 is activated, the motor rotates the rod 18, moving the rod longitudinally along the housing 12 between the positions of FIGS. 1A and 2A. The motor 22 is fluid activated according to the pressure of the fluid in the drill string 11. The control means 16 includes a control body which comprises five annular seal housing rings 28 and a lower sleeve assembly 30 defining a cylinder. Each of the seal housing rings 28 are secured together and to the sleeve assembly 30 by high tensile cap screws 32, which ensure correct rotational orientation of the rings 28. The rings 28 together define the chamber or inner bore 34 in which the rod 18 is located, and a number of seals 36 are provided between the rings 28 to seal the chamber 34. Referring now also to FIGS. 1D and 1E, there are shown enlarged views of part of the tool 10, taken along lines B-B and C-C of FIG. 1B, respectively. The sleeve assembly 30 includes an outer sleeve 31 and an inner sleeve 38, which defines a cylinder 42 in which part of the piston assembly 14 is located. The outer sleeve 30 and inner sleeve 38 are located by a sub 12a of the housing 12, which is in turn, coupled to a lower housing part 12b , and the housing part 12b defines the fluid exhaust which comprises a chamber 40, as will be described below. The inner sleeve 38 carries a number of sets of seals 42a, 42b and 42c, for sealing the inner sleeve 38 and for directing fluid into the cylinder 42. The piston assembly 14 includes an upper piston part 44 and a lower piston part 46 (shown to the right in FIGS. 1A and 2), coupled together by a hollow piston rod 48. When the tool 10 is open (FIG. 1A), fluid enters a muleshoe 12d of the housing 12 through a first flow port 50, flowing along the housing 12, exhausting through a lowermost outlet 51 and flowing to the drill bit 15. Movement of the piston assembly 14 between the open position and the closed position (FIG. 2), controlled by the control mechanism 2, moves the lower piston part 46 to close the first flow port 50, increasing annulus fluid pressure to generate a fluid pressure pulse. The piston part 46 includes a solid wall 47, whilst the end faces 49, 51 include apertures to allow fluid flow axially through the piston to a pressure isolation unit 58, which will be described below. Fluid is supplied to the control mechanism 2 to move the tool 10 between the first, open position and the second, closed position through an inlet path entrance port comprising a second tool fluid inlet 52. The inlet 52 is defined by an upper end of the sub 12a that carries a filter 54 for removing relatively large particles from the drilling fluid. The housing part 12b is coupled to a lower housing part 12c through a threaded, hollow seal end housing unit 56. This unit 56 seals the fluid exhaust chamber 40 and the piston rod 48, to prevent fluid escape from the chamber 40 during movement of the rod 48. Below the seal end housing unit 56, pressure isolation means in the form of a pressure isolation unit 58 isolates a lower end 60 of the piston rod 48, and thus the upper piston part 44, from the pressure of fluid outside the tool 10. This allows the upper piston part 44 to move and prevents hydraulic lock. The pressure isolation unit 58 includes a threaded housing 62 which couples the housing part 12c to the muleshoe 12d, and which includes two passages 64 and a pressure isolation chamber 66. The pressure isolation chamber 66 carries a seal 68 in which the lower end 60 of the piston rod 48 is moveably mounted, and is charged with a gas at surface pressure, before the tool 10 is run downhole. The passages 64 receive connecting rods 70, which secure the lower piston part 46 to the piston rod 48 through upper and lower piston connectors 72 and 74, respectively. Both the rods 70 are free to move within the passages 64, and are unsealed for fluid communication through the annulus between the outer surface of the rods 70 and the inner surface of the passages 64. This ensures that the pressure of the fluid on the upper and lower faces 76 and 78 of the lower piston part 46 are equal, to prevent hydraulic lock-up of the upper piston part 44. During movement of the upper piston part 44 to the second, closed position of FIG. 2, the lower end 60 of the piston rod 48 compresses the gas in the pressure isolation chamber 66. In general terms, operation of the tool 10 to move between the open position of FIG. 1A and the closed position of FIG. 2 is achieved in the following fashion. Fluid is supplied to the chamber 34 carrying the rod 18 from the drill string 11, through the second fluid inlet 52. Fluid supply from the chamber 34 into the cylinder 42 carrying the upper piston part 44 depends upon the longitudinal position of the rod 18. Thus, movement of the rod 18 in a direction along the length of the housing 12 selectively supplies and exhausts fluid to the cylinder 42. This moves the upper and lower piston parts 44 and 46 to close the first fluid inlet 50 (FIG. 2), which prevents fluid flowing through the muleshoe 12d to the drillbit. In this fashion, fluid flow is constrained to be directed through the baffle only. This restricts the flow of fluid through the drillstring, increasing fluid pressure and generating a fluid pressure pulse. Typically, the tool 10 is held in a closed position only for a short duration, to generate the pressure pulse. This is illustrated graphically in FIG. 2A, which is a graph of the annulus pressure (measured by pressure sensor 25) against time. The annulus pressure during a drilling operation (ylpsi) is typically in the region of 500 psi to 10,000 psi, depending upon the depth of the borehole (and thus the hydrostatic pressure). When it is desired to transmit data such as borehole inclination, measured by sensors in the electronics package 29, the tool 10 is closed (FIG. 2), restricting fluid flow in the string 11, increasing fluid pressure, and generating first fluid pressure pulse PP1. When detected at surface, this indicates that a measurement is about to be transmitted. The tool is reopened (FIG. 1A) and closed again to generate pressure pulse PP2, which indicates the start of a measuring period. The tool is then reopened once more, before a final pressure pulse PP3 is generated, indicating the end of the data transmission. The magnitude of the parameter (for example, borehole inclination) transmitted is determined by measuring the peak to peak time x1 between the pulses PP2 and PP3, which is equal to x3-x2. Alternatively, the time may be measured between return of fluid pressure to level y1. The structure and operation of the tool 10 will now be described in more detail with reference in particular to FIGS. 1D, 1E and FIGS. 3A to 4B. As shown in FIG. 1A, fluid enters the tool 10 through the second fluid inlet 52, passing through the filter 54 and into an annulus 82 defined between the sleeve 30, seal housing rings 28 and the outer housing 12. A seal 84 is provided to seal an upper end of the annulus 82. In a similar fashion, a seal (not shown) at a lower end of the annulus 82 directs fluid into the chamber 34. In FIGS. 1D and 1E, the five seal housing rings 28 have been numbered 28a-28e, respectively, for ease of reference. Six annular seals 86a-86f are mounted in the chamber 34 and the control rod 18 is slidable within the seals between the positions of FIGS. 1A and 2. Each respective pair of seals 86a/b; 86b/c; 86c/d; 86d/e; and 86e/f separate the chamber 34 into a number of secondary chambers 88a-88e, respectively. These chambers 88a-88e are isolated by the control rod 18, depending upon its longitudinal position. The rod 18 includes cut-away portions 90a, 90b and 90c, which are of reduced outer diameter compared to the remainder of the rod 18. Depending upon the position of the rod 18, these portions 90a-90c straddle respective ones of the seals 86a-86e, to allow fluid communication between adjacent chambers 88a-88e. Also, the outer and inner sleeves 30 and 38, together with the various seal housing rings 28a-28e, define the inlet flow path 92, tool flow paths 94, 96 and the exhaust flow paths 97, 112. The inlet flow path 92 includes an inlet flow port 100 opening onto the chamber 34. The tool flow path 94 defines a first tool flow path including a first tool flow port 102 opening onto the chamber 34 and a cylinder port 108 opening onto the cylinder 42. In a similar fashion, the tool flow path 96 defines a second tool flow path including a second tool flow port 104 opening onto the chamber 34 and a cylinder port 110, whilst the exhaust flow path 97 defines an exhaust flow port 106 opening onto the chamber 34, and this channel 97 communicates with an upper end 112 of the cylinder 42. The cylinder end 112 also forms an exhaust flow path in selective communication with a lower end of the chamber 34, as will be described below. FIGS. 3A and 3B show part of the tool 10 in the open position of FIG. 1A, and FIGS. 4A and 4B show the tool in the closed position of FIG. 2. FIGS. 3A and 4A are sectional views on line B-B of FIG. 1B, whilst FIGS. 3B. and 4B are sectional views on line C-C. To move the tool to the closed position, where the first fluid flow port 50 is closed, generating a pressure pulse, the motor 22 is activated to move the control rod 18 longitudinally in a direction towards the motor, to the position of FIGS. 4A and 4B. In this position, the cut-away portion 90b straddles the seal 86d, allowing flow between chambers 88c and 88d. This allows fluid to flow through the inlet flow path 92, through the inlet flow port 100 into the second tool flow port 104, along the second tool flow path 96, before discharging into the cylinder 42. This fluid acts against an upper piston face 114 of the upper piston part 44 (FIG. 4A). Simultaneously, the cut-away portion 90a straddles seal 86b, allowing flow between the chambers 88b and 88a. Therefore when fluid is supplied to the cylinder 42 through the second tool flow path 96, fluid is simultaneously exhausted from the cylinder 42, by downward movement of the upper piston part 44. This fluid flows through the port 108, through the first tool flow path 94 and into the chamber 34 through the first tool flow port 102. This fluid is then exhausted across seal 86b and out of chamber 88a into the exhaust path defined by the upper end 112 of the cylinder 42. The exhausted fluid flows through the inner bore 118 of the upper piston part 44, and through exhaust ports 120 into the fluid exhaust chamber 40, which is under a vacuum (reduced pressure) or contains gas at surface pressure. This movement of the upper piston part 44 brings the lower piston part 46 to the closed position of FIG. 2, generating the pressure pulse. When it is desired to re-open the housing 12, the upper piston part 44 is returned to the first position shown in FIGS. 3A and 3B. This is achieved by activating the motor 22 to rotate the control rod 18 in the opposite direction, to move it longitudinally downwardly away from the motor 22. In this position, the cut-away portion 90b now straddles the seal 86c, allowing flow from chamber 88c to chamber 88b. Fluid supplied to the chamber 34 through the inlet flow port 100 thus travels across seal 86c and enters the first tool flow path 94 through the first tool flow port 102. This fluid is supplied through port 108 into the cylinder 42, to act against a lower piston face 116 of the upper piston part 44 (FIG. 3A). Simultaneously, the cut-away portion 90c is moved to a position where it straddles the seal 86e (FIG. 3B), allowing flow across the seal 86e from chamber 88d to chamber 88e. This allows fluid to be exhausted from the cylinder 42 through the port 110, along the second tool flow path 96 and into the chamber 34, through the second tool flow port 104. The fluid travels across the seal 86e and into the exhaust flow path 97 via the exhaust flow port 106. Therefore this fluid is exhausted from the cylinder 42, through the chamber 34 and into the upper end 112 of the cylinder 42, through inner bore 118 of the upper piston part 44 and into the exhaust chamber 40. The exhaust chamber 40 is of a volume sufficient to contain fluid discharged from a large number of such cycles of the tool, typically of the order of 150 cycles. This is advantageous in that this allows multiple cycles of pressure pulses (and therefore transmission of data to surface) to be carried out before the tool 10 is pulled out of hole and the exhaust chamber 40 emptied ready for further use. As shown in FIG. 1C, optional backup-safety bleed ports 122 may be provided to provide a safety bleed from the cylinder 42 to annulus preventing surge. Turning now to FIG. 5, there is shown a downhole tool in accordance with an alternative embodiment of the present invention, the tool indicated generally by reference numeral 200 and comprising a centraliser. Like components of the centraliser 200 with the drift tool 10 of FIGS. 1-4B share the same reference numerals incremented by 200. As will be described below, the centraliser 200 includes a control mechanism 202 in accordance with an alternative embodiment of the present invention, similar to the control mechanism 2 of the downhole tool 10. The centraliser 200 is shown in FIG. 5 coupled to the drift tool 10 of FIGS. 1-4B, for centralising the tool 10 within a drill string 211, similar to the string 11 illustrated in FIG. 1. This ensures accurate inclination measurements of the borehole are obtained. The centraliser 200 is moveable between a deactivated position. shown in FIG. 5, and an activated position shown in FIG. 6 where fluid activated members comprising three centralising pistons 244 are urged radially outwardly to engage a wall 122 of the drill string 211. The centraliser is moved to the activated position under the control of the control mechanism 202, which will now be described, in conjunction with a wireline 124. The centraliser 200 is shown in more detail in the enlarged view of FIG. 7 and in FIG. 8, which is a top view of the centraliser shown in FIG. 7. The pistons 244 are shown in FIGS. 7 and 8 in a retracted position and are rotationally spaced 120° apart around the centraliser and axially staggered. The control mechanism 202 is shown in more detail in FIG. 9, which is a partially sectioned, exploded view of the centraliser. For clarity, only one of the centraliser pistons 244 is shown in FIG. 9. The flow control mechanism 202 controls the operation of the centraliser 200 and includes a body 212 defining a fluid chamber 234, also shown in the enlarged schematic view of FIG. 10. The mechanism 202 also includes an inlet flow path 292 for fluid flow into the chamber 234, at least one tool flow path in the form of tool flow path 294 for fluid flow between the chamber and part of the centraliser 200, and an exhaust flow path 297 for fluid flow from the chamber 234 to a fluid exhaust in the form of an exhaust chamber 240 (FIG. 13), which is sealed from well pressure. Control means 216 of the mechanism includes a moveable control rod or needle valve 218 mounted for movement within the chamber 234, for controlling flow into and out of the chamber 234 along the inlet flow path 292, the at least one tool flow path 294 and the exhaust flow path 297. Each centraliser piston 244 is mounted in a cylinder 242 for movement between the retracted and extended positions of FIGS. 5 and 6. The piston 244 is coupled to the chamber 234 through the tool flow path 294, for selectively exposing the piston 244 to hydrostatic wellbore pressure, to urge the piston radially outwardly for engaging the wall 122 of the drill string 211. This movement is controlled by movement of the control rod 218 within the chamber 234. In more detail, the centraliser 200 includes an upper housing 126 and a shaft 128 coupled to the control rod 218 and threaded to the upper housing 126 for movement together. The upper housing 126 is coupled to the body 212 and moveable in an axial direction on a stub 130 of the body 212. This movement of the housing 126 causes a corresponding movement of the control rod 218 within the chamber 234. An annular collar or plug 132 is mounted around the stub 130 and is moveable independently of the upper housing 126 and a hollow body 134 is movably mounted within the plug 132 and threaded to the stub 130. The body 134 defines a passage 136 in which the control rod shaft 128 is movably mounted and a threaded coupling 138 of the body 134 defines the chamber 234. The control rod 218 is mounted within the chamber 234 for movement with respect to first and second seal elements 286a, 286b which sealingly engage the control rod. As shown in FIG. 10 and the enlarged view of FIG. 11, the inlet flow path 292 extends through the body 134 and includes an inlet flow port 300 opening onto the chamber 234 and an entrance flow port 294 allowing fluid flow into the inlet flow path 292. In the deactivated position of FIG. 9, the entrance flow port 298 is closed by the plug 132, as will be described below. The entrance flow port 298 is closed during running-in of the centraliser 200. This prevents the centraliser from being inadvertently activated during run-in to the borehole. The stub 130 includes an annular groove (not shown) in an upper surface forming part of the inlet flow path 292. This facilitates connection of the body 134 to the stub as the rotational orientation of the body 134 does not need to be precisely determined; the groove ensures the inlet flow path in the stub 130 and body 134 are fluidly coupled. Each piston 244 is mounted in an opening 140 in the tool body 212 and a threaded housing connector 142 is mounted and sealed in the opening 140. The housing connector 142 is threaded to the body 212 and defines a passage 144 fluidly coupling the piston 244 to the tool flow path 294, which opens into the opening 140. The piston cylinder 242 is provided as a housing which is threaded and sealed to the housing connector 142 surrounding the piston 244 and the piston 244 includes a threaded stub 146 which extends through an opening 148 in an end of the cylinder housing 242. The piston 244 includes a first O-ring seal 150 which is larger than a second O-ring seal 152 mounted in the opening 148 and thus defines a larger piston area than the seal 152. A protective cover 153 is threaded to the piston stub 146 and defines an abutment surface for abutting and engaging the drill string wall 122. The cylinder 242 is charged with a gas, typically air at surface atmospheric pressure, before the centraliser 200 is run into the borehole. Thus, when a first face 314 of the piston 244 is exposed to hydrostatic well pressure, the seal 150, which is larger than the seal 152, causes a pressure force to be exerted on the piston face 314, which is greater than that exerted on the piston face 316, such that the piston 244 is urged radially outwardly to the extended position of FIG. 6, engaging the drill string wall 122. The method of operation of the centraliser 200 will now be described in more detail, with reference to FIGS. 11-13, which are enlarged, schematic illustrations of parts of the centraliser 200. In the running-in position of the centraliser 200 of FIG. 5, the upper housing 126 and thus the control rod shaft 128 and the control rod 218 are locked to the tool body 212. In this position, the inlet path entrance port 298 is open, however, the control rod 218 seals against the seal elements 286a, 286b, as shown in FIG. 10, to both close the tool inlet flow path 292 and the exhaust flow path 297. Thus, although the inlet path entrance port 298 is open, there is no flow through the chamber 234. When the downhole tool 10 has been located in a baffle 213 in the drill string 211, a locking mechanism, (not shown) releases the upper housing 126. A release tool 156 is mounted around the upper housing 126 and is located in an undercut 160 engaging a lower shoulder 158 of the housing. The release tool 156 is mounted on the wireline 124 and is moved upwardly by the wireline 124, to carry the upper housing 126 a short distance upwardly with respect to the tool body 212. Through the connection between the control rod shaft 128 and the control rod 218, this moves the control rod upwardly from the first, closed position of FIGS. 9, 10 and 11 to a second position, illustrated in FIG. 12 where there is a gap between an upper surface of the plug 132 and the upper housing 126. In this position, the control rod 218 has moved past the lower seal 286a, opening flow along the inlet flow path 292 into the chamber 234. Fluid enters the inlet entrance port 298 along an annulus 154 (FIG. 9) defined between the plug 132 and the upper housing 126. This provides communication through the chamber 234 and along the tool flow path 294. The tool inlet entrance port 298 is open to hydrostatic well pressure, therefore the piston 244 now experiences well pressure on the piston face 314, and is urged radially outwardly. Similar movement of each of the other pistons 244 centralises the body 212 of the centraliser and thus the downhole tool 10 within the drill string 211. It will be understood that the hydrostatic pressure of fluids in the drill string 211 are sufficient to activate the pistons 244, and thus that no fluid flow through the string is necessary. The centraliser will operate at a pressure of as low as 250 psi and in a range of 250 to 10,000 psi. However, the centraliser operates in fluid flow environments such as is typical downhole. When the centraliser 200 is in the activated position of FIG. 6, the centraliser exerts a sufficiently large force on the string wall 122 to clamp the drift tool 10 centrally within the string and also resists axial movement of the drift tool 10. When it is desired to deactivate the centraliser 200, it is necessary to move the pistons 244 to the retracted positions of FIG. 5. This is achieved by engaging the release tool 156 in the undercut 160 in engagement with a lower shoulder 162 of the plug 132, as shown in FIG. 6. A second upward movement of the release tool 156 initially carries the plug 132 upwardly to close the gap between the plug and the upper housing 126, and to close the entrance port 298. This closes the inlet flow path 292 and shuts off fluid communication between the chamber 234 and the exterior of the centraliser 200. A further upward movement of the plug 132 now carries the upper housing 126 a further distance upwardly with respect to the tool body 212. This moves the control rod 218 a further distance upwardly past the second seal 286b, opening flow through the chamber 234 between the tool flow path 294 and the exhaust flow path 297, whilst shutting off flow into the chamber 234 along the inlet flow path 292, as shown in FIG. 13. The exhaust chamber 240 is charged with a gas at surface atmospheric pressure or is under a vacuum. Accordingly, the pressure force exerted on the faces 314 of the pistons 244 is now greatly reduced. The force on the piston faces 316 is thus greater, urging the pistons 244 radially inwardly to the retracted position of FIG. 5. The centraliser 200 and downhole tool 10 may then be recovered to surface through the drill string 211. The tool may then be re-set and run-in again when required to centralise a tool within the drill string 211. Alternatively, the centraliser may be re-set downhole and thus may be used to perform a number of separate centralising operations before the centraliser is pulled out of the borehole. In alternative embodiments, other downhole tools may be provided incorporating the control mechanism or the control mechanism may be provided as part of a tool used to control other downhole tools; for example a downhole packer; a downhole valve such as an open/shut valve; a sliding sleeve; a downhole shutting tool (for shutting off a well); or a tool for providing temporary positioning of tools, such as cutting or patching tools, in tubing; or as a trigger for other devices such as sampling tools, perforating tools or any other downhole tool requiring positioning and/or activating. The fluid activated member may comprise a piston coupled to a sliding sleeve, a valve element such as a ball valve or flapper valve or to any other fluid activated member of a downhole tool. Various modifications may be made to the foregoing within the scope of the present invention. It will be understood that the control mechanism essentially acts as a trigger mechanism for activating any fluid activated (hydraulic) downhole tool. The control mechanism has the ability to hold the tool in a desired position or activation state until the control member is moved, allowing fluid to be used as a motive fluid for activation of the downhole tool. The centraliser may be used for centralising any downhole tool and may be used for centralising a tool within any tubular, such as casing, liner, production tubing or the like. The centraliser may equally be used in an open hole environment and thus may be used for centralising within an open borehole. The control mechanism may be provided as part of a downhole tool or may be provided separately and coupled to a downhole tool for controlling operation of the tool. Thus the control mechanism may be provided in a separate body or housing coupled to the downhole tool to be controlled. The control mechanism may be mechanically activated as described above, or may be activated in any other suitable fashion. Accordingly, the control member may be adapted to be moved in response to applied fluid pressure, fluid pressure sequencing or by electronic or electrical control. The drift tool may include a control mechanism of the type described in relation to the centraliser and vice-verse. It will equally be understood that the flow control mechanism may be used for controlling any type of fluid activated downhole tool and thus of any fluid activated member of a downhole tool. The centraliser or other downhole tool may include any suitable number of fluid activated members and may thus include any suitable number of pistons. The pistons may be provided at any desired rotational and axial spacing along a length of the centraliser.

20050110

20100525

20050602

67606.0

HARCOURT, BRAD

FLOW CONTROL MECHANISM FOR A DOWNHOLE TOOL

UNDISCOUNTED

ACCEPTED

ACCEPTED

Display driver circuits

Display driver circuitry for electro-optic displays, in particular active matrix displays using organic light emitting diodes. The circuitry includes a driver to drive an electro-optic element in accordance with a drive voltage, a photosensitive device optically coupled to the electro-optic display element to pass a current dependent upon illumination reaching the photosensitive device, a first control device coupled between the photosensitive device and a data line and responsive to a first control signal on a first control line to couple the photosensitive device to the data line, and a second control device coupled between the photosensitive device and the driver and responsive to a second control signal on a second control line to couple the photosensitive device to the driver. The circuit can be operated in a number of different modes and provides flexible control of an electro-display element such as an organic LED pixel.

1. Display element driver circuitry for driving an element of an electro-optic display, the circuitry having first and second control lines and a data line, the circuitry comprising: a driver to drive the electro-optic display element in accordance with a drive voltage; a photosensitive device optically coupled to the electro-optic display element to pass a current dependent upon illumination reaching the photosensitive device; a first control device coupled between the photosensitive device and the data line and responsive to a first control signal on the first control line to couple the photosensitive device to the data line; and a second control device coupled between the photosensitive device and the driver and responsive to a second control signal on the second control line to couple the photosensitive device to the driver. 2. Display element driver circuitry as claimed in claim 1, further comprising a storage element coupled to the second control device to memorize a drive voltage for the driver. 3. Display element driver circuitry as claimed in claim 2, wherein the storage element comprises a capacitor. 4. Display element driver circuitry as claimed in claim 3, wherein the driver comprises a field effect transistor (FET) and the capacitor comprises a gate capacitance of said FET. 5. Display element driver circuitry as claimed in claim 1, wherein said first and second control devices each comprise a FET switch. 6. An active matrix display comprising a plurality of electro-optic display elements, each display element having associated display element driver circuitry as claimed in claim 1. 7. An active matrix display as claimed in claim 6, further comprising a switch to selectively couple said data line to a data line driver and to a signal sense circuit. 8. An active matrix display as claimed in claim 6, further comprising control circuitry to drive said first and second control lines to operate the display in a plurality of modes. 9. An active matrix display as claimed in claim 8, wherein said modes include an ambient light compensate mode in which said control circuitry controls the display element driver circuitry to measure an ambient light level before writing data to the display. 10. An active matrix display as claimed in claim 8, wherein said modes include current driver mode in which the brightness of a said display element is set by a reference current on said data line. 11. An active matrix display as claimed in claim 8, wherein said modes include a first voltage drive mode in which the brightness of a said display element is set by a voltage on said data line. 12. An active matrix display as claimed in claim 8, wherein said modes include a second voltage drive mode in which the brightness of a said display element is set by a voltage on said data line and in which said second control line is driven to couple said photosensitive element and said driver whilst said display element is on. 13. An active matrix display as claimed in claim 8, further comprising a pattern sense input mode in which said control circuitry controls the display element driver circuitry to input a light pattern from said display using a plurality of said photosensitive devices associated with a corresponding plurality of said display elements. 14. Display element driver circuitry as claimed in claim 1, wherein a said electro-optic display element comprises an organic light emitting diode. 15. A method of operating display element driver circuitry as claimed in claim 1, the method comprising: controlling said circuitry to couple said photosensitive device to said data line; measuring a light level using said photosensitive device; controlling said circuitry to couple said driver to said data line; and driving said data line with a signal dependent upon said measuring. 16. A method of operating display element driver circuitry as claimed in claim 1, the method comprising: controlling said first and second control lines to assert and de-assert said first and second control signals together; and driving said data line with a reference current to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled. 17. A method of operating display element driver circuitry as claimed in claim 1, the method comprising: controlling said first and second control lines to assert and de-assert said first and second control signals together; and driving said data line with a reference voltage to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled. 18. A method as claimed in claim 16, further comprising: controlling said circuitry to couple said photosensitive device to said data line; measuring a light level using said photosensitive device; and controlling said circuitry to couple said driver to said data line; and wherein said driving drives said data line with a signal dependent upon said measuring. 19. A method of operating display element driver circuitry as claimed in claim 1, the method comprising: controlling said second control line to assert said second control signal to couple the photosensitive device to the driver; controlling said first control line to couple the photosensitive device to the data line to select the display element; driving said data line with a reference voltage to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled; and controlling said first control line to decouple the photosensitive device from the data line to deselect the display element whilst maintaining said second control signal to maintain the coupling of said photosensitive device to said driver. 20. A method of operating an active matrix display as a light pattern sensor, the active matrix display comprising a plurality of display elements, each display element having associated display element driver circuitry as claimed in claim 1, the method comprising: controlling the display element driver circuitry of a plurality of said display elements to couple the photosensitive device of each display element to the corresponding data line; and reading light pattern data from the display using the data line of each photosensitive device. 21. A method of controlling the light output from a pixel of an active matrix electroluminescent display, the pixel including an electroluminescent display element and a light sensor optically coupled to the electroluminescent display element to provide an optical feedback path for controlling the electroluminescent display element light output, the method comprising: measuring an ambient light level using the light sensor; and writing a light level signal to the pixel modified to compensate for said ambient light level. 22. A method as claimed in claim 15, further comprising writing an initial dark level signal to the display element or pixel prior to said measuring. 23. An active matrix display as claimed in claim 6, wherein said electro-optic display element comprises an organic light emitting diode. 24. A method as claimed in claim 17, further comprising: controlling said circuitry to couple said photosensitive device to said data line; measuring a light level using said photosensitive device; and controlling said circuitry to couple said driver to said data line; and wherein said driving drives said data line with a signal dependent upon said measuring. 25. A method as claimed in claim 18, further comprising writing an initial dark level signal to the display element or pixel prior to said measuring. 26. A method as claimed in claim 21, further comprising writing an initial dark level signal to the display element or pixel prior to said measuring.

This invention generally relates to display drivers for electro-optic displays, and in particular relates to circuitry for driving active matrix organic light emitting diode displays. Organic light emitting diodes (OLEDs) comprise a particularly advantageous form of electro-optic display. They are bright, colourful, fast-switching, provide a wide viewing angle and are easy and cheap to fabricate on a variety of substrates. Organic LEDs may be fabricated using either polymers or small molecules in a range of colours (or in multi-coloured displays), depending upon the materials used. Examples of polymer-based organic LEDs are described in WO 90/13148, WO 95/06400 and WO 99/48160; examples of so called small molecule based devices are described in U.S. Pat. No. 4,539,507. A basic structure 100 of a typical organic LED is shown in FIG. 1a. A glass or plastic substrate 102 supports a transparent anode layer 104 comprising, for example, indium tin oxide (ITO) on which is deposited a hole transport layer 106, an electroluminescent layer 108, and a cathode 110. The electro luminescence layer 108 may comprise, for example, a PPV (poly(p-phenylenevinylene)) and the hole transport layer 106, which helps match the hole energy levels of the anode layer 104 and electroluminescent layer 108, may comprise, for example, PEDOT:PSS (polystyrene-sulphonate-doped polyethylene-dioxythiophene). Cathode layer 110 typically comprises a low work function metal such as calcium and may include an additional layer immediately adjacent electroluminescent layer 108, such as a layer of aluminium, for improved electron energy level matching. Contact wires 114 and 116 to the anode the cathode respectively provide a connection to a power source 118. The same basic structure may also be employed for small molecule devices. In the example shown in FIG. 1a light 120 is emitted through transparent anode 104 and substrate 102 and such devices are referred to as “bottom emitters”. Devices which emit through the cathode may also be constructed, for example by keeping the thickness of cathode layer 110 less than around 50-100 nm so that the cathode is substantially transparent. Organic LEDs may be deposited on a substrate in a matrix of pixels to form a single or multi-colour pixellated display. A multicoloured display may be constructed using groups of red, green, and blue emitting pixels. In such displays the individual elements are generally addressed by activating row (or column) lines to select the pixels, and rows (or columns) of pixels are written to, to create a display. It will be appreciated that with such an arrangement it is desirable to have a memory element associated with each pixel so that the data written to a pixel is retained whilst other pixels are addressed. Generally this is achieved by a storage capacitor which stores a voltage set on a gate of a driver transistor. Such devices are referred to as active matrix displays and examples of polymer and small-molecule active matrix display drivers can be found in WO 99/42983 and EP 0,717,446A respectively. FIG. 1b shows such a typical OLED driver circuit 150. A circuit 150 is provided for each pixel of the display and ground 152, Vss 154, row select 164 and column data 166 busbars are provided interconnecting the pixels. Thus each pixel has a power and ground connection and each row of pixels has a common row select line 164 and each column of pixels has a common data line 166. Each pixel has an organic LED 156 connected in series with a driver transistor 158 between ground and power lines 152 and 154. A gate connection 159 of driver transistor 158 is coupled to a storage capacitor 160 and a control transistor 162 couples gate 159 to column data line 166 under control of row select line 164. Transistor 162 is a field effect transistor (FET) switch which connects column data line 166 to gate 159 and capacitor 160 when row select line 164 is activated. Thus when switch 162 is on a voltage on column data line 166 can be stored on a capacitor 160. This voltage is retained on the capacitor for at least the frame refresh period because of the relatively high impedances of the gate connection to driver transistor 158 and of switch transistor 162 in its “off” state. Driver transistor 158 is typically an FET transistor and passes a (drain-source) current which is dependent upon the transistor's gate voltage less a threshold voltage. Thus the voltage at gate node 159 controls the current through OLED 156 and hence the brightness of the OLED. The standard voltage-controlled circuit of FIG. 1b suffers from a number of drawbacks. The main problems arise because the brightness of OLED 156 is dependent upon the characteristics of the OLED and of the transistor 158 which is driving it. In general, these vary across the area of a display and with time, temperature, and age. This makes it difficult to predict in practice how bright a pixel will appear when driven by a given voltage on column data line 166. In a colour display the accuracy of colour representations may also be affected. Two circuits which partially address these problems are shown in FIGS. 2a and 2b. FIG. 2a shows a current-controlled pixel driver circuit 200 in which the current through an OLED 216 is set by setting a drain source current for OLED driver transistor 212 using a reference current sink 224 and memorising the driver transistor gate voltage required for this drain-source current. Thus the brightness of OLED 216 is determined by the current, Icol′, flowing into adjustable reference current sink 224, which is set as desired for the pixel being addressed. It will be appreciated that one current sink 224 is provided for each column data line 210 rather than for each pixel. In more detail, power 202, 204, column data 210, and row select 206 lines are provided as described with reference to the voltage-controlled pixel driver of FIG. 1b. In addition an inverted row select line 208 is also provided, the inverted row select line being high when row select line 206 is low and vice versa. A driver transistor 212 has a storage capacitor 218 coupled to its gate connection to store a gate voltage for driving the transistor to pass a desired drain-source current. Drive transistor 212 and OLED 216 are connected in series between a power 202 and ground 204 lines and, in addition, a further switching transistor 214 is connected between drive transistor 212 and OLED 216, transistor 214 having a gate connection coupled to inverted row select line 208. Two further switching transistors 220, 222 are controlled by non-inverted row select line 206. In the embodiment of the current-controlled pixel driver circuit 200 illustrated in FIG. 2a all the transistors are PMOS, which is preferable because of their greater stability and better resistance to hot electron effects. However NMOS transistors could also be used. This is also true of circuits according to the invention which are described below. In the circuit of FIG. 2a the source connections of the transistors are towards GND and for present generation OLED devices Vss is typically around −6 volts. When the row is active the row select line 206 is thus driven at −20 volts and inverted row select line 208 is driven at 0 volts. When row select is active transistors 220 and 222 are turned on and transistor 214 is turned off. Once the circuit has reached a steady state reference current Icol′ into current sink 224 flows through transistor 222 and transistor 212 (the gate of 212 presenting a high impedance). Thus the drain-source current of transistor 212 is substantially equal to the reference current set by current sink 224 and the gate voltage required for this drain-source current is stored on capacitor 218. Then, when row select becomes inactive, transistors 220 and 222 are turned off and transistor 214 is turned on so that this same current now flows through transistor 212, transistor 214, and OLED 216. Thus the current through OLED is controlled to be substantially the same as that set by reference current sink 224. Before this steady state is reached the voltage on capacitor 218 will generally be different from the required voltage and thus transistor 212 will not pass a drain source current equal to the current, Icol, set by reference sink 224. When such a mismatch exists a current equal to the difference between the reference current and the drain-source current of transistor 212 flows onto or off capacitor 218 through transistor 220 to thereby change the gate voltage of transistor 212. The gate voltage changes until the drain-source current of transistor 212 equals the reference current set by sink 224, when the mismatch is eliminated and no current flows through transistor 220. The circuit of FIG. 2a solves some of the problems associated with the voltage-controlled circuit of FIG. 1b as the current through OLED 216 can be set irrespective of variations in the characteristics of pixel driver transistor 212. However the circuit of FIG. 2a is still prone to variations in the characteristic of OLED 216 between pixels, between active matrix display devices, and over time. A particular problem with OLEDs is a tendency for their light output to decrease over time, dependent upon the current with which they are driven (this may be related to the passage of electrons through the OLED). Such degradation is particularly apparent in a pixellated display where the relative brightness of nearby pixels can easily be compared. A further problem with the circuit of FIG. 2a arises because each of transistors 212, 214 and 222 must be sufficiently physically large to handle the current through OLED 216, which is equal to the Icol reference current. Large transistors are generally undesirable and, depending upon the active matrix device structure, may also obscure or prevent the use of part of a pixel's area. In an attempt to address these additional problems there have been a number of attempts to employ optical feedback to control the OLED current. These attempts are described in WO 01/20591, EP 0,923,067A, EP 1,096,466A, and JP 5-035,207 and all employ basically the same technique. FIG. 2b, which is taken from WO 01/20591, illustrates the technique, which is to connect a photodiode across the storage capacitor. FIG. 2b shows a voltage-controlled pixel driver circuit 250 with optical feedback 252. The main components of the driver circuit 250 of FIG. 2b correspond to those of circuit 150 of FIG. 1b, that is, an OLED 254 in series with a driver transistor 256 having a storage capacitor 258 coupled to its gate connection. A switch transistor 260 is controlled by a row conductor 262 and, when switched on, allows a voltage on capacitor 258 to be set by applying a voltage signal to column conductor 264. Additionally, however, a photodiode 266 is connected across storage capacitor 258 so that it is reverse biased. Thus photo diode 266 is essentially non conducting in the dark and exhibits a small reverse conductance depending upon the degree of illumination. The physical structure of the pixel is arranged so that OLED 254 illuminates photodiode 266, thus providing an optical feedback path 252. The photocurrent through photodiode 266 is approximately linearly proportional to the instantaneous light output level from OLED 254. Thus the charge stored on capacitor 258, and hence the voltage across the capacitor and the brightness of OLED 254, decays approximately exponentially over time. The integrated light output from OLED 254, that is the total number of photons emitted and hence the perceived brightness of the OLED pixel, is thus approximately determined by the initial voltage stored on capacitor 258. The circuit of FIG. 2b solves the aforementioned problems associated with the linearity and variability of the driver transistor 256 and OLED 254 but exhibits some significant drawbacks in its practical implementation. The main drawback is that every pixel of the display needs refreshing every frame as storage capacitor 258 is discharged over no more than this period. Related to this, the circuit of FIG. 2b has a limited ability to compensate for ageing effects, again because the light pulse emitted from OLED 254 cannot extend beyond the frame period. Similarly, because the OLED is pulsed on and off it must be operated at an increased voltage for a given light output, which tends to reduce the circuit efficiency. Capacitor 258 also often exhibits non-linearities so that the stored charge is not necessarily linearly proportional to the voltage applied on column conductor 264. This results in non-linearities in the voltage-brightness relationship for the pixel as photodiode 266 passes a photocurrent (and hence charge) which is dependent upon the level of illumination it receives. A further problem with the use of optical feedback is the risk of ambient light affecting the feedback response unless care is taken with the physical layout of the relevant components. Finally, all the prior art designs lack operational flexibility. There is therefore a need for improved display driver circuitry for organic LEDs which addresses the above problems. According to a first aspect of the invention there is therefore provided display element driver circuitry for driving an element of an electro-optic display, the circuitry having first and second control lines and a data line, the circuitry comprising, a driver to drive the electro-optic display element in accordance with a drive voltage, a photosensitive-device optically coupled to the electro-optic display element to pass a current dependent upon illumination reaching the photosensitive device, a first control device coupled between the photosensitive device and the data line and responsive to a first control signal on the first control line to couple the photosensitive device to the data line; and a second control device coupled between the photosensitive device and the driver and responsive to a second control signal on the second control line to couple the photosensitive device to the driver. This configuration provides the flexibility for the driver circuitry to be operated in a number of different modes according to the required function of the display, the ambient light conditions, and other factors. The operation of these different modes is described in more detail below and allows the driver circuitry, for example, to be operated in a first mode under bright illumination and a second mode under dimmer ambient light. Furthermore, because the photosensitive device can be substantially isolated from the driver the same circuitry can be used for both driving a pixel of an electro-optic display and for sensing or reading an image, for example to operate the display as a sensor for a scanner. In a similar way the photosensitive device can also be used to measure an ambient light level before the pixel with which it is associated is switched on so that the pixel brightness can be set to compensate for an ambient light level and, in particular, so that data written to the driver circuitry to set a pixel brightness can take account of the effect ambient light might have on the optical coupling between the electro-optic display element and the photosensitive device. The input of the driver will generally have some associated input capacitance, but the circuit may further include an additional storage element coupled to the input of the driver and to the second control device to memorise a drive voltage for the display element. Preferably such a storage element comprises a capacitor which, for micro-displays, may be a digital capacitor. This capacitor may be integrated with the gate of a field effect transistor connected to the input of the driver. Preferably the first and second control devices each comprise a field effect transistor (FET) to provide a pair of controllable switches. This simplifies integration of the driver circuitry. An active matrix display with a plurality of pixels may be constructed by providing each pixel with such display element driver circuitry. The data lines may be connected to column (or row) lines of the display and the control lines to row (or column) control circuitry. In a preferred embodiment each column (or row) line connected to the data lines is provided with a switch to allow the data lines to be connected either to a data line driver to drive a voltage or current on the data line or to measurement circuitry to read one or more illumination levels from the photosensitive devices associated with each pixel. Such measurement circuitry can also be used to check the correct operation of the photosensitive device, for example to ensure the leakage current is below a permitted threshold. Preferably such an active matrix display also includes control circuitry to drive the first and second control lines to operate the display in a plurality of modes. One or more of these modes may be selected on installation of the device into a circuit, by effectively hard wiring the mode selection or the operating mode may be selected dynamically, for example according to prevailing operating conditions. In one mode of operation the pixels of the display are controlled to measure an ambient light level before data is written to the display. Data may be written using the circuitry in either a current-controlled or voltage-controlled mode, in the latter case with or without optical feedback. Thus, for example, a current-controlled mode with an initial measurement cycle may be employed for bright ambient illumination and a voltage-controlled mode with optical feedback, along the lines described with reference to FIG. 2b, may be employed with or without a measurement cycle in dim ambient illumination conditions. In conjunction with any of the above modes the driver circuitry for the pixels of the display may also be configured to use the photosensitive devices as an image sensor or scanner, for example once an appropriate drive voltage has been memorised by the storage element. This mode may also be used, for example, to provide a touch-sensitive display where the light pattern read from the display has sufficient resolution to detect a darkened area of the screen corresponding to a region of the display shielded from the ambient illumination by, for example, a finger tip. Alternatively, a stylus with a reflective tip may be employed and the photosensitive device of one pixel used to measure the light from neighbouring pixels scattered by the tip. Deconvoluting this signal from the optical feedback signal may be achieved by, for example, monitoring the feedback (reflected light) from neighbouring pixels to the pixel area concerned. Alternatively a significantly reduced voltage drive for a given requested photocurrent than in previous operation cycles may be used, due to an increased feedback to the photosensitive device. In a related aspect the invention also provides a method of operating the above-described display element driver circuitry the method comprising controlling said circuitry to couple said photosensitive device to said data line, measuring a light level using said photosensitive device, controlling said circuitry to couple said driver to said data line; and driving said data line with a signal dependent upon said measuring. Measuring the light level using the photosensitive device allows the control circuitry to drive the data line to compensate for the measured light level, and thus compensate for a background light level which may result from ambient illumination, or from other nearby emitting electro-optic display elements, or both. Preferably the method includes switching the display element off and optionally switching other nearby display elements off, before measuring the light level, for improved accuracy. This method may be employed before writing a light level signal to the display element in a selected one of the other operational modes of the circuitry. In a first operational mode the display element driver circuitry is operated by controlling said first and second control lines to assert and de-assert said first and second control signals together; and driving said data line with a reference current to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled. In a second operational mode the display element drive circuitry is operated by controlling said first and second control lines to assert and de-assert said first and second control signals together; and driving said data line with a reference voltage to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled. In a third operational mode the display element driver circuitry is operated by controlling said second control line to assert said second control signal to couple the photosensitive device to the driver, controlling said first control line to couple the photosensitive device to the data line to select the display element, driving said data line with a reference voltage to set a brightness for said display element when said driver, said photosensitive device and said data line are all coupled; and controlling said first control line to decouple the photosensitive device from the data line to deselect the display element whilst maintaining said second control signal to maintain the coupling of said photosensitive device to said driver. The invention also provides a method of operating an active matrix display as a light pattern or image sensor, the active matrix display comprising a plurality of display elements, each display element having associated display element driver circuitry, the method comprising, controlling the display element driver circuitry of a plurality of said display elements to couple the photosensitive device of each display element to the corresponding data line; and reading light pattern data from the display using the data line of each photosensitive device. In further aspect the invention provides a method controlling the light output from a pixel of an active matrix electroluminescent display, the pixel including an electroluminescent display element and a light sensor optically coupled to the electroluminescent display element to provide an optical feedback path for controlling the electroluminescent display element light output, the method comprising, measuring an ambient light level using the light sensor; and writing a light level signal to the pixel modified to compensate for said ambient light level. In all the above aspects of the invention the electro-optic or electroluminescent display element preferably comprises an organic light emitting diode. These and other aspects of the invention will now be further described, by way of example only, with reference to the accompanying figures in which: FIGS. 1a and 1b show, respectively, a basic organic LED structure, and a typical voltage-controlled OLED driver circuit; FIGS. 2a and 2b show, respectively, a current-controlled OLED driver circuit, and a voltage-controlled OLED driver circuit with optical feedback according to the prior art; FIG. 3 shows an organic LED driver circuit according to an embodiment of the present invention; and FIGS. 4a and 4b show vertical cross sections through device structures of OLED display elements with driver circuits incorporating optical feedback. Referring now to FIG. 3, this shows an organic LED driver circuit 300 which can be operated in a number of different modes. In an active matrix display typically each pixel is provided with such a driver circuit and further circuitry (not shown) is provided to address the pixels row-by-row, to set each row at the desired brightness. To power and control the driver circuitry and OLED display element the active matrix display is provided with a grid of electrodes including, as shown, a ground (GND) line 302, a power or Vss line 304, row select lines 306, 307 and a column data line 308. In the illustrated embodiment column data line 308 is connected to a switch 330 to selectively couple the column data line either to a reference current source (or sink) 324 or to measurement circuitry 328. The reference current source (or sink) 324 is preferably a programmable constant current generator to allow a current in column data line 308 to be adjusted to a desired level to set a pixel brightness, as described in more detail below. In other embodiments, however, a programmable voltage generator may be used additionally or alternatively to current generator 324, to allow the driver circuit to be used in other modes. Measurement circuitry 328 allows the driver circuit to be used to measure an ambient light level when switch 330 connects column data line 308 to the measurement circuitry. Row driver circuitry 332 controls the first and second row select lines 306 and 307 according to the operating mode of driver circuitry 300. The driver circuit 300 comprises a driver transistor 310 connected in series with an organic LED display element 312 between the GND 302 and Vss 304 lines. A storage capacitor 314, which may be integrated with the gate of transistor 310, stores a charge corresponding to a memorised gate voltage to control the drive current through OLED element 312. Control circuitry for the driver comprises two switching transistors 320,322 with separate, independently controllable gate connections coupled to first and second select lines 306 and 307 respectively. A photodiode 316 is coupled to a node 317 between transistors 320 and 322. Transistor 320 provides a switched connection of node 317 to column data line 308. Transistor 322 provides a switched connection of node 317 to a node 315 to which is connected storage capacitor 314 and the gate of transistor 310. In the circuit of FIG. 3 all the transistors are PMOS. Photodiode 316 is coupled between GND line 302 and line 317 so that it is reverse biassed. The photodiode is physically arranged with respect to the OLED display element 312 such that an optical feedback path 318 exists between OLED 312 and photodiode 316. In other words, OLED 312 illuminates photodiode 316 and this allows an illumination-dependent current to flow in a reverse direction through photodiode 316, that is from GND line 302 towards Vss. As the skilled person will understand, broadly speaking each photon generates an electron within photodiode 316 which can contribute to a photocurrent. When first select line 306 is active transistor 320 is on, that is the switch is “closed” and there is a relatively low impedance connection between column data line 308 and node 317. When first select line 306 is inactive transistor 320 is switched off and photodiode 316 is effectively isolated from column data line 308. When second select line 307 is active transistor 322 is switched on and nodes 315 and 317 are coupled; when second select line 307 is inactive transistor 322 is switched off and node 315 is effectively isolated from node 317. It can be seen that when both transistors 320 and 322 are switched off (i.e. both the first and second select lines 306 and 307 are inactive) photodiode 316 is effectively isolated from the remainder of the driver circuitry. Similarly when transistor 322 is off (second select line 307 is inactive) and transistor 320 is on (first select line 306 is active) photodiode 316 is effectively connected between ground (GND) line 302 and column data line 308. In this way photodiode 316 may be effectively isolated from the remainder of the driver circuitry and, when switch 330 connects column data line 308 to measurement circuitry 328, photodiode 316 may be used as a sensor to measure the local ambient light level. This ambient light level may result from the ambient light conditions in the local display environment or from light emitted from OLED 312 or the corresponding OLEDs in neighbouring pixels. Alternatively the photodiodes of a plurality of pixels may be used to read an image pattern using a display. The driver circuitry 300 may be operated in a current-controlled mode with optical feedback, in a voltage-controlled mode with optical feedback, and in a voltage-controlled mode without optical feedback. Any or all of these modes may be employed with a light measurement mode to make an ambient light measurement before data is written to a pixel, or to input an image after data is written to a pixel. In a first mode of operation first and second select lines 306 and 307 are connected together or driven in tandem by row drivers 332 so that the circuit operates as a current-controlled driver with optical feedback. When the switch 330 is in the position shown in FIG. 3 the programmable reference current generator 324 attempts to cause a reference current which will be referred to as Icol to flow to off-pixel Vss connection 326. In this mode line 317 may be referred to as a current sense line, passing a current Isense and line 315 may be referred to as a control line, passing a current Ierror to set a voltage on capacitor 314 to control OLED 312. When first and second (row)select lines 306 and 307 are active transistors 320 and 322 are on and Icol=Isense+Ierror and thus the current Ierror flows either onto or off capacitor 314 until OLED 312 illuminates photodiode 316 such that Isense=Icol. At this point the first and second row select lines 306 and 307 can be deactivated and the voltage required for this level of brightness is memorised by capacitor 314. The time required for the voltage on capacitor 314 to stabilise depends upon a number of factors, which may be varied in accordance with the desired device characteristics, and may be a few microseconds. Broadly speaking a typical OLED drive current is of the order of 1 μA whilst a typical photocurrent is around 0.1% of this, or of the order of 1 nA (in part dependent upon the photodiode area). It can therefore be seen that the power handling requirements of transistors 320 and 322 are negligible compared with that of the drive transistor 310, which must be relatively large. To speed up the settling time of the circuit it is preferable to use a relatively small value for capacitor 314 and a relatively large area photodiode to increase the photocurrent. This also helps reduce the risk of noise and stability at very low brightness levels associated with stray or parasitic capacitance on column data line 308. In a second mode the driver circuitry 300 is voltage controlled and operates in a similar manner to the prior art circuit of FIG. 1b, that is without optical feedback. As in the first mode of operation, the first and second select lines are connected together or driven in tandem by row drivers 332 but instead of column data line 308 being driven by a reference current generator 324, line 308 is driven by a voltage reference source, programmable to adjust the pixel brightness. The voltage source preferably has a low internal resistance to approximate a constant voltage source. In this second mode of operation when the first and second select lines 306 and 307 are active capacitor 314 is coupled to column data line 308 and is therefore charged to the voltage output by the reference voltage generator. The small reverse current through photodiode 316 due to illumination by OLED 312 has a substantially no effect on the voltage on line 308 because of the low internal resistance of the voltage source. Once capacitor 314 has been charged to the required voltage transistors 320 and 322 are switched off by deasserting the first and second select lines 306 and 307, so that capacitor 314 does not discharge through photodiode 316. In this mode of operation the pair of transistors 320 and 322 effectively perform the same function as transistor 162 in the circuit of FIG. 1b. In a third mode of operation the circuit is again driven by a programmable reference voltage source but the second select line is controlled so that it is always active (and hence so that transistor 322 is always on) whilst OLED 312 is on. In this way photodiode 316 is connected across storage capacitor 314 so that the circuit operates in substantially the same way as the circuit of FIG. 2b described above, transistor 320 performing the function of transistor 260 in FIG. 2b. In a simple embodiment the second select line 307 may simply be tied to a fixed voltage supply to ensure this line is always active. However transistor 322 need only be on long enough to ensure that capacitor 314 has enough time to discharge and thus it is still possible in this mode to switch off transistor 322 at times to allow photodiode 316 to be connected between lines 302 and 308 by transistor 320 and used as a sensor. In an improvement of this mode of operation the programmable reference voltage source can be arranged to deliver a predetermined charge to capacitor 314 since, when photodiode 316 is connected across capacitor 314, it is the charge on capacitor 314 which determines the apparent brightness of OLED 312 rather than the voltage itself. Delivering a predetermined charge to capacitor 314, rather than charging the capacitor to a reference voltage, reduces the effect of non-linearities in the charge-voltage characteristic of capacitor. In a preferred mode of operation the driver circuitry 300 is controlled to provide a measurement cycle before pixel illumination data is written to the circuit to set the brightness of OLED 312. To achieve this row driver circuitry 332 preferably controls the first and second select lines 306 and 307, and switch 330 by means of a control line 334, to switch transistor 322 off and transistor 320 on, to connect photodiode 316 to measurement circuitry 328. Measurement circuitry 328 can then measure the ambient light level in the vicinity of photodiode 316 and, optionally, can also perform additional tasks such as checking the proper functioning of the photodiode, for example by checking its leakage current. The measurement circuitry can be arranged to measure a photocurrent through photodiode 316, or a photovoltaic mode of operation of the photodiode may be employed when the photodiode is brightly illuminated, the photodiode operating as a photocell and measurement circuitry 328 measuring a voltage. The light level measurement may be used to determine the degree of illumination of OLED 312 or of the OLEDs of adjacent pixels or, for example, to characterise the drive circuit or OLED 312. In particular, however, the light level measured by photodiode 316 may be used to compensate for any disturbances to the operation of the above-described modes with optical feedback, for example by writing a modified reference current or voltage to the pixel to take account of the ambient light level. In a preferred embodiment, therefore, OLED 312 is switched off before a measurement is made using photodiode 316. In the third mode of operation described above OLED 312 will automatically be switched off after no more than one frame period, but in the first and second modes of operation the OLED may be switched off by writing a dark level signal to the pixel. In the above described modes it will be recognised that the first select line 306 in effect operates as a row select line whilst the second select line 307 operates as a combined mode and row select line. Thus in order to perform a (write black)-(measure)-(write level) cycle for a selected row the first select line 306 is held active whilst the second select line 307 is toggled from active during a write cycle to inactive or deasserted during a measure cycle. Referring now to FIG. 4, this shows, in outline, two alternative physical structures for OLED pixel driver circuits incorporating optical feedback (the drawings are not to scale). FIG. 4a shows a bottom-emitting structure 400 and FIG. 4b shows a top-emitter 450. In FIG. 4a an OLED structure 406 is deposited side-by-side with polysilicon driver circuitry 404 on a glass substrate 402. The driver circuitry 404 incorporates a photodiode 408 to one side of the OLED structure 406. Light 410 is emitted through the bottom (anode) of the substrate. FIG. 4b shows a cross section through an alternative structure 450 which emits light 460 from its top (cathode) surface. A glass substrate 452 supports a first layer 454 comprising the driver circuitry and including a photodiode 458. An OLED pixel structure 456 is then deposited over the driver circuitry 454. A passivation or stop layer may be included between layers 454 and 456. Where the driver circuitry is fabricated using (crystalline) silicon rather than polysilicon or amorphous silicon a structure of the type shown in FIG. 4b is required and substrate 452 is a silicon substrate. In the structures of FIGS. 4a and 4b the pixel driver circuitry may be fabricated by conventional means. The organic LEDs may be fabricated using either ink jet deposition techniques such as those described in EP 880303 to deposit polymer-based materials or evaporative deposition techniques to deposit small molecule materials. Thus, for example, so-called micro-displays with a structure of the type illustrated in FIG. 4b may be fabricated by ink jet printing OLED materials onto a conventional silicon substrate on which CMOS pixel driver circuitry has previously been fabricated. The illustrated embodiment of the driver circuit uses PMOS transistors but the circuits may be inverted and NMOS may be employed or, alternatively, a combination of PMOS and NMOS transistors may be used. The transistors may comprise thin film transistors (TFTs) fabricated from amorphous or poly-silicon on a glass or plastic substrate or conventional CMOS circuitry may be used. In other embodiments plastic transistors such as those described in WO 99/54936 may be employed, and the photodiode may comprise a reverse biased OLED to allow the entire circuitry to be fabricated from plastic. Similarly although the circuit has been described with reference to field effect transistors, bipolar transistors may also be used. The display element driver circuitry has been described with reference to its use for driving organic LEDs but the circuitry may also be employed with other types of electroluminescent display such as inorganic TFEL (Thin Film Electroluminescent) displays, gallium arsenide on silicon displays, porous silicon displays, photoluminescence quenching displays as described in UK patent application no. 0121077.2, and the like. Although the driver circuitry primarily finds applications in active matrix displays it may also be used with other types of display such as segmented displays and hybrid semi-active displays. The preferred photosensor is a photodiode which may comprise a PN diode in TFT technology or a PIN diode in crystalline silicon. However other photosensitive devices such as photoresistors and photosensitive bipolar transistors and FETs may also be employed, providing they have a characteristic in which a photocurrent is dependent upon their level of illumination. No doubt many other effective alternatives will occur to the skilled person and it should be understood that the invention is not limited to the described embodiments.

20040823

20081125

20050113

99568.0

BECK, ALEXANDER S

DISPLAY DRIVER CIRCUITS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method and device for authenticated access of a station to local data networks in particular radio data networks

The invention relates to methods, devices and systems for the authenticated access to a data network by means of a station (WH) compatible with a data network (WLAN), which permit an authentication of the station and user. A device, for example a mobile radio device, is used for the above, which is authenticated in another system. In addition to the authentication, in particular a charging of services in a data network or another communication system (GSM) which is accessible by means of the data network is thus possible.

1. A method for authenticated access by a station compatible with a data network, where access of the station is to an access point for such a data network, comprising: transmitting identification information to the access point; providing and transmitting an identifier via an interface to an authenticated devices of a system or network external to the access point, having an authenticating function, whereby the identification information is directly assigned to the device authenticated in the external system or network and, access to data of the authenticated device is available at a location of the station or of the access point; transmitting the identifier sent to the authenticated device to the station; transmitting the identifier to the access point; comparing the transmitted identifier with the sent identifier; and if the comparison is positive, enabling access of the station at least some services and functions at the access-point end or at the network end. 2. The method according to claim 1, wherein the identifier is randomly generated or is randomly selected from a list with a large number of redefined passwords or another entity at the access-point end or at the network end. 3. The method according to claim 1, wherein the transmission of the identifier is carried out by a short message service. 4. The method according to claim 1, wherein the transmission of the identifier is carried out by an indirect use of authentication functions in the system or network external to the access point or data network with the authenticated device. 5. The method according to claim 1, wherein a mobile station or a subscriber identification card of a cellular mobile radiocommunication system is used as the authenticated device of the system or network external to the access point or data network. 6. The method according to claim 1, wherein after authentication of the station compatible with the data network, the station accessing the access point to the data network, data relevant to charging is recorded at the access-point end or in a data network at the access-point end by the or an independent entity when the station accesses the access point, the data network and/or services. 7. The method according to claim 6, wherein in a first charging unit basic charging information is recorded and transmitted to a second charging unit which determines from the basic charging information charges to be billed. 8. The method according to claim 6, wherein the data relevant to charging is forwarded to an external charging entity of a third party or to a charging unit, interposed for authentication, of the system or network external to the access point or external to the data network, wherein either the third party and the charging unit are not involved in the authentication procedure or the authentication procedure is carried out independently of the charging method autonomously between the station and the access point or the entity at the access-point end. 9. The method according to claim 6, wherein charging information of a charging-relevant connection occurs as charging access to an IN-based payment system. 10. A data network, comprising: at least one interface-type access point for access to the data network by stations compatible with the data network at the subscriber end; an access control unit with an authentication memory in which authorized stations are registered; a first external network interfaces for access by the data network to an external system or network that is incompatible with the data network, wherein the access control unit which is configured to generate an identifier and to emit the identifier via the external system or network is provided; and a transmission device for transmitting the identifier transmitted via the external network or system to an authenticated device of the external network or system to the station and via the station for authentication of the station to the access control unit. 11. A modem or access point for access by means of stations compatible with a data network at a subscriber end to a wireless data network comprising: an interface for the data network; at least one additional interface for access to a network or system external to the data network; and an access control unit for independently checking an authentication status of the station and, where authentication is inadequate, for activating authentication of the station. 12. The modem or access point according to claim 11, wherein the access control unit is, where authentication is inadequate, configured to establish a connection to a separate authentication device or to carry out the authentication procedure independently. 13. The modem or access point according to claim 11, wherein the interface for the data network is configured for connecting the wireless data network to one of the stations or for connecting one of the stations directly. 14. The modem or access point according to claim 11, wherein the at least one additional interface is configured as a retrofittable or replaceable module which is adapted to the network or system external to the data network. 15. The modem or access point according to claim 11, wherein the access control unit is configured for generating an identifier after receipt of an identification information via the interface from the data network, emitting the identifier via the interface to the external network or system subsequently receiving the identifier transmitted via the external network or system via the local area network, and comparing the emitted and received identifier for deciding the approval of access to the data network. 16. The modem or access point according to claim 11, wherein the access control unit has equipment and functions for authentication and an interface module, wherein the interface module is configured as a modular device for connecting to at least one communication system or network external to the data network with secure authentication. 17. An authentication and/or charging system for a data network comprising: a station compatible with the data network accesses the data network; an authenticated device or an authenticated subscriber of the system or network external to the data network, wherein at the data-network end, authentication of the station is checked and arranged autonomously so as to enable direct or indirect assignment thereto. 18. An authentication and/or charging system for a data network comprising: a station compatible with the data network accesses the data network; and an identifier is sent from the data network via a system or network external to the data network to an authenticated station external to the data network of the external system or network, wherein the identifier is transmitted from the authenticated station to the station and is transmitted further from the station to the data network, and in the data network a comparison is carried out of the sent and received identifier for indirect authentication. 19. The charging and authentication system according to claim 18 for a data network, further comprising: a first authentication of the system in which charges accrue, with regard to the authenticity of the station compatible with the data network accessing the data network; and a second authentication with regard to the authenticity of the system in which charges accrue, is initiated in relation to an additional system receiving charging data. 20. The charging and authentication system for a data network according to a claim 18, wherein charging information relating to an accessing station is sent from the data network for charging to a device external to the data network, whereby charging is carried out independently of the authentication of the station. 21. The charging and authentication system for a data network or for an access point for a station compatible with the data network, according to claim 18, wherein a service provider offers access for a station compatible with the data network and prompts or carries out independently an authentication of the accessing station which is compatible with the data network, and transmits charging data to a charging unit of an external system or to a charging organization.

CLAIM FOR PRIORITY This application claims priority to International Application No. PCT/EP02/11910, which was published in the German language on May 1, 2003, which claims the benefit of priority to German Application No. 101 52 572.9 and European Application No. 011 25257.4, which were both filed in German and European languages, respectively. TECHNICAL FIELD OF THE INVENTION The invention relates to a method for accessing a data network and to a device for implementing such a method and to a charging method as a result of the authentication. BACKGROUND OF THE INVENTION A large number of different types of telecommunications and data networks for communicating and/or transmitting data are known. A distinction can be drawn here between two fundamentally different types of network. There are, on the one hand, the telecommunications networks, for example those conforming to the GSM (Global System for Mobile Telecommunications) or the UMTS (Universal Mobile Telecommunications System) standards, in which subscribers are authenticated and authorized when they sign on to the network concerned. An advantage in networks of this type is that as a result of the authentication procedure it is also possible to charge for services used. Furthermore, these generally cellular networks offer the opportunity of a high degree of mobility since a subscriber can move with his/her station from network cell to network cell. A disadvantage of these types of cellular telecommunications systems is that the administrative outlay is very high. Also, these telecommunications networks provide only a low data rate for radio interfaces. There are, on the other hand, data networks which are designed as local area networks or wireless local area networks (WLAN). Such data networks offer subscriber stations access that is very easy to administer. A further advantage consists in the considerably higher data rate by comparison with telecommunications networks at the interfaces to the subscriber station. A disadvantage of data networks of this type, however, is the lack of an authentication facility and consequently also the lack of a billing or charging facility. Currently, especially in the USA and Europe, it is almost exclusively products based on the IEEE 802.11 family which appear to be prevailing as local area networks with wireless subscriber access, with suitable Ethernet terminals already being provided as standard in many computers and portable computers (laptops, notebooks, PDAs, etc.). The radio interface defined under the IEEE 802.11b standard for accessing local area networks corresponds functionally to a wired connection to LANs which have now developed into the office standard. Interface cards for wireless access to local area networks, also referred to as NICs (network interface cards), are from an architectural point of view produced like standardized Ethernet cards and with today's operating systems can be installed using plug & play. Portable computers are readily upgradeable with appropriate interface cards unless they have already been delivered ex works with an integrated terminal for wired or wireless access to local area networks. With the next generations of operating systems (e.g. Windows XP from Microsoft) fully integrated support for wireless local area networks will be provided. With data rates of 11 Mbit/s at present and of 50 Mbit/s in future, subscribers will thus be provided with data rates that are considerably higher than the data rates which can be offered by the next third-generation mobile telecommunications (UMTS). Access to wireless local area networks for high-bit-rate connections is consequently preferable for transmitting large quantities of data, especially in connection with Internet access. Disadvantageously, the wireless local area networks cannot offer any authentication facility for stations or computers not already registered in the system. However, operators of wireless local area networks, for example in an airport area, have to offer access for a large number of different subscribers from different regions. In order to be able to authenticate a subscriber, the operator of the wireless local area network would have to conclude cross-license agreements with all possible Internet service providers (ISPs), of which, however, there are currently over 60,000 in Germany alone. Without authenticating subscribers or subscribers' stations, no billing of services used can occur since it is not even known to whom a bill could be sent. Access to wireless local area networks must therefore either be offered free of charge or as a prepaid service with payment in advance by means of credit card billing or the like. A further facility enabling authentication and billing consists in involving a billing company or clearing house which takes responsibility for the relevant contacts with as many Internet service providers worldwide as possible. A problem here, however, is that a large proportion of the revenues of the operator of a wireless local area network has to be transferred to the clearing house. Furthermore, the clearing house has to succeed in being able to contact each actual Internet service provider or at least a large number of Internet service providers, i.e. in concluding a large number of contracts itself. This solution, too, is consequently very difficult to manage. With regard to unauthorized access to data networks there is also increasingly the problem that unauthenticated content is being provided by subscribers of wireless local area networks. Only authentication could prevent extremist information or information that jeopardizes young people from being retrieved via the local area networks concerned and via access to the Internet. These problems can be solved by the operators of the mobile communications networks in a simple way. The cellular mobile communications networks have a large subscriber base that can be authenticated. Furthermore, these mobile communications networks have an accounting or billing system. By means of international roaming, subscribers who are registered or subscribed with another mobile communications network operator can also be serviced and authenticated. Since nowadays a majority of consumers in industrialized countries are mobile telephone subscribers, a mobile communications network operator can in principle contact virtually every consumer itself or with the aid of other mobile communications network operators. Initiatives as to how a mobile communications network operator can integrated wireless local area network into its own cellular mobile communications network are many and various. As the debate stands at present, a distinction is drawn between tight and loose coupling. Tight coupling is defined as full UMTS integration, i.e. one uses only the physical layer of the wireless local area network, while all higher protocol layers are taken over from UMTS and adapted. This solution is meanwhile no longer under discussion as it has proven not to make economic sense and to be technically difficult to implement. Among the variants of loose coupling currently being debated publicly are the two infrastructure-based coupling variants (e.g. ETSI BRAN) which are based on the use of a registered identification card (SIM: subscriber identification module) or the RADIUS PROTOCOL (RADIUS: Remote Access Dial-In User Access). In the case of the SIM-based variant, a SIM card is installed in a notebook or a network access card for said notebook. The wireless local area network system appears logically as a visitor local register (VLR) of the telecommunications network and is connected to the telecommunications network via the MAP (mobile application part). Economic success for the operator of the telecommunications network depends greatly, however, on whether in future every card for accessing wireless local area networks will contain a SIM card as standard. For this to occur, computer manufacturers and the standardization bodies for data networks and telecommunications networks would have to develop joint standards or a mobile communications network operator would have to subsidize this specific type of NIC. In the case of the RADIUS variant, the telecommunications network appears as an authentication, authorization and accounting server, as a result of which no modification of subscriber equipment is necessary. With regard to currently available hardware, access points (AP) which are based on the IEEE 802.11b standard are known, as analog modems for connecting to a telephone line, as ISDN cards for connecting to an So bus, as DSL modems for connecting to a DSL line, topologically as Ethernet bridges with a local area network terminal for connecting to a local area network and in further embodiments as a cable modem for connecting to a cable television network and as a router, for example with an Ethernet terminal without a bridge function. These access points consist of a radio access section for controlling access to the radio interface and an interface for connecting to the wired telecommunications or data network. The radio access section and the interface for the line-bound terminal are connected with hardware which also provides appropriate configuration management functions, etc. SUMMARY OF THE INVENTION The invention provides a method and device for authenticated access to local area networks, in particular wireless local area networks, which simplify the authentication and in particular facilitate the possibility of charging for services used with the aid of the local radio network. In one embodiment of the invention, there is a charging method for stations compatible with a data network, a data network unit, a network access device and charging systems. Authenticated access is defined as access to a data network, data or the like, where the accessing station or the operator thereof can be identified directly or indirectly. Data networks are local area networks in accordance with e.g. IEEE 802.11 or HiperLAN2. Stations compatible with a data network are accordingly computers, notebooks and the like which have a cable or wireless interface to such a data network. Access points, which are deemed to include hubs, bridges, network cards in computers and the like, serve as access for such a data network. The identification information can be a device number, an assigned telephone number, a password-type character string and the like, which are assigned to the station or the operator thereof. The identifier, e.g. a password, is provided on the other hand by the data network unit triggering authentication. The transmission path of a short message, a call or the like is listed for example as a path to an authenticated device that is protected against manipulation. The transmission of characteristic information to the access point or data network can occur e.g. by reading of a mobile telephone display, fax or the like by persons or else automatically by infrared interfaces or cable connections. For determining the authenticity of a subscriber or of a subscriber's station, a method is particularly advantageous in which characteristic information is transmitted by the data network over a secure path to a device external to the data network having authentication of subscribers or subscriber stations. The subscriber can transfer the characteristic information received on such a device manually after it has been shown on a display or by an automatic interface, e.g. via a cable connection or an infrared connection to the mobile host or computer. By this means, access can be gained on the one hand to secure authentication information of another system, of which at least the access code of the uniquely assignable device of the system with authentication is known in the data network. Advantageously, however, access does not have to be directly with further network-internal devices of the other system with the authentication function. The data network and the other system with an authentication function thus remain fully decoupled and enable nonetheless secure authentication of the mobile host or of the station with which the data network is being accessed, since the operation of this station can be carried out by a uniquely authenticatable subscriber in the other system. Advantageously, the identifier is randomly generated in the access point of the data network or of another device of the data network from the available standard character set. However, it is also possible for an identifier to be selected from a list containing a large number of passwords so that, to simplify transmission, words in users' normal vocabulary can be used. The transmission of the identifier to the device in the system with authentication can be carried out particularly easily by using the short message service (SMS). This procedure can readily be implemented for data network access in current and future cellular telecommunications systems with a very large distribution in the relevant user groups. The transmission of the identifier without any direct use of authentication functions in the system external to the data network is thus preferably understood as meaning that the operator of this external network enables a data transmission comparable with a normal telephone call or a short message transmission. The transmission of the identifier advantageously occurs without any direct use of the actual authentication functions in the system external to the data network. Direct communication with one or more of the devices and functions of the external system is not necessary. It is particularly advantageous here for the identifier to be transmitted via a mobile station and/or a SIM card of a cellular mobile communications system. After the authentication of the subscriber or of the station accessing the data network, a recording can be undertaken in the data network itself of data relevant to charging when the station accesses a certain service or for a certain period of time via the data network. Advantageously, data relevant to charging that is recorded in this way can be passed in accordance with a method having an independent inventive embodiment through to a separate central charging office or to a charging center of the system external to the data network. Methods of this type can be implemented in particular with a local area network or wireless local area network if, in addition to being equipped with an interface for access by a subscriber's station, an access control unit having usefully an authentication memory and a first interface for access from the data network to an external network, this network is also equipped with a special access control unit for generating an identifier and for emitting this identifier via the external network. The identifier can be transmitted via a second network device interface from the external network to the station connected to the data network, simultaneously enabling authentication of the station by the access control unit. Obvious solutions for implementing such a method in a data network equipped in such a manner are, in particular, modems and network access devices which have appropriate interfaces to the data network, e.g. an Ethernet terminal, and to the external network, e.g. a telephone line, as well as appropriate hardware and software for implementing an appropriate authentication procedure. Advantageously, such an access control unit has the devices and functions necessary for authentication as well as an interface module, the interface module being designed as a modular device for connecting to at least one external communications system or communications network with secure authentication so that replacing the interface module makes it possible to adapt to various types of external networks without any major structural outlay. In the other external communications system or communications network with an authentication function, few or no changes are required. Since, with regard to the authentication of a subscriber station accessing a wireless local area network, this communications system or communications network is used for carrying information relevant to authentication, no additional outlay is incurred with regard to subscriber authentication in this external network. The transmission of charging information from an access control unit of a wireless local area network to another external communications system sensibly occurs in the format and via the interfaces which are customary for the transmission of charging-relevant information within this network or to this network. Adaptations to different payment systems can take place either in the external network or else in the wireless local area network. The implementation of this method or the introduction of appropriate technical equipment is possible with minimum outlay. In particular, even very small local area networks or wireless local area networks can be included so that the sum total of many small and very small installations form a complete network which potential wireless data network customers can access. In such scenarios, no principal operator incurring a major financial risk is required, and the investments of the individual access providers, for example, hairdressing salons, restaurants, airport operators are limited due to the ease of implementation. In particular, this also enables mobile communications network operators to access such markets, the mobile communications network operators themselves being able to provide appropriate access to the data network or to render third parties' data network access usable for themselves. In essence, simple, commercially available mass-produced goods which can be obtained by the owners of portable computers and the like at low cost are used for installation. On account of the limited additional functions and additional equipment required at the data network access points, the installation costs are also low for the data network operator and, at less than 500 euros plus monthly Internet access fees, affordable. Even if no charging is undertaken, the use of such a system is advisable in terms of potential customer relations. Charging methods can be apportioned particularly well to different systems if basic charging information is recorded in a first charging unit which can be provided cost-effectively and transmitted to a more cost-intensive but in return centrally operable second charging unit which, from the basic charging information, determines fees to be charged. Areas of application are, due to the use of the unlicensed radio frequency band, private properties, businesses and divisions of companies. While in known systems prior registration and, in the case of charging, the involvement of charging companies or entities was necessary, under the method presented, authentication and consequently unique subscriber identification can be carried out if the data network can access another system or network with the appropriate information. In particular, the copyright status of contents in the network can thus also be checked. The access to cellular telecommunications networks is particularly advantageous since the mobile communications network operators possess the world's largest current subscriber base, use the world's most accepted current form of subscriber authentication and in their charging platform possess a simple collection system for third parties. A further advantageous feature lies in the fact that although the mobile communications network operator itself has fully transferred responsibility for authentication of the access of subscribers and subscriber devices to a third-party service provider, it can e.g. with modems or network access devices supply precisely the mechanisms which enable this service provider to carry out this authentication securely and reliably in the easiest way. On the hardware side, it is particularly advantageous to supply the appropriate equipment in the form of a modem, since a subscriber has only simple connections to make and can install the device such as a normal modem for access to a telecommunications network himself/herself easily and without any major technical outlay. Particular advantages consequently lie in the fact that two different types of network complement one another in that a high-bit-rate data network can indirectly access functions of a low-bit-rate telecommunications network with authentication functions. A data network, in particular a wireless data network, can thus autonomously carry out authentication of a subscriber's station and be connected to various networks for this purpose. The connection to external networks can be such that, from the viewpoint of the external network, a station belonging to that network is accessing or an external device is accessing a standard interface provided for this external device. Mobile communications network operators can offer third-party data network providers connection to their payment system and thus with minimum outlay also offer their mobile subscribers access to local area networks without being forced themselves to set up access points for data networks. In this context, the connection of access control units of wireless local area networks to charging and/or payment systems is advantageous. These systems find use in telecommunications networks, above all however in cellular mobile communications networks when charging information is to be transmitted from service providers outside the network. In this way it is, for example, possible to invoice for the purchase of articles over the mobile communications network. In such a case, the seller of articles uses the subscriber status of the customer with a mobile communications network operator so that the purchaser can then settle his/her account via his/her mobile communications network operator rather than, for example, via a credit card. Thus, the seller uses the collection functions which mobile communications network operators provide to third-party service providers. In this process, the seller is under obligation toward the mobile communications network operator to ensure that only charging information from fully authenticated subscribers is transmitted. Arrangements to this effect can be regulated e.g. in a contract such that the user (seller) of charging services of a mobile communications network operator be basically liable for the sums of money used. Using these methods, known in the art in other areas, which find use in commercial payment systems, e.g. the Siemens Pay@Once system, it is possible for a mobile communications network operator not only itself to offer services subject to a charge but also to arrange for its mobile communications customers to be offered additional services by third-parties, companies not belonging to the mobile communications network operator (untrusted partners). A key advantage of the method described consists in the fact that chargeable access to a local radio network can be offered by third parties, whose charging is carried out via the mobile communications network, without the mobile communications network operator itself having to provide the devices such as base stations necessary for radio-based local wireless network access. A mobile communications network operator can thus provide its customer with access to data networks even where this service is already being offered by another third party. It can sell or donate the devices and functions required to the third party. Third-party operators, e.g. content providers, can be motivated to offer access to local area networks themselves since these third-party operators can in a simple way utilize the authentication and collection facility of a mobile communications network. An independent authentication procedure can usefully be used for the authentication of the data network operator to a third party as the charging center or the like. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments will be described in detail below with reference to the drawings, in which: FIG. 1 shows components of a data network with a facility for accessing an external, authentication-capable communications system. FIG. 2 shows the sequence of an authentication method in the system. FIG. 3 shows diagrammatically a flowchart of the method. FIG. 4 shows an arrangement for charging. FIG. 5 shows a modular radio access point. DETAILED DESCRIPTION OF THE INVENTION Referring to FIG. 1, a sample local area network, in the preferred embodiment a wireless local area network WLAN, includes a large number of devices which are connected to one another by means of appropriate lines. The devices include routers and bridges for distributing data to a large number of network devices. While this type of local area network WLAN can be operated even without a controlling network device if the connected stations, in particular hosts, computers and the like possess an appropriate functionality for controlling access, in the preferred embodiment the local area network has a DHCP server for allocating temporary addresses in accordance with the Internet Protocol (IP). This DHCP server can be connected directly to a network line or an access router AR or be part of such an access router. The local area network also has access points AP for the access of wireless stations to the local area network. Such wireless stations can be computers, notebooks and the like which are equipped with a radio interface, for example an NIC (Network Internet Card), i.e. a network access card. Consequently, communication takes place from the station via its network access card NIC and the radio interface V1 configured at one of the access points AP to the wireless local area network WLAN. As an additional component, the wireless local area network WLAN has a network interface NI which enables access to a communications network with Internet access. The network interface here can advantageously be connected to the access router AR or also integrated in this access router. Integration is, however, also possible in another computer or the like connected to the wireless local area network WLAN. In the method described below for the loose coupling of a wireless local area network WLAN to a mobile communications network, in the embodiment shown a mobile communications network that conforms to the GSM standard, further devices and functions are accessed. Here, authentication and charging are decoupled both from one another and from direct communication with the external GSM network or system. The relevant architecture of a preferred wireless local area network system is shown in the symbolic representation sketched below the graphical representation of the network, which can be coupled to a variety of networks as a result of the decoupling of authentication and charging. Access to PLMN HLR/HSS (Public Land Mobile Network Home Location Register/Home Subscriber System), electronic trading systems (eCommerce), ISP AAA (Internet Service Provider Authentication Authorization Accounting), intelligent micropayment network systems (IN micropayment systems), etc. are mentioned as examples in addition to access to the GSM. The connection of these different systems or networks to the data network WLAN is via a network interface which has an appropriate interface module. The remaining blocks shown in the diagram can be used unchanged for the various external networks or external systems. Here, the generic modules include a user station or user application, e.g. a notebook with a wireless network card and an Internet browser, a radio access unit, e.g. a radio access point conforming to IEEE standard 802.11b which is connected to a local area network LAN, an access control unit or access control function which recognizes whether a subscriber is already authenticated or not and which if necessary enforces authentication, and an authentication function or authentication unit which carries out the authentication. Furthermore, a charging function or a charging system can be provided, which charging information generates, based on the period of service use, the quantity of data transmitted or the type of service used, subscriber-dependent billing datasets. Such functions and systems can, however, also be included in the network interface. The generic modules and functions can be used unchanged both in terms of their logical functions and with regard to their physical entities. The term ‘generic’ is thus deemed to refer, in particular, to a unit which in terms of its physical design and its logical function can be used unchanged, independently of an external system to which this generic device is connected. The individual devices and functions can be provided here as devices and functions separate from one another, can be components of other network devices or else be combined in a device referred to hereinafter as a service selection gateway SSG. The authentication function is designed in the embodiment described below to be provided by a network server or web server. The sequence of operations in the accessing of a network by a station WH and the corresponding authentication of this station or of the user assigned to this station is also described with reference to FIGS. 2 and 3. In a first step S1, the subscriber's station WH obtains via the radio interface V1 a wireless access to the access point AP of the wireless local area network WLAN, which is installed for example at an airport. After the assignment by the DHCP server of an IP (Internet Protocol) address to be used for access by the station WH in accordance with standardized functions for local area networks, the authentication is triggered when a service, e.g. Internet access, is accessed for the first time using the IP address or the globally unique MAC (Medium Access Control) address specific to the network access card. The access control function or access control unit has a memory in which a list is held scheduling which IP addresses WH-IP or MAC addresses WH-MAC are already listed as authenticated subscribers or authenticated subscriber stations (step S2). If it is ascertained in a step S3 that the checked IP address WH-IP or MAC address WH-MAC belongs to a previously authenticated subscriber or subscriber terminal, access to the required services which are being offered with the aid of or by the local area network is cleared. Otherwise, access can, for example, be restricted to free local services, for example departure boards at airports, or any data access disabled or a fresh authentication procedure started. For non-authenticated IP or MAC addresses, the service selection gateway SSG or the access control unit located therein imports in place of the required Internet page a portal page which prompts the subscriber or operator of the station WH to enter unique identification features, e.g. username and password. These parameters are used for authentication. If this is successful, then the access control function is instructed to clear the subscriber, i.e. to allow him/her access to the required Internet page, so that the subscriber has free access to the required service or the Internet. When the portal page is transmitted in a step S4, in particular an access number for a telephone, in particular a cellular telephone of the subscriber, can be requested in addition to or instead of the unique identification features. After the access number or telephone number (mobile directory number) has been input in a step S5 by the subscriber or operator of the station WH, the identification number or telephone number is sent via the access point AP to the service selection gateway SSG in a step S6. In a subsequent step S7, the service selection gateway generates, in the event that authentication is possible with the details given but a telephone number of this type is specified, a password. The password is transmitted as an identifier to the appropriate telephone via the appropriate communications network assigned to the telephone number. Other suitable data terminals, for example fax machines, can be used instead of a telephone. It is essential that the identifier be transmitted via a telecommunications network, data network or system which permits a unique and reliable assignment of subscribers, in which network or system a certain person is uniquely assigned to the specified telephone number as a subscriber or as a certain data terminal. The identifier can and is directed to this person. In the embodiment shown, the identifier is transmitted in a step S8b as a short message service SMS via a telecommunications network to a mobile station, in particular a cellular telephone of the GSM network with the assigned mobile directory number MSISDN. In parallel with this, a password request is sent in a step S8a as a portal page to the station WH. In a next step S9, the subscriber reads off the identifier from his/her cellular telephone and inputs said information into his/her station WH. After it has been confirmed, the identifier or this password is sent in a step S10 by the station WH via the access point AP to the service selection gateway SSG. In the next step S11, a check is made in the service selection gateway SSG as to whether the identifier or the password matches the password originally generated and issued or has been changed in a permissible manner, for example, by means of encryptions. If not, an error message is output in step S12 to the station WH and the procedure terminated or a repeat request for authentication information is initiated in step S4. If in step S11 the identifier is ok, the station WH is cleared in step S13 for the requested or permitted access to special services and/or the Internet. A restriction of the call duration can be provided for here. Optionally, a recording of charging information can also be initiated in a step S14. Such charging information is transmitted in a step S15 to an appropriate charging service e.g. of a third party or of the operator of the network or system used for the authentication (step S15). A random method can be used when selecting the password or the identifier, but it is also possible to use a memory containing a large number of terms from which one term is selected on a random basis in each case and transmitted via the authentication-capable network or system. Alternatively or additionally, passwords can be preset, for example for airport officials at an airport, which passwords can be entered by subscribers as part of the authentication procedure either directly or, for example in the event of their having been forgotten, in order for it to be possible for them to be resent to them. In summary, the subscriber or operator of a station WH to be connected to the wireless local area network WLAN enters instead of a password his/her mobile directory number (MSISDN) in the portal page, the authentication function generates a password and sends this password as an identifier by short message service SMS to a mobile radiocommunication terminal (GSM terminal). The subscriber transmits the password received to the station and can thus be uniquely authenticated by the authentication function in the service selection gateway SSG. In this way, while the operator of the data network has only one telephone number as a possible unique assignment to the subscriber, a further assignment to the subscriber is possible, if needed, e.g. if personal address data is specified incorrectly by the station user, by means of an appropriate later access to the databases of the telecommunications system. By this means, the subscriber is ultimately, and in the most reliable and trustworthy manner currently known, also authenticated for the authentication function of the wireless local area network. Furthermore, it is possible to invoice the subscriber for any charging information via a charging service used as an intermediary, a corresponding charging organization or the operator of the mobile communications network. In particular, a fiduciary relationship has only to exist between the authentication server and the telecommunications network which was used as an intermediary for the authentication, but not between the subscriber and the operator of the data network. A wallet server can also be used as an intermediary charging organization or charging service, which wallet server functions in the manner of a collection agency. The use of the mobile communications system hereinbefore is only a means to the end of authentication and is not intended to exclude any other type of network connection. The authentication function and the access control function can be accommodated in one entity, e.g. a computer, but can also be provided separately in a central and/or multiple satellite devices. This is illustrated in the Figures by means of the division into a web server i-noc for carrying out the authentication and an access unit i-sat containing the access control unit. The radio access unit and the access control unit record among other things information for charging. If the authentication function is set up in an independent device i-noc, such an authentication device i-noc can also supply multiple access control units i-sat. In particular, it is then advantageous to install the authentication device i-noc at a location close to or in an external network with a reliable independent authentication function or with the operator of a charging system, e.g. with the operator of the mobile communications network GSM or a broker. This enables provision of a costly authentication device i-noc at a central location and the connection of a large number of readily configured and cost-effective access control units i-sat in individual local networks WLAN or access points AP. Advisably, a secure IP-based connection conforming to e.g. RADIUS or HTTP-S (Hypertext Transmission Protocol—Secure) is established for the connection between separate access control units i-sat and an authentication device i-noc. In addition to the transmission of charging information to a so-called wallet server, the charging information can also be transmitted directly to the operator for example of a mobile communications network used for the authentication; charging or payment platforms available there can be used. Payment platforms exist for example as intelligent network functions for micropayment solutions. Such a charging method is described below with reference to FIG. 4. Currently standard mobile communications networks have an intelligent network (IN) with the aid of which they can offer help services or supplementary services for their mobile telephony customers, e.g. call forwarding to a voice mailbox. These systems generally consist of a service switching point SSP and a service control point SCP. The former recognizes for example from the call number dialed that an IN service is required, the latter recognizes the required service and enables the provision and charging of the same. Service control points SCP are generally implemented on server platforms. Mobile communications network operators can now give third parties access to this generally very complex system if third parties would like to offer their own services and to use the mobile communications network operator's payment system as a type of collection system, which is where the term micropayment stems from. To this end, the connection is provided to a payment platform or a payment server, the interface being based upon a simple, generally IP-based, protocol, rather than using complex protocols which conform for example with CCS7 or INAP. In such a system, however, exactly the same problem of trust arises as in the prior art. If the seller of services or of data network access connects to such a charging system and is at the same time a wholly owned subsidiary of a mobile communications network operator, then charging requests from the seller can be accepted. The seller is then given an account in the payment server. However, if the seller is not a trustworthy seller, e.g. an unknown data network operator, then a wallet server is generally used as an intermediary. This wallet server can then, in addition to banks or trustworthy sellers, transmit invoices direct to the mobile communications network operator's payment system or charging system. To facilitate this, the web server in the embodiment hereinabove is supplemented by an appropriate extended network interface. By this means, charging information can be transmitted inserted in appropriate messages of the mobile communications collection system. In order to be able to determine the end of the charging, an override can be made to IN services, for example a weather service, which enable a time-out. Using the procedure and devices described hereinabove, a wireless local area network can autonomously carry out authentications of connected stations or of subscribers assigned to these stations, it being possible for authentication information to be used from various different networks and systems with appropriately secure authentication facilities. A mobile communications network operator can connect external suppliers of local area networks to its charging or payment system and thus with minimum outlay offer its own mobile communications customers access to local area networks without itself being compelled to provide access points and data networks. Furthermore, a mobile communications network operator can obtain access to local area networks for its customers even at locations where this service is already being offered by another third party, by selling or donating to this third party the necessary devices and software functions. Moreover, third-party operators, e.g. content providers can be motivated to offer access facilities to wireless local area networks themselves since these can also exploit the mobile communications network's facility for authentication and thus for collection. Referring to FIG. 5, a particularly preferred radio access point consists of a modular device. A radio element serves to connect external wireless stations to a wireless local area network conforming e.g. to the Ethernet standard. A modem element is also connected to the Ethernet line. The modem element has the devices and functions of the service selection gateway, i.e. the access control unit and function, a call or connection section and modularly replaceable interface devices for connecting to an external communications system or network. A modular device configured in this way conceals the service functionality, looks like a modem and offers, depending on the structural configuration, facilities for connecting to a large number of different types of communications systems and networks, such as e.g. ISDN or DSL. The aforementioned connection facilities serve not only the authentication described hereinabove, but also to provide an Internet access or other physical connections between the different types of systems. The various network types can thus be connected to the external interface, whereby access for sending short messages SMS to a mobile telephone in the GSM network can be via a 2 Mbit line of an interposed IP backbone.

<SOH> BACKGROUND OF THE INVENTION <EOH>A large number of different types of telecommunications and data networks for communicating and/or transmitting data are known. A distinction can be drawn here between two fundamentally different types of network. There are, on the one hand, the telecommunications networks, for example those conforming to the GSM (Global System for Mobile Telecommunications) or the UMTS (Universal Mobile Telecommunications System) standards, in which subscribers are authenticated and authorized when they sign on to the network concerned. An advantage in networks of this type is that as a result of the authentication procedure it is also possible to charge for services used. Furthermore, these generally cellular networks offer the opportunity of a high degree of mobility since a subscriber can move with his/her station from network cell to network cell. A disadvantage of these types of cellular telecommunications systems is that the administrative outlay is very high. Also, these telecommunications networks provide only a low data rate for radio interfaces. There are, on the other hand, data networks which are designed as local area networks or wireless local area networks (WLAN). Such data networks offer subscriber stations access that is very easy to administer. A further advantage consists in the considerably higher data rate by comparison with telecommunications networks at the interfaces to the subscriber station. A disadvantage of data networks of this type, however, is the lack of an authentication facility and consequently also the lack of a billing or charging facility. Currently, especially in the USA and Europe, it is almost exclusively products based on the IEEE 802.11 family which appear to be prevailing as local area networks with wireless subscriber access, with suitable Ethernet terminals already being provided as standard in many computers and portable computers (laptops, notebooks, PDAs, etc.). The radio interface defined under the IEEE 802.11b standard for accessing local area networks corresponds functionally to a wired connection to LANs which have now developed into the office standard. Interface cards for wireless access to local area networks, also referred to as NICs (network interface cards), are from an architectural point of view produced like standardized Ethernet cards and with today's operating systems can be installed using plug & play. Portable computers are readily upgradeable with appropriate interface cards unless they have already been delivered ex works with an integrated terminal for wired or wireless access to local area networks. With the next generations of operating systems (e.g. Windows XP from Microsoft) fully integrated support for wireless local area networks will be provided. With data rates of 11 Mbit/s at present and of 50 Mbit/s in future, subscribers will thus be provided with data rates that are considerably higher than the data rates which can be offered by the next third-generation mobile telecommunications (UMTS). Access to wireless local area networks for high-bit-rate connections is consequently preferable for transmitting large quantities of data, especially in connection with Internet access. Disadvantageously, the wireless local area networks cannot offer any authentication facility for stations or computers not already registered in the system. However, operators of wireless local area networks, for example in an airport area, have to offer access for a large number of different subscribers from different regions. In order to be able to authenticate a subscriber, the operator of the wireless local area network would have to conclude cross-license agreements with all possible Internet service providers (ISPs), of which, however, there are currently over 60,000 in Germany alone. Without authenticating subscribers or subscribers' stations, no billing of services used can occur since it is not even known to whom a bill could be sent. Access to wireless local area networks must therefore either be offered free of charge or as a prepaid service with payment in advance by means of credit card billing or the like. A further facility enabling authentication and billing consists in involving a billing company or clearing house which takes responsibility for the relevant contacts with as many Internet service providers worldwide as possible. A problem here, however, is that a large proportion of the revenues of the operator of a wireless local area network has to be transferred to the clearing house. Furthermore, the clearing house has to succeed in being able to contact each actual Internet service provider or at least a large number of Internet service providers, i.e. in concluding a large number of contracts itself. This solution, too, is consequently very difficult to manage. With regard to unauthorized access to data networks there is also increasingly the problem that unauthenticated content is being provided by subscribers of wireless local area networks. Only authentication could prevent extremist information or information that jeopardizes young people from being retrieved via the local area networks concerned and via access to the Internet. These problems can be solved by the operators of the mobile communications networks in a simple way. The cellular mobile communications networks have a large subscriber base that can be authenticated. Furthermore, these mobile communications networks have an accounting or billing system. By means of international roaming, subscribers who are registered or subscribed with another mobile communications network operator can also be serviced and authenticated. Since nowadays a majority of consumers in industrialized countries are mobile telephone subscribers, a mobile communications network operator can in principle contact virtually every consumer itself or with the aid of other mobile communications network operators. Initiatives as to how a mobile communications network operator can integrated wireless local area network into its own cellular mobile communications network are many and various. As the debate stands at present, a distinction is drawn between tight and loose coupling. Tight coupling is defined as full UMTS integration, i.e. one uses only the physical layer of the wireless local area network, while all higher protocol layers are taken over from UMTS and adapted. This solution is meanwhile no longer under discussion as it has proven not to make economic sense and to be technically difficult to implement. Among the variants of loose coupling currently being debated publicly are the two infrastructure-based coupling variants (e.g. ETSI BRAN) which are based on the use of a registered identification card (SIM: subscriber identification module) or the RADIUS PROTOCOL (RADIUS: Remote Access Dial-In User Access). In the case of the SIM-based variant, a SIM card is installed in a notebook or a network access card for said notebook. The wireless local area network system appears logically as a visitor local register (VLR) of the telecommunications network and is connected to the telecommunications network via the MAP (mobile application part). Economic success for the operator of the telecommunications network depends greatly, however, on whether in future every card for accessing wireless local area networks will contain a SIM card as standard. For this to occur, computer manufacturers and the standardization bodies for data networks and telecommunications networks would have to develop joint standards or a mobile communications network operator would have to subsidize this specific type of NIC. In the case of the RADIUS variant, the telecommunications network appears as an authentication, authorization and accounting server, as a result of which no modification of subscriber equipment is necessary. With regard to currently available hardware, access points (AP) which are based on the IEEE 802.11b standard are known, as analog modems for connecting to a telephone line, as ISDN cards for connecting to an So bus, as DSL modems for connecting to a DSL line, topologically as Ethernet bridges with a local area network terminal for connecting to a local area network and in further embodiments as a cable modem for connecting to a cable television network and as a router, for example with an Ethernet terminal without a bridge function. These access points consist of a radio access section for controlling access to the radio interface and an interface for connecting to the wired telecommunications or data network. The radio access section and the interface for the line-bound terminal are connected with hardware which also provides appropriate configuration management functions, etc.

<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a method and device for authenticated access to local area networks, in particular wireless local area networks, which simplify the authentication and in particular facilitate the possibility of charging for services used with the aid of the local radio network. In one embodiment of the invention, there is a charging method for stations compatible with a data network, a data network unit, a network access device and charging systems. Authenticated access is defined as access to a data network, data or the like, where the accessing station or the operator thereof can be identified directly or indirectly. Data networks are local area networks in accordance with e.g. IEEE 802.11 or HiperLAN2. Stations compatible with a data network are accordingly computers, notebooks and the like which have a cable or wireless interface to such a data network. Access points, which are deemed to include hubs, bridges, network cards in computers and the like, serve as access for such a data network. The identification information can be a device number, an assigned telephone number, a password-type character string and the like, which are assigned to the station or the operator thereof. The identifier, e.g. a password, is provided on the other hand by the data network unit triggering authentication. The transmission path of a short message, a call or the like is listed for example as a path to an authenticated device that is protected against manipulation. The transmission of characteristic information to the access point or data network can occur e.g. by reading of a mobile telephone display, fax or the like by persons or else automatically by infrared interfaces or cable connections. For determining the authenticity of a subscriber or of a subscriber's station, a method is particularly advantageous in which characteristic information is transmitted by the data network over a secure path to a device external to the data network having authentication of subscribers or subscriber stations. The subscriber can transfer the characteristic information received on such a device manually after it has been shown on a display or by an automatic interface, e.g. via a cable connection or an infrared connection to the mobile host or computer. By this means, access can be gained on the one hand to secure authentication information of another system, of which at least the access code of the uniquely assignable device of the system with authentication is known in the data network. Advantageously, however, access does not have to be directly with further network-internal devices of the other system with the authentication function. The data network and the other system with an authentication function thus remain fully decoupled and enable nonetheless secure authentication of the mobile host or of the station with which the data network is being accessed, since the operation of this station can be carried out by a uniquely authenticatable subscriber in the other system. Advantageously, the identifier is randomly generated in the access point of the data network or of another device of the data network from the available standard character set. However, it is also possible for an identifier to be selected from a list containing a large number of passwords so that, to simplify transmission, words in users' normal vocabulary can be used. The transmission of the identifier to the device in the system with authentication can be carried out particularly easily by using the short message service (SMS). This procedure can readily be implemented for data network access in current and future cellular telecommunications systems with a very large distribution in the relevant user groups. The transmission of the identifier without any direct use of authentication functions in the system external to the data network is thus preferably understood as meaning that the operator of this external network enables a data transmission comparable with a normal telephone call or a short message transmission. The transmission of the identifier advantageously occurs without any direct use of the actual authentication functions in the system external to the data network. Direct communication with one or more of the devices and functions of the external system is not necessary. It is particularly advantageous here for the identifier to be transmitted via a mobile station and/or a SIM card of a cellular mobile communications system. After the authentication of the subscriber or of the station accessing the data network, a recording can be undertaken in the data network itself of data relevant to charging when the station accesses a certain service or for a certain period of time via the data network. Advantageously, data relevant to charging that is recorded in this way can be passed in accordance with a method having an independent inventive embodiment through to a separate central charging office or to a charging center of the system external to the data network. Methods of this type can be implemented in particular with a local area network or wireless local area network if, in addition to being equipped with an interface for access by a subscriber's station, an access control unit having usefully an authentication memory and a first interface for access from the data network to an external network, this network is also equipped with a special access control unit for generating an identifier and for emitting this identifier via the external network. The identifier can be transmitted via a second network device interface from the external network to the station connected to the data network, simultaneously enabling authentication of the station by the access control unit. Obvious solutions for implementing such a method in a data network equipped in such a manner are, in particular, modems and network access devices which have appropriate interfaces to the data network, e.g. an Ethernet terminal, and to the external network, e.g. a telephone line, as well as appropriate hardware and software for implementing an appropriate authentication procedure. Advantageously, such an access control unit has the devices and functions necessary for authentication as well as an interface module, the interface module being designed as a modular device for connecting to at least one external communications system or communications network with secure authentication so that replacing the interface module makes it possible to adapt to various types of external networks without any major structural outlay. In the other external communications system or communications network with an authentication function, few or no changes are required. Since, with regard to the authentication of a subscriber station accessing a wireless local area network, this communications system or communications network is used for carrying information relevant to authentication, no additional outlay is incurred with regard to subscriber authentication in this external network. The transmission of charging information from an access control unit of a wireless local area network to another external communications system sensibly occurs in the format and via the interfaces which are customary for the transmission of charging-relevant information within this network or to this network. Adaptations to different payment systems can take place either in the external network or else in the wireless local area network. The implementation of this method or the introduction of appropriate technical equipment is possible with minimum outlay. In particular, even very small local area networks or wireless local area networks can be included so that the sum total of many small and very small installations form a complete network which potential wireless data network customers can access. In such scenarios, no principal operator incurring a major financial risk is required, and the investments of the individual access providers, for example, hairdressing salons, restaurants, airport operators are limited due to the ease of implementation. In particular, this also enables mobile communications network operators to access such markets, the mobile communications network operators themselves being able to provide appropriate access to the data network or to render third parties' data network access usable for themselves. In essence, simple, commercially available mass-produced goods which can be obtained by the owners of portable computers and the like at low cost are used for installation. On account of the limited additional functions and additional equipment required at the data network access points, the installation costs are also low for the data network operator and, at less than 500 euros plus monthly Internet access fees, affordable. Even if no charging is undertaken, the use of such a system is advisable in terms of potential customer relations. Charging methods can be apportioned particularly well to different systems if basic charging information is recorded in a first charging unit which can be provided cost-effectively and transmitted to a more cost-intensive but in return centrally operable second charging unit which, from the basic charging information, determines fees to be charged. Areas of application are, due to the use of the unlicensed radio frequency band, private properties, businesses and divisions of companies. While in known systems prior registration and, in the case of charging, the involvement of charging companies or entities was necessary, under the method presented, authentication and consequently unique subscriber identification can be carried out if the data network can access another system or network with the appropriate information. In particular, the copyright status of contents in the network can thus also be checked. The access to cellular telecommunications networks is particularly advantageous since the mobile communications network operators possess the world's largest current subscriber base, use the world's most accepted current form of subscriber authentication and in their charging platform possess a simple collection system for third parties. A further advantageous feature lies in the fact that although the mobile communications network operator itself has fully transferred responsibility for authentication of the access of subscribers and subscriber devices to a third-party service provider, it can e.g. with modems or network access devices supply precisely the mechanisms which enable this service provider to carry out this authentication securely and reliably in the easiest way. On the hardware side, it is particularly advantageous to supply the appropriate equipment in the form of a modem, since a subscriber has only simple connections to make and can install the device such as a normal modem for access to a telecommunications network himself/herself easily and without any major technical outlay. Particular advantages consequently lie in the fact that two different types of network complement one another in that a high-bit-rate data network can indirectly access functions of a low-bit-rate telecommunications network with authentication functions. A data network, in particular a wireless data network, can thus autonomously carry out authentication of a subscriber's station and be connected to various networks for this purpose. The connection to external networks can be such that, from the viewpoint of the external network, a station belonging to that network is accessing or an external device is accessing a standard interface provided for this external device. Mobile communications network operators can offer third-party data network providers connection to their payment system and thus with minimum outlay also offer their mobile subscribers access to local area networks without being forced themselves to set up access points for data networks. In this context, the connection of access control units of wireless local area networks to charging and/or payment systems is advantageous. These systems find use in telecommunications networks, above all however in cellular mobile communications networks when charging information is to be transmitted from service providers outside the network. In this way it is, for example, possible to invoice for the purchase of articles over the mobile communications network. In such a case, the seller of articles uses the subscriber status of the customer with a mobile communications network operator so that the purchaser can then settle his/her account via his/her mobile communications network operator rather than, for example, via a credit card. Thus, the seller uses the collection functions which mobile communications network operators provide to third-party service providers. In this process, the seller is under obligation toward the mobile communications network operator to ensure that only charging information from fully authenticated subscribers is transmitted. Arrangements to this effect can be regulated e.g. in a contract such that the user (seller) of charging services of a mobile communications network operator be basically liable for the sums of money used. Using these methods, known in the art in other areas, which find use in commercial payment systems, e.g. the Siemens Pay@Once system, it is possible for a mobile communications network operator not only itself to offer services subject to a charge but also to arrange for its mobile communications customers to be offered additional services by third-parties, companies not belonging to the mobile communications network operator (untrusted partners). A key advantage of the method described consists in the fact that chargeable access to a local radio network can be offered by third parties, whose charging is carried out via the mobile communications network, without the mobile communications network operator itself having to provide the devices such as base stations necessary for radio-based local wireless network access. A mobile communications network operator can thus provide its customer with access to data networks even where this service is already being offered by another third party. It can sell or donate the devices and functions required to the third party. Third-party operators, e.g. content providers, can be motivated to offer access to local area networks themselves since these third-party operators can in a simple way utilize the authentication and collection facility of a mobile communications network. An independent authentication procedure can usefully be used for the authentication of the data network operator to a third party as the charging center or the like.

20041018

20100713

20050303

64856.0

DOAN, KIET M

METHOD AND DEVICE FOR AUTHENTICATED ACCESS OF A STATION TO LOCAL DATA NETWORKS IN PARTICULAR RADIO DATA NETWORKS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for embossed and colourless decoration and bonding of a fabric web and device therefor

The invention concerns a method for producing three-dimensional colourless designs in a non-woven fabric or like material entirely bonded. Said method consists in subjecting the fibers to a blowing process through openings which form the design, then in optionally bonding them in the openings, since the fibers in the openings are only displaced therein with limited depth, and are subsequently needle bonded against a supplementary support.

1. Method for colorless plastic patterning and strengthening of a fabric web of fibers that is not woven or knitted, namely, a nonwoven made up of substantially finite fibers such as synthetic staple fibers or also natural fibers, characterized in that the fibers of the fabric web lying in a first plane provided with the intended pattern are partly displaced by high-energy water jets into a second plane and there held up against further displacement by an existing resistance, the impinging liquid is drained off, and the fibers of the fabric web in the two planes are intertwined with one another by the action of the water jets so that the nonwoven is strengthened over its entire area and with a pattern. 2. Device for carrying out the method of claim 1, having a substrate (5) present in the direction of the flowing water jets, which is only partly liquid-permeable and is open with a pattern (7), and a pressurized-water bar assigned to this substrate for the production of fine water jets (4) distributed over the working width, characterized in that a further substrate (12), likewise braced and liquid-permeable and provided as a supporting resistance for the fibers displaced by the pattern-imparting substrate (5), is arranged beneath the pattern-imparting substrate (5). 3. Device according to claim 2, characterized by consisting of a supporting, intrinsically stable, liquid-permeable drum such as a perforated drum (11), which is externally surrounded by a fine-meshed screen belt (12) such as a spun lace belt and the latter is surrounded by a pattern-imparting, likewise liquid-permeable belt (5) or foil to which the pressurized-water bar (3) is radially outwardly assigned. 4. Device according to claim 3, characterized in that the fine-meshed spun bond belt (12) is braced on the perforated drum (11) via a further interposed coarse-meshed screen fabric (13).

The invention relates to a method for colorless plastic patterning and strengthening of a fabric web of fibers that is not woven or knitted, i.e., of a nonwoven made up of substantially finite but also endless fibers such as synthetic staple fibers or also natural fibers. U.S. Pat. No. 5,115,544 discloses provision of a screen with a number of profile-imparting elevations against which the nonwoven to be patterned is pressed by water jets. Depending on what figures are applied as elevations on the endless screen or bent into the screen, highly varied patterns, including perforated patterns, can be generated. The fibers are laterally displaced next to the elevations by the water jets, so that the elevations are substantially free of fibers. A similar disclosure is provided by EP-A-0 511 025, according to which elevations on a screen likewise ensure the colorless pattern. Here, hot air can also be employed as the medium for moving the fibers. Further, DE-A-21 09 143 discloses moving a template with cutouts corresponding to the desired pattern over the fabric web, against which cutouts hot air is blown under pressure. However, this method, known from the color printing process, has likewise proved unsatisfactory. The same is true for the idea of DE-A-20 211 188—in which the patterning is effected by the template, likewise with hot air—that the air causes individual fibers of the pile-like fabric web to shrink as desired for the pattern. In addition, reference should also be made to EP-A-0 423 619, according to which the fibers of a nonwoven are moved against a perforated drum by water jets in order to move the fibers into the holes of the perforated drum. In this way there results a nonwoven with a thin back and a front pattern side with fibers of the nonwoven there strongly concentrated in pattern fashion. The concentration of the fibers is undefinable in particular in the thickness of the nonwoven and the strengthening of the nonwoven is nearly equal to zero in the region of the pattern-fashion thickenings. The fibers of the nonwoven are shifted by the water jets into the recesses of the perforated drum in pattern fashion, but there is no strengthening of the fibers in the recesses. Starting from the method of the type stated at the outset, the goal is to find a method by which, without great expense, a pattern can be continuously induced in the nonwoven or the like, which pattern is clearly defined in height as well, in which the moved fibers are likewise mutually interlaced and thus strengthened. In order to achieve this goal, the invention provides that the fibers of the fabric web lying in a first plane provided with the intended pattern are partly displaced by high-energy water jets into a second plane and there held up against further displacement by an existing resistance, the impinging liquid is drained off, and the fibers of the fabric web in the two planes are intertwined with one another by the action of the water jets so that the nonwoven is strengthened over its entire area and with a pattern. Essential for clearly delimited patterning in a nonwoven uniformly strengthened over the entire area, similarly to a watermark in a paper, is the prevention of tearing of the nonwoven into two planes upon hydrodynamic needling. Strengthening should be the same everywhere, no holes of any kind should appear, and also the thickness of the nonwoven in the two planes should remain equal and invariant. A device for carrying out the method is provided with a substrate present in the direction of the flowing water jets, which is only partly liquid-permeable and is open with a pattern. There, further, there is a pressurized-water bar assigned to this substrate for the production of fine water jets distributed over the working width. This device is now supplemented by a further substrate, likewise braced and liquid-permeable and provided as a supporting resistance for the fibers displaced by the pattern-imparting substrate, arranged beneath the pattern-imparting substrate. The device could advantageously be made up of a supporting, intrinsically stable, liquid-permeable drum such as a perforated drum, which is externally surrounded by a fine-meshed perforated belt such as a spun lace belt, and this by a pattern-imparting and likewise liquid-permeable belt or foil to which the pressurized-water bar is radially outwardly assigned. It is further advantageous to brace the spun lace belt on the perforated drum with a further, coarser screen fabric. A device of the type according to the invention is depicted in exemplary fashion in the drawings, in which: FIG. 1 shows in cross section a permeable perforated drum, held under suction, for production of a patterned nonwoven with the nozzle bar outwardly assigned to the perforated drum, and FIG. 2 shows the jacket of the perforated drum of FIG. 1 in enlarged depiction, and FIG. 3 shows the jacket of the perforated drum of FIG. 2 with supplemented structure. Further peripheral components are also associated with perforated drum 1 visible in FIG. 1, but these are omitted here for the sake of clarity. Nonwoven 2 to be patterned runs directly over perforated drum 1, to which one or a plurality of nozzle bars 3 are directly externally assigned. Respective nozzle bar 3 is arranged axially parallel to perforated drum 1 and is provided, on its underside assigned to perforated drum 1, with a row of nozzles, not depicted here, for the discharge of water jets 4. As usual, perforated drum 1 is placed under suction for the extraction of the sprayed-on water, to which end a suction tube 8 is centrally arranged inside perforated drum 1, which suction tube has suction slots 10 extending to perforated drum 1, to which slots nozzle bars 3 are in turn assigned. According to FIG. 1, perforated drum 1 is made up of a seamless perforated drum wall 11, which is provided as a backing element for further form elements slipped onto the outside. The holes of perforated drum wall 11 can be stamped into a metal sheet or the wall can have another stable structure. According to FIG. 2, a fine screen fabric, a spun lace belt 12, is slipped onto the perforated drum wall, onto which belt a metal sheet 5 provided with a pattern of holes is slipped in turn. Holes 7 are therefore drawn with various diameters. Of course, holes 7 can also have shapes other than round; any pattern, including a large-area pattern, is conceivable here. If now water jets 4 impinge on nonwoven 2, which is smooth on both sides, the fibers in the region of holes 7 move into these holes and the nonwoven is needled and strengthened on webs 9 between holes 7. The motion of the fibers into holes 7 of thin patterned sheet 5 is limited, however, because a fine screen fabric 12 is arranged beneath patterned sheet 5, which screen fabric can be viewed as a spun lace belt in itself. Normally it serves as substrate for a nonwoven to be smoothly needled. The sprayed-on water penetrates through belt 12 and is extracted inside perforated drum 1. The fibers, however, remain lying on belt 12 and are also needled, i.e., strengthened, there by the water jets. In this way a plastic pattern arises on one side in a nonwoven strengthened over its entire area. In FIG. 3 the structure of the perforated drum jacket is the same as in FIG. 2, but a coarser screen fabric 13 has been slipped in between spun lace belt 12 and supporting perforated drum wall 11, which coarser screen fabric increases the spacing between the supporting perforated drum surface and spun lace belt 12. This equalizes the water flow from screen belt 12 to the through-flow openings of perforated drum 11 and the webs between the through-flow openings no longer form an obstacle to the through flow.

20050228

20071218

20050721

94843.0

VANATTA, AMY B

METHOD FOR EMBOSSED AND COLOURLESS DECORATION AND BONDING OF A FABRIC WEB AND DEVICE THEREFOR

UNDISCOUNTED

ACCEPTED

ACCEPTED

Re-transmitter and digital broadcast receiving system

Information indicating which of channels is selected in a digital broadcasting receiver 17 is fed from a control signal transmitter 16 to a retransmitter 14. A terrestrial wave digital broadcasting wave from a transmitting station is inputted to a channel selection filter 6 through an indoor receiving antenna 1 and an automatic gain controller 4 in the retransmitter 14, and only a signal having a frequency component corresponding to the channel selected by the digital broadcasting receiver 17 is extracted, and is transmitted toward the digital broadcasting receiver 17 by a retransmission indoor antenna 13 through a variable gain amplifier 7.

1. A retransmitter characterized by comprising: a high-frequency input unit to which a receiving antenna for receiving a digital broadcasting wave is connected; a high-frequency output unit to which a retransmission antenna for retransmitting the digital broadcasting wave is connected; means for acquiring a frequency selection signal which is a signal fed from a digital broadcasting receiver and corresponds to indication as to which channel is selected by the digital broadcasting receiver; and selecting and feeding means for selecting, out of high-frequency signals inputted from said high-frequency input unit, the high-frequency signal having a frequency corresponding to said frequency selection signal and feeding the selected high-frequency signal to said high-frequency output unit. 2. In the retransmitter according to claim 1, a retransmitter characterized in that an indoor receiving antenna is mounted as the receiving antenna on said high-frequency input unit, the retransmission antenna is mounted on said high-frequency output unit, and the respective directions of polarization of the indoor receiving antenna and the retransmission antenna are perpendicular to each other. 3. In the retransmitter according to claim 1 or 2, a retransmitter characterized in that an indoor receiving antenna is mounted as the receiving antenna on said high-frequency input unit, the retransmission antenna is mounted on said high-frequency output unit, and the indoor receiving antenna and the retransmission antenna are arranged with a conductor interposed therebetween such that the respective directions of transmission are opposite to each other. 4. In the retransmitter according to claim 1 or 2, a retransmitter characterized in that said selecting and feeding means comprises first gain control means for making the level of the high-frequency signal inputted from the high-frequency input unit constant, a pass frequency variable filter for selecting the high-frequency signal having the frequency corresponding to the frequency selection signal, and second gain control means for controlling transmission power of the selected high-frequency signal. 5. In the retransmitter according to claim 1 or 2, a retransmitter characterized by further comprising means for acquiring an ON/OFF control signal fed from said digital broadcasting receiver and a power switch, and by being turned on and off under control from said digital broadcasting receiver. 6. In the retransmitter according to claim 1 or 2, a retransmitter characterized by further comprising means for acquiring a gain control signal fed from said digital broadcasting receiver and feeding a control signal to the second gain control means, and that the transmission power of the high-frequency signal is controlled by the second gain control means under control from said digital broadcasting receiver. 7. In the retransmitter according to claim 1 or 2, a retransmitter characterized in that a signal from said digital broadcasting receiver is received by wireless. 8. A digital broadcasting receiving system characterized by comprising: the retransmitter according to claim 1 or 2; and a digital broadcasting receiver having means for feeding a signal to the retransmitter. 9. In the digital broadcasting receiving system according to claim 8, a digital broadcasting receiving system characterized in that the digital broadcasting receiver comprises selecting and controlling means for performing processing for acquiring the quality of a receiving signal of a digital broadcasting wave from the retransmitter, processing for acquiring the quality of a receiving signal of a digital broadcasting wave from a transmitting station, and processing for comparing the qualities of both the receiving signals to judge which of the digital broadcasting waves is to be employed. 10. A digital broadcasting receiving system comprising the retransmitter according to claim 2; and a digital broadcasting receiver having means for feeding a signal to the retransmitter, characterized in that the digital broadcasting receiver comprises an indoor receiving antenna having a first receiving element for receiving a digital broadcasting wave which is a horizontally polarized wave and a second receiving element for receiving a digital broadcasting wave which is a vertically polarized wave, and selecting and controlling means for performing processing for selecting one of the elements and acquiring the quality of the receiving signal of the digital broadcasting wave from the retransmitter, processing for selecting the other element and acquiring the quality of the receiving signal of the digital broadcasting wave from the transmitting station, and processing for comparing the qualities of both the receiving signals to judge which of the digital broadcasting waves is to be employed. 11. In the digital broadcasting receiving system according to claim 9, a digital broadcasting receiving system characterized by storing in a memory the results of the judgment for each of the channels by said selecting and controlling means, and utilizing, when the channel for which the results of the judgment have already been stored is selected, the results of the judgment which have already been stored, to omit the processing for the judgment by the selecting and controlling means.

TECHNICAL FIELD The present invention relates to a retransmitter that receives digital broadcasting and retransmits the received digital broadcasting to a digital broadcasting receiver, and a digital broadcasting receiving system. BACKGROUND ART In a digital broadcasting system, a video/audio signal is compressed using a digital signal compression technique, and a stream (a transport stream) obtained by subjecting video/audio digital signals in a plurality of programs to time-division multiplexing is broadcast. On the other hand, a broadcasting receiver that receives such digital broadcasting selects one of a plurality of channels in digital broadcasting received through an antenna by a tuner, selects one of a plurality of programs included in the one channel by demultiplexing processing, and decodes a digital signal on the selected channel to output a video/audio signal. When terrestrial wave digital broadcasting is received, a usage way in which an indoor antenna is used is assumed. However, it is expected that a receiving error occurs because a sufficient quality of a receiving signal is not obtained depending on the positional relationship among the indoor antenna, a window of a house, and a transmitting station. Therefore, it is considered that a retransmitter (repeater) is placed at the window of the house, for example, to amplify a digital broadcasting wave received by an antenna of the retransmitter and emit the amplified digital broadcasting wave toward the indoor antenna of the digital broadcasting receiver. When such retransmission is made, however, oscillation easily occurs by coupling an input and an output. Therefore, the distance between a receiving antenna and a transmission antenna must be increased, thereby increasing the size of the retransmitter. Further, it is considered that retransmission is made at a frequency different from a broadcasting frequency. However, a digital broadcasting signal is fed with service information added thereto. When the frequency is changed by retransmission, the actual receiving frequency and the frequency of the service information do not coincide with each other on the side of the receiver. Consequently, the service information must be rewritten and retransmitted by the retransmitter, so that the configuration becomes complicated, resulting in increased cost. In view of the foregoing circumstances, an object of the present invention is to provide a retransmitter and a digital broadcasting receiving system that can suitably make retransmission without changing a frequency. DISCLOSURE OF INVENTION In order to solve the above-mentioned problem, a retransmitter according to the present invention is characterized by comprising a high-frequency input unit to which a receiving antenna for receiving a digital broadcasting wave is connected, a high-frequency output unit to which a retransmission antenna for retransmitting the digital broadcasting wave is connected, means for acquiring a frequency selection signal which is a signal fed from a digital broadcasting receiver and corresponds to indication as to which channel is selected by the digital broadcasting receiver, and selecting and feeding means for selecting, out of high-frequency signals inputted from the high-frequency input unit, the high-frequency signal having a frequency corresponding to the frequency selection signal and feeding the selected high frequency signal to the high-frequency output unit. In the above-mentioned configuration, when the channel is selected in the digital broadcasting receiver, the selected channel is recognized on the side of the retransmitter, and the high-frequency signal (digital broadcasting wave) having the frequency corresponding to the selected channel out of the high-frequency signals inputted from the high-frequency input unit is selected and fed to the high-frequency output unit, and is fed to the digital broadcasting receiver by the retransmission antenna. The retransmitted may be so configured that an indoor receiving antenna is mounted as the receiving antenna on the high-frequency input unit, the retransmission antenna is mounted on the high-frequency output unit, and the respective directions of polarization of the indoor receiving antenna and the retransmission antenna are perpendicular to each other. The retransmitter may be so configured that an indoor receiving antenna is mounted as the receiving antenna on the high-frequency input unit, the retransmission antenna is mounted on the high-frequency output unit, and the indoor receiving antenna and the retransmission antenna are arranged with a conductor interposed therebetween such that the respective directions of transmission are opposite to each other. The selecting and feeding means may comprise first gain control means for making the level of the high-frequency signal inputted from the high-frequency input unit constant, a pass frequency variable filter for selecting the high-frequency signal having the frequency corresponding to the frequency selection signal, and second gain control means for controlling transmission power of the selected high-frequency signal. The retransmitter may be so configured as to further comprise means for acquiring an ON/OFF control signal fed from the digital broadcasting receiver and a power switch, and as to be turned on and off under control from the digital broadcasting receiver. The retransmitter may be so configured as to further comprise means for acquiring a gain control signal fed from the digital broadcasting receiver and feeding a control signal to the second gain control means, and that the transmission power of the high-frequency signal is controlled by the second gain control means under control from the digital broadcasting receiver. The retransmitter may be so configured that a signal from the digital broadcasting receiver is received by wireless. Furthermore, a digital broadcasting receiving system according to the present invention is characterized by comprising any one of the above-mentioned retransmitters, and a digital broadcasting receiver having means for feeding a signal to the retransmitter. In the digital broadcasting receiving system, the digital broadcasting receiver may comprise selecting and controlling means for performing processing for acquiring the quality of a receiving signal of a digital broadcasting wave from the retransmitter, processing for acquiring the quality of a receiving signal of a digital broadcasting wave from a transmitting station, and processing for comparing the qualities of both the receiving signals to judge which of the digital broadcasting waves is to be employed. A digital broadcasting receiving system according to the present invention is a digital broadcasting receiving system comprising a retransmitter in which the respective directions of polarization of an indoor receiving antenna and a retransmission antenna are perpendicular to each other, and a digital broadcasting receiver having means for feeding a signal to the retransmitter, wherein the digital broadcasting receiver may comprise a receiving antenna having a first receiving element for receiving a digital broadcasting wave which is a horizontally polarized wave and a second receiving element for receiving a digital broadcasting wave which is a vertically polarized wave, and selecting and controlling means for performing processing for selecting one of the elements and acquiring the quality of the receiving signal of the digital broadcasting wave from the retransmitter, processing for selecting the other element and acquiring the quality of the receiving signal of the digital broadcasting wave from the transmitting station, and processing for comparing the qualities of both the receiving signals to judge which of the digital broadcasting waves is to be employed. The digital broadcasting receiving system may be so configured as to store in a memory the results of judgment for each of channels by the selecting and controlling means, and utilizing, when the channel for which the results of the judgment have already been stored is selected, the results of the judgment which have already been stored, to omit the processing for the judgment by the selecting and controlling means. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a block diagram showing, in a digital broadcasting receiving system according to an embodiment of the present invention, a digital broadcasting receiver in detail; FIG. 2 is a block diagram showing, in a digital broadcasting receiving system according to an embodiment of the present invention, a retransmitter in detail; and FIG. 3 is a perspective view showing an antenna attached to a retransmitter used in a digital broadcasting receiving system according to an embodiment of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION An embodiment of the present invention will be described on the basis of FIGS. 1 to 3. In FIG. 1, an indoor antenna 15 has a first receiving element 15a for receiving a digital broadcasting wave which is a horizontally polarized wave and a second receiving element 15b for receiving a digital broadcasting wave which is a vertically polarized wave. Processing for judging which of the elements feeds a receiving signal to be employed is performed by a terrestrial wave digital tuner 21 on the basis of a command from a microcomputer 31. The terrestrial wave digital tuner 21 extracts, out of received high-frequency digital modulation signals (digital broadcasting waves), the digital modulation signal having a particular frequency. The terrestrial wave digital tuner 21 comprises a demodulation circuit, an inverse interleave circuit, an error correcting circuit, and so on, thereby demodulating the selected digital modulation signal to output a transport stream. Further, the terrestrial wave digital tuner 21 produces the C/N (carrier-to-noise ratio) or the error rate (the value of the quality of a receiving signal) of the received digital broadcasting wave, and feeds the produced C/N or error rate to the microcomputer 31. A demultiplexer (DEMUX) 22 separates the transport stream received from the terrestrial wave digital tuner 21 into a video stream and an audio stream based on MPEG2 (Moving Picture Experts Group2) and PSI/SI (Program Specific Information/Service Information). The demultiplexer 22 feeds the video stream and the audio stream to an AV decoder 23, and feeds the PSI/SI to the microcomputer 31. A plurality of channels are multiplexed on the transport stream. Processing for selecting any of the channels can be performed by extracting from the PSI/SI data indicating which of packet IDs is used to multiplex the arbitrary channel in the transport stream. Further, the transport stream can be selected on the basis of information in the PSI/SI. The AV decoder 23 comprises a video decoder for decoding the video stream and an audio decoder for decoding the audio stream. The video decoder decodes a variable length code which has been inputted, to find a quantization factor and a motion vector, thereby carrying out inverse DCT (Discrete Cosine Transformation), motion compensation control based on the motion vector, and the like. The audio decoder decodes a coded signal which has been inputted, to produce audio data. The video data generated by the decoding is outputted to a video processing circuit 24, and the audio data is outputted to an audio processing circuit 25. The video processing circuit 24 receives the video data from the AV decoder 23, and subjects the received video data to digital-to-analog (D/A) conversion, to produce a video signal. The audio signal processing circuit 25 receives the audio data outputted from the AV decoder 4, and subjects the received audio data to D/A conversion, to produce an analog signal of a right (R) sound and an analog signal of a left (L) sound. A drive circuit 26 receives the video signal, and produces an RGB signal and a synchronizing signal, to drive a CRT 27. A speaker 33 receives the analog audio signal, to output an audio. An OSD (On-Screen Display) circuit 30 outputs to an adder 34 bit map data based on character information and figure information which are instructed to output from the microcomputer 31. The adder 34 superimposes the bit map data into a video. A remote control transmitter 28 is a transmitter for sending out a command to a broadcasting receiver 17. The remote control transmitter 28 is provided with a power key, a channel designation key, and so on. When the keys provided in the remote control transmitter 28 are operated, signal light (a remote control signal) meaning a command corresponding to the keys is sent out from a light emitter (not shown). A remote control signal receiver 29 receives the signal light, converts the received signal light into an electric signal, and feeds the electric signal to the microcomputer 31. A memory (e.g., an EEPROM (Electrically Erasable and Programmable Memory) 32 stores various types of programs for performing predetermined operations, and others. Further, the memory 32 stores information related to the direction of polarization of a direct digital broadcasting wave from a broadcasting station (i.e., information which of the first receiving element 15a and the second receiving element 15b receives a direct digital broadcasting wave from the broadcasting station). A user can enter the information using the remote control transmitter 28, a setting switch (not shown), etc. Further, the memory 32 stores the C/N or the error rate (the value of the quality of a receiving signal) acquired by the tuner 21 for each of channels. A control signal transmitter 16 feeds various types of control signals (e.g., an infrared signal) to a retransmitter 14 on the basis of a command from the microcomputer 31. The microcomputer 31 performs processing for driving the control signal transmitter 16 in order to control the retransmitter 14 and selection control as to whether the direct digital broadcasting wave from the broadcasting station is employed or a digital broadcasting wave from the retransmitter 14 is employed in addition to program selection processing by the user using the remote control transmitter 28 or the like. The selection control will be described in detail later. As shown in FIG. 2, the retransmitter 14 is provided with an RF (high-frequency) input unit 3 having a switch 3a. The switch 3a has two inputs. An indoor receiving antenna 1 is connected to one of the inputs, and an outdoor receiving antenna (not shown) can be connected to the other input through an antenna connector 2. The switch 3a is manually operated by the user. A terrestrial wave digital broadcasting wave from a transmitting station (not shown) is converted into an electric signal by the indoor receiving antenna 1 or the outdoor receiving antenna, and the electric signal is inputted to an automatic gain controller (AGC) 4 through the RF input unit 3. The automatic gain controller 4 is so configured as to input an output signal fed back from a detector (DET) 5, to keep the level of a receiving signal constant. Specifically, the automatic gain controller 4 cancels the level fluctuation of a transmission path between the transmitting station and the indoor receiving antenna 1 and operates such that the level of a receiving signal inputted to a channel selection filter 6 becomes constant. The channel selection filter 6 can vary a frequency at its pass center by an applied control voltage. The control voltage is applied from a control signal demodulator (Dec) 10, and corresponds to a channel selected in the digital broadcasting receiver 17. A signal having a frequency component corresponding to the channel selected in the digital broadcasting receiver 17 is extracted by the channel selection filter 6, and is fed to a variable gain amplifier (Gain) 7. The variable gain amplifier 7 inputs a control voltage fed by the control signal demodulator 10, amplifies the signal at a gain based on the control voltage, and feeds the amplified signal to a low-pass filter (LPF) 8. The low-pass filter (LPF) 8 reduces higher harmonics included in the signal, and feeds the signal to a retransmission indoor antenna 13. A digital broadcasting wave having a frequency component corresponding to the channel selected in the digital broadcasting receiver 17 is transmitted toward the digital broadcasting receiver 17 by the retransmission indoor antenna 13. The retransmission indoor antenna 13 and the indoor receiving antenna 1 are arranged with a flat plate-shaped conductor 18 in an approximately square shape interposed therebetween such that the respective directions of transmission are opposite to each other, to configure one antenna set, as shown in FIG. 3. The respective directions of polarization of the indoor receiving antenna 1 and the retransmission indoor antenna 1 are perpendicular to each other. The retransmission device 14 is in a form in which it is accommodated in a case sealed so as not to be subjected to radio interference by transmission/receiving and is added to the antenna set. A signal receiver 9 receives a control signal from the control signal transmitter 16 provided on the side of the digital broadcasting receiver 17, converts the received control signal into an electric signal, and feeds the electric signal to the control signal demodulator 10. The control signal demodulator 10 demodulates the received control signal to decode an instruction, to carry out ON/OFF control of a power switch 11, gain control of the variable gain amplifier 7, and change control for a frequency at the pass center of the channel selection filter 6. In order to carry out the change control for the frequency at the pass center, the retransmitter 14 may comprise a correspondence table between a control signal (a code) from the digital broadcasting receiver 17 and a control voltage value (a control voltage applied to the channel selection filter 6). Alternatively, a signal representing a control voltage value (a control voltage applied to the channel selection filter 6) itself based on the selected channel may be fed from the digital broadcasting receiver 17. The power switch 11 is a switch for choosing whether or not power from a power input unit 12 is supplied to the automatic gain controller 4 or the like (ON/OFF of the retransmitter 14). The power from the power input unit 12 is always supplied to the control signal demodulator 10 without through the power switch 11. The control signal transmitter 16 provided on the side of the digital broadcasting receiver 17 is controlled by the microcomputer 31 contained in the digital broadcasting receiver 17. The microcomputer 31 drives the control signal transmitter 16 on the basis of a channel selection signal which will be received when the user selects the channel in the remote control transmitter 28, and transmits to the retransmitter 14 information indicating which channel is selected (which frequency should be selected and passed). Similarly, the control signal transmitter 16 is driven, thereby making it possible to feed to the retransmitter 14 signals for carrying out ON/OFF control of the power switch 11 and gain control of the variable gain amplifier 7. Description is now made of receiving processing by a digital broadcasting receiving system. As the setting of such a system, the installation of the retransmitter 14 is first adjusted. In the adjustment of the installation, a plane of polarization of the indoor receiving antenna 1 coincides with the direction of polarization of the direct digital broadcasting wave from the broadcasting station (consequently, the direction of polarization of a retransmitted wave is perpendicular to the direction of polarization of the direct digital broadcasting wave). Further, the direction of polarization of the direct digital broadcasting wave from the broadcasting station is registered in the digital broadcasting receiver 17 so that the plane of polarization of radio waves to be received by the indoor antenna 15 can be recognized when the direction of polarization of the indoor antenna 15 is switched in order to select and receive the direct wave and the retransmitted wave. When the direct digital broadcasting wave from the transmitting station is a horizontally polarized wave, for example, the retransmitted wave is a vertically polarized wave. Therefore, the digital broadcasting receiver 17 performs processing for employing the receiving signal from the second element 15b in the indoor antenna 15 when it receives the retransmitted wave, while performing processing for employing the receiving signal from the first element 15a when it receives the direct wave which is a horizontally polarized wave. When the digital broadcasting receiver 17 is turned on, an instruction to turn on the power to the retransmitter 14 is not issued at the beginning, and the receiving of the direct digital broadcasting wave from the transmitting station is tried by the indoor receiving antenna 15. At this time, the direct wave which is a horizontally polarized wave is received. Therefore, the receiving signal from the first element 15a is employed, and the value of the quality of the receiving signal at this time is stored in the memory 32. The digital broadcasting receiver 17 then transmits a signal to be a command to turn on the power, a signal indicating which channel is selected, and so on to the retransmitter 14. Further, switching processing is performed such that the receiving signal from the second element 15b is employed. The retransmitter 14 receives the above-mentioned signal in the control signal receiver 9. The control signal demodulator 10 demodulates the above-mentioned signal to grasp the contents of control, to turn on the power switch 11 as well as generate a control voltage corresponding to the center frequency of the channel selection filter 6 in correspondence with the selected channel. Further, a control voltage for the variable gain amplifier 7 for determining the level of a transmission output is also generated. By such processing, out of broadcasting waves received in the indoor receiving antenna 1, the broadcasting wave on the channel which will be received by the digital broadcasting receiver 17 is transmitted from the retransmission indoor antenna 13 as a broadcasting wave which is a polarized wave perpendicular to the indoor receiving antenna 1. The digital broadcasting receiver 17 receives the broadcasting wave from the retransmitter 14 in the second element 15b, to acquire the value of the receiving quality thereof. A control signal is transmitted to the retransmitter 14 so as to control transmission power from the variable gain amplifier 7 such that the value of the receiving quality of the broadcasting wave from the retransmitter 14 is the best while comparing the value of the receiving quality of the broadcasting wave from the retransmitter 14 and the value of the receiving quality of the direct wave already stored in the memory 32. When there is no case where the value of the receiving quality of the broadcasting wave from the retransmitter 14 exceeds the value of the receiving quality of the direct wave already stored in the memory 32, the digital broadcasting receiver 17 feeds a command signal for turning off the power to the retransmitter 14 such that the power switch 11 is turned off in order to perform direct receiving from the transmitting station without using the retransmitter 14. The digital broadcasting receiver 17 employs the first element 15a in the indoor receiving antenna 15 to change the direction of polarization of the indoor receiving antenna 15 for the purpose of receiving the direct broadcasting wave. On the other hand, when the value of the receiving quality of the broadcasting wave from the retransmitter 14 exceeds the value of the receiving quality of the direct wave stored in the memory 32, the retransmitter 14 remains in a state where the power thereto is turned on, and the indoor antenna 15 remains in a state where the second element 15b is employed. When a viewer operates the remote control transmitter 28 to change the channel, processing for selecting one of the elements in the indoor receiving antenna 15 and acquiring the quality of the receiving signal of the digital broadcasting wave from the retransmitter 14, processing for selecting the other element and acquiring the quality of the receiving signal of the digital broadcasting wave from the transmitting station, and processing for comparing the qualities of both the receiving signals and judging which of the digital broadcasting waves is to be employed are performed, as in the foregoing. When the viewer turns off the power to the digital broadcasting receiver 17 or switches the broadcasting receiving mode into a mode for receiving a broadcasting wave other than a terrestrial wave, for example, a satellite system or a cable, the digital broadcasting receiver 17 feeds a control signal by the control signal transmitter 16 to turn off the power switch 11 in the retransmitter 14. If it is judged once which of the direct wave and the retransmitted wave is preferable with respect to each of the channels, the judgment may be registered in the memory 32 in the digital broadcasting receiver 17, not to perform an operation for selecting and confirming preferable receiving conditions of the direct wave/retransmitted wave at the time of changing the channel. It is considered that such a period during which the selecting and confirming operation is not performed is a period to the next day or to the time when one week has elapsed, to the time when a reconfirmation command is next issued to the digital broadcasting receiver 17 by the user, or the like. The operation for selecting and confirming the preferable receiving conditions of the direct wave/retransmitted wave may be performed along with the existent station channel search made when the system is installed or after the user moves into a new house. When an area where the system is installed is found, and the receiving conditions of radio waves in the area are found, it may be previously found which of the direct wave and the retransmitted wave is preferable with respect to each of the channels. In such a case, information may be registered in the memory 32 in the digital broadcasting receiver 17 without performing a selecting and confirming operation. When a stable receiving signal is introduced into a house by a cable from an antenna installed outdoors, the outdoor antenna may be connected to an external antenna input terminal 2, to switch the switch 3 toward the external antenna input terminal 2. As described in the foregoing, the retransmitter 14 does not retransmit all broadcasting waves in a broadcasting band but synchronizes with a channel to be received by the digital broadcasting receiver 17 to selectively retransmit only a frequency band on the received channel, thereby making it possible to reduce coupling between transmission and receiving units. In the present embodiment, the retransmission indoor antenna 13 and the indoor receiving antenna 1 are arranged with the conductor 18 interposed therebetween such that the respective directions of transmission are opposite to each other, and the respective directions of transmission and receiving can be made to actually differ from each other by 180 degrees, although transmission and receiving points come close to each other, thereby making it possible to reduce the detouring of a transmitted wave and a received wave. Further, in the present embodiment, the respective directions of polarization of the indoor receiving antenna 1 and the retransmission indoor antenna 13 are perpendicular to each other. Accordingly, the transmitted wave and the received wave are easy to separate, thereby making it possible to suppress oscillation. As described in the foregoing, according to the present invention, even when the digital broadcasting receiver is installed in a place spaced apart from a window, stable receiving can be performed using the indoor receiving antenna by a retransmitted wave from the retransmitter. The retransmitter makes retransmission without changing a frequency from the transmitting station. Therefore, the necessity of replacing service information is eliminated, thereby making it possible to simplify circuits constituting the retransmitter.

<SOH> BACKGROUND ART <EOH>In a digital broadcasting system, a video/audio signal is compressed using a digital signal compression technique, and a stream (a transport stream) obtained by subjecting video/audio digital signals in a plurality of programs to time-division multiplexing is broadcast. On the other hand, a broadcasting receiver that receives such digital broadcasting selects one of a plurality of channels in digital broadcasting received through an antenna by a tuner, selects one of a plurality of programs included in the one channel by demultiplexing processing, and decodes a digital signal on the selected channel to output a video/audio signal. When terrestrial wave digital broadcasting is received, a usage way in which an indoor antenna is used is assumed. However, it is expected that a receiving error occurs because a sufficient quality of a receiving signal is not obtained depending on the positional relationship among the indoor antenna, a window of a house, and a transmitting station. Therefore, it is considered that a retransmitter (repeater) is placed at the window of the house, for example, to amplify a digital broadcasting wave received by an antenna of the retransmitter and emit the amplified digital broadcasting wave toward the indoor antenna of the digital broadcasting receiver. When such retransmission is made, however, oscillation easily occurs by coupling an input and an output. Therefore, the distance between a receiving antenna and a transmission antenna must be increased, thereby increasing the size of the retransmitter. Further, it is considered that retransmission is made at a frequency different from a broadcasting frequency. However, a digital broadcasting signal is fed with service information added thereto. When the frequency is changed by retransmission, the actual receiving frequency and the frequency of the service information do not coincide with each other on the side of the receiver. Consequently, the service information must be rewritten and retransmitted by the retransmitter, so that the configuration becomes complicated, resulting in increased cost. In view of the foregoing circumstances, an object of the present invention is to provide a retransmitter and a digital broadcasting receiving system that can suitably make retransmission without changing a frequency.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram showing, in a digital broadcasting receiving system according to an embodiment of the present invention, a digital broadcasting receiver in detail; FIG. 2 is a block diagram showing, in a digital broadcasting receiving system according to an embodiment of the present invention, a retransmitter in detail; and FIG. 3 is a perspective view showing an antenna attached to a retransmitter used in a digital broadcasting receiving system according to an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20040428

20091124

20050127

57267.0

HUYNH, AN SON PHI

RE-TRANSMITTER AND DIGITAL BROADCAST RECEIVING SYSTEM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Device and method for carrying out multichannel acoustic echo cancellation with a variable number of channels

The present invention relates to a device and method for carrying out acoustic echo cancellation (2) when playing back C-channel audio signals on a D-channel audio signal transmission system with C<D. This invention can be used, for example, in videoconferencing, in which a variable number of active speakers are spatially played back according to the seating positions thereof. The aim of the invention is to solve for the poor convergence of the adaptive echo cancellation when the loudspeaker signals are strongly correlated. The invention provides that in addition to the known method of subjecting audio signals to preprocessing (V1, . . . , VD), which preferably induces a decorrelation, C output signals of the preprocessing units are selected by a channel combining device (5) and distributed to the loudspeakers (L1, . . . , LD), several signals being played back on a number of loudspeakers. Said aim is achieved by the reduction of the channels from D to C and by virtue of the fact that only the C signals are subjected to an adaptive matching.

1. Device for multichannel acoustic echo compensation for acoustic interfaces, which includes the following: a multichannel audio signal processing unit (1); D audio signal channels (LK1, . . . , LKD) going out from the multichannel audio signal processing unit (1); wherein each audio signal channel has a respective audio signal preprocessing unit (V1, . . . , VD) assigned to the audio channel; wherein at least one loudspeaker (L1, . . . , LD) is assigned to each audio signal channel; wherein one branch line (A1, . . . , AD) is branched off to a D-channel adaptive filter (2) from each audio signal channel between the particular assigned preprocessing unit (V1, . . . , VD) and the particular assigned at least one loudspeaker (L1, . . . , LD) a microphone (M) connected to the adaptive filter (2) a microphone channel (MK) leading back from the adaptive filter to the multichannel audio signal processing unit (1); a channel combination device; wherein a preprocessing unit (V1, . . . , VD) is assigned to each audio channel; and wherein the channel-combination device (5) is arranged between the preprocessing units (V1, . . . , VD). 2. Device according to claim 1, further comprising: a transfer section (8) between the multichannel audio signal processing unit (1) and the channel-combination device (5), through which the C number of channels actually to be occupied by the multichannel audio signal processing unit (1) can be transmitted to the channel-combination device (5). 3. Device according to claim 1, further comprising: a transfer logic (7) which is applied between the channel-combination device (5) and the adaptive filter (2) and which communicates with these, and an intermediate buffer (4) which communicates with the transfer logic (7). 4. Device for multichannel acoustic echo compensation according to claim 3, wherein the intermediate buffer has a buffer capacity for D-L filter coefficients transmitted by the transfer logic, where D is the number of channels of the system and L is the number of filter coefficients for a particular channel. 5. Method for multichannel acoustic echo compensation for acoustic interfaces wherein a number D of loudspeaker channel signals are always subjected to signal preprocessing before they are transmitted to the loudspeakers (L1, . . . , LD) the loudspeaker channel signals are additionally branched to a device (2) for adaptive filtering of loudspeaker signals, where the branched loudspeaker signals are subjected to adaptive adjustment to produce an echo compensation signal, which is deducted from a microphone signal for the purposes of minimization of the echo and the microphone signals echo-minimized in this way are transmitted to a multichannel audio signal processing unit (1) for further processing and renewed output as loudspeaker channel signals; after signal preprocessing, individual ones of the D loudspeaker signals are so combined that only C<D combination signals remain which are transmitted through the assigned C loudspeaker channels to D loudspeakers, and that only these C combination signals are subjected to adaptive adjustment. 6. Method according to claim 5, which further comprises, as additional steps, that before a change of a number of X actually-used channels to Y≠X actually-used channels, the filter coefficients which are already identified for the X channels for adaptive adjustment to produce an echo compensation signal of an adaptive filter (2), are subjected to intermediate storage, and that after changing back the number from Y channels to the original used number of X channels, the intermediate-buffered filter coefficients are used as start values for the necessary recalculation of filter coefficients for a renewed adaptive adjustment, in order to accelerate the convergence for further adjustment.

The present invention concerns a device and a method for multichannel acoustic echo compensation with variable number of channels as they are used especially for acoustic human-machine interfaces with hands-free devices and multichannel output, in order to make multichannel full-duplex communication possible. The basic problems of acoustic echo compensation are described in detail in the review article “Stereophonic Acoustic Echo Cancellation—An Overview of the Fundamental Problem”, IEEE Signal Processing Letters, Vol. 2, No. 8, August 1995, by M. Mohan Sondhi et al. If only a single full-duplex audio channel is used for bi-directional speech transfer between a first as well as a second audio transmission and receiving unit in acoustic human-machine interfaces, for example, microphones, loudspeakers in video conference systems or telephone conference systems, then, an acoustic echo compensation can be performed by using adaptive filters in order to suppress undesirable echoes which arise from feedback between loudspeakers and microphones in the first and second audio transmission and receiving units. In conventional single-channel acoustic echo compensators, the use of a single FIR (finite impulse response) filter with adaptive adjustable filter coefficients is sufficient to model the acoustic pulse response of the echo path. An estimated signal for the echo modeled by the adapted filter is then deducted from the actual echo signal to obtain an error signal, which is adjusted to the echo path which may possibly change in the course of time, by permanent adaptive continued regulation of the filter coefficients, so that the error signal is continuously kept as low as possible. However, especially in video conference or telephone conference transmissions, it may be desirable, using of several acoustic transmission channels, each with at least one assigned loudspeaker, to transfer an acoustic pattern which is as true to the room as possible, from a first to a second audio transmission and receiving unit. For example, this is of interest, when several speakers are located in a first room, from whom the speech sound is to be transferred to a receiver in a second room. If one then uses two or more acoustic transmission channels to a second room, where a listener is located, then this listener receives a stereo or multichannel acoustic pattern from the first room, which makes it easier for him, for example, to assign the speech sound to the individual speakers. As explained by the above review article, for example, also in “Stereo Projection Echo Canceller with True Echo Path Estimation”, Proc. IEEE International Conference on Acoustics, Speech and Signal Processing (ICASSP 95), Detroit, Mich., USA, PP. 3059-3062, May 1995, by S. Shimauchi et al. or “A better understanding and an improved solution to the problems of stereophonic acoustic echo cancellation”, Proc. IEEE International Conference on Acoustics, Speech, and Signal Processing (ICASSP 97), Munich, pp. 303-306, April 1997, by J. Benesty et al., however, due to the mutual influence of the individual transmission channels among one another, in the case of stereo or multichannel compensation, a number of additional problems occur in comparison to the mono-channel situation, where an individual adaptive filter is sufficient for echo compensation. Various solution sets for problems that occur in the multichannel case are especially explained in the article “Stereophonic Acoustic Echo Cancellation—An Overview and Recent Solutions”; Proc. 6th Int. Workshop on Acoustic Echo and Noise Control, Pocono Manor, Pa., USA pp. 12-19, September 1999, by S. Makino et al. Individually, the following are dealt with: addition of statistically independent noise signals to the loudspeaker signals, nonlinear signal processing; the use of decorrelation filters, the use of various time-variable filter techniques, and the use of special adaptive algorithms in the filters. Especially in the multichannel case, according to our state of knowledge today, signal processing for partial (not detectable) decorrelation of the loudspeaker signals is necessary in order to make unequivocal convergence of adaptive filters to the true room pulse responses possible. As already stated, the basic idea of echo compensation is to simulate, using digital filter structures, the echo paths which arise from the interplay of certain loudspeaker characteristics, a certain room acoustics and a certain microphone characteristics. This will be explained below in more detail with the aid of FIG. 3. In the case of the echo compensation device according to the state of the art shown there, the audio signals emitted by a multichannel audio signal processing unit 1, are sent through separate loudspeaker channels LK1, . . . , LKD to the corresponding loudspeakers L1, . . . , LD. A channel-specific pre-processing unit V1, . . . , VD is located in each section of the loudspeaker channels LK1, . . . , LKD. The audio signals running through the pre-processing units V1, . . . , VD can each be locked there individually in a channel-specific manner. The loudspeakers L1, . . . , LD assigned individually to loudspeaker channels LK1, . . . , LKD emit acoustic signals corresponding to the received audio signals into the surrounding room. Furthermore, a microphone M is provided which serves as input interface for acoustic signals, for example, speech sounds from a person speaking into the microphone. The microphone M converts the received acoustic signals into microphone signals, which are sent back to the multichannel audio signal processing unit 1 through a microphone channel MK for further processing. The acoustic signals radiated by loudspeakers L1, . . . , LD are superimposed depending on the structures in the room, in which the loudspeakers L1, . . . , LD are set up, and are also received by microphone M. As a result of this, echo signals are produced, because the acoustic signals emitted by the loudspeakers L1, . . . , LD are received by the microphone M, from there are sent to the multichannel audio signal processing unit 1, from where, under certain circumstances, are sent again to loudspeakers L1, . . . , LD. The basic idea of echo compensation is to compensate by digital filter structures the “echo paths” arising from the interaction of the acoustic signals emitted by the loudspeakers L1, . . . , LD and from their difference paths predetermined by the spatial propagation conditions to microphone M and by the microphone characteristics. This occurs by the fact that such digital filter structures produce estimate signals for the echo signals expected through the echo paths and that the estimate signals are subtracted from the microphone signals which contain the actual echo signals. If there was exact agreement between the real room pulse responses and the pulse responses of the digital filter, the echo signals would be extinguished in the microphone signal. However, since the echo paths generally have a very complex structure which is not known beforehand and which, in addition, can change in time, the echo paths must be continuously reidentified, that is, adaptively identified. The adaptive filter 2 shown in FIG. 3 serves this purpose: the audio signals entered through channels LK1, . . . , LKD to loudspeakers L1, . . . , LD are introduced to this filter through branch lines A1, . . . , AD. In the adaptive filter 2 the audio signals introduced through branch lines A1, . . . , AD are superimposed on weighting coefficients (filter coefficients) to be optimized, according to specified adaptation algorithms. The adaptive adjustment is based on mathematical models which provide adjustment of the temporarily valid filter coefficients to the temporarily valid echo path conditions. In order to make unequivocal convergence of the filter coefficients to the true room pulse responses possible in the multichannel case, the signal pre-processing, which is necessary according to our present-day knowledge (see, for example, the article by J. Benesty et al. mentioned above) for partial (acoustically not detectable) decorrelation of the loudspeaker signals, is carried out in the preprocessing units V1, . . . , VD shown in FIG. 1. However, it can be shown theoretically and experimentally that, in spite of this preprocessing, the expenditure for echo compensation generally increases with increasing number of channels and the convergence behavior of the individual channel signals to be superimposed in the adaptive filter becomes worse. If D different preprocessing units are used then this leads to very slow convergence of the filter coefficients when the actual number of channels C of the audio signal is smaller than the actual number of channels D, that is, when C<D. This case is typical for the use in multimedia terminal equipment (for example, when a multimedia terminal equipment is used as stereo television unit, with which a broadcast is considered in which the tone is displayed only with one mono-channel. The performance of multichannel echo compensation for acoustic interfaces in multimedia terminals is a relatively new application. Conventional attachments for telephone conference applications provide a fixed channel number, D, for the audio signals. The relatively slow convergence behavior arises in this case by insufficient decorrelation of originally exactly the same audio signals which are passed through separate audio channels. The solution set known from the article by J. Benesty et al. cited above as state of the art provides D equal nonlinear preprocessing units, as a result of which the above problem is lessened. In any case, in this way the decorrelation possibilities are also limited, especially when the signals of the individual channels differ mainly in their levels (for example, in case of intensity stereophony). Therefore, the task of the present invention is to overcome the disadvantages of the devices known from the art for multichannel acoustic echo compensation with a variable number of channels. Especially, it is the task of the present invention to provide a device for multichannel acoustic echo compensation with a variable number of channels for the case in which the actually-used number of channels, C, is smaller than the number of actually present channels, D, and where the problems arising in connection with decorrelation in connection with the state of the art are avoided. Furthermore, it is a task of the present invention to provide methods for multichannel echo compensation where the number of channels used, C, is smaller than the number of channels actually present, D. According to the invention, these tasks are solved by a device according to claim 1 as well as by a method according to claim 5. The dependent claims concern advantageous embodiments of the present invention. The approach according to the invention for echo compensation in the reproduction of C-channeled audio signals on a D-channel system (C<D) makes use of the fact that the number of channels of the audio signal is known (for example, when stereo information is present in a television signal). Therefore, it is possible to decorrelate only the C<D actually-used audio channels through independently operating preprocessing units. The remaining D—C loudspeaker signals are then combined only with the actually-used C audio channels (for example, in the mono case both loudspeaker signals are connected to channel 1 of a stereo system). The advantages and characteristics of the present invention follow from the explanation of preferred practical examples given below in combination with the drawings. The following are shown: FIG. 1 shows a schematic representation of a first embodiment of a device according to the invention for multichannel echo compensation. FIG. 2 shows a schematic representation of a second embodiment of a device according to the invention for multichannel echo compensation. FIG. 3 shows a schematic representation of a known device for multichannel echo compensation according to the state of the art. A first embodiment of a device according to the invention for echo compensation will be explained below as an example based on FIG. 1. Here, elements which were already explained in combination with the state of the art according to FIG. 3 are provided with identical reference numbers to those in FIG. 3 and will not be explained in more detail below. In addition to the elements shown in FIG. 3, FIG. 1 shows the first embodiment of a device according to the invention and a channel combination device 5 which is provided between the D preprocessing units V1, . . . , VD and the branch lines A1, . . . , AD leading to the adaptive filter 2. Furthermore, a data line 8 is provided between the multichannel audio signal processing unit 1 and the channel-combination device 5. The multichannel audio signal processing unit 1 transmits through data line 8 the C channels actually to be used to channel-combination device 5, and this number of channels can be smaller than the number D of the total channels actually present. Using channel-combination device 5, always several loudspeakers, which are supposed to receive exactly the same audio signals, are connected to a single common inlet line, and namely according to the number C of channels actually to be used, which is provided by the multichannel audio signal processing unit 1 to the channel-combination device 5. The channel-combination device 5 decouples then the unnecessary D—C preprocessing units from the loudspeakers. In the most general case, this is done by simply connecting several loudspeakers with an inlet line in the channel-combination device 5. Thus, the unnecessary D—C preprocessing units are decoupled from the loudspeakers. In other words: Through D loudspeaker channels LK1, . . . , LKD, the loudspeaker channel signals LS1, . . . , LSD entered by the multichannel audio signal processing installations 1 are combined with one another in the channel-combination device 5 by superimposing individual loudspeaker signals to one another loudspeaker signals so that at the exit of the channel-combination device, only C<D independent output signals are present. This will be explained in the following example: in case of a reduction from seven input loudspeaker channel signals LS1, LS2, LS3, LS4, LS5, LS6, LS7 to four signals LS1, LS23, LS4, LS567, the entering loudspeaker channel signals LS1 and LS4 are left unchanged, but the loudspeaker channel signals LS2 and LS3 are combined to a signal LS23 and the loudspeaker channel signals LS5, LS6 and LS7 are combined to a signal LS567. These four output signals LS1, LS23, LS4 and LS567 can then be introduced, for example, to the seven loudspeakers that were provided in this case as follows: LS1 to L1, LS23 to L2 and to L3, LS4 to L4, LS567 to L5, L6 and L7. With the measures according to the invention, the additional convergence problems of the filter coefficients are avoided, which do occur in the conventional multichannel echo compensation with loudspeaker signals at reduced number of channels. When using a device according to the invention for multichannel echo compensation, in which, using a channel-combination device, only C<D audio channels are actually utilized, the performance that can be achieved with a D-channel echo compensator (D>C) is comparable to that achievable with a conventional only C-channel echo compensator. All this is possible with an extremely small additional expenditure, namely by providing the said channel-combination device 5. The approach according to the invention is independent of the actual adjustment algorithm used, of the actual preprocessing method used, and of channel number D of the system. For echo compensation in the case of C channels, in a device according to the invention, a maximum of C of the actually-present D preprocessing units are used. In order to achieve maximum efficiency, exactly C different preprocessing units must be used. A second embodiment of the device according to the invention for echo compensation is explained now in more detail with the aid of FIG. 2. In this embodiment, the elements shown in FIG. 1 are complemented by an intermediate buffer 6 as well as by a transfer logic 7. The intermediate buffer 6 is in connection with a transfer logic 7 through a bi-directional bus line 9, and the transfer logic is again in connection with the adaptive filter 2 through a bi-directional bus line 10. In addition, the transfer logic 7 is connected to the channel-combination device 5 through a unidirectional bus line 11. Intermediate buffer 6 serves for storage of estimated pulse responses which had been determined previously by the adaptive filter 2 and which were transported through the bi-directional bus line 10 into the transfer logic 7 and from there, through bi-directional bus line 9 into intermediate buffer 6. In a system with D loudspeaker channels and an adaptive filter 2, in which a number L of filter coefficients is provided for each loudspeaker channel, sufficient memory must be present in the intermediate buffer 6 in order to be able to store L filter coefficients for the maximum number of the D channels used. That is, the possibility must exist to store D L estimated filter coefficients. The transfer logic 7 receives from the channel-combination device 5 through bus line 11 the indices of the presently-used channels, the number of which is smaller than or equal to the number D of the actually-available channels. The meaning of such buffer storage of estimated pulse responses (filter coefficients) is the following: if one changes from a number of channels X originally used during an operational phase a to a different number and from a number of channels Y during an operational phase b, and again during a following operational phase c change back to the number of channels X, then, at the beginning of operational phase c, the filter coefficients already used until the end of operational phase a can be recaptured as starting values for renewed adjustments necessary due to any changes in room acoustics that could have occurred in the meantime. In order to make this procedure more understandable, let us discuss, for example, the following scenario: in a multimedia television system with 5-channel Dolby surround-sound installation, certain television broadcasts (for example, feature films) are received with a 5-channel tone. Other television broadcasts (for example, commercials or newscasts) are received, however, for example, with only 2-channel tones, or even with 1-channel tone (mono). The reduced number of tone channels were then equally reproduced through the 5-channel Dolby surround-sound installation. This occurs, as explained above, by the combination of individual loudspeaker channel signals to combination signals. If now a viewer first views, for example, a television broadcast with 5-channel tones, then when using a device according to the invention and a method according to the invention, multichannel echo compensation is utilized for a given set of acoustic conditions in the room for the determination of certain filter coefficients in the adaptive filter 2 shown in FIG. 2. Now, if the viewer now, for example, switches from the just-viewed television broadcast with 5-channel tones to another television broadcast with 2-channel tones (stereo tone), then an adaptive adjustment must be carried out again for the 5 signals emitted by the channel combination device 5, that is, 2 new filter coefficients for the 2-channel case must be calculated in the adaptive filter 2. If the viewer then switches back again to the originally-watched television broadcast with 5-channel tones, then adjustment of the adaptive filters for the 5-channel case is necessary again. If the room acoustic conditions in the meantime were unaltered, then the adaptive filter 2 now will find the same filter coefficients for the 5-channel case which were present before switching from the 5-channel tone broadcast to the 2-channel tone broadcast. In order to save the time period that the adaptive filter needs to converge again to the filter coefficients suitable for the 5-channel case, with the aid of the measures according to claim 6, one can simply use again the filter coefficients that were suitable before switching from the 5-channel transmission to the 2-channel transmission at constant room acoustic conditions as before, which were stored in buffer 6 for intermediate storage. Even when during the time span until the renewed switching back to the 5-channel transmission, a change would have occurred in the acoustic conditions in the room (for example, because people left the room or came in), in practice it should be assumed that these changes are so slight that the filter coefficients which were stored in buffer 6 would still be relatively suitable for the new acoustic conditions in the room, and thus would be very good starting values for a renewed adjustment process of the adaptive filters 2, so that, based on the predetermined start values, the time duration needed for reaching a convergent state of the filter coefficients is usually significantly shorter than when the adaptive filter with arbitrary start values would have to perform complete new calculation of the adaptive filter coefficients for the 5-channel tone case with changed room acoustic conditions. This method of buffer storage of previously-determined filter coefficients naturally makes sense even when first the switch is from a smaller number of audio channels used (for example, 2) to a larger number of audio channels used (for example, 5) and then again switching back to the original smaller number. For the compensation unit even at C<D independent audio channels, a D-channel adaptive filter is used since the computing capacity would have to be dimensioned for D channels anyway in order to be able to cover even the case when all D channels are to be used. If the other D—C loudspeaker signals are combined with the C actually-used audio channels, then all physically correct echo paths could no longer be identified separately; however, this is not necessary in this case since the correlation between loudspeakers that are connected directly to one another cannot be altered. REFERENCE LIST 1 Multichannel audio signal processing unit 2 Adaptive filter 5 Channel-combination device 6 Buffer 7 Transfer logic 8 Data line 9, 10 Bi-directional bus line 11 Unidirectional bus line A1, . . . , AD Branch lines L1, . . . , LD Loudspeakers LK1, . . . , LKD Loudspeaker channels LS1, . . . , LSD Loudspeaker channel signals M Microphone MK Microphone channel V1, . . . , VD Preprocessing units a, b, c Operational phases X, Y Number of channels used

20040921

20060613

20050303

63354.0

HAROLD, JEFFEREY F

DEVICE AND METHOD FOR CARRYING OUT MULTICHANNEL ACOUSTIC ECHO CANCELLATION WITH A VARIABLE NUMBER OF CHANNELS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Alpha-form or beta-form crystal of acetanilide derivative

To provide novel crystals useful as an ingredient for the production of a diabetes remedy. The invention is concerned with α-form crystal and β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. The α-form crystal does not exhibit hygroscopicity and has stability such that it can be used as a medicine, and is useful for mass synthesis in the industrial production. The β-form crystal does not relatively exhibit hygroscopicity and is also useful as a production intermediate of the α-form crystal.

1. An α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide. 2. An α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having a heat absorption peak at 142 to 146° C. in the DSC analysis. 3. An α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 2θ(°) in the powder X-ray diffraction. 4. An α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having a heat absorption peak at 142 to 146° C. in the DSC analysis and having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 2θ(°) in the powder X-ray diffraction. 5. A pharmaceutical composition comprising the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 1 and a pharmaceutically acceptable carrier. 6. A diabetes remedy comprising the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 1 and a pharmaceutically acceptable carrier. 7. A β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide. 8. A β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having heat absorption peaks at 90 to 110° C. and at 142 to 146° C. in the DSC analysis. 9. A β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having main peaks at around 9.68, 19.76, 20.72, 22.10 and 23.52 in the terms of 2θ(°) in the powder X-ray diffraction. 10. A β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide having heat absorption peaks at 90 to 110° C. and at 142 to 146° C. in the DSC analysis and having main peaks at around 9.68, 19.76, 20.72, 22.10 and 23.52 in the terms of 2θ(°) in the powder X-ray diffraction. 11. A pharmaceutical composition comprising the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 7 and a pharmaceutically acceptable carrier. 12. A diabetes remedy comprising the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide according to claim 7 and a pharmaceutically acceptable carrier.

TECHNICAL FIELD The present invention relates to an α-form crystal or β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide which is useful as a diabetes remedy and to a drug containing the same, especially a diabetes remedy. BACKGROUND ART The present inventors have reported that (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride represented by the following chemical structural formula has both an insulin secretion promoting action and an insulin sensitivity potentiating action, further has anti-obesity and anti-hyperlipemia actions due to a selective stimulating action to β3-receoptors and is a useful compound for remedy of diabetes (WO 99/20607, Example 41). However, since this dihydrochloride has strong hygroscopicity and is unstable, its use as a medicine was still problematic. Medicines are required to be stable against humidity, temperature, light, and the like over a long period of time and also to have stability in the formulation step. If medicines have strong hygroscopicity, they physically and chemically change or cause such an inconvenience that the water content is different depending upon lots. Accordingly, it is necessary to always store them in a drying chamber or to provide a drying step, which is not preferable from the standpoint of industrial use. DISCLOSURE OF THE INVENTION Under such technical circumstances, the present inventors have made extensive and intensive investigations about the foregoing compound described in Example 41 of WO 99/20607 and found novel α-form crystal (hereinafter simply referred to as “α-form crystal”) and β-form crystal (hereinafter simply referred to as “β-form crystal”) of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenyleth-yl)amino]ethyl]acetanilide. Both of these two novel crystals are of a free base and are distinguished from each other by powder X-ray diffraction spectrum and DSC analysis. The previously obtained dihydrochloride crystal was a strongly hygroscopic and unstable crystal such that it exhibits a rapid increase in hygroscopicity from a relative humidity of 80% and holds moisture of about 14% at a relative humidity of 90%. In contrast, the “α-form crystal” of the invention has a moisture-holding amount of not more than 0.2% over the entire range of relative humidity from 5% to 95%, is a stable crystal not exhibiting hygroscopicity, and is suitable for use as a medicine. Further, in the “β-form crystal”, an increase in the weight is observed from a relative humidity of about 20%, and it holds moisture of about 3% and has weak hygroscopicity. However, this crystal is a metastable-form crystal and can be used as a medicine. Also, the “1-form crystal” is useful as a production intermediate of the “α-form crystal”. Each of the α-form crystal and the β-form crystal is characterized by the following crystal lattice spacings [2θ(°)] of powder X-ray diffraction spectrum and heat absorption peak of DSC analysis. Incidentally, with respect to the powder X-ray diffraction, in determining the identity of crystal, crystal lattice spacings and an overall pattern are important in the nature of data. On the other hand, since a relative intensity can vary a little depending upon the direction of crystal growth, particle size and measurement condition, it should not be strictly interpreted. TABLE 1 (α-Form Crystal) Crystal lattice Crystal lattice spacing Relative intensity spacing Relative intensity 5.32 Strong 19.04 Slightly strong 8.08 Strong 20.20 Slightly strong 15.28 Slightly strong 23.16 Slightly strong 17.88 Slightly strong 24.34 Slightly strong TABLE 2 (β-Form Crystal) Crystal lattice Crystal lattice spacing Relative intensity spacing Relative intensity 9.68 Medium 22.10 Medium 19.76 Slightly strong 23.52 Medium 20.72 Medium Also, in the DSC analysis, the α-form crystal had a heat absorption peak at 142 to 146° C., and the β-form crystal had heat absorption peaks at 90 to 110° C. and at 142 to 146° C., respectively. The measurement of the powder X-ray diffraction was carried out using MAC Science MXP18TAHF22 under the following conditions. Tube: Cu, tube current: 40 mA, tube voltage: 40 kV, sampling width: 0.020°, scanning rate: 3°/min, wavelength: 1.54056 angstrom, measurement diffraction angle range (20): 5 to 40°. Thermal analyses (DSC and TGA) were respectively carried out under the following conditions. DSC: Perkin-Elmer Pyris 1, from 25° C. to 250° C. (10° C./min), N2 (20 mL/min), aluminum-made sample pan. TGA: Perkin-Elmer TGA 7, from 25° C. to 250° C. (10° C./min), N2 (20 mL/min), platinum-made sample pan. Nuclear magnetic resonance (NMR) spectra were measured using JEOL JNM-LA400 and JEOL JNM-A500, and tetramethylsilane (TMS) was used as an internal standard. Mass analysis spectra were measured using JEOL DX-300 and JEOL LX-2000. Further, the invention relates to a drug containing the α-form crystal or β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, especially a diabetes remedy having both an anti-obesity action and an anti-hyperlipemia action. Administration of a drug containing the crystal of the invention as a starting material for the production of medicines may be either oral administration by, for example, tablet, pill, capsule, granule, or powder, or parenteral administration by, for example, inhaling agent. Examples of the solid composition for oral administration include tables, powders, and granules. In such a solid composition, one or more active substances are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium metasilicate aluminate. The composition may also contain inert additives such as lubricants such as magnesium stearate; disintegrants such as carboxylmethyl starch sodium; and auxiliary solubilizers according to customary manners. If desired, tablets or pills may be coated with sugar coat or with gastric or enteric coating agents. The dose may be appropriately decided depending upon each particular case while taking into consideration of symptom, age, sex, etc. of the subject to be administered but is usually from about 0.01 mg/kg to 100 mg/kg per day for an adult in the case of oral administration, and that is administered at a time or by dividing into 2 to 4 times. (Production Method) The α-form crystal can be obtained by adding a recrystallization solvent (37% to 50% ethanol aqueous solution) to the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide, dissolving the β-form crystal by heating at about 70 to 80° C., and then gradually cooling the solution at a rate of about 10° C. per hour. Though the α-form crystal is likely crystallized in the large-scale production in the industrial production, it can be preferentially crystallized upon seeding with the α-form crystal. The β-form crystal can be obtained by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride to a mixed solution of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 2-aminothiazol-4-yl-acetic acid, concentrated hydrochloric acid and water at room temperature and neutralizing the resulting acidic solution to form a wet cake of the β-form crystal. (The wet cake as referred to herein means the state where the crystal is wetted by the solvent.) Also, the β-form crystal can be obtained by adding a recrystallization solvent (37% to 50% ethanol aqueous solution) to the present β-form crystal, dissolving the β-form crystal by heating at about 70 to 80° C., and after setting up an external temperature at 20° C., rapidly cooling the solution. Also, the β-form crystal can be preferentially crystallized upon seeding with the β-form crystal. As described previously, since the isolated β-form crystal can be again converted into the α-form after dissolution by heating, the β-form crystal is useful as a production intermediate of the α-form crystal. BEST MODE FOR CARRYING OUT THE INVENTION The invention will be specifically described below with reference to Examples 1 to 4, but it should not be construed that the scope of the invention is limited thereto. Since the starting compound was produced by a different method from that described in WO 99/20607, it will be described as Referential Examples 1 to 3. The synthesis routes of Referential Examples 1 to 3 and Examples 1 to 4 are illustrated below. Further, the production method of a crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride will be described as Comparative Referential Example. Synthesis Route: REFERENTIAL EXAMPLE 1 To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrochloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 L of N,N-dimethylformamide, 3.93 kg of hydroxybenztriazole and 5.58 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0.28 kg of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with 110 L of water and extracted with ethyl acetate (60 L and 30 L). The organic layer was washed successively with 60 L of a 1M hydrochloric acid aqueous solution, 60 L of a 20% potassium carbonate aqueous solution and water (60 L and 60 L), and then concentrated in vacuo at 10 to 19° C. The residue was dissolved in 35 L of toluene by heating (at 87° C.), cooled, and then stirred at 20° C. overnight. A formed crystal was collected by filtration and washed with 10 L of toluene, followed by drying in vacuo. There was thus obtained 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as a pale yellow crystal. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm)=2.87 (2H, t, J=7.2 Hz), 3.30 to 3.46 (2H, m), 4.85 (1H, d, J=4.8 Hz), 6.12 (1H, d, J=4.8 Hz), 7.20 to 7.33 (5H, m), 7.40 (2H, d, J=8.0 Hz), 8.04 to 8.12 (3H, m). FAB-MS m/z: 301 (M+H)+. (Another method) Production method using 4-nitrophenylethylamine 1/2 sulfate: To a mixture of 9.77 g of 4-nitrophenylethylamine 1/2 sulfate, 6.00 g of (R)-mandelic acid, 4.70 g of potassium carbonate and 60 mL of N,N-dimethylformamide, 6.14 g of hydroxybenztriazole and 8.70 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0.87 g of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution, 20% potassium carbonate aqueous solution and water, and then concentrated in vacuo. The residue was recrystallized from toluene to obtain 10.4 g of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as a pale yellow crystal. REFERENTIAL EXAMPLE 2 A mixture of 7.51 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 23 L of 1,3-dimethyl-2-imidazolidinone and 23 L of tetrahydrofuran was cooled to −18° C., to which was then dropped 49.4 kg of 1M borane-tetrahydrofuran solution at not higher than −7° C. Thereafter, the temperature was increased to 70° C., and the mixture was stirred for 5 hours. The reaction mixture was cooled to −12° C., to which were then added 2.9 kg of methanol and 5.9 kg of concentrated hydrochloric acid at not higher than 5° C. The mixture was stirred at 68° C. for one hour and concentrated in vacuo such that the inner volume became 50 L. 60 kg of 30% K2CO3 aqueous solution and 6 L of water were added, and the mixture was extracted with 75 L of ethyl acetate. The organic layer was washed with 75 L and concentrated in vacuo. The residue was added with and dissolved in 75 L of isopropanol at 40° C., and the solution was crystallized from 2.46 kg of concentrated hydrochloric acid, followed by stirring at 23° C. overnight. A crystal was collected by filtration and washed with 38 L of isopropanol, followed by drying in vacuo. There was thus obtained 7.29 kg of (R)-2-[[2′-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm)=3.00 to 3.08 (1H, m), 3.15 to 3.30 (5H, m), 5.00 to 5.05 (1H, m), 6.23 (1H, d, J=4.0 Hz), 7.29 to 7.35 (1H, m), 7.36 to 7.43 (4H, m), 7.57 (2H, d, J=8.4 Hz), 8.21 (2H, d, J=8.4 Hz), 9.12 (2H, br). FAB-MS m/z: 287 (M+H)+. REFERENTIAL EXAMPLE 3 A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 110 L of methanol and 1.20 kg of wet 10% palladium-carbon (wetting rate: 54.2%) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The residue was added with and dissolved in 40 L of methanol at 40° C., and the solution was crystallized from 220 L of diisopropyl ether, followed by stirring at 20° C. overnight. A crystal was collected by filtration and washed with 30 L of diisopropyl ether, followed by drying in vacuo. There was thus obtained 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride. (Another method) Method of using ethyl acetate as crystallization solvent: A mixture of 15.0 g of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride, 90 mL of methanol and 655 mg of wet 10% palladium-carbon (wetting rate: 54.2%) was stirred under a hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered. The filtrate was heated, to which was then intermittently added ethyl acetate while concentrating the methanol solution by heating, to form a slurry. A generated crystal was collected by filtration and washed with ethyl acetate, followed by drying in vacuo. There was thus obtained 12.9 g of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm)=2.76 to 2.90 (2H, m), 2.95 to 3.16 (4H, m), 4.95 to 5.11 (3H, m), 6.20 (1H, d, J=4.0 Hz), 6.53 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.28 to 7.43 (5H, m), 8.97 (1H, br), 9.29 (1H, br). FAB-MS m/z: 257 (M+H)+. Example 1 Production of the β-Form Crystal To a mixed solution of 8.00 g of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride, 4.32 g of 2-aminothiazol-4-yl-acetic acid, 2.64 g of concentrated hydrochloric acid and 120 mL of water, 5.76 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at room temperature, and the mixture was stirred for one hour. A mixed solution of 2.40 g of sodium hydroxide and 40 mL of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water, followed by drying in vacuo. There was thus obtained 9.93 g of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. EXAMPLE 2 Production of the β-Form Crystal Through Wet Cake of the β-Form Crystal To a mixed solution of 13.50 kg of (R)-2-[[2-(4-aminophenyl) ethyl]amino]-1-phenylethanol monohydrochloride, 7.29 kg of 2-aminothiazol-4-yl-acetic acid, 4.46 kg of concentrated hydrochloric acid and 270 L of water, 9.73 kg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) was added at 15° C., and the mixture was stirred for one hour. A mixed solution of 4.10 kg of sodium hydroxide and 110 L of water was dropped in the reaction solution, thereby undergoing crystallization. A generated crystal was collected by filtration and washed with water to obtain 26.2 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. This crystal was used for recrystallization as it was in the wet state. 26.2 kg of the wet cake of the β-form crystal was added with and dissolved in 180 L of water and 140 L of ethanol by heating at about 80° C., and an external temperature was set up at 20° C., thereby rapidly cooling the solution. A generated crystal was filtered and dried to obtain 15.40 kg of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. Powder X-ray diffraction diagram and thermal analysis diagram of the β-form crystal are shown in FIG. 1 and FIG. 2, respectively. (Another method) (Recrystallization upon seeding with the β-form crystal): A mixture of 7.54 g of the β-form crystal, 60 mL of ethanol and 90 mL of water was dissolved by heating and cooled, to which was then added 380 mg of the β-form crystal at 45° C. Thereafter, the mixture was stirred under ice cooling for 15 minutes. A crystal was filtered and dried to obtain 6.93 g of the β-form crystal. EXAMPLE 3 Production of the α-Form Crystal from the β-Form Crystal A mixture of 15.30 kg of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide, 180 L of water and 120 L of ethanol was dissolved by heating at about 80° C. and cooled, to which was then added 15.0 g of the α-form crystal at 50° C. Thereafter, the mixture was cooled to 20° C. A crystal was filtered and dried to obtain 14.24 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. A powder X-ray diffraction diagram of the α-form crystal is shown in FIG. 3. EXAMPLE 4 Production of the α-Form Crystal from Wet Cake of the β-Form Crystal The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80° C., and the solution was cooled at a rate of about 10° C. per hour, to which was then added 8.4 g of the α-form crystal at 55° C. Thereafter, the mixture was cooled to 20° C. A crystal was filtered and dried to obtain 6.56 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. Powder X-ray diffraction diagram and thermal analysis diagram of the α-form crystal are shown in FIG. 4 and FIG. 5, respectively. 1H-NMR (DMSO-d6, 500 MHz) δ (ppm)=1.60 (1H, s), 2.59 to 2.66 (4H, m), 2.68 to 2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J=8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J=8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+. COMPARATIVE REFERENTIAL EXAMPLE (PRODUCTION OF DIHYDROCHLORIDE) 20.0 g of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide was dissolved in 1,4-dioxane, to which was then added 8.41 mL of concentrated hydrochloric acid. A generated crystal was collected by filtration to obtain 25.0 g of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride. A powder X-ray diffraction diagram of the dihydrochloride crystal is shown in FIG. 6. 1H-NMR (DMSO-d6, 400 MHz) δ (ppm)=2.90 to 3.08 (3H, m), 3.10 to 3.21 (3H, m), 3.75 (2H, s), 4.99 to 5.03 (1H, m), 6.69 (1H, s), 7.20 (2H, d, J=8.8 Hz), 7.28 to 7.43 (5H, m), 7.59 (2H, d, J=8.8 Hz), 8.94 (1H, brs), 9.17 (2H, br), 9.40 (1H, brs). FAB-MS m/z: 397 (M+H)+. INDUSTRIAL APPLICABILITY The α-form crystal of the invention does not exhibit hygroscopicity and is stable, and therefore, can be used as a medicine and is useful as a medicine. Though the β-form crystal of the invention exhibits weak hygroscopicity, it is stable and useful as a production intermediate of the α-form crystal. Also, these crystals have both an insulin secretion promoting action and an insulin sensitivity potentiating action and are useful for remedy of diabetes. The usefulness of these crystals as medicines has been ascertained by the following hygroscopicity test and hypoglycemic test. 1. Hygroscopicity test: The hygroscopicity was measured using VTI SGA-100 under the following conditions. Temperature: 25° C., measurement range: from 5 to 95% of relative humidity, measurement interval: 5% of relative humidity. As a result, the crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibited a rapid increase in the weight from a relative humidity of about 80%, held moisture of about 14% at a relative humidity of 90%, and exhibited strong hygroscopicity (see FIG. 7). On the other hand, the α-form crystal of the invention had a moisture-holding amount of not more than 0.2% over the entire range of relative humidity from 5% to 95% and did not exhibit hygroscopicity (see FIG. 9). Also, in the β-form crystal, an increase in the weight was observed from a relative humidity of about 20%, and it held moisture of about 3% and exhibited weak hygroscopicity (see FIG. 8). The foregoing crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride exhibits strong hygroscopicity, and the physical and chemical nature and physical properties of the crystal vary and are unstable. On the other hand, the α-form crystal of the invention does not exhibit hygroscopicity and is excellent in stability, and therefore, is suitable as a starting material for the production of medicines. Though the “β-form crystal” has weak hygroscopicity, it is a metastable-form crystal and can be used as a medicine. 2. Hypoglycemic Test in kk Mice (Insulin Resistance Model: Obesity and Hyperglycemia) Male kk mice (blood glucose level: 200 mg/dL or more) were measured for blood glucose level under feeding and then randomly classified into groups. The drug to be tested was compulsorily orally administered once daily for 7 days, and the blood glucose level after 15 to 18 hours from the final administration was compared with that before the administration (n=6). The blood was collected from a tail vein of the mouse using a glass capillary (previously treated with heparin), a protein was removed therefrom, and the amount of glucose in the supernatant (mg/dL) was measured by calorimetric determination by means of the glucose oxidase method. Further, a dose by which the blood glucose level was reduced by 30% as compared with that before the administration of the drug to be tested was expressed as an ED30 value. As a result, the α-form crystal exhibited a strong activity such that the ED30 value in the oral administration was not more than 3.5 mg/kg/day. 3. Usefulness of the β-Form Crystal as a Production Intermediate: The β-form crystal is also useful as a production intermediate of the α-form crystal. The β-form crystal can be surely and simply obtained by quenching in the industrial production. Since the β-form crystal has high solubility in a recrystallization solvent (37% to 50% ethanol aqueous solution) as compared with the α-form crystal, the α-form crystal can be easily obtained by recrystallization of the β-form crystal. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a powder X-ray diffraction diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 2 is a thermal analysis diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 3 is a powder X-ray diffraction diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 4 is a powder X-ray diffraction diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 5 is a thermal analysis diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 6 is a powder X-ray diffraction diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide dihydrochloride. FIG. 7 is a hygroscopicity curve diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide dihydrochloride. FIG. 8 is a hygroscopicity curve diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 9 is a hygroscopicity curve diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). In the drawings, “Intensity” stands for the intensity; “Temperature” stands for the temperature; “Heat Flow Endo Up” stands for the heat absorption; “Weight” stands for the weight; “Adsorption” stands for the adsorption; “Desorption” stands for the desorption; “Isotherm” stands for the curve; and “RH” stands for the relative humidity, respectively.

<SOH> BACKGROUND ART <EOH>The present inventors have reported that (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide dihydrochloride represented by the following chemical structural formula has both an insulin secretion promoting action and an insulin sensitivity potentiating action, further has anti-obesity and anti-hyperlipemia actions due to a selective stimulating action to β 3 -receoptors and is a useful compound for remedy of diabetes (WO 99/20607, Example 41). However, since this dihydrochloride has strong hygroscopicity and is unstable, its use as a medicine was still problematic. Medicines are required to be stable against humidity, temperature, light, and the like over a long period of time and also to have stability in the formulation step. If medicines have strong hygroscopicity, they physically and chemically change or cause such an inconvenience that the water content is different depending upon lots. Accordingly, it is necessary to always store them in a drying chamber or to provide a drying step, which is not preferable from the standpoint of industrial use.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a powder X-ray diffraction diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 2 is a thermal analysis diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 3 is a powder X-ray diffraction diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 4 is a powder X-ray diffraction diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (crystal of the invention). FIG. 5 is a thermal analysis diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 6 is a powder X-ray diffraction diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide dihydrochloride. FIG. 7 is a hygroscopicity curve diagram of the crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide dihydrochloride. FIG. 8 is a hygroscopicity curve diagram of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). FIG. 9 is a hygroscopicity curve diagram of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (crystal of the invention). In the drawings, “Intensity” stands for the intensity; “Temperature” stands for the temperature; “Heat Flow Endo Up” stands for the heat absorption; “Weight” stands for the weight; “Adsorption” stands for the adsorption; “Desorption” stands for the desorption; “Isotherm” stands for the curve; and “RH” stands for the relative humidity, respectively. detailed-description description="Detailed Description" end="tail"?

20040429

20080311

20050106

96407.0

STOCKTON, LAURA LYNNE

ALPHA-FORM OR BETA-FORM CRYSTAL OF ACETANILIDE DERIVATIVE

UNDISCOUNTED

ACCEPTED

ACCEPTED

Conveyor unit for conveying flat objects

A conveyor unit for conveying flat objects includes at least first, second and third endless belts, together with a cylinder. The first endless belt extends along a part of the circumference of the cylinder and forms, with the cylinder circumference, a section of a path of conveyance for the objects. The second and third belts define another section of the path of conveyance.

1-17. (Cancelled) 18. A conveyor unit for conveying flat objects comprising: a collection cylinder having a circumferential surface, said collection cylinder being located after, in a direction of object travel, a cutter unit; a first endless belt extending around a portion of said collection cylinder and cooperating with said collection cylinder circumferential surface and defining a section of a conveying path; a second endless belt and a cooperating third endless belt defining a balance of said conveying path, said first and third endless belts defining a first side of said conveying path, said second conveyor belt and said collection cylinder circumferential surface defining a second side of said conveying path; and a drive mechanism, adapted to be controlled independently of a rotating speed of said collection cylinder, and driving said second and third endless belts, said third endless belt being mechanically coupled to said second endless belt, said drive mechanism including a frequency-regulated motor. 19. A conveyor unit for conveying flat objects comprising: a collection cylinder having a circumferential surface, said collection cylinder being located after, in a direction of object travel, a cutter unit; a first endless belt extending around a portion of said collection cylinder and cooperating with said collection cylinder circumferential surface and defining a section of a conveying path; a second endless belt and a cooperating third endless belt defining a balance of said conveying path, said first and third endless belts defining a first side of said conveying path, said second conveyor belt and said collection cylinder circumferential surface defining a second side of said conveying path; a drive mechanism adapted to be regulated independently of a rotary speed of said collection cylinder, and driving said second and third endless belts; and a regulating device controlling a speed of said second and third endless belts drive mechanism and adapted to control said second and third endless belt speeds with respect to said rotating speed of said collection cylinder by using a variable proportionality factor. 20. A conveyor unit for conveying flat objects comprising: a collection cylinder having a circumferential surface, said collection cylinder being located after, in a direction of object travel, a cutter unit; a first endless belt extending around a portion of said collection cylinder and cooperating with said collection cylinder circumferential surface and defining a section of a conveying path; a second endless belt and a cooperating third endless belt defining a balance of said conveying path, said first and third endless belts defining a first side of said conveying path, said second conveyor belt and said collection cylinder circumferential surface defining a second side of said conveying path; and a speed-transforming gear coupling said second and third endless belts to said collection cylinder, said speed-transforming gear having a gear ratio selected such that a speed of said second and third endless belts is equal to a circumferential speed of said collection cylinder and wherein said third endless belt is mechanically coupled to said second endless belt. 21. A conveyor unit for conveying flat objects comprising: a collection cylinder having a circumferential surface, said collection cylinder being located after, in a direction of object travel, a cutter unit; a first endless belt extending around a portion of said collection cylinder and cooperating with said collection cylinder circumferential surface and defining a section of a conveying path; a second endless belt and a cooperating third endless belt defining a balance of said conveying path, said first and third endless belts defining a first side of said conveying path, said second conveyor belt and said collection cylinder circumferential surface defining a second side of said conveying path; a drive mechanism for driving said second and third endless belts at a controlled speed; and a third endless belt deflection roller and a first endless belt deflection roller positioned directly adjacent each other, said third endless belt deflection roller defining an end of said third endless belt conveying path, said first endless belt deflection roller defining a start of said first endless belt conveying path, said first endless conveying belt being arranged for transporting signatures in cooperation with said collection cylinder. 22. The conveyor unit of claim 19 wherein said third endless belt is mechanically coupled to said second endless belt. 23. The conveyor unit of claim 18 wherein said third endless belt is driven at the same speed as said second endless belt. 24. The conveyor unit of claim 19 wherein said third endless belt is driven at the same speed as said second endless belt. 25. The conveyor unit of claim 20 wherein said third endless belt is driven at the same speed as said second endless belt. 26. The conveyor unit of claim 21 wherein said third endless belt is driven at the same speed as said second endless belt. 27. The conveyor unit of claim 18 further including a regulating device adapted to control speeds of said second and third endless belts with respect to a speed of said first endless belt and a circumferential speed of said collection cylinder. 28. The conveyor unit of claim 27 further including a variable proportionality factor usable in said regulating device. 29. The conveyor unit of claim 27 further including a belt speed sensor connected to said regulating device. 30. The conveyor unit of claim 28 further including a conveyed object thickness sensor connected to said regulating device. 31. The conveyor unit of claim 27 further including a conveyed object thickness sensor connected to said regulating device. 32. The conveyor unit of claim 28 further including a conveyed object thickness sensor connected to said regulating device. 33. The conveyor unit of claim 31 wherein said conveyed object thickness sensor is arranged before, in a conveying direction, said conveyor unit. 34. The conveyor unit of claim 32 wherein said conveyed object thickness sensor is arranged before, in a conveying direction, said conveyor unit. 35. The conveyor unit of claim 18 wherein said first endless belt is driven by frictional contact with said collection cylinder circumferential surface. 36. The conveyor unit of claim 21 wherein said first endless belt is driven by frictional contact with said collection cylinder circumferential surface. 37. The conveyor unit of claim 21 wherein said drive mechanism includes a frequency-regulated motor. 38. The conveyor unit of claim 18 further including an intermediate wheel between said drive mechanism and said second and third endless belts. 39. The conveyor unit of claim 19 further including an intermediate wheel between said drive mechanism and said second and third endless belts. 40. The conveyor unit of claim 20 further including an intermediate wheel between said drive mechanism and said second and third endless belts. 41. The conveyor unit of claim 21 further including an intermediate wheel between said drive mechanism and said second and third endless belts. 42. The conveyor unit of claim 18 wherein said second and third endless belts are out of contact with said collection cylinder. 43. The conveyor unit of claim 19 wherein said second and third endless belts are out of contact with said collection cylinder. 44. The conveyor unit of claim 20 wherein said second and third endless belts are out of contact with said collection cylinder. 45. The conveyor unit of claim 21 wherein said second and third endless belts are out of contact with said collection cylinder. 46. The conveyor unit of claim 18 wherein a start of said section of said conveying path follows an end of said balance of said conveying path. 47. The conveyor unit of claim 19 wherein a start of said section of said conveying path follows an end of said balance of said conveying path. 48. The conveyor unit of claim 20 wherein a start of said section of said conveying path follows an end of said balance of said conveying path. 49. The conveyor unit of claim 18 further including a last deflection roller of said third endless belt and a first deflection roller of said first endless belt, said last deflection roller and said first deflection roller being arranged directly adjacent. 50. The conveyor unit of claim 19 further including a last deflection roller of said third endless belt and a first deflection roller of said first endless belt, said last deflection roller and said first deflection roller being arranged directly adjacent. 51. The conveyor unit of claim 20 further including a last deflection roller of said third endless belt and a first deflection roller of said first endless belt, said last deflection roller and said first deflection roller being arranged directly adjacent. 52. The conveyor unit of claim 21 further including a last deflection roller of said third endless belt and a first deflection roller of said first endless belt, said last deflection roller and said first deflection roller being arranged directly adjacent.

FIELD OF THE INVENTION The present invention is directed to a conveyor unit for flat objects. The conveyor unit has at least first and second endless belts and a cylinder embodied as a collection cylinder. BACKGROUND OF THE INVENTION Conveyor units are typically employed in folding apparatus, for example, for conveying signatures which had been previously cut from a web of an imprinted material. The signatures each consist of a variable number of sheets which are not connected to each other. For conveying the signatures, it is therefore of great importance that the two endless belts and the cylinder of the conveyor unit move at exactly matched speeds in order to avoid any shearing forces acting on signatures clamped between them, which shearing forces could lead to deformation and to fanning of the signatures in the course of their being transported. In conventional conveyor units of the above-mentioned type, the first endless belt, which partially loops around the surface of the cylinder, is driven by the cylinder, by friction. Therefore, if no objects are conveyed between them, the path speed of the first belt corresponds to the circumferential speed of the cylinder. If conveyed objects are located in the area of the loop between the cylinder and the first belt, this has an effect on the speed of the first belt, which acts as it would with an increase of the diameter of the cylinder. Therefore, the speed of the first belt increases in accordance with the thickness of the objects to be conveyed. The movement of the second belt is coupled to the rotation of the cylinder at a fixedly set transmission ratio via a speed-transforming gear. Therefore, the speed of the second belt is constant. This results in the two belts only running exactly at the same speed at a defined thickness of the objects to be conveyed, so that the objects are not subjected to shearing forces only during this operating condition. DE 94 17 127 U1 and EP 0205143 A2 both describe a collection cylinder, against whose circumference a belt system rests and which is provided with sheets via two further cooperating belt systems. U.S. Pat. No. 5,405,126 describes a folding apparatus with belts driven by an electric motor. U.S. Pat. No. 3,363,520 discloses a collection cylinder for sheets, having several belts. One belt is driven by the collection cylinder. SUMMARY OF THE INVENTION The object of the present invention is directed to providing a conveyor unit for flat objects. In accordance with the invention, this object is attained by the provision of a conveyor unit for conveying flat objects and having at least first and second endless belts and a cylinder which is embodied as a collection cylinder. The conveyor unit is located downstream of a cutter unit. A conveying path is defined, on one side, by at least the first endless belt, and on the other side by a portion of the circumference of the cylinder and the second endless belt. The first endless belt extends around a portion of the circumference of the cylinder. The conveyor path is defined, with respect to the second endless belt, by a third endless belt. The advantages which can be gained by the present invention consist, in particular, in that it is possible to provide synchronous running between both sides of the conveying path over their entire length even in case of different thicknesses of the object to be conveyed. Objects can thus be conveyed gently and free of shearing forces. For this purpose, it has been provided that the conveying path of the conveyor unit is divided into two sections which follow each other. In one section, a portion of the circumference of the cylinder and the first conveyor belt lie opposite each other. A second conveyor belt and a third conveyor belt lie opposite each other in a second section. It is possible by the use of a coupling, and in particular by the use of a mechanical coupling, to reduce deviations in the speed of the movement of the second and third endless belts to exactly zero. Accordingly, regardless of the length of the section of the conveying path delimited by these endless belts, no shearing of the conveyed products can occur. In accordance with a first, simple preferred embodiment of the present invention, the second and the third endless belts are coupled to the rotating movement of the cylinder by a speed-transforming gear. The transmission ratio of the speed-transforming gear is fixed in such a way that the speeds of the second and third endless belts coincide exactly with the circumferential speed of the cylinder. In accordance with a more elaborate preferred embodiment of the present invention, a drive mechanism for the second and third endless belt can be regulated independently of the rotary speed of the cylinder. By this, it is possible to adjust the speed of the second and third belts in response to the respective thickness of the conveyed product, and to adjust the speed of the first endless belt resulting from this. Small deviations from a speed of the second and third belts, which would be optimal in view of the deformation-free conveyance of the products and in view of their actual speed, can be tolerated more easily than in connection with the above explained conveyor unit. With the conveyor unit in accordance with the present invention, such a deviation leads to only a slight tensional stress or to a slight transient compression of the products in the course of their transfer from one section of the conveyor unit to the other, depending on which one is the faster. No shearing can occur. For such shearing to occur, it would be necessary that the belts of different speeds be located opposite each other. The optimum speed must equal the speed of the first endless belt or must equal the circumferential speed of the cylinder, or must lie between these two values. The mean value of the speeds of the first belt and of the cylinder, in particular, can be used as the optimal speed. This corresponds to the position of the neutral fiber of the product, i.e. to a position of a fictional line in the product located exactly in the center of the product which neutral fiber, in the course of the product being conveyed on the cylinder, is neither stretched nor compressed. A regulating device is usefully assigned to this drive mechanism, and works toward accomplishing a matching of the speeds of the second and third belts with the optimal speed. This regulating device preferably proportionally regulates the speed of the second belt by a variable proportionality factor in relation to the speed of rotation of the cylinder. By adjusting the proportionality factor, as a function of the thickness of the conveyed objects, the stretching or compression stress imparted to the conveyed objects, during the transfer of the conveyed objects from one section of the conveying path to the other, is minimized. For determining the proportionality factor, the regulating device can be coupled with a sensor for measuring the speed of the first belt. The speed of the first belt varies linearly with the thickness of the conveyed object. Freedom from stretching or compression stresses can be achieved by a simple matching of the speeds of all belts. A further option lies in coupling a sensor, which is usable for detecting the thickness of the objects, with the regulating device. Such a sensor can be arranged, in particular, prior to the inlet of the conveyor unit. The belt speeds of the conveyor unit can then be matched to a changed product thickness even before the object on which the thickness measurement was performed, reaches the conveyor unit. BRIEF DESCRIPTION OF THE DRAWING A preferred embodiment of the present invention is represented in the sole drawing and will be described in greater detail in what follows. The sole drawing FIGURE represents a schematized section through a conveyor unit in accordance with the present invention. DESCRIPTION OF THE PREFERRED EMBODIMENT The conveyor unit of the present invention, as shown in the sole drawing FIGURE, is arranged following a cutter unit that is formed of a cutter cylinder 02 and a grooved cylinder 03 located opposite it. By the operation of this cutter unit, a web 01 of material, for example a paper web 01, which has been cut in a superstructure located above the cutter unit, and not shown in the sole drawing, into strands with the aid of several rotating linear cutters, which strands are placed one above the other, and the web of material 01 is cut into individual signatures in the cutter unit. Therefore, the signatures consist of a different number of sheets of paper lying on top of each other, which sheets of paper are not firmly attached to each other and which are therefore open at all four sides. The path along which the signatures are conveyed in the conveyor unit located after the cutter unit can be divided into two sections. A first section 08, is one in which the signatures are conveyed, pressed against each other, between two endless belts 06, 05, called a second and third endless belt here. A second section 09, is one in which the signatures are conveyed between a first endless belt 04 and a cylinder 07, for example a collection cylinder 07 of a rotary printing press. In a transition zone between the first section 08 and the second section 09, the signatures are conducted through a wedge-shaped tongue 17, which is situated on the side facing the collection cylinder 07. A lower deflection roller 18, which carries the third endless belt 05, has been mounted, which lower deflection roller 18 is pivotable around a pivot shaft 19 and which maintains the tension of the third endless belt 05, and in this way provides access to the tongue 17 for exchanging or for performing maintenance on tongue 17. The collection cylinder 07 is driven by a motor, which is not specifically represented in the drawings. The first endless belt 04, which forms the second section 09 of the conveyor unit and which loops around the collection cylinder 07 over an angle area of approximately 180°, is driven by friction resulting from its contact with the peripheral surface of the collection cylinder 07. When the signatures are conveyed in the second section 09, they transfer the driving force from the collection cylinder 07 to the first endless belt 04. Because of their greater relative distance from the center of rotation of the collection cylinder 07, with respect to the inside portion of the signatures, the outside portion of the signatures, i.e. the signature portion facing away from the collection cylinder 07 have a slightly greater path speed than the surface area of the collection cylinder 07 itself. The speed difference is proportional to the thickness of the signatures. Therefore, the speed of the first endless belt 04 is automatically adapted to the changing thickness of the signatures. The second endless belt 06, and the third endless belt 05 are together driven at the same speed via an intermediate drive wheel 11 by a drive mechanism 12, which drive mechanism 12 may be, for example, a frequency-regulated motor 12. In this way, no shearing at all can occur during the transport of the signatures in the first section 08 of the conveyor unit. The speed of the motor 12 is regulated by a regulating device 13, whose job is to maintain the path speeds of the two endless belts 05, 06 at a suitable value which is matched to the transport speed of the signatures in the second section 09 of the conveyor unit, and in this way, to prevent the sheets of the signatures from being displaced, in relation to each other, during their transition from the first section 08 to the second section 09, or to prevent the signatures from being compressed, so that the signatures become unsightly or unusable. A first option for controlling the path speed of the three endless belts 04, 05, 06 is to match the speed of the second and third endless belt 06 or 05 to that of the first endless belt 04. The result is that a signature which is transferred from the first section 08 to the second section 09 of the conveying path is not subjected to any stretching or compression, at least on their side facing the third and first endless belts 05 or 04. Since, as described above, the speed of the first endless belt 04 is a function of the speed of the collection cylinder 07 and of the thickness of the signatures to be conveyed, an active regulation of the speed of the various endless belts is necessary. In accordance with the present invention, the regulating device 13 is connected with two speed sensors for sensing the path speeds of the third and the second endless belts 05, or 06 , and acts toward the matching of these two path speeds. The speed sensors can be angle of rotation sensors, for example, which are respectively arranged at a deflection roller 14 or 16 of the third or second endless belt 05, 06, and which transmit a pulse to the regulating device 13 every time the deflection rollers 14, 16 have traveled over a fixed angle of rotation. These angle of rotation sensors are preferable identically constructed and are mounted on the deflection rollers 14, 16 which rollers 14, 16 are of identical radii. In this case, the regulating device 13 can assure an identical path speed of the two endless belts 05, 06 by maintaining a constant, and preferably diminishing phase offset between the pulses provided by the two sensors. In that case, the speed of the second and third endless belts 06, 05 is proportional to the speed of the collection cylinder 07 in accordance with a proportionality factor, wherein the proportionality factor is determined by the thickness of the signatures conveyed between the collection cylinder 07 and the first endless belt 04. Another option for regulating the speed of the second endless belt 06 is to connect the regulating device 13 on the one side with a sensor for the speed of the first endless belt 04 or for the rotational speed of the collection cylinder 07, and on the other side with a sensor for the thickness of the signatures to be conveyed. The regulating device 13 then calculates a speed to be maintained by the motor 12 from the measured speed of the first endless element 04, corrected by a proportionality factor which is determined depending on the measured thickness of the signatures to be conveyed. A sensor, for determining the thickness of the signatures to be conveyed or for determining a value proportional to the signature thickness, can be arranged at a location which is arbitrary, to a large extent, in the conveyor unit or, even better, at a location adjacent the web 01 of material prior to the intake of the web of material into the conveyor unit. It is also conceivable that an operator can set a known thickness of the signatures, the number of sheets in the signature, and their basis weight, or other arbitrary equivalent combinations of parameters in a control unit of the regulating device. An operator can also perform subsequent corrections with such a control unit if it is noticed that the signatures conveyed by the conveyor unit are being sheared or have been sheared. In accordance with a simplified second preferred embodiment of the present invention, the intermediate drive wheel 11, which drives both the two endless belts 05, 06, is coupled by a gear which is not specifically represented, and having a fixed gear ratio, to the rotation of the collection cylinder 07. The gear ratio of the not depicted gear has been selected to be such that the path speed of the two endless belts 05, 06 is equal to the circumferential speed of the collection cylinder 07. With this embodiment, the third endless belt 05 runs slightly slower than the first endless belt 04 following it in the conveying path. As a result of the equality of the path speeds of the endless belts 05, 06 and the circumferential speed of the collection cylinder 07, a signature is not subjected to any shearing or compression forces at the transition between the first conveyor section 08 and the second conveyor section 09, at least at the signature side facing the second endless belt 06 and the collection cylinder 07. A slight stretching stress can occur at the opposite side of the substrate in contact with the endless belts 05, 04, since the endless belt 04 moves slightly faster than the endless belt 05. Such a stretching stress can be acceptable in the situation of small thicknesses of the signatures, and therefore in the case of small differences between the speeds of the first endless belt 04 and of the remaining endless belts 05, 06. However, if the thickness of the signatures becomes too great, and if therefore the speed difference between the collection cylinder 07 and the first endless belt 04 becomes too great, a slight shearing force might occur on the signatures during the transfer of a signature between the two conveyor sections 08 and 09. In contrast thereto, with the use of the above-described first embodiment, only a compression force acts on the signature at the moment of transfer. This compression force cannot result in a sliding of individual sheets of the signature. In the situation of processing thick signatures the technically more elaborate first embodiment might be preferred over the simpler, and more cost-effective second one. In principle it is, of course, possible to set any arbitrary speed, which arbitrary speed lies between the circumferential speed of the collection cylinder 07 and the path speed of the first endless belt 04, as the conveying speed of the conveying endless belts 05, 06 of the first section 08. If, for example, the average value of the circumferential speed of the collection cylinder 07 and the path speed of the endless belt 04 in the second conveying section is selected as the path speed of the first conveying section 08, a slight compression or speed reduction acts on the surface of the signature facing the collection cylinder 07 during the transfer to the second section, while the oppositely located surface of the signature facing the endless belts 05, 04 is stretched or accelerated. While preferred embodiments of a conveyor unit for conveying flat objects, in accordance with the present invention, have been set forth fully and completely hereinabove, it will be apparent to one of skill in the art that various changes in, for example, the size of the collection cylinder, the type of web being conveyed, and the like could be made without departing from the true spirit and scope of the present invention which is accordingly to be limited only by the following claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Conveyor units are typically employed in folding apparatus, for example, for conveying signatures which had been previously cut from a web of an imprinted material. The signatures each consist of a variable number of sheets which are not connected to each other. For conveying the signatures, it is therefore of great importance that the two endless belts and the cylinder of the conveyor unit move at exactly matched speeds in order to avoid any shearing forces acting on signatures clamped between them, which shearing forces could lead to deformation and to fanning of the signatures in the course of their being transported. In conventional conveyor units of the above-mentioned type, the first endless belt, which partially loops around the surface of the cylinder, is driven by the cylinder, by friction. Therefore, if no objects are conveyed between them, the path speed of the first belt corresponds to the circumferential speed of the cylinder. If conveyed objects are located in the area of the loop between the cylinder and the first belt, this has an effect on the speed of the first belt, which acts as it would with an increase of the diameter of the cylinder. Therefore, the speed of the first belt increases in accordance with the thickness of the objects to be conveyed. The movement of the second belt is coupled to the rotation of the cylinder at a fixedly set transmission ratio via a speed-transforming gear. Therefore, the speed of the second belt is constant. This results in the two belts only running exactly at the same speed at a defined thickness of the objects to be conveyed, so that the objects are not subjected to shearing forces only during this operating condition. DE 94 17 127 U1 and EP 0205143 A2 both describe a collection cylinder, against whose circumference a belt system rests and which is provided with sheets via two further cooperating belt systems. U.S. Pat. No. 5,405,126 describes a folding apparatus with belts driven by an electric motor. U.S. Pat. No. 3,363,520 discloses a collection cylinder for sheets, having several belts. One belt is driven by the collection cylinder.

<SOH> SUMMARY OF THE INVENTION <EOH>The object of the present invention is directed to providing a conveyor unit for flat objects. In accordance with the invention, this object is attained by the provision of a conveyor unit for conveying flat objects and having at least first and second endless belts and a cylinder which is embodied as a collection cylinder. The conveyor unit is located downstream of a cutter unit. A conveying path is defined, on one side, by at least the first endless belt, and on the other side by a portion of the circumference of the cylinder and the second endless belt. The first endless belt extends around a portion of the circumference of the cylinder. The conveyor path is defined, with respect to the second endless belt, by a third endless belt. The advantages which can be gained by the present invention consist, in particular, in that it is possible to provide synchronous running between both sides of the conveying path over their entire length even in case of different thicknesses of the object to be conveyed. Objects can thus be conveyed gently and free of shearing forces. For this purpose, it has been provided that the conveying path of the conveyor unit is divided into two sections which follow each other. In one section, a portion of the circumference of the cylinder and the first conveyor belt lie opposite each other. A second conveyor belt and a third conveyor belt lie opposite each other in a second section. It is possible by the use of a coupling, and in particular by the use of a mechanical coupling, to reduce deviations in the speed of the movement of the second and third endless belts to exactly zero. Accordingly, regardless of the length of the section of the conveying path delimited by these endless belts, no shearing of the conveyed products can occur. In accordance with a first, simple preferred embodiment of the present invention, the second and the third endless belts are coupled to the rotating movement of the cylinder by a speed-transforming gear. The transmission ratio of the speed-transforming gear is fixed in such a way that the speeds of the second and third endless belts coincide exactly with the circumferential speed of the cylinder. In accordance with a more elaborate preferred embodiment of the present invention, a drive mechanism for the second and third endless belt can be regulated independently of the rotary speed of the cylinder. By this, it is possible to adjust the speed of the second and third belts in response to the respective thickness of the conveyed product, and to adjust the speed of the first endless belt resulting from this. Small deviations from a speed of the second and third belts, which would be optimal in view of the deformation-free conveyance of the products and in view of their actual speed, can be tolerated more easily than in connection with the above explained conveyor unit. With the conveyor unit in accordance with the present invention, such a deviation leads to only a slight tensional stress or to a slight transient compression of the products in the course of their transfer from one section of the conveyor unit to the other, depending on which one is the faster. No shearing can occur. For such shearing to occur, it would be necessary that the belts of different speeds be located opposite each other. The optimum speed must equal the speed of the first endless belt or must equal the circumferential speed of the cylinder, or must lie between these two values. The mean value of the speeds of the first belt and of the cylinder, in particular, can be used as the optimal speed. This corresponds to the position of the neutral fiber of the product, i.e. to a position of a fictional line in the product located exactly in the center of the product which neutral fiber, in the course of the product being conveyed on the cylinder, is neither stretched nor compressed. A regulating device is usefully assigned to this drive mechanism, and works toward accomplishing a matching of the speeds of the second and third belts with the optimal speed. This regulating device preferably proportionally regulates the speed of the second belt by a variable proportionality factor in relation to the speed of rotation of the cylinder. By adjusting the proportionality factor, as a function of the thickness of the conveyed objects, the stretching or compression stress imparted to the conveyed objects, during the transfer of the conveyed objects from one section of the conveying path to the other, is minimized. For determining the proportionality factor, the regulating device can be coupled with a sensor for measuring the speed of the first belt. The speed of the first belt varies linearly with the thickness of the conveyed object. Freedom from stretching or compression stresses can be achieved by a simple matching of the speeds of all belts. A further option lies in coupling a sensor, which is usable for detecting the thickness of the objects, with the regulating device. Such a sensor can be arranged, in particular, prior to the inlet of the conveyor unit. The belt speeds of the conveyor unit can then be matched to a changed product thickness even before the object on which the thickness measurement was performed, reaches the conveyor unit.

20040511

20060307

20050127

58371.0

YAN, REN LUO

CONVEYOR UNIT FOR CONVEYING FLAT OBJECTS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method for producing an impact-resistant polymethymethacrylate, and corresponding polymethylmethacrylate (pmma)

The invention relates to a novel, impact-resistant polymer based on PMMA.

1. Plastic moulding obtainable by polymerizing a mixture made from 65-99.5% by weight of methyl methacrylate 0-3% by weight of an unsaturated carboxylic acid 0.5-35% by weight of an impact modifier 0-1% by weight of crosslinker 0.5-1% by weight of stabilizer 0.001-0.1% by weight of initiator 0.01-1.0% by weight of release agent and 0.001-0.031% by weight of regulator 2. Plastic moulding according to claim 1, wherein the impact modifier, in the form of a masterbatch, comprises PMMA and impact modifier. 3. Plastic moulding according to claim 2, wherein the masterbatch is eemposed-comprises of 10-50% by weight of an impact modifier and 50-90% of a PMMA. 4. A noise barrier, which comprises: the plastic moulding according to claim 1. 5. A balcony cladding, which comprises: the plastic moulding according to claim 1. 6. A method for reducing noise, which comprises: interposing an article comprising the plastic moulding of claim 1 proximal to a noise source.

FIELD OF THE INVENTION The invention relates to impact-modified polymethyl methacrylate (PMMA) and to a process for preparing the polymethyl methacrylate, and also to articles which can be produced from the impact-modified PMMA. PRIOR ART Impact-modified PLEXIGLAS® moulding compositions are known, and are marketed by Röhm GmbH & Co. KG, for example with the grade names PLEXIGLAS®zkBR, PLEXIGLAS®zkHC, PLEXIGLAS®zkHT, PLEXIGLAS®zkHF, and PLEXIGLAS®zk. Examples of the uses of the impact-modified moulding compositions are household articles, lamp covers, sanitary items, roofing material, and the surface-finishing of plastics via coextrusion. The brochure “Schlagzähe PLEXIGLAS®-Formmassen” [Impact-modified PLEXIGLAS® moulding compositions] from Röhm GmbH & Co. KG (No. 10/1001/06003 (d)) gives information on the other properties, such as Vicat softening point (B/50) (ISO 306), and Charpy impact and Charpy low-temperature impact strength (ISO 179). PLEXIGLAS®GS is obtained by polymerizing methyl methacrylate and, where appropriate, other monomers and auxiliaries in the cell(-casting) process. It has a higher-molecular-weight than PLEXIGLAS®XT and is therefore not capable of further processing by extrusion or injection moulding. The forming methods used are either machining or thermoforming. Similar qualities are also supplied by other producers. The following table compares the properties of PLEXIGLAS®GS and PLEXIGLAS®XT: PLEXIGLAS ® GS PLEXIGLAS ® XT Cast Extruded Absolutely colourless and Absolutely colourless and clear clear Fracture-resistant Fracture-resistant to impact-modified (RESIST) Unequalled weathering and Unequalled weathering and ageing resistance ageing resistance High-quality surface and Very good surface planarity Solid sheets, blocks Solid sheets, pipes, rods, pipes, rods and bars multiwall sheets, corrugated sheets, mirrors From 2 to 200 mm solid From 1.5 to 25 mm thickness thickness for solid sheets, 16 and 32 mm for multiwall sheets Standard formats up to Standard formats up to 4050 × 2050 mm 3050 × 2030 mm (+extended lengths) Over 30 standard colours Over 20 standard colours Good resistance to dilute Good resistance to dilute acids acids PLEXIGLAS ® GS PLEXIGLAS ® XT Cast Extruded Limited resistance to Limited resistance to organic solvents organic solvents Good resistance to alkalis Good resistance to alkalis Very easy to work, similar Easy to work, similar to to hardwood hardwood Easily thermoformable with Very easy to thermoform wide processing latitude under ideal consistent conditions Capable of very good and Capable of very good secure adhesion, e.g. adhesion, and this includes using reactive adhesives the use of solvent-based (e.g. ACRIFIX ® 190, 192) adhesive (e.g. ACRIFIX ® 116, 117) Capable of combustion Capable of combustion approximately as hardwood; approximately as hardwood; very little smoke very little smoke generated generated Usable up to about 80° C. Usable up to about 70° C. There has been no lack of attempts to extend the impact-modified properties to cast materials. DE 1 964 913 describes weathering-resistant, highly impact-resistant resins made from styrene or methyl methacrylate in the presence of a rubber-like copolymer made from α-olefins, and of a copolymer based on the monomers butene, isobutylene or liquid paraffin. The resin contains at least 50% by weight of styrene. EP 325 875 (Norsolor) describes a resin made from an interpenetrating network based on polysiloxane and polyacrylate. The resultant plastic moulding can be further processed to give many different items. The light transmission of the resultant articles is not particularly high. EP 447 309 (Atochem) discloses a copolymer based on polymethyl methacrylate and polyurethane. Vicat points up to 107° C. and impact strength (Charpy) of 39 kJ/m2 are measured. U.S. Pat. No. 5,084,495 solves the problem of incorporating impact-modifying particles obtained by an (aqueous) suspension polymerization process into a methyl methacrylate matrix prior to polymerization. The entire aqueous dispersion of the impact modifier is mixed with methyl methacrylate (MMA), the water is separated off, and the remainder is the organic portion of the impact modifier in the MMA. The process is inconvenient, and requires auxiliaries for breaking the dispersion of the impact modifier and a particular apparatus for phase separation. Object An object was to find a process which produces a moulding (PMMA) and which does not require interpenetrating networks, polyurethane copolymers or inconvenient isolation steps for the impact modifier. It is also advantageous for the production of the novel mouldings to be possible on existing machinery without major modification. Achievement of Object It has been found that an impact-modified plastic moulding can be obtained by dissolving impact modifier or impact-modifier-containing PMMA in MMA or in MMA which has undergone incipient polymerization (syrup) and then pouring the solution into a cell and polymerizing the same by the process known per se. This gives a cast plastic moulding with the properties of a PLEXIGLAS®GS moulding known per se with increased impact strength. The other advantageous properties, such as weathering resistance and ageing resistance, resistance to chemicals and hot water, optical brilliance and good formability, are retained. The matrix material used may comprise a mix which comprises the usual stabilizers and which comprises other additives. An example of a mix for the matrix material: 98-99% by weight of methyl methacrylate 0-0.3% by weight of an unsaturated carboxylic acid 0-1% by weight of crosslinker 0.5-1% by weight of stabilizers 0-0.01% by weight of regulator 0-0.01% by weight of initiator 0.01-1.0% by weight of release agent Examples of compounds which may be used as crosslinker are glycol dimethacrylate and triallyl cyanurate. Examples of compounds which may be used as stabilizers are benzotriazoles, HALS products or sterically hindered phenols, and mixtures of the abovementioned components. HALS compounds are sterically hindered amines, as described by way of example in JP 0347856. These hindered amine light stabilizers scavenge the free radicals which form during exposure to radiation. Examples of compounds used as regulators are γ-terpines and terpinols. The initiators used may comprise any of the commercially available free-radical initiators, such as 2,2′-azobis(isobutyronitrile). Examples of the unsaturated carboxylic acid which may be used are methacrylic acid and acrylic acid. The impact modifier used may comprise a core-shell or a core-shell I-shell II impact modifier. An example of a core-shell I-shell II impact modifier has the following composition: Core: 94-97% by weight of methyl methacrylate 2-5% by weight of ethyl acrylate 1-0.1% by weight of crosslinker Shell I 79-82% by weight of butyl acrylate 13-18% by weight of styrene or α-methylstyrene 0.1-1% by weight of crosslinker Shell II 90-98% by weight of methyl methacrylate 10-2% by weight of ethyl acrylate Examples of the crosslinker which may be used in the impact modifier (core or shell I) are di(meth)acrylates, divinylbenzenes, and allyl (meth)acrylates. It is also possible to use a mixture of the crosslinkers components. The core:shell I:shell II ratio is 20-30:30-50:20-40% by weight. Examples of impact modifiers and their preparation are described in EP 0 828 772, or U.S. Pat. No. 3,793,402 or U.S. Pat. No. 4,690,986. It is possible to use the impact modifier not only in pure powder form but also in the form of a masterbatch. The underlying composition used for the masterbatch may be a commercially available PLEXIGLAS® moulding composition, such as PLEXIGLAS®7H or PLEXIGLAS®6N or PLEXIGLAS®7N. These moulding compositions are marketed by Röhm GmbH & Co. KG. It is also possible for the underlying composition used for the masterbatch to be pellets made from PLEXIGLAS®GS grades. The masterbatch is prepared by a conventional melt coagulation/compounding process. The amount of impact modifier in the masterbatch may be from 10 to 50% by weight, based on the total weight of the masterbatch. EXAMPLES Sheets with dimensions 2100×1290×4.0 mm are produced by the usual casting process between glass plates. The casting process is described by way of example in “Kunststoff-Handbuch” [Plastics handbook], Vol. IX, p. 15, Carl Hanser Verlag, 1975 or in “Ullmanns Enzyclopädie der technischen Chemie” [Ullmann's encyclopaedia of industrial chemistry], Vol. 19, p. 22, 4th Edition, Verlag Chemie (198). The inventive composition used was a mixture made from 80% by weight of MMA and 20% by weight of an impact modifier mixture with the following composition: 63.254 % by weight of PLEXIGLAS ® Y7H 36.746 % by weight of an impact modifier with core- shell I-shell II structure Core: 23% by weight, based on the impact modifier, of copolymers made from MMA and crosslinker Shell I: 47% by weight, based on the impact modifier, of copolymer made from the following: butyl acrylate, styrene and a crosslinker Shell II: 30% by weight, based on the impact modifier, of copolymer made from the following: MMA, styrene, butyl acrylate, ethyl acrylate and a crosslinker. The comparison used comprised a commercially available PLEXIGLAS®GS 233 produced by Röhm GmbH & Co. KG. The sheet made from PLEXIGLAS® GS 233 had the same dimensions as the sheet produced according to the invention. Formulation Comparison: of the Unit PLEXIGLAS ® GS 233 invention Charpy kJ/m2 18.4 34.7 Vicat ° C. 115.75 113.3 Modulus of elasticity 3.227 2.890 Light transmittance % 92.45 92.05 Charpy impact strength was determined ti ISO 179/1fU. The equipment is produced and marketed by the company Coesfeld. VICAT point was determined to DIN 306. Modulus elasticity was determined to ISO 527. The results show that production of an impact-modified cast material from MMA and copolymerized impact modifier was successful, the cast material having the usual advantageous properties of a PLEXIGLAS®GS material alongside markedly increased impact strength. These plates were colourless and clear, and did not show evidence of break-away from the glass plate or of adhesion to the glass plate. The mouldings of the invention are suitable for any of the applications which have hitherto used PLEXIGLAS®GS or XT. Its higher impact strength also makes it particularly suitable for application in balcony cladding (colourless, coloured, transparent or opaque), as material for sunbeds, for noise barriers on traffic routes and for hoardings.

<SOH> FIELD OF THE INVENTION <EOH>The invention relates to impact-modified polymethyl methacrylate (PMMA) and to a process for preparing the polymethyl methacrylate, and also to articles which can be produced from the impact-modified PMMA.

20040511

20070206

20050421

75225.0

HARLAN, ROBERT D

METHOD FOR PRODUCING AN IMPACT-RESISTANT POLYMETHYLMETHACRYLATE, AND CORRESPONDING POLYMETHYLMETHACRYLATE (PMMA)

UNDISCOUNTED

ACCEPTED

ACCEPTED

Load receiving means for a system for operating storage units

The invention relates to a system for operating storage units. The inventive system enables quick storage and removal therefrom and exhibits an optimum redundancy capacity. In order to counteract shortfalls in individual shelf operation devices, the inventive load receiving means acts as a support for a system for operating storage units, especially high shelf storage units, comprising means for mechanical connection to shelf unit, a lift device and a device arranged thereon for the transversal movement of loads, whereby the means for connection to a shelf unit has an electric drive unit with a pinion gear, driving a toothed rack and the toothed rack is arranged and embodied in such a way that when the pinion gear is rotated said toothed rack moves laterally outside the load receiving means, and the toothed racks are respectively provided with means which protrude from the ends thereof above the load receiving means, engaging into corresponding receiving devices on the shelf units.

1. A system for feeding store units, in particular high rack stores, consisting of a plurality of rack units that are designed and arranged in a room such that at least one equidistant alley is formed, at least one rack feeding device consisting of a traversing means adapted to be moved on rails in the longitudinal direction of the alley; a control unit for controlling the movement of the traversing means; means for determining the position of the traversing means in the alley; a load receiving means hanging on cables beneath the traversing means; means for determining the position of the load receiving means relative to the traversing means; means for mechanical connection of the load receiving means with a rack unit. 2. The system according to claim 2, wherein the means for mechanical connection of the load receiving means consists of a first and a second component, and wherein the first component is arranged at the load receiving means and gets into contact with the second component by means of shifting devices, wherein the second component is arranged at the tack unit and comprises receiving means that are designed like claws, into which the first component is adapted to engage. 3. The system according to claim 1, wherein the control unit in the traversing means comprises at least one processor and one memory, and wherein a data processing program is stored in the memory, which calculates, by using at least the position and/or the velocity data of the traversing means and of the load receiving means, a traversing path from a first place to a second place in the alley. 4. The system according to claim 3, wherein the control unit of a traversing means is in contact with the control unit of an at least second traversing means, and wherein the data of motion are exchanged. 5. The system according to claim 1, wherein the load receiving means comprises a lifting device. 6. The system according to claim 5, wherein the lifting device is operated via eccentric discs. 7. The system according to claim 5, wherein a device for transversal movement is provided on the lifting device. 8. The system according to claim 7, wherein the device for transversal movement comprises push elements that are designed like a telescope and that are adapted to be horizontally extended via a mechanical drive. 9. The system according to claim 8, wherein the push elements engage positively with one another and support one another in the extended state. 10. The system according to claim 9, wherein the push elements are designed to be equally extendable on both sides of the load receiving means. 11. A load receiving means for use in a system according to claim 1, comprising means for the mechanical connection with a rack unit, a lifting device, and a device for transversal movement of loads arranged thereon. 12. The load receiving means according to claim 11, wherein the means for connecting with a rack unit comprises an electric drive with a pinion that drives a gear rod, and wherein the gear rod is arranged and designed such that it extends laterally out of the load receiving means on rotation of the pinion, and wherein the gear rods each comprise means at their ends projecting over the load receiving means that engage with appropriate receiving devices at the rack units. 13. The load receiving means according to claim 12, wherein the means at the end of each gear rod substantially consist of two truncated conical bodies, the tapered end faces of which are connected with one another via a cylindrical body.

The subject matter of the present invention is a system for feeding storing units, in particular high rack units, by the assistance of a rack feeding device that always provides appropriate ground clearance beneath a load receiving means. For realizing rationalization effects in storage logistics, efforts have been undertaken to comprise individual storing units in space and to thus increase storage capacities. In order to be, nevertheless, capable of achieving favorable access times, i.e. storing and transferring times, it is necessary to provide, in addition to the designing of appropriate rack units, systems and concepts that enable the storing and transfer of goods of varying dimensions, varying weight and distribution of gravity in a target and time-orientated manner, and to provide appropriate redundancy capacities to safeguard against a possible failure of these rack feeding devices. It is therefore an object of the present invention to provide a system for feeding storing units which, on the one hand, is capable of achieving short storing and transferring times and, on the other hand, comprises an optimum redundancy capacity to encounter a failure of individual rack feeding devices as good as ever possible. This object is solved by the system for feeding storing units, in particular high rack stores, in accordance with the invention, consisting of a plurality of rack units that are designed and arranged in a room such that at least one equidistant alley is formed, further consisting of at least one rack feeding device that consists of a traversing means movable on rails in longitudinal direction of the alleys; a control unit for controlling the movement of the traversing means; means for determining the position of the traversing means in the alley; a load receiving means in accordance with the invention hanging on cables beneath the traversing means; means for determining the position of the load receiving means vis-à-vis the traversing means; means for mechanically connecting the load receiving means with a rack unit. Advantageous further developments of the present invention are characterized in the subclaims. The system for feeding storing units in accordance with the invention substantially consists of individual rack feeding devices with two dynamic components each, the traversing means and the load receiving means, as well as a static component, the rack store consisting of individual rack store units of any length and extension. The two dynamic components are connected with one another via dimensionally instable connecting elements, for instance steel cables, chains, or the like. As statically fixed component of the system according to the invention, a plurality of rack units, preferably high rack store units, are provided which are separated from one another by equidistant alleys and can be arranged in rooms of almost any size. Functioning Principle of the System According to the Invention By means of the system according to the invention, any goods can be efficiently stored in and transferred from a store and, due to the possibility of arranging a plurality of rack feeding devices in one rack alley and of also operating them simultaneously, short access time and thus high efficiency is achieved. After the building up of the high rack units, with both the number of storing units positioned on top of each other and the length of the storing units and the number of the respective alleys being optional, the rack feeding devices are arranged in the appropriate alleys. Due to the existing ground clearance beneath each traversing means and load receiving means it is possible to provide a traversing means with load receiving means arranged thereon at every single level. In a high rack store that comprises, for instance, 5 rack units and 6 rack levels, it is, for instance, possible to arrange a maximum of 6 rack feeding devices each in the 4 equidistant alleys and, in the case of need, to operate all 6 rack feeding devices in correspondence with a control program, so that a total of 24 rack feeding devices is available. In accordance with the invention, the storing of loads of any design, i.e. loads of varying sizes, varying weight and varying dimensions, is performed as follows: 1. Receiving of the load by means of a lifting device that is integrated in the load receiving means, wherein a shifting means allowing a transversal movement of the load is positioned at the lifting device; 2. “Centering” of the load on the load receiving means; 3. Simultaneously/subsequently to “2.”—Calculating of a traversing path starting out from the instant position to the target place; 4. Starting to move the traversing means in the direction of the target place; 5. Controlling of the course of motions of the traversing means and of the load receiving means; 6. Arrival at the target place (e.g. target rack unit), wherein both the traversing means and the load receiving means have completely terminated their course of motions; 7. Locking of the load receiving means on the level of the target rack unit by per-forming a positive or frictional connection with the adjacent rack units; 8. Rising of the load by means of the lifting device; 9. Transversal movement of the load by means of integrated shifting means; 10. Placing of the load in the appropriate target rack unit; 11. Lowering of the lifting device and reversion of the transversal movement; 12. Releasing of the anchoring in the rack unit; 13. Optional signal of readiness for the next storing/transferring order. In accordance with the invention, all rack feeding devices positioned in an alley are coordinated via an appropriate control means, i.e. a control system knows, due to appropriate sensor units, the respective state of movement and place of each rack feeding device at any time and is thus capable of preventing a collision of rack feeding devices that are moving simultaneously in an alley. To this end, each rack feeding device possesses control electronics that determine the state of movement or rest via appropriate sensors or measuring means and transmits same to a central control unit. For determining the respective state of movement, a rack feeding device comprises a control unit that is preferably positioned in the traversing means and controls or regulates both the drive of the traversing means and the drive of the cable coils. Furthermore, the traversing means comprises means to determine the relative position of the load receiving means hanging on the ropes vis-a-vis the traversing means, wherein the dynamic change of position of the load receiving means is in particular determined on the basis of the movement of the traversing means. The relative position of the load receiving means is, for instance, possible via a distance measurement between the traversing means and the load receiving means, or via appropriate angle measurements of the two units relative to one another, with the measurements being of the optical, mechanical, or electrical type. Since the measurement results with respect to the relative position of the load receiving means vis-à-vis the traversing means are implemented in appropriate calculation algorithms so as to avoid undesired oscillation situations of the load receiving means, a correspondingly high precision and quick determination of the measured value is required. A preferred determination of the measured value is, for instance, achieved by means of the goniometry method and appropriate goniometry devices, which are described in DE 101 22 142.8. Due to the control means that is preferably integrated in the traversing means, it is possible to move each rack feeding device between the starting and the target place such that substantially no pendulum oscillations of the load receiving means arise, but that merely one single amplitude oscillation arises, i.e. the load receiving means, due to its inertia, starts moving later than the traversing means and thus follows the traversing means. On braking of the traversing means the deceleration is controlled such that the load receiving means comes to stop at the target place substantially simultaneously with the traversing means. Due to the fact that the control system permanently knows the precise position of the traversing means and of the load receiving means hanging thereon, all the relative movements in an alley can be reliably adjusted with respect to one another, so that a collision of individual traversing means with load receiving means can be avoided. By the arrangement of a plurality of traversing means in one rack alley it is possible to replace failed track feeding devices at least partially in their function, so that accessibility to the loads and goods stored can always be guaranteed. Only on failure of the uppermost rack feeding device can the goods stored in the uppermost level no longer be accessed. On failure of a rack feeding device thereunder it is, however, always possible to fulfill the tasks from a rack feeding device positioned thereabove, so that even a total failure of several rack feeding devices will not result in a substantial restriction of the availability of the goods stored, unless the uppermost rack feeding device is affected. First Component Traversing Means The load receiving means hangs on dimensionally instable connecting elements, for instance steel cables, chains, or the like, on a traversing means. Every single traversing means is rail-bound on a particular level of the storage system according to the invention, which it never leaves. Only for storing or transferring the loads or for transporting to remote store units may appropriate rails also be positioned outside the rack store units. The following units are integrated in the traversing means: control unit; drive unit for the traversing means; drive unit for the cable coils; guiding unit for rail guidance In accordance with the invention, a control unit is integrated in every traversing means, and all control units of the traversing means available in one alley are connected with one another via appropriate communication interfaces. The communication of the individual control units may, for instance, be performed wireless via a radio signal, or in an optical manner. The coordination and adjustment of the course of motions of the respective rack feeding devices is advantageously performed by a central control unit. This central control unit may be positioned stationary at a rack unit or else in a mobile manner at a selected traversing means. In addition to appropriate means for receiving corresponding movement data, each control unit comprises at least one processor with a computer program stored therein, by means of which, on the basis of the position data determined for the traversing means and the load receiving means, the course of motions of these two units to the target place is controlled. Control Unit In order to avoid undesired oscillating motions of the load receiving means during movement, various methods may be performed. In the scope of a control loop it is, for instance, possible to compare actual values with corresponding desired values of a course of motions of the load receiving means calculated pursuant to the criteria of optimum control, and to perform a continuous control. With another method it is possible, starting out from an actual position of the load receiving means, to always calculate a new traversing path and to determine the cable lengths at the cable coils and the deceleration or acceleration of the traversing means accordingly. To avoid oscillating motions, the system according to the invention may have an influence on at least two setting parameters: the acceleration or deceleration of the traversing means and the modification of the cable length in the front or rear region of the load receiving means. The program algorithms stored in the control unit modify, according to need (i.e., for instance, taking into account the present state of the system, in particular the position and velocity of the load receiving means, the position of the target place, the position and velocity of the other traversing means in the alley, the present cable lengths, and the cable lengths at the target place), the parameters velocity and acceleration of the traversing means and the cable lengths, where necessary each in the front and rear regions of the load receiving means. Path Measuring Device for Traversing Means For determining the respective position of the traversing means, appropriate path measuring systems are provided on the traversing means or in the track unit serving to transport the traversing means, respectively, said path measuring systems enabling to determine the precise position of each traversing means in an alley. These path measuring systems may, for instance, be based on appropriate induction sensors, or may, by means of laser beams that are reflected by a reference plate, determine data that are transmitted to the control unit for further processing. From the data of the position determination or modification, respectively, such obtained, the velocity and acceleration/deceleration and their modification can be calculated by means of appropriate data processing programs, so that the relative state of movement of the traversing means vis-à-vis the rack unit is always known. Other path measuring systems that are based on an optical functioning are also possible. Drive Unit of the Traversing Means In order to guarantee a reliable drive of the traversing means, these are expediently equipped with wheels, so that a corresponding force/moment transmission on a rail can be performed. Expediently, at least two pairs of wheels (i.e. in a front region and a rear region) are provided at the traversing means, with both pairs of wheels advantageously being designed to be driven so as to be able to realize a reliable drive performance even with heavy loads. Advantageously, the rail is provided with a substantially plane surface on which the drive wheels can roll. It is, however, also possible to design the rails as gear rods, so that appropriate gearwheels are used for driving. Furthermore, it is possible to perform the driving of the traversing means via appropriate conveyor belts. If the drive unit is, for instance, integrated in a rack unit and the traversing means is driven via appropriate drive belts or bands, the loading weight to be accelerated or decelerated, respectively, can be reduced by the mass of the drive unit. The traversing means according to the invention is driven by at least one electric motor that transfers, via appropriate gear rods, the driving torque to at least two driving wheels and thus accelerates or decelerates the traversing means. Advantageously, at least one side of the traversing means according to the invention is guided over an appropriate rail guiding, so that track fidelity within a certain tolerance is guaranteed over the entire length of the rail. Cable Coils at the Traversing Means For rising and lowering of the load receiving means, four coils are expediently provided on which the dimensionally instable connecting element is wound up. In order to always guarantee an orientation of the load receiving means that is desired in correspondence with the control, at least two cable coils are driven synchronously; expediently, the two rear and front cable coils each are synchronized. It is, however, also possible to only position two coils at the traversing means, for instance, to reduce the weight or to avoid means for synchronizing the cable coils. Inertia Brake The load receiving means is fixed to the traversing means at four dimensionally instable connecting elements, preferably steel cables, and the respective length of extension can be determined by cable length transmitters that are integrated in the respective cable coils as well as by an appropriate goniometry device. To avoid, however, damage of the individual mechanical elements in the load receiving means by an undesired collision of the load receiving means with the traversing means, an appropriate device is provided at the load receiving means and at the traversing means, said device effecting a reliable deceleration and stopping of the cable coils. This inertia brake consists of two components, a first component positioned at the traversing means and a second component provided at the load receiving means. The first component advantageously consists of a truncated conical recess and a switching device positioned thereabove in the center, said switching device being directly connected to the current supply of the electrically driven cable coils. The second component has a truncated conical body that is positioned, supported by a spring, on a bolt and rests substantially with positive fit in the truncated conical recess after having been inserted therein. In another preferred embodiment of the inertia brake according to the invention, a sleeve-like device incorporating electrical switching elements is provided at the traversing means, and a mandrel-like device is positioned as a counterpart at the load receiving means, said mandrel-like device successively actuates the corresponding electrical switching elements on penetrating into the sleeve-like device and thus, on arriving at a particular switch, completely stops the drive of the cable coils. Expediently, these switches may be designed as magnetic switches that are positioned around the periphery of the sleeve-like device and thus successively trigger corresponding contacts on penetration of the mandrel-like device. A program means connected therebehind evaluates these contact signals and successively decelerates the drives of the cable coils, so that these have come to a stop on a complete penetration of the mandrel-like device in the sleeve-like device. A mechanical abutment contact may expediently be provided additionally, said abutment contact abruptly stopping the drives of the cable coils on a complete penetration of the mandrel-like device. Second Component Load Receiving Means The load receiving means consists of a plurality of assemblies, the lifting device, the device for transversal moving, and the arresting means. Lifting Device To realize the required lifting motion, the load receiving means comprises a lifting device in accordance with the invention. In order to be able to reliably and safely place the load on the load receiving means, possibly a rack store unit, and on any transfer place, it is necessary to lift or lower, respectively, the load appropriately. As a technical prerequisite for a reliable and safe lifting and lowering of a load it has to be ensured that both the load receiving, i.e. the lifting of the load, is effected with a slowly increasing lifting force, and the lowering of the load is also performed without any jerks, i.e. with a continuous decreasing of the lifting force, so that also sensitive loads such as pallets with glasses or sensitive electronic devices will not be damaged by possible impacts during lowering or lifting. When providing a lifting device it is, due to the restricted space capacity on the load receiving device, necessary to realize the lifting device with as small dimensions as possible and to keep the weight low so as to maximally exhaust the loading capacity of the load receiving means. In accordance with the invention, the lifting device is realized by an eccentric disc that is driven via a shaft. Expediently, a load carrying platform is formed at the load receiving means, said load carrying platform being, at its bottom, mounted on eccentric discs and comprising a lateral guidance, preferably via appropriate pins running in oblong holes or through prisms sliding in appropriate angular recesses. By an appropriate contour design of the eccentric discs it is possible to optimally adapt the respective lowering and lifting velocity since the course of motions can be influenced by the shaping of the eccentric disc. A plurality of such eccentric discs is expediently arranged below the load carrying platform, so that the load is distributed substantially regularly to the corresponding eccentric disc. In another embodiment of the lifting device according to the invention it is possible to use, instead of the eccentric discs, so-called cams or camshafts that similarly lift or lower the load, respectively. In a further embodiment of the lifting device according to the invention, the lifting or the lowering may be effected via an appropriate hydraulic or pneumatic device. Here, it must always be taken care that smooth lifting and lowering is performed via appropriate balancing means. In particular with hydraulically or pneumatically operated lifting devices there is the danger that loads with an eccentric center of gravity charge the individual lifting devices with different strength and that smooth lifting or lowering will thus not be possible. In a further embodiment of the lifting device according to the invention, a lifting or lowering motion can be performed via a gear rod with an appropriate pinion, or a plurality of gear rods and appropriate pinions. A smooth lifting or lowering motion also has to be taken care of here so as to avoid especially a canting of the gear rods with the pinions. In a further embodiment of the lifting device according to the invention, spindles, preferably four spindles, are arranged below the load carrying platform, and the rotation of the individual spindles relative to one another is adjusted via a coupling means, so that a smooth lifting or lowering motion can be guaranteed. Device for Transversal Movement In order to store or transfer the load positioned on the load receiving means in/from the corresponding store units, i.e. to transport load from a place positioned laterally next to the load receiving means onto the load receiving means, it is necessary to integrate a device for transversal movement in the load receiving means. In accordance with the invention, a horizontally shiftable platform is arranged on the load receiving means, on which push elements that are engaging each other like a telescope are designed such that small dimensions exist in the state of rest, on the one hand, and that both sides of the load receiving means can be equally fed in the load-receiving state, on the other hand. The static loading of the push elements will have to be introduced in the load receiving means such that a reliable and safe operation can be ensured even when the transversal shifting means has been extended to its maximum. Advantageously, the transversal shifting means is constructed of a multiplicity of individual elements adapted to be telescoped and operatively interconnected via drive elements, wherein these drive elements can expediently be cables, tie rods, or other dimensionally instable drive elements. In another preferred embodiment of the transversal shifting device according to the invention, the drive of the individual elements is performed via gear rods and appropriate pinions, with the gear rods being provided as movable elements and being driven via appropriate pinions. Advantageously, a lateral distance is to be bridged by the transversal shifting means which corresponds at least to the breadth of the load receiving means according to the invention, advantageously even exceeds this dimension. Arresting Means After having arrived at a target place in a store rack unit or a corresponding transfer/store unit, the load receiving means according to the invention is connected with both directly adjacent store rack units via an appropriate mechanical arresting means such that a transfer or storing of loads, in particular heavy loads, becomes possible. The load receiving means will have to be connected with the respective store rack units such that also dynamic forces, although unintentionally, for instance an oscillating of the load due to immovable parts, can always be absorbed since the arresting means according to the invention reliably fixes the load receiving means to the rack units during transfer and storage. Advantageously, the respective arresting means consist of two complementary components, a first component provided at the store rack units as receiving means, and a second component being arranged at the load receiving means. In accordance with the invention, the load receiving means is fixed with at least two, preferably four arresting means, wherein the arresting means are advantageously pushed into appropriate receiving units that are designed like claws, and remain there. The spreading of the arresting means is expediently performed via suitable devices such as gear rods and pinions, pneumatic/hydraulic means, or swiveling devices adapted to perform an appropriate locking. The following technical side conditions have to be met with the design of the arresting means: radial centering assistance; axial centering assistance; vertical degree of freedom; vertical assumption of force. In accordance with the invention, four arresting means are provided at the load receiving means, each of which has a maximum distance to the others and which are designed to be synchronously lockable in pairs so as to avoid a canting of the load receiving means between the store rack units. A preferred embodiment of the system according to the invention will be explained in more detail in the following by means of drawings. The drawings show: FIG. 1 a schematic side view of the rack feeding device according to the invention; FIG. 2 a schematic sectional view through the drive unit of the traversing means; FIG. 3 a schematic sectional view of the cable coils on the traversing means; FIG. 4 a schematic sectional view through the traversing means with cable coils and drive unit; FIG. 5 a sectional view through the lateral guidance of the traversing means; FIG. 6a a sectional representation of the lifting device; FIG. 6b a top view of the lifting device; FIG. 7 a schematic side view of the device for transversal movement in accordance with the invention; FIG. 8 a side view and a top view of the arresting means; FIG. 9 a schematic side view and sectional representation of the inertia brake. The rack feeding device 1 according to the invention shows, in accordance with FIG. 1, the traversing means 100 with the load receiving means 200 hanging underneath on cables 141a, 141b. The traversing means 100 with the schematically represented control unit 120 is mounted to be movable on rails 164, with the rails 164 being arranged in the respective rack units (not illustrated) at different levels. In addition to the steel cables 141a to 141d (141a and 141b are illustrated) there exists a connection between the traversing unit 100 and the load receiving means 200 via the goniometry system 170a, 170b, which is effected by means of dimensionally instable connecting means 171a, 171b. In order to obtain a certain clearance for the transport of the load 50, stationary rod-like devices 172 are positioned on the load receiving means 200, to which the dimensionally instable connecting elements 171a, 171b are inseparably fastened. In the state of the traversing means 100 and of the load receiving means 200 illustrated in FIG. 1, the load receiving means 200 is positioned at a distance below the traversing means 100, so that the inertia brake 150 does not have any effect. When the cable coils 142a, 142b are actuated and wind up the cable 141a and 141b further than in the state shown, the inertia brake 150 is activated, and on obtaining a certain distance between the load receiving means 200 and the traversing means 100, the drive of the cable coils 142a, 142b will be stopped. FIG. 2 shows a schematic sectional representation of a drive unit of the traversing means 100. The electric drive 132 that is illustrated in part is connected to a transmission 131, and the drive moment is transferred from the transmission 131 to the drive wheels 165a, 165b by means of gear rods 133a, 133b. The gear rods 133a, 133b are advantageously designed as cardan rods and are thus adapted to offset certain differences in level between the rails 164 and the drive wheels 165a, 165b arranged thereon. For lifting and lowering the load receiving means 200, at least two pairs of cable coils 142a, 142b (142c, 142d are not illustrated) are arranged on the traversing means 100, on which four cables 141a, 141b, 141c, and 141d are wound up. The cables 141a, 141b, 141c, and 141d are expediently connected inseparably with the load receiving means 200, and the cable coils 142a, 142b are synchronized with one another via a drive 144, and the cable coils 142c, 142d are also synchronized with one another via an appropriate drive (not illustrated). The respective cable coil drives are, like the drive of the traversing means 132, controlled by the control unit 120. In the sectional representation according to FIG. 4, the arrangement of the drive unit 130 with the respective components (drive unit 132, transmission 131, gear rods 133a, 133b), and the cable coils 142a, 142b and their drive 144 are illustrated together with the control unit 120. In the detailed view according to FIG. 5, the lateral guidance of the traversing unit 100 is shown, which is arranged in the front and rear region of the traversing means 100. For lateral guidance, the rail arrangement 164 comprises a rail bead 162 leading vertically downwards, at which two guide wheels 161a, 161b adhere to. These guide wheels 161a, 161b are mounted on bolts 166 via appropriate roller bearings 163, which are connected via a fastener sheet 167 to the traversing means 100. By the lateral guidance of the traversing means it is prevented that the drive wheels 165a, 165b, 165c, 165d leave the rails 164 or collide with individual rack units. The lifting device 210 integrated in the load receiving means 200 comprises four eccentric discs 211a, 211b, 211c, and 211d that are arranged in pairs on shafts 116, 117. For driving the shafts 116, 117, they each comprise pinions 213a, 213b that are connected with one another by means of drive chain 214 and are jointly driven by the drive unit 212 via an appropriate drive chain 215. When the drive unit 212 is set in motion, it drives the drive chain 215, so that the shaft 17 is directly set in rotation and simultaneously sets the shaft 216 in rotation via the drive chain 214. Both rotational motions of the shafts 216 and 217 are synchronized by the arrangement illustrated in FIG. 6, so that the rotational motions of the eccentric discs 211a, 211b, 211c, 211d are also taking place synchronously. In order to ensure a lateral guidance of the load carrying platform 219, appropriate guiding elbows 218a, 218b are provided at the two opposite sides of the load carrying platform 219. Expediently, a rail element of trapezoid design, which is arranged at the load carrying platform 219, runs over guidance rolls 220a, 220b, 220c, 220d that are illustrated in FIG. 6 and are positioned on the frame of the load receiving means 200, so that merely a degree of freedom in the vertical direction exists for the movement of the load carrying platform 219. In the device for transversal movement 230 illustrated schematically in FIG. 7, the individual elements 231, 232, and 233 are, for reasons of clarity, represented on different levels and not—as technically realized—on one level. The three individual elements 231, 232, 233 each are connected with one another via dimensionally instable connecting elements 234 and 235. The lowermost level illustrated in FIG. 7, which is designated as individual element 231, is arranged on the load carrying platform 219 and rigidly connected therewith. The individual element 232 is positioned inside the individual element 231 and is connected therewith via the connecting element 234. The individual element 233 is positioned inside the individual element 232 and is connected therewith via the connecting element 235. The connecting element 235 consists of two branches, each of which is connected to the individual element 231 and the individual element 233, and is deflected via direction changing elements 236 that are arranged at the individual element 232. The connecting element 234 that is designed as drive element consists of one branch only and connects the individual elements 232 and 231 with one another. The connecting element 235 is also deflected via appropriate direction changing elements 237 that are arranged at the respective end of the individual element 231. On rotation of the drive element 238 in the direction indicated by the arrow, the connecting element 234 is deflected via the direction changing element 237 also in the direction of the arrow and exerts a force on the individual element 232, so that this also starts to move in the direction of the arrow. By the movement of the individual element 232 in the direction of the arrow, the connecting element 235 is also conveyed by the direction changing elements 236, so that the individual element 233 also starts to move in the direction of the arrow. As soon as the drive 238 stops, the respective transversal movement of the individual elements 232 and 233 is also stopped, and the individual elements 232, 233 start to move in the opposite direction when the direction of rotation of the drive 238 is reversed. Expediently, the connecting elements 234, 235 are designed as a chain. The arresting means 250 according to FIG. 8 shows two elements 251a, 251b that are designed in the form of arbors, comprising at their one end a gear rod profile each and at their other end arresting elements 253a, 253b, 254 adapted to engage in corresponding arresting means receiving means 255 positioned at the rack units 2. In accordance with FIG. 8, the arresting means are formed of two pyramid-truncated bodies 253a, 253b each, the tapered faces of which are connected with one another via a cylindrical body 254. The surface shells of the pyramid-truncated bodies 253a, 253b serve as a centering assistance for the corresponding arresting means receiving elements 255. On actuation of the drive 252, the arbor-like elements 251a, 251b perform an opposite movement and spread the arresting means 253a, 253b, 254 into the arresting means receiving elements 255, so that the load receiving means 200 is positively connected with the thus adjacent rack units 2 (not illustrated). In order to be able to detect the time of arresting, the drive 252 is, for instance, equipped with an appropriate momentum sensor, or sensors report a corresponding touching contact between the arresting means receiving elements and the cylindrical body, so that the drive 252 receives a corresponding signal and stops a further spreading of the arbors 251a and 251b. FIG. 9 illustrates the inertia brake 150 according to the invention, which prevents a collision of the load receiving means 200 with the traversing means 100. To this end, a bolt 157 is positioned at a suitable position on the load receiving means 200, said bolt being preferably welded to the load receiving means 200. A truncated conical body 151 is slidingly arranged at the bolt 157, with a support of the truncated conical body 151 being performed via a coil spring 156, and the movability of the truncated conical body 151 being ensured via a sliding bushing 153 and a disc 155a positioned directly thereto. In order to prevent loosening of the truncated conical body 151 from the bolt 157, the truncated conical body 151 is secured with a disc 155b and a corresponding nut 158. A sensor 159 is positioned adjacent to the truncated conical body 151, said sensor being aligned and designed such that a vertical movement of the truncated conical body 151 triggers a corresponding signal that is processed in the control unit. A truncated conical recess 152 is formed at the traversing unit 100, the contour of which is the complementary of the truncated conical body 151. In the case of a corresponding vertical movement of the load receiving means 200, the truncated conical body 151 immerses, on achieving a certain distance between the load receiving means 200 and the traversing means 100, in the truncated conical recess 152 and snuggles thereagainst with positive fit. By the sliding bearing of the truncated conical body 151 on the bolt 157, there is effected, on continuation of the vertical movement of the load receiving means 200, a shifting movement on the bolt 157, opposite to the spring force of the coil spring 156, so that the truncated conical body 151 performs a relative movement vis-a-vis the sensor 159. The signal produced by this movement of the truncated conical body is processed in the control unit 120 and results in a stopping of the cable coil drives 144. In order to nevertheless effect a reliable stopping of the cable coil drives 144 on failure of the sensor 159, a switching element 161 is furthermore provided, said switching element 161 being arranged at the traversing means 100 such that, on a further vertical movement of the load receiving means 100, the nut 158 that is positioned on the bolt 157 abuts on a switching arm 160 and abruptly interrupts the electrical supply of the coil drives.

20041015

20110322

20050324

68450.0

KEENAN, JAMES W

SYSTEM FOR FEEDING STORING UNITS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Microreactor system

The invention related to a microreactor system for the continuous synthesis, which provides defined reaction chambers and conditions for said synthesis, as well as to the uses of said microreactor in carrying out a chemical reaction. According to said invention, (a) said mircoreactor system (11) is of modular design, (b) a processing unit (10) is made up of processing modules which are connected to each other by frictional engagement and (c) the fluid connections in said processing unit (10) can be obtained by the frictional connection of said processing modules.

1-29. (canceled) 30. Micro-reactor system (11) for continuous synthesis, providing defined reaction spaces and conditions for the synthesis, wherein the modularly constructed micro-reactor system (11) comprises (a) a processing unit (10) assembled from processing modules (38, 40, 42, 44) which can be non-positively connected with one another, fluid connections between adjacent processing modules (38, 40, 42, 44) and/or between the processing modules (38, 40, 42, 44) and the micro-reactor system (11), which can be achieved by the non-positive connection of the processing modules (38, 40, 42, 44), characterized in that the fluid connections are formed by fluid-carrying connecting elements (50), with the two ends of the fluid-carrying connecting elements being insertable in suitable connection openings (54) of two adjacent processing modules (38, 40, 42, 44) and/or of a processing modules and the micro-reactor system (11) for transporting fluid media through the processing modules and/or the micro-reactor system. 31. Micro-reactor system (11) of claim 30, characterized in that the connecting elements (50) have an exterior cross-section that is tapered on one end or on both ends. 32. Micro-reactor system (11) according to claim 31, characterized in that the connecting elements (50) for connecting two opposing, in particular circular, connection openings (54) are formed as connecting tubes having a conical taper on both ends. 33. Micro-reactor system (11) of claim 31, characterized in that the connecting elements (50) contact an edge of the connection openings (54) along a line. 34. Micro-reactor system (11) according to claim 30, characterized in that the connecting elements (50) are releasably or non-releasably connected with the processing modules (38, 40, 42, 44) and/or the Micro-reactor system (11). 35. Micro-reactor system according to claim 30, characterized in that the non-positive connection is implemented via mechanical, hydraulic, pneumatic and/or electrical elements. 36. Micro-reactor system according to claim 30, characterized in that the processing unit (10) is fitted in a holding device (12). 37. Micro-reactor system according to claim 30, characterized in that the holding device comprises at least to support plates (14, 16), between which the processing modules (38, 40, 42, 44) can be clamped. 38. Micro-reactor system according to claim 30, characterized in that the support plates (14, 16) have connection openings (54) and/or integrated connecting elements (50) on their inside facing the processing modules (38, 40, 42, 44), and that the connecting elements (50) in conjunction with corresponding connection openings 54 disposed on the top side and/or bottom side of the processing modules (38, 40, 42, 44) are capable of establishing a fluid connection. 39. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) can be positioned between the processing modules by using a device (58). 40. Micro-reactor system of claim 39, characterized in that the device (58) itself is used for sealing the fluid connection between two processing modules. 41. Micro-reactor system of claim 39, characterized in that the positioning device (58) is made of a plastically deformable or an elastic material. 42. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) are formed of a metal, in particular stainless steel. 43. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) are formed of glass, ceramic or semiconductor materials. 44. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) are made of plastic. 45. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) formed on the basis of hard materials are coated with a plastically deformable material or an elastically deformable material. 46. Micro-reactor system according to claim 30, characterized in that the connecting elements (50) are made of the same material as the processing modules (38, 40, 42, 44). 47. Micro-reactor system according to claim 30, characterized in that the connecting system includes sealing elements (60) for completely sealing the connection openings (54). 48. Micro-reactor system according to claim 39, characterized in that the positioning device (58) is formed in particular as a plate and is arranged between the processing modules (38, 40, 42, 44) and/or between the processing modules (38, 40, 42, 44) and the support plates (14, 16). 49. Micro-reactor system according to claim 48, characterized in that the positioning device (50) can be used to align the connecting elements (50) and/or sealing elements (60) relative to the processing modules (38, 40, 42, 44) and/or the support plates (14, 18), respectively. 50. Micro-reactor system according to claim 37, characterized in that the exterior sides of the support plates (14, 16) include connecting sites (22) for peripheral devices, in particular a reactant feed (24, 26), a withdrawal device for the product (34), or thermostats (28, 30). 51. Micro-reactor system according to claim 30, characterized in that the micro-reactor system includes a sensor unit (62) as a self-contained interchangeable functional unit. 52. Micro-reactor system of claim 51, characterized in that the sensor unit (82) includes sensors (40) for acquiring measurement values, such as temperature, pressure, flow, radiation, concentration, distance, viscosity and the like. 53. Micro-reactor system according to claim 30, characterized by a force sensor for measuring the clamping force of the holding device (12). 54. Micro-reactor system according to claim 30, characterized by a distance sensor (46) for measuring the distance between the support plates (14, 16). 55. Micro-reactor system according to claim 30, characterized in that the micro-reactor system includes a control unit (68) for monitoring, operating, regulating and/or controlling the synthesis process flow. 56. Micro-reactor system according to claim 30, characterized in that the micro-reactor system includes at least two processing units (70, 72) connected in parallel and/or in series. 57. Micro-reactor system according to claim 30, characterized in that two or more processing units that can be individually provided with processing modules can be connected successively in series, so that the fluid flow of the entire reaction chain can be centrally monitored, controlled, regulated and/or operated from one control unit (66). 58. Use of a micro-reactor according to claim 30 for carrying out a chemical reaction.

The invention relates to a micro-reactor system for the continuous synthesis with the features recited in the preamble of claim 1. A successful chemical synthesis—in both inorganic and organic chemistry—requires strict adherence to numerous reaction conditions. For example, the temperature, the concentration of the reactants, their retention time and hence the reaction time in the reactor, the pressure and the medium in which the reaction is to take place, have to be optimized in order to obtain the highest possible yield, while also taking into consideration their cost-effectiveness. The reaction mixture must almost always be post-processed for purifying the reaction products. If the individual processing steps are performed in a stationary reactor system, then a number of processing steps are required during the synthesis which typically have to be carried out manually, which is time-consuming and requires additional personnel. Stationary or semi-stationary syntheses (in batch or semi-batch reactors) have the disadvantage that the operating parameters derived from a known system cannot always be applied to a larger starting batch. The larger starting batch must frequently be optimized from the start, for example, due to problems associated with dissipation of the reaction heat. One solution is provided by so-called continuous synthesis processes, where the reactants are introduced into a transportable medium, where they react with each other, with a product being withdrawn at another location—optionally after additional processing steps. Such systems have so far been mainly employed in large-scale industrial operations that produce basic chemical materials. The starting batches in laboratory-scale experiments or in the production of special pharmaceutical products are mostly too small to perform the syntheses common in large plants. During the past years, micro-reactor systems have been developed that advantageously employ a continuous process flow, while being configured for a much smaller total throughput. The micro-reactors offer a defined reaction space which frequently includes additional structural elements that affect the reaction conditions. For example, EP 1 031 375 A2 discloses a micro-reactor for carrying out chemical reactions that has individual, freely exchangeable micro-structured elements. Micro-reactors of the aforedescribed type can advantageously carry out process syntheses under continuous synthesis conditions, which thus far have been known only from large-scale facilities. The thermal aspect of the reaction can be controlled with hitherto unmatched precision, because the walls between the passageways transporting the reaction medium and a heat exchange medium can frequently be made very thin. The small volumes, where very small material quantities can react with each other, allow a very safe process control, in particular when carrying out critical or dangerous syntheses. Such micro-reactors have in common that they can consist of individual processing modules designed for different tasks. The processing modules provide defined reaction spaces where the reactants are mixed and react with each other by thermal initiation or control. Additional processing modules retain the reaction medium and allow post-processing by, for example, extraction, phase separation or annealing. The individual processing modules must be in fluid communication with each other. A micro-reactor system is described in WO 95/26796 to Bard et al., which is based on the aforedescribed modular concept. The individual processing modules are mounted on the side of a support structure. The support structure includes small channels that provide a fluid connection between the individual processing modules of the micro-reactor. For example, a reactor module, a separation module and an analyzer module are sequentially arranged on the support structure. The connecting channels of the disclosed micro-reactor system are disadvantageously fixedly integrated in the support structure, representing a fixed connection system. This limits the flexibility of the micro-reactor system which hence cannot be adapted to the often different requirements of the chemical synthesis. Ehrfeld et al. (WO 00/62018) describe a micro-reactor system that is composed of individual processing modules. The individual processing modules are provided with connecting elements via a connection system. The connecting elements are non-positively connected during assembly in such a way that fluid channels leading from one processing module to the next are connected with each other so as to form a seal to the outside. Connecting elements are considered to be formfittingly connected when they represent an integral part of the modules. A distinction is made between formfitting and non-positive connections. With the first type of connections, the force is transmitted as a result of their form or shape, whereas with the latter type of connections, the force is transmitted through friction forces (K. H. Decker: “Machine Elements—Design and Computation), 10th printing, Carl Hanser Verlag, Vienna, 1990, p. 212). This publication does not suggest the integration of sensors and actuators in the system which is required for regulation and control. It is therefore an object of the invention to provide a micro-reactor system that is made of easily exchangeable processing modules and that includes a very simple and flexible connection system for the media to be transported in the micro-reactor system. The micro-reactor system should preferably be compact, easy to operate and adapted to be automated, and the sensor and actuator units for the system control should be readily adaptable to different requirements. The object is solved by the micro-reactor system for continuous synthesis with the features recited in claim 1. A compact and highly flexible micro-reactor system that can be optimally adapted to the different requirements of the chemical synthesis can be provided by a) constructing the micro-reactor system in a modular fashion, b) assembling a processing unit from processing modules which can be non-positively connected with each other, and c) establishing the fluid connections of the processing unit through the non-positive connection of the processing modules. In a preferred embodiment of the invention, the non-positive connection between adjacent processing modules can be achieved by connecting elements that are releasably or non-releasably connected with the processing modules and/or with the micro-reactor system, wherein fluid-conducting connections between the processing modules themselves or between the processing modules and external connections of the micro-reactor system can be provided by these connecting elements. With this approach, the fluid connection for the process between the processing modules themselves and with the external connections of the micro-reactor system is safe and always reproducible. Preferably, support plates are provided which preferably have connection openings and/or integrated connecting elements on the interior sides facing the processing modules. Therefore, the connecting elements are either already a fixed component of the support plates or are placed at a suitable location during assembly of the processing unit. Preferably, an additional holding device transmits the clamping forces required for achieving the non-positive connection to all connecting elements of the connection system. The connecting elements are hereby plastically or elastically deformed so as to provide a reliable seal between the connection openings and the connecting element. The clamping forces can be generated by mechanical, hydraulic, pneumatic and/or electric elements. The connecting elements for connecting two opposing and preferably circular connection openings are preferably formed as connecting tubes having two ends with respective conical end sections, i.e., the connecting tubes are shaped as a double-cone. Other embodiments can also be envisioned. For example, the connecting elements can have the shape of a bi-pyramid, so that they can be sealingly inserted into four-sided or square connection openings. With these embodiments, the connecting element and the edge of the connection openings contact each other along a line, resulting in large sealing forces and hence a reliable seal. The connection system also includes sealing elements for completely sealing the connection openings, if there is no fluid medium be transported through these openings. These sealing elements can have the same basic construction as the connecting elements, except that they do not provide a fluid connection. According to another preferred embodiment of the invention, a preferably plate-shaped positioning device is disposed between the processing modules and/or between the processing modules and the support plates, which can be used to align the connecting elements and/or sealing elements relative to the processing modules and/or support plates. This arrangement facilitates positioning and installation as well as removal of individual processing modules. The connecting elements are preferably fabricated of the same material as the processing modules to reduce the risk of an adverse interaction with the fluid media, reactants and products and to eliminate sealing problems caused by dissimilar thermal expansion coefficients. In particular, they can be made of inert materials, such as metal, glass, ceramic, semiconductor materials or plastic. Large clamping forces can advantageously be tolerated by using harder materials. Preferably, the connecting element is coated with a plastically deformable material or an elastically deformable material, in particular a metal, thus further improving the sealing characteristic. All potential embodiments of the connecting elements and the sealing elements have in common that very short fluid connections can be realized between the adjacent processing modules or between the processing modules and the connecting plate. Such short fluid connections improve the process reliability of the described micro-reactor system. The exterior surfaces of the support plates include different connecting sites to provide a fluid connection from the processing units to the periphery for example feed units for feeding the reactants, withdrawal devices for removing the products or thermostats. A sensor unit can also be associated with the individual modules of the micro-reactor as self-contained exchangeable functional units. The sensor unit includes sensors for acquiring measurement values, such as temperature, pressure, flow, radiation, concentration, distance or viscosity of the medium. In particular, a force sensor can be provided for measuring the clamping forces of the holding device, or a distance sensor can be provided for measuring the distance between the support plates. The synthesis can be regulated or controlled based on the measurement values provided by the sensor unit. A user can control, optionally adjust and also automate particular process flows by using a control unit. Other preferred embodiments of the invention are recited as additional features in the dependent claims. Embodiments of the invention will now be described with reference to the appended drawings. It is shown in FIG. 1 a block diagram of a micro-reactor system for continuous synthesis, including a processing unit (10) with four processing modules, connecting elements (50) and sealing elements (60), a holding device (12) with a bottom plate and a top plate (14, 16) and a clamping element (18), as well as fluid connections for reaction media, (24, 26, 32, 34) and heat carrying media (28:30), and sensor unit (46, 48); FIG. 2 a schematic cross-sectional view through a processing unit in the region of two processing modules; FIG. 3 two schematic cross-sectional views of conical connecting elements of the connection system; FIG. 4 a schematic diagram of a micro-reactor system with a control unit for a single-stage synthesis; and FIG. 5 a schematic diagram of a device for a two-stage synthesis with two micro-reactor systems and a control unit. FIG. 1 shows schematically a processing unit 10 representing a central component of a micro-reactor system 11 according to the invention for continuous synthesis. The processing unit 10 includes the individual processing modules 38, 40, 42, 44. The processing unit 10 is encompassed by a holding device 12 with two support plates 14, 16 and at least one clamping element 18. The individual processing modules 38, 40, 42, 44 of the processing unit 10 are clamped in the holding device 12 in a manner described below. Preferably, a clamping element 18 is provided to produce uniform clamping forces. The clamping element 18 provides the necessary clamping force for reliably positioning and sealing the processing modules 38, 40,42, 44 by mechanical, hydraulic, pneumatic and/or electrical means. Connecting sites 22 for providing a fluid connection of the processing unit 10 are provided on the periphery of the support plates 14, 16. In the present example, two feed units are provided for feeding a first and/or second reactant (reactant feed 24, 26). Two thermostats 28: 30 are provided for controlling the temperature of the processing modules 38, 40, 42, 44 by supplying or removing a suitable heat exchange medium. Another connecting site 22 is provided for connecting a feed unit that can introduce an additional medium for post-processing of the reaction mixture (additional medium feed 32). A withdrawal device 34 located in the region of the support plates 16 for removing the products and/or the additional post-processing medium is also schematically indicated. The various processing modules 38, 40, 42, 44 are typically made of metal (in particular stainless-steel), glass, ceramic, a semiconductor material (in particular silicon-based) or plastic. The materials are selected based on their intended use. An interior surface of the processing modules 38, 40, 42, 44 is micro-mechanically structured in a known fashion, as described for example in EP 1123 734 A2. At least one channel extending through the system is connected with an inlet and an outlet of the processing modules 38, 40, 42, 44 (connection openings 54). The various reaction spaces cooperate to form the volume in which the desired synthesis is performed. In addition to the channels carrying-the reaction media there are provided additional structures that transport, for example, the heat exchange medium received from the thermostats 28, 30 close to the reaction medium. The thermal reaction conditions can be precisely adjusted due to the very small wall thickness between the channels for the heat exchange medium and the reaction medium. In addition, corresponding connection openings 54 in the processing modules 38, 40, 42, 44 have to be provided for the heat exchange medium. The exemplary processing unit 10 depicted in FIG. 1 includes a total of four processing modules 38, 40, 42, 48. The two reactants are initially fed by the feed units 24, 26 to a first processing module 38, where the two reactants are mixed and react with each other, with the temperature controlled by the thermostat 21. (The design of the processing modules 38 is described, for example, in EP 1 123 734 A2). The reaction medium is introduced via the connection system, which will be described below in more detail, into a second processing module 40 and a third processing module 42, which are used to provide a certain retention time and reaction time for the reaction medium. The reaction time can be adjusted by varying the number of employed processing modules that define the reaction time. The second and third processing module 40 and 42 can also be temperature-controlled by the thermostat 30. A post-processing step is carried out in a following fourth processing module 44, where an additional medium supplied by the feed unit 32 can be mixed with the reaction medium. For example, H2O can be added to collect reactive intermediate stages by terminating the reaction (“quenching”). Other post-processing steps, such as continuous mixing of a two-phase reaction medium, extraction of by-products, filtration, phase-separation, drying, crystallization, rectification, distillation or absorption are also feasible. The various processing steps can be combined in any way and are designed to operate continuously. The reaction medium is finally removed from the processing unit by the device 34. Thermal control of the reaction conditions for the continuous synthesis is, of course, not limited—as in the depicted examples—to the region of the processing modules 38, 40, 42, 44, but can also be achieved in the region of the reactant feed 24, 26, the feed 32 for the additional medium, and the withdrawal devices 32, 34 for the product and for the additional medium by using suitable thermostats. The micro-reactor system 11 includes a sensor unit 62 that is integrated in the holding device 12 and/or provided as a self-contained exchangeable functional unit of the system. Shown here is an exemplary distance sensor 46 which measures the distance between the support plates 14 and 16 and thereby indirectly provides a measurement value with the identity and number of processing modules. A force sensor that is integrated in the holding device 12 monitors the tensioning force. Additional sensors 48 are associated with the individual processing modules 38, 40, 42, 44. These sensors can measure measurement values, such as temperature, pressure, flow, radiation, concentration and the viscosity of the medium. Such sensors 48 are known and will therefore not be described in detail. It should only be kept in mind that the sensors 48 represent completely self-contained and exchangeable functional units that can be associated with the various processing modules 38, 40, 42, 44 depending on the particular requirements. The connecting system which enables the various media to be fed to and withdrawn from the processing modules 38, 40, 42, 44, is based on conical connecting elements 50. During assembly of the processing unit 10, the geometry of the connecting elements 50 aids in the exact positioning of the individual processing modules 38, 40, 42, 44 and automatically seals the connecting system due to the non-positive connection that is provided by the clamping force produced by the holding device 12. For a more detailed understanding of connecting system, FIG. 2 shows a schematic cross-sectional view through a processing unit 10 with only two processing modules 38, 40 for the reaction and retention of the reaction medium. A connecting tube that is integrated in the support plates 14, 16 and has a conical taper in the direction of the processing modules 38, 40, forms the connecting element 50 in the region of the support plates 14, 16. The top and bottom sides of the processing modules 38, 40 include the necessary connection openings 54. A connecting tube having a conical taper on both ends is arranged as a connecting element 50 between the processing modules 38, 40. The fluid reaction medium can enter an exit through the connecting element 50. It is absolutely necessary that such connection system is leak-tight and flexible. The connecting elements 50 should be made of the same material as the processing modules 38, 40 to eliminate/reduce incompatibilities. In addition, polymeric sealing materials which can corrode in the presence of aggressive reaction media can thereby be eliminated. The connecting sites 22 can be reliably sealed by applying the highest clamping force that can be produced by the holding device 12. Metals, in particular stainless-steel, but also glass, ceramic or plastic can be used. Silicon-based semiconductor materials can also be used. When using very hard materials, an elastic or a plastic deformation of the connecting elements 50 required for sealing can only be generated by applying a very large force. In this case, the connecting elements 50 can advantageously be coated with a softer material, preferably a metal. With a stacked arrangement of the processing modules, the connecting elements 50 need to bridge only very small distances. By this approach, connections that are not temperature-controlled and that could easily cause crystallization and/or dissociation of thermally unstable materials, can be kept very short. Moreover, dead spaces which adversely affect the characteristic retention time, can be kept extremely small. A plate-shaped positioning device 58 that holds the connecting element 50 facilitates the relative alignment of the processing modules 38, 40 as well as their installation and removal. For this purpose, the positioning device 58 includes corresponding recesses in which the connecting elements 50 can be inserted. The positioning devices 58 are either made of the same material as the processing modules 38, 40, or have preferably plastically deformable or elastic properties. If connecting elements 50 are not used between the processing modules, then the device 58 itself can function as a seal between two processing modules. A fluid connection between adjacent processing modules is hereby provided by the openings in the device 58. Optionally, existing recesses can be used to receive the connecting elements 50 as a fluid connection. If only a very small dead space can be tolerated, then the openings must be as small as possible. If a fluid connection is not to be established between the processing modules, then a sealing element 60 instead of the connecting elements 50 is inserted between the two connection openings 54. For example, as shown in FIG. 1, the heat exchange medium of the thermostats 28, 30 between the processing modules 38, 40 are separated from each other by such sealing element 60. The sealing element 60 also functions as a support element for transmitting the clamping force generated by the holding device 12 as uniformly as possible to the individual processing modules 38, 40, 42, 44. Conical connecting elements 50 can advantageously fittingly engage with connection openings 54 that have different open cross-sections (FIG. 3). Greater manufacturing tolerances of the individual opening cross-sections can thus be tolerated. FIG. 4 shows a schematic diagram of a micro-reactor system 11 which can be used for carrying out a single-stage synthesis under continuous conditions. The processing unit 10 includes a total of three processing modules 38, 40, 44—the first module 38 for mixing and reaction, the second module 40 for retention, and the third module 40 for post-processing. The product is subsequently collected through the withdrawal device 34 in a suitable container. The fluid connection within the processing unit 10 is provided by the aforedescribed connection system with the conical connecting elements 50, as indicated by the dotted arrow. A sensor unit 62 can be used to measure operating parameters, such as temperature, pressure, concentration of the reactants, flow conditions or the viscosity of the reaction medium. The micro-reactor system also includes an actuator unit 64 with actuators that can be used selectively to change physical states of the reaction medium (temperature, pressure, flow velocity, concentration, phase state, etc.). The entire process flow of the synthesis can therefore be controlled and automated. A control unit 66 with an easily comprehensible user and control interface further simplifies the operation. The control unit 66 can be used to control and optionally set/reset all relevant process parameters. The information network that connects the sensor unit 62, the actuator unit 64 and the control unit 66 is indicated by arrows. In an automated environment, the number or type of the employed processing modules 38, 40, 44 can be determined with a distance sensor 46 (as with the processing unit 10 depicted in FIG. 1), which then also allows determination of the entire internal reaction and retention volume of the processing unit 10. A desired retention time can be obtained by automatically control the flow velocity. Performing purge cycles for cleaning the processing unit 10 can also be a part of the automation. The temperature of the individual processing modules 38, 40, 44 of the processing unit 10 as well as of the withdrawal device 34 and the reactant feeds 24, 26 can be individually controlled by employing suitable thermostats. The temperature-controllable region 68 is indicated by a dotted border. If two-stage or multistage syntheses are to be performed, then several micro-reactor systems 11 can be connected in series and also connected with a control unit 66. FIG. 5 shows such a micro-reactor system for a two-stage synthesis. A first processing unit 70 supplies an intermediate product which is fed with an additional reactant via a suitable device 72 into a second processing unit 74. After a reaction between the intermediate product and the additional reactants and post-processing of the reaction medium, the desired end product can be collected with the withdrawal device 34. The various processing units 70, 74 of these micro-reactor systems can each be equipped with exemplary processing modules 38, 40, (42 in stage 1), 44, and with a self-contained sensor unit 62 and actuator unit 64. The entire reaction chain can be monitored, controlled and operated centrally from the control unit 66. List of Reference Characters 10 processing unit 11 micro-reactor system 12 holding device 14, 16 support plates 18 clamping element 22 connecting site 24, 26 reactant feed 28, 30 thermostats 32 additional medium feed 34 withdrawal device for the product 38 processing module for the reaction 40 first processing module for providing retention/reaction time 42 second processing module for providing retention/reaction time 44 processing module for post-processing 46 distance sensor 48 additional sensors 50 connecting elements 54 connection openings 58 positioning device 60 sealing element 62 sensor unit 64 actuator unit 66 control unit 68 temperature-controllable region 70 first processing unit 72 device for temperature-controllable fluid connection between the withdrawal device of a first and a second reaction stage 74 second processing unit

20040818

20081223

20050203

76980.0

SEIFU, LESSANEWORK T

MICROREACTOR SYSTEM

SMALL

ACCEPTED

ACCEPTED

Random number string output apparatus, random number string output method, program, and information recording medium

A random number sequence output apparatus (101) includes a sequence acceptance unit (102) for accepting input of a numerical sequence, an initial value setting unit (103) for accepting an initial value and causing a storage unit (104) to store this, an output unit (105) for outputting a new value stored in the storage unit (104), a calculation unit (106) for applying a predetermined rational map stored in he storage unit (104) each time the output unit (105) outputs a value and further applying a predetermined calculation unit to the value and value extracted from the numerical sequence accepted by the sequence acceptance unit (102), and an updating unit (104) to store the value of the result of calculation performed by the calculation unit (106), thereby performing updating.

1. A random number string output apparatus (101) that comprises a sequence acceptance unit (102), an initial value setting unit (103), a storage unit (104), an output unit (105), a calculation unit (106), and an updating unit (107), characterized in that: said sequence acceptance unit (102) accepts input of a numeral sequence; said initial value setting unit (103) accepts input of an initial value, and the initial value is stored to the storage unit (104); said output unit (105) outputs the value each time a new value is stored to the storage unit (104); said calculation unit (106) applies a predetermined rational map to the value stored in the storage unit (104), and further calculates, by carrying out a predetermined operation to the value of above and a value sequentially extracted from the numerical sequence accepted by the sequence acceptance unit (102), and said updating unit (107) updates by storing the results of the value calculated by the calculation unit (106) to the storage unit (104); said storage unit stores the value at a fixed-point notation of a predetermined number of bits; the predetermined operation inverts the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in a case where a value sequentially extracted from the numerical sequence is a predetermined value, and said predetermined rational map is a Chebyshev map T (a, •) of an a th (a≧2) degree defined by T (a, cos θ)=cos (aθ) towards an integer number a. 2. The random number string output apparatus (101) according to claim 1, characterized by cyclic shifting a bit string of a fixed-point notation of a predetermined number of bits of the value, by the number of bits corresponding to predetermined value, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 3. The random number string output apparatus (101) according to claim 1, characterized by adding or subtracting the predetermined value to the bit string of a fixed-point notation of a predetermined number of bits of the value, looking at the string as an unsigned integer, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 4. The random number string output apparatus (101) according to claim 2, characterized by exchanging the bits of two predetermined positions of the bit string of a fixed-point notation of a predetermined number of bits of the value, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 5. The random number string output apparatus (101) according to any one of claims 1 to 4, characterized in that: the numerical sequence has a length T that repeats a binary sequence (including a gold code, an M sequence, and a Baker sequence, etc.), taking a value of 0 or 1, and the bit of the predetermined position is a least significant bit of the fixed-point notation, and the predetermined value is 1. 6. A random number string output method using a storage unit that stores values, comprising a sequence acceptance step, an initial value setting step, an output step, a calculation step, and an updating step, and is characterized in that: the sequence acceptance step accepts input of a numerical sequence; the initial value setting step accepts input of an initial value, and stores the value in said storage unit; the output step outputs the value each time a new value is stored in said storage unit; the calculation step applies a predetermined rational map to the value stored in the storage unit, and further calculates, by carrying out a predetermined operation to the value of above and a value sequentially extracted from the numerical sequence accepted in the sequence acceptance step, and the updating step updates by storing the results of the value calculated in the calculation step, to said storage unit; the value at a fixed-point notation of a predetermined number of bits is stored to said storage unit in said initial value setting step and said updating step; the predetermined operation inverts the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in a case where a value sequentially extracted from the numerical sequence is a predetermined value, and said rational map is a Chebyshev map T (a, •) of an ath (a≧2) degree defined by T (a, cos θ)=cos (aθ) towards an integer number a. 7. The random number string output method according to claim 6, characterized by cyclic shifting a bit string of a fixed-point notation of a predetermined number of bits of the value, by the number of bits corresponding to the predetermined value, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 8. The random number string output method according to claim 6, characterized by adding or subtracting the predetermined value to the bit string of a fixed-point notation of a predetermined number of bits of the value, looking at the string as an unsigned integer, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 9. The random number string output method according to claim 6, characterized by exchanging the bits of two predetermined positions of the bit string of a fixed-point notation of a predetermined number of bits of the value, instead of inverting the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in said predetermined operation. 10. The random number string output method according to any one of claims 6 to 9, characterized in that: the numerical sequence is a length T, and is a sequence that repeats a binary sequence (including a gold code, an M sequence, and a Baker sequence, etc.), taking a value of 0 or 1; the bit of the predetermined position is a least significant bit of the fixed-point notation, and the predetermined value is 1. 11. A program that controls a computer to function as the random number string output apparatus according to any one of claims 1 to 4. 12. A program that controls a computer to execute the random number string output method according to any one of claims 6 to 9. 13. A computer readable information recording medium (including a compact disk, a flexible disk, a hard disk, a magnetic optical disk, a digital video disk, a magnetic tape, and a semiconductor memory) characterized by storing the program according to claim 11.

TECHNICAL FIELD The present invention relates to a random number sequence output apparatus, a random number sequence output method, a program for realizing the random number sequence output apparatus and the random number sequence output method, and a computer readable information recording medium that stores the program. BACKGROUND ART Conventionally, an art of generating a random number sequence by a chaos map applying a Chebyshev polynomial is known. This art of generating sets a sequence x0, x1, x2, . . . , that is obtained by providing an initial value x0 (−1<x0<1) towards a recurrence formula xi+1=T(a, xi)(i≧0) applying a Chebyshev map T (a, x1) of an ath (a≧2) degree defined by T(a, cos θ)=cos(aθ) towards an integer a. Other than the Chebyshev map, methods applying various rational functions are proposed. According to this art, it is known that by performing calculation of the recurrence formula by a rational number, a pseudorandom number sequence without a cycle can be obtained, and the distribution of the generated random numbers can be analytically expressed. However, even in a case of calculating a recurrence formula by a rational expression of an infinite precision, it is preferable that a generating method for various random numbers is realized. In a case where the calculation of the recurrence formula is performed by a fixed-point notation of a predetermined precision or by a floating-point notation, a problem that, a cycle appears in the sequence that is obtained, and that there is a case that the cycle is short. Further, there is a problem that the distribution of the generated sequence differs from the distribution of the above that can be analytically expressed, in that the obtained distribution becomes a singular one because of the short periodicity. The present invention is a method for avoiding these kinds of problems, and the purpose of the present invention is to provide a random number sequence output apparatus, a random number sequence output method, a program for realizing the two, and a computer readable information recording medium that stores the program. DISCLOSURE OF INVENTION To achieve the object of the above, according to the basis of the present invention, the invention of below will be disclosed. A random number sequence output apparatus according to a first aspect of the present invention, comprises a sequence acceptance unit, an initial value setting unit, a storage unit, an output unit, a calculation unit, and an updating unit, and is structured as below. Namely, the sequence acceptance unit accepts input of a numeral sequence. The initial value setting unit accepts input of an initial value, and the initial value is stored to the storage unit. The output unit outputs the value each time a new value is stored to the storage unit. The calculation unit applies a predetermined rational map to the value stored in the storage unit, and further calculates, by carrying out a predetermined operation to the value of above and a value sequentially extracted from the numerical sequence accepted by the sequence acceptance unit. The updating unit updates by storing the results of the value calculated by the calculation unit to the storage unit. In the random number sequence output apparatus according to the present invention, the predetermined rational map may be structured to be a Chebyshev map of equal to or higher than a second degree. In the random number sequence output apparatus according to the present invention, the storage unit may be structured to store the value at a fixed-point notation of a predetermined number of bits. In the random number sequence output apparatus according to the present invention, the predetermined operation may be structured to invert the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value, in a case where a value sequentially extracted from the numerical sequence is a predetermined value. In the random number sequence output apparatus according to the present invention, the numerical sequence may be structured so that the sequence that has a length T repeats a binary sequence (including a gold code, an M sequence, and a Baker sequence, etc.), taking a value of 0 or 1, and that the bit of the predetermined position may be a least significant bit of the fixed-point notation, and the predetermined value may be 1. A random number sequence output method according to another aspect of the present invention comprises a sequence acceptance step, an initial value setting step, an output step, a calculation step, and an updating step, and is structured as below. Namely, the sequence acceptance step accepts input of a numerical sequence. The initial value setting step accepts input of an initial value, and stores the value in the storage unit. The output step outputs the value each time a new value is stored in the storage unit. The calculation step applies a predetermined rational map to the value stored in the storage unit, and further calculates, by carrying out a predetermined operation to the value of above and a value sequentially extracted from the numerical sequence accepted in the sequence acceptance step. The updating step updates by storing the results of the value calculated in the calculation step, to the storage unit. In the random number sequence output method according to the present invention, the predetermined rational map may be structured to be a Chebyshev map of equal to or higher than a second degree. In the random number sequence output method according to the present invention, it may be structured so that the value is stored in a fixed-point notation of a predetermined bit to the storage unit, in the initial value setting step and the updating step. In the random number sequence output method according to the present invention, the predetermined operation may be structured to invert the bits of a redetermined position of a fixed-point notation of the predetermined number of bits of the value, in a case where a value sequentially extracted from the numerical sequence is a predetermined value. In the random number sequence output method according to the present invention, the numerical sequence may be structured so that a sequence that has a length T repeats a binary sequence (including a gold code, an M sequence, and a Baker sequence, etc.), taking a value of 0 or 1, and that the bit of the predetermined position is a least significant bit of the fixed-point notation, and the predetermined value is 1. A program according to another aspect of the present invention is structured to control a computer (including an ASIC (Application Specific Integrated Circuit), a DSP (Digital Signal Processor), or an FPGA (Field Programmable Gate Array), etc.,) to function as the above random number sequence output apparatus, or to control the computer to execute the above random number sequence output method. The program of the present invention may be stored to a computer readable information recording medium (including a compact disk, a flexible disk, a hard disk, a magnetic optical disk, a digital video disk, a magnetic tape, and a semiconductor memory). The above random number sequence output apparatus and the random number output method may be realized by executing the program of the present invention by a general computer, a portable telephone, a PHS (Personal Handyphone System) device, a portable terminal such as a game device, etc., an information processing device, such as a parallel computer, etc., an ASIC, a DSP, or an FPGA, etc., that comprises a storage device, a calculating device, an output device, and a communication device, etc. Independent from these devices, the information recording medium of the resent invention can be distributed or sold in stores, etc., or the program of the resent invention may be distributed and sold via a computer communication network. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a diagram showing an outline structure of a random number sequence generating apparatus according to an embodiment of the present invention. FIG. 2 is a flowchart showing a random number sequence generating method executed in the random number sequence generating apparatus. FIG. 3 is an explanatory diagram showing a situation of a case where a fixed point notation of N bits is adopted FIG. 4 is diagram showing a situation of a Chebyshev map. FIG. 5 is a graph showing a sequence distribution, in a case where a sequence is generated by a Chebyshev map at a rational number notation of an infinite precision. FIG. 6 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out at an 8 bit precision. FIG. 7 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at an 8 bit precision. FIG. 8 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out at a 12 bit precision. FIG. 9 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 12 bit precision. FIG. 10 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out in a 16 bit precision. FIG. 11 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 16 bit precision. BEST MODE FOR CARRYING OUT THE INVENTION (Embodiment of the Invention) An embodiment of the present invention will be described below. The embodiments described below are illustrated and do not restrict the scope of the invention. It is therefore possible for those skilled in the art to employ embodiments in which those individual elements or all the elements are replaced with their equivalent elements, but those embodiments are also included in the scope of the invention. FIG. 1 is a diagram showing a schematic structure of a random number sequence generating apparatus according to an embodiment of the present invention. FIG. 2 is a flowchart showing processing of a random number sequence generating method executed in the random string generating apparatus. Below, descriptions will be made with reference to these drawings. A random number sequence output apparatus 101 comprises a sequence acceptance unit 102, an initial value setting unit 103, a storage unit 104, an output unit 105, a calculation unit 106, and an updating unit 107. First, the sequence acceptance unit 102 accepts input of a numerical sequence (step S201). The numerical sequence is typically a repetition of a binary sequence, such as a gold code, an M sequence, and a Baker sequence, etc. The gold code and the M sequence is a pseudorandom number sequence of a value of 0 or 1 of a cycle T−2n−1. The sequence acceptance unit 102 accepts a numerical sequence of a length T as an integer value, stores the integer value, and as will be later described, may cyclic shift (also called “rotate” and “shift rotate”) the integer value, after using the integer value to sequentially obtain the least significant bit of the integral value. The initial value setting unit 103 accepts input of an initial value (step S202), and the initial value is stored to the storage unit 104 (step S203). The storage unit 104 typically stores values at a fixed-point notation of a predetermined bit number. FIG. 3 shows a situation where a fixed-point notation of N bits is adopted. FIG. 3 illustrates a case of fixed-points of 0 to 1. Placing the order from the highest-order bit to the least significant bit in an order of b0, b1, b2, . . . , bN-1, each of them takes a value of 1 or 0. This fixed-value notation: Σn=0N−1(½)n+1bn. corresponds to a value of equal to or higher than 0 and less than 1. In most calculators, when looking at this fixed-value notation as an unsigned integer, the fixed-value notation corresponds to an integer value of: Σn=0N−12N−1−nbn Other than this, in a case of a fixed-point number of −1 to 1, any one of b0 to bN−1 (typically b0) is set as a code bit, and the fixed-point notation is expressed by the left others. For example, in a case where b0 is set as the code bit, the fixed-point notation by b0 to bN−1 corresponds to: Σn=1N−1(½)nbn in the case of b0=0, and corresponds to: −Σn=1N−1(½)nbn in the case of b0=1. Further, the output unit 105 outputs this, each time a new value is stored to the storage unit 104 (step S204). Then, each time the output unit 105 outputs a value, the calculation unit 106 applies a predetermined rational map to the value stored in the storage unit 104 (step S205), and further calculates, by carrying out a predetermined operation (hereinafter referred to as “harnessing”) to the value of above and a value sequentially extracted from the numerical sequence accepted by the sequence acceptance unit 102 (step S206). Typically, the predetermined rational map is a Chebyshev map of a degree equal to or higher than a second degree. FIG. 4 is a graph showing a situation of a Chebyshev map. The Chebyshev map can be expressed as below, by polynomials: T(0, x)=1 T(1, x)=x T(2, x)=2x2−1 T(3, x)=4x3−3x Each polynomial of the Chebyshev polynomial y=T(a, x) is a rational map that maps an open interval of −1<x<1 to an open interval of −1<y<1. In FIG. 4, a Chebyshev polynomial of a second to fifth degree is shown in a graph in the form of y=T(2, x), y=T(3, x), y=T(4,x), and y=T(5, x). The horizontal axis is the x axis, and the vertical axis is the y axis. Moreover, typically, in a case where the value sequentially extracted from the numerical sequence is a predetermined value, a bit harnessing operation inverts the bits of a predetermined position of a fixed-point notation of the predetermined number of bits of the value. Namely, in a case where the predetermined value is 1, a bit harnessing operation inverts the value of the least significant bit bN−1. As described above, from the numeral sequence with an origin of an M-sequential, etc., a value of 0 or 1 can be obtained. However, looking at this “value of 0 or 1” and the fixed-point notation stored in the storage unit 106 as an “unsigned integer”, the exclusive OR of the two is calculated, and this can be stored in the storage unit 106. An embodiment of calculating an exclusive OR with a bit of another position, and not the least significant bit, can be adopted. However, it is preferable that the it is not the code bit. The updating unit 107 updates by storing the results of the value calculated by he calculation unit 106 to the storage unit 104 (step S207), and returns to step S204. The operation of bit harnessing may be another mode. For example, according to the above fixed-point notation, no matter what the value of b0 to bN−1is, because the fixed-point that expresses the value is in the range of −1 to 1, various bit calculations, etc., can be considered. For example, a calculation of below can be considered. Cyclic shifting the bit sequence of the fixed-point notation, by the value sequentially extracted (0 or 1) from the numerical sequence. Adding the value sequentially extracted (0 or 1) from the numerical sequence to a value looking at the bit sequence of the fixed-point notation as an “unsigned integer”. Subtracting the value sequentially extracted (0 or 1) from the numerical sequence, from a value looking at the bit sequence of the fixed-point notation as an “unsigned integer”. Exchanging the value of bit bp and bit bq concerning predetermined integers p and q, (0≦p, q≦N−1), in a case where the values sequentially extracted from the numerical sequence is a pre-set value (for example, 1). Concerning these calculations, it can be determined which calculation to adopt, considering the cycle of the sequence that can be obtained. (Results of Experiment) FIG. 5 is a graph showing a sequence distribution, in a case where a sequence is generated by a Chebyshev map at a rational number notation of an infinite precision. FIG. 6 is a graph showing a sequence distribution, in a case where a bit harnessing operation is not carried out at an 8 bit precision. FIG. 7 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at an 8 bit precision. FIG. 8 is a graph showing a sequence distribution, in a case where a bit harnessing operation is not carried out at a 12 bit precision. FIG. 9 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 12 bit precision. FIG. 10 is a graph showing a sequence distribution, in a case where a bit harnessing operation is not carried out in a 16 bit precision. FIG. 11 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 16 bit precision. Comparing these graphs, in the sequence distributions where a bit harnessing operation is not carried out, there is a large deviation, and there is a large difference compared to the sequence distributions where rational number notation of an infinite precision is adopted. However, using the method of the present embodiment, it can be seen that the sequence distributions where a bit harnessing operation is carried out is similar to sequence distributions where rational number notation of an infinite precision is adopted, and a good pseudorandom number is obtained. Looking at the cycle of the output sequence, by carrying out a bit harnessing operation in the same way as the present embodiment, it can be seen that in most cases, the cycle becomes longer by several times or dozens of times. Therefore, a more preferable pseudorandom number sequence can be obtained. Those skilled in the art can carry out the present invention by embodiments other than the preferred embodiment described in the description, which is illustrated and do not restrict the scope of the invention, and understands that the present invention is limited only by the scope of claims. Equivalents to the specific embodiment argued in the description can also carry out the present invention in the same way. The patent application is based on Japanese Patent Application No. 2001-339429 filed with the Japan Patent Office on Nov. 5, 2001, the complete disclosure of which is hereby incorporated by reference. INDUSTRIAL APPLICABILITY As described above, according to the present invention, a random number sequence output apparatus, a random number sequence output method, a program for realizing the random number sequence output apparatus and the random number sequence output method, and a computer readable information recording medium that stores the program, can be provided.

<SOH> BACKGROUND ART <EOH>Conventionally, an art of generating a random number sequence by a chaos map applying a Chebyshev polynomial is known. This art of generating sets a sequence x 0 , x 1 , x 2 , . . . , that is obtained by providing an initial value x 0 (−1<x 0 <1) towards a recurrence formula in-line-formulae description="In-line Formulae" end="lead"? x i+1 =T ( a, x i )( i≧ 0) in-line-formulae description="In-line Formulae" end="tail"? applying a Chebyshev map T (a, x 1 ) of an a th (a≧2) degree defined by in-line-formulae description="In-line Formulae" end="lead"? T ( a , cos θ)=cos( a θ) in-line-formulae description="In-line Formulae" end="tail"? towards an integer a. Other than the Chebyshev map, methods applying various rational functions are proposed. According to this art, it is known that by performing calculation of the recurrence formula by a rational number, a pseudorandom number sequence without a cycle can be obtained, and the distribution of the generated random numbers can be analytically expressed. However, even in a case of calculating a recurrence formula by a rational expression of an infinite precision, it is preferable that a generating method for various random numbers is realized. In a case where the calculation of the recurrence formula is performed by a fixed-point notation of a predetermined precision or by a floating-point notation, a problem that, a cycle appears in the sequence that is obtained, and that there is a case that the cycle is short. Further, there is a problem that the distribution of the generated sequence differs from the distribution of the above that can be analytically expressed, in that the obtained distribution becomes a singular one because of the short periodicity. The present invention is a method for avoiding these kinds of problems, and the purpose of the present invention is to provide a random number sequence output apparatus, a random number sequence output method, a program for realizing the two, and a computer readable information recording medium that stores the program.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a diagram showing an outline structure of a random number sequence generating apparatus according to an embodiment of the present invention. FIG. 2 is a flowchart showing a random number sequence generating method executed in the random number sequence generating apparatus. FIG. 3 is an explanatory diagram showing a situation of a case where a fixed point notation of N bits is adopted FIG. 4 is diagram showing a situation of a Chebyshev map. FIG. 5 is a graph showing a sequence distribution, in a case where a sequence is generated by a Chebyshev map at a rational number notation of an infinite precision. FIG. 6 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out at an 8 bit precision. FIG. 7 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at an 8 bit precision. FIG. 8 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out at a 12 bit precision. FIG. 9 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 12 bit precision. FIG. 10 is a graph showing a sequence distribution, in a case where bit harnessing is not carried out in a 16 bit precision. FIG. 11 is a graph showing a sequence distribution, in a case where the above embodiment is adopted at a 16 bit precision. detailed-description description="Detailed Description" end="lead"?

20041012

20081230

20050210

63075.0

MAI, TAN V

RANDOM NUMBER STRING OUTPUT APPARATUS, RANDOM NUMBER STRING OUTPUT METHOD, PROGRAM, AND INFORMATION RECORDING MEDIUM

UNDISCOUNTED

ACCEPTED

ACCEPTED

Method and injection molding machine for the production of elastomer and duromer molded items

A method for the production of elastomer and duromer molded items in an injection molding process using an injection molding machine with a respectively separately heatable filling unit, injection unit and cross-linking tool. The filling unit is heated to a temperature which is non-critical with regard to the cross-linking reaction of the plastic to be treated. The injection unit is heated to a temperature which is slightly below the cross-linking temperature of the molding material used.

1-8. (Canceled). 9. A method for producing elastomer molded parts and duromer molded parts using an injection molding machine comprising a separately heatable filling unit, injection unit and cross-linking tool, comprising the steps of: introducing molding compound into the injection unit; heating the filling unit to a temperature that is non-critical with regard to the cross-linking reaction of a plastic to be treated; and heating the injection unit to a temperature that is slightly below the cross-linking temperature of the molding compound. 10. The method as recited in claim 9, wherein the injection unit is heated such that a retention time of the molding compound in the injection unit is minimized. 11. An injection molding machine for cross-linking molding compounds comprising: a filling unit; an injection unit; and a cross-linking tool, wherein the filling unit, the injection unit and the cross-linking tool are each configured to be separately brought to predetermined temperatures, and wherein the injection unit has an annular cylinder having an annular piston. 12. The injection molding machine as recited in claim 11, wherein the injection unit is heated to a temperature that is slightly below the cross-linking temperature. 13. The injection molding machine as recited in claim 11, wherein the annular cylinder and the cylinder core are provided with heating elements. 14. The injection molding machine as recited in claim 13, wherein the heating elements of the annular cylinder and of the cylinder core are configured to be simultaneously and synchronously regulated. 15. The injection molding machine as recited in claim 11, wherein a volume of a cross-linking molding compound is contained in a space in the annular piston and is heated to nearly the cross-linking temperature, said volume corresponds to the volume of the tool cavity. 16. The injection molding machine as recited in claim 11, wherein the annular piston space is configured so as to be able to be closed off on its underside by a slider.

FIELD OF THE INVENTION The present invention relates to a method for producing elastomer and duromer molded parts. More particularly, the present invention relates to a method for producing elastomer and duromer molded parts using injection molding methods and injection molding machines each having a separately heatable filling unit, injection unit and cross-linking tool. The filling unit and the injection unit being heated to a temperature that is not critical for the cross-linking reaction of the plastic to be treated. At the same time, an injection molding machine for carrying out the method is described. BACKGROUND INFORMATION Injection molding methods and the injection molding machines required for them are widespread. In order to achieve good utilization of the machines, it is attempted to make vulcanization times as short as possible. The vulcanization time of component parts having a wall thickness of 1 cm is several minutes. In order to decrease the vulcanization time, an injection molding machine has become known from U.S. Pat. No. 4,370,150, in which a periodically operating heating device is put in between the filling unit and the cross-linking tool, in which a part of the elastomer pressed in by the filling unit is heated to a temperature which just about corresponds to the cross-linking temperature in the cross-linking tool. The cross-linking process is repeated for each injection procedure. Here, a kind of pre-cross-linking of the elastomer takes place, so that the final cross-linking in the cross-linking tool is very much shortened in time. Such a device, however, has the disadvantage that, in the heating zone, cross-linking may occur, which impedes the injection procedure. In the usual injection molding machines for producing elastomer and duromer molded parts, the molding compound in the filling unit is plastified at a temperature that is non-critical to the cross-linking reaction, mostly between 70° and 90° C. Only after injection into the cross-linking tool, which is preheated to the cross-linking temperature, does the cross-linking reaction begin. Cross-linking reaches its maximum speed when the molding compound has reached the cross-linking temperature. Because of the low heat conductivity of the cross-linking molding compounds, the cycle time of the individual injection procedure is essentially determined by the cross-linking time. In this context, the heat transportation from the wall of the tool to the inner part of the molded part, so as to reach a maximum cross-linking speed, is the deciding factor. SUMMARY OF THE INVENTION The present invention is based on the object of further developing the injection molding method and the appertaining injection molding machine, in order to increase their productivity. The cross-linking time in the cross-linking tool of especially thick-walled molded parts is to be clearly reduced. In addition, the molded part should have a more uniform cross-linking structure. According to an exemplary embodiment of the present invention, the injection unit itself is heated to a temperature that is slightly below the cross-linking temperature. In experiments it was shown that, by this measure, the vulcanization time was reduced quite considerably. The retention time of the elastomer in the injection unit is preferably reduced to a minimum. Additional parts on the injection molding machine, such as the special heating path named above, are not required. The injection molding machine for carrying out the method is provided in a known manner with a filling unit, an injection unit and a cross-linking tool, which are separately heatable. In order to achieve a retention time of the molding compound that is as short as possible after leaving the filling unit, the injection unit is furnished with an annular cylinder having an annular piston. The heating of the annular cylinder and of the core of the cylinder may be done by appropriately designed heating elements. These heating elements may be regulated simultaneously and synchronously. The advantage of the preheating of the molding compound in the injection unit is that, directly after the complete filling of the cavity in the cross-linking tool, cross-linking begins at maximum speed. In spite of the poor heat conductivity properties of the molding compounds to be cross-linked, an essentially homogeneous temperature distribution is achieved over the entire cross section. This, in turn, causes a largely uniform cross-linking structure over the entire component part thickness, since the cross-linking reactions sets in in all regions of the material that has been preheated close to the cross-linking temperature inside the cavity, approximately simultaneously at maximum speed. This enables one to achieve a high quality of the elastomer molded parts, at shortened cycle time, in the production of the parts. The cylinder chamber is preferably heated to at least 90% of the cross-linking temperature. Very favorable results are obtained if the heating is carried out up to 95 to 98% of the cross-linking temperature. As a rule, the volume of the molding compound contained in the cylinder chamber and heated close to cross-linking temperature is selected so that it corresponds to the volume of the tool cavity. A complete exchange of the molding compound in the cylinder chamber is thereby ensured. The piston ring space is able to be closed off on its underside by a slider. The volume for individual injection procedures may be varied by the appropriate development of the piston stroke. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is schematic illustration of an example embodiment of the injection molding machine of the present invention during filling. FIG. 2 is a schematic illustration of an example embodiment of the injection molding machine of the present invention after filling. FIG. 3 is a schematic illustration of an example embodiment of the injection molding machine of the present invention prepared for the injection procedure. FIG. 4 is a schematic illustration of an example embodiment of the injection molding machine of the present invention after carrying out the injection procedure. DETAILED DESCRIPTION In FIG. 1, an injection molding machine 1 is shown schematically, which is made up of filling unit 2, injection unit 3 and cross-linking tool 4. Injection molding machine 1 is shown during the filling procedure. Molding compound 6 introduced into feed region 5 is conveyed by wormgear 7 and the piston of filling unit 2 into ring space 8 of injection unit 3. Annular piston 9 moves upwards in this context, as shown by arrow 10. Pressure piston 11 is affixed at the upper end of annular piston 9, and it is needed for the injection procedure. Wormgear 7 is driven by motor 12, using a gear 13 placed in between. Wormgear housing 14 is furnished with separate heater to correct temperature 15. Ring cylinder 16 is equipped with heater to correct temperature 17. Preferably, cylinder core 18 is also furnished with heater to correct temperature 19. Cross-linking tool 4, which is located below injection unit 3, is provided with its own heater 20. The volumes of tool cavity 21 and of piston ring 8 are matched to each other in such a way that a filling of piston ring space 8 corresponds to a filling of tool cavity 21. A slider 22 at the underside of annular piston space 8 is used to close piston ring space 8 after filling. The reference numerals in the following figures correspond to the parts described in FIG. 1. In FIG. 2 the filling of piston ring space 8 is closed off. Wormgear 7 is standing still. Slider 22 has closed off annular piston space 8. As in FIG. 1, the temperature at the filling unit is ca 80° C., the temperature at injection unit 3 is ca 165° C., and the temperature at cross-linking tool is ca 180° C. In FIG. 3, injection unit 3 is connected to cross-linking unit 4, and the slider is open. Filling unit 2 is still in a position of rest. Injection unit 3 begins the injection procedure, which is indicated by arrow 30. The temperatures set in all three machine parts are maintained. FIG. 4 shows the end of the injection procedure. Annular piston 9 has reached the stop at its lower end, and molding compound 6 has been squeezed out of piston ring space 8 into cavity 21 of cross-linking tool 4. This ends one cycle of the injection procedure, and the procedure is able to begin anew when the parts are assembled as in FIG. 1.

<SOH> BACKGROUND INFORMATION <EOH>Injection molding methods and the injection molding machines required for them are widespread. In order to achieve good utilization of the machines, it is attempted to make vulcanization times as short as possible. The vulcanization time of component parts having a wall thickness of 1 cm is several minutes. In order to decrease the vulcanization time, an injection molding machine has become known from U.S. Pat. No. 4,370,150, in which a periodically operating heating device is put in between the filling unit and the cross-linking tool, in which a part of the elastomer pressed in by the filling unit is heated to a temperature which just about corresponds to the cross-linking temperature in the cross-linking tool. The cross-linking process is repeated for each injection procedure. Here, a kind of pre-cross-linking of the elastomer takes place, so that the final cross-linking in the cross-linking tool is very much shortened in time. Such a device, however, has the disadvantage that, in the heating zone, cross-linking may occur, which impedes the injection procedure. In the usual injection molding machines for producing elastomer and duromer molded parts, the molding compound in the filling unit is plastified at a temperature that is non-critical to the cross-linking reaction, mostly between 70° and 90° C. Only after injection into the cross-linking tool, which is preheated to the cross-linking temperature, does the cross-linking reaction begin. Cross-linking reaches its maximum speed when the molding compound has reached the cross-linking temperature. Because of the low heat conductivity of the cross-linking molding compounds, the cycle time of the individual injection procedure is essentially determined by the cross-linking time. In this context, the heat transportation from the wall of the tool to the inner part of the molded part, so as to reach a maximum cross-linking speed, is the deciding factor.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is based on the object of further developing the injection molding method and the appertaining injection molding machine, in order to increase their productivity. The cross-linking time in the cross-linking tool of especially thick-walled molded parts is to be clearly reduced. In addition, the molded part should have a more uniform cross-linking structure. According to an exemplary embodiment of the present invention, the injection unit itself is heated to a temperature that is slightly below the cross-linking temperature. In experiments it was shown that, by this measure, the vulcanization time was reduced quite considerably. The retention time of the elastomer in the injection unit is preferably reduced to a minimum. Additional parts on the injection molding machine, such as the special heating path named above, are not required. The injection molding machine for carrying out the method is provided in a known manner with a filling unit, an injection unit and a cross-linking tool, which are separately heatable. In order to achieve a retention time of the molding compound that is as short as possible after leaving the filling unit, the injection unit is furnished with an annular cylinder having an annular piston. The heating of the annular cylinder and of the core of the cylinder may be done by appropriately designed heating elements. These heating elements may be regulated simultaneously and synchronously. The advantage of the preheating of the molding compound in the injection unit is that, directly after the complete filling of the cavity in the cross-linking tool, cross-linking begins at maximum speed. In spite of the poor heat conductivity properties of the molding compounds to be cross-linked, an essentially homogeneous temperature distribution is achieved over the entire cross section. This, in turn, causes a largely uniform cross-linking structure over the entire component part thickness, since the cross-linking reactions sets in in all regions of the material that has been preheated close to the cross-linking temperature inside the cavity, approximately simultaneously at maximum speed. This enables one to achieve a high quality of the elastomer molded parts, at shortened cycle time, in the production of the parts. The cylinder chamber is preferably heated to at least 90% of the cross-linking temperature. Very favorable results are obtained if the heating is carried out up to 95 to 98% of the cross-linking temperature. As a rule, the volume of the molding compound contained in the cylinder chamber and heated close to cross-linking temperature is selected so that it corresponds to the volume of the tool cavity. A complete exchange of the molding compound in the cylinder chamber is thereby ensured. The piston ring space is able to be closed off on its underside by a slider. The volume for individual injection procedures may be varied by the appropriate development of the piston stroke.

20041101

20080819

20050317

69857.0

HEITBRINK, JILL LYNNE

METHOD AND INJECTION MOLDING MACHINE FOR THE PRODUCTION OF ELASTOMER AND DUROMER MOLDED ITEMS

SMALL

ACCEPTED

ACCEPTED

Pre-processed feature ranking for a support vector machine

Features are preprocessed (204) to minimize classification error in a Support Vector Machines (200) used to identify patterns in large databases. Pre-processing (204) is performed to constrain features used to train (210) the SVM learning machine. Live data (226) is collected and processed (232) with SVM.

1. A computer-implemented method for selecting a subset of features for processing in a learning machine, wherein the features correspond to a dataset to be analyzed for patterns, the method comprising: ranking the features according to a distance between extremal points of two classes of interest; and selecting the subset of features having the highest rank. 2. The method of claim 1, wherein the learning machine is a support vector machine. 3. The method of claim 1, further comprising pre-processing the dataset by normalizing the data. 4. The method of claim 3, wherein the step of pre-processing comprises: arranging the data in a matrix having rows and columns; first normalizing the columns of the matrix; second normalizing the rows of the matrix; and third normalizing the columns of the matrix. 5. The method of claim 1, wherein the dataset comprises gene expression data obtained from DNA micro-arrays. 6. The method of claim 5, wherein the gene expression data is obtained from tissue from patients with renal cancer. 7. A computer-implemented method for selecting a subset of features for processing in a learning machine, wherein the features correspond to a dataset to be analyzed for patterns, the method comprising: determining a margin between extremal points of two classes of interest; and ranking the subset of features according to the size of the margin, wherein the largest margin corresponds to the highest rank. 8. The method of claim 7, wherein the learning machine is a support vector machine. 9. The method of claim 7, further comprising pre-processing the dataset by normalizing the data. 10. The method of claim 9, wherein the step of pre-processing comprises: arranging the data in a matrix having rows and columns; first normalizing the columns of the matrix; second normalizing the rows of the matrix; and third normalizing the columns of the matrix. 11. The method of claim 7, wherein the dataset comprises gene expression data obtained from DNA micro-arrays. 12. The method of claim 11, wherein the gene expression data is obtained from tissue from patients with renal cancer. 13. A method for diagnosing renal cancer in a patient comprising: entering gene expression data into a computer adapted for implementing a learning machine, the gene expressions data comprising gene expression levels in tissue obtained from the patient for a gene selected from the group consisting of small inducible cytokine A2 (monocyte chemotactic protein 1) and ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit, isoform 1, cardiac muscle.

RELATED APPLICATIONS The present application claims priority of U.S. provisional application Ser. No. 60/347,562, and for U.S. national stage purposes, is a continuation-in-part of International Application Serial No. PCT/US02/16012 filed May 20, 2002 which claims priority to U.S. provisional applications Ser. No. 60/292,133, filed May 18, 2001, Ser. No. 60/292,221, filed May 23, 2001, and Ser. No. 60/332,021, filed Nov. 21, 2001, and is a continuation-in-part of U.S. patent application Ser. No. 10/057,849, filed Jan. 24, 2002, which is a continuation-in-part of application Ser. No. 09/633,410, filed Aug. 7, 2000, which is a continuation-in-part of application Ser. No. 09/578,011, filed May 24, 2000, which is a continuation-in-part of application Ser. No. 09/568,301, filed May 9, 2000, now issued as U.S. Pat. No. 6,427,141, which is a continuation of application Ser. No. 09/303,387. filed May 1, 1999, now issued as U.S. Pat. No. 6,128,608, which claims priority to U.S. provisional application Ser. No. 60/083,961, filed May 1, 1998. This application is related to co-pending applications Ser. No. 09/633,615, Ser. No. 09/633,616, and Ser. No. 09/633,850, all filed Aug. 7, 2000, which are also continuations-in-part of application Ser. No. 09/578,011. This application is also related to applications Ser. No. 09/303,386 and Ser. No. 09/305,345, now issued as U.S. Pat. No. 6,157,921, both filed May 1, 1999, and to application Ser. No. 09/715,832, filed Nov. 14, 2000, all of which also claim priority to provisional application Ser. No. 60/083,961. Each of the above-identified applications is incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to the use of learning machines to identify relevant patterns in datasets containing large quantities of diverse data, and more particularly to a method and system for selection of features within the data sets which best enable identification of relevant patterns. BACKGROUND OF THE INVENTION Knowledge discovery is the most desirable end product of data collection. Recent advancements in database technology have lead to an explosive growth in systems and methods for generating, collecting and storing vast amounts of data. While database technology enables efficient collection and storage of large data sets, the challenge of facilitating human comprehension of the information in this data is growing ever more difficult. With many existing techniques the problem has become unapproachable. Thus, there remains a need for a new generation of automated knowledge discovery tools. As a specific example, the Human Genome Project has completed sequencing of the human genome. The complete sequence contains a staggering amount of data, with approximately 31,500 genes in the whole genome. The amount of data relevant to the genome must then be multiplied when considering comparative and other analyses that are needed in order to make use of the sequence data. To illustrate, human chromosome 20 alone comprises nearly 60 million base pairs. Several disease-causing genes have been mapped to chromosome 20 including various autoimmune diseases, certain neurological diseases, type 2 diabetes, several forms of cancer, and more, such that considerable information can be associated with this sequence alone. One of the more recent advances in determining the functioning parameters of biological systems is the analysis of correlation of genomic information with protein functioning to elucidate the relationship between gene expression, protein function and interaction, and disease states or progression. Proteomics is the study of the group of proteins encoded and regulated by a genome. Genomic activation or expression does not always mean direct changes in protein production levels or activity. Alternative processing of mRNA or post-transcriptional or post-translational regulatory mechanisms may cause the activity of one gene to result in multiple proteins, all of which are slightly different with different migration patterns and biological activities. The human proteome is believed to be 50 to 100 times larger than the human genome. Currently, there are no methods, systems or devices for adequately analyzing the data generated by such biological investigations into the genome and proteome. In recent years, machine-learning approaches for data analysis have been widely explored for recognizing patterns which, in turn, allow extraction of significant information contained within a large data set that may also include data consists of nothing more than irrelevant detail. Learning machines comprise algorithms that may be trained to generalize using data with known outcomes. Trained learning machine algorithms may then be applied to predict the outcome in cases of unknown outcome, i.e., to classify the data according to learned patterns. Machine-learning approaches, which include neural networks, hidden Markov models, belief networks and kernel-based classifiers such as support vector machines, are ideally suited for domains characterized by the existence of large amounts of data, noisy patterns and the absence of general theories. Support vector machines are disclosed in U.S. Pat. Nos. 6,128,608 and 6,157,921, both of which are assigned to the assignee of the present application and are incorporated herein by reference. The quantities introduced to describe the data that is input into a learning machine are typically referred to as “features”, while the original quantities are sometimes referred to as “attributes”. A common problem in classification, and machine learning in general, is the reduction of dimensionality of feature space to overcome the risk of “overfitting”. Data overfitting arises when the number n of features is large, such as the thousands of genes studied in a microarray, and the number of training patterns is comparatively small, such as a few dozen patients. In such situations, one can find a decision function that separates the training data, even a linear decision function, but it will perform poorly on test data. The task of choosing the most suitable representation is known as “feature selection”. A number of different approaches to feature selection exists, where one seeks to identify the smallest set of features that still conveys the essential information contained in the original attributes. This is known as “dimensionality reduction” and can be very beneficial as both computational and generalization performance can degrade as the number of features grows, a phenomenon sometimes referred to as the “curse of dimensionality.” Training techniques that use regularization, i.e., restricting the class of admissible solutions, can avoid overfitting the data without requiring space dimensionality reduction. Support Vector Machines (SVMs) use regularization, however even SVMs can benefit from space dimensionality (feature) reduction. The problem of feature selection is well known in pattern recognition. In many supervised learning problems, feature selection can be important for a variety of reasons including generalization performance, running time requirements and constraints and interpretational issues imposed by the problem itself. Given a particular classification technique, one can select the best subset of features satisfying a given “model selection” criterion by exhaustive enumeration of all subsets of features. However, this method is impractical for large numbers of features, such as thousands of genes, because of the combinatorial explosion of the number of subsets. One method of feature reduction is projecting on the first few principal directions of the data. Using this method, new features are obtained that are linear combinations of the original features. One disadvantage of projection methods is that none of the original input features can be discarded. Preferred methods incorporate pruning techniques that eliminate some of the original input features while retaining a minimum subset of features that yield better classification performance. For design of diagnostic tests, it is of practical importance to be able to select a small subset of genes for cost effectiveness and to permit the relevance of the genes selected to be verified more easily. Accordingly, the need remains for a method for selection of the features to be used by a learning machine for pattern recognition which still minimizes classification error. SUMMARY OF THE INVENTION In an exemplary embodiment, the present invention comprises preprocessing a training data set in order to allow the most advantageous application of the learning machine. Each training data point comprises a vector having one or more coordinates. Pre-processing the training data set may comprise identifying missing or erroneous data points and taking appropriate steps to correct the flawed data or as appropriate remove the observation or the entire field from the scope of the problem. In a preferred embodiment, pre-processing includes reducing the quantity of features to be processed using feature selection methods selected from the group consisting of recursive feature elimination (RFE), minimizing the number of non-zero parameters of the system (l0-norm minimization), evaluation of cost function to identify a subset of features that are compatible with constraints imposed by the learning set, unbalanced correlation score and transductive feature selection. The features remaining after feature selection are then used to train a learning machine for purposes of pattern classification, regression, clustering and/or novelty detection. In a preferred embodiment, the learning machine is a kernel-based classifier. In the most preferred embodiment, the learning machine comprises a plurality of support vector machines. A test data set is pre-processed in the same manner as was the training data set. Then, the trained learning machine is tested using the pre-processed test data set. A test output of the trained learning machine may be post-processing to determine if the test output is an optimal solution based on known outcome of the test data set. In the context of a a kernel-based learning machine such as a support vector machine, the present invention also provides for the selection of at least one kernel prior to training the support vector machine. The selection of a kernel may be based on prior knowledge of the specific problem being addressed or analysis of the properties of any available data to be used with the learning machine and is typically dependant on the nature of the knowledge to be discovered from the data. Kernels are usually defined for patterns that can be represented as a vector of real numbers. For example, linear kernels, radial basis function kernels and polynomial kernels all measure the similarity of a pair of real vectors. Such kernels are appropriate when the patterns are best represented as a sequence of real numbers. An iterative process comparing postprocessed training outputs or test outputs can be applied to make a determination as to which kernel configuration provides the optimal solution. If the test output is not the optimal solution, the selection of the kernel may be adjusted and the support vector machine may be retrained and retested. Once it is determined that the optimal solution has been identified, a live data set may be collected and pre-processed in the same manner as was the training data set to select the features that best represent the data. The pre-processed live data set is input into the learning machine for processing. The live output of the learning machine may then be post-processed by interpreting the live output into a computationally derived alphanumeric classifier or other form suitable to further utilization of the SVM derived answer. In an exemplary embodiment a system is provided enhancing knowledge discovered from data using a support vector machine. The exemplary system comprises a storage device for storing a training data set and a test data set, and a processor for executing a support vector machine. The processor is also operable for collecting the training data set from the database, pre-processing the training data set, training the support vector machine using the pre-processed training data set, collecting the test data set from the database, pre-processing the test data set in the same manner as was the training data set, testing the trained support vector machine using the pre-processed test data set, and in response to receiving the test output of the trained support vector machine, post-processing the test output to determine if the test output is an optimal solution. The exemplary system may also comprise a communications device for receiving the test data set and the training data set from a remote source. In such a case, the processor may be operable to store the training data set in the storage device prior pre-processing of the training data set and to store the test data set in the storage device prior pre-processing of the test data set. The exemplary system may also comprise a display device for displaying the post-processed test data. The processor of the exemplary system may further be operable for performing each additional function described above. The communications device may be further operable to send a computationally derived alphanumeric classifier or other SVM-based raw or post-processed output data to a remote source. In an exemplary embodiment, a system and method are provided for enhancing knowledge discovery from data using multiple learning machines in general and multiple support vector machines in particular. Training data for a learning machine is pre-processed. Multiple support vector machines, each comprising distinct kernels, are trained with the pre-processed training data and are tested with test data that is pre-processed in the same manner. The test outputs from multiple support vector machines are compared in order to determine which of the test outputs if any represents an optimal solution. Selection of one or more kernels may be adjusted and one or more support vector machines may be retrained and retested. When it is determined that an optimal solution has been achieved, live data is pre-processed and input into the support vector machine comprising the kernel that produced the optimal solution. The live output from the learning machine may then be post-processed as needed to place the output in a format appropriate for interpretation by a human or another computer. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a flowchart illustrating an exemplary general method for increasing knowledge that may be discovered from data using a learning machine. FIG. 2 is a flowchart illustrating an exemplary method for increasing knowledge that may be discovered from data using a support vector machine. FIG. 3 is a flowchart illustrating an exemplary optimal categorization method that may be used in a stand-alone configuration or in conjunction with a learning machine for pre-processing or post-processing techniques in accordance with an exemplary embodiment of the present invention. FIG. 4 is a functional block diagram illustrating an exemplary operating environment for an embodiment of the present invention. FIG. 5 is a functional block diagram illustrating a hierarchical system of multiple support vector machines. FIG. 6 shows graphs of the results of using RFE. FIG. 7 shows the results of RFE after preprocessing. FIG. 8 shows the results of RFE when training on 100 dense QT_clust clusters. FIG. 9 shows a comparison of feature (gene) selection methods for colon cancer data. FIG. 10 shows the selection of an optimum number of genes for colon cancer data. FIGS. 11a-f are plots comparing results with SVM and l0-SVM approximation for learning sparse and non-sparse target functions with polynomials of degree 2 over 5 inputs, where FIGS. 11a and 11b show the results of SVM target functions ƒ(x)=x1x2+x3 and ƒ(x)=x1, respectively; and FIGS. 11c-f provide the results for 95%, 90%, 80% and 0% sparse poly degree 2, respectively. FIGS. 12a-f are plots comparing results with SVM and l2-AL0M SVM approximation for learning sparse and non-sparse target functions with polynomials of degree 2 over 10 inputs, where FIGS. 12a and 12b show the results of SVM target functions ƒ(x)=x1x2+x3 and ƒ(x)=x1, respectively; and FIGS. 12c-f provide the results for 95%, 90%, 80% and 0% sparse poly degree 2, respectively. FIGS. 13a-b are plots of the results of a sparse SVM and a classical SVM, respectively, using a RBF kernel with a value of σ=0.1. FIGS. 14a-d are plots of the results of a sparse SVM (a,c) and a classical SVM (b,d). FIGS. 15a-d are plots of the results of performing guaranteed-distortion mk-vector quantization on two dimensional uniform data with varying distortion levels, where the quantizing vectors are m=37, 11, 6 and 4,respectively. FIG. 16 is a plot of showing the Hamming distance for a dataset having five labels and two possible label sets. FIG. 17 illustrates a simple toy problem with three labels, one of which is associated with all inputs. FIG. 18 is a histogram of error in the binary approach in the toy problem of FIG. 17. FIGS. 19a-c are histograms of the leave-one-out estimate of the Hamming Loss for the Prostate Cancer Database relating to the embodiment of feature section in multi-label cases where FIG. 19a is a histogram of the errors for a direct approach; FIG. 19b is a histogram of the errors for the binary approach; and FIG. 19c is a histogram of the errors for the binary approach when the system is forced to output at least one label. FIG. 20a-c are histograms of the leave-one-out estimate of the Hamming Loss for the Prostate Cancer Database relating to the embodiment of feature section in multi-label cases where FIG. 20a is a histogram of the errors for the direct approach; FIG. 20b is a histogram of the errors for the binary approach; and FIG. 20c is a histogram of the errors for the binary approach when the system is forced to output at least one label. FIG. 21 shows the distribution of the mistakes using the leave-one-out estimate of the Hamming Loss for the Prostate Cancer Database using 4 labels with Feature selection. FIG. 21a is a histogram of the errors for the direct approach where the value of one bars is 11. FIG. 21b is a histogram of the errors for the binary approach, where the values of the bars are from left to right: 12 and 7. FIGS. 22a and b are plots showing the results of the transductive SVM using the CORRub feature selection method: FIG. 22a provides the results for 4 to 20 features compared with the inductive SVM method; FIG. 22b provides the results for the transductive method using 4 to 100 features. FIGS. 23a and b are plots showing the results of the transductive CORRub2 method compared to the inductive version of the CORRub2 method, with FIG. 23a showing the results or 4 to 25 features and FIG. 23b the results for 4 to 100 features. FIG. 24 is a scatter plot of the seven tumors in the two first gene principal components in an analysis of renal cancer. FIG. 25 is a graph of the distribution of margin values for 4 samples of one class drawn at random according to N(0,1) and 3 samples of another class drawn at random according to N(0,1). FIG. 26 is a plot of the criteria for gene ranking, where FIG. 26a illustrates results for a typical sample drawn from well-separated classes and FIG. 26b illustrates results for a model of an insignificant gene by randomly drawing examples of both classes from the same distribution N(0,1). FIG. 27 is a plot of genes called “significant” versus estimated falsely significant genes for comparing criteria of gene ranking. FIG. 28 is a pair of graphs showing results of SF-SVM analysis of expression data for two genes potentially related to the diseases, selected using the multiclass method, where FIG. 28a is the plot for small inducible cytokine A2 (monocyte chemotactic protein 1, homologous to mounse Sig-je) and FIG. 28b is the plot for ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit, isoform 1, cardiac muscle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides methods, systems and devices for discovering knowledge from data using learning machines. Particularly, the present invention is directed to methods, systems and devices for knowledge discovery from data using learning machines that are provided information regarding changes in biological systems. More particularly, the present invention comprises methods of use of such knowledge for diagnosing and prognosing changes in biological systems such as diseases. Additionally, the present invention comprises methods, compositions and devices for applying such knowledge to the testing and treating of individuals with changes in their individual biological systems. Preferred embodiments comprise detection of genes involved with prostate cancer and use of such information for treatment of patients with prostate cancer. As used herein, “biological data” means any data derived from measuring biological conditions of human, animals or other biological organisms including microorganisms, viruses, plants and other living organisms. The measurements may be made by any tests, assays or observations that are known to physicians, scientists, diagnosticians, or the like. Biological data may include, but is not limited to, clinical tests and observations, physical and chemical measurements, genomic determinations, proteomic determinations, drug levels, hormonal and immunological tests, neurochemical or neurophysical measurements, mineral and vitamin level determinations, genetic and familial histories, and other determinations that may give insight into the state of the individual or individuals that are undergoing testing. Herein, the use of the term “data” is used interchangeably with “biological data”. While several examples of learning machines exist and advancements are expected in this field, the exemplary embodiments of the present invention focus on kernel-based learning machines and more particularly on the support vector machine. The present invention can be used to analyze biological data generated at multiple stages of investigation into biological functions, and further, to integrate the different kinds of data for novel diagnostic and prognostic determinations. For example, biological data obtained from clinical case information, such as diagnostic test data, family or genetic histories, prior or current medical treatments, and the clinical outcomes of such activities, can be utilized in the methods, systems and devices of the present invention. Additionally, clinical samples such as diseased tissues or fluids, and normal tissues and fluids, and cell separations can provide biological data that can be utilized by the current invention. Proteomic determinations such as 2-D gel, mass spectrophotometry and antibody screening can be used to establish databases that can be utilized by the present invention. Genomic databases can also be used alone or in combination with the above-described data and databases by the present invention to provide comprehensive diagnosis, prognosis or predictive capabilities to the user of the present invention. A first aspect of the present invention facilitates analysis of data by pre-processing the data prior to using the data to train a learning machine and/or optionally post-processing the output from a learning machine. Generally stated, pre-processing data comprises reformatting or augmenting the data in order to allow the learning machine to be applied most advantageously. More specifically, pre-processing involves selecting a method for reducing the dimensionality of the feature space, i.e., selecting the features which best represent the data. Methods which may be used for this purpose include recursive feature elimination (RFE), minimizing the number of non-zero parameters of the system, evaluation of cost function to identify a subset of features that are compatible with constraints imposed by the learning set, unbalanced correlation score, inductive feature selection and transductive feature selection. The features remaining after feature selection are then used to train a learning machine for purposes of pattern classification, regression, clustering and/or novelty detection. In a manner similar to pre-processing, post-processing involves interpreting the output of a learning machine in order to discover meaningful characteristics thereof. The meaningful characteristics to be ascertained from the output may be problem- or data-specific. Post-processing involves interpreting the output into a form that, for example, may be understood by or is otherwise useful to a human observer, or converting the output into a form which may be readily received by another device for, e.g., archival or transmission. FIG. 1 is a flowchart illustrating a general method 100 for analyzing data using learning machines. The method 100 begins at starting block 101 and progresses to step 102 where a specific problem is formalized for application of analysis through machine learning. Particularly important is a proper formulation of the desired output of the learning machine. For instance, in predicting future performance of an individual equity instrument, or a market index, a learning machine is likely to achieve better performance when predicting the expected future change rather than predicting the future price level. The future price expectation can later be derived in a post-processing step as will be discussed later in this specification. After problem formalization, step 103 addresses training data collection. Training data comprises a set of data points having known characteristics. This data may come from customers, research facilities, academic institutions, national laboratories, commercial entities or other public or confidential sources. The source of the data and the types of data provided are not crucial to the methods. Training data may be collected from one or more local and/or remote sources. The data may be provided through any means such as via the internet, server linkages or discs, CD/ROMs, DVDs or other storage means. The collection of training data may be accomplished manually or by way of an automated process, such as known electronic data transfer methods. Accordingly, an exemplary embodiment of the learning machine for use in conjunction with the present invention may be implemented in a networked computer environment. Exemplary operating environments for implementing various embodiments of the learning machine will be described in detail with respect to FIGS. 4-5. At step 104, the collected training data is optionally pre-processed in order to allow the learning machine to be applied most advantageously toward extraction of the knowledge inherent to the training data. During this preprocessing stage a variety of different transformations can be performed on the data to enhance its usefulness. Such transformations, examples of which include addition of expert information, labeling, binary conversion, Fourier transformations, etc., will be readily apparent to those of skill in the art. However, the preprocessing of interest in the present invention is the reduction of dimensionality by way of feature selection, different methods of which are described in detail below. Returning to FIG. 1, an exemplary method 100 continues at step 106, where the learning machine is trained using the pre-processed data. As is known in the art, a learning machine is trained by adjusting its operating parameters until a desirable training output is achieved. The determination of whether a training output is desirable may be accomplished either manually or automatically by comparing the training output to the known characteristics of the training data. A learning machine is considered to be trained when its training output is within a predetermined error threshold from the known characteristics of the training data. In certain situations, it may be desirable, if not necessary, to post-process the training output of the learning machine at step 107. As mentioned, post-processing the output of a learning machine involves interpreting the output into a meaningful form. In the context of a regression problem, for example, it may be necessary to determine range categorizations for the output of a learning machine in order to determine if the input data points were correctly categorized. In the example of a pattern recognition problem, it is often not necessary to post-process the training output of a learning machine. At step 108, test data is optionally collected in preparation for testing the trained learning machine. Test data may be collected from one or more local and/or remote sources. In practice, test data and training data may be collected from the same source(s) at the same time. Thus, test data and training data sets can be divided out of a conunon data set and stored in a local storage medium for use as different input data sets for a learning machine. Regardless of how the test data is collected, any test data used must be pre-processed at step 110 in the same manner as was the training data. As should be apparent to those skilled in the art, a proper test of the learning may only be accomplished by using testing data of the same format as the training data. Then, at step 112 the learning machine is tested using the pre-processed test data, if any. The test output of the learning machine is optionally post-processed at step 114 in order to determine if the results are desirable. Again, the post processing step involves interpreting the test output into a meaningful form. The meaningful form may be one that is readily understood by a human or one that is compatible with another processor. Regardless, the test output must be post-processed into a form which may be compared to the test data to determine whether the results were desirable. Examples of post-processing steps include but are not limited of the following: optimal categorization determinations, scaling techniques (linear and non-linear), transformations (linear and non-linear), and probability estimations. The method 100 ends at step 116. FIG. 2 is a flow chart illustrating an exemplary method 200 for enhancing knowledge that may be discovered from data using a specific type of learning machine known as a support vector machine (SVM). A SVM implements a specialized algorithm for providing generalization when estimating a multi-dimensional function from a limited collection of data. A SVM may be particularly useful in solving dependency estimation problems. More specifically, a SVM may be used accurately in estimating indicator functions (e.g. pattern recognition problems) and real-valued functions (e.g. function approximation problems, regression estimation problems, density estimation problems, and solving inverse problems). The SVM was originally developed by Vladimir N. Vapnik. The concepts underlying the SVM are explained in detail in his book, entitled Statistical Leaning Theory (John Wiley & Sons, Inc. 1998), which is herein incorporated by reference in its entirety. Accordingly, a familiarity with SVMs and the terminology used therewith are presumed throughout this specification. The exemplary method 200 begins at starting block 201 and advances to step 202, where a problem is formulated and then to step 203, where a training data set is collected. As was described with reference to FIG. 1, training data may be collected from one or more local and/or remote sources, through a manual or automated process. At step 204 the training data is optionally pre-processed. Those skilled in the art should appreciate that SVMs are capable of processing input data having extremely large dimensionality, however, according to the present invention, pre-processing includes the use of feature selection methods to reduce the dimensionality of feature space. At step 206 a kernel is selected for the SVM. As is known in the art, different kernels will cause a SVM to produce varying degrees of quality in the output for a given set of input data. Therefore, the selection of an appropriate kernel may be essential to the desired quality of the output of the SVM. In one embodiment of the learning machine, a kernel may be chosen based on prior performance knowledge. As is known in the art, exemplary kernels include polynomial kernels, radial basis classifier kernels, linear kernels, etc. In an alternate embodiment, a customized kernel may be created that is specific to a particular problem or type of data set. In yet another embodiment, the multiple SVMs may be trained and tested simultaneously, each using a different kernel. The quality of the outputs for each simultaneously trained and tested SVM may be compared using a variety of selectable or weighted metrics (see step 222) to determine the most desirable kernel. In still another embodiment which is particularly advantageous for use with structured data, locational kernels are defined to exploit patterns within the structure. The locational kernels are then used to construct kernels on the structured object. Next, at step 208 the pre-processed training data is input into the SVM. At step 210, the SVM is trained using the pre-processed training data to generate an optimal hyperplane. Optionally, the training output of the SVM may then be post-processed at step 211. Again, post-processing of training output may be desirable, or even necessary, at this point in order to properly calculate ranges or categories for the output. At step 212 test data is collected similarly to previous descriptions of data collection. The test data is pre-processed at step 214 in the same manner as was the training data above. Then, at step 216 the pre-processed test data is input into the SVM for processing in order to determine whether the SVM was trained in a desirable manner. The test output is received from the SVM at step 218 and is optionally post-processed at step 220. Based on the post-processed test output, it is determined at step 222 whether an optimal minimum was achieved by the SVM. Those skilled in the art should appreciate that a SVM is operable to ascertain an output having a global minimum error. However, as mentioned above, output results of a SVM for a given data set will typically vary with kernel selection. Therefore, there are in fact multiple global minimums that may be ascertained by a SVM for a given set of data. As used herein, the term “optimal minimum” or “optimal solution” refers to a selected global minimum that is considered to be optimal (e.g. the optimal solution for a given set of problem specific, pre-established criteria) when compared to other global minimums ascertained by a SVM. Accordingly, at step 222, determining whether the optimal minimum has been ascertained may involve comparing the output of a SVM with a historical or predetermined value. Such a predetermined value may be dependant on the test data set. For example, in the context of a pattern recognition problem where data points are classified by a SVM as either having a certain characteristic or not having the characteristic, a global minimum error of 50% would not be optimal. In this example, a global minimum of 50% is no better than the result that would be achieved by flipping a coin to determine whether the data point had that characteristic. As another example, in the case where multiple SVMs are trained and tested simultaneously with varying kernels, the outputs for each SVM may be compared with output of other SVM to determine the practical optimal solution for that particular set of kernels. The determination of whether an optimal solution has been ascertained may be performed manually or through an automated comparison process. If it is determined that the optimal minimum has not been achieved by the trained SVM, the method advances to step 224, where the kernel selection is adjusted. Adjustment of the kernel selection may comprise selecting one or more new kernels or adjusting kernel parameters. Furthermore, in the case where multiple SVMs were trained and tested simultaneously, selected kernels may be replaced or modified while other kernels may be re-used for control purposes. After the kernel selection is adjusted, the method 200 is repeated from step 208, where the pre-processed training data is input into the SVM for training purposes. When it is determined at step 222 that the optimal minimum has been achieved, the method advances to step 226, where live data is collected similarly as described above. By definition, live data has not been previously evaluated, so that the desired output characteristics that were known with respect to the training data and the test data are not known. At step 228 the live data is pre-processed in the same manner as was the training data and the test data. At step 230, the live pre-processed data is input into the SVM for processing. The live output of the SVM is received at step 232 and is post-processed at step 234. The method 200 ends at step 236. FIG. 3 is a flow chart illustrating an exemplary optimal categorization method 300 that may be used for pre-processing data or post-processing output from a learning machine. Additionally, as will be described below, the exemplary optimal categorization method may be used as a stand-alone categorization technique, independent from learning machines. The exemplary optimal categorization method 300 begins at starting block 301 and progresses to step 302, where an input data set is received. The input data set comprises a sequence of data samples from a continuous variable. The data samples fall within two or more classification categories. Next, at step 304 the bin and class-tracking variables are initialized. As is known in the art, bin variables relate to resolution, while class-tracking variables relate to the number of classifications within the data set. Determining the values for initialization of the bin and class-tracking variables may be performed manually or through an automated process, such as a computer program for analyzing the input data set. At step 306, the data entropy for each bin is calculated. Entropy is a mathematical quantity that measures the uncertainty of a random distribution. In the exemplary method 300, entropy is used to gauge the graduations of the input variable so that maximum classification capability is achieved. The method 300 produces a series of “cuts” on the continuous variable, such that the continuous variable may be divided into discrete categories. The cuts selected by the exemplary method 300 are optimal in the sense that the average entropy of each resulting discrete category is minimized. At step 308, a determination is made as to whether all cuts have been placed within input data set comprising the continuous variable. If all cuts have not been placed, sequential bin combinations are tested for cutoff determination at step 310. From step 310, the exemplary method 300 loops back through step 306 and returns to step 308 where it is again determined whether all cuts have been placed within input data set comprising the continuous variable. When all cuts have been placed, the entropy for the entire system is evaluated at step 309 and compared to previous results from testing more or fewer cuts. If it cannot be concluded that a minimum entropy state has been determined, then other possible cut selections must be evaluated and the method proceeds to step 311. From step 311 a heretofore untested selection for number of cuts is chosen and the above process is repeated from step 304. When either the limits of the resolution determined by the bin width has been tested or the convergence to a minimum solution has been identified, the optimal classification criteria is output at step 312 and the exemplary optimal categorization method 300 ends at step 314. The optimal categorization method 300 takes advantage of dynamic programming techniques. As is known in the art, dynamic programming techniques may be used to significantly improve the efficiency of solving certain complex problems through carefully structuring an algorithm to reduce redundant calculations. In the optimal categorization problem, the straightforward approach of exhaustively searching through all possible cuts in the continuous variable data would result in an algorithm of exponential complexity and would render the problem intractable for even moderate sized inputs. By taking advantage of the additive property of the target function, in this problem the average entropy, the problem may be divide into a series of sub-problems. By properly formulating algorithmic sub-structures for solving each sub-problem and storing the solutions of the sub-problems, a significant amount of redundant computation may be identified and avoided. As a result of using the dynamic programming approach, the exemplary optimal categorization method 300 may be implemented as an algorithm having a polynomial complexity, which may be used to solve large sized problems. As mentioned above, the exemplary optimal categorization method 300 may be used in pre-processing data and/or post-processing the output of a learning machine. For example, as a pre-processing transformation step, the exemplary optimal categorization method 300 may be used to extract classification information from raw data. As a post-processing technique, the exemplary optimal range categorization method may be used to determine the optimal cut-off values for markers objectively based on data, rather than relying on ad hoc approaches. As should be apparent, the exemplary optimal categorization method 300 has applications in pattern recognition, classification, regression problems, etc. The exemplary optimal categorization method 300 may also be used as a stand-alone categorization technique, independent from SVMs and other learning machines. FIG. 4 and the following discussion are intended to provide a brief and general description of a suitable computing environment for implementing biological data analysis according to the present invention. Although the system shown in FIG. 4 is a conventional personal computer 1000, those skilled in the art will recognize that the invention also may be implemented using other types of computer system configurations. The computer 1000 includes a central processing unit 1022, a system memory 1020, and an Input/Output (“I/O”) bus 1026. A system bus 1021 couples the central processing unit 1022 to the system memory 1020. A bus controller 1023 controls the flow of data on the I/O bus 1026 and between the central processing unit 1022 and a variety of internal and external I/O devices. The I/O devices connected to the I/O bus 1026 may have direct access to the system memory 1020 using a Direct Memory Access (“DMA”) controller 1024. The IO devices are connected to the I/O bus 1026 via a set of device interfaces. The device interfaces may include both hardware components and software components. For instance, a hard disk drive 1030 and a floppy disk drive 1032 for reading or writing removable media 1050 may be connected to the I/O bus 1026 through disk drive controllers 1040. An optical disk drive 1034 for reading or writing optical media 1052 may be connected to the I/O bus 1026 using a Small Computer System Interface (“SCSI”) 1041. Alternatively, an IDE (Integrated Drive Electronics, i.e., a hard disk drive interface for PCs), ATAPI (ATtAchment Packet Interface, i.e., CD-ROM and tape drive interface), or EIDE (Enhanced IDE) interface may be associated with an optical drive such as may be the case with a CD-ROM drive. The drives and their associated computer-readable media provide nonvolatile storage for the computer 1000. In addition to the computer-readable media described above, other types of computer-readable media may also be used, such as ZIP drives, or the like. A display device 1053, such as a monitor, is connected to the I/O bus 1026 via another interface, such as a video adapter 1042. A parallel interface 1043 connects synchronous peripheral devices, such as a laser printer 1056, to the I/O bus 1026. A serial interface 1044 connects communication devices to the I/O bus 1026. A user may enter commands and information into the computer 1000 via the serial interface 1044 or by using an input device, such as a keyboard 1038, a mouse 1036 or a modem 1057. Other peripheral devices (not shown) may also be connected to the computer 1000, such as audio input/output devices or image capture devices. A number of program modules may be stored on the drives and in the system memory 1020. The system memory 1020 can include both Random Access Memory (“RAM”) and Read Only Memory (“ROM”). The program modules control how the computer 1000 functions and interacts with the user, with I/O devices or with other computers. Program modules include routines, operating systems 1065, application programs, data structures, and other software or firmware components. In an illustrative embodiment, the learning machine may comprise one or more pre-processing program modules 1075A, one or more post-processing program modules 1075B, and/or one or more optimal categorization program modules 1077 and one or more SVM program modules 1070 stored on the drives or in the system memory 1020 of the computer 1000. Specifically, pre-processing program modules 1075A, post-processing program modules 1075B, together with the SVM program modules 1070 may comprise computer-executable instructions for pre-processing data and post-processing output from a learning machine and implementing the learning algorithm according to the exemplary methods described with reference to FIGS. 1 and 2. Furthermore, optimal categorization program modules 1077 may comprise computer-executable instructions for optimally categorizing a data set according to the exemplary methods described with reference to FIG. 3. The computer 1000 may operate in a networked environment using logical connections to one or more remote computers, such as remote computer 1060. The remote computer 1060 may be a server, a router, a peer device or other common network node, and typically includes many or all of the elements described in connection with the computer 1000. In a networked environment, program modules and data may be stored on the remote computer 1060. The logical connections depicted in FIG. 4 include a local area network (“LAN”) 1054 and a wide area network (“WAN”) 1055. In a LAN environment, a network interface 1045, such as an Ethernet adapter card, can be used to connect the computer 1000 to the remote computer 1060. In a WAN environment, the computer 1000 may use a telecommunications device, such as a modem 1057, to establish a connection. It will be appreciated that the network connections shown are illustrative and other devices of establishing a communications link between the computers may be used. In another embodiment, a plurality of SVMs can be configured to hierarchically process multiple data sets in parallel or sequentially. In particular, one or more first-level SVMs may be trained and tested to process a first type of data and one or more first-level SVMs can be trained and tested to process a second type of data. Additional types of data may be processed by other first-level SVMs. The output from some or all of the first-level SVMs may be combined in a logical manner to produce an input data set for one or more second-level SVMs. In a similar fashion, output from a plurality of second-level SVMs may be combined in a logical manner to produce input data for one or more third-level SVM. The hierarchy of SVMs may be expanded to any number of levels as may be appropriate. In this manner, lower hierarchical level SVMs may be used to pre-process data that is to be input into higher level SVMs. Also, higher hierarchical level SVMs may be used to post-process data that is output from lower hierarchical level SVMs. Each SVM in the hierarchy or each hierarchical level of SVMs may be configured with a distinct kernel. For example, SVMs used to process a first type of data may be configured with a first type of kernel while SVMs used to process a second type of data may utilize a second, different type of kernel. In addition, multiple SVMs in the same or different hierarchical level may be configured to process the same type of data using distinct kernels. FIG. 5 illustrates an exemplary hierarchical system of SVMs. As shown, one or more first-level SVMs 1302a and 1302b may be trained and tested to process a first type of input data 1304a, such as mammography data, pertaining to a sample of medical patients. One or more of these SVMs may comprise a distinct kernel, indicated as “KERNEL 1” and “KERNEL 2”. Also, one or more additional first-level SVMs 1302c and 1302d may be trained and tested to process a second type of data 1304b, which may be, for example, genomic data for the same or a different sample of medical patients. Again, one or more of the additional SVMs may comprise a distinct kernel, indicated as “KERNEL 1” and “KERNEL 3”. The output from each of the like first-level SVMs may be compared with each other, e.g., 1306a compared with 1306b; 1306c compared with 1306d, in order to determine optimal outputs 1308a and 1308b. Then, the optimal outputs from the two groups or first-level SVMs, i.e., outputs 1308a and 1308b, may be combined to form a new multi-dimensional input data set 1310, for example, relating to manmmography and genomic data. The new data set may then be processed by one or more appropriately trained and tested second-level SVMs 1312a and 1312b. The resulting outputs 1314a and 1314b from second-level SVMs 1312a and 1312b may be compared to determine an optimal output 1316. Optimal output 1316 may identify causal relationships between the mammography and genomic data points. As should be apparent to those of skill in the art, other combinations of hierarchical SVMs may be used to process either in parallel or serially, data of different types in any field or industry in which analysis of data is desired. Feature Selection: Feature Selection by Recursive Feature Elimination. The problem of selection of a small amount of data from a large data source, such as a gene subset from a microarray, is particularly solved using the methods, devices and systems described herein. Previous attempts to address this problem used correlation techniques, i.e., assigning a coefficient to the strength of association between variables. In a first embodiment described herein, support vector machines methods based on recursive feature elimination (RFE) are used. In examining genetic data to find determinative genes, these methods eliminate gene redundancy automatically and yield better and more compact gene subsets. The methods, devices and systems described herein can be used with publicly-available data to find relevant answers, such as genes determinative of a cancer diagnosis, or with specifically generated data. The illustrative examples are directed at gene expression data manipulations, however, any data can be used in the methods, systems and devices described herein. There are studies of gene clusters discovered by unsupervised or supervised learning techniques. Preferred methods comprise application of SVMs in determining a small subset of highly discriminant genes that can be used to build very reliable cancer classifiers. Identification of discriminant genes is beneficial in confirming recent discoveries in research or in suggesting avenues for research or treatment. Diagnostic tests that measure the abundance of a given protein in bodily fluids may be derived from the discovery of a small subset of discriminant genes. In classification methods using SVMs, the input is a vector referred to as a “pattern” of n components referred to as “features”. F is defined as the n-dimensional feature space. In the examples given, the features are gene expression coefficients and the patterns correspond to patients. While the present discussion is directed to two-class classification problems, this is not to limit the scope of the invention. The two classes are identified with the symbols (+) and (−). A training set of a number of patterns {x1, x2, . . . xk, . . . xl} with known class labels {y1, y2, . . . yk, . . . yl}, ykε{−1,+1}, is given. The training patterns are used to build a decision function (or discriminant function) D(x), that is a scalar function of an input pattern x. New patterns are classified according to the sign of the decision function: D(x)>0→xε class(+); D(x)<0→xε class(−); D(x)=0, decision boundary; where ε means “is a member of”. Decision boundaries that are simple weighted sums of the training patterns plus a bias are referred to as “linear discriminant functions”, e.g., D(x)=w•x+b, (1) where w is the weight vector and b is a bias value. A data set is said to be linearly separable if a linear discriminant function can separate it without error. Feature selection in large dimensional input spaces is performed using greedy algorithms and feature ranking. A fixed number of top ranked features may be selected for further analysis or to design a classifier. Alternatively, a threshold can be set on the ranking criterion. Only the features whose criterion exceed the threshold are retained. A preferred method uses the ranking to define nested subsets of features, F1⊂F2⊂ . . . ⊂ F, and select an optimum subset of features with a model selection criterion by varying a single parameter: the number of features. Errorless separation can be achieved with any number of genes greater than one. Preferred methods comprise use of a smaller number of genes. Classical gene selection methods select the genes that individually best classify the training data. These methods include correlation methods and expression ratio methods. While the classical methods eliminate genes that are useless for discrimination (noise), they do not yield compact gene sets because genes are redundant. Moreover, complementary genes that individually do not separate well are missed. A simple feature ranking can be produced by evaluating how well an individual feature contributes to the separation (e.g. cancer vs. normal). Various correlation coefficients have been proposed as ranking criteria. For example, see, T. K. Golub, et al, “Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring”, Science 286, 531-37 (1999). The coefficient used by Golub et al. is defined as: ωi=(μi(+)−μi(−))/(σi(+)+σi(−)) (2) where μi and σi are the mean and standard deviation, respectively, of the gene expression values of a particular gene i for all the patients of class (+) or class (−), i=1, . . . n. Large positive ωi values indicate strong correlation with class (+) whereas large negative ωi values indicate strong correlation with class (−). The method described by Golub, et al. for feature ranking is to select an equal number of genes with positive and with negative correlation coefficient. Other methods use the absolute value of ωi as ranking criterion, or a related coefficient, (μi(+)−μi(−))2/(σi(+)2+σi(−)2). (3) What characterizes feature ranking with correlation methods is the implicit orthogonality assumptions that are made. Each coefficient ωi is computed with information about a single feature (gene) and does not take into account mutual information between features. One use of feature ranking is in the design of a class predictor (or classifier) based on a pre-selected subset of genes. Each feature which is correlated (or anti-correlated) with the separation of interest is by itself such a class predictor, albeit an imperfect one. A simple method of classification comprises a method based on weighted voting: the features vote in proportion to their correlation coefficient. Such is the method used by Golub, et al. The weighted voting scheme yields a particular linear discriminant classifier: D(x)=w•(x−μ), (4) where w is ωi=(μi(+)−μi(−))/(σi(+)+σi(−)) and μ=(μ(+)+μ(−))/2 Another classifier or class predictor is Fisher's linear discriminant. Such a classifier is similar to that of Golub et al. where w=S−1(μ(+)+μ(−)), (5) where S is the (n,n) within class scatter matrix defined as S = ∑ x ∈ X ⁡ ( + ) ⁢ ⁢ ( x - μ ⁡ ( + ) ) ⁢ ( x - μ ⁡ ( + ) ) T + ⁢ ⁢ ∑ x ∈ X ⁡ ( - ) ⁢ ⁢ x - μ ⁡ ( - ) ) ⁢ ( x - μ ⁡ ( - ) ) T , ( 6 ) where μ is the mean vector over all training patters and X(+) and X(−) are the training sets of class (+) and (−), respectively. This form of Fisher's discriminant implies that S is invertible, however, this is not the case if the number of features n is larger than the number of examples e since the rank of S is at most l. The classifiers of Equations 4 and 6 are similar if the scatter matrix is approximated by its diagonal elements. This approximation is exact when the vectors formed by the values of one feature across all training patterns are orthogonal, after subtracting the class mean. The approximation retains some validity if the features are uncorreclated, that is, if the expected value of the product of two different features is zero, after removing the class mean. Approximating S by its diagonal elements is one way of regularizing it (maling it invertible). However, features usually are correlated and, therefore, the diagonal approximation is not valid. One aspect of the present invention comprises using the feature ranking coefficients as classifier weights. Reciprocally, the weights multiplying the inputs of a given classifier can be used as feature ranling coefficients. The inputs that are weighted by the largest values have the most influence in the classification decision. Therefore, if the classifier performs well, those inputs with largest weights correspond to the most informative features, or in this instance, genes. Other methods, known as multivariate classifiers, comprise algorithms to train linear discriminant functions that provide superior feature ranking compared to correlation coefficients. Multivariate classifiers, such as the Fisher's linear discriminant (a combination of multiple univariate classifiers) and methods disclosed herein, are optimized during training to handle multiple variables or features simultaneously. For classification problems, the ideal objective function is the expected value of the error, i.e., the error rate computed on an infinite number of examples. For training purposes, this ideal objective is replaced by a cost function J computed on training examples only. Such a cost function is usually a bound or an approximation of the ideal objective, selected for convenience and efficiency. For linear SVMs, the cost fumction is: J=(½)∥w∥2, (7) which is minimized, under constraints, during training. The criteria (ωi)2 estimates the effect on the objective (cost) function of removing feature i. A good feature ranking criterion is not necessarily a good criterion for ranking feature subsets. Some criteria estimate the effect on the objective function of removing one feature at a time. These criteria become suboptimal when several features are removed at one time, which is necessary to obtain a small feature subset. Recursive Feature Elimination (RFE) methods can be used to overcome this problem. RFE methods comprise iteratively 1) training the classifier , 2) computing the ranking criterion for all features, and 3) removing the feature having the smallest ranking criterion. This iterative procedure is an example of backward feature elimination. For computational reasons, it may be more efficient to remove several features at a time at the expense of possible classification performance degradation. In such a case, the method produces a “feature subset ranking”, as opposed to a “feature ranking”. Feature subsets are nested, e.g., F1⊂F2⊂ . . . ⊂F. If features are removed one at a time, this results in a corresponding feature ranking. However, the features that are top ranked, i.e., eliminated last, are not necessarily the ones that are individually most relevant. It may be the case that the features of a subset Fm are optimal in some sense only when taken in some combination. RFE has no effect on correlation methods since the ranking criterion is computed using information about a single feature. In the present embodiment, the weights of a classifier are used to produce a feature ranking with a SVM (Support Vector Machine). The present invention contemplates methods of SVMs used for both linear and non-linear decision boundaries of arbitrary complexity, however, the example provided herein is directed to linear SVMs because of the nature of the data set under investigation. Linear SVMs are particular linear discriminant classifiers. (See Equation 1). If the training set is linearly separable, a linear SVM is a maximum margin classifier. The decision boundary (a straight line in the case of a two-dimension separation) is positioned to leave the largest possible margin on either side. One quality of SVMs is that the weights ωi of the decision function D(x) are a function only of a small subset of the training examples, i.e., “support vectors”. Support vectors are the examples that are closest to the decision boundary and lie on the margin. The existence of such support vectors is at the origin of the computational properties of SVM and its competitive classification performance. While SVMs base their decision function on the support vectors that are the borderline cases, other methods such as the previously-described method of Golub, et al., base the decision function on the average case. A preferred method of the present invention comprises using a variant of the soft-margin algorithm where training comprises executing a quadratic program as described by Cortes and Vapnik in “Support vector networks”, 1995, Machine Learning, 20:3, 273-297, which is incorporated herein by reference in its entirety. The following is provided as an example, however, different programs are contemplated by the present invention and can be determined by those skilled in the art for the particular data sets involved. Inputs comprise training examples (vectors) {x1, xl, . . . xk . . . xl} and class labels {y1, y2 . . . yk . . . yl}. To identify the optimal hyperplane, the following quadratic program is executed: { Minimize ⁢ ⁢ over ⁢ ⁢ α k ⁢ : J = ( 1 / 2 ) ⁢ ∑ hk ⁢ ⁢ y h ⁢ y k ⁢ α h ⁢ α k ⁡ ( x h · x k + λδ hk ) - ∑ k ⁢ ⁢ α k subject ⁢ ⁢ to ⁢ : 0 ≤ α k ≤ C ⁢ ⁢ and ⁢ ⁢ ∑ k ⁢ ⁢ α k ⁢ y k = 0 ( 8 ) with the resulting outputs being the parameters αk, where the summations run over all training patterns xk that are n dimensional feature vectors, xh•xk denotes the scalar product, yk encodes the class label as a binary value=1 or −1, δhk is the Kronecker symbol (δhk=1 if h=k and 0 otherwise), and λ and C are positive constants (soft margin parameters). The soft margin parameters ensure convergence even when the problem is non-linearly separable or poorly conditioned. In such cases, some support vectors may not lie on the margin. Methods include relying on λ or C, but preferred methods, and those used in the Examples below, use a small value of λ (on the order of 10−14) to ensure numerical stability. For the Examples provided herein, the solution is rather insensitive to the value of C because the training data sets are linearly separable down to only a few features. A value of C=100 is adequate, however, other methods may use other values of C. The resulting decision function of an input vector x is: D(x)=w·x+b (9) with w = ∑ k ⁢ ⁢ α k ⁢ y k ⁢ x k ⁢ ⁢ and ⁢ ⁢ b = 〈 y k - w · x k 〉 The weight vector w is a linear combination of training patterns. Most weights αk are zero. The training patterns with non-zero weights are support vectors. Those having a weight that satisfies the strict inequality 0<αk<C are marginal support vectors. The bias value b is an average over marginal support vectors. The following sequence illustrates application of recursive feature elimination (RFE) to a SVM using the weight magnitude as the ranking criterion. The inputs are training examples (vectors): X0=[x1, x2, . . . xk . . . xl]T and class labels Y=[y1, y2 . . . Yk . . . yl]T. Initalize: Subset of surviving features s=[1,2, . . . n] Features ranked list r=[] Repeat until s=[] Restrict training examples to good feature indices X=X0(:,s) Train the classifier α=SVM train(X,y) Compute the weight vector of dimension length(s): w = ∑ k ⁢ ⁢ α k ⁢ y k ⁢ x k Compute the ranking criteria ci=(ωi)2, for all i Find the feature with smallest ranking criterion f=arginin(c) Update feature ranked list r=[s(f),r] Eliminate the feature with smallest ranking criterion s=s(1:f−1,f=1:length (s)) The output comprises feature ranked list r. The above steps can be modified to increase computing speed by generalizing the algorithm to remove more than one feature per step. In general, RFE is computationally expensive when compared against correlation methods, where several thousands of input data points can be ranked in about one second using a Pentium® processor, and weights of the classifier trained only once with all features, such as SVMs or pseudo-inverse/mean squared error (MSE). A SVM implemented using non-optimized MatLab® code on a Pentium® processor can provide a solution in a few seconds. To increase computational speed, RFE is preferrably implemented by training multiple classifiers on subsets of features of decreasing size. Training time scales linearly with the number of classifiers to be trained. The trade-off is computational time versus accuracy. Use of RFE provides better feature selection than can be obtained by using the weights of a single classifier. Better results are also obtained by eliminating one feature at a time as opposed to eliminating chunks of features. However, significant differences are seen only for a smaller subset of features such as fewer than 100. Without trading accuracy for speed, RFE can be used by removing chunks of features in the first few iterations and then, in later iterations, removing one feature at a time once the feature set reaches a few hundreds. RFE can be used when the number of features, e.g., genes, is increased to millions. In one example, at the first iteration, the number of genes were reached that was the closest power of two. At subsequent iterations, half of the remaining genes were eliminated, such that each iteration was reduced by a power of two. Nested subsets of genes were obtained that had increasing information density. RFE consistently outperforms the naïve ranking, particularly for small feature subsets. (The naïve ranking comprises ranking the features with (ωi)2, which is computationally equivalent to the first iteration of RFE.) The naïve ranking organizes features according to their individual relevance, while RFE ranking is a feature subset ranking. The nested feature subsets contain complementary features that individually are not necessarily the most relevant. An important aspect of SVM feature selection is that clean data is most preferred because outliers play an essential role. The selection of useful patterns, support vectors, and selection of useful features are connected. Pre-processing can have a strong impact on SVM-RFE. In particular, feature scales must be comparable. One pre-processing method is to subtract the mean of a feature from each feature, then divide the result by its standard deviation. Such pre-processing is not necessary if scaling is taken into account in the computational cost function. Another pre-processing operation can be performed to reduce skew in the data distribution and provide more uniform distribution. This pre-processing step involves taking the log of the value, which is particularly advantageous when the data consists of gene expression coefficients, which are often obtained by computing the ratio of two values. For example, in a competitive hybridization scheme, DNA from two samples that are labeled differently are hybridized onto the array. One obtains at every point of the array two coefficients corresponding to the fluorescence of the two labels and reflecting the fraction of DNA of either sample that hybridized to the particular gene. Typically, the first initial preprocessing step that is taken is to take the ratio a/b of these two values. Though this initial preprocessing step is adequate, it may not be optimal when the two values are small. Other initial preprocessing steps include (a−b)/(a+b) and (log a−log b)/(log a+log b). Another pre-processing step involved normalizing the data across all samples by subtracting the mean. This preprocessing step is supported by the fact that, using tissue samples, there are variations in experimental conditions from microarray to microarray. Although standard deviation seems to remain fairly constant, the other preprocessing step selected was to divide the gene expression values by the standard deviation to obtain centered data of standardized variance. To normalize each gene expression across multiple tissue samples, the mean expression value and standard deviation for each gene was computed. For all the tissue sample values of that gene (training and test), that mean was then subtracted and the resultant value was divided by the standard deviation. In some experiments, an additional preprocessing step was added by passing the data through a squashing function [ƒ(x)=c antan (x/c)] to diminish the importance of the outliers. In a variation on several of the preceding pre-processing methods, the data can be pre-processed by a simple “whitening” to make data matrix resemble “white noise.” The samples can be pre-processed to: normalize matrix columns; normalize matrix lines; and normalize columns again. Normalization consists of subtracting the mean and dividing by the standard deviation. A further normalization step can be taken when the samples are split into a training set and a test set. The mean and variance column-wise was computed for the training samples only. All samples (training and test samples) were then normalized by subtracting that mean and dividing by the standard deviation. In addition to the above-described linear example, SVM-RFE can be used in nonlinear cases and other kernel methods. The method of eliminating features on the basis of the smallest change in cost function can be extended to nonlinear uses and to all kernel methods in general. Computations can be made tractable by assuming no change in the value of the α's. Thus, the classifer need not be retrained for every candidate feature to be eliminated. Specifically, in the case of SVMs, the cost function to be minimized (under the constraints 0≦αk≦C and Σkαkγk=0) is: J=(½)αTHα−αT1, (10) where H is the matrix with elements γkγkK(xkxk), K is a kernel function that measures the similarity between xh and xk,, and 1 is an l dimensional vector of ones. An example of such a kernel function is K(xhxk)=exp(−γ∥ xh−xk∥2). (11) To compute the change in cost function caused by removing input component i, one leaves the α's unchanged and recomputes matrix H. This corresponds to computing K(xh (−i), xk (−i), yielding matrix H(−i), where the notation (−i) means that component i has been removed. The resulting ranking coefficient is: DJ(i)=(½)αT Hα−(½)αTH(−i)α (12) The input corresponding to the smallest difference DJ(i) is then removed. The procedure is repeated to carry out Recursive Feature Elimination (RFE). The advantages of RFE are further illustrated by the following example, which is not to be construed in any way as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims. EXAMPLE 1 Analysis of Gene Patterns Related to Colon Cancer Analysis of data from diagnostic genetic testing, microarray data of gene expression vectors, was performed with a SVM-RFE. The original data for this example was derived from the data presented in Alon et al., 1999. Gene expression information was extracted from microarray data resulting, after pre-processing, in a table of 62 tissues×2000 genes. The 62 tissues include 22 normal tissues and 40 colon cancer tissues. The matrix contains the expression of the 2000 genes with highest minimal intensity across the 62 tissues. Some of the genes are non-human genes. The data proved to be relatively easy to separate. After preprocessing, it was possible to a find a weighted sum of a set of only a few genes that separated without error the entire data set, thus the data set was linearly separable. One problem in the colon cancer data set was that tumor samples and normal samples differed in cell composition. Tumor samples were normally rich in epithelial cells wherein normal samples were a mixture of cell types, including a large fraction of smooth muscle cells. While the samples could be easily separated on the basis of cell composition, this separation was not very informative for tracking cancer-related genes. The gene selection method using RFE-SVM is compared against a reference gene selection method described in Golub et al, Science, 1999, which is referred to as the “baseline method” Since there was no defined training and test set, the data was randomly split into 31 samples for training and 31 samples for testing. In Golub et al., the authors use several metrics of classifier quality, including error rate, rejection rate at fixed threshold, and classification confidence. Each value is computed both on the independent test set and using the leave-one-out method on the training set. The leave-one-out method consists of removing one example from the training set, constructing the decision function on the basis only of the remaining training data and then testing on the removed example. In this method, one tests all examples of the training data and measures the fraction of errors over the total number of training examples. The methods of this Example uses a modification of the above metrics. The present classification methods use various decision functions (D(x) whose inputs are gene expression coefficients and whose outputs are a signed number indicative of whether or not cancer was present. The classification decision is carried out according to the sign of D(x). The magnitude of D(x) is indicative of classification confidence. Four metrics of classifier quality were used: (1) Error (B1+B2)=number of errors (“bad”) at zero rejection; (2) Reject (R1+R2)=minimum number of rejected samples to obtain zero error; Extremal margin (E/D)=difference between the smallest output of the positive class samples and the largest output of the negative class samples (rescaled by the largest difference between outputs); and Median margin (M/D)=difference between the median output of the positive class samples and the median output of the negative class samples (resealed by the largest difference between outputs). Each value is computed both on the training set with the leave-one-out method and on the test set. The error rate is the fraction of examples that are misclassified (corresponding to a diagnostic error). The error rate is complemented by the success rate. The rejection rate is the fraction of examples that are rejected (on which no decision is made because of low confidence). The rejection rate is complemented by the acceptance rate. Extremal and median margins are measurements of classification confidence. Note that the margin computed with the leave-one-out method or on the test set differs from the margin computed on training examples sometimes used in model selection criteria. A method for predicting the optimum subset of genes comprised defining a criterion of optimality that uses information derived from training examples only. This criterion was checked by determining whether the predicted gene subset performed best on the test set. A criterion that is often used in similar “model selection” problems is the leave-one-out success rate Vsuc. In the present example, it was of little use since differentiation between many classifiers that have zero leave-one-out error is not allowed. Such differentiation is obtained by using a criterion that combines all of the quality metrics computed by cross-validation with the leave-one-out method: Q=Vsuc+Vacc+Vext+Vmed (13) where Vsuc is the success rate, Vacc the acceptance rate, Vext the extremal margin, and Vmed is the median margin. Theoretical considerations suggested modification of this criterion to penalize large gene sets. The probability of observing large differences between the leave-one-out error and the test error increases with the size d of the gene set, according to ε(d)=sqrt(−log(α)+log(G(d)))·sqrt(p(1−p)/n) (14) where (1−α) is the confidence (typically 95%, i.e., α=0.05), p is the “true” error rate (p<=0.01), and n is the size of the training set. Following the guaranteed risk principle, a quantity proportional to ε(d) was subtracted from criterion Q to obtain a new criterion: C=Q−2 ε(d) (15) The coefficient of proportionality was computed heuristically, assuming that Vsuc, Vacc, Vext and Vmed are independent random variables with the same error bar ε(d) and that this error bar is commensurate to a standard deviation. In this case, variances would be additive, therefore, the error bar should be multiplied by sqrt(4). A SVM-RFE was run on the raw data to assess the validity of the method. The colon cancer data samples were split randomly into 31 examples for training and 31 examples for testing. The RFE method was run to progressively downsize the number of genes, each time dividing the number by 2. The pre-processing of the data for each gene expression value consisted of subtracting the mean from the value, then dividing the resultby the standard deviation. The leave-one-out method with the classifier quality criterion was used to estimate the optimum number of genes. The leave-one-out method comprises taking out one example of the training set. Training is then performed on the remaining examples, with the left out example being used to test the trained classifier. This procedure is iterated over all the examples. Each criteria is computed as an average over all examples. The overall classifier quality criterion is calculated according to Equation 13. The classifier is a linear classifier with hard margin. Results of the SVM-RFE as taught herein show that at the optimum predicted by the method using training data only, the leave-one-out error is zero and the test performance is actually optimum. The optimum test performance had an 81% success rate without pre-processing to remove skew and to normalize the data. This result was consistent with the results reported in the original paper by Alon et al. Moreover, the errors, except for one, were identified by Alon et al. as outliers. The plot of the performance curves as a function of gene number is shown in FIG. 6. The predictor of optimum test success rate (diamond curve), which is obtained by smoothing after substracting ε from the leave-one-out quality criterion, coincides with the actual test success rate (circle curve) in finding the optimum number of genes to be 4. When used in conjunction with pre-processing according to the description above to remove skew and normalize across samples, a SVM-RFE provided further improvement. FIG. 7 shows the results of RFE after preprocessing, where the predicted optimum test success rate is achieved with 16 genes. The reduced capacity SVM used in FIG. 6 is replaced by plain SVM. Although a log2 scale is still used for gene number, RFE was run by eliminating one gene at a time. The best test performance is 90% classification accuracy (8 genes). The optimum number of genes predicted from the classifier quality based on training data information only is 16. This corresponds to 87% classification accuracy on the test set. Because of data redundancy, it was possible to find many subsets of genes that provide a reasonable separation. To analyze the results, the relatedness of the genes should be understand. While not wishing to be bound by any particular theory, it was the initial theory that the problem of gene selection was to find an optimum number of genes, preferably small, that separates normal tissues from cancer tissues with maximum accuracy. SVM-RFE used a subset of genes that were complementary and thus carried little redundant information. No other information on the structure and nature of the data was provided. Because data were very redundant, a gene that had not been selected may nevertheless be informative for the separation. Correlation methods such as Golub's method provide a ranked list of genes. The rank order characterizes how correlated the gene is with the separation. Generally, a gene highly ranked taken alone provides a better separation than a lower ranked gene. It is therefore possible to set a threshold (e.g. keep only the top ranked genes) that separates “highly informative genes” from “less informative genes”. The methods of the present invention such as SVM-RFE provide subsets of genes that are both smaller and more discriminant. The gene selection method using SVM-RFE also provides a ranked list of genes. With this list, nested subsets of genes of increasing sizes can be defined. However, the fact that one gene has a higher rank than another gene does not mean that this one factor alone characterizes the better separation. In fact, genes that are eliminated in an early iteration could well be very informative but redundant with others that were kept. The 32 best genes as a whole provide a good separation but individually may not be very correlated with the target separation. Gene ranking allows for a building nested subsets of genes that provide good separations, however it provides no information as to how good an individual gene may be. Genes of any rank may be correlated with the 32 best genes. The correlated genes may be ruled out at some point because of their redundancy with some of the remaining genes, not because they did not carry information relative to the target separation. The gene ranking alone is insufficient to characterize which genes are informative and which ones are not, and also to determine which genes are complementary and which ones are redundant. Therefore, additional pre-processing in the form of clustering was performed. To overcome the problems of gene ranking alone, the data was preprocessed with an unsupervised clustering method. Genes were grouped according to resemblance (according to a given metric). Cluster centers were then used instead of genes themselves and processed by SVM-RFE to produce nested subsets of cluster centers. An optimum subset size can be chosen with the same cross-validation method used before. Using the data, the QTclust clustering algorithm was used to produce 100 dense clusters. (The “quality clustering algorithm” (QTclust) is well known to those of skill in the field of analysis of gene expression profiles.) The similarity measure used was Pearson's correlation coefficient (as commonly used for gene clustering). FIG. 8 provides the performance curves of the results of RFE when trained on 100 dense QTclust clusters. As indicated, the predicted optimum number of gene cluster centers is 8. The results of this analysis are comparable to those of FIG. 7. With unsupervised clustering, a set of informative genes is defined, but there is no guarantee that the genes not retained do not carry information. When RFE was used on all QTclust clusters plus the remaining non-clustered genes (singleton clusters), the performance curves were quite similar, though the top set of gene clusters selected was completely different and included mostly singletons. The cluster centers can be substituted by any of their members. This factor may be important in the design of some medical diagnosis tests. For example, the administration of some proteins may be easier than that of others. Having a choice of alternative genes introduces flexibility in the treatment and administration choices. Hierarchical clustering instead of QTclust clustering was used to produce lots of small clusters containing 2 elements on average. Because of the smaller cluster cardinality, there were fewer gene alternatives from which to choose. In this instance, hierarchical clustering did not yield as good a result as using QTclust clustering. The present invention contemplates use of any of the known methods for clustering, including but not limited to hierarchical clustering, QTclust clustering and SVM clustering. The choice of which clustering method to employ in the invention is affected by the initial data and the outcome desired, and can be determined by those skilled in the art. Another method used with the present invention was to use clustering as a post-processing step of SVM-RFE. Each gene selected by running regular SVM-RFE on the original set of gene expression coefficients was used as a cluster center. For example, the results described with reference to FIG. 7 were used. For each of the top eight genes, the correlation coefficient was computed with all remaining genes. The parameters were that the genes clustered to gene i were those that met the following two conditions: higher correlation coefficient with gene i than with other genes in the selected subset of eight genes, and correlation coefficient exceeding a threshold θ. Compared to the unsupervised clustering method and results, the supervised clustering method, in this instance, does not provide better control over the number of examples per cluster. Therefore, this method is not as good as unsupervised clustering if the goal is the ability to select from a variety of genes in each cluster. However, supervised clustering may show specific clusters that have relevance for the specific knowledge being determined. In this particular embodiment, in particular, a very large cluster of genes was found that contained several muscle genes that may be related to tissue composition and may not be relevant to the cancer vs. normal separation. Thus, those genes are good candidates for elimination from consideration as having little bearing on the diagnosis or prognosis for colon cancer. An additional pre-processing operation involved the use of expert knowledge to eliminating data that are known to complicate analysis due to the difficulty in differentiating the data from other data that is known to be useful. In the present Example, tissue composition-related genes were automatically eliminated in the pre-processing step by searching for the phrase “smooth muscle”. Other means for searching the data for indicators of the smooth muscle genes may be used. The number of genes selected by Recursive Feature Elimination (RFE) was varied and was tested with different methods. Training was done on the entire data set of 62 samples. The curves represent the leave-one-out success rate. For comparison, the results obtained using several different methods for gene selection from colon cancer data are provided in FIG. 9. SVM-RFE is compared to Linear Discriminant Analysis (LDA)-RFE; Mean Squared Error (Pseudo-inverse)-(MSE)-RFE and the baseline method (Golub, 1999). As indicated, SVM-RFE provides the best results down to 4 genes. An examination of the genes selected reveals that SVM eliminates genes that are tissue composition-related and keeps only genes that are relevant to the cancer vs. normal separation. Conversely, other methods retain smooth muscle genes in their top ranked genes which aids in separating most samples, but is not relevant to the cancer vs. normal discrimination. All methods that do not make independent assumptions outperform Golub's method and reach 100% leave-one-out accuracy for at least one value of the number of genes. LDA may be at a slight disadvantage on these plots because, for computational reasons, RFE was used by eliminating chunks of genes that decrease in size by powers of two. Other methods use RFE by eliminating one gene at a time. Down to four genes, SVM-RFE provided better performance than the other methods. All methods predicted an optimum number of genes smaller or equal to 64 using the criterion of the Equation 15. The genes ranking 1 through 64 for all the methods studied were compared. The first gene that was related to tissue composition and mentions “smooth muscle” in its description ranks 5 for Golub's method, 4 for LDA, 1 for MSE and only 41 for SVM. Therefore, this was a strong indication that SVMs make a better use of the data compared with other methods since they are the only methods that effectively factors out tissue composition-related genes while providing highly accurate separations with a small subset of genes. FIG. 10 is a plot of an optimum number of genes for evaluation of colon cancer data using RFE-SVM. The number of genes selected by recursive gene elimination with SVMs was varied and a number of quality metrics were evaluated include error rate on the test set, scaled quality criterion (Q/4), scaled criterion of optimality (C/4), locally smoothed C/4 and scaled theoretical error bar (ε/2). The curves are related by C=Q−2ε. The model selection criterion was used in a variety of other experiments using SVMs and other algorithms. The optimum number of genes was always predicted accurately, within a factor of two of the number of genes. Feature Selection by Minimizing l0-norm. A second method of feature selection according to the present invention comprises minimizing the l0-norm of parameter vectors. Such a procedure is central to many tasks in machine learning, including feature selection, vector quantization and compression methods. This method constructs a classifier which separates data using the smallest possible number of features. Specifically, the lo-norm of w is minimized by solving the optimization problem min w ⁢  w  0 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( 〈 w , x i 〉 + b ) ≥ 1 , ( 16 ) where ∥w∥0=card {ωi|ωi≠0}. In other words, the goal is to find the fewest non-zero elements in the vector of coefficients ω. However, because this problem is combinatorially hard, the following approximation is used: min w ⁢ ∑ j = 1 n ⁢ ⁢ ln ⁡ ( ɛ +  w j  ) ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( 〈 w , x i 〉 + b ) ≥ 1 ( 17 ) where ε<<1 has been introduced in order to avoid ill-posed problems where one of the ωj is zero. Because there are many local minima, Equation 17 can be solved by using constrained gradient. Let ωi(ε), also written ωi when the context is clear, be the minimizer of Equation 17, and ω0 the minimizer of Equation 16, which provides ∑ j = 1 n ⁢ ⁢ ln ⁡ ( ɛ +  ( w l ) j  ) ≤ ∑ j = 1 n ⁢ ⁢ ln ⁡ ( ɛ +  ( w 0 ) j  ) ( 18 ) ⁢ ≤ ∑ ( w 0 ) j = 0 ⁢ ⁢ ln ⁡ ( ɛ ) ⁢ ∑ ( w 0 ) j ≠ 0 ⁢ ⁢ ln ⁡ ( ɛ +  ( w 0 ) j  ) ( 19 ) ⁢ ≤ ( n -  w 0  0 ) ⁢ ln ⁡ ( ɛ ) + ∑ ln ⁡ ( ɛ +  ( w 0 ) j  ) . ( 20 ) The second term of the right hand side of Equation 20 is negligible compared to the 1n(ε) term when ε is very small. Thus, ( n -  w l  0 ) ⁢ ln ⁡ ( ɛ ) + ∑ ( w l ) j ≠ 0 ⁢ ln ⁡ ( ɛ +  ( w l ) j  ) ≤ ( n -  w 0  0 ) ⁢ ln ⁡ ( ɛ ) ( 21 )  w l  0 ≤  w 0  0 - ∑ ( w l ) j ≠ 0 ⁢ ⁢ ln ⁡ ( ɛ +  ( w l ) j  ) ln ⁡ ( 1 / ɛ ) . ( 22 ) Depending on the value of (ωi(ε))j, the sum on the right-hand side can be large or small when ε→0. This will depend mainly on the problem at hand. Note, however, that if ε is very small, for example, if ε equals the machine precision, then as soon as (ωi)j is Ω(1), the zero norm of ωi is the same as the zero norm of ω0. The foregoing supports that fact that for the objective problem of Equation 17 it is better to set ωj to zero whenever possible. This is due to the form of the logarithm function that decreases quickly to zero compared to its increase for large values of ωj. Thus, it is better to increase one ωj while setting another to zero rather than making a compromise between both. From this point forward, it will be assumed that ε is equal to the machine precision. To solve the problem of Equation 17, an iterative method is used which performs a gradient step at each iteration. The method known as Franke and Wolfe's method is proved to converge to a local minimum. For the problem of interest, it takes the following form, which can be defined as an “Approximation of the l0-norm Minimization”, or “AL0M”: 1. Start with ω=(1, . . . , l) 2. Assume ωk is given. Solve min ⁢ ∑ j = 1 n ⁢ ⁢  w j  ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( 〈 w , ( x i * w k ) 〉 + b ) ≥ 1. ( 23 ) 3. Let {circumflex over (ω)} be the solution of the previous problem. Set ωk+1=ωk≠{circumflex over (ω)}. 4. Repeat steps 2 and 3 until convergence. AL0M solves a succession of linear optimization problems with non-sparse constraints. Sometimes, it may be more advantageous to have a quadratic programming formulation of these problems since the dual may have simple constraints and may then become easy to solve. As a generalization of the previous method, the present embodiment uses a procedure referred to as “l2-AL0M” to minimize the l0 norm as follows: 1. Start with ω=(1, . . . , l) 2. Assume ωk is given. Solve min w ⁢  w  2 2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( 〈 w , ( x i * w k ) 〉 + b ) ≥ 1. ( 24 ) 3. Let {circumflex over (ω)} be the solution of the previous problem. Set ωk+1=ωk≠{circumflex over (ω)}. 4. Repeat steps 2 and 3 until convergence. This method is developed for a linearly-separable learning set. When many classes are involved, one could use a classical trick that consists of decomposing the multiclass problem into many two-class problems. Generally, a “one-against-all” approach is used. One vector ωc and one bias bc are defined for each class c, and the output is computed as f ⁡ ( x ) = arg ⁢ ⁢ max c ⁢ 〈 w c , x 〉 + b c . ( 25 ) Then, the vector ωc is learned by discriminating the class c from all other classes. This gives many two-class problems. In this framework, the minimization of the l0-norm is done for each vector ωc independently of the others. However, the true l0-norm is the following: ∑ c = 1 K ⁢  w c  0 ( 26 ) where K is the number of classes. Thus, applying this kind of decomposition scheme adds a suboptimal process to the overall method. To perform a l0-norm minimization for the multi-class problems, the above-described l2 approximation method is used with different constraints and a different system: 1. ⁢ ⁢ Start ⁢ ⁢ with ⁢ ⁢ w c = ( 1 , … ⁢ , 1 ) , ⁢ for ⁢ ⁢ c = 1 , … ⁢ , K ⁢ ⁢ ⁢ 2. ⁢ ⁢ Assume ⁢ ⁢ W k = ( w 1 k , … ⁢ , w c k , … ⁢ , w K k ) ⁢ ⁢ is ⁢ ⁢ given . ⁢ Solve ⁢ ⁢ ⁢ min w ⁢ ∑ c = 1 K ⁢  w c  2 2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ ⁢ 〈 w c ⁡ ( i ) , ( x i * w c ) ⁢ i ) k ) 〉 - 〈 w c , ( x i * w c k ) 〉 + b c ⁡ ( i ) - b c ≥ 1 ( 27 ) for c=1, . . . , K. 3. Let Ŵ be the solution to the previous problem. Set Wk+1=Wk*Ŵ. 4. Repeat steps 2 and 3 until convergence. As for the two-class case, this procedure is related to the following minimization problem: min w ⁢ ∑ c = 1 K ⁢ ⁢ ∑ j = 1 n ⁢ ln ( ɛ +  ( w c ) j  ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w c ⁡ ( i ) , ( x i * w c ⁡ ( i ) k ) 〉 - 〈 w c , ( x i * w c k ) 〉 + b c ⁡ ( i ) - b c ≥ 1 ⁢ for ⁢ ⁢ k = 1 , … ⁢ , C . ( 28 ) In order to generalize this algorithm to the non-linear case, the following dual optimization problem must be considered: max α i ⁢ - 1 2 ⁢ ∑ i , j = 1 1 ⁢ α i ⁢ α j ⁢ y i ⁢ y j ⁢ 〈 x i , x 〉 + ∑ i = 1 1 ⁢ α i ⁢ ⁢ subject ⁢ ⁢ to ⁢ ⁢ ∑ i = 1 1 ⁢ α i ⁢ y i ( 29 ) where C≧αi≧0 and where αi are the dual variables related to the constraints yi(<w,xi>+b)≧1−ξi. The solution of this problem can then be used to compute the value of w and b. In particular, 〈 w , x 〉 = ∑ i = 1 l ⁢ α i ⁢ y i ⁢ 〈 x i , x 〉 . ( 30 ) This means that the decision function of Equation 1, which may also be represented as D(x)=sign (<w,x>+b), can only be computed using dot products. As a result, any kind of function k(. , .) can be used instead of <. , .> if k can be understood as a dot-product. Accordingly, the function Φ(x)=φ1(x), . . . , φi(x)εl2 which maps points xi into a feature space such that k(x1, x2) can be interpreted as a dot product in feature space. To apply the procedure in feature space it is necessary to compute element-wise multiplication in feature space. In order to avoid directly computing vectors in feature space, this multiplication is performed with kernels. Multiplications in feature space are of the form φ(x)* φ(y). First, consider feature spaces which are sums of monomials of order d. That is, kernels that describe feature spaces of the form φd(x)=(x1l, . . . , x1d :i≦i1, i2, . . . , id≦N). Next, perform an element-wise multiplication in this space: φd(x)*φd(y)=(xi1yi1 . . . xidyid :i≦i1,i2, . . . ,id≦N), which is equal to φd(x*y)=(xi1yi1 . . . xidyid :i≦i1,i2, . . . , id≦N). Therefore, instead of calculating φ(x)*φ(y), the equivalent expression can be calculated, avoiding computation of vector in feature space. This can be extended to feature spaces with monomials of degree d or less (polynomials) by noticing that φ1:d(x)=(φp(x):1≦p≦d) and φ1:d(x*y)=φ1:d(x)*φ1:d(y). (31) Applying this to the problem at hand, one needs to compute both w*xi and ((w*xi), xj). The following shows how to approximate such a calculation. After training an SVM, minimizing the l2-norm in dual form, one obtains the vector ω expressed by coefficients α w = ∑ i = 1 l ⁢ α i ⁢ y i ⁢ ϕ ⁡ ( x i ) . ( 32 ) The map φ(xi)→φ(xi)*ω must be computed to calculate the dot products (the kernel) between training data. Thus, a kernel function between data points xi and xj is now kM1(xi,xj)=((φ(xi)*ω),(φ(xj)*ω))=(φ(xi)*φ(xj),(ω*ω)). (33) Let the vector si be the vector that scales the original dot product on iteration i+1 of the algorithm. Then, so is the vector of ones, s1=(ω*ω) and, in general, si=si−1*(ω*ω) when ω is the vector of coefficients from training on step i. Thus, the kernel function on iteration i+1 is ks1(xi,xj)=((φ(xi)*φ(xj),si). Considering the kernel for iteration 2, s1, k s i ⁡ ( x i , x j ) = ⁢ 〈 ( ϕ ⁡ ( x i ) * ϕ ⁡ ( x j ) , s i 〉 = ⁢ 〈 ( ϕ ⁡ ( x i ) * s i ) , ϕ ⁡ ( x j ) 〉 Now, s1=(ω*ω). For polynomial type kernels utilizing Equations 31 and 32, s 1 = ∑ n , m = 1 l ⁢ α n ⁢ α m ⁢ y n ⁢ y m ⁢ ϕ ⁡ ( x n * x m ) . ( 34 ) This produces the kernel ks1(xi,xj)=Σαiαjyiyjk(xn *xm *xi,xj), and in general on step n>0, s n = ∑ i 1 , … ⁢ , i n l ⁢ α i 1 ⁢ y i 1 ⁢ ⁢ … ⁢ ⁢ α i n ⁢ y i n ⁢ ϕ ⁡ ( x i 1 * ⁢ … ⁢ * ⁢ … ⁢ ⁢ x i n ) , ⁢ k s n ⁡ ( x i , x j ) = ∑ i 1 , … ⁢ , i n l ⁢ α i 1 ⁢ y i 1 ⁢ ⁢ … ⁢ ⁢ α i n ⁢ y i n ⁢ k ⁡ ( x i 1 * … ⁢ * ⁢ … ⁢ ⁢ x i n * x i , x j ) . ( 35 ) As this can become costly to compute after iteration 2, the vector s1 can be computed at each step as a linear combination of training points, i.e., sn=Σβinφ(xi) ksn(xi,xj)=Σβknk(xk *xi,xj) This can be achieved by, at each step, approximating the expansion ( w * w ) = ∑ n , m = 1 l ⁢ α n ⁢ α m ⁢ y n ⁢ y m ⁢ ϕ ⁡ ( x n * x m ) with w approx 2 = ∑ i = 1 l ⁢ β i ⁢ ϕ ⁡ ( x i ) . The coefficients βi are found using a convex optimization problem by minimizing in the l2-norm the different between the true vector and the approximation. That is, the following is minimized:  w approx 2 - ( w * w )  2 2 = ⁢  ∑ i = 1 l ⁢ β i ⁢ ϕ ⁡ ( x i ) - ∑ n , m = 1 l ⁢ α n ⁢ α m ⁢ y n ⁢ y m ⁢ ϕ ⁡ ( x n * x m )  2 2 = ⁢ ∑ i , j = 1 l ⁢ β i ⁢ β j ⁢ k ⁡ ( x i , x j ) - 2 ⁢ ∑ i , n , m = 1 l ⁢ β i ⁢ α n ⁢ α m ⁢ y n ⁢ y m ⁢ k ⁡ ( x n * x m , x i ) + const . ( 36 ) Similarly, an approximation for si=si−1 *(ω*ω) can also be found, again approximating the expansion found after the * operation. Finally, after the final iteration (p) test points can be classified using ƒ(x)=(ω,(x*sp−1))+b. (37) It is then possible to perform an approximation of the minimization of the l0-norm in the feature space for polynomial kernels. Contrary to the linear case, it is not possible to explicitly look at the coordinates of the resulting ω. It is defined in feature space, and only dot product can be performed easily. Thus, once the algorithm is finished, one can use the resulting classifier for prediction, but less easily for interpretation. In the linear case, on the other hand, one may also be interested in interpretation of the sparse solution, i.e., a means for feature selection. To test the AL0M approach, it is compared to a standard SVM with no feature selection, a SVM using RFE, and Pearson correlation coefficients. In a linear problem, six dimensions out of 202 were relevant. The probability of y=1 or −1 was equal. The first three features {x1, x2, x3 } were drawn as xi=yN(i,1) and the second three features {x4, x5, x6 } were drawn as xi=N(0,1) with a probability of 0.7. Otherwise, the first three features were drawn as xi=yN(0,1) and the second three as xi=yN(i−3,1). The remaining features are noise xi=N(0,20), i=7, . . . , 202. The inputs are then scaled to have a mean of zero and a standard of one. In this problem, the first six features have redundancy and the rest of the features are irrelevant. Linear decision rules were used and feature selection was performed selecting the two best features using each of the above-mentioned methods along with AL0M SVMs, using both l1 and l2 multiplicative updates. Training was performed on 10, 20 and 30 randomly drawn training points, testing on a further 500 points, and averaging test error over 100 trials. The results are provided in Table 1. For each technique, the test error and standard deviation are given. TABLE 1 Method 10 pts. 20 pts. 30 pts. SVM 0.344 ± 0.07 0.217 ± 0.04 0.162 ± 0.03 CORR SVM 0.274 ± 0.15 0.157 ± 0.07 0.137 ± 0.03 RFE SVM 0.268 ± 0.15 0.114 ± 0.10 0.075 ± 0.06 2-AL0M SVM 0.270 ± 0.15 0.097 ± 0.10 0.063 ± 0.05 1-AL0M SVM 0.267 ± 0.16 0.078 ± 0.06 0.056 ± 0.04 AL0M SVMs slightly outperform RFE SVMs, whereas conventional SVM overfit. The to approximation compared to RFE also has a lower computational cost. In the RFE approach, n iterations are performed, removing one feature per iteration, where n is the number of input dimensions. As described with regard to the previous embodiment, RFE can be sped up by removing more than one feature at a time. Table 2 provides the p-values for the null hypothesis that the algorithm in a given row does not outperform the algorithm in a given column using the Wilcoxon signed rank test. The Wilcoxon test evaluates whether the generalization error of one algorithm is smaller than another. The results are given for 10, 20 and 30 training points. TABLE 2 l1-AL0M Method SVM CORR RFE l2-AL0M SVM SVM SVM (10 pts) 1 1 1 1 1 (20 pts) 1 1 1 1 1 (30 pts.) 1 1 1 1 1 CORR (10 pts.) 0 1 0.33 0.37 0.34 (20 pts) 0 1 1 1 1 (30 pts.) 0 1 1 1 1 RFE (10 pts.) 0 0.67 1 0.56 0.39 (20 pts) 0 0 1 0.98 1 (30 pts.) 0 0 1 0.96 1 l2-AL0M (10 pts.) 0 0.63 0.44 1 0.35 (20 pts) 0 0 0.02 1 0.97 (30 pts.) 0 0 0.04 1 0.97 l1-AL0M (10 pts.) 0 0.66 0.61 0.65 1 (20 pts) 0 0 0 0.03 1 (30 pts.) 0 0 0 0.03 1 For 20 and 30 training points, the l1-AL0M SVM method outperforms all other methods. The next best results are obtained with the l2-AL0M SVM. This ranking is consistent with the theoretical analysis of the algorithm—the l2-nor-m approximation should not be as good at choosing a small subset of features relative to the l1 approximation which is closer to the true l0-norm minimization. EXAMPLE 2 Colon Cancer Data Sixty-two tissue samples probed by oligonucleotide arrays contain 22 normal and 40 colon cancer tissues that must be discriminated based upon the expression of 2000 genes. Splitting the data into a training set of 50 and a test set of 12 in 500 separate trials generated a test error of 16.6% for standard linear SVMs. Then, the SVMs were trained with features chosen by three different input selection methods: correlation coefficients ( “CORR”), RFE, and the l2-norm approach according to the present embodiment. Subsets of 2000, 1000, 500, 250, 100, 50 and 20 genes were selected. The results are provided in the following Table 3. TABLE 3 # of Features CORR SVM RFE SVM l2-AL0M 2000 16.4% ± 8 16.4% ± 8 16.4% ± 8 1000 17.7% ± 9 16.4% ± 9 16.3% ± 9 500 19.1% ± 9 15.8% ± 9 16.0% ± 9 250 18.2% ± 10 16.0% ± 9 16.5% ± 9 100 20.7% ± 10 15.8% ± 9 15.2% ± 9 50 21.6% ± 10 16.0% ± 9 15.1% ± 10 20 22.3% ± 11 18.1% ± 10 16.8% ± 10 AL0M SVMs slightly outperform RFE SVMs, whereas correlation coefficients (CORR SVM) are significantly worse. Table 4 provides the p-values using the Wilcoxon sign rank test to demonstrate the significance of the difference between algorithms, in showing that RFE SVM and l2-AL0M outperform correlation coefficients. l2-AL0M outperforms RFE for small feature set sizes. TABLE 4 Method 2000 1000 500 250 100 50 20 CORR < RFE 0.5 0 0 0 0 0 0 CORR < l2-AL0M 0.5 0 0 0 0 0 0 RFE < l2-AL0M 0.5 0.11 0.92 0.98 0.03 0.002 0.001 EXAMPLE 3 Lymphoma Data The gene expression of 96 samples is measured with microarrays to give 4026 features, with 61 of the samples being in classes “DLCL”, “FL”, or “CL” (malignant) and 35 labeled otherwise (usually normal.) Using the same approach as in the previous Example, the data was split into training sets of size 60 and test sets of size 36 over 500 separate trials. A standard linear SVM obtains 7.14% error. The results using the same feature selection methods as before are shown in Table 5. TABLE 5 Features CORR SVM RFE SVM l2-AL0M SVM 4026 7.13% ± 4.2 7.13% ± 4.2 7.13% ± 4.2 3000 7.11% ± 4.2 7.14% ± 4.2 7.14% ± 4.2 2000 6.88% ± 4.3 7.13% ± 4.2 7.06% ± 4.3 1000 7.03% ± 4.3 6.89% ± 4.2 6.86% ± 4.2 500 7.40% ± 4.3 6.59% ± 4.2 6.48% ± 4.2 250 7.49% ± 4.5 6.16% ± 4.1 6.18% ± 4.2 100 8.35% ± 4.6 5.96% ± 4.0 5.96% ± 4.1 50 10.14% ± 5.1 6.70% ± 4.3 6.62% ± 4.2 20 13.63% ± 5.9 8.08% ± 4.6 8.57% ± 4.5 RFE and the approximation to the l2-AL0M again outperform correlation coefficients. l2-AL0M and RFE provided comparable results. Table 6 gives the p-values using the Wilcoxon sign rank test to show the significance of the difference between algorithms. TABLE 6 Features CORR < RFE CORR < l2-AL0M RFE < l2-AL0M 4026 0.5 0.5 0.5 3000 0.578 0.578 0.5 2000 0.995 0.96 0.047 1000 0.061 0.04 0.244 500 0 0 0.034 250 0 0 0.456 100 0 0 0.347 50 0 0 0.395 20 0 0 0.994 EXAMPLE 4 Yeast Dataset A microarray dataset of 208 genes (Brown Yeast dataset) was discriminated into five classes based on 79 gene expressions corresponding to different experimental conditions. Two 8 cross-validation runs were performed. The first run was done with a classical multiclass SVM without any feature selection method. The second run was done with a SVM and a pre-processing step using the multiclass l2-AL0M procedure to select features. Table 7 shows the results, i.e., that the l2-AL0M multiclass SVM outperforms the classical multiclass SVM. As indicated, the number of features following feature selection is greatly reduced relative to the original set of features. TABLE 7 Test Error No. of Features multiclass SVM 4.8% 79 l2-AL0M multiclass SVM 1.3% 20 As an alternative to feature selection as a pre-processing step, it may be desirable to select a subset of features after mapping the inputs into a feature space while preserving or improving the discriminative ability of a classifier. This can be distinguished from classical feature selection where one is interested in selecting from the input features. The goal of kernel space feature selection is usually one of improving generalization performance rather than improving running time or attempting to interpret the decision rule. An approach to kernel space feature selection using l2-AL0M is compared to the solution of SVMs on some general toy problems. (Note that input feature selection methods such as those described above are not compared because of ω is too large in dimension, such methods cannot be easily used.) Input spaces of n=5 and n=10 and a mapping into feature space of polynomial of degree 2, i.e., φ(x)=φ1:2(x) were chosen. The following noiseless problems (target functionals) were chosen: (a) ƒ(x)=x1 x2+x3, (b) ƒ(x)=x1; and randomly chosen polynomial functions with (c) 95%, (d) 90%, (e) 80% and (f) 0% sparsity of the target. That is, d % of the coefficients of the polynomial to be learned are zero. The problems were attempted for training set sizes of 20, 50, 75 and 100 over 30 trials, and test error measured on a further 500 testing points. Results are plotted in FIG. 11a-f for n=5 and FIG. 12a-f for n=10. The dotted lines in the plots represent the performance of a linear SVM on a particular problem, while the solid line represent the AL0M -SVM performance. Multiplicative updates were attempted using the method described above for polynomial kernels (see, e.g., Equation 31). Note that comparing to the explicit calculation of ω, which is not always possible if ω is large, the performance was identical. However, this is not expected to always be the case since, if the required solution does not exist in the span of the training vectors, then Equation 36 could be a poor approximation. In problems (a) through (d), shown in FIGS. 11a-d and 12a-d, the l2-AL0M SVM clearly outperforms SVMs. This is due to the norm that SVMs use. The l2-norm places a preference on using as many coefficients as possible in its decision rule. This is costly when the number of features one should use is small. In problem (b) (FIGS. 11b and 12b), where the decision rule to be learned is linear (just one feature), the difference is the largest. The linear SVM outperforms the polynomial SVM, but the AL0M feature selection method in the space of polynomial coefficients of degree 2 outperforms the linear SVM. This suggests that one could also try to use this method as a crude form of model selection by first selecting a large capacity model then reducing the capacity by removing higher order polynomial terms. Problems (e) and (f) (FIGS. 11e-f and 12e-f) show an 80% and 0% sparse, respectively. Note that while the method outperforms SVMs in the case of spare targets, it is not much worse when the target is not sparse, as in problem (f). In problem (e), the AL0M method is slightly better than SVMs when there are more than 50 training points, but worse otherwise. This may be due to error when making sparse rules when the data is too scarce. This suggests that it may be preferable in certain cases to choose a rule that is only partially sparse, i.e., something in between the l2-norm and l0-norm. It is possible to obtain such a mixture by considering individual iterations. After one or two iterations of multiplicative learning, the solution should still be close to the l2-norm. Indeed, examining the test error after each of one, two and three iterations with 20 or 50 training points on problem (e), it is apparent that the performance has improved compared to the l2-norm (SVM) solution. After further iterations, performance deteriorates. This implies that a method is needed to determine the optimal mixture between the l0-norm and l2-norm in order to achieve the best performance. In application to feature selection, the l0-norm classifier separates data using the least possible number of features. This is a combinatorial optimization problem which is solved approximately by finding a local minimum through the above-described techniques. These features can then be used for another classifier such as a SVM. If there are still too many features, they can be ranked according to the absolute value of the weight vector of coefficient assigned to them by the separating hyperplane. Feature selection methods can also be applied to define very sparse SVM. For that purpose, it is useful to review the primal optimization problem from which SVMs are defined: min w , ξ i ⁢  w  2 2 + C ⁢ ∑ i = 1 l ⁢ ξ i subject to: yi((ω, x1)+b)≧1−ξi ξi≧0 It is known that solutions {circumflex over (ω)} of such problems are expressed as a combination of the kernels k(xi,.): w ^ = ∑ i = 1 l ⁢ α i ⁢ y i ⁢ k ( x i ⁢ … ⁢ ) ( 38 ) and the non-zero αi′s are called the support vectors in the sense that they support the computation of the vector {circumflex over (ω)}. One of the positive properties that has been underlined by many theoretical bounds is that when this number is small, the generalization error should be small as well. The proof of such results relies on compression arguments and it is generally believed that compression is good for learning. Following the latter assertion and applying the l0-norm minimization to the vector (α1, . . . , αl), the goal is to obtain a linear model with as few non-zero αi as possible. The problem to be addressed is: min α i , ξ i ⁢  α  0 ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( ∑ j = 1 l ⁢ α j ⁢ k ⁡ ( x j , x i ) ) ≥ 1 ( 39 ) To solve this problem, the previously-described approximation is used. The slack variables ξi are no longer used since the approach has been defined for hard margin (C=+∞) only. The following routine is used to address the non-separable datasets, 1. Start with α=( 1, . . . , 1) 2. Assume αk is given, and solve min ⁢ ∑ j = 1 n ⁢  α j  ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y i ⁡ ( 〈 a , ( k ( x i , … ⁢ ) * α k ) 〉 + b ) ≥ 1 ( 40 ) 3. Let {acute over (α)} be the solution of the previous problem. Set αk+1=αk*{acute over (α)}. 4. Go back to 2. The present method tends to behave like a SVM but with a very sparse expansion (see Equation 38). To illustrate, the following simple example is used. The learning set consists of 100 points in [0,1]2 with ±1 targets as they are drawn in FIG. 13. For this learning set, multiple runs of a classic SVM and a sparse SVM were run. A radial basis function (RBF) kernel with a value of σ=0.1 was used. In FIG. 13a, the result of the sparse SVM is shown, while FIG. 13b shows the result of a classic SVM. In this problem, the parse-SVM obtains a sparser and a better solution in terms of generalization error. At a first sight, this can be interpreted as a consequence of existing theoretical results about sparsity that say that sparsity is good for generalization. However, in this case, sparsity is more related to full compression than to computational dependence. “Computational dependence” here means that the outcome of the algorithm depends only on a small number of points in the learning set. For example, the support vectors of a SVM are the only points in the learning set that are used and the optimization procedure would have given the same linear model if only these points had been considered. In the present method, the resulting linear model depends on all of the training points since all of these points have been used in the optimization to reach a local minimum of the concave problem at hand. If one point is changed, even if it does not occur in the final expansion (Equation 38), it may still have a role in orienting the optimization procedure to the current local minimum rather than to another one. To further analyze the difference between a SVM and the sparse-SVM, the former example is continued but with a smaller value of σ. FIGS. 14a-b represent the separation obtained for a SVM and the sparse-SVM respectively, plotted for σ=0.01. The circled points in the plots indicate learning points with a non-zero α1. Thus, it can be seen that the number of non-zero α1′s is smaller with the sparse-SVM than for a classical SVM. The resulting separation is not very smooth and the margin tends to be small. This behavior is enhanced when σ=0.001, the results of which are shown in FIGS. 14c-d. Then, nearly all of the non-zero αi′s of the sparse-SVM are from the same class and the system has learned to answer with roughly always the same class (the circles) except in small regions. The preceding approach can be used in a kernel-based vector quantization (VQ) method to provide a set of codebook vectors. VQ tries to represent a set of l data vectors x1, . . . , xlεχ (40) by a reduced number of m codebook vectors γ1 , . . . γm εχ, (41) such that some measure of distortion is minimized when each x is represented by the nearest (in terms of some metric on χ)y. Often, codebooks are constructed by greedy minimization of the distortion measure, an example being the overall l2 error. E VQ = ∑ i = 1 l ⁢  x i - y ⁡ ( x i )  2 , where ( 42 ) y ⁡ ( x i ) = argmin ⁢  y j ⁢ x i ⁢ y j  2 . ( 43 ) In practice, one specifies m, initializes y, and minimizes a distortion measure such as Equation 42. Given receiver knowledge of the codebook, each x can then be compressed into log2 m bits. Now, consider the case where it is desired to guarantee (for the training set) a maximum level of distortion for any encoded x and automatically find an appropriate value for m. A restriction that must be imposed is that the codebook vectors must be a subset of the data. Finding the minimal such subset that can represent the data with a given level of distortion is a combinatorially hard problem, however an effective sparse codebook can be obtained using the above-described techniques. VQ algorithms using multiplicative updates can be obtained according to the following: Given the data of Equation 40, χ is some space endowed with a metric d. For purposes of this discussion, the term “kernel” will be used in a broader sense to mean functions k:χ×χ→R (44) not necessarily satisfying the conditions of Mercer's theorem. Of particular interest is the kernel that indicates whether two points lie within a distance of R≧0, k(x, x′)=1{(x,x′)εχ×χ:d(x,x′)≦R}. (45) Now considering what is sometimes called the “empirical kernel map”, φl(x)=(k(x1, x), . . . , k(xl, x)), (46) a vector ω ε Rl can be found such that ωT φl(x1)>0 (47) holds true for all i=1, . . . , l. Then each point xi lies within a distance R of some point xj which has a positive weight ωj>0, i.e., the points with positive weights form a R-cover of the whole set. To see this, note that otherwise all nonzero components of ω would be multiplied by a component φl which is 0, and the above dot product would equal 0. Therefore, up to an accuracy of R (measured in the metric d), the xj with nonzero coefficients ωj can be considered an approximation of the complete training set. (Formally, they define a R-cover of the training set in the metric d.) In order to keep the number of nonzero coefficients small, the following optimization problem is considered: for some q≧0, compute: min w ∈ R l ⁢  w  q ( 48 ) subject to: ωT φl(xi)≧1. (49) In this formulation, the constraint of Equation 47 has been slightly modified. To understand this, note that if a vector ω satisfies Equation 47, it can be rescaled to satisfy Equation 49. For the optimization, however, Equation 49 must be used to ensure that the target function of Equation 48 cannot be trivially minimized by shrinking ω. In vector quantization, the goal is to find a small codebook of vectors to approximate the complete training set. Ideally, q=0 would be used, in which case ∥ω∥q would simply count the number of nonzero coefficients of ω. In practice, q=1 or q=2 is used, since both lead to nice optimization problems. Using this elementary optimization procedure, the multiplicative updated rule is applied. While q=1 already leads to fairly sparse expansions without the multiplicative rule, q=2 does not. However, with the multiplicative rule, both values of q performed fairly well. At the end of the optimization, the nonzero ωi corresponds to a sufficient set of codebook vectors yi. Occasionally, duplicate codebook vectors are obtained. This occurs if the R-balls around two vectors contain identical subsets of the training set. To avoid this, a pruning step is performed to remove some of the remaining redundant vectors in the codebook, by sequentially removing any codebook vector that does not exclusively explain any data vector. Equivalently, the pruning step can be applied to the training set before training. If there are two points whose R-balls cover the same subsets of the training set, they can be considered equivalent, and one of them can be removed. Typically, the pruning results in the removal of a further 1-5% of the codebook. Although the present approach is much faster than a combinatorial approach, it will still suffer from computational problems if the dataset is too large. In that case, chunking or decomposition methods can be employed. Such methods include (1) where the inner optimization uses the l2-norm, it has a structure similar to the standard SVM optimization problem. In this case, SVM chunking methods can be used. (2) Forms of chunking can be derived directly from the problem structure. These include greedy chunking, SV-style chunking, and parallel chunking. Greedy chunking involves two steps. In Step 1, start with a first chunk of 0<l0<l datapoints. Solve the problem for these points, obtaining a set of m≦l0 codebook vectors. Next, go through the remaining l−l0 points and discard all points that have already been covered. In the nth step, provided there are still points left, talke a new chunk of l0 from the remaining set, find the codebook vectors, and removed all points which are already covered. The set of codebook vectors chosen in this manner forms a R-cover of the dataset. In the extreme case where l0=1, this reduces to a greedy covering algorithm. In the other extreme, where l0=l, it reduces to the original algorithm. SV style chunking has the following inner loop: Step 1: Start with the first chunk of 0<l0<l datapoints. Solve the problem for these points, obtaining a set of m≦l0 codebook vectors and discarding the rest from the current chunk. Next, start going through the remaining l−l0 points and fill up the current chunk until is has size l0 again. In Step n, provided there are still points left and the current chunk has size smaller than l0, proceed as above and fill it up. If it is already full, remove a fixed number of codebook vectors along with all points falling into their respective r-balls. Once this is finished, go back and check to see whether all points of the training set (apart from those which were removed along with their codebook vectors) are r-covered by the final chunk. Any points which do not satisfy this are added to the chunk again, using the above technique for limiting the chunk size. Note that there is no guarantee that all points will be covered after the first loop. Therefore, in the SV-style chunking algorithm, the inner loop must be repeated until everything is covered. In parallel chunking, the dataset is split into p parts of equal size. The standard algorithm is run on each part using a kernel of width R/2. Once this is done, the union of all codebooks is formed and a cover is computed using width R/2. By the triangular inequality, a R-cover of the whole dataset is obtained. There is no restriction on adding points to the training set. If there is a way to select points which will likely by good codebook vectors, then the algorithm will automatically pick them in its task of finding a sparse solution. Useful heuristics for finding such candidate points include a scheme where, for each codebook vector, a new point is generated by moving the codebook vector in the direction of a point having the property that, among all points that are coded only by the present codebook vector, has the maximum distance to that codebook vector. If the distance of the movement is such that no other points leave the cover, the original codebook vector can be discarded in favor of the new one. The use of the multiplicative rule avoids a somewhat heuristic modification of the objective function (or of the kernel) that the original approach required. EXAMPLE 5 Vector Quantization As a simple illustrative example, FIG. X+4 shows quantizations obtained using the multiplicative kernel VQ algorithm (mk-VQ) of two-dimensional data uniformly distributed in the unit square, for values of maximum distortion R=0.1, 0.2, 0.3 and 0.4, and d being the Euclidean l2 distance. In all cases, the proposed algorithm finds solution which are either optimal or close to optimal. Optimality is assessed using the following greedy covering algorithm. At each step, find a point with the property that the number of points contained in a R-ball around it is maximal. Add this point to the codebook, remove all points in the ball from the training set, and, if there are still points left, go back to the beginning. In FIGS. 15a-d, for l=300, the m quantizing vectors, found automatically, are shown circled. Their numbers are m=37, 11, 6, 4, which are shown in FIGS. 15a-d, respectively. Using the greedy covering algorithm, guaranteed lower bounds on the minimal number of codebook vectors were found. The bound values are 23, 8, 4, 3. The circles of d(x, y)=R are shown for each codebook vector. The VQ method described herein allows an upper bound to be specified on the distortion incurred for each coded vector. The algorithm automatically determines small codebooks covering the entire dataset. It works on general domains endowed with a metric, and could this equally well be used to compute coverings of function spaces. The algorithm could be used for data reduction as a pre-processing step, e.g., for classification, by separating the codebook vectors with a margin larger than R. Target values can be incorporated in the constraint such that it is preferable for the algorithm to find “pure clusters”. It should be noted that although the term vector quantization has been used, the method can be applied to non-vectorial data, as long as it is possible to define a suitable distance measure d. VQ methods may also be used to compress or encode images. Use of l0-norm for multi-label problems. The preceding method for feature selection can be used in cases of multi-label problems such as frequently arise in bioinformatics. The same multiplicative update rule is used with the additional step of computing the label sets size s(x) using ranking techniques. In order to compute the ranking, a cost function and margin for multi-label models are defined. Cost functions for multi-label problems are defined as follows: Denote by χ an input space. An output space is considered as the space formed by all the sets of integer between 1 and Q identified as the labels of the learning problem. Such an output space contains 2Q elements and one output corresponds to one set of labels. The goal is to find from a learning set S={(x1,Y1), . . . ,(xm, Y1)}⊂(χ×γ)”’ drawn identically and independently (i.i.d.) from an unlnown distribution D, a function ƒ such that the following generalization error is as low as possible: R(ƒ)=E(x,Y)=D[c(ƒ,x,Y)] (50) The function c is a real-valued loss and can take different forms depending on how it is viewed. Here, two types of loss are considered. The first is the “Hamming Loss”, which is defined as HL ⁡ ( f , x , Y ) = 1 Q ⁢  f ⁡ ( x ) ⁢ Δ ⁢ ⁢ Y  ( 51 ) where Δ stands for the symmetric difference of sets. Note that the more ƒ(x) is different from Y, the higher the error. Missing one label in Y is less important than missing two, which seems quite natural in many real situations. As an example, consider that the labels are possible diseases related to different genes. Many genes can share the same disease and lead to many diseases at the same time. Predicting only one disease although there are three is worse than predicting only two. Having a Hamming Loss of 0.1 means that the expected number of times a pair (x, yk) has been misclassified is 0.1. Note that if the Hamming Loss is scaled by Q, it is equal to the average number of wrong labels for each point. Any function from χ to Y can be evaluated by the Hamming loss. In some cases, another type of loss is considered. Let (r1(x), . . . ,rQ(x)) where rk: χ→R, k=1, . . . ,Q, be real numbers which are large if k is a label of x and low otherwise. Assume a perfect predictor s(x) of the size of the label sets of x. The output ƒ(x) is computed by talking the indices of the first largest s(x) elements in (r1(x), . . . , rQ(x)). Such a function ƒ is referred as “ranking based”. Denote by Y the complementary set of Y in {1, . . . ,Q}. The Ranking Loss is define as: RL ⁡ ( f , x , Y ) = 1  Y  ⁢  Y ^  ⁢  ( i , j ) ∈ Y ⁢ ⁢ x ⁢ ⁢ Y ^ ⁢ ⁢ s . t . ⁢ r i ⁡ ( x ) ≤ r j ⁡ ( x )  ( 52 ) When s(x) is not given, it must be learned from the data. To assess the quality of different predictors of the size of the label sets, the Size Loss is defined as: SL ⁡ ( s , x , Y ) = 1 Q ⁢  Y ⁢  - s ⁡ ( x )  ( 53 ) Note that a failure in prediction of the correct size Y is weighted differently depending on how different the prediction is from the true value. This is motivated by the same reasoning as for the Hamming Loss. In the following, only linear models are used to perform the ranking and to learn the size of the label sets. Note, however, that the methods described herein are not intended to be limited to linear models, and that the methods may be transformed in non-linear methods by using the “kernel trick” as is known in the art. For purposes of further discussion, it will be assumed that X is a finite dimensional real space that can be thought of as Rd where d is the number of features of the inputs. Given Q vectors ω1, . . . , ωQ and Q bias b1, . . . , bQ, there are two ways of computing the output—the binary approach and the ranking approach. With the binary approach: ƒ(x)=sign((ω1x)+b1, . . . , (ωQ, x)+bQ) (54) where the sign function applies component-wise. The value of ƒ(x) is a binary vector from which the set of labels can be retrieved easily by stating that label k is in the set ((ωk,x)+bk)≧0. This way of computing the output is discussed below. The natural cost function for such a model is the Hamming Loss. With the ranking approach, assume that s(x), the size of the label set for the input x, is known, and define: rk(x)=(ωk,x)+bk (55) and consider that a label k is in the label set of x iff rk(x) is among the first s(x) elements (r1(x), . . . , rQ(x)). For both systems, the empirical error measured by the appropriate cost function must be minimized while at the same time controlling the complexity of the resulting model. This reasoning is based on the principle that having a large margin plus a regularization method leads to a good system. First looking at the binary approach, it is assumed that the function ƒ is computed as in Equation 54. This means that the decision boundaries are defined by the hyperplanes (ωk, x) +bk=0. By analogy with the two-class case, the margin off on (x, Y) is defined as the signed distance between (<ω1,x>)+b1, . . . , <ωQ, x>+bQ) and the decision boundary. It is equal to: min k ⁢ y k ⁢ 〈 w k , x 〉 + b k  w k  ( 56 ) where yk is a binary element equal to +1 if label k is in Y, and −1 otherwise. For a learning set S, the margin can also be defined as: min ( x , Y ) ∈ S ⁢ y ⁢ k ⁢ 〈 w k , ⁢ x 〉 + b k  w k  ( 57 ) Assuming that the Hamming Loss on the learning set S is zero, the large margin paradigm we follow consists in maximizing the margin. By normalizing the parameters (ωk, bk) such that: ℄(x, Y)εS, yk((ωk,x)+bk)≧1 (58) with an equality for at least one x, the margin on S={(xi , Yi)}i=1, . . . Q is equal to mink ∥ωk∥−1. Here, Y1 is identified with its binary representation: (yi1, . . . , YiQ) ε{−1, +1}Q. Maximizing the margin or minimizing its inverse yields to the following problem: min w k ⁢ b k ⁢ max k ⁢  w k  2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y ik ⁡ ( 〈 w k , x i 〉 + b k ) ≥ 1 , for ⁢ ⁢ i = 1 , … ⁢ , m ( 59 ) Up to this point, it has assumed that the Hamming Loss is zero, which is unlikely to be the case in general. The Hamming Loss can be computed as: HL ⁡ ( f , x , Y ) = 1 Q ⁢ ∑ k = 1 Q ⁢ θ ⁡ ( - y ik ⁡ ( 〈 w k , x i 〉 + b k ) ) ( 60 ) where θ(t)=0 for t≦0 and θ(t)=1 for t≧0. The previous problem can be generalized by combining the minimization of the Hamming Loss and the maximization of the margin: min w k ⁢ b k ⁢ ( max k ⁢  w k  2 ) + C ⁢ ∑ i = 1 m ⁢ 1 Q ⁢ ∑ k = 1 Q ⁢ θ ⁡ ( - 1 + ξ ik ) ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y ik ⁡ ( 〈 w k , x i 〉 + b k ) ≥ 1 - ξ ik , for ⁢ ⁢ i = 1 , … ⁢ , m ξ ik ≥ 0 ⁢ ( 61 ) This problem is non-convex and difficult to solve. (It inherits from the NP-Hardness of the related two-class problems which is a classical SVM with threshold margin.) A simpler approach is to upper bound the θ(−1+τ) flnction by the linear problem, which yields: min w k ⁢ b k ⁢ ( max k ⁢  w k  2 ) + C Q ⁢ ∑ i = 1 m ⁢ ∑ k = 1 Q ⁢ ξ ik ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ y ik ⁡ ( 〈 w k , x i 〉 + b k ) ≥ 1 - ξ ik , for ⁢ ⁢ i = 1 , … ⁢ , m ⁢ ξ ik ≥ 0 ⁢ ( 62 ) This problem is a convex problem with linear constraints and can be solved by using a gradient descent or other classical optimization method. Note that when the constant C is infinite, which corresponds to the case where the minimization of the Hamming Loss is actually the main objective function, then the system is completely decoupled and the optimization can be done on each parameter (ωk, bk) independently. For finite C, the optimization cannot be done so easily, unless the maximum over the ωk′s is approximated by: max k ⁢  w k  2 ≤ ∑ k = 1 Q ⁢  w k  2 ≤ Q ⁢ ⁢ max k ⁢  w k  2 ( 63 ) In this case, the problem becomes completely separated in the sense that optimizing with respect to ωk does not influence the optimization with respect to ωl for l≠k. Note that the optimization procedure is the same as the one-against-all approach developed in the multi-class setting. In Equation 62, the Hamming Loss is replaced by its linear approximation (here computed on (x, Y)): AHL ⁡ ( ( w k , b k ) k = 1 ⁢ … ⁢ , Q , ⁢ x , Y ) ⁢ 1 Q ⁢ ∑ k = 1 Q ⁢  - 1 + y k ⁡ ( 〈 w k , x 〉 + b k )  + ( 64 ) where |.|+ is a function from R to R+ that is the identity on R+ and that equals zero on R. This linear system is then designed to minimize the AHL function rather than the Hamming distance between the binary representation of the label sets and the function ƒ defined in Equation 53. During training, it tends to place the output ƒ(x) close to the targets Y in terms of the distance derived from the AHL. When a new input x is given, the output of ƒ should then be computed via: f ⁡ ( x ) = arg ⁢ ⁢ min Y ∈ y ⁢ ∑ k = 1 Q ⁢  - 1 + y k ⁡ ( 〈 w k , x 〉 + b k )  + ( 65 ) where γ contains all label sets that are potential outputs. When all label sets are acceptable outputs (γ={−1, +1}Q, Equation 65 is rewritten as Equation 54. In some cases where all label sets are not allowed (γ{−1, +1}Q), both computations are different (see FIG. 16) and ƒ(x) should be calculated as above rather than using Equation 54. Such cases arise when, e.g., a Error Correcting Output Code (ECOC) is used to solve multi-class problems. T. G. Dietterich and G. Bakiri in “Solving multiclass learning problems via error-correcting output codes”, Journal of Artificial Intelligence Research, 2:263-286, 1995, incorporated herein by reference, present a method based on error correcting code which consists in transforming a multi-class problem into a multi-label one and in using the fact that not all label sets are allowed. When the learning system outputs an impossible label set, the choice of the correcting code makes it possible to find a potentially correct label set whose Hamming distance is the closest to the output. If the system derived from Equation 62 is used with the ECOC approach, considering that the Hamming Loss is not the quantity that is minimized, the computation of the output should be done by minimizing the Hamming distance via Equation 65, which can be rewritten as: f ⁡ ( x ) = arg ⁢ ⁢ min Y ∈ y ⁢ ∑ k = 1 Q ⁢  y k - σ ⁡ ( 〈 w k , x 〉 + b k )  ( 66 ) where σ is the linear function thresholded at −1 (resp. +1) with value −1 (resp. +1). Referring to FIG. 16, assume there are 5 labels and there are only two possible label sets: one denoted by Y, with binary representation (1, . . . , 1) and the other one Y2=(−1, . . . , −1). The real values (ωk, x)+−bk are plotted for k=1, . . . , 5, shown as black spots. The Hamming distance between the output and Y1 is 4, although it is 1 for Y2. Recall that the Hamming distance is computed on the signed vector of the output. The AHL between the output and Y1 is 4.2 although it is 5.8 for Y2. If the final output is computed with the Hamming distance, then Y2 is chosen. If it is computed via the AHL, then Y1 is chosen. Choosing the Hamming Loss leads naturally to a learning system that is very close to the one obtained from the binary approach. This suffers from a certain inability to separate points when simple configurations occur, e.g., when there are few labels and some points fall in multiple classes. This can be addressed by using the ranking approach. The ranking approach can be broken down into two parts, the first of which is to optimize the Ranking Loss. The second part is obtained by minimizing the Size Loss 1/Q||Y|−s(x)|. This second part is actually almost a regression problem and can be solved with the approaches known in the prior art. The goal is to define a linear model that minimizes the Ranking Loss while having a low complexity. The notion of complexity is the margin. For systems that rank the values of <ωk, x>+bk, the decision boundaries for x are defined by the hyperplanes whose equations are <ωk−wl, x>+bk−b1=0, where k belongs to the label sets of x while l does not. So, the margin of (x, Y) can be expressed as: min k ∈ Y , l ∈ Y _ ⁢ 〈 w k - w l , x 〉 + b k - b l  w k - w l  ( 67 ) Considering that all the data in the learning set S are well ranked, the parameters ωk′s can be normalized such that: (ωk−ωl,x)+bk−bl≧1 (68) with equality for some x part of S, and (k,1)εY×Ŷ. Maximizing the margin on the whole learning set can then be done via: max w j , j = 1 , … ⁢ , Q ⁢ min ( x , Y ) ∈ Sk ∈ Y , l ∈ Y ^ ⁢ 1  w k - w l  2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w k - w l , x i 〉 + b k - b l ≥ 1 , ( k , l ) ∈ Y i × Y ^ i ( 69 ) In the case where the problem is not ill-conditioned (two labels are always co-occuring), the objective function can be replaced by: max w j ⁢ min k , l ⁢ 1  w k - w l  2 The previous problem can then be recast as: min w j , j = 1 , … ⁢ , Q ⁢ max k , l ⁢  w k - w l  2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w k - w l , x i 〉 + b k - b l ≥ 1 , ( k , l ) ∈ Y i × Y ^ i ( 70 ) To provide a simpler optimization procedure, this maximum is approximated by the sum, which leads to the following problem (in the case the learning set can be ranked exactly): min w j , j = 1 , … ⁢ , Q ⁢ ∑ k , l = 1 Q ⁢  w k - w l  2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w k - w l , x i 〉 + b k - b l ≥ 1 , ( k , l ) ∈ Y i × Y ^ i ( 71 ) Note that a shift in the parameters ωk does not change the ranking. Thus, it can be required that ∑ k = 1 Q ⁢ w k = 0 , adding this constraint. In this case, Equation 71 is equivalent to: min w j , j = 1 , … ⁢ , Q ⁢ ∑ k Q ⁢  w k  2 ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w k - w l , x i 〉 + b k - b l ≥ 1 , ( k , l ) ∈ Y i × Y ^ i . ( 72 ) To generalize this problem in the case where the learning set cannot be ranked exactly, the same reasoning is followed as for the binary case: the ultimate goal would be to minimize the margin and simultaneously minimize the Ranking Loss. The latter can be expressed directly by extending the constraints of the previous problems. If <ωk−ω1, xi>+bk−b1>1−ξlkl for (k, l)εY1×Ŷi, then the Ranking Loss on the learning set S is: ∑ i = 1 m ⁢ 1  Y i  ⁢  Y ^ i  ⁢ ∑ θ ⁡ ( - 1 + ξ kl ) k , l ∈ ( Y l × Y ^ l ) ( 73 ) Once again, the functions θ(−1+ξikl) can be approximated by only ξikl, which gives the final quadratic optimization problem: min w j , j = 1 , … , Q ⁢ ∑ k Q ⁢  w k  2 + C ⁢ ∑ i = 1 m ⁢ 1  Y i ⁢  Y ^ i  ⁢ ∑ ( k , l ) ∈ Y i × Y ^ , ⁢ ξ ikl ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 w k - w l , x i 〉 + b k - b l ≥ 1 - ξ ikl , ( k , l ) ∈ Y i × Y ^ i ⁢ ξ ikl ≥ 0 ( 74 ) In the case where the label sets Yi have all a size of 1, the optimization problem is the same as has been derived for multi-class Support Vector Machines. For this reason, the solution of this problem is referred to as a multi-label ranking Support Vector Machine (MLR-SVM). “Categorical regression” can be thought of as the problem of minimizing the loss: CR ⁡ ( s , x , y ) = 1 Q ⁢  s ⁡ ( x ) - y  ( 75 ) where y is the label of x (here there is only one label for a x). The term “regression” derives from the fact that this cost function is a so cost function as in regression while “categorical” comes from the fact that s(x) is discrete. Such a setting arises when the mistakes are ordered. For example, one could imagine a situation where predicting label 1 although the true label is 4 is worse than predicting label 3. Consider the task of predicting the quality of a web page from labels provided by individuals. The individuals rate the web page as “very bad”, “bad”, “neutral”, “good” or “very good”, and the point is not only to have few mistakes, but to be able to minimize the difference between the prediction and the true opinion. A system that outputs “very bad” although the right answer is “very good” is worse than a system giving the “good” answer. Conversely, a “very good” output although it is “very bad” is worse than “bad”. Such a categorical regression is in a way related to ordinal regression, the difference being no order on the targets is assumed; only order on the mistakes. Categorical regression (CR) can be dealt with using the multi-label approach. This approach provides a natural solution of the categorical regression problem when the right setting is used. Rather than coding the labels as integers, encode them as binary vector of {+1, −1} components: label ⁢ ⁢ i = ( 1 , … ⁢ , 1 , ︸ i ⁢ ⁢ times - 1 , … ⁢ , - 1 ) ( 76 ) With this encoding, the loss CR defined previously can be expressed in terms of the Hamming Loss: CR(s,x,y)=HL({tilde over (s)},x,Y) where {tilde over (s)} is the function s when its output is encoded as in Equation 76, and Y is the encoded label corresponding to y. The minimization of the Hamming Loss leads naturally to the binary approach for the multi-label problem. Thus, the same system as the one defined in the binary approach section will be used. In other words, a linear system composed of many two-class sub-systems that learn how to recognize when the components of the label associated to x is +1 or −1 will be used. All possible label sets are not allowed here. As for the ECOC approach discussed previously, the function s is thus computed via Equation 66 where γ contains labels 1, . . . , Q encoded as Equation 76. To sum up briefly, the multi-label model is decomponsed into two parts, both based on dot products and linear models. The first part ranks the labels and is obtained via Equation 74. The result is a set of parameters (ωk1 ,bk1)k=1, . . . Q. The ranking is done on the outputs rk(x)=<ωk1, x>+bk for k =1, . . . Q. The second part of the model predicts the size of each label sets and is obtained through Equation 62, where the maximum has been replaced by a sum. The result is also a set of parameters (ωk2, bk2)k=1, . . . ,Q. The output is computed by talking the integer whose representation (Equation 76) is the closest from the vector: (σ((ω12,x)+b12), . . . ,σ((ωQ2,x)+bQ2)) (77) in terms of the l1, distance. The function σ is the linear function thresholded at −1 (resp. +1) with value −1 (resp. +1). Then, the output s(x) of this second model is used to compute the number of labels one has to consider in the ranking obtained by the first model. Solving a constrained quadratic problem requires an amount of memory that is quadratic in terms of the learning set size. It is generally solved in O (m3) computational steps where the number of labels have been put into the O. Such a complexity is too high to apply these methods in many real datasets. To avoid this limitation, Franke and Wolfe's linearization method (described above regarding the AL0M embodiment) is used in conjunction with a predictor-corrector logarithmic barrier procedure. To solve Equation 74, the dual variables αikl>0 are related to the constraints are introduced: (ωk−ω1,x1)+bk−b1−1+ξikl≧0 (78) and the variables ηikl≧0 related to the constraints εikl ≧0. The lagrangian can then be computed: L = ⁢ 1 2 ⁢ ∑ k = 1 Q ⁢  w k  2 + C ⁢ ∑ i = 1 m ⁢ 1  Y i ⁢  Y ^ i  ⁢ ∑ ( k , l ) ∈ Y i × Y ^ i ⁢ ξ ikl - … ⁢ ∑ i = 1 m ⁢ ∑ ( k , l ) ∈ Y i × Y ^ i ⁢ α ikl ⁡ ( 〈 w k - w l , x i 〉 + b k - b l - 1 + ξ ikl ) - ⁢ ∑ i = 1 m ⁢ ∑ ( k , l ) ∈ Y i × Y ^ i ⁢ η ikl ( 79 ) Setting ∂bk,, L=0 at the optimum yields: ∑ i = 1 m ⁢ ⁢ ∑ ( j , l ) ∈ ( Y l , Y _ l ) ⁢ c ijl ⁢ α ijl = 0 ⁢ ⁢ with c ijl = ⁢ { 0 if ⁢ ⁢ j ≠ k ⁢ ⁢ and ⁢ ⁢ l ≠ k - 1 if ⁢ ⁢ j = k ⁢ + 1 if ⁢ ⁢ l = k ⁢ ( 80 ) Note that cijl depends on k. Note that the index k has been dropped to avoid excessive indices. Setting ∂ξiklL=0 yields: C  Y i  ⁢  Y _ i  = α ikl + η ikl ( 81 ) Then, setting ∂ωkL=0 yields: w k = ∑ i = 1 m ⁢ ( ∑ ( j , l ) ∈ ( Y i , Y ^ i ) ⁢ c ijl ⁢ α ijl ) ⁢ x i ( 82 ) where cijl is related to index k via Equation 80. For the sake of notation, define: β ki = ∑ ( j , l ) ∈ ( Y i , Y _ i ) ⁢ c ijl ⁢ α ijl ⁢ ⁢ Then ⁢ : ⁢ ⁢ w k = ∑ i = 1 m ⁢ β ki ⁢ x i . ( 83 ) The dual of Equation 74 can then be expressed. In order to have as simple notation as possible, it will be expressed with both variables,βki and αikl. max - 1 2 ⁢ ∑ k = 1 Q ⁢ ∑ h , i = 1 m ⁢ β kh ⁢ β ki ⁢ 〈 x h , x i 〉 + ∑ i = 1 m ⁢ ∑ ( k , l ) ∈ ( Y i , Y _ i ) ⁢ α ikl subject ⁢ ⁢ to ⁢ : ⁢ ⁢ α ikl ∈ [ 0 , C C i ] ∑ i = 1 m ⁢ ∑ ( j , l ) ∈ ( Y i , Y _ i ) ⁢ c ijl ⁢ α ijl = 0 , for ⁢ ⁢ k = 1 , … ⁢ , Q ( 84 ) The first box constraints are derived according to Equation 81, by using the fact that ηikl≧0. The solution is a set of variables αikl from which ωk, k=1, . . . , Q can be computed via Equation 82. The bias bk, k=1, . . . , Q are derived by using the Karush-Kuhn-Tucker conditions: αikl((ωk−ω1, x1)+bk−b1−1+ξikl)=0 (85) (C−αikl)ξikl=0 (86) For indices (i, k, l) such that αikl ε(0, C): (ωk−ωi,xi)+bk=bi=1 Since ωk and ωl are already known, this equation can be used to compute the differences between bk and bl. Note that if a primal-dual method is used to solve the dual 10, the variables bk, k=1, . . . , Q are directly derived as the dual of the constraints ∑ i = 1 m ⁢ ∑ ( j , l ) ∈ ( Y i , Y _ i ) ⁢ c ijl ⁢ α ijl = 0. The dual problem has an advantage compared to its primal counterpart. First, it contains only Q equality constraints and many box constraints. The latter are quite easy to handle in many optimization methods. The main problem in this case concerns the objective function: it is a quadratic function that cannot be solved directly except by storing its whole Hessian. In the case when the number of points is large as well as the number of classes, the number of variables may be too important to take a direct approach. For this reason, an approximation scheme from Franke and Wolfe is followed. max α ⁢ g ⁡ ( α ) ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 α k , α 〉 = 0 , for ⁢ ⁢ k = 1 , … ⁢ , Q ⁢ ⁢ α j ∈ [ 0 , C ] ( 87 ) where the vectors α1 have the same dimensionality as the vector α. The procedure is as follows: 1. start with α0=(0, . . . , 0) 2. Assume at iteration p, αp is given. Solve the linear problem: max α ⁢ 〈 ∇ g ( α p 〉 , α ⁢ ⁢ subject ⁢ ⁢ to ⁢ : ⁢ ⁢ 〈 α k , α 〉 = 0 , for ⁢ ⁢ k = 1 , … ⁢ , Q ⁢ ⁢ α j ∈ [ 0 , C ] ( 88 ) Let α* be the optimum. 3. Compute λε[0,1] such that g(αp+λ(α*−αp)) is minimum. Let λ* be this value. 4. Set αp+1=αp+λ*(α*−αp). 5. End the procedure if λ=0 or if αp+1−αp has a norm lower than a fixed threshold. The purpose of this procedure is to transform a difficult quadratic problem into many simple linear problems. As shown by Franke and Wolfe, such a procedure converges. To apply it to the problem at hand, the gradient of the dual objective function must be computed. For that purpose, new vectors are introduced: ν k p = ∑ i = 1 m ⁢ ⁢ β ki p ⁢ x i ( 89 ) where βo are computed from Equation 83 in terms of the αp ikl. The latter are the current values of the parameter optimized using Franke and Wolfe's method. At the optimum, ωk=νk. At iterations, the objective function can thus be expressed as: - 1 2 ⁢ ∑ k = 1 Q ⁢ ⁢  ν k p  2 + ∑ i = 1 m ⁢ ⁢ ∑ ( k , l ) ∈ ( Y i , Y ^ i ) ⁢ ⁢ α ikl ( 90 ) where the first part of the equation is the I part the second part is the J part. The J part can be differentiated directly. The I part can be differentiated as: ∂ I ∂ α ikl = ⁢ ∑ j = 1 Q ⁢ ⁢ 〈 ∇ ν j p ⁢ I , ∇ α ikl ⁢ ν j p 〉 = ⁢ 〈 ν k p , x i 〉 - 〈 ν l p , x i 〉 ( 91 ) The computation of the gradient of the objective function can thus be done directly as soon as the vectors vkp are given. The vectors are expressed in terms of the αpikl and only dot products between them and the xl′s are needed, which means that this procedure can also be used for kernels. Denoting by W(α) the objective function of Equation 83 the final algorithm is as follows. 1. Start with α=(0, . . . ,0)εRsα, where s α = ∑ i = 1 m ⁢ ⁢  Y i  ⁢  Y ^ i  . 2. Set c ijl k = { 0 if ⁢ ⁢ j ≠ k ⁢ ⁢ and ⁢ ⁢ l ≠ k - 1 if ⁢ ⁢ j = k + 1 if ⁢ ⁢ l = k 3. For k=1, . . . , Q and i=1, . . . , m,compute: β ki = ∑ ( j , l ) ∈ ( Y i , Y ^ i ⁢ ⁢ c ijl k ⁢ α ijl 4. For k=1, . . . , Q and j=1, . . . , m,compute: ∑ i = 1 m ⁢ ⁢ β ki ⁢ 〈 x i , x j 〉 5. Set gikl=−((ωk,x1)−(ω1,x1))+1 6. Solve min α new ⁢ 〈 g , α new 〉 with the constraints α ijl new ∈ [ 0 , C C i ] and ∑ i = 1 m ⁢ ⁢ ∑ ( j , l ) ∈ ( Y i , Y ^ i ) ⁢ ⁢ c ijl k ⁢ α ijl = 0 , for ⁢ ⁢ k = 1 , … ⁢ ⁢ Q 7. Find λεR such that: W(α+λαnew) be maximum and α+λαnew satisfies the previous constraints. 8. Set α=α+λαnew. 9. Unless convergence, go back to Step 3. To create the non-linear version of this algorithm, just replace the dot products (xi,xj) by kernels k (xi,xj). Using the preceding steps, the memory cost of the method becomes then O(mQQmax) where Qmax is the maximum number of labels in the Y. In many applications, the total number of labels is much larger than Qmax. The time cost of each iteration is O(m2Q) EXAMPLE 6 Toy Problem A simple toy problem is depicted in FIG. 17. There are three labels, one of which (label 1) is associated to all inputs. The learning sets were of size 50. Both the binary approach and the direct approach were applied with ranking, as described previously. Each optimization problem was solved for C=∞. The Hamming Loss for the binary approach was 0.08 although for the direct approach it was 0. To demonstrate the nature of the error that occurs using the binary approach, the distribution of missed classes is represented in FIG. 18. The x-axis represents the number of erroneous labels (missed or added) for the learning set of 50 elements; the y-axis represents the number of points out of 50. In the following, the error for a multi-label system is represented using this charts and the Hamming Loss. Such a representation enables assessment of the quality of a multi-label classifier with respect to many criterion, namely, the number of misclassified points, the number of classes that are badly predicted, etc. Note that the Hamming Loss is proportional to the sum of the height of the bars scaled by their coordinates. EXAMPLE 7 Prostate Cancer Dataset The dataset is formed by 67 examples in a space of 7129 features and of 9 labels. The inputs are results of Micro-array experiments on different tissues coming from patients with different form of Prostate Cancer. The nine labels are described in Table 8 and represent either the position of the tissue in the body (peripheral zone, etc . . .) or the degree of malignity of the disease (G3-G4 Cancer). Note that label 4 has only one point which implies that a direct approach will have a leave-one-out Hamming Loss of at least 0.02 (corresponding to the error when the points labelled Stroma is out). TABLE 8 No. of points Label Description in class 1 Peripheral Zone 9 2 Central Zone 3 3 Dysplasia (Cancer precursor stage) 3 4 Stroma 1 5 Benign Prostate Hyperplasia 18 6 G3 (cancer) 13 7 G4 (cancer) 27 8 LCM (Laser confocal microscopy) 20 9 2-amplifications (related to PCR) 34 Two labels have a particular meaning. The LCM label is associated with examples that have been analyzed with a Laser Confocal Microscopy technique, and the 2-amplifications label refer to examples that have had two amplifications during the PCR. These two labels are discarded so that the remaining problem is one of separating different tissue types, thus reducing the number of labels to 7. The label sets have a maximum size of 2. To assess the quality of the classifier, a leave-one-out estimate of the Hamming Loss was computed for the direct approach as well as for the binary approach with linear models and a constant C=∞). This produced an error of 0.11 for the direct approach and of 0.09 for the binary approach. FIGS. 19a-c shows the distribution of the errors for the direct and the binary approach in the leave-one-out estimate of the Hamming Loss. FIG. 19a shows the errors for the direct approach, where the values of the bars are from left to right: 4, 19 and 3. FIG. 19b shows the errors for the binary approach where the values of the bars are from left to right: 20, 10 and 1. FIG. 19c shows the errors for the binary approach when the system is forced to output at least one label, where the values of the bars are from left to right: 9, 16 and 2. The direct approach yields mistakes on 26 points although the binary approach makes mistakes on 31 points. In terms of the Hamming Loss, the binary approach is the best although in terms of the number of correctly classified input points, the direct approach wins. As previously discussed, the binary approach is naturally related to the Hamming Loss and it seems quite natural that it minimizes its value. On the other hand, if one wants to minimize the number of points where there is an error, the direct approach is better. In the direct approach, the empty label set output is not possible. If the binary system is forced to provide at least one label on all the input sample, the Hamming Loss for the binary becomes 0.10, and the number of points where there is an error is 27. Thus, both direct and binary systems are quite close. Since the goal in this particular application is to discriminate the malign cells from the benign ones, the multi-labelled approach was applied for labels 4-7 only, reducing the number of labels to 4 and the number of points in the learning set to 56. With the same setting as above, the leave-one-out estimate of the Hamming Loss was 0.14 for the direct approach, and 0.14 for the binary approach. The same experiment as above was performed by computing the Hamming Loss of the binary system when the latter is forced to give at least one label, producing a Hamming Loss of 0.16. In this particular application, the direct approach is better, yielding a system with the same or a lower Hamming Loss than the binary approach. The results of the leave-one-out estimate of the Hamming Loss for the Prostate Cancer Database using 4 labels are provided in FIG. 20a-c. FIG. 20a is a histogram of the errors for the direct approach, where the values of the bars are from left to right: 2, 13 and 1). FIG. 20b is a histogram of the errors for the binary approach, where the values of the bars are from left to right: 12, 8 and 1. FIG. 20c is a histogram of the errors for the binary approach when the system is forced to output at least one label, where the values of the bars are from left to right: 7, 13 and 1. The partial conclusion of these experiments is that defining a direct approach does not provide significant improvement over a simple binary approach. Given the nature of the problem we have considered, such a conclusion seems quite natural. It is interesting to note that both the direct and the binary approach give similar results even though the direct approach has not been defined to minimize the Hamming Loss. The above methods can be applied for feature selection in a multi-label problem in combination with the method for minimization of the lonorm of a linear system that was discussed relative to the previous embodiment. Note that multi-label problems are omnipresent in biological and medical applications. Consider the following multiplicative update rule method: 1. Inputs: Learning set S=((xi,Yi))i−1, . . . m. 2. Start with ω1, b1, . . . , ωQ,bQ)=(0, . . . , 0). 3. At iteration t, solve the problem: min w k , b k ⁢ ∑ k = 1 m ⁢ ⁢  w k  2 ( 92 ) subject to: (ωk*ωki,x1)−(ω1*ω1i,x1)+bk−b1≧1, for (k,l)εYi→Ŷ1 where ω*ωi is the component-wise multiplication between ω and ωi. 4. Let ω be the solution. Set: ωt+1=ω*ωt. 5. Unless ωt+1=ωt, go back to step 2. 6. Output ωt+1. This method is an approximation scheme to minimize the number of non-zero components of (ω1, . . . , ωQ) while keeping the constraints of Equation 92 satisfied. It is shown to converge in the prior discussion. If the multi-label problem is actually a ranking problem, then this feature selection method is appropriate. For real multi-label problems, a step is still missing, which is to compute the label sets size s(x). Using the Prostate Cancer Database, assume that the value of the label set sizes is known. First, consider the entire dataset and compute how many features can be used to find the partial ranking between labels. Nine features are sufficient to rank the data exactly. Next, use the feature selection method in conjunction with a learning step afterwards to see if choosing a subset of features provide an improvement in the generalization performance. For this purpose, a leave-one-out procedure is used. For each point in the learning set, remove that point, perform the feature selection and run a MLR-SVM with the selected features, compute the Hamming Loss on the removed point. All SVMs were trained with C=∞. The results are summarized in Table 9. The mean of features is given with its standard deviation in parenthesis. The number of errors counts the number of points that have been assigned to a wrong label set. TABLE 9 No. of Hamming No. of Features Loss Errors Direct + Direct 9.5 (±1) 0.10 11 Direct + Binary 9.5 (±1) 0.11 19 FIG. 21 shows the distribution of the mistakes using the leave-one-out estimate of the Hamming Loss for the Prostate Cancer Database using 4 labels with Feature selection. FIG. 21a is a histogram of the errors for the direct approach where the value of one bars is 11. FIG. 21b is a histogram of the errors for the binary approach, where the values of the bars are from left to right: 12 and 7. This comparison may seem a little biased since the function s(x) that computes the size of the label sets is known perfectly. Note, however, that for the binary approach, feature selection preprocessing provides a better leave-one-out Hamming Loss. There are also fewer mislabeled points than there are if no feature selection is used. Although the preceding discussion has covered only linear systems, the inventive method can be applied to more complex problems when only dot-products are involved. In this case, the kernel trick can be used to transform a linear model into a potentially highly non-linear one. To do so, it suffices to replace all the dot products (xi,xj) by k(xi,xj) where k is a kernel. Examples of such kernels are the gaussian kernel exp (−∥xi−xj∥2 /σ2) or the polynomial kernel ((xi,xj)+1)d for dεN\{0}. }. If these dot products are replaced, it becomes apparent that the other dot products (ωk, xt) can also be computed via Equation 81 and by linearity of the dot product. Thus, the MLR-SVM and the ML-SVM introduced can also be defined for different dot product computed as kernels. Feature Selection by Unbalanced Correlation. A fourth method for feature selection used the unbalanced correlation score (CORRub) according to criterion f i = ∑ i ⁢ ⁢ X ij ⁢ Y i ( 93 ) where the score for feature j is ƒj and a larger score is assigned to a higher rank. Before this method is described, note that due to the binary nature of the features, this criterion can also be used to assign rank to a subset of features rather than just a single feature. This can be done by computing the logical OR of the subset of features. If this new vector is designated as x, compute ∑ i ⁢ ⁢ x i ⁢ Y i . A feature subset which has a large score can thus be chosen using a greedy forward selection scheme. This score favors features correlated with the positive examples, and thus can provide good results for very unbalanced datasets. The dataset used for testing of the CORRub feature selection method concerns the prediction of molecular bioactivity for drug design. In particular, the problem is to predict whether a given drug binds to a target site on thrombin, a key receptor in blood clotting. The dataset was provided by DuPont Pharmaceuticals. The data was split into a training and a test set. Each example (observation) has a fixed length vector of 139,351 binary features (variables) in {0,1}. Examples that bind are referred to as having label +1 (and hence being called positive examples). Conversely, negative examples (that do not bind) are labeled −1. In the training set there are 1909 examples, 42 of which are which bind. Hence the data is rather unbalanced in this respect (42 positive examples is 2.2% of the data). The test set has 634 examples. The task is to determine which of the features are critical for binding affinity and to accurately predict the class values using these features. Performance is evaluated according to a weighted accuracy criterion due to the unbalanced nature of the number of positive and negative examples. That is, the score of an estimate Y of the labels Y is: l weighted ⁡ ( Y , Y ^ ) = 1 2 ⁢ ( # ⁢ { Y ^ ⁢ : ⁢ Y = 1 ⋀ Y ^ = 1 } # ⁢ { Y ⁢ : ⁢ Y = 1 } ) + ⁢ ⁢ # ⁢ { Y ^ ⁢ : ⁢ Y = - 1 ⋀ Y ^ = - 1 } # ⁢ { Y ⁢ : ⁢ Y = - 1 } ( 94 ) where complete success is a score of 1. In this report we also multiply this score by 100 and refer to it as percentage (weighted) success rate. Also of interest is (but less important) is the unweighted success rate. This is calculated as: l unweighted ⁡ ( Y , Y ^ ) = ∑ i ⁢ ⁢ 1 2 ⁢  Y ^ i - Y i  . ( 95 ) An important characteristic of the training set is that 593 examples have all features equal to zero. 591 of these examples are negative and 2 of these are positive (0.3%). In the training set as a whole, 2.2% are positive, so new examples with all features as zero should be classified negative. As not much can be learned from these (identical) examples, all but one were discarded, which was a negative example. The primary motivation for doing this was to speed up computation during the training phase A summary of some characteristics of the data can be found in Table 10 below. Considering the training data as a matrix X of size 1909×139351, the number of nonzero features for each example, and the number of nonzero values for each feature were computed. TABLE 10 Type min max mean median std Nonzeros ⁢ ⁢ in ⁢ ⁢ example ⁢ ⁢ i , s i = ∑ j ⁢ X ij 1 29744 950 136 2430 Nonzeros ⁢ ⁢ in ⁢ ⁢ feature ⁢ ⁢ j , f i = ∑ i ⁢ X ij 1 634 13.01 5 22.43 The results show that the data is very sparse. Many features have only a few nonzero values. If there are noisy features of this type, it can be difficult to differentiate these features from similarly sparse vectors which really describe the underlying labeling. This would suggest the use of algorithms which are rather suspicious of all sparse features (as the useful ones cannot be differentiated out). The problem, then, is whether the non-sparse features are discriminative. The base classifier is a SVM. The current experiments employ only linear functions (using the kernel K=X* X′) or polynomial functions K=(X*X′+1)d, where X is the matrix of training data. For use in unbalanced datasets, methods are used to control training error. To introduce decision rules which allow some training error (SVMs otherwise try to correctly separate all the data) one can modify the kernel matrix by adding a diagonal term. This controls the training error in the following way. An SVM minimizes a regularization term R (a term which measures the smoothness of the chosen function) and a training error term multiplied by a constant C:R+C*L. Here, L = ∑ i ⁢ ⁢ ξ i 2 where ξl=Yi−Ŷi (the estimate Ŷ of the label Y for example i is a real value) and so the size of the diagonal term is proportional to 1/C. Large values of the diagonal term will result in large training error. Although there are other methods to control training error, the following method is adopted for use on unbalanced datasets. In this method, there is a trade off of errors between negative and positive examples in biological datasets achieved by controlling the size of the diagonal term with respect to the rows and columns belonging to negative and positive examples. The diagonal term is set to be n(+)/n* m for positive examples and n(−)/n*m for negative examples, where n(+) and n(−) are the number of positive and negative examples respectively, n=n(+) +n(−) and m is the median value of the diagonal elements of the kernel. After training the SVM and obtaining a classifier control of the false positive/ false negative trade off, ROCS (receiver operating characteristics) is evaluated for this classifier. This can be done by considering the decision function of an SVM which is a signed real value (proportional to the distance of a test point from the decision boundary). By adding a constant to the real value before taking the sign, a test point is more likely to be classified positive. A very small number of features (namely, 4) was chosen using the REF, lo-norm and CORRub three feature selection methods to provide a comparison. For CORRub the top 4 ranked features are chosen using Equation 93. In all cases, the features chosen were tested via cross validation with the SVM classifier. The cross validation was eight-fold, where the splits were random except they were forced to be balanced, i.e., each fold was forced to have the same ratio of positive and negative examples. (This was necessary because there were only 42 positive examples (40, if one ignores the ones with feature vectors that are all zeros). If one performed normal splits, some of the folds may not have any positive examples.) The results are given in Table 11 below, which shows the cross validation score (cv), the training score and the actual score on the test set for each features selection method. The score function is the lweighted of Equation 94, i.e., optimal performance would correspond to a score of 1. TABLE 11 cv train test RFE 0.5685 ± 0.1269 0.7381 0.6055 l0-C 0.6057 ± 0.1264 0.7021 0.4887 CORRub 0.6286 ± 0.1148 0.6905 0.6636 Note that the test score is particularly low on the l0- C method. Recall that the balance between classifying negative and positive points correctly is controlled by the diagonal term added to the kernel, which was fixed a priori. It is possible that by controlling this hyperparameter one could obtain better results, and it may be that the different systems are unfairly reflected, however this requires retraining with many hyperparameters. Compensation for the lack of tuning was attempted by controlling the threshold of the real valued function after training. In this way one obtains control of the number of false negatives and false positives so that as long as the classifier has chosen roughly the correct direction (the correct features and resulting hyperplane), results can improve in terms of the success rate. To verify this method, this parameter was adjusted for each of the algorithms, then the maximum value of the weighted CV (cross validation) success rate was taken. This is shown in Table 12 with the values cvmax, trainmax and testmax. TABLE 12 cmmax trainmax testmax RFE 0.6057 ± 0.1258 0.7381 0.6137 l0-C 0.6177 ± 0.1193 0.8079 0.5345 CORRub 0.6752 ± 0.1788 0.8669 0.7264 The best performance on the test set is 72.62%. The best results were given by the unbalanced correlation score (CORRub) method. The two other features selection methods appear to overfit. One possible reason for this is these methods are not designed to deal with the unbalanced nature of the training set. Moreover, the methods may be finding a too complex combination of features in order to maximize training score (these methods choose a subset of features rather than choosing features independently). Note also that both methods are in some sense backward selection methods. There is some evidence to suggest that forward selection methods or methods which treat features independently may be more suitable for choosing very small numbers of features. Their failure is entirely plausible in this situation given the very large number of features. The next step in the analysis of the dataset was to select the type of kernel to be used. Those considered were linear kernels and polynomials of degrees 2 and 3. The results are given in Tables 13 and 14. TABLE 13 cv train test CORRub linear 0.6286 ± 0.1148 0.6905 0.6636 CORRub poly 2 0.6039 ± 0.1271 0.6905 0.6165 CORRub poly 3 0.5914 ± 0.1211 0.6429 0.5647 TABLE 14 cvmax trainmax testmax CORRub linear 0.6752 ± 0.1788 0.8669 0.7264 CORRub poly 2 0.6153 ± 0.1778 0.8669 0.7264 CORRub poly 3 0.6039 ± 0.1446 0.8201 0.7264 Next, the number of features chosen by the CORRub method was adjusted. The greedy algorithm described above was used to add n=1, . . . ,16 more features to the original 4 features that had been selected independently using Equation 93. Tests were also run using only 2 or 3 features. The results are given in the Tables 15a, b and c. TABLE 15a fea- tures 2 3 4 5 6 7 8 train 0.5833 0.6905 0.6905 0.7262 0.7500 0.8212 0.8212 test 0.4979 0.6288 0.6636 0.6657 0.6648 0.7247 0.7221 cv 0.5786 0.6039 0.6286 0.6745 0.7000 0.6995 0.6992 (cv- 0.0992 0.1271 0.1448 0.2008 0.1876 0.1724 0.1722 std) TABLE 15b fea- tures 9 10 11 12 13 14 15 train 0.8212 0.8212 0.8093 0.8095 0.8095 0.8095 0.8452 test 0.7449 0.7449 0.7449 0.7336 0.7346 0.7346 0.7173 cv 0.7341 0.7341 0.7216 0.7218 0.7140 0.7013 0.7013 (cv- 0.1791 0.1791 0.1773 0.1769 0.1966 0.1933 0.1933 std) TABLE 15c features 16 17 18 19 20 train 0.8452 0.8452 0.8571 0.8571 0.8571 test 0.6547 0.6701 0.6619 0.6905 0.6815 cv 0.7013 0.7013 0.7013 0.7010 0.7007 (cv-std) 0.1933 0.1933 0.1933 0.1934 0.1940 In Tables 16a-c, the same results are provided showing the maximum value of the weighted success rate with respect to changing the constant factor added to the real valued output before thresholding the decision rule (to control the tradeoff between false positives and false negatives). The best success rate found on the test set using this method is 75.84%. Cross-validation (CV) results indicate that 9 or 10 features produce the best results, which gives a test score of 74.49%. TABLE 16a features 2 3 4 5 6 7 8 trainmax 0.8431 0.8669 0.8669 0.9264 0.9502 0.8212 0.8212 testmax 0.5000 0.6308 0.7264 0.7264 0.7275 0.7247 0.7250 cvmax 0.6624 0.6648 0.6752 0.7569 0.7460 0.7460 0.7489 (cvmax-std) 0.1945 0.0757 0.1788 0 0.1949 0.1954 0.1349 TABLE 16b features 9 10 11 12 13 14 15 trainmax 0.8212 0.8212 0.8212 0.8450 0.8450 0.8450 0.8571 testmax 0.7449 0.7449 0.7472 0.7574 0.7584 0.7584 0.7421 cvmax 0.7583 0.7599 0.7724 0.7729 0.7731 0.7734 0.7713 (cvmax-std) 0.1349 0.1349 0.1349 0.1245 0.1128 0.1187 0.1297 TABLE 16c features 16 17 18 19 20 trainmax 0.8571 0.8571 0.8690 0.8690 0.8690 testmax 0.7454 0.7277 0.7205 0.7289 0.7156 cvmax 0.7963 0.7838 0.7815 0.7713 0.7669 (cvmax-std) 0.1349 0.1297 0.1349 0.1245 0.1349 Note that the training score does not improve as expected when more complicated models are chosen. This is likely the result of two factors: first, the size of the diagonal term on the kernel may not scale the same resulting in a different value of the cost function for training errors, and second (which is probably the more important reason) training error is only approximately minimized via the cost function employed in SVM which may suffer particularly in this case of unbalanced training data. Based on the CV results, linear functions were selected for the rest of the experiments. To provide a comparison with the SVM results, a C4.5 (decision tree) classifier and k-nearest neighbours (k-NN) classifier were each run on the features identified by cross validation. SVMs gave a test success of 0.7449, but standard C4.5 gave a test success of 0.5. The problem is that the standard version of C4.5 uses the standard classification loss as a learning criterion and not a weighted loss. Therefore, it does not weight the importance of the positive and negative examples equally and, in fact, in the training set classifies all examples negative. “Virtual” training examples were created by doubling some of the points to make the set seem more balanced, however, this did not help. It appears that the C4.5 algorithm internally would need to be modified internally to make it work on this dataset. p In the k-NN comparison, the decision rule is to assign the class of the majority of the c-nearest neighbors xi=1, . . . l of a point x to be classified. However, the distance measure was altered so that if xi is a positive example, the measure of distance to x was scaled by a parameter λ. By controlling λ, one controls the importance of the positive class. The value of λ could be found by maximizing over success rates on the training set, but in the present experiments, the maximum performance on the test set over the possible choices of λ to get an upper bound on the highest attainable success rate of k-NN was observed. The results for this method (k-NNmax) and conventional k-NN are given in Table 17. These results fall short of the previously-described SVM results (0.7449) with SVM outperforming both variations of k-NN for all values of the hyperparameters. TABLE 17 k 1 2 3 4 5 6 7 8 k-NN 0.57 0.20 0.64 0.63 0.63 0.37 0.50 0.50 k-NNmax 0.59 0.35 0.65 0.65 0.65 0.41 0.50 0.50 The present embodiment of the feature selection method was compared against another standard: correlation coefficients. This method ranks features according to the score  μ ( + ) - μ ( - ) σ ( + ) + σ ( - )  , where μ(+) and μ(−) are the mean of the feature values for the positive and negative examples respectively, and σ(+) and σ(−) are their respective standard deviations. The results of this comparison are given below in Table 18. Overall, correlation coefficients are a poor feature selector, however, SVMs perform better than either of the other classifiers (k-NN or C4.5) using feature selection based on correlation coefficients. TABLE 18 features 2 4 6 8 10 12 14 16 18 SVMmax 0.62 0.62 0.59 0.59 0.52 0.52 0.50 0.51 0.50 k-NNmax 0.62 0.59 0.53 0.55 0.53 0.51 0.52 0.51 0.52 C4.5 0.62 0.57 0.55 0.51 0.49 0.52 0.53 0.51 0.51 Also considered was the following feature selection scoring method which involved selecting the features with the highest unbalanced correlation score without any entry assigned to negative samples. This can be achieved by computing the score f i = ∑ Y i = 1 ⁢ ⁢ X ij - λ ⁢ ∑ Y i = - 1 ⁢ ⁢ X ij for large values of λ. However, in practice, if λ≧3, the results are the same on this dataset. The results for the unbalanced correlation score with no negative entries are shown in Table 19 using an OR function as the classifier. The test success rates are slightly better than those obtained for the previous correlation score (in which λ=1), but the advantage is that there are fewer hyperparamers to adjust. Unfortunately, the cross validation results do not accurately reflect test set performance, probably because of the non-iid nature of the problem. Because of its simplicity, this feature selection score is used in the following description of transductive algorithms. TABLE 19a Feat. 1 2 3 4 5 6 7 8 9 10 Tr. 66.6 66.6 66.6 66.6 66.6 66.6 71.4 76.1 76.1 76.1 Ts. 63.0 72.8 74.6 74.9 74.99 75.3 76.9 74.4 74.7 74.6 TABLE 19b Feat. 11 12 13 14 15 16 17 18 19 20 Tr. 76.1 76.1 76.1 76.1 76.1 77.3 77.3 77.3 79.7 80.9 Ts. 73.4 73.4 73.4 76.2 76.2 75.7 75.0 73.8 69.5 65.0 In inductive inference, which has been used thus far in the learning process, one is given data from which one builds a general model and then applies this model to classify new unseen (test) data. There also exists another type of inference procedure, so called transductive learning, in which one takes into account not only given data (the training set) but also the (unlabeled) data that one wishes to classify. In the strictest sense, one does not build a general model (from specific to general), but classifies the test examples directly using the training examples (from specific to specific). As used herein, however, algorithms are considered which take into account both the labeled training data and some unlabeled data (which also happens to be the test examples) to build a more accurate (general) model in order to improve predictions. Using unlabeled data can become very important with a dataset where there are few positive examples, as in the present case. In the following sections, experiments with a simple transduction algorithm using SVMs are shown to give encouraging results. A naive algorithm was designed to take into account information in the test. First, this algorithm used the SVM selected via cross validation. Then, calculated the real valued output y=g(x) of this classifier on the test set was calculated. (Before taking the sign—this is proportional to the distance from the hyperplane of a test point). These values were then used as a measure of confidence of correct labeling of those points. Next, two thresholds t1<t2 were selected to give the sets A={x1: g(xi)<t1} and B={xi:g(xi)>t2}, where it is assumed that the points in set A have label −1 and B have label +1. The thresholds t1 and t2 should be chosen according to the conditional probability of y given the distance from the hyperplane. In this experiment the thresholds were hand-selected based upon the distribution of correctly labeled examples in cross validation experiments. Feature selection is performed using CORRub using both the training set and the sets A and B to provide a sort of enlarged training set. Then, a SVM is trained on the original training set with the n best features from the resulting correlation scores. For each n, the best scores of the SVM were calculated by adjusting the threshold parameter. This scheme could be repeated iteratively. The results of the transductive SVM using CORRub feature selection compared with the inductive version, shown Tables 20a and b and FIG. 22, were quite positive. The best success rate for the transductive algorithm is 82.63% for 30-36 features. TABLE 20a feature 2 4 6 8 10 SVM-TRANSmax 0.7115 0.7564 0.7664 0.7979 0.8071 SVMmax 0.7574 0.7264 0.7275 0.7250 0.7449 TABLE 20b feature 12 14 16 18 20 SVM-TRANSmax 0.8152 0.8186 0.8206 0.8186 0.8219 SVMmax 0.7574 0.7584 0.7454 0.7205 0.7156 In order to simplify the transduction experiments, a transductive approach of the CORRub method was applied. This should remove some of the hyperparameters (e.g the hyperparameters of the SVM and make the computations faster, facilitating computation of several iterations of the transduction procedure, and the corresponding cross validation results. To apply the transductive approach, a simple probabilistic version of the algorithm set forth above was designed: 1. Add the test examples to the training set but set their labels yi=0 so their labels are unknown. 2. Choose n features using the score for a feature j, f j = ∑ Y l > 0 ⁢ Y i ⁢ X ij + 3 ⁢ ∑ Y l < 0 ⁢ Y i ⁢ X ij ; ( the ⁢ ⁢ CORR ub ⁢ ⁢ method ) . 3. For each test example recalculate their labels to be: yi=f(g(xi)) where g(xi) is the sum of the values of the features (the features were selected in the previous step). The function f can be based on an estimate of the conditional probability of y given g(xi). In this case, the selected function was f(x)=tanh(sx/n−b) where s and b were estimated to be the values s=4 and b=0.15. These values were selected by performing cross validation on different feature set sizes to give the values g(xi) of left out samples. The values are then selected by measuring the balanced loss after assigning labels. 4. Repeat from step 2 until the features selected do not change or a maximum number of iteration have occured. FIG. 23 shows the results of the transductive CORRub2 method compared to the inductive version for from 4 to 100 features. The best success rate for the transductive algorithm is 82.86%. Again, the transductive results provide improvement over the inductive method. The transductive results are particularly robust with increasing numbers of features, up to one hundred features. After 200 features the results start to diminish, yielding only 77% success. At this same point, the inductive methods give 50% success, i.e., they no longer learn any structure. For 1000 features using the transductive method one obtains 58% and for 10000 features one no longer learns, obtaining 50%. Note also that for CORR (the inductive version), the cross validation results do not help select the correct model. This may be due to the small number of positive examples and the non-iid nature of the data. As the cross validation results are more or less equal in the transductive case as the number of features increases, it would be preferable to choose a smaller capacity model with less features, e.g, 10 features. Table 21 provides the results of the tranductive CORRub2 method, while Table 22 provides the results of the CORRub2 inductive method, for test success, cross validation success and the corresponding standard deviation. TABLE 21 features 1 5 10 15 20 25 30 35 40 TRANS 0.6308 0.7589 0.8163 0.8252 0.8252 0.8252 0.8252 0.8252 .08252 test TRANS 0.6625 0.6746 0.6824 0.6703 0.6687 0.6687 0.6683 0.6683 0.6683 cv TRANS 0.074 0.089 0.083 0.088 0.089 0.090 0.089 0.089 0.089 cv-std TABLE 22 features 1 11 21 31 41 CORRub2 test 0.6308 0.7315 0.6165 0.5845 0.5673 CORRub2 cv 0.5176 0.6185 0.6473 0.6570 0.6677 CORRub2 cv-std 0.013 0.022 0.032 0.04 0.04 In summary, feature selection scores and forward selection schemes which take into account the unbalanced nature of the data, as in the present example, are less likely to overfit than more complex backward selection schemes. Transduction is useful in taking into account the different distributions of the test sets, helping to select the correct features. Single Feature Selection Using Ranking by Margin Value The present method of feature selection comprises means for estimating the number of variables falsely called “significant” when variable selection is performed according to the SF-SVM (single feature support vector machine) criterion. In the case of the specific data, the goal is to select a subset of variables from a large costly microarray to construct less costly microarrays and perform more extensive experiments. The variables are ranked in order of best fit to achieve this separation and predict the fraction of false positives. While the present method is described in terms of gene selection, it should be noted that the method may be similarly applied to selection of other features. In one embodiment, the design specifications of the low cost arrays are set, e.g. a maximum of n=500 variables on the array with a fraction of false positive not exceeding ƒ=10%. A high cost array with a larger number of variables n′>>n is then chosen. The number p of experiments to be run on the large cost arrays is determined. The p experiments are run on the n′ variable arrays and the SF-SVM method to rank the variables is used. The top n most promising variables are selected. The fraction g of falsely significant genes using the method outlined in the report are estimated. If g>ƒ more experiments on the large costly arrays need to be run and the whole procedure is iterated until g<ƒ. EXAMPLE 8 Renal Cancer Dataset The present example selects a subset of genes that are most characteristic of renal malignancies. The data consists of gene expression coefficients recorded with an expensive DNA microarray technology for a very small number of tumors (7 samples). The goal is to select the most promising subset of genes to design less expensive microarrays which include the selected subset of genes only, in order to conduct more extensive experiments. Results are presented using Support Vector Machine techniques. Gene expression coefficients obtained from measurements on cDNA microarrays such as those available from Incyte Genomics, Inc. (Palo Alto, Calif.) were used for analysis. The data consists of seven arrays recording the relative expression coefficients of renal epithelial neoplasms. In each case, the cancerous tissue was hybridized competitively with normal tissue from the same patient. Positive numbers mean upregulation of the gene in cancer compared to normal, negative numbers indicate downregulation of the gene in cancer compared to normal (Ratios have been log 2 transformed). The data includes 5312 gene expression coefficients per tumor along with clone ID and a brief gene description for each coefficient is also listed. Tumors are traditionally grouped according to cytogenic abnormalities. The seven arrays used to generate the dataset correspond to the following tissue types: Conventional (four samples) representing stages IIA, IIB, III and IV; Oncocytoma (two samples), types A and B; and Chromophobe (1 sample). The characteristics of the types of cells are summarized below: Conventional (also known as “Clear Cell”): This is the most common tissue type, representing 75-85% of tumors. Half of the patients presenting with conventional RCC (renal cell carcinoma) are already in advanced stage The Robson staging classification divides stages into: confinement to the renal parenchyma (stage I), tumor extension into the perirenal fat (stage II), tumor involvement of the renal vein or inferior vena cava (stage IIIa), or tumor involvement of local hilar lymph node or other vascular structures (stage IIIb). Stage IV classifies tumors involving adjacent organs or distant metastasis. Conventional RCC develops in approximately one-third of patients with von Hippel-Lindau Syndrome. This is a deletion in the 3p region of the chromosome where a tumor suppressor gene is located. Mutations or deletions here can cause a loss of control, allowing certain cancers to develop where they would ordinarily be suppressed. Conventional RCC does not respond well to chemotherapy. Other agents must be used, such a cytoldnes (IL2, Interferon alpha), or anti-angiogeneis agents to cut off blood supply. Surgery is commonly performed for all three, since a tissue sample must be obtained to diagnose based on the characteristics of the tissue. Chromophobic: This type represents 5% of tumors which are low grade tumors which they have malignant potential. Oncocytoma: This type is uncommon, with benign tumors which can metastasize and turn into the chromophobic type. For analysis, the problem can be viewed as a two class or multiclass problem. Conventional cells always stand alone as a distinct entity. The chromophobe and oncocytomas can be grouped together because they are much more similar to each other than to the conventional type. In the first part of the study, the examples were split into two classes: all “conventional” (samples 1-4), and the others (samples 5-7). This allowed the application of a SF-SVM to derive statistically significant results for the screening of genes that are relevant to renal diseases. Multi-class methods were used to analyze the second phase data set collected using a smaller subset of pre-selected genes but a larger number of tumors. This complements an analysis based on clustering (unsupervised learning). The present method of feature selection provides for ranking of genes according to how well they separate tumor categories, making direct use of the knowledge of these categories in a supervised learning scheme. The SF-SVM uses the size of the gap (margin) between classes as a ranking criterion. It is compared with a reference method using differences in mean class values. Both criteria use normalized gene expressions to account for each “gene-specific scatter”, which is not taken into account in the fold change criterion. The reliability of the ranking is then quantified statistically. The data was pre-processed by successively normalizing the columns, the rows and then, again, the columns of the matrix. Normalization consists of subtracting the mean and dividing by the standard deviation. A singular value decomposition of the original data and of the preprocessed data was performed. In both cases the six first singular values were significantly different from zero. The seven tumor examples were plotted in the space of the first two gene eigenvectors, both for non-normalized and normalized data. In both cases, the first class (tumors 1-4) was separated from the second class (tumors 5-7) along the first principal component (projection in the direction of the first eigenvector). The grouping of the tumors into sub-categories was not apparent. FIG. 24 provides the scatter plot for the normalized data for the different tissue types separated into two classes according to the first principal component (horizontal axis.) For class 1, the circle designates Conventional, stage II (“Conv. II”), the solid square designates Conv. III, and the plus sign corresponds to Conv. IV. For class 2, the open square corresponds to oncocytoma and the open diamond corresponds to chromophobe. The preceding confirms the results obtained by clustering and supports the fact that tumors 1-4 are well separated from tumors 5-7 The exploratory data analysis indicated that class 1 (tumors 1-4) and class 2 (tumors 5-7) are easily separated. Genes are ranked according to how significantly they separate one class from the other. Using the SVM criterion, the number of genes falsely called significant in any given list of genes can be estimated. The result is compared to that obtained by the classical t-test method as a reference statistical method. The size of the data set (seven tumors) does not permit classical machine learning analysis in which the data are split into a training set and a test set, or even to perform cross-validation experiments. Therefore, classical statistics methods of gene ranking evaluation were used. This differs from previous studies in which a novel criterion for gene ranking developed for prostate cancer data analysis was used. Single Feature SVM ranks the genes according to their margin value, i.e., the distance between the extremal points of the two classes under study. For example, assume a gene is, on average, overexpressed for class 1 examples and underexpressed for class 2 examples. The margin is computed as the difference between the minimum value of the class 1 examples and the maximum value of the class 2 examples. To perform that analysis, it is important that the gene expression coefficients be normalized according to the pre-processing steps described above. Other methods typically rank genes according to the average difference in expression coefficient. SF-SVM provides a better confidence that the genes selected are truly significant. Values for the top genes that were selected using SF-SVM are given in Tables 23 and 24. Table 23 includes genes underexpressed for class 1 (conventional) and overexpressed for class 2 (chromophobe/oncocytoma), while Table 24 lists genes overexpressed for class 1 and underexpressed for class 2. In both tables, the “Margin” is the SF-SVM ranking criterion. Its exponentiated value “Expmar” is also provided. All genes listed have a p-value less than 0.001. The sixth through nineteenth genes in Table 23 have a p-value less than 0.0005 and first five genes in the list have a p-value less than 0.0001. In Table 24, all genes have a probability less than 0.001 to be false positive. The first three genes listed in Table 24 have a probability of less than 0.0001 to be false positive, while the fourth through fourteenth entries have a probability of less than 0.0005 to be false positive. TABLE 23 Gene Margin Expmar Description 2082 1.56849 4.79938 acetyl-Coenzyme A acetyltransferase 1 (acetoacetyl Coenzyme A thiolase) {Incyte PD: 3425159} 2634 1.56815 4.79778 glutamate decarboxylase 1 (brain, 67 kD) {Incyte PD: 2498815} 2326 1.51024 4.52781 JTV1 gene {Incyte PD: 1579679} 2754 1.47959 4.39115 glutaryl-Coenzyme A dehydrogenase {Incyte PD: 1998421} 30 1.45895 4.30143 KIAA0196 gene product {Incyte PD: 620885} 3508 1.36831 3.92871 Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 26539 {Incyte PD: 1653974} 4614 1.35769 3.8872 complement component 1, q subcomponent binding protein {Incyte PD: 1552335} 4450 1.33749 3.80945 NADH dehydrogenase (ubiquinone) Fe-S protein 4 (18 kD) (NADH- coenzyme Q reductase) {Incyte PD: 2883487} 4020 1.33483 3.79935 conserved helix-loop-helix ubiquitous kinase {Incyte PD: 2746918} 1736 1.33048 3.78285 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2) {Incyte PD: 661259} 4070 1.32378 3.7576 Homo sapiens KB07 protein mRNA, partial cds {Incyte PD: 62790} 4316 1.31658 3.73064 junction plakoglobin {Incyte PD: 820580} 2169 1.30404 3.68415 ESTs {Incyte PD: 2591352} 3466 1.30024 3.67017 ESTs {Incyte PD: 2472605} 648 1.28479 3.61389 solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 {Incyte PD: 1684954} 4947 1.25411 3.50471 Incyte EST {Incyte PD: 1992727} 4370 1.24593 3.47615 solute carrier family 9 (sodium/hydrogen exchanger), isoform 1 (antiporter, Na+/H+, amiloride sensitive) {Incyte PD: 2054252} 1623 1.21608 3.37393 retinitis pigmentosa GTPase regulator {Incyte PD: 311313} 306 1.21478 3.36955 protein kinase, cAMP-dependent, regulatory, type II, beta {Incyte PD: 1968465} 4475 1.18853 3.28226 KIAA0580 protein {Incyte PD: 2722216} 4468 1.18521 3.27138 Down syndrome candidate region 1-like 1 {Incyte PD: 1375877} 151 1.18385 3.26693 peroxisomal biogenesis factor 7 {Incyte PD: 2722756} 4159 1.15796 3.18344 hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein), alpha subunit {Incyte PD: 1600442} 3126 1.11533 3.05056 KE2 protein {Incyte PD: 1994340} TABLE 24 Gene Margin Expmar Description 2986 1.58551 4.881779 tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) {Incyte PD: 1998269} 2041 1.478624 4.386906 major histocompatibility complex, class II, DO beta {Incyte PD: 2200211} 4015 1.409464 4.093759 guanylate binding protein 1, interferon-inducible, 67 kD {Incyte PD: 521139} 509 1.36113 3.900598 bone morphogenetic protein 1 {Incyte PD: 1804401} 423 1.321147 3.747718 interferon regulatory factor 7 {Incyte PD: 2308952} 1930 1.31463 3.723373 vimentin {Incyte PD: 1522716} 3717 1.262751 3.535132 KIAA0677 gene product {Incyte PD: 876860} 3040 1.262751 3.535132 N-acetylglucosaminyl transferase component Gpi1 {Incyte PD: 1511484} 1270 1.254365 3.50561 adenosine A3 receptor {Incyte PD: 1989534} 4086 1.231158 3.425193 major histocompatibility complex, class II, DR beta 1 {Incyte PD: 2683564} 3412 1.221229 3.391351 chromosome condensation 1 {Incyte PD: 3180854} 422 1.215801 3.372994 delta sleep inducing peptide, immunoreactor {Incyte PD: 2307314} 1387 1.212219 3.360933 Human mRNA for SB classII histocompatibility antigen alpha- chain {Incyte PD: 1994472} 1396 1.196186 3.307477 solute carrier family 21 (prostaglandin transporter), member 2 {Incyte PD: 1648449} 929 1.13331 3.10592 vesicle-associated membrane protein 5 (myobrevin) {Incyte PD: 122826} 3389 1.092242 2.98095 lymphoid blast crisis oncogene {Incyte PD: 3029331} It was verified that CD74 is overexpressed in conventional, not in oncocytomas. (Its rank is 34, which is too low to appear in Table 24). The p-values mentioned in the legend of the tables are computed as described in the following discussion. In the genes listed in Tables 23 and 24 having p-values less than 0.001, it is expected that only of the order of 5 genes at most will be random genes having no significance for the separation. To compute the probabilities of false positive, the distribution of margin values for an identical number of examples as in the study (4 of one class and 3 of the other) were numerically evaluated. The examples of the two classes are drawn at random according to N(0,1). After resealing, gene expression coefficients that are pure “noise” and do not carry information would be expected to be drawn according to the Normal law N(0,1) for both classes. The p-values are tabulated in Table 25, which provides the probabilities of obtaining a margin value equal to or larger than the tabulated margin for examples drawing at random according to N(0,1). To build the table, 100000 drawings of four examples were taken for class 1 and 3 for class 2 according to N(0,1). With each drawing, the margin was computed. The estimated p-value is the fraction of drawings in which the margin exceeds the corresponding value given in the table. TABLE 25 pvalue margin expmar = exp(margin) 0.500000 −1.83 0.16 0.100000 −0.55 0.57 0.050000 −0.21 0.81 0.010000 0.41 1.50 0.005000 0.63 1.88 0.001000 1.09 2.98 0.000500 1.19 3.28 0.000100 1.37 3.94 <0.000050 2.07 7.96 FIG. 25 is a plot of the distribution of margin values for the combination of samples used to build Table 25. A few values extracted from this plot are shown in Table 25 For example, only 0.01 (1%) of “random” genes have a margin exceeding 0.41. A larger fraction of real genes separate the two classes with a margin exceeding that value (398 genes, that is 7% of the 5312 in the data set). Thus, among these 398 genes that have margin values exceeding 0.41, it is expected that, at most, 53 genes will be falsely called significant. All methods rank genes according to how well the examples of one class are separated from the examples of the other class using a given criterion. The genes are indexed with the letter i and ωi is the ranking criterion for a given gene. (+) denotes the class for which gene i is overexpressed on average and class and (−) the other class δi is denoted by the sign of ωi (gene polarity), which is +1 if class (+) coincides with class 1 and −1 otherwise. Genes with positive ωi are overexpressed for class 1 and underexpressed for class 2. Two types of criteria are compared, which are the difference in mean values and the difference in extremal values. (1) Difference in mean values: Several methods are based on the difference in mean expression value of the two classes μi(+) and μi(−), normalized with a coefficient that reflects the intrinsic scatter of gene expression values of that gene. Typically, an average of the two intra-class standard deviations σi(+) and σi(−) is considered, e.g. for Golub's method ωi=δi(μi(+)−μi(−))/(σi(+)+σi(−)) and for Fisher's criterion (sometimes referred to as single feature-linear disriminant analysis (SF-LDA)) ωi=δi(μi(+)−μi(−))/sqrt(p(+) σi(+)2+p(−) σi(−)2). Other similar criteria include the t-test criterion and SAM that are well known to those of skill in the art. (2) Difference in extremal values: The criterion that used above is based on the difference in extremal values (margin). si(+) is defined as the smallest observed value of class (+) and si(−) the largest observed value of class (−). The criterion is then ωi=δi exp(si(+)−si(−)). The exponentiation permits accounting for overlapping classes that have negative margins. The SF-SVM criterion is not normalized. FIG. 26 provides plots of the hypothetical distributions of gene expression coefficients of a given gene for two categories of samples, where class (−) is indicated by the “●” on the curve and class (+) by the “+” on the curve. Sets of examples drawn from those distributions are indicated by “●” and “+” on the horizontal arrow. Criteria to determine whether a given gene separates the two classes are derived by examining either the difference in mean values μi(+)−μi(−) or the difference in extremal values si(+)−si(−). FIG. 26a illustrates a typical sample drawn from well separated classes. FIG. 26b models a purely insignificant gene by drawing at random examples of both classes from the same distribution N(0,1). It is unlikely that the means of the examples of the two classes will be well separated. It is even more unlikely that the extremal values will be separated by a positive margin. For both type of criteria, it is possible to assess the fraction of genes falsely called significant in a given list of genes. A gene is called “significant” for the class separation at hand if its criterion exceeds a certain threshold value. To estimate the number of genes falsely called significant, the above-described method for determining statistical significance can be used. The estimated p-value is the fraction of drawings in which the criterion exceeds a given threshold. Therefore, for any criterion threshold value, it is possible to obtain an upper bound estimate of the number of genes called significant that are plotted as a function of the number of genes called significant. FIG. 27 provides a plot of an estimated upper bound on the number of genes falsely called significant as a function of the number of genes called significant. The estimate uses 100000 genes drawn at random according to N(0,1). The results using the SF-LDA (t-test) method are indicated by the curve with circles. The other line indicates the results of the SF-SVM, with the dashed portion of that line, below the intersection of the two lines, corresponding to genes that separate the two classes perfectly. The SF-SVM criterion that uses the difference between extremal points as ranking criterion incurs a smaller number of genes falsely called significant than does the SF-LDA criterion that uses the difference of the means. Above the point where the two curves cross, SF-LDA becomes more reliable. The SF-SVM criterion appears to be slightly superior to the SF-LDA criterion because, for a given number of genes called significant, it provides a smaller estimated number of genes falsely called significant where positive margins (genes separating perfectly the two classes) can be defined. Looking at the multi-class problem, a Support Vector Machine method is applied for finding genes that can discriminate between diseases with a large margin. In this case, “margin” means the difference of gene expression between two borderline patients carrying a different disease. The small number of patients in each disease category does not allow the quantitative assessment of the validity of the approach on the present dataset. Noentheless, the method will become useful when larger numbers of patients become available. Similar to the two class problem, genes can be ranked according a criterion that characterize how well they individually discriminate between classes. As discussed above, two types of methods can be used: (1) methods based on differences in mean values; and (2) methods based on margins The well known Fisher criterion or Linear Discriminant Analysis (LDA) criterion pertains to the first method, while the SVM criterion pertain to the second method. The multi-class criteria are generalizations of the two-class criteria explained previously. In the experiments, the data is first normalized as described above. The problem is considered as having five classes (in this case, diseases) based on the five tissue types discussed above: Conventional II (2 patients); Conventional III (1 patient); Conventional IV (1 patient); Oncocytoma (2 patients); and Chromophobe (1 patient). The multi-class gene ranking method was applied to select 19 genes that are potentially related to the target, which are listed in Table 26. TABLE 26 small inducible cytokine A2 (monocyte {Incyte PD: 1511342} chemotactic protein 1, homologous to mouse Sig-je) creatine kinase, mitochondrial 2 (sarcomeric) {Incyte PD: 57382} ribosomal protein S11 {Incyte PD: 1813409} zinc finger protein 238 {Incyte PD: 2555828} cytochrome P450, subfamily IIJ {Incyte PD: 1597231} (arachidonic acid epoxygenase) polypeptide 2 mal, T-cell differentiation protein {Incyte PD: 504786} lectin, galactoside-binding, soluble, 3 (galectin 3) {Incyte PD: 2921194} abundant in neuroepithelium area {Incyte PD: 637576} Vimentin {Incyte PD: 1522716} KIAA0439 protein {Incyte PD: 1712888} defensin, beta 1 {Incyte PD: 2912830} ESTs {Incyte PD: 1644648} thrombospondin 2 {Incyte PD: 2804667} parvalbumin {Incyte PD: 2289252} propionyl Coenzyme A carboxylase, {Incyte PD: 196975} alpha polypeptide ATP synthase, H+ transporting, {Incyte PD: 3206210} mitochondrial F1 complex, alpha subunit, isoform 1, cardiac muscle collagen, type I, alpha 1 {Incyte PD: 782235} ATPase, H+ transporting, {Incyte PD: 2676425} lysosomal (vacuolar proton pump), beta polypeptide, 56/58 kD, isoform 1 ESTs {Incyte PD: 1635864} Among the listed genes, two genes are shown which exhibit a pattern for which patients from the same class are grouped and disease grades show a progression for the “conventional” patients. Referring to FIG. 28, the expression of the two genes potentially related to the five diseases is classified using the multi-class method. FIG. 28a shows the results for small inducible cytokine A2 (monocyte chemotactic protein 1, homologous to mouse Sig-je), {Incyte PD:1511342}. FIG. 28b shows the results for ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit, isoform 1, cardiac muscle {Incyte PD:3206210}. The legend indicates the names of the different classes with abbreviations where (Conv=Conventional, Onc=Oncocytoma and Chromo=Chromophobe). Using the genes identified according to the present method, gene expression levels in tissue from patients can be tested for screening for genetic pre-disposition to and diagnosis of renal cancer and for treatment and monitoring of response to treatments such a chemotherapy or other appropriate therapy for renal cancer. The present method of feature selection uses statistical methods to estimate the fraction of genes that might be falsely called significant in a given list of genes that appear to separate well the 4 examples of conventional RCC from the 3 examples of chromophobe or oncocytoma. The two methods used are the conventional t-test (SF-LDA) and SF-SVM. Both methods are in good agreement, however, genes that separate perfectly the two classes identified by SF-SVM do so with a smaller predicted number of genes falsely called significant. The gene ranking provided can be used to select genes that are most promising to build a new microarray with a more directed approach. It should be noted that, because of the small number of examples available, there is a certain degree of uncertainty as to the validity of the genes identified. In the top 1000, about ⅓ of the genes are suspicious. This number drops to ⅛ in the list of top 40 genes of Table 23 and 24. Given enough examples, statistical tests similar to those used for the two-class problem would to assess the number of genes falsely called significant with respect to the multi-class separation. Such a quantitative evaluation of the discriminant power of the genes can be performed with on the order of 30 patients per disease category. According to the present invention, a number of different methods are provided for selection of features for use in a learning machine using data that best represents the essential information to be extracted from the data set. The inventive methods provide advantages over prior art feature selection methods by taking into account the interrelatedness of the data, e.g., multi-label problems. The features selection can be performed as a pre-processing step, prior to training the learning machine, and can be done in either input space or feature space. It should be understood, of course, that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications or alterations may be made therein without departing from the spirit and the scope of the invention as set forth in the appended claims. Such alternate embodiments are considered to be encompassed within the spirit and scope of the present invention. Accordingly, the scope of the present invention is described by the appended claims and is supported by the foregoing description.

<SOH> BACKGROUND OF THE INVENTION <EOH>Knowledge discovery is the most desirable end product of data collection. Recent advancements in database technology have lead to an explosive growth in systems and methods for generating, collecting and storing vast amounts of data. While database technology enables efficient collection and storage of large data sets, the challenge of facilitating human comprehension of the information in this data is growing ever more difficult. With many existing techniques the problem has become unapproachable. Thus, there remains a need for a new generation of automated knowledge discovery tools. As a specific example, the Human Genome Project has completed sequencing of the human genome. The complete sequence contains a staggering amount of data, with approximately 31,500 genes in the whole genome. The amount of data relevant to the genome must then be multiplied when considering comparative and other analyses that are needed in order to make use of the sequence data. To illustrate, human chromosome 20 alone comprises nearly 60 million base pairs. Several disease-causing genes have been mapped to chromosome 20 including various autoimmune diseases, certain neurological diseases, type 2 diabetes, several forms of cancer, and more, such that considerable information can be associated with this sequence alone. One of the more recent advances in determining the functioning parameters of biological systems is the analysis of correlation of genomic information with protein functioning to elucidate the relationship between gene expression, protein function and interaction, and disease states or progression. Proteomics is the study of the group of proteins encoded and regulated by a genome. Genomic activation or expression does not always mean direct changes in protein production levels or activity. Alternative processing of mRNA or post-transcriptional or post-translational regulatory mechanisms may cause the activity of one gene to result in multiple proteins, all of which are slightly different with different migration patterns and biological activities. The human proteome is believed to be 50 to 100 times larger than the human genome. Currently, there are no methods, systems or devices for adequately analyzing the data generated by such biological investigations into the genome and proteome. In recent years, machine-learning approaches for data analysis have been widely explored for recognizing patterns which, in turn, allow extraction of significant information contained within a large data set that may also include data consists of nothing more than irrelevant detail. Learning machines comprise algorithms that may be trained to generalize using data with known outcomes. Trained learning machine algorithms may then be applied to predict the outcome in cases of unknown outcome, i.e., to classify the data according to learned patterns. Machine-learning approaches, which include neural networks, hidden Markov models, belief networks and kernel-based classifiers such as support vector machines, are ideally suited for domains characterized by the existence of large amounts of data, noisy patterns and the absence of general theories. Support vector machines are disclosed in U.S. Pat. Nos. 6,128,608 and 6,157,921, both of which are assigned to the assignee of the present application and are incorporated herein by reference. The quantities introduced to describe the data that is input into a learning machine are typically referred to as “features”, while the original quantities are sometimes referred to as “attributes”. A common problem in classification, and machine learning in general, is the reduction of dimensionality of feature space to overcome the risk of “overfitting”. Data overfitting arises when the number n of features is large, such as the thousands of genes studied in a microarray, and the number of training patterns is comparatively small, such as a few dozen patients. In such situations, one can find a decision function that separates the training data, even a linear decision function, but it will perform poorly on test data. The task of choosing the most suitable representation is known as “feature selection”. A number of different approaches to feature selection exists, where one seeks to identify the smallest set of features that still conveys the essential information contained in the original attributes. This is known as “dimensionality reduction” and can be very beneficial as both computational and generalization performance can degrade as the number of features grows, a phenomenon sometimes referred to as the “curse of dimensionality.” Training techniques that use regularization, i.e., restricting the class of admissible solutions, can avoid overfitting the data without requiring space dimensionality reduction. Support Vector Machines (SVMs) use regularization, however even SVMs can benefit from space dimensionality (feature) reduction. The problem of feature selection is well known in pattern recognition. In many supervised learning problems, feature selection can be important for a variety of reasons including generalization performance, running time requirements and constraints and interpretational issues imposed by the problem itself. Given a particular classification technique, one can select the best subset of features satisfying a given “model selection” criterion by exhaustive enumeration of all subsets of features. However, this method is impractical for large numbers of features, such as thousands of genes, because of the combinatorial explosion of the number of subsets. One method of feature reduction is projecting on the first few principal directions of the data. Using this method, new features are obtained that are linear combinations of the original features. One disadvantage of projection methods is that none of the original input features can be discarded. Preferred methods incorporate pruning techniques that eliminate some of the original input features while retaining a minimum subset of features that yield better classification performance. For design of diagnostic tests, it is of practical importance to be able to select a small subset of genes for cost effectiveness and to permit the relevance of the genes selected to be verified more easily. Accordingly, the need remains for a method for selection of the features to be used by a learning machine for pattern recognition which still minimizes classification error.

<SOH> SUMMARY OF THE INVENTION <EOH>In an exemplary embodiment, the present invention comprises preprocessing a training data set in order to allow the most advantageous application of the learning machine. Each training data point comprises a vector having one or more coordinates. Pre-processing the training data set may comprise identifying missing or erroneous data points and taking appropriate steps to correct the flawed data or as appropriate remove the observation or the entire field from the scope of the problem. In a preferred embodiment, pre-processing includes reducing the quantity of features to be processed using feature selection methods selected from the group consisting of recursive feature elimination (RFE), minimizing the number of non-zero parameters of the system (l 0 -norm minimization), evaluation of cost function to identify a subset of features that are compatible with constraints imposed by the learning set, unbalanced correlation score and transductive feature selection. The features remaining after feature selection are then used to train a learning machine for purposes of pattern classification, regression, clustering and/or novelty detection. In a preferred embodiment, the learning machine is a kernel-based classifier. In the most preferred embodiment, the learning machine comprises a plurality of support vector machines. A test data set is pre-processed in the same manner as was the training data set. Then, the trained learning machine is tested using the pre-processed test data set. A test output of the trained learning machine may be post-processing to determine if the test output is an optimal solution based on known outcome of the test data set. In the context of a a kernel-based learning machine such as a support vector machine, the present invention also provides for the selection of at least one kernel prior to training the support vector machine. The selection of a kernel may be based on prior knowledge of the specific problem being addressed or analysis of the properties of any available data to be used with the learning machine and is typically dependant on the nature of the knowledge to be discovered from the data. Kernels are usually defined for patterns that can be represented as a vector of real numbers. For example, linear kernels, radial basis function kernels and polynomial kernels all measure the similarity of a pair of real vectors. Such kernels are appropriate when the patterns are best represented as a sequence of real numbers. An iterative process comparing postprocessed training outputs or test outputs can be applied to make a determination as to which kernel configuration provides the optimal solution. If the test output is not the optimal solution, the selection of the kernel may be adjusted and the support vector machine may be retrained and retested. Once it is determined that the optimal solution has been identified, a live data set may be collected and pre-processed in the same manner as was the training data set to select the features that best represent the data. The pre-processed live data set is input into the learning machine for processing. The live output of the learning machine may then be post-processed by interpreting the live output into a computationally derived alphanumeric classifier or other form suitable to further utilization of the SVM derived answer. In an exemplary embodiment a system is provided enhancing knowledge discovered from data using a support vector machine. The exemplary system comprises a storage device for storing a training data set and a test data set, and a processor for executing a support vector machine. The processor is also operable for collecting the training data set from the database, pre-processing the training data set, training the support vector machine using the pre-processed training data set, collecting the test data set from the database, pre-processing the test data set in the same manner as was the training data set, testing the trained support vector machine using the pre-processed test data set, and in response to receiving the test output of the trained support vector machine, post-processing the test output to determine if the test output is an optimal solution. The exemplary system may also comprise a communications device for receiving the test data set and the training data set from a remote source. In such a case, the processor may be operable to store the training data set in the storage device prior pre-processing of the training data set and to store the test data set in the storage device prior pre-processing of the test data set. The exemplary system may also comprise a display device for displaying the post-processed test data. The processor of the exemplary system may further be operable for performing each additional function described above. The communications device may be further operable to send a computationally derived alphanumeric classifier or other SVM-based raw or post-processed output data to a remote source. In an exemplary embodiment, a system and method are provided for enhancing knowledge discovery from data using multiple learning machines in general and multiple support vector machines in particular. Training data for a learning machine is pre-processed. Multiple support vector machines, each comprising distinct kernels, are trained with the pre-processed training data and are tested with test data that is pre-processed in the same manner. The test outputs from multiple support vector machines are compared in order to determine which of the test outputs if any represents an optimal solution. Selection of one or more kernels may be adjusted and one or more support vector machines may be retrained and retested. When it is determined that an optimal solution has been achieved, live data is pre-processed and input into the support vector machine comprising the kernel that produced the optimal solution. The live output from the learning machine may then be post-processed as needed to place the output in a format appropriate for interpretation by a human or another computer.

20050131

20090106

20050616

86878.0

FERNANDEZ RIVAS, OMAR F

PRE-PROCESSED FEATURE RANKING FOR A SUPPORT VECTOR MACHINE

UNDISCOUNTED

ACCEPTED

ACCEPTED

Current detecting circuit and actuator driving apparatus

By switching the NMOS (11) on and off, a drive current passes through a solenoid (15). The drive current passes through a conversion circuit (16), and an amplifier circuit (17) outputs a current detection result by amplifying the output voltage of the conversion circuit (16). Because a plurality of resistor elements (161 to 16n) that constitute the conversion circuit (16), together with elements that constitute the amplifier circuit (17) are formed diffused to a semiconductor substrate (100), even if the attribute changes by the conversion circuit (16) generating heat, by the drive current, the amplifier circuit (17) becomes approximately the same temperature, and the attribute changes. Therefore, a highly accurate current detection becomes possible without using components for temperature correction.

1. A current detection circuit comprising: a conversion circuit (16), which generates, when a current, that is a detection target, passes there through, an electronic signal corresponding to the current that passes; and an amplifier circuit (17), which amplifies the electronic signal generated by said conversion circuit (16), wherein said conversion circuit (16) and said amplifier circuit (17) are formed on a common substrate (100). 2. The current detection circuit according to claim 1, further comprising: a switching element (11) that connects a power source (12) and an actuator (15), which is a drive target, on an off, wherein: said conversion circuit (16) is constituted by a circuit that generates an electronic signal that corresponds to a current that passes through the actuator (15) by the connection therewith being switched on and off, by the switching on and off of said switching element (11); said amplifier circuit (17) amplifies the electronic signal that corresponds to the current that passes through the actuator (15), which the conversion circuit (16) outputs, and said switching element (11), said conversion circuit (16), and said amplifier circuit (17) are formed on a common substrate (100). 3. The current detection circuit according to claim 2, wherein: said conversion circuit (16) is constituted by a plurality of conversion elements (161 to 16n) that convert the current that passes through said actuator (15) to a voltage, and generates said electronic signal. 4. The current detection circuit according to claim 3, wherein: the plurality of conversion elements (161 to 16n) that constitute said conversion circuit (16) are formed diffused to said substrate (100). 5. The current detection circuit according to claim 3, wherein: the plurality of conversion elements (161 to 16n) are constituted by resistive elements. 6. The current detection circuit according to claim 3, wherein: said amplifier circuit (17) comprises a plurality of gain setting circuits (21 to 23) that set the gain of the amplifier circuit (17). 7. The current detection circuit according to claim 6, wherein: the plurality of gain setting circuits (21 to 23) are formed diffused to said substrate (100). 8. The current detection circuit according to claim 7, wherein: each of the plurality of gain setting circuits (21 to 23) is constituted by a plurality of resistive elements. 9. The current detection circuit according to claim 7, wherein: said conversion circuit (16) is constituted by a plurality of conversion elements (161 to 16n) that convert the current that passes through said actuator (15) to a voltage, and generates said electronic signal; said amplifier circuit (17) comprises a plurality of gain setting circuits (21 to 23) that set the gain of the amplifier circuit (17), and said plurality of gain setting circuits (21 to 23) are formed close to the conversion elements (161 to 16n) of said substrate (100). 10. The current detection circuit according to claim 9, wherein: each of the plurality of gain setting circuits (21 to 23) is constituted by a plurality of elements, and the plurality of elements (161 to 16n) and said plurality of conversion elements that constitute the plurality of gain setting circuits (21 to 23) are formed diffused to said substrate (100). 11. The current detection circuit according to claim 8, wherein: the plurality of conversion elements (161 to 16n) and the plurality of gain setting circuits (21 to 23) are placed at a thermally close position. 12. The current detection circuit according to claim 7, wherein: said plurality of gain setting circuits (21 to 23) are constituted by resistive circuits. 13. The current detection circuit according to claim 1, wherein: said substrate (100) is formed by a semiconductor substrate. 14. The current detection circuit according to claim 1, wherein: said amplifier circuit (17) comprises gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of said conversion circuit (16) and said gain setting circuits (21 to 23) is constituted by a plurality of elements, wherein the plurality of elements that constitute said conversion circuit (16) and the plurality of elements that constitute said gain setting circuits (21 to 23) are placed close to each other. 15. The current detection circuit according to claim 1, wherein: said amplifier circuit (17) comprises gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of said conversion circuit (16) and said gain setting circuits (21 to 23) is constituted by a plurality of elements, wherein at least one part of elements that constitute said gain setting circuits (21 to 23) is arranged in between the elements that constitute said conversion circuit (16). 16. The current detection circuit according to claim 1, wherein: said conversion circuit (16) generates heat by said current passing through; said amplifier circuit (17) comprises gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of said conversion circuit (16) and said gain setting circuits (21 to 23) is constituted by a plurality of elements, and are placed so that the elements that constitute said conversion circuit (16) and the elements that constitute said gain setting circuits (21 to 23) are heated by the heat from said conversion circuit (16). 17. The current detection circuit according to claim 16, wherein: the plurality of elements that constitute said conversion circuit (16) and said gain setting circuits (21 to 23) are placed so that the temperature of the elements that constitute gain setting circuits (21 to 23) rises in accordance with the rise of temperature of the elements that structure the conversion circuit (16), and the temperature of elements that constitute gain setting circuits (21 to 23) falls, in accordance with the fall of temperature of the elements that structure the conversion circuit (16). 18. The current detection circuit according to claim 17, wherein: each of the conversion circuit (16) and the plurality of gain setting circuits (21 to 23) is constituted by a plurality of resistive elements. 19. An actuator drive unit that comprises the current detection circuit according to claim 1, which further includes a switching element (11) which connects a power source (12) and an actuator (15), that is a drive target, on an off, in response to a control signal, and a control circuit (13), which provides said control signal to said switching element (11) in accordance with the output of said amplifier circuit (17), wherein: said conversion circuit (16) generates an electronic signal that corresponds to a current that passes through the actuator (15) by the connection therewith being switched on and off, by the switching on and off of said switching element (11), and said amplifier circuit (17) amplifies the electronic signal that corresponds to the current that passes through the actuator (15), which the conversion circuit (16) outputs.

TECHNICAL FIELD The present invention relates to a current detection circuit and an actuator drive unit. BACKGROUND ART Recent automobiles, etc., load electronic components for control, and carry out high-speed electronic control with a high accuracy. For example, automatic vehicles carry out electronic control applying hydraulic pressure, to realize automatic transmission. Automatic vehicles load a solenoid for electronically controlling hydraulic pressure, and a solenoid drive unit for passing a current through the solenoid. Art concerning the solenoid drive unit is recited in for example, FIG. 2 of Unexamined Japanese Patent Application KOKAI Publication No. H8-240277. The content of this publication is incorporated herein. FIG. 8 is a diagram showing an outline structure of a conventional solenoid drive unit shown in FIG. 2 of the aforementioned publication. A solenoid drive unit 80 is constituted by an N-channel type MOS transistor (hereinafter referred to as NMOS) 81, a battery 82, a control circuit 83, a diode 84, a solenoid 85, a resistance 86, an amplifier 87, a resistance 88, and a capacitor 89. The solenoid drive unit 80 passes a current to a coil of the solenoid 85, and drives the solenoid 85, by exciting the current. A drain of the NMOS 81 is connected to a positive electrode of the battery 82. A gate of the NMOS 81 is connected to the control circuit 83. A source of the NMOS 81 is connected to a cathode of the diode 84 and one end 85a of the solenoid 85. A negative electrode of the battery 82 is connected to a ground. The control circuit 83 provides a control signal S83 to the gate of the NMOS 81. An anode of the diode 84 is connected to the ground. Another end 85b of the solenoid 85 is connected to one end of the resistance 86. The other end of the resistance 86 is connected to the ground. The resistance 86 is a conversion circuit that converts a current that passes through the solenoid 85 to a corresponding voltage. Both ends of the resistance 86 are connected to a positive input terminal (+) and a negative input terminal (−) of the amplifier 87. An output terminal of the amplifier 87 is connected to one end of the resistance 88. The other end of the resistance 88 is connected to one electrode of the capacitor 89. The other electrode of the capacitor 89 is connected to the ground. FIGS. 9A to D are wave form diagrams for describing the operation of the solenoid drive unit 80 in FIG. 8. Operation of the solenoid drive unit 80 will be described with reference to FIG. 9. In the solenoid drive unit 80, as shown in FIG. 9A, the control circuit 83 provides a control signal S83 that repeats a high level (hereinafter referred to as “H”) and a low level (hereinafter referred to as “L”) to the gate of the NMOS 81. When the control signal S83 is “H”, the NMOS 81 is turned on, and connects one end 85a of the solenoid to the positive electrode of the battery 82. By this, a power source current I1 passes through the negative electrode of the battery 82 via the positive electrode of the battery 82, the resistance 86, and the ground. When the control signal S83 changes to “L”, the NMOS 81 is turned off. When the NMOS is turned off, a counter electromotive force occurs at the solenoid 85. By this counter electromotive force, a regenerative current I0 passes through the anode of the diode 84, the cathode of the diode 84, the solenoid 85, the resistance 86 and a loop of the ground, from the ground. By the current I1 and the regenerative current I0 passing, a voltage proportional to the current that passes through the solenoid 85, is generated at both ends of the resistance 86. The amplifier 87 amplifies the difference of voltage of the voltage input to the negative input terminal and the voltage input to the positive input terminal, and outputs a voltage signal 87 that pulsates, as shown in FIG. 9C. The smoothing circuit that is constituted by the resistance 88 and the capacitor 89, smoothes and outputs, as shown in FIG. 9D, the voltage signal S87 that the amplifier 87 outputs. The smoothed voltage signal S87 output from the smoothing circuit is for example, fed back to the control circuit 83. The control circuit 83 changes the duty ratio of the control signal S83, based on the smoothed voltage signal fed back from the smoothing circuit. Namely, the control circuit 83 carries out PWM (Pulse Width Modulation) control. By this, the current that passes through the solenoid 85 is optimized. The output of the smoothing circuit is for example, A/D converted, and provided to a processor for vehicle control, which is not shown in the drawings. The conventional solenoid drive unit 80 has the problems of below. The NMOS 81, witch is a switching element, and the resistance 86, which is a conversion circuit, both generate heat, because a current for driving solenoid 85 passes through. Therefore, the NMOS 81 and the resistance 86 are embedded in an Electronic Control Unit (ECU) as different components. However, by separating the two components, the temperature in the ECU becomes uneven, and because temperature of each component varies, it is difficult to detect a current (a current that passes through the solenoid 85) accurately. To accurately detect a current, a component for temperature correction, which is not shown in the drawings, is placed in the ECU. Therefore, the number of components increases, and low-cost of the ECU is difficult. Because the solenoid drive unit is constituted by a plurality of components, miniaturization of the ECU is also difficult. The same problems exist not only in the solenoid drive unit, but also in other drive units of actuators, such as a motor, etc. DISCLOSURE OF INVENTION The present invention has been made in consideration of the above, and an object of the present invention is to provide a current detection circuit and/or an actuator drive unit, which makes a highly accurate current detection possible, without needing components for temperature correction. Another object of the present invention is to provide a current detection circuit and/or an actuator drive unit that has few components. Still another object of the present invention is to provide a highly reliable temperature detection circuit and/or a solenoid drive unit. To achieve the above objects, a current detection circuit according to a first aspect of the present invention comprises: a conversion circuit (16), which generates, when a current, that is a detection target, passes there through, an electronic signal corresponding to the current that passes; and an amplifier circuit (17), which amplifies the electronic signal generated by the conversion circuit (16), wherein the conversion circuit (16) and the amplifier circuit (17) are formed on a common substrate (100). The current detection circuit may further comprise a switching element (11) that connects a power source (12) and an actuator (15), which is a drive target, on an off, wherein: the conversion circuit (16) may be constituted by a circuit that generates an electronic signal that corresponds to a current that passes through the actuator (15) by the connection therewith being switched on and off, by the switching on and off of the switching element (11); the amplifier circuit (17) may amplify the electronic signal that corresponds to the current that passes through the actuator (15), which the conversion circuit (16) outputs, and the switching element (11), the conversion circuit (16), and the amplifier circuit (17) may be formed on a common substrate (100). The conversion circuit (16) may be constituted by a plurality of conversion elements (161 to 16n) that convert the current that passes through the actuator (15) to a voltage, and may generate the electronic signal. The plurality of conversion elements (161 to 16n) that constitute the conversion circuit (16) may be formed diffused to the substrate (100). The plurality of conversion elements (161 to 16n) may be constituted by resistive elements. The amplifier circuit (17) may comprise a plurality of gain setting circuits (21 to 23) that set the gain of the amplifier circuit (17). The plurality of gain setting circuits (21 to 23) may be formed diffused to the substrate (100). Each of the plurality of gain setting circuits (21 to 23) may be constituted by a plurality of resistive elements. The conversion circuit (16) may be constituted by a plurality of conversion elements (161 to 16n) that convert the current that passes through the actuator (15) to a voltage, and may generate the electronic signal; the amplifier circuit (17) may comprise a plurality of gain setting circuits (21 to 23) that set the gain of the amplifier circuit (17), and the plurality of gain setting circuits (21 to 23) may be formed close to the conversion elements (161 to 16n) of the substrate (100). Each of the plurality of gain setting circuits (21 to 23) may be constituted by a plurality of elements, and the plurality of elements and the plurality of conversion elements that constitute the plurality of gain setting circuits (21 to 23) may be formed diffused to the substrate (100). The plurality of conversion elements (161 to 16n) and the plurality of gain setting circuits (21 to 23) may be placed at a thermally close position. The plurality of gain setting circuits (21 to 23) may be constituted by resistive circuits. The substrate (100) may be formed by a semiconductor substrate. The amplifier circuit (17) may comprise gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of the conversion circuit (16) and the gain setting circuits (21 to 23) may be constituted by a plurality of elements, wherein the plurality of elements that constitute the conversion circuit (16) and the plurality of elements that constitute the gain setting circuits (21 to 23) are placed close to each other. The amplifier circuit (17) may comprise gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of the conversion circuit (16) and the gain setting circuits (21 to 23) may be constituted by a plurality of elements, wherein at least one part of elements that constitute the gain setting circuits (21 to 23) is arranged in between the elements that constitute the conversion circuit (16). The conversion circuit (16) may generate heat by the current passing through; the amplifier circuit (17) may comprise gain setting circuits (21 to 23), the gain changing in accordance with the attribute of the gain setting circuits (21 to 23), and each of the conversion circuit (16) and the gain setting circuits (21 to 23) may be constituted by a plurality of elements, and may be placed so that the elements that constitute the conversion circuit (16) and the elements that constitute the gain setting circuits (21 to 23) are heated by the heat from the conversion circuit (16). The plurality of elements that constitute the conversion circuit (16) and the gain setting circuits (21 to 23) may be placed so that the temperature of the elements that constitute gain setting circuits (21 to 23) rises in accordance with the rise of temperature of the elements that structure the conversion circuit (16), and the temperature of elements that constitute gain setting circuits falls, in accordance with the fall of temperature of the elements that structure the conversion circuit (16). Each of the conversion circuit (16) and the plurality of gain setting circuits (21 to 23) may be constituted by a plurality of resistive elements. To achieve the above objects, an actuator drive unit according to a second aspect of the present invention comprises the current detection circuit according to the first aspect, which further includes a switching element (11) that connects a power source (12) and an actuator (15), which is a drive target, on an off, in response to a control signal, and a control circuit (13), which provides the control signal to the switching element (11) in accordance with the output of the amplifier circuit (17), wherein: the conversion circuit (16) generates an electronic signal that corresponds to a current that passes through the actuator (15) by the connection therewith being switched on and off, by the switching on and off of the switching element (11), and the amplifier circuit (17) amplifies the electronic signal that corresponds to the current that passes through the actuator (15), which the conversion circuit (16) outputs. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a diagram showing an example of a structure of a solenoid drive unit according to an embodiment of the present invention. FIG. 2A is a diagram showing an example of a structure of an amplifier circuit AA in FIG. 1. FIG. 2B is a diagram showing an example of a structure of an amplifier circuit AB in FIG. 1. FIG. 3 is an explanatory diagram showing a layout example of the solenoid drive unit. FIGS. 4A to D are wave form diagrams for describing the operation of the solenoid drive unit in FIG. 1. FIG. 5 is a diagram showing an example of modification (first modification example) of the solenoid drive unit. FIG. 6 is a diagram showing an example of modification (second modification example) of the solenoid drive unit. FIG. 7 is a diagram showing an example of modification (third modification example) of the solenoid drive unit. FIG. 8 is a diagram showing a conventional solenoid drive unit. FIGS. 9A to D are wave form diagrams for describing the operation of the solenoid drive unit in FIG. 8. BEST MODE FOR CARRYING OUT THE INVENTION As shown in FIG. 1, a solenoid drive unit 10 according to an embodiment of the present invention is constituted by an N-channel MOS transistor (hereinafter referred to as NMOS) 11, a power source 12, a control circuit 13, a diode 14, a solenoid 15, a conversion circuit 16, an amplifier circuit 17, and a smoothing circuit 18. The NMOS 11, the control circuit 13, the diode 14, the conversion circuit 16, the amplifier circuit 17, and the smoothing circuit 18 are formed on a common semiconductor substrate 100. The NMOS 11 functions as a current switch, and the drain thereof is connected to the positive electrode of the power source 12. The gate of the NMOS 11 is connected to the control circuit 13. The source of the NMOS 11 is connected to a cathode of the diode 14 and one end 15a of a coil of the solenoid 15. When the NMOS 11 is turned on, a power source current 11 from the power source 12 is passed through the coil of the solenoid 15. The negative electrode of the battery 12 is connected to a ground. The control circuit 13 provides a control signal SC to the gate of the NMOS 11, and turns on/off the NMOS 11. The anode of the diode 14 is connected to the ground. The cathode of the diode 14 is connected to a connection point of the source of the NMOS 11 and one end 15a of the coil of the solenoid 15. The diode 14 passes through from the ground to the one end 15a of the solenoid 15, a regenerative current I0, which occurs by counter electromotive force generated in the coil of the solenoid 15 when the NMOS 11 is turned off. The conversion circuit 16 is constituted by a plurality of resistor elements 161 to 16n that are connected in parallel, in between another end 15b of the coil of the solenoid 15, and the ground. The conversion circuit 16 converts to a voltage corresponding to a current passing thought the solenoid 15. By applying the common art of semiconductor resistor element manufacturing, the converter 16 can produce physically one resistor element having an equal capacity (value of resistance, current capacity, etc.). However, the conversion circuit 16 is constituted by a parallel circuit of a plurality of resistor elements. FIGS. 2A and B are drawings showing an example of a structure of the amplifier circuit 17. As the amplifier circuit 17, an amplifier circuit AA shown in FIG. 2A, an amplifier circuit AB shown in FIG. 2B, or an amplifier circuit that has combined the amplifier circuit AA and the amplifier circuit AB is used. A resistive circuit 21 that is constituted by a plurality of resistor elements that are serially connected, a resistive circuit 22 that is constituted by a plurality of resistor elements that are serially connected, and a resistive circuit 23 that is constituted by a plurality of resistor elements that are serially connected, are provided on the amplifier circuit AA, amplifier circuit AB, or the amplifier circuit that has combined the amplifier circuit AA and the amplifier circuit AB. The resistive circuits 21 to 23 are for adjusting the gain (amplification factor) of the amplifier circuit 17. By applying the common art of semiconductor resistor element manufacturing, physically one resistive element that has an equal capacity (value of resistance, capacity of current, etc.) as the plurality of resistive elements can be manufactured. However, the conversion circuit 16 is constituted by a combination of a plurality of resistor elements. In the amplifier circuit AA, one end of the resistive circuit 21 is connected to a positive input terminal (+). One end of the resistive circuit 22 is connected to one end of the resistive circuit 23, and the other end of the resistive circuit 23 is connected to a negative input terminal (−) of the resistive circuit 23. Four PNP-type transistors 30, 31, 32, and 33 wherein an emitter is commonly connected to the power source, and a current source 34, are set in the amplifier circuit AA. The base of the transistor 30 is connected to the base and the collector of the transistor 31. The collector of the transistor 30 is connected to the collector of an NPN-type transistor 35, and the emitter of the transistor 35 is connected to another end of the resistive circuit 21. The current source 34 is connected to a base of the transistor 35, a collector and a base of the NPN-type transistor 36, a collector and a base of the NPN-type transistor 37, and a base of the NPN-type transistor 38. An emitter of the transistor 36 is connected to another end of the resistive circuit 21. An emitter of the transistors 37 and 38 are connected to another end of the resistive circuit 22. A collector of the transistor 31 is connected to a collector of the transistor 38. Bases of the transistors 32 and 33 are connected to a collector of the transistor 32. A collector of the transistor 32 is connected to a collector of a PNP-type transistor 40 wherein a base thereof is connected to a collector of the transistor 30. An emitter of the transistor 40 is connected at a connection point of the resistive circuit 22 and the resistive circuit 23. A collector of the transistor 33 is connected to one end of a resistance 41. The other end of the resistance 41 is grounded. In this kind of amplifier circuit AA, when the regenerative current I0 is passing through the conversion circuit 16, the transistors 30, 31, 35 to 38, and the current source 34 become a constant current source circuit, and passes a current through to the transistor 40, so that the current that passes through the resistive circuit 21, and the current that passes through the resistive circuit 22 are equal. The current that goes through the transistor 40 corresponds to the regenerative circuit I0. The transistor 33 passes through a current that is proportional to the current that passes through the transistor 40, to the resistance 41. The resistance 41 generates a voltage corresponding to the regenerative circuit I0, as a current detection signal. On the other hand, the amplifier circuit AB comprises two NPN-type transistors 45 and 46 that each have emitters grounded, and a current source 47. A base of the transistor 45 is connected to a base and collector of the transistor 46. A collector of the transistor 45 is connected to a collector of the PNP-type transistor 48. An emitter of the transistor 48 is connected to one end of the resistive circuit 21. The current source 47 is connected to a base of the transistor 48, and at the same time to a collector and a base of the PNP-type transistor 49, a collector and a base of the PNP-type transistor 50, and a base of the PNP-type transistor 51. An emitter of the transistor 49 is connected to an emitter of the transistor 48. A collector of the transistor 51 is connected to a collector of the transistor 46. An emitter of the transistor 51 and an emitter of the transistor 50 are connected to one end of the resistive circuit 23. The other end of the resistive circuit 23 is connected to one end of the resistive circuit 22, and the other end of the resistive circuit 22 is connected to a positive input terminal (+). The other end of the resistive circuit 21 is connected to a negative input terminal (−). At a connection point of the resistive circuit 23 and the resistive circuit 22, an emitter of the PNP-type transistor 52 is connected. A base of the transistor 52 is connected to a collector of the transistor 48, and a collector of the transistor 52 is connected to one end of a resistance 53. The other end of the resistance 53 is grounded. In this kind of amplifier circuit AB, when the regenerative current 11 is passing through the conversion circuit 16, by the NMOS 11 being switched on, the transistors 45, 46, and 48 to 51 and the current source 47 become a constant current source circuit, and passes a current through to the transistor 52, so that the current that passes through the resistive circuit 21, and the current that passes through the resistive circuit 23 are equal. The current that goes through the transistor 52 corresponds to the regenerative circuit I1. The resistance 53 generates a voltage corresponding to the regenerative circuit I1, as a current detection signal. The smoothing circuit 18 is constituted by a resistance 18a wherein one end is connected to an output terminal of the amplifier circuit 17, and a capacitor 18b which is connected in between another end of a resistance 17a and a ground. The connection point of the resistance 18a and the capacitor 18b forms the output terminal of the smoothing circuit 17, and smoothes the output signal of the amplifier circuit 17. FIG. 3 is a diagram for describing an example of a layout of the solenoid drive unit 10. The NMOS 11 as a switching element, and the peripheral circuits including the control circuit 13, the conversion circuit 16, the amplifier circuit 17, and the smoothing circuit 18, are for example, as shown in FIG. 3, laid out in a semiconductor substrate 100. Resistor elements 161 to 16n that structure the conversion circuit 16 are connected parallel at the semiconductor substrate 100, and are arranged dispersed. The resistive circuits 21 to 23 that determine the gain of the amplifier circuit 17 are arranged between the dispersed resistor elements 161 to 16n. In this way, by structuring the conversion circuit 16 with the plurality of resistor elements 161 to 16n, and arranging them dispersed, generation area of heat becomes wider. The resistive circuits 21 to 23 also receive effect of heat equally, by structuring each of the resistive circuits 21 to 23 with a plurality of resistor elements, and arranging them in between the resistor elements 161 to 16n of the conversion circuit 16. In other words, the resistive circuits 21 to 23 and the conversion circuit 16 are closely combined thermally. When the conversion circuit 16 generates heat by a current that passes through the solenoid 15, the temperature of the resistive circuits 21 to 23 rise in accordance with the amount of generated heat thereof. Therefore, a highly accurate detection result is obtained without the need to install components and elements for temperature correction, to maintain the gain of the amplifier circuit 17 suitably. To heighten the effects of above, it is preferable to arrange the resistor elements 161 to 16n and the resistive circuits 21 to 23 closely. Next, an operation of when the solenoid drive unit 10 in FIG. 1, drives the solenoid 15, and detects a current that passes through the solenoid 15, will be described. FIGS. 4A to D are wave form charts for describing operations of the solenoid drive unit 10 in FIG. 1. The control circuit 13 provides a control signal SC, whose level is repeated between a high level (hereinafter referred to as “H”) and a low level (hereinafter referred to as “L”), as shown in FIG. 4A, to the gate of the NMOS 11, for driving the NMOS 11 to switch it on and off. When the control signal SC is “H”, the NMOS 11 is at an on state, and the NMOS 11 passes the power source current I1, shown in FIG. 4B, to the solenoid 15 from the power source 12. The power source current I1 that passed through the solenoid 15 passes through to the ground, being divided to the resistor elements 161 to 16n in the conversion circuit 16. When the control signal is “L”, the NMOS 11 is at an off state, and the power source 12 and the solenoid 15 are disconnected. When the power source 12 and the solenoid 15 are disconnected, the voltage of the other end 15a of the solenoid 15, where one end 15b is connected to the ground, reduces by a counterelectromotive force, and forward voltage is applied to the diode 14. The diode 14, which is applied to the forward voltage, becomes a conducting state, and passes through the regenerative current I0 shown in FIG. 4B, from the ground to the other end 15a of the solenoid 15. The current I0 that passed through the solenoid 15 passes through the ground, being divided to the resistor elements 161 to 16n in the conversion circuit 16. By this, the solenoid 15 is driven by the power source current I1 and the regenerative current I0. At both ends of the conversion circuit 16, a voltage signal that corresponds to the currents I0 and I1, appears. When applying an amplifier circuit that synthesized the amplifier circuit AA in FIG. 2A and the amplifier circuit AB in FIG. 2B, as the amplifier circuit 17, the amplifier circuit 17 amplifies the voltage signal corresponding to the currents I0 and I1 that the conversion circuit 16 generates, and outputs a voltage that pulsates, such as shown in FIG. 4C. The output voltage of the amplifier circuit 17 is output to the smoothing circuit 18, as the current detection signal. The gain of the current detection signal that the amplifier circuit 17 outputs, is set in the resistive circuits 21 to 23. The smoothing circuit 18 smoothes the output voltage of the amplifier circuit 17, such as shown in FIG. 4D. The output of the smoothing circuit 18 is for example, A/D converted, and provided to processors for vehicle control, which is not shown in the drawings. The control circuit 13 controls the control signal, in accordance with the level of the signal that the smoothing circuit 18 outputs. For example, the control circuit 13 controls the frequency of the pulse of the control signal SC, or controls the pulse width, so that the signal level of the output signal of the smoothing circuit 18 becomes a desired level. Here, as described above, the conversion circuit 16 is constituted by a plurality of resistor elements 161 to 16n, and are arranged dispersed. By this, the generation area of heat becomes a wide range. Also, by each of the resistive circuits 21 to 23 being constituted by a plurality of resistor elements 161 to 16n, and arranging them in between the resistor elements 161 to 16n, the effect of heat can be equally received. In other words, the resistive circuits 21 to 23 and the conversion circuit 16 are closely combined thermally. When the conversion circuit 16 generates heat by a current that passes through the solenoid 15, the temperature of the resistive circuits 21 to 23 rise in accordance with the amount of generated heat thereof. On the contrary, when the current that passes through the solenoid 15 decreases, and the temperature of the conversion circuit 16 falls, the temperature of the resistive circuits 21 to 23 also fall. Therefore, even if the value of resistance of the conversion circuit 16 changes in accordance with heat, the value of resistance of the resistive circuits 21 to 23, which set the gain of the current detection signal, also changes in the same way. Therefore, a highly accurate detection result is obtained without the need to install components and elements for temperature correction, to maintain the gain of the amplifier circuit 17 suitably. As the above, the solenoid drive unit 10 of the present embodiment, has the advantages of below. Because the NMOS 11, the control circuit 13, the conversion circuit 16, the amplifier circuit 17, and the smoothing circuit 18 are formed on the common semiconductor substrate 100, using a semiconductor device manufacturing process, the number of components can be reduced. Because the NMOS 11, the control circuit 13, the conversion circuit 16, the amplifier circuit 17, and the smoothing circuit 18 are formed on the common semiconductor substrate 100, temperature distribution can be made uniform, and a highly accurate current detection is possible, without the need to install components for temperature correction. By these advantages, low cost of the solenoid drive unit becomes possible. Because the conversion circuit 16 is constituted by the plurality of resistor elements 161 to 16n, and further arranged dispersed, heat generating area spreads, and the temperature of the semiconductor substrate 100 can be made even more uniform. Because each of the resistive circuits 21 to 23 is constituted by a plurality of resistor elements, and are placed in between the plurality of resistor elements 161 to 16n in the conversion circuit 16, the thermal coupling of the resistive circuits 21 to 23 and the conversion circuit 16 improves, and accuracy of current detection can be highly maintained. The present invention is not limited to the above embodiment, and various modification is possible. As an example of modification, there is an embodiment as below. In the above embodiment, the resistive circuits 21 to 23 in the amplifier circuit 17 and the plurality of resistor elements 161 to 16n are constituted by pure resistance. These resistor elements for example, diffuse impurities in the semiconductor substrate, and are constituted by a region of an arbitrary impurity concentration (electric conductivity). Or, an insulating film may be placed on the semiconductor substrate, and the resistor elements may be constituted by a semiconductor or a resistance layer formed on the insulating film. Furthermore, the resistor elements do not have to be constituted by pure resistance, and may be constituted by a MOS transistor which has a predetermined voltage applied to the gate thereof, or a bipolar transistor which has an arbitrary voltage applied to the base thereof. Namely, an arbitrary circuit element may be applied, as long as it functions as an equivalent resistance. FIGS. 5 and 6 are each diagrams showing an example of a modification of the solenoid drive unit 10. Even if the NMOS 11, the diode 14, the conversion circuit 16, the amplifier circuit 17, and the smoothing circuit 18 are connected as FIGS. 5 and 6, the solenoid 15 can be current driven. As shown in FIG. 7, the smoothing circuit 18 may be changed to a sample and hold circuit 19 that samples the output signal of the amplifier circuit 17 at a set timing, and retains the output signal. In the above embodiment, the conversion circuit 16 is constituted by the parallel circuit of the plurality of resistor elements. However, the conversion circuit 16 may be constituted by a series circuit of a plurality of resistor elements. Each of the resistive circuits 21 to 23 for determining the gain, is constituted by the series circuit of the plurality of resistor elements. However, each of the resistive circuits 21 to 23 may be constituted by a parallel circuit of a plurality of resistor elements. In this case also, it is preferable that the resistor elements, which constitute the conversion circuit 16 are arranged dispersed, and that the resistor elements, which constitute the resistive circuits 21 to 23 are arranged dispersed, between thereof. The arrangements of the conversion circuit 16 and the resistive circuits 21 to 23 are also arbitrary, as long as the heat generated by the conversion circuit 17 is transmitted to the resistive circuits 21 to 23, and the variation of the resistance of the resistor elements that constitute the conversion circuit 16 can follow the variation of the resistance of the resistive circuits 21 to 23. For example, the resistor elements that constitute the conversion circuit 16 may be arranged in a loop-shape, and the resistive circuits 21 to 23 may be placed in the loop. Or, the conversion circuit 16 may be placed in one place, and the resistive circuits 21 to 23 may be arranged closely around the vicinity thereof. In the above embodiment, an example of applying the present invention to a detection circuit of a solenoid drive current is described. However, the present invention can be widely applied in a case of converting a current to a voltage using resistance, and amplifying the voltage. For example, a current subject to detection is not limited to a solenoid drive current, and the present invention can be applied for detection of an arbitrary drive current of an actuator, such as for example, a pulse motor, and a stepping motor, etc. Various embodiments of the present invention described above are intended to illustrate the present invention, and are not for limiting the invention. Namely, various modifications made within the meaning of an equivalent of the claims of the invention and within the claims are to be regarded to be in the scope of the present invention. This application is based on Japanese Patent Application No. 2001-368125 filed with the Japan Patent Office on Dec. 3, 2001, including specification, claims, drawings and summary. The disclosure of the above Japanese Patent Application is incorporated herein by reference in its entirety. INDUSTRIAL APPLICABILITY The present invention can be applied to an area of industry, which uses actuator drive circuits.

<SOH> BACKGROUND ART <EOH>Recent automobiles, etc., load electronic components for control, and carry out high-speed electronic control with a high accuracy. For example, automatic vehicles carry out electronic control applying hydraulic pressure, to realize automatic transmission. Automatic vehicles load a solenoid for electronically controlling hydraulic pressure, and a solenoid drive unit for passing a current through the solenoid. Art concerning the solenoid drive unit is recited in for example, FIG. 2 of Unexamined Japanese Patent Application KOKAI Publication No. H8-240277. The content of this publication is incorporated herein. FIG. 8 is a diagram showing an outline structure of a conventional solenoid drive unit shown in FIG. 2 of the aforementioned publication. A solenoid drive unit 80 is constituted by an N-channel type MOS transistor (hereinafter referred to as NMOS) 81 , a battery 82 , a control circuit 83 , a diode 84 , a solenoid 85 , a resistance 86 , an amplifier 87 , a resistance 88 , and a capacitor 89 . The solenoid drive unit 80 passes a current to a coil of the solenoid 85 , and drives the solenoid 85 , by exciting the current. A drain of the NMOS 81 is connected to a positive electrode of the battery 82 . A gate of the NMOS 81 is connected to the control circuit 83 . A source of the NMOS 81 is connected to a cathode of the diode 84 and one end 85 a of the solenoid 85 . A negative electrode of the battery 82 is connected to a ground. The control circuit 83 provides a control signal S 83 to the gate of the NMOS 81 . An anode of the diode 84 is connected to the ground. Another end 85 b of the solenoid 85 is connected to one end of the resistance 86 . The other end of the resistance 86 is connected to the ground. The resistance 86 is a conversion circuit that converts a current that passes through the solenoid 85 to a corresponding voltage. Both ends of the resistance 86 are connected to a positive input terminal (+) and a negative input terminal (−) of the amplifier 87 . An output terminal of the amplifier 87 is connected to one end of the resistance 88 . The other end of the resistance 88 is connected to one electrode of the capacitor 89 . The other electrode of the capacitor 89 is connected to the ground. FIGS. 9A to D are wave form diagrams for describing the operation of the solenoid drive unit 80 in FIG. 8 . Operation of the solenoid drive unit 80 will be described with reference to FIG. 9 . In the solenoid drive unit 80 , as shown in FIG. 9A , the control circuit 83 provides a control signal S 83 that repeats a high level (hereinafter referred to as “H”) and a low level (hereinafter referred to as “L”) to the gate of the NMOS 81 . When the control signal S 83 is “H”, the NMOS 81 is turned on, and connects one end 85 a of the solenoid to the positive electrode of the battery 82 . By this, a power source current I 1 passes through the negative electrode of the battery 82 via the positive electrode of the battery 82 , the resistance 86 , and the ground. When the control signal S 83 changes to “L”, the NMOS 81 is turned off. When the NMOS is turned off, a counter electromotive force occurs at the solenoid 85 . By this counter electromotive force, a regenerative current I 0 passes through the anode of the diode 84 , the cathode of the diode 84 , the solenoid 85 , the resistance 86 and a loop of the ground, from the ground. By the current I 1 and the regenerative current I 0 passing, a voltage proportional to the current that passes through the solenoid 85 , is generated at both ends of the resistance 86 . The amplifier 87 amplifies the difference of voltage of the voltage input to the negative input terminal and the voltage input to the positive input terminal, and outputs a voltage signal 87 that pulsates, as shown in FIG. 9C . The smoothing circuit that is constituted by the resistance 88 and the capacitor 89 , smoothes and outputs, as shown in FIG. 9D , the voltage signal S 87 that the amplifier 87 outputs. The smoothed voltage signal S 87 output from the smoothing circuit is for example, fed back to the control circuit 83 . The control circuit 83 changes the duty ratio of the control signal S 83 , based on the smoothed voltage signal fed back from the smoothing circuit. Namely, the control circuit 83 carries out PWM (Pulse Width Modulation) control. By this, the current that passes through the solenoid 85 is optimized. The output of the smoothing circuit is for example, A/D converted, and provided to a processor for vehicle control, which is not shown in the drawings. The conventional solenoid drive unit 80 has the problems of below. The NMOS 81 , witch is a switching element, and the resistance 86 , which is a conversion circuit, both generate heat, because a current for driving solenoid 85 passes through. Therefore, the NMOS 81 and the resistance 86 are embedded in an Electronic Control Unit (ECU) as different components. However, by separating the two components, the temperature in the ECU becomes uneven, and because temperature of each component varies, it is difficult to detect a current (a current that passes through the solenoid 85 ) accurately. To accurately detect a current, a component for temperature correction, which is not shown in the drawings, is placed in the ECU. Therefore, the number of components increases, and low-cost of the ECU is difficult. Because the solenoid drive unit is constituted by a plurality of components, miniaturization of the ECU is also difficult. The same problems exist not only in the solenoid drive unit, but also in other drive units of actuators, such as a motor, etc.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a diagram showing an example of a structure of a solenoid drive unit according to an embodiment of the present invention. FIG. 2A is a diagram showing an example of a structure of an amplifier circuit AA in FIG. 1 . FIG. 2B is a diagram showing an example of a structure of an amplifier circuit AB in FIG. 1 . FIG. 3 is an explanatory diagram showing a layout example of the solenoid drive unit. FIGS. 4A to D are wave form diagrams for describing the operation of the solenoid drive unit in FIG. 1 . FIG. 5 is a diagram showing an example of modification (first modification example) of the solenoid drive unit. FIG. 6 is a diagram showing an example of modification (second modification example) of the solenoid drive unit. FIG. 7 is a diagram showing an example of modification (third modification example) of the solenoid drive unit. FIG. 8 is a diagram showing a conventional solenoid drive unit. FIGS. 9A to D are wave form diagrams for describing the operation of the solenoid drive unit in FIG. 8 . detailed-description description="Detailed Description" end="lead"?

20040510

20080909

20050106

62527.0

PATEL, DHARTI HARIDAS

CURRENT DETECTING CIRCUIT AND ACTUATOR DRIVING APPARATUS

UNDISCOUNTED

ACCEPTED

ACCEPTED

Stress sensor

A stress sensor having a post (6) fixed to or integrated with the surface of an insulation substrate (1) capable of determining the direction and magnitude of a stress applied to the post (6) from changes in the characteristics of a strain gauge (2) made by a stimulus to the strain gauge (2) caused by the stress, wherein a stress to the post (6) can be converted efficiently into changes in the characteristics of the strain gauge (2). Consequently, the stress sensor has a strain gauge (2)-disposed member provided with a locally-easy-to-deform portion where the strain gauge (2) is disposed. The strain gauge (2) is a resistance element (8) and is disposed on the surface of the insulation substrate (1), the insulation substrate mainly contains a resin material, and the easy-to-deform portion is preferably a thin-wall portion (7).

1. A stress sensor for electronic devices, having a post fixed to or integrated with a surface of an insulation substrate capable of determining a direction and a magnitude of a stress applied to the post from changes in characteristics of a strain gauge made by a stimulus to the strain gauge caused by the stress, wherein the insulation substrate includes a depression formed in one surface of the insulation substrate as a thin-wall portion, and the strain gauge is arranged at a surface of the insulation substrate opposite to the depression, and the strain gauge is arranged crossing the depression. 2. A stress sensor, comprising: an insulation substrate, having a depression in a surface thereof; a post, whose bottom is fixed in the depression such that the bottom of the post is embedded in the depression; a strain gauge, arranged at the insulation substrate at a position corresponding to a profile of the bottom of the post with the insulation substrate there-between; wherein the strain gauge is arranged crossing the profile, and the stress sensor determines a direction and a magnitude of a stress applied to the post from changes in characteristics of a strain gauge made by a stimulus to the strain gauge caused by the stress. 3. The stress sensor as claim 1, wherein the strain gauge is arranged at a smooth surface of the insulation substrate. 4. The stress sensor as claim 1, wherein the strain gauge is a resistance element produced by a screen-printing process and has a characteristic corresponding to a resistance thereof. 5. The stress sensor as claim 1, wherein the insulation substrate is mainly made of a resin material, and the post has a higher rigidity than that of the resin material, and the post has a higher rigidity than that of the resin material. 6. The stress sensor as claim 1, wherein the depression is a locally thin-wall portion of the insulation substrate. 7. The stress sensor as claim 6, wherein the depression is filled with a material softer than that of the insulation substrate. 8. The stress sensor as claim 1, wherein the depression is a line-shaped. 9. The stress sensor as claim 8, wherein the line-shaped depression is substantially perpendicular to straight lines extending from the post to edges of the insulation substrate. 10. The stress sensor as claim 1, comprising strain gauges located on four positions along two perpendicular lines on the surface of the insulation substrate, wherein the perpendicular lines intersect at a center of a effect region for sensing of the surface of the insulation substrate, wherein the strain gauges are arranged equidistant along the intersection of the two perpendicular lines, and the center of the surface of the insulation substrate is substantially equivalent to the center of the effect region for sensing and the center of a bottom of the post, and the post is fixed to or integrated with the insulation substrate. 11. The stress sensor as claim 2, wherein the strain gauge is a resistance element produced by a screen-printing process and has a characteristic corresponding to a resistance thereof. 12. The stress sensor as claim 2, wherein the insulation substrate is mainly made of a resin material, and the post has a higher rigidity than that of the resin material, and the post has a higher rigidity than that of the resin material. 13. The stress sensor as claim 2, comprising strain gauges located on four positions along two perpendicular lines on the surface of the insulation substrate, wherein the perpendicular lines intersect at a center of a effect region for sensing of the surface of the insulation substrate, wherein the strain gauges are arranged equidistant along the intersection of the two perpendicular lines, and the center of the surface of the insulation substrate is substantially equivalent to the center of the effect region for sensing and the center of a bottom of the post, and the post is fixed to or integrated with the insulation substrate

FIELD OF THE INVENTION The present invention relates to a stress sensor for pointing device of personal computers, multi-function/multi-direction switch of electronic devices etc. DESCRIPTION OF RELATED ART The Japanese Patent Laid-open Publication No. JP-2000-267803 discloses a stress sensor which has a post fixed to or integrated with the surface of an insulation substrate capable of determining the direction and magnitude of a stress applied to the post from changes in the characteristics of a strain gauge made by a stimulus to the strain gauge caused by the stress. The structure of the stress gauge is shown in FIG. 6(a). Resistance elements 22 serving as strain gauges are located on four positions along two perpendicular lines on the surface of the substrate 20, wherein the perpendicular lines intersect at the center of the surface of the substrate 20. The strain gauges 2 are arranged equidistant along the intersection of the two perpendicular lines. The center of the surface of the substrate 20 is substantially equivalent to the center of the bottom of the post 30 with a squared-shaped bottom profile. The resistance elements 22 are fixed on the substrate 20 such that each of the edges of the profile 30b of the post bottom is opposite to each of the resistance elements 22. FIG. 6(b) shows the operation of the strain gauge in the case when a stress of X direction (i.e. any transverse direction) applies to the post 30. FIG. 6(c) shows the operation of the strain gauge in the case when a stress of a Z direction (i.e. downward direction) applies to the post 30. In the both operations of FIGS. 6(b) and 6(c), solder 32 are fixed at the ends of the substrate 20 through a circuit plate 31, and the stress makes the portions of the substrate 20 corresponding to the profile 30b of the bottom of the post flex. The resistance elements 22 located in the portion stretch or contract due to the stress. The resistance of the resistance element 22 changes accordingly. However, the sensitivity (i.e. output) corresponding to the stress applied to the post 30 is small. The stress applied to the post 30 cannot be efficiently converted into the change of the resistance. One of the objects of the present invention is to provide a stress sensor wherein a stress to the post can be converted efficiently into changes in the characteristics of the strain gauge. SUMMARY OF THE INVENTION: For solving the above problems, the present invention provides a stress sensor comprising a post 6 fixed to or integrated with a surface of an insulation substrate 1. The stress sensor is capable of determining a direction and a magnitude of a stress applied to the post 6 from changes in characteristics of a strain gauge 2 made by a stimulus to the strain gauge 2 caused by the stress, wherein a member with the strain gauge 2 arranged thereon has a locally-easy-to-deform portion, and the strain gauge 2 is arranged at the locally easy-to-deform portion. If there is a locally-easy-to-deform portion in the member with the strain gauges 2 arranged thereon, the stress is easily transferred to the member with the strain gauges 2 arranged thereon and the stress is easily concentrated at the easy-to-deform portion. Because the strain gauge 2 is arranged at the easy-to-deform portion, the strain gauge can get big stimulus and the characteristics of the strain gauge 2 changes largely. Thus, the stress to the post 6 can be efficiently converted into changes of characteristics of the strain gauge 2 to solve the above problem. The word “locally” means a location on the member close to the region where the strain gauges 2 are arranged and an extension region accordingly. As shown in FIG. 1, thin-wall portion 7 is formed on the insulation substrate 1, and the strain gauges 2 are arranged crossing the thin-wall portion 7. The reason for defining the word “locally” into “narrow region” is in the point of maintaining the stress sensor in a desired strength. If it is only to efficiently convert a stress to the post 6 into changes of characteristic of the strain gauges 2, the whole region (as shown in FIG. 1) or a part of the region surrounded by the thin-wall portion 7 (as shown in FIG. 1(b)) of the insulation substrate 1 can be thin. However, with this kind of structure, in the case when the bottom profile of the post 6 stimulates the thin-wall portion 7 too much, the insulation substrate 1 is plastically deformed. The present invention is to eliminate this disadvantage. According to the stress sensor of the present invention, the strain gauges 2 can be formed on the surface of the insulation substrate 1 and can be formed on the side surface of the post 6 as long as having a mechanism for stimulating the resistance element 2 caused by a stress to the post 6. The stimulus can change the electrical characteristic of the strain gauges 2. The flexing (i.e. deformation) of the side surface of the post 6 or the insulation substrate 1 results in the stretching or contracting of the strain gauges 2 and the pressing of or removal of the pressing of the strain gauges. The stretching and contracting of the strain gauge 2 are shown as FIGS. 6(b) and 6(c). The resistance of the resistance element becomes large due to the stretching of the resistance element 22 and becomes small due to the contracting of the resistance element 22. The example for pressing or removal of the pressing of the strain gauges 2 is that the strain gauges 2 are arranged between the bottom of the post 6 and the insulation substrate 1. Due to the pressing of the strain gauges 2, the strain gauges 2 and the easy-to-deform portions of the member with the strain gauges 2 arranged thereon are deformed at the same time to generate large changes of characteristic. By removing the pressing, the characteristic returns to the status prior to the pressing. Generally speaking, a stress sensor should comprise a control portion for detecting and calculating electrical characteristic such as the resistance to function as a stress sensor. The sentence “the post 6 is fixed on the surface of the insulation substrate 1” means that the post 6 and the substrate 1 are different members and are fixed with each other via an adhesion. Moreover, the sentence “the post 6 is integrated with the substrate 1” means the post 6 and the substrate 1 are formed into one body. “The bottom profile of the post” of the latter represents the portion corresponding to “the bottom profile of the post” of the former. Elements that changes the electrical characteristic due to a stress applied thereon, such as the resistance element 8 as shown in FIG. 1(b) is suitable to be the strain gauge 2. Except the resistance element 8, a chip-migration resistor having a thin or thick film formed on the insulation substrate 1 or a piezoelectrical element such as piezoelectrical ceramic comprising PZT (lead ziconate titanate) is preferred to be the strain gauge 2. The easy-to-deform portion is the thin-wall portion 7 formed in the insulation substrate 1 as shown in FIG. 1, for example. Methods of forming the thin-wall portions 7 are described as follows. The thin-wall portions 7 together with the insulation substrate 1 can be formed using a formation-mold method. Alternatively, the insulation substrate 1 can be cut into slots. Alternatively, the insulation substrate 1 can be partially laser-melted to form slots. With the laser-melting method, the width of the thin-wall portion 7 can be narrowed to tens of micro-meter by easily adjusting the beam diameter. This method is preferred for large-scale production. From the point of narrowing the width of the thin-wall portion 7, the width of the thin-wall portion 7 can be restrained and the stress sensor can maintain a desired strength. It is preferable fill the thin-wall portion 7 with a material softer than that of the member with the strain gauges 2 arranged thereon. Because of the thin-wall portion 7, the member with the strain gauges 2 arranged thereon is possible to be plastically deformed due to a stress to the post 6. In this case, since there exists a soft material, the easy-to-deform portion is not extremely damaged and the soft material strengthens the thin-wall portion 7. By adjusting the filling amount, selecting places to be filled and selecting the filler material, the converting ratio of changes of the characteristic of the strain gauge where a stress is applied can be adjusted. By changing the filling status of the thin-wall portion 7, such as by adjusting the overflow amount for overflowing the filler and by adjusting the overflow status of the overflow distance, the converting ratio can be adjusted. In the case when the member with the strain gauges 2 arranged thereon is made of ceramic, the soft material can be plastic with a strengthened fiber. In the case when the member with the strain gauges 2 arranged thereon is made of plastic with a strengthened fiber such as epoxy mixed with a glass fiber, the soft material can be a material cured from an epoxy resin without a fiber or a material cured from a silicon resin paste or other rubber material. Moreover, the thin-wall portion 7 as shown in FIG. 1(a) is not visible in FIG. 1(b) due to the arrangement of the thin-wall portion 7 originally. For easy understanding, the thin-wall portion 7 is especially shown in FIG. 1(b). According to the structure of the present invention, the strain gauges 2 as shown in FIG. 1(b) are arranged on the insulation substrate 1. It is preferred that the line-shaped easy-to-deform portions (i.e. the thin-wall portion) are perpendicular to the straight lines connecting the post 6 and the edges of the insulation substrate 1. With this structure (i.e. representing the line-shaped structure, hereinafter), the loss of a stress to the post 6 can be extremely decreased and the stress can be transferred to the easy-to-deform portion (i.e. the thin-wall portion 7). Thus a stress to the post 6 can be efficiently converted into changes of the characteristic of the strain gauges 2. The reasons for the advantages are as followings. The minimum region for flexing (i.e. deforming) the insulation substrate 1 to function the stress sensor is the existing region of the strain gauge 2 (resistance element 8). If there is no easy-to-deform portion (i.e. the thin-wall portion 7), a stress to the post 6 effects the whole insulation substrate 1. That is to say some region that is unnecessary to be flexed is still flexed. The region that is unnecessary to be flexed includes the outer region of the insulation substrate 1 beyond the strain gauges 2 (i.e. the edges of the insulation substrate 1) and the region within adjacent strain gauges 2 in the insulation substrate 1. The stress for flexing the unnecessary region cannot be detected from the strain gauge 2 and will become a stress loss. In the case when easy-to-deform portion (i.e. the thin-wall portion 7) is dot-shaped rather than line-shaped, the stress for flexing the insulation substrate 1 where no dots exist and no strain gauges 2 exist will become a stress loss. However, if the interval from dot to dot is small, it is substantially a line-shaped and almost with no stress-loss. In this condition, the dot-shaped easy-to-deform portion has the same structure and effects as the line-shaped one and can be regarded as a line-shaped one. Because of the line-shaped structure, a stress loss is decreased and a stress can be efficiently concentrated at the easy-to-deform portion (i.e. thin-wall portion). The forming of the line-shaped structure on the side surface of the post 6 is achieved by forming continuous or intermittent slots around the post 6. A modified example for the line-shaped structure is a top view of FIG. 2. The strain gauges 2 are arranged at the backside of the insulation substrate 1 as shown in FIG. 2. As shown in FIG. 2(a), the bottom of the post 6 is square-shaped and each of the strain gauges 2 are arranged at the backside of the insulation substrate 1 corresponding to each of the edges of the square, i.e. each of the thin-wall portions 7 individually corresponds to each of the strain gauges 2 without connecting to each other. FIG. 2(b) is the structure of FIG. 1(b), wherein the thin-wall portion 7 is dot-shaped and the dots close to each other to substantially form a line-shaped structure. As shown in FIG. 2(c), the bottom of the post 6 is circular-shaped and the thin-wall portion 7 is ring-shaped. Even with this structure, the thin-wall portion 7 is substantially perpendicular to the straight lines connecting the post 6 and edges of the insulation substrate 1. FIG. 2(d) turns the thin-wall portion 7 of FIG. 2(c) into dot-shaped and the interval from dot to dot is small such that it can be regarded as a line-shaped structure. FIG. 2(e) turns the thin-wall portion 7 of FIG. 2(c) into individual without connecting to each other. In the case, when each of the thin-wall portions 7 individually corresponds to each of the strain gauges 2 without connecting to each other, and in the case when the thin-wall portion 7 is dot-shaped with a close dot-to-dot interval that is substantially regarded as a line-shaped structure, both of the case have a stress-loss. However, in some cases, the member with the strain gauges arranged thereon with a lower strength is better. This is because the condition for maintaining the member such as the insulation substrate 1 with the strain gauges 2 arranged thereon in a desired strength and the condition for decreasing a stress loss or keeping a high output of a stress sensor are hardly to be all satisfied at the same time. The two conditions are almost contrary to each other. Thus, the stress sensor of the present invention should be designed according the two conditions. Moreover, in the case when the stress loss can be ignored or is no concern, such as, it is expected that the stress exceeding the require magnitude for stimulating the strain gauges 2, the thin-wall portion 7 is preferred to be individually corresponding to each of the strain gauges 2 without connecting to each other, and the thin-wall portion 7 is also preferred to be dot-shaped with a close dot-to-dot interval such that the dot-shaped thin-wall portion 7 is regarded as a line-shaped structure. In the explanation to the line-shaped structure, the easy-to-deform portion of the In the explanation to the line-shaped structure, the easy-to-deform portion of the present invention is represented by a thin-wall portion 7. However, the line-shaped easy-to-deform portion is not limited to the thin-wall portion. For example, the material of the easy-to-deform portion can be different from that of the insulation substrate 1. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1(a) and 1(b) show a side view and a bottom view of a stress sensor of the present invention. FIG. 2 shows top views of strain sensor of the present invention. FIG. 3 shows the status of input and out of electrical signals in the strain sensor of the present invention. FIGS. 4(a), 4(b) and 4(c) show a side view, a bottom view and a top view of the stress sensor according to one embodiment of the present invention. FIGS. 5(a), 5(b) and 5(c) show a side view prior to the embedding of the post, a side view of the embedding of the post and a top view of the stress sensor according to another embodiment of the present invention. FIG. 6(a) shows the structure of a conventional stress sensor. FIGS. 6(b) and 6(c) show the operation of the conventional stress sensor. 1 . . . insulation substrate 2 . . . strain gauge 3 . . . resistance element 5 . . . conductor 6 . . . post 7 . . . thin-wall portion 8 . . . resistance element 10 . . . terminal 12 . . . support cavity 14 . . . trimmable chip resistor 16 . . . substrate cavity 18 . . . terminal collection portion 19 . . . depression 20 . . . substrate 22 . . . resistance element 23 . . . post operation portion 24 . . . conductor 30 . . . post 30b . . . bottom profile of the post 31 . . . circuit plate 32 . . . solder DESCRIPTION OF THE PREFERRED EMBODIMENTS A stress sensor according to one embodiment of the present invention is applied to a pointing device of a personal computer. FIG. 4 shows a laminated plate (i.e. insulation substrate 1) of 0.8 mm thickness that is mainly made of an epoxy resin mixed with a glass fiber. Thin-wall portions 7 as shown in FIG. 4 are formed by using a press-formation mold. The thin-wall portions 7 with a thickness of 10% of the insulation substrate 1, i.e. about 80 μm are formed. The thin-wall portions 7 in FIG. 4(a) are not visible in FIG. 4(b) due to the arrangement of the thin-wall portions 7 originally. For easily understanding, the thin-wall portions 7 are especially shown in FIG. 4(b). Copper foils of thickness of 18 μm serving as conducting layers are attached to two sides of the insulation substrate 1. A circuit pattern (i.e. conductor 5) is formed on the laminated plate with two-side-copper-foil as the insulation substrate 1. Finally the insulation substrate 1 is patterned on the surface and inside of the insulation substrate 1, such that the resistance elements 8, the trimmable chip resistors 14 and the terminals 10 are electrically connected as shown FIG. 3. In the first step of patterning, some through holes are formed for forming electrical connection path extending from the surface to the inside of the laminated plate with two-side-copper-foil. In the second step of patterning, a conductivity layer is formed at inner-sidewall of the through holes by copper-electroless-plating and copper-electroplating in sequence. In and after the third step of patterning, the conductivity layer on the surface is partially removed by photo-etching of the dry film photoresist to obtain a conductor 5. In FIG. 4, the paths from the end of the conductor 5 to the terminal collection portions 18 are omitted in drawing. By using each of the resistance elements 8 (i.e. R1˜R4) and trimmable chip resistors 14 (i.e. Rtrim 1˜4), a bridge circuit as shown in FIG. 3 is formed as the path. The terminals (i.e. Vcc, GND, Yout, Xout) in the terminal collection portions 18 are arranged in a predetermined interval. Each insulation substrate 1 of one unit of the large substrate is punched to form notches for the substrate cavities 16, support cavities 12 and terminal collection portions 18 as shown in FIG. 6. The support cavities 12 formed in the sensor portion of the substrate 1 of one unit are located as 4 apexes of a square. An intersection of the diagonals of the square is substantially equivalent to the center of the bottom profile of the post 6 that is arranged later. By using screen-printing with a resistance paste made of resin (i.e. carbon-resin), resistors 3 is formed and cured as shown in FIG. 6. Furthermore, in order to protect the resistors 13, a paste made of silicon resin is used for screen-printing. The paste is then cured to form a passivation film. A resistance element 8 is obtained. The trimmable chip resistors 14 that are electrically connected with each of the resistance elements 8 in series through conductivity 5 by using a reflow method as shown in FIG. 3. The trimmable chip resistors 14 are arranged at one surface opposite to the resistance elements 8 in the sensor portion of the substrate 1. After that, for adjusting the summation of the resistance of the resistance elements 8 and the trimmable chip resistors 14 that are connected with the resistance elements 8 in series, the trimmable chip resistors 14 are trimmed by a laser. The reason why the resistors 3 constructing the resistance elements 8 are not trimmed is because the resistors 3 have resin portion and the trimmed insulation substrate 1 mainly made of resin will cause resistance unstable. The trimming by laser is conducted at a very high temperature, which is unsuitable to the resin. The alumina-made post 6 whose bottom profile is square-shaped is fixed at each unit of the insulation substrate 1. The bottom of the post 6 is arranged on the insulation substrate 1 opposite the surface where resistance elements 8 are arranged. The post 6 is fixed at each unit of the insulation substrate 1 in a manner that the center of the bottom is substantially the same as that of the insulation substrate 1. The assembly of the stress sensor is obtained. The tolerance range of the shift of the post 6 is within the area surrounded by the thin-wall portions 7. FIG. 6 shows the conventional stress sensor whose tolerance range of the shift of the post is very small. This is because the maximum flexing position of the substrate 20 corresponds to the bottom profile of the post 6 and the position is highly related to the performance of the stress sensor. For this point of view, the shift of the post 6 is some how released which is an advantage of the stress sensor of the present invention compared to the conventional one. The large substrate is cut and separated by disc cutter along cutting lines (i.e. visible lines or invisible lines) on the surface of the large substrate into stress sensors according to the one unit of the insulation substrate 1. In this example, the post 6 is fixed prior to the cutting and the performance of working ability is good. This is because the process of installing the post 6 onto each of the insulation substrates 1 having a stress sensor thereon after cutting is a disadvantage in transferring and handling and is more complex comparing with the process of the large substrate. The stress sensor comprises strain gauges 2 located on four positions along two perpendicular lines on the surface of the insulation substrate 1, wherein the perpendicular lines intersect at the center of effect region for sensing of the surface of the insulation substrate 1. The strain gauges 2 are arranged equidistant along the intersection of the two perpendicular lines. The center of the surface of the insulation substrate 1 is substantially equivalent to the center of the effect region for sensing and the center of the bottom of the post 6. With this structure, the stress sensor which has the post 6 fixed to or integrated with the insulation substrate 1 is provided. The stress sensor is fixed onto the frame of an electronics through the support cavities 12. Under a fix condition, the peripheral portion of the substrate 3 beyond the substrate cavities 16 deforms little even when a stress is applied to the post 2 and serving as a non-deforming portion. The portion within the substrate cavities 16 deforms if a stress is applied to the post 5 and serves as a deforming portion that makes the resistance element 8 stretch or contract. The whole region of the deforming portion is the “effect region for sensing” of the substrate 1 for sensor portion. Because the trimmable chip resistors 14 are arranged at the non-deforming portions, the influence due to a stress applied on the post 2 on changes of resistance is little. In this example, the insulation substrate 1 is made of epoxy resin mixed with a glass fiber. In other words, the insulation substrate 1 is mainly made of resin material. The material of the insulation substrate 1 can be replaced by ceramic such as alumina. However, in the case when a thin-wall portion 7 as the example is formed in a ceramic, the ceramic is easily damaged starting from this portion. Moreover, it is difficult to form a locally-easy-to-deform portion in a ceramic material. Thus, the resin material is preferred to be the main composition of the insulation substrate 1. FIG. 3 shows input and output statuses of electrical signals of the stress sensor of the present invention. Four sets of resistance elements and trimmable chip resistors construct a bridge circuit. A predetermined voltage is applied between the voltage terminals (Vcc)-(GND) of the bridge circuit. A Y-direction stress sensor is constructed by analyzing the resistance element 8 (R1, 2) at the left side of FIG. 3 and the trimmable chip resistor 14 (Rtrim1, 2) through the Y terminal (Yout). A X-direction stress sensor is constructed by analyzing the resistance element 8 (R3, 4) at the right side of FIG. 3 and the trimmable chip resistor 14 (Rtrim3, 4). Moreover, in the case when the top of the post is pressed downward (Z-direction), the resistance of each of the resistance element increases. This condition is different from the X-direction and Y-direction stress and can be detected. By adding some functions with respect to the downward stress (Z-direction), the stress sensor can have multi-functions. In this example, the stress sensor of the present invention is used as pointing device of a computer, that is capable to be divided into signals for clicking the mouse. Moreover, in the case of using the stress sensor of the present invention to a multi-function/multi-direction switch of a small portable machine such as a cell phone, the downward stress lasting for a predetermined interval can correspond to an power on/off command of the portable machine. Whether the trimmable chip resistor 14 is to be used or not depends on the material of construction of the resistance elements and the material of the insulation substrate 1. For example, if the material of the substrate 1 for sensor portion is ceramic, in the case when the material of the resistor 3 is metal glaze, even when the resistor 3 constructing the resistance elements 8 is trimmed by a laser, the instability of the resistance can be negligible. In this case, the stress sensor can be constructed without a trimmable chip resistor 14. If it is necessary to use trimmable chip resistor 14 for any other reason, the trimmable chip resistor 14 of course can be used. Furthermore, substrate cavities 16 may be set, for example, for making the insulation substrate 1 flex easily and guiding the flexure of the insulation substrate 1 towards the desired direction. With the easy-to-deform portions such as the thin-wall portions 7, it plays both of the above roles as the substrate cavities 16 does. A part of the process for opening the insulation substrate 1 (i.e. opening the substrate cavities 16) can be omitted, which is a merit. (Another Embodiment) FIG. 5 shows another embodiment of the present invention. As shown in FIG. 5, the stress sensor has a depression 19 in the insulation substrate 1. The depression 19 is embedded within the bottom of the post 6. Strain gauges 2 are arranged at the surface of the insulation substrate 1 at a position corresponding to the profile of the depression 19 with the insulation substrate 1 there-between. The stress sensor can determine the direction and magnitude of a stress applied to the post 6 from changes in the characteristics of a strain gauge 2 made by stimulus to the strain gauge 2 caused by the stress. FIG. 5(a) shows the status before the bottom of the post 6 is embedded into the depression 19. FIG. 5(b) shows the status after the embedding. In this condition, the bottom profile of the post 6 is substantially equivalent to the profile of the depression 19. In the embedding status, it is preferred that no gap exists between the bottom of the post 6 and the depression 19. If a gap exists between the bottom of the post 6 and the depression 19, the bottom of the post 6 stimulating the bottom of the depression 19 will be regarded equivalent to the thin-wall portions 7 of the insulation substrate 1 such that the bottom of the depression 19 is plastically deformed. The stress sensor is also considered to maintain a desired strength. In the case when an over stress is applied on the post of the stress sensor shown in FIG. 5, the stress is shared by the inner-sidewall of the depression 19. The over stress can be restrained from being applied on the bottom of the depression 19. Moreover, because the bottom of the post 6 is fixed in the depression 19 under a condition that the bottom of the post 6 has been embedded into the depression 19, the effects of stress-sharing can be increased. It is known from prior art (FIG. 6) that the stress applied to the post 6 is concentrated in the insulation substrate 1 at a location of the bottom profile of the post. In the stress sensor of FIG. 5, the stress is also concentrated at the profile of the depression 19 where the bottom profile of the post 6 is located. Therefore, by arranging the strain gauge 2 at the profile of the depression 19, a stress to the post 6 can be converted efficiently into changes in the characteristics of the strain gauge 2. Because of the above reasons, the stress sensor as shown in FIG. 5 can maintain a desired strength and can efficiently convert a stress to the post 6 into changes in the characteristics of the strain gauge 2. Thus, the insulation substrate 1 of the present invention is unnecessary to be flexed towards one side as the conventional one does. The distance from the bottom profile of the post 6 to the ends of the insulation substrate 1 need not necessarily be as large as the conventional one. The stress sensor can be smaller than the conventional one (FIG. 6). These merits also exist in the stress sensor as shown in FIGS. 1, 2 and 4. It is preferred that the material of the post 6 has a rigidity higher than or equivalent to that of the material of the insulation substrate 1. Thus, the insulation substrate 1 can be flexed easily and a stress to the post 6 can be transferred to the strain gauge 2 with a high efficiency. In the case when the insulation substrate 1 is made of an epoxy resin mixed with glass fiber, the material of the post 6 is preferably a ceramic such as alumina. The material for fixing the post 6 and the insulation substrate 1 is preferably an adhesive such as epoxy. The embedding process is preferably implemented during the assembling process from the efficiency point of view. In the case when loading the post 6 on the insulation substrate 1 of a conventional stress sensor, the shift of the post 6 causes the shift of the characteristics of the stress sensor. However, with the stress sensor as shown in FIG. 5, one need not worry about the shift of the characteristic of the stress sensor due to the shift of the post 6. Because the arranging position of the post 6 can be determined in advance. INDUSTRIAL APPLICATION According to an embodiment of the present invention, a stress sensor is provided to efficiently convert a stress to the post into changes in characteristics of the strain gauge. In this condition, the stress sensor can be maintained in a desired strength.

<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a stress sensor for pointing device of personal computers, multi-function/multi-direction switch of electronic devices etc.

<SOH> SUMMARY OF THE INVENTION: <EOH>For solving the above problems, the present invention provides a stress sensor comprising a post 6 fixed to or integrated with a surface of an insulation substrate 1 . The stress sensor is capable of determining a direction and a magnitude of a stress applied to the post 6 from changes in characteristics of a strain gauge 2 made by a stimulus to the strain gauge 2 caused by the stress, wherein a member with the strain gauge 2 arranged thereon has a locally-easy-to-deform portion, and the strain gauge 2 is arranged at the locally easy-to-deform portion. If there is a locally-easy-to-deform portion in the member with the strain gauges 2 arranged thereon, the stress is easily transferred to the member with the strain gauges 2 arranged thereon and the stress is easily concentrated at the easy-to-deform portion. Because the strain gauge 2 is arranged at the easy-to-deform portion, the strain gauge can get big stimulus and the characteristics of the strain gauge 2 changes largely. Thus, the stress to the post 6 can be efficiently converted into changes of characteristics of the strain gauge 2 to solve the above problem. The word “locally” means a location on the member close to the region where the strain gauges 2 are arranged and an extension region accordingly. As shown in FIG. 1 , thin-wall portion 7 is formed on the insulation substrate 1 , and the strain gauges 2 are arranged crossing the thin-wall portion 7 . The reason for defining the word “locally” into “narrow region” is in the point of maintaining the stress sensor in a desired strength. If it is only to efficiently convert a stress to the post 6 into changes of characteristic of the strain gauges 2 , the whole region (as shown in FIG. 1 ) or a part of the region surrounded by the thin-wall portion 7 (as shown in FIG. 1 ( b )) of the insulation substrate 1 can be thin. However, with this kind of structure, in the case when the bottom profile of the post 6 stimulates the thin-wall portion 7 too much, the insulation substrate 1 is plastically deformed. The present invention is to eliminate this disadvantage. According to the stress sensor of the present invention, the strain gauges 2 can be formed on the surface of the insulation substrate 1 and can be formed on the side surface of the post 6 as long as having a mechanism for stimulating the resistance element 2 caused by a stress to the post 6 . The stimulus can change the electrical characteristic of the strain gauges 2 . The flexing (i.e. deformation) of the side surface of the post 6 or the insulation substrate 1 results in the stretching or contracting of the strain gauges 2 and the pressing of or removal of the pressing of the strain gauges. The stretching and contracting of the strain gauge 2 are shown as FIGS. 6 ( b ) and 6 ( c ). The resistance of the resistance element becomes large due to the stretching of the resistance element 22 and becomes small due to the contracting of the resistance element 22 . The example for pressing or removal of the pressing of the strain gauges 2 is that the strain gauges 2 are arranged between the bottom of the post 6 and the insulation substrate 1 . Due to the pressing of the strain gauges 2 , the strain gauges 2 and the easy-to-deform portions of the member with the strain gauges 2 arranged thereon are deformed at the same time to generate large changes of characteristic. By removing the pressing, the characteristic returns to the status prior to the pressing. Generally speaking, a stress sensor should comprise a control portion for detecting and calculating electrical characteristic such as the resistance to function as a stress sensor. The sentence “the post 6 is fixed on the surface of the insulation substrate 1 ” means that the post 6 and the substrate 1 are different members and are fixed with each other via an adhesion. Moreover, the sentence “the post 6 is integrated with the substrate 1 ” means the post 6 and the substrate 1 are formed into one body. “The bottom profile of the post” of the latter represents the portion corresponding to “the bottom profile of the post” of the former. Elements that changes the electrical characteristic due to a stress applied thereon, such as the resistance element 8 as shown in FIG. 1 ( b ) is suitable to be the strain gauge 2 . Except the resistance element 8 , a chip-migration resistor having a thin or thick film formed on the insulation substrate 1 or a piezoelectrical element such as piezoelectrical ceramic comprising PZT (lead ziconate titanate) is preferred to be the strain gauge 2 . The easy-to-deform portion is the thin-wall portion 7 formed in the insulation substrate 1 as shown in FIG. 1 , for example. Methods of forming the thin-wall portions 7 are described as follows. The thin-wall portions 7 together with the insulation substrate 1 can be formed using a formation-mold method. Alternatively, the insulation substrate 1 can be cut into slots. Alternatively, the insulation substrate 1 can be partially laser-melted to form slots. With the laser-melting method, the width of the thin-wall portion 7 can be narrowed to tens of micro-meter by easily adjusting the beam diameter. This method is preferred for large-scale production. From the point of narrowing the width of the thin-wall portion 7 , the width of the thin-wall portion 7 can be restrained and the stress sensor can maintain a desired strength. It is preferable fill the thin-wall portion 7 with a material softer than that of the member with the strain gauges 2 arranged thereon. Because of the thin-wall portion 7 , the member with the strain gauges 2 arranged thereon is possible to be plastically deformed due to a stress to the post 6 . In this case, since there exists a soft material, the easy-to-deform portion is not extremely damaged and the soft material strengthens the thin-wall portion 7 . By adjusting the filling amount, selecting places to be filled and selecting the filler material, the converting ratio of changes of the characteristic of the strain gauge where a stress is applied can be adjusted. By changing the filling status of the thin-wall portion 7 , such as by adjusting the overflow amount for overflowing the filler and by adjusting the overflow status of the overflow distance, the converting ratio can be adjusted. In the case when the member with the strain gauges 2 arranged thereon is made of ceramic, the soft material can be plastic with a strengthened fiber. In the case when the member with the strain gauges 2 arranged thereon is made of plastic with a strengthened fiber such as epoxy mixed with a glass fiber, the soft material can be a material cured from an epoxy resin without a fiber or a material cured from a silicon resin paste or other rubber material. Moreover, the thin-wall portion 7 as shown in FIG. 1 ( a ) is not visible in FIG. 1 ( b ) due to the arrangement of the thin-wall portion 7 originally. For easy understanding, the thin-wall portion 7 is especially shown in FIG. 1 ( b ). According to the structure of the present invention, the strain gauges 2 as shown in FIG. 1 ( b ) are arranged on the insulation substrate 1 . It is preferred that the line-shaped easy-to-deform portions (i.e. the thin-wall portion) are perpendicular to the straight lines connecting the post 6 and the edges of the insulation substrate 1 . With this structure (i.e. representing the line-shaped structure, hereinafter), the loss of a stress to the post 6 can be extremely decreased and the stress can be transferred to the easy-to-deform portion (i.e. the thin-wall portion 7 ). Thus a stress to the post 6 can be efficiently converted into changes of the characteristic of the strain gauges 2 . The reasons for the advantages are as followings. The minimum region for flexing (i.e. deforming) the insulation substrate 1 to function the stress sensor is the existing region of the strain gauge 2 (resistance element 8 ). If there is no easy-to-deform portion (i.e. the thin-wall portion 7 ), a stress to the post 6 effects the whole insulation substrate 1 . That is to say some region that is unnecessary to be flexed is still flexed. The region that is unnecessary to be flexed includes the outer region of the insulation substrate 1 beyond the strain gauges 2 (i.e. the edges of the insulation substrate 1 ) and the region within adjacent strain gauges 2 in the insulation substrate 1 . The stress for flexing the unnecessary region cannot be detected from the strain gauge 2 and will become a stress loss. In the case when easy-to-deform portion (i.e. the thin-wall portion 7 ) is dot-shaped rather than line-shaped, the stress for flexing the insulation substrate 1 where no dots exist and no strain gauges 2 exist will become a stress loss. However, if the interval from dot to dot is small, it is substantially a line-shaped and almost with no stress-loss. In this condition, the dot-shaped easy-to-deform portion has the same structure and effects as the line-shaped one and can be regarded as a line-shaped one. Because of the line-shaped structure, a stress loss is decreased and a stress can be efficiently concentrated at the easy-to-deform portion (i.e. thin-wall portion). The forming of the line-shaped structure on the side surface of the post 6 is achieved by forming continuous or intermittent slots around the post 6 . A modified example for the line-shaped structure is a top view of FIG. 2 . The strain gauges 2 are arranged at the backside of the insulation substrate 1 as shown in FIG. 2 . As shown in FIG. 2 ( a ), the bottom of the post 6 is square-shaped and each of the strain gauges 2 are arranged at the backside of the insulation substrate 1 corresponding to each of the edges of the square, i.e. each of the thin-wall portions 7 individually corresponds to each of the strain gauges 2 without connecting to each other. FIG. 2 ( b ) is the structure of FIG. 1 ( b ), wherein the thin-wall portion 7 is dot-shaped and the dots close to each other to substantially form a line-shaped structure. As shown in FIG. 2 ( c ), the bottom of the post 6 is circular-shaped and the thin-wall portion 7 is ring-shaped. Even with this structure, the thin-wall portion 7 is substantially perpendicular to the straight lines connecting the post 6 and edges of the insulation substrate 1 . FIG. 2 ( d ) turns the thin-wall portion 7 of FIG. 2 ( c ) into dot-shaped and the interval from dot to dot is small such that it can be regarded as a line-shaped structure. FIG. 2 ( e ) turns the thin-wall portion 7 of FIG. 2 ( c ) into individual without connecting to each other. In the case, when each of the thin-wall portions 7 individually corresponds to each of the strain gauges 2 without connecting to each other, and in the case when the thin-wall portion 7 is dot-shaped with a close dot-to-dot interval that is substantially regarded as a line-shaped structure, both of the case have a stress-loss. However, in some cases, the member with the strain gauges arranged thereon with a lower strength is better. This is because the condition for maintaining the member such as the insulation substrate 1 with the strain gauges 2 arranged thereon in a desired strength and the condition for decreasing a stress loss or keeping a high output of a stress sensor are hardly to be all satisfied at the same time. The two conditions are almost contrary to each other. Thus, the stress sensor of the present invention should be designed according the two conditions. Moreover, in the case when the stress loss can be ignored or is no concern, such as, it is expected that the stress exceeding the require magnitude for stimulating the strain gauges 2 , the thin-wall portion 7 is preferred to be individually corresponding to each of the strain gauges 2 without connecting to each other, and the thin-wall portion 7 is also preferred to be dot-shaped with a close dot-to-dot interval such that the dot-shaped thin-wall portion 7 is regarded as a line-shaped structure. In the explanation to the line-shaped structure, the easy-to-deform portion of the In the explanation to the line-shaped structure, the easy-to-deform portion of the present invention is represented by a thin-wall portion 7 . However, the line-shaped easy-to-deform portion is not limited to the thin-wall portion. For example, the material of the easy-to-deform portion can be different from that of the insulation substrate 1 .

20040505

20060509

20050224

64118.0

NOORI, MASOUD H

STRESS SENSOR

UNDISCOUNTED

ACCEPTED

ACCEPTED

Optometric device

In an optometric apparatus of the present invention, optometric apparatus bodies 5l and 5r independently driven in right-and-left and up-and-down directions for optometry of an examinee 4, respectively, are provided on both sides of a face receiving device 6.

1. An optometric apparatus, comprising optometric apparatus bodies driven independently in fore-and-aft, right-and-left and up-and-down directions, respectively, for respective optometry of an examinee, provided on both sides of a face receiving device. 2. The optometric apparatus according to claim 1, wherein the optometric apparatus bodies have a function to measure objective refraction and subjective refraction of both right and left eyes of the examinee at the same time, and comprise a mechanism rotating with a cycloduction point of the right and the left eyes to be examined as a center. 3. The optometric apparatus according to claim 1, further comprising an auto-alignment mechanism for automatically executing alignment for eyes to be examined is provided on the optometric apparatus bodies. 4. The optometric apparatus according to claim 1, further comprising a monitor screen to present an image of an anterior ocular segment of an eye to be examined to an optometric assistant, provided at each of the optometric apparatus bodies. 5. The optometric apparatus according to claim 1, further comprising a monitor screen for explanation of optometry procedures by the examinee himself/herself through movie playing. 6. The optometric apparatus according to claim 1, wherein comparison is made between a vision when recommended spectacles are worn and a vision with naked eyes or with dioptric power of currently used glasses. 7. The optometric apparatus according to claim 3, wherein the optometric apparatus is connected to a lens meter for measuring optical characteristics of a pair of spectacle lenses mounted to a spectacle frame, data of the optical characteristics of the spectacle lenses is inputted from the lens meter, and an initial value of PD value at auto-alignment is set based on the PD value as the optical characteristics data. 8. The optometric apparatus according to claim 7, wherein the lens meter measures the optical characteristics of the pair of spectacle lenses mounted to the spectacle frame at the same time. 9. The optometric apparatus according to claim 7, wherein the auto-alignment is carried out while maintaining the PD value. 10. The optometric apparatus according to claim 3, wherein an initial value of PD value is set according to age and sex of the examinee. 11. The optometric apparatus according to claim 3, wherein an initial setting of PD value is cancelled when alignment for one of the right and left eyes to be examined is gained, and data of the alignment is used as the alignment data for the other eye to be examined so that alignment of the other eye to be examined can be automatically executed. 12. The optometric apparatus according to claim 5, wherein an image of an anterior ocular segment of the eye to be examined is presented on the monitor screen for explaining the optometry procedures by the examinee himself/herself by the movie playing. 13. An optometric apparatus, comprising an optometric apparatus body which comprises an optical system for presenting targets for a left eye to the left eye, and an optometric apparatus body which comprises an optical system for presenting targets for a right eye to the right eye. 14. The optometric apparatus according to claim 13, further comprising a fusion target presenting optical system for presenting fusion targets at binocular optometry of eyes to be examined, provided in each of the optical systems. 15. An optometric apparatus, comprising an optometric apparatus body comprising a mirror opposing a left eye in which a measurement optical system for objective measurement of the left eye is built, an optometric apparatus body comprising a mirror opposing a right eye in which a measurement optical system for objective measurement of the right eye is built, and an optotypes examining device presenting optotypes from behind through the right and the left mirrors. 16. The optometric apparatus according to claim 2, wherein, after subjective refractive measurement for far targets, the targets are moved to a predetermined near distance and the right and the left optometric apparatus bodies are rotated with the cycloduction point of the right and the left eyes to be examined as the center according to the predetermined near distance so as to execute objective measurement of both eyes. 17. The optometric apparatus according to claim 16, further comprising a calculating means for calculating a difference between an objective refractive measurement value for the far targets and an objective refractive measurement value for the both eyes at the predetermined near distance, and a determining means for determining accommodative functional disorder or necessity for the predetermined near distance based on a calculation result. 18. The optometric apparatus according to claim 16, wherein, when moving the targets to the predetermined near distance, step feeding of the targets is executed so as to carry out the objective measurement for both eyes at the same time in every time of execution of the step feeding. 19. The optometric apparatus according to claim 16, wherein the targets are Landolt rings and by having a lever tilted in a direction of a cut in the Landolt ring to see if a direction in which the lever is tilted matches the direction of the cut, whether the examinee is paying attention to the Landolt ring or not is checked. 20. The optometric apparatus according to claim 19, wherein, when the direction in which the lever is tilted matches the direction of the cut in the Landolt ring, objective measurement is started. 21. The optometric apparatus according to claim 20, wherein different Landolt rings are presented to the examinee at every measurement if an average is to be obtained by executing the objective measurement several times. 22. The optometric apparatus according to claim 17, wherein, when moving the targets to the predetermined near distance, step feeding of the targets is executed so as to carry out the objective measurement for both eyes at the same time in every time of execution of the step feeding.

TECHNICAL FIELD The present invention relates to an optometric apparatus which enables optometric measurement by an examinee himself/herself or an optometric assistant with less experience. BACKGROUND ART There is known an optometric apparatus constituted so that ocular refractivity of the right and left eyes of an examinee can be measured at the same time subjectively and objectively (See Japanese Patent Laid-Open No. 2000-83900). This conventional optometric apparatus is so constituted that the examinee takes optometry following instructions of an optometrist. However, optometric measurement of the examinee by the optometrist is not favorable in view of efficient management and cost reduction. Also, recently, in the case of accommodative functional disorder such as near-vision disorder, asthenopia, sense of blear, etc. or in the case that abnormality of convergence and accommodation systems are suspected, when carrying out prescription of spectacles for reading or health management of VDT (video display terminal) workers and so on, accommodative functions such as accommodative near point, accommodative ability and accommodative dynamics are measured. For measurement of accommodative functions, subjective methods such as Ishihara's near point meter and accommodo-poly-recorder and objective methods such as infrared optometer and front-open type infrared optometer are used. For measurement of subjective accommodative near point, 0.6 Landolt-ring targets and bar targets on near-distance optotypes are usually made to approach from the distance where an examinee can see the clearest at a constant rate of a target moving speed of 2.5 cm/sec to 5 cm/sec, and the distance where occurrence of even a slight blur is sensed is recorded as a near point. The infrared optometer of the objective method has renovated a normal autorefractometer, in which an ocular refractive state of horizontal meridians when a target is moved at a constant speed is continuously measured so as to record dynamic characteristics of accommodation. The front-open type optometer records accommodation change of both eyes by moving a real space in front of the eyes with the target as an external target in the state close to natural vision. However, in the subjective measurement of accommodative near point, after an examinee has learned blur of targets and subjective sensing standard of clear vision by practice, a distance where blur is sensed when a target is moved from a long distance to a short distance (disappearance threshold) and a distance where clear vision is enabled when the target is moved from the short distance to the long distance on the contrary (appearance threshold) are measured 3 times, respectively, and an average value of the both is set as a near point. The measurement depends on subjective response and is subject to large fluctuation due to instability in subjective sensing standard between blur and clear visions of targets and uncertainty in target following motion and response of the examinee, which is particularly unsuitable for measurement of infants. The measurement by the infrared optometer is carried out with one eye shielded and a target moved on the optical axis of one eye as accommodation stimulation, and it is different from daily relations between convergence and accommodation. Accommodation and convergence are increased/decreased together in the daily life and in an unseparable relation with each other. Accommodation measurement with one eye shielded has a problem that accurate measurement of accommodative near point and accommodative ability is not possible. With the measurement by the front-open type infrared optometer, external targets are utilized to present targets in the state closer to the natural vision, but it has a problem that a range of target movement is restricted and accommodative near point including far point can not be measured. The present invention has been made in view of the above circumstances and its object is to provide an optometric apparatus which enables optometric measurement by an examinee himself/herself or an optometric assistant with less experience. Also, an object of the present invention is to provide an optometric apparatus which presents targets to both eyes while maintaining the relation between accommodation and convergence, capable of measurement of accommodative functions in a wide target moving range, maintains the relation between accommodation stimulation and convergence constant, capable of easy measurement of accommodation regardless of refraction error of an examinee, and is suitable for diagnosis of cases such as near-vision disorder, asthenopia, blear, etc. and suspected abnormality in convergence and accommodation systems in the clinical ophthalmology as well as judgment when carrying out prescription of spectacles for reading and health management of VDT (video display terminal) workers, especially an optometric apparatus which can easily measure the relation between accommodation and convergence. DISCLOSURE OF INVENTION An optometric apparatus according to claim 1 is characterized in that optometric apparatus bodies which are driven independently in fore-and-aft, right-and-left and up-and-down directions, respectively, for respective optometry of an examinee are provided on both sides of a face receiving device. The optometric apparatus according to claim 2 is characterized in that the optometric apparatus bodies have a function to measure objective refraction and subjective refraction of both eyes at the same time, and a mechanism rotating with a cycloduction point of the right and the left eyes to be examined as a center is provided. The optometric apparatus according to claim 3 is characterized in that an auto-alignment mechanism for automatically executing alignment for eyes to be examined is provided on the optometric apparatus bodies. The optometric apparatus according to claim 4 is characterized in that a monitor screen to present an image of an anterior ocular segment of eye to be examined to an optometric assistant is provided at each of the optometric apparatus bodies. The optometric apparatus according to claim 5 is characterized in that a monitor screen for explanation of optometry procedure by the examinee himself/herself through movie playing is provided. The optometric apparatus according to claim 6 is characterized in that comparison can be made between a vision when recommended spectacles are worn and a vision with naked eyes or with dioptric power of currently used glasses. The optometric apparatus according to claim 7 is characterized in that the optometric apparatus is connected to a lens meter for measuring optical characteristics of a pair of spectacle lenses mounted to a spectacle frame, data of the optical characteristics of the spectacle lenses is inputted from the lens meter, and an initial value of PD value at auto-alignment is set based on the PD value as the optical characteristics data. The optometric apparatus according to claim 8 is characterized in that the lens meter measures the optical characteristics of the pair of spectacle lenses mounted to the spectacle frame at the same time. The optometric apparatus according to claim 9 is characterized in that the auto-alignment is carried out while maintaining the PD value. The optometric apparatus according to claim 10 is characterized in that an initial value of PD value is set according to age and sex of the examinee. The optometric apparatus according to claim 11 is characterized in that an initial setting of PD value is cancelled when alignment for one of the right and left eyes to be examined is gained, and data of the alignment is used as the alignment data for the other eye to be examined so that alignment of the other eye to be examined can be automatically executed. The optometric apparatus according to claim 12 is characterized in that an image of an anterior ocular segment of the eye to be examined is presented on the monitor screen for explaining the optometry procedure by the examinee himself/herself by the movie playing. An optometric apparatus according to claim 13 is characterized in that an optometric apparatus body in which an optical system for presenting targets for a left eye to the left eye is built and an optometric apparatus body in which an optical system for presenting targets for a right eye to the right eye is built are provided. The optometric apparatus according to claim 14 is characterized in that a fusion target presenting optical system for presenting fusion targets at binocular optometry of eyes to be examined is provided in each of the optical systems. An optometric apparatus according to claim 15 is characterized in that an optometric apparatus body having a mirror opposing a left eye in which a measurement optical system for objective measurement of the left eye is built, an optometric apparatus body having a mirror opposing a right eye in which a measurement optical system for objective measurement of the right eye is built, and an optotypes examining device presenting optotypes from behind through the right and the left mirrors are provided. The optometric apparatus according to claim 16 is characterized in that, after subjective refractive measurement for far targets, the targets are moved to a predetermined near distance and the right and the left optometric apparatus bodies are rotated with the cycloduction point of the right and the left eyes to be examined as the center according to the predetermined near distance so as to execute objective measurement of both eyes. The optometric apparatus according to claim 17 is characterized in that there are provided a calculating means for calculating a difference between an objective refractive measurement value for the far targets and an objective refractive measurement value for the both eyes at the predetermined near distance and a determining means for determining accommodative functional disorder or necessity for the predetermined near distance based on the calculation result. The optometric apparatus according to claim 18 is characterized in that, when moving the targets to the predetermined near distance, step feeding of the targets is executed so as to carry out the objective measurement for both eyes at the same time in every time of the execution of the step feeding. The optometric apparatus according to claim 19 is characterized in that the targets are Landolt rings and by having a lever tilted in a direction of a cut in the Landolt ring to see if a direction in which the lever is tilted matches the direction of the cut, whether the examinee is paying attention to the Landolt ring or not is checked. The optometric apparatus according to claim 20 is characterized in that, when the direction in which the lever is tilted matches the direction of the cut in the Landolt ring, objective measurement is started. The optometric apparatus according to claim 21 is characterized in that different Landolt rings are presented to the examinee at every measurement if an average is to be obtained by executing the objective measurement several times. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an explanatory view showing an outline of an optometric apparatus according to the present invention. FIG. 2 is an appearance drawing of the optometric apparatus shown in FIG. 1. FIG. 3 is a view showing an optical system of the optometric apparatus shown in FIG. 1. FIG. 4 is a view showing the optical system for the left eye shown in FIG. 3 in the enlarged manner. FIG. 5 is a plan view of the optical system for the left eye shown in FIG. 4. FIG. 6 is a view showing the optical system for the right eye shown in FIG. 3 in the enlarged manner. FIG. 7 is a plan view of the optical system for the right eye shown in FIG. 6. FIG. 8 is a block diagram of a control system of the optometric apparatus according to the present invention. FIG. 9 is a view showing a connection form between the optometric apparatus and a lens meter, in which (a) is an explanatory view showing the state where the lens meter is disposed in the neighborhood of the optometric apparatus and connected to a monitor device through an RS232C cable, (b) is a view showing the state where the lens meter is disposed far from the optometric apparatus and the lens meter and the optometric apparatus are connected to the monitor device through the RS232C cable, and (c) is a view showing the state where a plurality of the optometric apparatuses and the monitor devices are arranged and the lens meter is connected to the monitor device through LAN. FIG. 10 is an appearance view of the lens meter shown in FIG. 9. FIG. 11 is a flowchart showing an example of optometric procedures of the optometric apparatus according to the present invention, in which (a) is a flowchart for those who have not worn spectacle glasses or contact lenses, (b) is a flowchart for those who wear spectacle glasses, and (c) is a flowchart for those who wear contact lenses. FIG. 12 is a view showing a landscape chart to be displayed on a liquid crystal display of the optical system shown in FIGS. 5 and 7. FIG. 13 is an explanatory view of an anterior ocular segment image displayed on a display screen of the liquid crystal display shown in FIG. 2, in which (a) is a view showing an anterior ocular segment image displayed on the display screen for the left eye and (b) is a view showing an anterior ocular segment image displayed on the display screen for the right eye. FIG. 14 is an explanatory view showing an example of auto-alignment, in which (a) shows the state where alignment is not gained, (b) shows the state where alignment is being gained and (c) shows the state where alignment is gained. FIG. 15 is an explanatory view showing another example of auto-alignment, in which (a) shows the state where alignment is not gained, (b) shows the state where alignment is gained for the left eye, (c) shows the relation between the body portion and the eye to be examined when gaining alignment for the right eye using the data when the alignment is gained for the left eye and (d) shows the state where alignment is gained for both eyes. FIG. 16 is a view showing an example of a red and green chart, in which (a) shows the red and green chart for the left eye, (b) shows the red and green chart for the right eye and (c) shows how a target is seen when the right and the left red and green charts are seen with both eyes with emmetropia. FIG. 17 is a view showing an example of an astigmatic chart. FIG. 18 is a view showing an example of a cross-cylinder chart. FIG. 19 is a view showing an example of cross heterophoria chart, in which (a) shows the cross heterophoria chart for the left eye, (b) shows the cross heterophoria chart for the right eye and (c) shows how a target is seen when both cross heterophoria charts are seen with emmetropic both eyes. FIG. 20 is a view showing an example of a stereoscopic vision chart, in which (a) shows the stereoscopic vision chart for the left eye, (b) shows the stereoscopic vision chart for the right eye, (c) shows how a target is seen when the stereoscopic vision chart is seen by emmetropic both eyes and (d) shows the state where a fusion frame is presented. FIG. 21 is a view showing an example of a near chart. FIG. 22 is a view showing an example of a Landolt ring. FIG. 23 is a perspective view showing an example of a cross cylinder lens. FIG. 24 is a view showing an example of a fusion frame chart. FIG. 25 is a view showing a variation of the optometric apparatus of the present invention and explanatory view with an optotypes device provided behind the optometric apparatus. FIG. 26 is an explanatory view showing an internal constitution of the optotypes examining device. FIG. 27 is a perspective view showing an example of polarized glasses. FIG. 28 is an explanatory view of a polarization axis of a polarization plate. FIG. 29 is a view showing an example of display of a measurement result. FIG. 30 is a perspective view showing an example of a rotary prism. FIG. 31 is a block diagram showing an outline constitution of the optical system of a variation 2 of the optometric apparatus according to the present invention. FIG. 32 is a view showing a detailed constitution of the optical system for the right eye shown in FIG. 31. FIG. 33 is a flowchart for explaining action of the variation 2 of the optometric apparatus of the present invention. BEST MODE FOR CARRYING OUT OF THE INVENTION In FIG. 1, 1 is an optometric table whose height can be adjusted vertically, 2 is an optometric apparatus disposed on the optometric table 1, 3 is an optometric chair and 4 is an examinee seated on the optometric apparatus. The optometric apparatus 2 has, as shown in FIG. 2, a base portion 5a, a driving mechanism box 5b, a right-and-left pair of body portions 5l and 5r with a built-in measurement optical system which will be mentioned later and a face receiving device 6. The body portions 5l and 5r are supported by supports 5p and 5q. The face receiving device 6 is provided with a pair of supports 6a and 6b and a jaw receiver 6d. The pair of supports 6a and 6b is provided with an arc-state forehead receiver 6c. The jaw receiver 6d can be adjusted in the vertical direction by knobs 6e and 6e. Also, the forehead receiver 6c can be adjusted in the fore-and-aft direction. In the driving mechanism box 5b, an XYZ driving mechanism (not shown) for independently driving the supports 5p and 5q, respectively, are provided. For this XYZ driving mechanism, a pulse driving motor and a feeding screw are used, for example, and a known constitution can be employed. Also, in the driving mechanism box 5b, a rotary driving mechanism for rotating and driving the supports 5p and 5q independently in the horizontal and opposite direction to each other is provided. In this rotary driving mechanism, combination of a pulse motor and a gear may be used. The body portions 5l and 5r have a function for objective measurement and subjective refractive measurement for both eyes at the same time and are rotated with the cycloduction point of the right and left eyes to be examined as the center. A joystick lever (hereinafter referred to as a lever) 6h is provided on the base 5a, and this lever 6h is provided with a button 6g. The measurement optical system of the body portion 5l has an anterior ocular segment photography optical system 30L shown in FIGS. 3 through 5, an XY alignment optical system 31L, a fixation optical system 32L and a refractive measurement optical system 33L. The measurement optical system of the body portion 5r has an anterior ocular segment photography optical system 30R shown in FIGS. 3, 6 and 7, an XY alignment optical system 31R, a fixation optical system 32R and a refractive measurement optical system 33R. Since the measurement optical system of the body portion 5l and the measurement optical system of the body portion 5r are symmetrical, the measurement optical system of the body portion 5l will be explained. The anterior ocular segment photography optical system 30L has an anterior ocular segment illumination optical system 34 and a photographic optical system 35. The anterior ocular segment illumination optical system 34 has a light source 36 for anterior ocular segment illumination, a diaphragm 36a and a projection lens 37 for projecting the light from the light source 36 to the anterior ocular segment of an eye E to be examined. The photographic optical system 35 has a prism P into which a reflected light from the anterior ocular segment of the eye E to be examined enters, an objective lens 38, a dichroic mirror 39, a diaphragm 40, a dichroic mirror 41, relay lenses 42 and 43, a dichroic mirror 44, a CCD lens (imaging lens) 45, and a CCD (image pickup means) 46. The XY alignment optical system 31L has an alignment illumination optical system 47 and a photographic optical system 35 as an alignment light-receiving optical system. The alignment illumination optical system 47 has, as shown in FIG. 4, an illumination light source 48 for alignment, a diaphragm 49 as an alignment target, a relay lens 50, the dichroic mirror 41, the diaphragm 40, the dichroic mirror 39, the objective lens 38 and the prism P. The fixation optical system 32L has a liquid crystal display 53 for displaying fixation targets and charts for subjective optometry, a half mirror 54, a collimator lens 55, rotary prisms 55A and 55B, a reflecting mirror 56, a moving lens 57, relay lenses 58 and 59, cross cylinder lenses (VCC lenses) 59A and 59B, a reflecting mirror 60, dichroic mirrors 61 and 39, the objective lens 38 and the prism (may be a mirror) P. For the rotary prisms 55A and 55B, publicly known ones shown in FIG. 30 are used, and when they are rotated in the direction opposite to each other, a prism amount can be continuously changed, while when rotated integrally in the same direction, a prism base direction is rotated. The rotary prisms 55A and 55B presents a target 71A shown in FIG. 19(a) to the left eye and a target 71B shown in FIG. 19(b) to the right eye to be used for heterophoria measurement. For emmetropia, as shown in FIG. 19(c), the target 71A and the target 71B are crossed with each other at the center, but if there is heterophoria, they are separated. The rotary prisms 55A and 55B are used, as shown in FIG. 19(c), for measurement of a prism amount with which the target 71A and the target 71B cross each other at the center. For the cross cylinder lenses (VCC lenses) 59A and 59B, those known shown in FIG. 23 are used, and when they are rotated in the direction opposite to each other, astigmatic dioptric power is changed, while when they are rotated integrally in the same direction, the cylinder axis is rotated. Here, the targets are presented using the liquid crystal display 53, but those known which presents targets by background illumination can be used by providing targets on a turret disk. In the fixation optical system 32L, the moving lens 57 can be moved in the optical axis direction by a pulse motor PMa according to refractive power of an eye to be examined. By this, fixation and fogging for the eye to be examined is enabled. At the fixation target optical system 32L, a fusion target presenting optical system 32L′ is provided. The fusion target presenting optical system 32L′ is constituted by an LED 53A as an illumination light source, a collimator lens 53B, a fusion frame chart 53D and a total reflection mirror 53E. At the fusion frame chart 53D, as shown in FIG. 24, a square-shaped transmission window 53F and a light-shielding portion 53G are formed. On the collimator lens 53B, a diffusion surface is provided so that the fusion frame chart 53D is evenly illuminated. In the embodiment of the present invention, the fusion target presenting optical system 32L′ is provided, but a fusion frame 53F can be directly provided at a target of the liquid crystal display 53. The refractive measurement optical system 33L has a measurement flux projecting optical system 62 and a measurement flux light-receiving optical system 63. The measurement flux projecting optical system 62 has a light source 64 for measurement such as an infrared LED, a collimator lens 65, a conical prism 66, a ring target 67, a relay lens 68, a ring-state diaphragm 69, a perforated prism 70 with a through hole 70a formed at the center, the dichroic mirrors 61 and 39, the objective lens 38 and the prism P. Also, the measurement flux light-receiving optical system 63 has the prism P for receiving reflected light from an fundus oculi Ef of the eye E to be examined, the objective lens 38, the dichroic mirrors 39 and 61, the through hole 70a of the perforated prism 70, a reflecting mirror 71, a relay lens 72, a moving lens 73, a reflecting mirror 74, the dichroic mirror 44, the CCD lens 45 and CCD 46. Since the optical system of the body portion 5r is almost the same as the optical system of the body portion 51, its explanation is omitted. The control system of the body portions 5l and 5r is shown in FIG. 8. The driving devices 20, 24, 26, and 28, the illumination light source 36 for observing the anterior ocular segment, the liquid crystal display (fixation target light source) 53, the light source 64 for measurement, the pulse motor PMa, etc. are operated/controlled by an operation control circuit 62 shown in FIG. 8. Also, into the operation control circuit 62, a detection signal from the CCD 46 is inputted. The control system of the body portion 5r is the same as the control system of the body portion 5l. The entire control circuit has, as shown in FIG. 8, an operation control circuit 63 for controlling control circuits 62′ and 62′ of the body portions 5l and 5r. To this operation control circuit 63, a tilting detection sensor 12b for detecting tilting operation of the button 6g and the lever 6h and a rotation sensor 12c for detecting rotating operation around the axis of the lever 12 are connected. Also, to the operation control circuit 63, liquid crystal displays 64l and 64r as monitor devices and a monitor device 64q are connected. The liquid crystal display 64l is, as shown in FIG. 2, provided on the front of the body portion 5l to play a role of displaying an anterior ocular segment image of the left eye of the eye E to be examined. The display 64r is provided on the front of the body portion 5r to play a role of displaying an anterior ocular segment image of the right eye of the eye E to be examined. The monitor device 64q is mounted to a support 64s set up on the base 5a. The monitor device 64 presents a monitor screen for explaining measurement procedures by an examinee himself/herself on its display screen 64q′ by movie playing. To the optometric apparatus, a lens meter 1000 is connected. The connection form of the lens meter 1000 can be any of FIGS. 9(a) to 9(c). The appearance of the lens meter 1000 is shown, for example, in FIG. 10. This lens meter 1000 has a function to measure optical characteristics of spectacle lenses 1006L and 1006R with right and left frames of spectacles 1006 at the same time. In FIG. 10, 1007L and 1007R are push levers of the spectacle lenses 1006L and 1006R. When the spectacles 1006 are placed on a spectacle set table 1001 of this lens meter 1000, a detection pin (not shown) provided on the spectacle set table 1001 detects setting of the spectacles 1006. By this, the push levers 1007L and 1007R are automatically lowered, the spectacles 1006 are fixed by pressing claws 1008L and 1008R, and the optical characteristics data of the right and left spectacle lenses 1006L and 1006R is taken at the same time by the measurement optical system built in the lens meter 1000. Also, based on the optical characteristics data of the right and left spectacle lenses 1006L and 1006R, a PD value of the examinee (who wears glasses) is obtained. For the structure of the measurement optical system of this lens meter 1000, two publicly known measurement optical systems can be used in principle, and detailed constitution is described, for example, in the Japanese Patent Application No. 2000-399801. In the embodiment of the present invention, the lens meter shown in FIG. 10 is used, but publicly known auto-lens meter having a PD measurement function can be also used. The optical characteristics data of the spectacle lenses of the lens meter 1000 is inputted into the operation control circuit 63. The operation control circuit 63 also plays a role to display an optical characteristics value of the spectacle lenses, a PD value, on a display screen 64q′ of the monitor device 64q. It is preferable to make initial setting of the body portions 5l and 5r using this PD value in the case of wearers of spectacle lenses. In this optometric apparatus 2, an optometry routine shown in FIGS. 11(a) through (c) can be executed respectively for those who have not worn spectacles or contact lenses, for examinees who wear spectacles and for examinees who wear contact lenses. The details of this optometry routine will be described later. Upon entry to a shop by an examinee, the monitor device 64q is turned on, and a predetermined matter is displayed on the display screen 64q′. According to the instructions displayed on the display screen 64q′ of the monitor device 64q, the examinee operates a touch panel of the display screen 64q′. For example, the examinee inputs sex, age, wearing of spectacles/contact lens or not, etc. are inputted according to the instructions on the touch panel. At the same time, instruction matters are guided in voice. For those who wear spectacles, the optical characteristics value data (dioptric power) of the spectacles 1006 is measured by the lens meter 1000. When this series of diagnostic interviews are finished, explanation of operational procedures of the optometric apparatus 2 is shown by movie on the display screen 64q′ of the monitor device 64q. And when the examinee sits down, places the jaw on the jaw receiver 6d and puts the forehead on the forehead receiver 6c, for auto-alignment for the left eye EL and the right eye ER of the examinee, the light source 36 for observing the anterior ocular segment, the illumination light source 48 for alignment and the liquid crystal display 53 in the body portions 5l and 5r are lighted. The light of a fixation target displayed on the liquid crystal display 53 is projected to the fundus oculi Ef of the left eye EL and the right eye RL of the examinee through the reflecting mirror 54, the collimator lens 55, the reflecting mirror 56, the moving lens 57, the relay lenses 58 and 59, the reflecting mirror 60, the dichroic mirrors 61 and 39, the objective lens 38 and the prism P. On the liquid crystal display 53, a landscape chart 99 as a target is displayed, and the landscape chart 99 is presented to the examinee 4 as shown in FIG. 12. Also, the operation control circuit 63 adjusts the body portions 5l and 5r in the right-and-left direction through initial setting so that the distance between centers of the prisms P and P (optical axes OL and OR) of the body portions 5l and 5r shall be an average distance between pupils of an adult examinee (PD value=66 mm). On the other hand, the examinee 4 adjusts the height of the jaw receiver and so on so that the examinee can see the landscape chart 99 as the fixation target. The illumination light from the light source 36 for illuminating the anterior ocular segment is projected to the anterior ocular segment of the left eye EL and the right eye RL through the diaphragm 36a and the projection lens 37, and the anterior ocular segment is illuminated. The reflected light from the anterior ocular segment of the left eye and the right eye is projected to the CCD (image pickup means) 46 through the prism P, the objective lens 38, the dichroic mirror 39, the diaphragm 40, the dichroic mirror 41, the relay lenses 42 and 43, the dichroic mirror 44 and the CCD lens (imaging lens) 45. And an anterior ocular segment image EL′ of the left eye EL of the CCD 46 is imaged on the CCD 46. Also, the operation control circuit 62 displays an anterior ocular segment image EL′ of the left eye EL on a liquid crystal display 64l of the body portion 5l as shown in FIG. 13(a) based on an output signal from the CCD 46. Similarly, an anterior ocular segment image ER′ of the right eye ER is displayed on the liquid crystal display 64r of the body portion 5r as shown in FIG. 13(b). In the meantime, alignment flux from the illumination light source 48 for XY alignment is projected to a cornea CL of the left eye EL of the examinee through the diaphragm 49 as the alignment target, the relay lens 50, the dichroic mirror 41, the diaphragm 40, the dichroic mirror 39, the objective lens 38 and the prism P. And the reflected light from the cornea CL is imaged on the CCD (image pickup means) 46 through the prism P, the objective lens 38, the dichroic mirror 39, the diaphragm 40, the dichroic mirror 41, the relay lenses 42 and 43, the dichroic mirror 44 and the CCD lens (imaging lens) 45, and a luminescent spot image EP from the cornea CL is formed on the CCD 46. Moreover, the operation control circuit 62 displays the luminescent spot image EP together with the anterior ocular segment image EL′ of the left eye EL on the liquid crystal display 64l based on the output signal. Similarly, the luminescent spot image EP together with the anterior ocular segment image ER′ of the right eye RL are displayed on the liquid crystal display 64r of the body portion 5r. The operation control circuit 63 drives and controls the driving devices 20 and 26 so that the signal from the luminescent spot image EP from the CCD 46 enters a predetermined range S2 at the center of the CCD 46, that is, in the direction where the optical axis of the left eye EL of the examinee 4 matches the center of the prism P of the body portion 5l (optical axis OL). With this driving, the operation control circuit 63 stops operation of the driving devices 20 and 26 when the optical axis OL of the left eye EL of the examinee 4 enters the allowable range S2 almost matching the center of the prism P of the body portion 64l (optical axis OL) and completes the XY alignment for the left eye EL of the body portion 64l. The alignment for the right eye RL is the same as above. The operation control circuit 63 drives and controls the Z (fore and aft) directional driving device 24 so that the luminescent spot image EP of the CCD 46 becomes clear when the XY alignment for the left eye EL of the body portion 5l is completed and moves and controls the body portion 64l in the direction of the optical axis OL (fore-and-aft direction). When it is detected that the luminescent spot image EP of the CCD becomes clear, the operation control circuit 46 stops driving of the Z (fore and aft) directional driving device 24, assuming that the Z alignment has been completed. The alignment in the Z direction for the right eye ER is the same as above. FIG. 13 shows the state where the luminescent spot image EP of the right eye ER enters the predetermined range S2 and the luminescent spot image EP of the left eye EL does not enter the predetermined range S2. When the auto-alignment is completed, the operation control circuit 63 operates and controls the operation control circuit 62 of the body portion 64l and the operation control circuit 62 of the body portion 64r, respectively, lights the light sources 64 and 64 for measurement of the right and the left body portions 64l and 64r, respectively, injects infrared measurement flux from these light sources 64 and 64 for measurement and starts measurement of ocular refractivity of the left eye EL and the right eye ER of the examinee at the same time. The flux from the light source 64 for measurement is projected to the fundus oculi Ef of the left eye EL and the right eye ER of the examinee 4 through the measurement flux projecting optical system 62. The measurement flux from the light source 64 for measurement is led to the ring target 67 through the collimator lens 65 of the body 51 and the conical prism 66. The ring-state measurement flux having passed the ring target 67 is projected to the fundus oculi Ef of the left eye EL and the right eye ER of the examinee through the relay lens 68, the ring-state diaphragm 69, the perforated prism 70 with the through hole 70a formed at the center, the dichroic mirrors 61 and 39, the objective lens 38 and the prism P. The ring-state measurement flux projected to the fundus oculi Ef is reflected by the findus oculi Ef. This reflected light is imaged by the CCD 46 into a ring-state reflected image through the measurement flux light-receiving optical system 63, that is, the prism P, the objective lens 38, the dichroic mirrors 39 and 61, the through hole 70a of the perforated prism 70, the reflecting mirror 71, the relay lens 72, the moving lens 73, the reflecting mirror 74, the dichroic mirror 44, the CCD lens 45, etc. A detection signal from this CCD 46 is inputted to the operation control circuit 62 of the body portion 641. When the detection signal is inputted from the CCD 46, this operation control circuit 62 objectively measures ocular refractivity of the left eye EL and the right eye ER from the size and the shape of the ring-state reflected image imaged on the CCD camera 46. Since details of measurement principle of this objective ocular refractive power is publicly known, its detailed description is omitted. Hereinafter, how to use the optometric apparatus according to the present invention will be described. 1. Diagnostic interview is made while having the examinee 4 watch the display screen 64q′ of the monitor device 64q. 2. Operational procedures of the optometric apparatus are displayed on the display screen 64′ of the monitor device 64q and the operational procedures are explained with guidance in voice. After that, individual measurement is started when optometric measurement is selected. 3. Measurement of corrected visual acuity of a contact-lens wearer (1) When this measurement is selected, power-saving mode of the body portions 5l and 5r is canceled, simultaneously. The liquid crystal display (also called as the light source for target illumination) 53, the measurement light source (also called as LED) 64, the CCD camera 46 and so on are turned on. (2) The body is set to be initialized. The PD value shall be an average distance between pupils of 66 mm. The target shall be the landscape chart 99 shown in FIG. 12 for both eyes EL and ER. (3) With announcement of “Visual acuity when a contact lens is worn will be measured. Now, measurement method will be explained,” characters are displayed on the display screen 64′ of the monitor device 64q. (4) How to use the optometric apparatus 2 is played by movie on the monitor device 64q with voice. How to set on the face and how to operate the lever 6h which will be explained in the following is played by movie. (5) Then, voice guidance is given, saying “Now, visual acuity will be measured. Hold the lever 6h and look into the visual acuity tester with your contact lens on. Adjust the jaw receiver 6d. Can you see the picture of a house 99′? If not, make adjustment so that you can see it.” (6) The customer fixes the face with the jaw receiver 6d and the forehead receiver 6c and holds the lever 6h. (7) Auto-alignment function is started for both eyes at the same time. (8) The auto-alignment is repeated at the next step till alignment is matched, and finished when the alignment is matched. a) The number of auto-alignment times at the initial position shall be 2 retries and 3 times in total. b) If NG is given for both eyes at a) step, after announcement of “Position of the apparatus will be adjusted,” an optical base (which is a base for each of the supports 5p and 5q and constitutes a part of a three-dimensional driving mechanism) is moved to the right by 5 mm while maintaining the PD value (L) of 66 mm. c) Auto-alignment is carried out 3 times. d) If NG is given for both eyes at c) step, after announcement of “Position of the optometric apparatus 2 will be adjusted,” the position is moved to the left of the initial position by 5 mm while maintaining the PD value (L) of 66 mm. e) Auto-alignment is carried out 3 times. f) If NG is given for both eyes at e) step, after announcement of “Position of the apparatus will be adjusted,” the position is moved to above the initial position by 5 mm while maintaining the PD value (L) of 66 mm. g) Auto-alignment is carried out 3 times. h) If NG is given for both eyes at g) step, after announcement of “Position of the apparatus will be adjusted,” the position is moved to below the initial position by 5 mm while maintaining the PD value (L) of 66 mm. i) Auto-alignment is carried out 3 times. FIG. 14 shows an example of the procedures and this FIG. 14 show a positional relation of the optical axes OL and OR of the body portions 5l and 5r against the eyes EL and ER to be examined. In this FIG. 14, EPR is an actual pupil of the eyes EL and ER to be examined. Also, F1 is a midline of the face of the examinee 4 and F2 shows the position of an origin in the X direction of the body portions 5l and 5r. Δ′ is a displacement amount between the midline and the origin position in the X direction. Moreover, SIL and SIR show moving ranges in the vertical and the horizontal directions of the body portions 5l and 5r at auto-alignment. FIG. 14(a) shows the state where the luminescent spot image EP is displaced diagonally above both for the right and the left eyes EL and ER. In this case, drive the body portions 5l and 5r to the right while maintaining the PD value at the initial value to have the state as shown in FIG. 14(b). And if the luminescent spot image EP is displaced from the predetermined range S2 even after that, the body portions 5l and 5r are driven in the upper or the lower direction. In the case shown in FIG. 14(b), since the luminescent spot image EP is displaced above, the body portions 5l and 5r are moved in the upper direction by 5 mm, for example, and the luminescent spot image EP enters the predetermined range S2 as shown in FIG. 14(c) and then, the auto-alignment is completed. Thus, by combining the alignment procedures in (a) through (h) as appropriate, auto-alignment can be executed. If the PD value of the spectacle lens is known in advance, this PD value is set as the initial value (initial amount) and a probability of success of auto-alignment in a short time can be further improved. Also, when the initial value of the PD value is set according to the age and sex of the examinee 4, the success probability of auto-alignment in a short time can be also improved. Other than the above, auto-alignment can be made according to the procedures which will be explained hereinafter. j) If alignment is gained for one of the eyes at any step of a) through i), y and z values are fixed and the y and z values for the eye for which alignment is gained are set for the y and z values for the NG′d eye and after announcement of “Position of the apparatus will be adjusted,” the x value of the NG'd eye is enlarged by 5 mm. For example, as shown in FIG. 15, when the PD value of the examinee 4 is unknown, and the PD value of the examinee 4 is larger than the average interpupillery distance L=66 mm, as shown in FIG. 15(a), there can be a case where even the auto-alignment moving ranges SIL and SIR of the body portions 51 and 5r can not cover. In this case, for example, if the body portions 5l and 5R are moved to the left while maintaining the initial set value of the PD value (L=66 mm), as shown in FIG. 15(b), the luminescent spot image EP of the left eye EL enters the predetermined range S2, and auto-alignment for the left eye EL is achieved. The auto-alignment values (x, y, z) at this time are memorized. And the initial set value of the PD value is cancelled, and the set value from the origin F2 of the body portion 5r is set to (33 mm+x), while maintaining the y and z values, and the body portion 5r is moved in the right-and-left direction within the range of the moving range SIR, as shown in FIG. 15(c). If it does not enter the predetermined range S2 even after executing this reciprocal movement in the right-and-left direction several times, the moving range SIR of the body portion 5r for the auto-alignment is further enlarged as shown in FIG. 15(d). Then, the luminescent spot image EP enters the predetermined range S2, and therefore, when alignment is gained for one eye to be examined, the initial set value of the PD value is cancelled and the (x, y, z) values when alignment is gained for one eye to be examined are used as alignment data for the other eye to be examined, and auto-alignment is executed so as to further improve and accelerate alignment success probability. k) Auto-alignment is carried out 3 times. l) If NG is still given at the k) step, after announcement of “Position of the apparatus will be adjusted,” the x value of the NG'd eye is further enlarged by 5 mm. m) The steps j) through l) are repeated in the PD moving range. n) At any of the steps a) through m) where alignment is gained, auto-alignment is finished, x, y, z positions are detected and the PD value is obtained. (9) Measurement of corrected visual acuity of the right eye of a contact-lens wearer a) At the stage where alignment is gained, after announcement of “Do not narrow your eye,” a target with the acuity value of 0.1 is presented to the right eye. b) Next, the liquid crystal display (target illumination light source) 53 for the left eye is turned off. c) Voice guidance is given, saying “Tit the lever 6h in the direction of the cut in the target. If you can not see it, press the button 6g of the lever 6h.” d) The customer tilts the lever 6h in the direction of the cut in the Landolt ring. e) It is determined if the presented target matches the direction in which the lever 6h is tilted. f) After determining the direction of the cut in the Landolt ring and the direction in which the lever 6h is tilted, with the announcement of “How about this?” the next target is presented to the right eye. (10) Algorithm to determine visual acuity is as explained as follows. a) If the direction of the cut in the Landolt ring matches the direction in which the lever 6h is tilted, 1-step increase is made. b) When NG is given during the increasing steps, presentation is made 4 times at the maximum. c) During the steps of increasing the visual acuity value, if the direction of the cut is changed with the same acuity value, the horizontal direction and the vertical direction are presented alternately. Also, the right and left in the horizontal direction and up and down in the vertical direction are presented at random. d) In the 4 presentations at the maximum, 2 NG's make the value below it assumed to be the acuity. 3 OKs are determined as that acuity value is held by the examinee, and 1-step increase is made. e) As soon as the acuity value is determined, the liquid crystal display (illumination light source) 53 for the left eye is turned on, and the landscape chart 99 to be seen by both eyes is presented. f) The acuity value is memorized. (11) Measurement of corrected visual acuity of the left eye of a contact-lens wearer a) A target with the acuity value of 0.1 is presented to the left eye, and the target illumination light source for the right eye is turned off. b) The same procedures to (9) c) through (10) d) are carried out. c) As soon as the acuity value for the left eye is determined at the step (10) d), the target illumination light source for the right eye is turned on, and the landscape chart 99 for both eyes is presented. 4. Measurement of naked vision (right eye, left eye, both eyes) (1) The power-saving mode of the body portions is canceled. The chart illumination, the measurement LED, the CCD camera and so on are turned on. (2) The body is set to be initialized. The PD shall be 66 mm. The target shall be the landscape chart 99 for both eyes. (3) Voice guidance is given, saying “Please look at the display screen (display screen 64q′). Now, measurement method will be explained.” (4) How to use the optometric apparatus is played by movie with voice. How to set the face and how to operate the joystick lever 6h which will be explained in the following is played by movie. (5) Then, voice guidance is given, saying “Now, optometry will be started. Hold the lever 6h and look into the visual acuity tester. Adjust the jaw receiver 6d. Can you see the picture of a house 99? If not, adjust it to a position where you can see it. Look into the tester so that you can see the chart at the center of the field of vision. When you are ready, press the button 6g of the lever 6h.” (6) The customer places the face on the jaw receiver 6d and the forehead receiver 6c and presses the button 6g of the lever 6h. (7) Auto-alignment function is started for both eyes at the same time. Then, the same operation as the measurement of the corrected visual acuity for a contact-lens wearer (9) is carried out. (8) Measurement of the visual acuity of the right naked eye a) At the stage where alignment is gained, after announcement of “Do not narrow your eye,” a target with the acuity value of 0.1 is presented to the right eye. b) Next, the target illumination light source for the left eye is turned off. c) Next, the same operation as the steps for measurement of corrected visual acuity for a contact-lens wearer (9) c) through (10) d) is carried out. d) The visual acuity value is memorized. (9) Measurement of the visual acuity of the left naked eye. a) Atarget with the visual acuity value of 0.1 is presented to the left eye. b) The target illumination light source for the left eye is turned on, and the target illumination light source for the right eye is turned off. c) The same operation as the step (8) c) is carried out. d) As soon as the visual acuity value for the left eye is determined, the target illumination light source for the right eye is turned on and the landscape chart 99 is presented to both eyes. e) The visual acuity value is memorized. (10) Optometry for both-eyes a) The visual acuity values of the right eye and the left eye measured at the step (8) and the step (9) are compared, and a target with the visual acuity value lower than the lower visual acuity value by 1 step is presented. b) If the direction in which the lever 6h is tilted matches the direction of the cut in the Landolt ring at the first presentation, the same steps as the measurement of corrected visual acuity for a contact-lens wearer (10) a) through d) are carried out. c) If the direction in which the lever 6h is tilted does not match the direction of the cut in the Landolt ring at the first presentation, the visual acuity value is lowered till OK d) At the OK stage, then, the visual acuity value is raised. e) If NG is given during the increasing steps, presentation is made 4 times at the maximum. f) During the steps of increasing the visual acuity value, if the direction of the cut is changed with the same acuity value, the horizontal direction and the vertical direction are presented alternately. Also, right and left in the horizontal direction and up and down in the vertical direction are presented at random. g) In the 4 presentations at the maximum, 2 NG's make the value below it assumed to be the acuity. 3 OKs are determined as that visual acuity value is held by the examinee, and 1-step increase is made. h) As soon as the visual acuity value is determined, the landscape chart 99 is presented to both eyes. i) The visual acuity value is memorized. (11) Announcement is made, saying “Optometry with naked eyes is finished.” 5. Optometry when spectacles are worn (right eye, left eye, both eyes) (1) Announcement is made, saying “Optometry when you are wearing glasses will be started.” (2) S, C and A values obtained by measurement of dioptric power of spectacles are set. (3) A target with the visual acuity value 0.5 (the first target to be presented is not limited to 0.5. Arbitrary visual acuity values are chosen according to the eye to be examined. The same applies to the following) is presented to the right eye. (4) Then, the target illumination light source for the left eye is turned off. a) The customer tilts the lever 6h in the direction of the cut in the Landolt ring. b) It is determined if the presented target matches the direction in which the lever is tilted. c) After determining the direction of the cut in the Landolt ring and the direction in which the lever 6h is tilted, with the announcement of “How about this?” the next target is presented to the right eye. (5) Algorithm to determine visual acuity value is explained as follows. a) If the direction in which the lever is tilted matches the direction of the cut in the Landolt ring at the first presentation, the steps (10) (a) through (d) of the measurement for corrected visual acuity of a contact-lens wearer is followed. b) If the direction in which the lever is tilted does not match the direction of the cut in the Landolt ring at the first presentation, the visual acuity value is lowered till OK c) At the OK stage, then, the visual acuity value is raised. d) If NG is given during the increasing steps, presentation is made 4 times at the maximum. e) During the steps of increasing the visual acuity value and changing the cut direction with the same visual acuity value, presentation is made in the horizontal direction and the vertical direction alternately. Also, right and left in the horizontal direction and up and down in the vertical direction are presented at random. f) In the 4 presentations at the maximum, 2 NG's make the value below it assumed to be the acuity. 3 OKs are determined as that acuity value is held by the examinee, and 1-step increase is made. g) As soon as the visual acuity value is determined, the landscape chart 99 is presented to both eyes. h) The visual acuity value is memorized. (6) Optometry for the left eye when spectacles are worn a) The visual acuity value 0.5 is presented to the left eye. b) The target illumination light source for the right eye is turned off at the same time. c) The same procedure as the optometry (4) a) through (5) g) when spectacles are worn. d) The visual acuity value is memorized. (7) Optometry for both eyes a) The illumination light source for the right eye is turned on, and the landscape chart 99 is presented to both eyes. b) The visual acuity values of the right eye and the left eye measured at the step (5) and the step (6) are compared, and a target with the visual acuity lower value than the lower visual acuity value by 1 step is presented to both eyes. c) Next, measurement is made according to the optometry (4) a) through (5) g) for the right eye when spectacles are worn. d) The visual acuity value is memorized. e) The landscape chart 99 is presented to both eyes. 6. Objective refractive measurement (1) At the stage where 4. Measurement of naked vision or 5. Optometry when spectacles are worn is finished, the objective refractive measurement mode is automatically set. a) The landscape chart 99 is presented to both eyes as a target. b) PD shall be the PD value previously obtained. (2) Announcement is made, saying “Necessary dioptric power of the spectacles will be obtained. Please look into the optometric machine.” Then, announcement is made, saying “Please blink several times.” After 1 second, announcement is made, saying “Please keep your eyes wide open and do not blink for some time.” (3) Auto-alignment is made for both eyes at the same time. (4) Simultaneous objective measurement is made for both eyes. (5) Representative values of display of S, C and A data are displayed/outputted. 7. Optometry based on objective refractive measurement results (right eye, left eye, both eyes) (1) Optometry for the right eye a) When the objective measurement for both eyes is completed, announcement is made, saying “Refractive measurement values were obtained. Optometry will be made by these refractive measurement values.” b) S, C and A values obtained by objective refractive measurement are set for both eyes. c) A target with the visual acuity value of 0.5 is presented to the right eye. d) At the same time, the target illumination light source for the left eye is turned off. e) Announcement is made, saying “Please tilt the lever 6h in the direction of the cut in the target.” f) The same measurement as the optometry (4) a) through (5) g) when spectacles are worn is made in the following. g) The visual acuity value is memorized. (2) Optometry for the left eye a) The S, C and A values for the left eyes are set for the objective refractive measurement values. b) The illumination for the left eye is turned on, while the illumination for the right eye is turned off c) A target with the visual acuity value of 0.5 is presented to the right eye. d) Announcement is made, saying “Please tilt the lever 6h in the direction of the cut in the target.” e) The same procedures as the optometry (4) a) through (5) i) when spectacles are worn are carried out. f) The visual acuity value is memorized. (3) Optometry for both eyes a) The illumination for the right eye is turned on. b) The objective refractive measurement value is set for both eyes. c) The objective refractive measurement values of the right eye and the left eye based on the objective refractive measurement are compared, and a target with the visual acuity value lower than the lower visual acuity value by 1 step is presented. d) Announcement is made, saying “Please tilt the lever 6h in the direction of the cut in the target.” e) The same procedures as the optometry (4) a) through (5) g) when spectacles are worn are carried out. f) The visual acuity value is memorized. g) The landscape chart 99 is presented to both eyes. 8. Precision determination of spherical dioptric power by R & G test (red and green test) and optometry (right eye, left eye) (1) Red/green chart for binocular balance FIG. 16 shows an example of the red/green chart for binocular balance, in which FIG. 16(a) shows a target 70A of the red/green chart for the left eye and FIG. 16(b) shows a red/green chart 70B for the right eye, and FIG. 16(c) shows how the targets 70A and 70B are seen when seen by both eyes with emmetropia. (2) How the target is seen a) Right eye: A numeral target “9” with the upper side in the visual field of green and a numeral target “6” with the lower side in the visual field of red. b) Left eye: A numeral target “3” with the left side in the visual field of green and a numeral target “5” with the right side in the visual field of red ((3) S, C and A values obtained in the objective refractive measurement are set for both eyes). (4) R & G test for the right eye a) The red/green chart for binocular balance is presented. b) For the left eye, the illumination light source is turned off at the same time the target is presented. (5) Announcement is made, saying “Please open your eyes widely.” (6) Auto-alignment is carried out for both eyes at the same time. (7) A question is made in voice, saying “Are the red and green targets seen in the same way? Or either of which is clearer?” (8) Announcement is made, saying “If you see them in the same way, please press the button 6g of the lever 6h. If they are seen differently, please tilt the lever 6h in the direction seen more clearly.” a) If the lever 6h is tilted in the upper side (green is seen more clearly), +0.25D is added to the spherical dioptric power, and announcement is made, saying “Are the red and green targets seen in the same way? Or either of which is clearer?” b) If the lever 6h is tilted in the lower side (red is seen more clearly), −0.25D is added to the spherical dioptric power, and announcement is made, saying “Are the red and green targets seen in the same way? Or either of which is clearer?” (9) How to determine spherical dioptric power a) When the button 6g of the lever 6h is pressed, it is finished with the D value at that time. b) After the lever 6h is tilted in the upper side (green) and S+0.25 is added, when the lever 6h is tilted in the lower side (red), it is finished with the D value at that time. c) After the lever 6h is tilted in the lower side (red) and S−0.25 is added, when the lever 6h is tilted in the upper side (green), it is finished with the D value with S+0.25D added. (11) Optometry for the right eye after the R & G test a) As soon as the spherical dioptric power is determined, the visual acuity value of 0.5 is presented. b) Announcement is made, saying “Please tilt the lever 6h in the direction of the cut of the target.” c) The same measurement as the optometry (4) a) though (5) i) when spectacles are worn is carried out in the following. d) The D value and the visual acuity value for the right eye are memorized. (10) R & G test for the left eye, optometry a) The target illumination light source for the left eye is turned on, while the target illumination light source for the right eye is turned off. b) The left eye views a numeral target “3” in the green visual field and a numeral target “5” with the right side in the red visual field. c) After that, description in 8. (5) through (10) c) is followed with replacement of “upper” by “left” and “lower” by “right.” d) As soon as the visual acuity value is determined, the illumination light source for the right eye is turned on, and the landscape chart 99 is presented to both eyes. e) The D chart and the visual acuity value for the left eye are memorized. 9. Astigmatic test If the visual acuity value obtained by 8. R & G test result (10) d) or (11) e) is less than 0.7, a check test is made to see if astigmatism is corrected or not. For this, the astigmatic test chart shown in FIG. 17 is used. (1) It is determined if the visual acuity values of the left eye and the right eye are less than 0.7 or not. In the case of only one of them, a check test is made to see astigmatism is corrected or not for the eye in the order of the right eye and then, the left eye, if the values of both eyes are less than 0.7. In the following, description is made for the case where the visual acuity value for the right eye is less than 0.7. (2) Astigmatic test for the right eye: Announcement is made, saying “Astigmatic test will be made. The astigmatic test will be explained.” (3) How to use the apparatus is played with voice by movie. (4) Announcement is made, saying “Measurement will be started. Hold the lever 6h and look into the optometric machine.” (5) Announcement is made, saying “Are all the lines seen equally? If so, tilt the lever 6h to the front, and if there is any bold line, tilt the lever 6h to the back.” (6) If tilted to the front (seen equally), the visual acuity value of 0.5 is presented. a) Announcement is made, saying “Tit the lever in the direction of the cut of the target.” b) The same procedure in 5. Optometry when spectacles are worn (4) a) through (5) g). c) The visual acuity value is determined. (7) Comparison is made with the visual acuity value obtained in 8. R & G test (10) d) or (11) e). a) If the visual acuity value is the same or the present visual acuity value is better, the present visual acuity value is set as the visual acuity value of the customer. b) If the visual acuity value obtained in 8. R & G test (10) d) or (11) e) is better, the value obtained in 8. R & G test (10) d) or (11) e) is set as the visual acuity value of the customer. c) The D value and the visual acuity value are memorized. (8) If the lever 6h is tilted to the back (not equal but there is a bold line.), the visual acuity value obtained in 9. R & G test (10) d) or (11) e) is set as the visual acuity value of the customer. In this case, a comment that “A bold line remains in the astigmatic test.” is given on the display of the 18. Measurement result, which will be described later. Or it returns to 6. Objective refractive measurement. 10. Cross cylinder test (hereinafter referred to as CC test) The cross cylinder chart shown in FIG. 18 is used. 10-1. Precision determination method of cylinder axis 10-1-1. Precision determination procedure of cylinder axis in general subjective Refractive Measuring Method An intermediate axis of a cross cylinder lens ±0.5D is set to the cylinder axis obtained roughly, and the intermediate axis is reversed as a rotational axis. How both of them are seen by reversal is compared, and always on the better side, both the cylinder axis obtained by the outline and the intermediate axis of the cross cylinder lens are rotated by 50 in the direction of the negative axis of the cross cylinder lens. By repeating this, an angle where there is no difference between both sides by reversal in how they are seen is obtained, and it shall be set as an accurate astigmatic dioptric power. 10-1-2. Application example of an embodiment of the present invention. The refractivity obtained by the R & G test is set as Dθ, 1 (S1, C1, A1), the refractivity of the cross cylinder lens ±0.5D as Dθ, 2 (S2, C2, A2) and the synthetic refractivity of Dθ, 1 and Dθ, 2 as Dθ, 0 (S0, C0, A0). Since the intermediate axis of Dθ, 2 is set to the cylinder axis A1 of Dθ, 1, and reversed with the intermediate axis as the rotational axis, there is a relation of A2=A1±45° between the axial angles A1 and A2 of Dθ, 1 and Dθ, 2. Here, the synthetic refractivity Dθ, 0 (S0, C0, A0) of the Dθ, 1 and Dθ, 2 is obtained from the following formula. Numeral 1 (1) General formula S 0 = ( S 1 + S 2 + C 1 + C 2 2 ) - C 0 1 ( a ) C 0 = ± ⁢ ( C 1 2 + C 2 2 + 2 ⁢ C 1 ⁢ C 2 ⁢ cos ⁢ ⁢ 2 ⁢ ( A 1 - A 2 ) ) ( b ) A 0 = 1 2 ⁢ tan - 1 ⁢ C 1 ⁢ sin ⁢ ⁢ 2 ⁢ ⁢ A 1 + C 2 ⁢ ⁢ sin ⁢ ⁢ 2 ⁢ ⁢ A 2 C 1 ⁢ ⁢ cos ⁢ ⁢ 2 ⁢ ⁢ A 1 + C 2 ⁢ cos ⁢ ⁢ 2 ⁢ ⁢ A 2 ( c ) 10-1-3. Precision determination procedure of cylinder axis (1) The landscape chart 99 is presented to both eyes. (2) Announcement is made, saying “Precision measurement of cylinder axis will be started. Two visions will be compared. If the first “1” is seen better, tilt the lever 6h to the left, while if the next “2” is seen better, tilt the lever 6h to the right. If the visions are the same, press the button 6g of the lever 6h.” (3) The target illumination light source for the left eye is turned off. (4) The target for both eyes is switched to CC chart. (5) −0.5D is temporarily added to the spherical dioptric power S1 of both eyes. (6) Precision determination of cylinder axis of the right eye a) The target illumination light source for the right eye is turned off, and the synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1+45° is set. Hereinafter, this state is referred to as (A+). b) The target illumination light source for the right eye is turned on, “Between how this “1” is seen and” is uttered, and (A+) is presented. c) The target illumination light source for the right eye is turned off, and the synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1−45° is set. Hereinafter, this state is referred to as (A−). d) The target illumination light source for the right eye is turned on, “how this “2” is seen, which is seen better?” is uttered, and (A−) is presented. e) (A+) is presented, a sequence that ““1”, and” is uttered, (A−) is presented and ““2.” How about it?” is repeated. f) If the lever 6h is tilted to the left, it is assumed that A1=A1+5°, while if tilted to the right, it is assumed that A1=A1−5°. Naturally, A2 is changed according to that. g) If the button 6g of the lever 6h is pressed, the angle at that time shall be the final axial angle. If the lever 6h is tilted in the opposite direction such that (A+) to (A−) or (A−) to (A+), an average value of both angles shall be the final axial angle. (7) Precision determination of cylinder axis of the left eye a) The target illumination light source for the right eye is turned off. b) The synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1+45° is set for the left eye. Hereinafter, this state is referred to as (A+). c) The target illumination light source for the left eye is turned on, “Between how this “1” is seen and” is uttered, and (A+) is presented. d) The following procedure shall be the same as steps in (6) c) through g) with the “right eye” reading as the “left eye.” (8) When the final axial angle for the left eye is determined, the target illumination light source for the left eye is turned off. 10-2. Precision determination of astigmatic dioptric power 10-2-1. Precision determination procedure of cylinder axis in general subjective refractivity measuring method A negative axis or a positive axis of the cross cylinder lenses 59A and 59B is matched to the axis of a cylindrical lens of the body and reversed with the intermediate axis as the rotational axis, as with the precision determination of the cylinder axis, and the visions of both eyes are compared. If there is less flow in an image when the negative axis of the cross cylinder lenses 59A and 59B is matched to the axis of the cylindrical lens of the body, C-0.25D is added. In the meantime, if there is less flow in an image when the positive axis is matched to axis of the cylindrical lens of the body, C-0.25D is subtracted. In this way, visions in both sides are compared by reversal, and the weaker cylindrical lens power is determined as the final cylinder axis according to the principle that the cylindrical lens power when visions seem the same in both sides, or if there is a slight difference, the weakest negative power is selected. 10-2-2. Application example of an embodiment of the present invention The refractivity obtained by the objective refractive measurement shall set as Dθ, 1 (S1, C1, A1), the refractivity of the cross cylinder lens ±0.5D as Dθ, 2 (S2, C2, A2) and the synthetic refractivity of Dθ, 1 and Dθ, 2 as Dθ, 0 (S0, C0, A0). Since the negative axis or the positive axis Dθ, 2 is set o the cylinder axis A1 of Dθ, 1, and reversed with the intermediate axis as the rotational axis, there is a relation of A2=A1±90° between the axial angles A1 of Dθ, 1 and Dθ, 2 and A2 of the cross cylinder axis. Two ways of synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 are obtained. 10-2-3. Precision determination procedure of astigmatic dioptric power (1) Announcement is made, saying “Precision measurement of astigmatic dioptric power axis will be started. Two visions will be compared. If the first “1” is seen better, tilt the lever 6h to the left, while if the next “2” is seen better, tilt the lever 6h to the right. If the visions are the same, press the button 6g of the lever 6h.” (2) Precision determination of astigmatic dioptric power for the right eye a) The synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1+90° is set. Hereinafter, this state is referred to as (P+). b) The target illumination light source for the right eye is turned on, “Between how this “1” is seen and” is uttered, and (P+) is presented. c) The target illumination light source for the right eye is turned off, and the synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1 is set. Hereinafter, this state is referred to as (P−). d) The target illumination light source for the right eye is turned on, “how this “2” is seen, which is seen better?” is uttered, and (P−) is presented. e) (P+) is presented, a sequence that ““1” and” is uttered, (P−) is presented and ““2.” How about it?” is repeated. f) If the lever 6h is tilted to the left, {1: (P+)}, +0.25D is added to C1, while if tilted to the right, {2: (P−)} and −0.25D is added to C1. g) If the button 6g of the lever 6h is pressed, the angle at that time shall be the final astigmatic dioptric power. h) If the lever 6h is tilted to the right after the lever 6h is tilted to the left and +0.25D is added to C1, the astigmatic dioptric power at that time shall be the final astigmatic dioptric power. On the contrary, if the lever 6h is tilted to the left after the lever 6h is tilted to the right and −0.25D is added to C1, +0.25D is added to C1, and this value shall be the final astigmatic dioptric power. (3) Precision determination of astigmatic dioptric power for the right eye. a) The target illumination light source for the right eye is turned off. b) The synthetic refractivity Dθ, 0 (S0, C0, A0) of Dθ, 1 and Dθ, 2 when A2=A1+90° is set for the left eye. Hereinafter, this state is referred to as (P+). c) The target illumination light source for the left eye is turned on, “Between how this “1” is seen and” is uttered, and (P+) is presented. d) The same procedure as the steps in 10-2-3. (2) c) through h) are executed in the following. (4) The target illumination light source for the left eye is turned off. The illumination is turned off for both eyes. (5) Except the cross cylinder lens ±0.5D, A1 obtained by the precision determination procedure for the cylinder axis in 10-1-3 is set and C′1 obtained by the precision determination procedure for the astigmatic dioptric power in 10-2-2 is set for both eyes. (6)-0.50D added in the step (5) in 10-1-3 is subtracted. (7) The landscape chart 99 is presented to both eyes, and the target illumination light source for both eyes is turned on. 11. Binocular balance test (1) How the target is seen a) Right eye: A numeral target “9” with the upper side in the visual field of green and a numeral target “6” with the lower side in the visual field of red. b) Left eye: A numeral target “3” with the left side in the visual field of green and a numeral target “5” with the right side in the visual field of red. c) Both eyes: 4 numeral targets arranged in the form of a rhomboid in the green or red vision in the vertical and horizontal directions. (2) How to measure a) S, C and Avalues obtained by 9. CC test are set. b) The binocular balance chart is set respectively for the right eye and the left eye. c) Announcement is made, saying “Are the 4 numerals seen equally clearly? Or is there any difference in how they are seen?” d) Announcement is made, saying “If the 4 numerals are seen equally clearly, press the button 6g of the lever 6h. If there is any difference in how they are seen, tilt the lever 6h in the direction of the most clearly seen numeral.” e) After the lever 6h is tilted, announcement is made again, saying “Tilt the lever 6h in the direction of the second clearly seen numeral.” f) Processing is made following the list below according to the direction where the lever 6h is tilted in the steps d) and e). TABLE 1 Direction where the lever is Direction where the lever is tilted first time tilted next Action {circle over (1)} Down(Right Eye, Red Field) Right(Left Eye, Red Field) Binocular balance is good. Right(Left Eye, Red Field) Down(Right Eye, Red Field) Finished. {circle over (2)} Up(Right Eye, Green Field) Left(Left Eye, Green Field) Overcorrection for both eyes. Left(Left Eye, Green Field) Up(Right Eye, Green Field) S + 0.25 D is added to both eyes. {circle over (3)} Down(Right Eye, Red Field) Left(Left Eye, Green Field) Left eye is somewhat overcorrected. Left(Left Eye, Green Field) Down(Right Eye, Red Field) S + 0.25 D is added to the left eye. {circle over (4)} Up(Right Eye, Green Field) Right(Left Eye, Red Field) Right eye is somewhat overcorrected. Right(Left Eye, Red Field) Up(Right Eye, Green Field) S + 0.25 D is added to the right eye. g) Other than {circle over (1)} in the list in f), return to the step b) after correction of spherical dioptric power according to respective action. h) The sequence is repeated till the button 6g of the lever 6h is pressed in d) or {circle over (1)} in f) is reached. 12. Optometry by binocular balance test (1) Setting of S, C and Avalues a) The S, C and A values obtained by binocular balance test are set for both eyes. b) Announcement is made, saying “Dioptric power of spectacles recommended for you was obtained. Then, optometry will be made with this spectacle dioptric power.” (2) Optometry is carried out for the right eye, left eye and both eyes 13. Check of the Optometric Results 13-1. For those Wearing Spectacles (1) Announcement is made, saying “Vision with naked eyes, that with the present spectacles and that with the spectacles recommended for you will be shown.” (2) Every time, the measurement result shown to the customer is indicated by a white line or a white square on the display screen 64q′ of the monitor device 64q. (3) Announcement is made, saying “Vision with naked eyes will be shown.” (4) S and C values are set to 0D for both eyes, and the customer is made to gaze the landscape chart 99 for 3 seconds, for example. (5) Announcement is made, saying “Next, vision with the currently used spectacles will be shown.” (6) If dioptric power of the spectacles was measured, S, C and A values are set to the dioptric power measurement value of the spectacles, and the customer is made to gaze the target for 3 seconds, for example. (7) Announcement is made, saying “With the spectacles recommended for you this time, you can see like this.” (8) The S, C and A values (recommended refractivity) by the results of 11. Binocular balance test are set, and the customer is made to gaze the target for 3 seconds, for example. (9) Announcement is made, saying “With the spectacles recommended for you this time, you can see like this. If this vision which is generally easy to see and hard to be tired is OK, please press the button 6g of the lever 6h,” and it is presented for 4 seconds, for example. If the lever 6h is pushed during this 4-second period, the recommended refractivity is set as the selected refractivity and finished. (10) If the button 6g of the lever 6h is not pressed during the 4 seconds, announcement is made, saying “If you want to check how you can see with the currently used spectacles, please tilt the lever 6h to the right,” and it is presented for 4 seconds, and if the lever 6h is not operated for the 4 seconds, the recommended refractivity is set as the selected refractivity and finished. (11) If the lever 6h is tilted to the right during the 4 seconds, the dioptric power of the spectacles is set for both eyes, and announcement is made, saying “This is how you see with the currently used spectacles. If this is OK for you, please press the button 6g of the lever 6h,” it is presented for 4 seconds. If the button 6g of the lever 6h is pressed during this 4-second period, the dioptric power of the spectacles is set as the selected refractivity and finished. (12) If the button 6g of the lever 6h is not pressed during the 4 seconds, announcement is made, saying “If you want to check how you can see with the spectacles recommended fro you, please tilt the lever 6h to the left,” and it is presented for 4 seconds, and if the lever 6h is not operated for the 4 seconds, the recommended refractivity is set as the selected refractivity and finished. (13) At the same time as finish, the selected refractivity is set for both eyes. (14) Either of the “spectacles dioptric power” or “recommended refractivity” selected as the selected refractivity is shown in red characters of 19. Display of measurement results, which will be mentioned later. 13-2. For those who wear contact lenses and those who do not wear spectacles or contact lenses (1) Announcement is made, saying “How you can see with your naked eyes and with the spectacles recommended for you are shown.” (2) Every time, the measurement result shown to the customer is indicated by a white line or a white square on the display screen 64q′ of the monitor device 64q. (3) Announcement is made, saying “Vision with naked eyes will be shown.” (4) S and C values are set to 0D for both eyes, and the customer is made to gaze the landscape chart 99 for 3 seconds. (5) Announcement is made, saying “With the spectacles this time, you can see like this.” (6) The S, C and A values by the results of 11. Binocular balance test (hereinafter referred to as recommended refractivity) are set and the customer is made to gaze for 3 seconds. (7) The recommended refractivity is set as the selected refractivity and finished. (8) The “recommended refractivity” selected as the selected refractivity is shown in red characters by 18. Display of measurement results. 14. Cross heterophoria test FIG. 19 shows an example of a cross heterophoria test chart, in which FIG. 19(a) shows a target 71A of the cross heterophoria test chart for the left eye, FIG. 19B shows a target 71B of the cross heterophoria test chart for the right eye, and FIG. 19(c) shows how the targets 71A and 71B are seen by normal binocular visions. Table 2 shows how the heterophoria is seen. TABLE 2 How it is seen Heterophoria Prescription Orthotopic Estophoria BO (base-out) prism is added. Exophoria BI (base-in) prism is added. Left-eye hyperphoria BU (base-up) prism is added to the right eye. BD (base-down) prism is added to the left eye. Right-eye hyperphoria BD prism is added to the right eye. BU prism is added to the left eye (1) How to measure a) The cross heterophoria chart shown in FIG. 19 is set for both eyes. At this time, the LED 53A shown in FIGS. 5 and 7 are lighted, and a fusion frame 53F is shown respectively to both eyes. The reason will be explained below. There are heterophoria and heterotropia in ocular deviation. The heterophoria is an ocular deviation in which both eyes are oriented properly to an object to be gazed in a daily private life and binocular single vision is made all the time, but when one eye is covered, the line of vision is slightly deviated, while the heterotropia is an ocular deviation in which whether one eye is covered or not, the line of vision is deviation all the time, and the object to be gazed is diplopia all the time. When a person who has heterophoria, not heterotropia, gazes an object in the natural world, the object does not become diplopia but it is seen overlapped, which does not hinder daily life. However, if the optical system for the left eye and the optical system for the right eye are provided separately, and such an optical system is employed that a target for the left eye is presented to the left eye and the target for the right eye is presented to the right eye through each of the optical system, differently from watching objects in the natural world, when a person with heterophoria sees each of the targets with both eyes, when the target seen by the left eye is different from the target seen by the right eye, the target seen by the left eye might not match the target seen by the right eye. Also, even if the target presented to the left eye is the same as the target presented to the right eye, in the case of optometry with a one-letter target with a narrow visual field or near optometric test with further convergence, the target seen by the left eye can not be fused with the target seen by the right eye in some cases. Anyone can have more or less heterophoria, but normal binocular vision is made in the daily life. The cross heterophoria test in the form of the embodiment of the present invention presents a fusion frame in such a manner that a target presented to the left eye and the target presented to the right eye are surrounded, and its object is to extract examinees who can not fuse images even if there is a fusion frame, which brings about abnormality in daily binocular vision function. Also, in the case of optometry, a fusion frame is presented, and an examinee who does not have any trouble in daily life even if he/she has heterophoria can make binocular vision easily. b) Announcement is made, saying “Can you see the 4 lines? If so, please press the button 6g of the lever 6h. If you see only horizontal 2 lines, tilt the lever 6h to the right or left, and if you see only vertical 2 lines, tilt the lever 6h to the front or back.” c) If the lever 6h is tilted to the right or left, suppression is acting on the right eye, and if tilted to the front or back, the suppression is acting on the left eye, and the heterophoria test is not possible. “Heterophoria: Requires close examination” is memorized and the examination is finished. d) If the button 6g of the lever 6h is pressed, announcement is made, saying “Are the centers of the horizontal line and the vertical line overlapped? If overlapped, press the button 6g of the lever 6h. If the vertical line is on the right hand side, tilt the lever 6h to the right, and if on the left, tilt the lever 6h to the left.” e) If the button 6g is pressed, “Heterophoria: Normal” is memorized and the heterophoria test is finished. If the lever 6h is tilted to the right, BO prism is set for both eyes at the same time, while if tilted to the left, BI prism is set for both eyes at the same time. The minimum unit of prism conversion shall be 0.5 Δ. f) If the lever 6h is tilted to the right, announcement is made, saying “Tilt the lever 6h to the right or left till the vertical line matches the center position of the horizontal line, and when matched, press the button 6g of the lever 6h. g) Until the button 6g of the lever 6h is pressed, the number of times that the lever 6h is tilted to the right or left is counted. If the lever is tilted to the left after being tilted to the right, it makes 0 times on balance. The right is BO (esophoria), the left is BI (exophoria) and the number of times being tilted ×0.5 is a prism amount (Δ). h) For the horizontal heterophoria, “BO (or BI) Δ” is memorized. i) If the button 6g of the lever 6h is pressed, announcement is made, saying “Are the centers of the horizontal line and the vertical line overlapped? If overlapped, press the button 6g of the lever 6h. If the vertical line is on the upper side, tilt the lever 6h upward, and if on the lower side, tilt the lever 6h downward.” j) If the lever 6h is tilted upward, the right eye assumes BD prism and the left eye for BU prism, while if tilted downward, the right eye assumes the BU prism and the left eye for the BD prism. k) Announcement is made, saying “Till the vertical line matches the center of the horizontal line, tilt the lever 6h upward or downward, and when matched, press the button 6g of the lever 6h.” l) Until the button 6g of the lever 6h is pressed, the number of times that the lever 6h is tilted upward or downward is counted. If the lever is tilted downward after being tilted upward, it makes 0 times on balance. The up is the right-eye hyperphoria, the down is the left-eye hyperphoria and the number of times being tilted in each direction x0.5 is a prism amount (Δ). m) For the vertical heterophoria, “Right eye BD A” is memorized. Also, “Left eye BD Δ” is memorized. (2) The cross heterophoria test is finished, and the landscape chart 99 is presented. 15. Stereoscopic vision test (1) Chart FIG. 20 shows a test chart for stereoscopic vision, in which FIG. 20(a) shows a target 72A of the stereoscopic vision test chart for the left eye, FIG. 20(b) shows a target 72B of the stereoscopic vision test chart for the right eye, and FIG. 20(c) shows how the targets 72A and 72B are seen by both eyes with emmetropia. In this stereoscopic test chart, fusion stimulation 72C is provided at the center of the test chart for the left eye, and fusion stimulation 72D is provided at the center of the test chart for the right eye. The 4 straight lines of the target 72A and the target 72B have a staged stereoscopic parallax against the fusion stimulation 72C and the fusion stimulation 72D. For example, the stereoscopic parallax is 40″ on the right side, 1′ on the lower side, 2′ on the upper side and 4′ on the left side. (2) How to measure a) The stereoscopic chart shown in FIG. 20 is presented. b) Announcement is made, saying “Are the 4 straight lines seen like relief ? Tilt the lever 6h in the order from the highest relief. If they are not seen like relief, press the button 6g of the lever 6h.” c) If the button 6g of the lever 6h is pressed, “Stereoscopic: Requires close examination” is memorized and the test is finished. d) If the lever 6h is tilted in the order of “left,” “up,” “down” and “right,” “Stereoscopic: Normal” is memorized and the test is finished. e) If the order is wrong, steps b) through d) are repeated and if a correct answer can not be gained, “Stereoscopic: Requires close examination” is memorized and the test is finished. f) The landscape chart 99 is presented. 16. Binocular simultaneous objective refractive measurement for near targets (1) Convergence of the optometric apparatus body According to the PD distance, the optometric apparatus body is converted to a near setting distance d1 mm. A pitch angle of the optometric apparatus body (angle of convergence) 0 can be obtained from the following equation: θ=tan−1((PD/2)/d1) (2) Setting of near distance and angle of convergence a) The target illumination light source for both eyes is turned off. b) A subjective measurement result for the far targets is set for both eyes. Here, the subjective measurement result means “13. Selected refractivity selected at check of the optometric test results.” c) As a target, the landscape chart 99 or a target with the visual acuity value larger than the visual acuity value based on the S, C and Avalues of the subjective refractive measurement results (binocular balance) by 2 steps or 3 steps is presented to both eyes. In the case of a one letter target, a fusion frame is lighted. d) The right and the left optometric apparatus bodies are rotated around the cycloduction point of the right and left eyeballs to be examined by the angle of convergence θ against the set near distance d1 mm. e) The target light source for both eyes is lighted. (3) Auto-alignment is carried out for both eyes at the same time. (4) Announcement is made, saying “Please blink several times.” After 1 second, announcement is made, saying “Please keep your eyes wide open and do not blink for some time,” and “Tilt the lever 6h in the direction of the cut of the target.” (5) The response by the lever 6h and the direction of the cut in the target are determined, and if they match each other, go on to the next step. (6) Binocular simultaneous objective measurement is carried out 3 times, for example. (7) A difference between representative values of the S, C and A values of the measurement results of the objective measurement and the subjective refractive measurement value is outputted for display. (8) How to understand the measurement results. For example, if the binocular objective refractive measurement is carried out by setting the near distance d1 to 33 cm after the subjective refractive measurement for far targets, in the case of the eye to be examined with sufficient accommodation without accommodative functional disorder, the difference between the subjective refractive measurement value for the far target and the objective refractive measurement value measured by setting the near distance to 33 cm becomes 3D, regardless of abnormal refractivity of the examinee, and if the difference between the subjective refractive measurement value for the far target and the objective refractive measurement value by setting the near distance to 33 cm is 3D, it can be determined that the relation between accommodation and convergence is normal. The accommodation degrades with age, and the value of a normal examinee is well known. Accommodation according to age is obtained objectively for near distance and compared with average accommodation for the age and if it is remarkably degraded, accommodative functional disorder can be suspected in the clinical ophthalmology. Also, from the viewpoint of prescription of spectacles for near distance, if the difference between the subjective refractive measurement value for the far targets and the objective refractivity value when set to the near distance 33 cm is 3D, it can be determined that the examinee have sufficient accommodation for the near distance 33 cm. Spectacles for near distance are generally prescribed for examinees of 45 years old or above from the relation between accommodation and age, but by making binocular objective refractive measurement for near targets, whether spectacles for near distance are necessary or not can be objectively determined easily. Besides the above, this is effective for health management for VDT (video display terminal) workers. Here, the accommodative functional disorder means lack of accommodation despite the young age. Here, the position of a target is set to d1=33 cm from the position of a far distance while omitting the positions in the middle, but it is possible that the target is moved in steps from the position of a far distance toward the near distance d1 and stopped at the position after stepped movement and measurement operation (3) through (6) is carried out. If the simultaneous objective measurement is executed by setting the target at the position of the near distance d1 form the position of the far distance while omitting the positions in the middle, targets can not be seen sometimes, but if measurement is made by moving the targets in steps in this way, accommodation is changed gradually, and accurate measurement can be made without losing the targets. In the above, the difference between subjective refractive measurement value for the far target and the binocular objective refractive measurement target at a predetermined near distance is defined as accommodation, but the difference between the binocular objective refractive measurement value for the far targets and the binocular objective refractive measurement value at a predetermined near distance may be defined as accommodation. 17. Near distance test (1) Measurement of near distance dioptric power The test chart for near distance shown in FIG. 21 is used. Announcement is made, saying “Near distance test will be carried out. The near distance test will be explained.” (2) The near distance testing method is played with voice by movie. a) The near distance test chart is explained. b) Demonstration of “similarly clearly seen” and “the horizontal line is clear, but the vertical line is blurred,” are played. c) Explanation of lever operation is played by movie. (3) Setting of angle of convergence a) The target illumination light source for both eyes is turned off. b) The target shall be the near distance test chart shown in FIG. 21. c) S and C are converted to the state where a cross cylinder of ±0.5D is added. The conversion formula is a publicly known formula. d) While converging to the pitch angle 0 for the near distance d1 mm obtained in (1) convergence of the body, a near distance test initial value As according to the age obtained from the following formula is added to both eyes. General formula of accommodation Ac for an age x Under 55 years old: Ac=12.5−0.2× 55 years old and above: Ac=7.0−0.1× Addition power Ad1 for the near distance d1 mm Ad1=(1000/d1)−(Ac)×(1/2) A near distance test initial value As according to the age is added. As=−{(1000/d1)−Ad1}=−(Ac)×(1/2) A calculation example of the near distance test initial value As according to the age is shown in Table 3 below. TABLE 3 Calculation example of near distance test initial value As according to age Age x Accommodation Ac Initial value As 40 4.5 −2.25 42 4.1 −2.05 45 3.5 −1.75 48 2.9 −1.45 50 2.5 −1.25 52 2.1 −1.05 55 1.5 −0.75 60 1.0 −0.50 65 0.5 −0.25 e) The target light source for both eyes is lighted. (4) Announcement is made, saying “Near distance test will be made. Please hold the lever 6h and look into the optometric tester.” (5) Auto-alignment is executed for both eyes at the same time. (6) Announcement is made, saying “Are the vertical line and the horizontal line seen equally thick? If they are seen equally thick, press the button 6g of the lever 6h. If the horizontal line is seen thick and the vertical line is seen thin, tilt the lever 6h to the right or left, and if the vertical line is seen thick and the horizontal line is seen thin, tilt the lever 6h to the front or back.” a) If the button 6g of the lever 6h is pressed at the first presentation (the horizontal line is seen as thick as the horizontal line.), a value obtained by adding (1000/d1) to Table 3. “Near distance test initial value As according to age” obtained in (4) d) shall be an addition power. b) If the lever 6h is tilted to the left or right at the first presentation (the horizontal line is seen thick, and the vertical line is seen thin.), a spherical dioptric power +0.25D is added to both eyes at the same time. c) Announcement is made, saying “Are the vertical line and the horizontal line seen equally thick? If they are seen equally thick, press the button 6g of the lever 6h. If the horizontal line is seen thick and the vertical line is seen thin, tilt the lever 6h to the left or right, and if the vertical line is seen thick and the horizontal line is seen thin, tilt the lever 6h to the front or back.” d) If the lever 6h is tilted to the left or right (the horizontal line is seen thick and the vertical line is seen thin.), a spherical dioptric power+0.25D is added to both eyes at the same time. e) Announcement is made, saying “How about it?” f) Until the button 6g of the lever 6h is pressed or the lever 6h is tilted to the front or back, the steps e) and f) are repeated. g) When the button 6g is pressed or the lever 6h is tilted to the front or back, the sum of a value obtained by adding (1000/d1) to the value in Table 3 and a spherical dioptric power added till the button 6g of the lever 6h is pressed (the number of times that the button 6g of the lever 6h is pressed is counted) or tilted to the front or back (the number of times that the lever is tilted to the front or back is not counted) shall be the addition power, announcement is made, saying “Your near distance addition power is . . . D.” and the near distance test is finished. h) If the lever 6h is tilted to the front or back at the first presentation (the vertical line is seen thick and the horizontal line is seen thin), a spherical dioptric power of −0.25D is added to both eyes at the same time. i) Announcement is made, saying “Are the vertical line and the horizontal line seen equally thick? If they are seen equally thick, press the button 6g of the lever 6h. If the horizontal line is seen thick and the vertical line is seen thin, tilt the lever 6h to the left or right, and if the vertical line is seen thick and the horizontal line is seen thin, tilt the lever 6h to the front or back.” j) If the lever 6h is tilted to the front or back (the vertical line is seen thick and the horizontal line is seen thin.), a spherical dioptric power −0.25D is added to both eyes at the same time. k) Announcement is made, saying “How about it?” l) Until the button 6g of the lever 6h is pressed or the lever 6h is tilted to the right or left, the steps k) and 1) are repeated. m) When the button 6g is pressed or the lever 6h is tilted to the right or left, the sum of a value obtained by adding (1000/d1) to the value in Table 3 and a spherical dioptric power added till the button 6g of the lever 6h is pressed (the number of times that the button 6g of the lever 6h is pressed is counted) or tilted to the right or left (the number of times that the lever is tilted to the right or left is counted) shall be the addition power, announcement is made, saying “Your distance addition power is . . . D.” and the near distance test is finished. n) The landscape chart 99 is presented to both eyes. o) The near distance addition power is memorized. p) S, C and A are converted to the state where ±0.5D cross cylinder lens is subtracted for both eyes. 18. Visual acuity for near distance test (1) Only when the near distance test has been carried out. (2) Auto-alignment is carried out for both eyes at the same time. (3) Near visual acuity test for both eyes. a) Announcement is made, saying “Near visual acuity test for both eyes is carried out.” b) The Landolt ring target 0.5 shown in FIG. 22 is set for both eyes. The fusion frame 53F is also presented at the same time. c) Announcement is made, saying “Tilt the lever 6h in the direction of the cut of the target.” d) The customer tilts the lever 6h in the direction of the cut of the Landolt ring. e) It is determined if the presented target matches the direction in which the lever 6h is tilted. f) After determining the direction of the cut in the Landolt ring and the direction in which the lever 6h is tilted, the target of the next step is presented to both eyes at the same time. g) Then, the steps of 5. Optometry when spectacles are worn (4) a) through (5) g) are followed. h) The visual acuity value is memorized. i) The landscape chart 99 is presented to both eyes. 19. An example of display of measurement results is shown in FIG. 29. 20. Measurement finished. (1) With announcement saying “All the optometry has been finished,” it is displayed in characters on the display screen 64q′. (2) Then, announcement is made, saying “Remove your face from the apparatus and look at the monitor device 64q. The measurement results are displayed on the monitor device 64q′.” (3) The apparatus is set to be initialized. a) PD shall be 66 mm. The target shall be the landscape chart 99 for both eyes. b) The body shall be brought into the sleep state. (Variation 1) FIG. 25 is an explanatory diagram showing a variation of an optometric apparatus according to the present invention, and 100 refers to the optotypes examining device. This optotype examining device 100 has an enclosure 101 shown in FIG. 26, and the inside of this enclosure 101 is a camera obscura. In this enclosure 101, a target illumination optical system 102 and a concave mirror 103 are provided. In the target illumination optical system 102, a light source 104, a condenser lens 105, a diffusing plate 106, a target 107 and a polarizing plate 108 are provided. The diffusing plate 106 is used to soften illumination light, and the target 107 is illuminated through the diffusing plate 106. As the target 107, each of the above-mentioned targets is used. Into the target illumination optical system 102, the target 107 is selected and inserted. The polarizing plate 108 is provided in the neighborhood of the target 107. This polarizing plate 108 is inserted into the optical path of the target illumination optical system 102 at a binocular vision functional test. Between the concave mirror 103 and the target illumination optical system 102, a semitransparent mirror 109 is arranged at an angle of 45 degrees to an optical axis O′ of the illumination optical system 102. This semitransparent mirror 109 is formed by placing a dielectric film onto a parallel plane glass plate. The target is transmitted through the semitransparent mirror 109 as shown by a symbol P1′ and projected onto the concave mirror 103, reflected by this concave mirror 103 and oriented toward the semitransparent mirror 109 again as shown by a symbol P2′, and by this semitransparent mirror 109, as shown by a symbol P3′, projected in the direction where the right and the left mirrors P′ exist, and through this mirror P′, an image of the target is presented to the left eye and the right eye. When binocular vision functional test is to be carried out, an examinee visually checks an image 107′ by wearing polarized spectacles 110 shown in FIG. 27. A polarized lens 110a of the polarized spectacles 110 has a polarization axis 111 with the right 45 degrees, while the other polarized lens 110b has a polarization axis 112 of the left 45 degrees. Thus, as shown in FIG. 28, a polarization axis 113 of a half 108a corresponding to the polarized lens 110a of the polarizing plate 108 is designed with the right 45 degrees, a polarization axis 114 of 108b corresponding to the polarized lens 110b of the polarizing plate 108 is set to the right 45 degrees, an image of one of the targets can be seen by the left eye, and an image 107′ of the target 107 can be seen by the right eye. The constitution of this optotypes device 100 is disclosed in the Japanese Patent Application No. 5-204402, for example. Variation 2) FIG. 31 is an explanatory diagram of a variation 2 of the optometric apparatus according to the present invention, in which an outline block diagram of the optical system for the right eye of the body portion 5r is shown, and FIG. 32 shows detailed constitution of the optical system for the right eye. In this FIG. 31, 120 shows an optical system for the right eye of the body portion 5r. Since the constitution of an optical system for the left eye of the body portion 5l is the same as the optical system for the right eye, its explanation is omitted, and only the optical system 120 for the right eye will be described. The optical system 120 for the right eye has, as shown in FIG. 31, a target projection optical system g′ for distance matching between the eye E to be examined and the body portion 5r and a ring-pattern projection optical system f′ for projecting a plurality of ring patterns toward the cornea of the eye E to be examined. This target projection optical system g′ consists of, as shown in FIG. 31, LED 121 and 122 and projecting lenses 123 and 124. A target light flux from the LED 121 and 122 of the target projection optical system g′ is projected from two diagonal directions onto the cornea of the eye E to be examined through a mirror 125. The ring-pattern projection optical system f′ consists of, as shown in detail in FIG. 32, a ring-state illumination light source 127 and a ring pattern 126, and a concentric circular ring pattern image is projected similarly to the cornea of the eye E to be examined through the mirror 125. The ring-pattern projection optical system f′ is also used as an anterior ocular segment illumination light source. The optical system 120 for the right eye is provided with a light-receiving optical system a′ for observation of the anterior ocular segment and alignment of the body portion 5r for the eye to be examined as well as measurement of corneal radius of curvature distribution, a target projection optical system b′ for measurement of refractivity which projects a target for measuring the refractivity of the eye E to be examined to the fundus oculi Ef, a light-receiving optical system c′ for receiving reflected light flux from the fundus oculi Ef, a target projection optical system d′ for projecting a target for fixation and fogging vision of the eye E to be examined and a target projection optical system e′ for projecting a target for alignment in the direction crossing the optical axis of the eye E to be examined and the objective lens 38 of the body portion 5r, that is, in the up-and-down and the right-and-left directions. The target projection optical system e′ is composed of a target LED 128 and a dichroic mirror 129. The target light flux from the target LED 128 is reflected by the dichroic mirror 129, transmitted through the dichroic mirror 130 and projected to the cornea of the eye E to be examined through the objective lens 38 and the mirror 125. The light-receiving optical system a′ has the objective lens 38, a dichroic mirror 130, a diaphragm 131, relay lenses 132 and 133, a dichroic mirror 134, an imaging lens 135 and an image pickup element 136. The diaphragm 131 is disposed at a focus position of the objective lens 38 and used as so-called telecentric diaphragm. A ray of light passing through the center of this diaphragm 131 is in parallel with the optical axis of the objective lens 38 on the eye to be examined. Reflected light from the cornea by the target light flux from the target projection optical system e′, diffused and reflected light from the cornea and the anterior ocular segment by the ring pattern 127 of the ring-pattern projection optical system f′ and reflected light from the cornea by the target light flux from the target projection optical system g′ are received by the image pickup element 136 through each optical element of the light-receiving optical system a′. The image receiving output of the image pickup element 136 is inputted to the monitor device 137. The target projection optical system d′ is provided with a lamp 138, a collimator lens 139, a rotating plate 140, a mirror 141, a relay lens 142, a mirror 143, a moving lens 144 for adjusting visibility of the eye to be examined, relay lenses 145 and 146, variable cross cylinders 147 and 148 for correction of astigmatism, a mirror 149 and a dichroic mirror 150. The rotating plate 140 is rotated and driven by a motor 151, and a fixation marker, a Landolt ring, etc. are provided on the rotating plate 140. The fixation marker 152 is projected to the eye E to be examined through the mirror 141, the relay lens 142, the mirror 143, the moving lens 144, the relay lenses 145 and 146, the variable cross cylinders 147 and 148, the dichroic mirrors 150 and 130, the objective lens 38 and the mirror 125. By this, the eye E to be examined is fixed to the fixation marker 152, and the examiner carries out the anterior ocular segment observation of the eye E to be examined and alignment of the body portion 5r while watching the monitor device 137. In the state where the alignment is completed, curvature distribution of the cornea is measured first. Since a ring pattern projected image of the ring pattern 126 formed on the cornea is imaged on the image pickup element 136 and a reflected luminescent spot image of the target light flux by the LED 128 is projected, by obtaining a distance to each of the ring images with this luminescent spot image as a reference on the image pickup element 136, the curvature distribution of the cornea can be obtained. It is also possible to obtain the corneal curvature distribution by calculating the distance from the center of a ring image with the smallest diameter of the concentric ring pattern images to each of the ring images. The target projection optical system b′ for measuring refractivity is comprised of a light source 153 for measuring ocular refractivity, a relay lens 154, a conical prism 155, a measurement ring target 156, a relay lens 157, a pupil ring diaphragm 158 and a triangular prism 159. The pupil ring diaphragm 158 is a ring-state diaphragm formed by etching on the lens. The pupil ring diaphragm 158 is disposed at a conjugation position with the pupil of the eye E to be examined. When measurement of the corneal curvature distribution is finished, the light source 153 for measuring ocular refractivity is lighted and led to the relay lens 154, the conical prism 155, the measurement ring target 156, the relay lens 157, the pupil ring diaphragm 158 and the triangular prism 159, reflected by this triangular prism 159, the dichroic mirrors 150 and 130, led to the objective lens 38, transmitted through this objective lens 38, reflected by the mirror 125 and led to the pupil of the eye E to be examined. Since the pupil ring diaphragm 158 is conjugated with the pupil, the light flux emitted from the light source 153 for measuring ocular refractivity becomes a ring-state light flux on the pupil and projected to the fundus ocuh Ef as a measurement light flux. The measurement light flux reflected by the findus oculi Ef of the eye E to be examined is led to the light-receiving optical system c′ through the mirror 125, the objective lens 38, the dichroic mirrors 130 and 150 and the triangular prism 159. The light-receiving optical system c′ has a triangular prism 159, a mirror 160, a relay lens 161, a moving lens 162 and a mirror 163. The moving lens 162 is moved corresponding to the refractivity of the eye E to be examined. The measurement light flux reflected by the fundus oculi Ef is transmitted through a center part 159a of the triangular prism 159, reflected by the mirror 160 and imaged on the image pickup element 136 through the relay lens 161, the moving lens 162, the mirror 163, the dichroic mirror 134 and the imaging lens 135. A reflecting surface 159b and a surface 159c on the opposite side of the triangular prism 159 are provided at a conjugation position with the pupil, and etching is given so that the reflection light flux from the findus oculi Ef emitted from the pupil passes only the central optical axis portion of the triangular prism 159. The measurement light flux reflected by the findus oculi Ef is changed in the shape according to the refractivity of the eye E to be examined and imaged on the image pickup element 136. The refractivity of the eye E to be examined is obtained from the shape. Here, in order to improve measurement accuracy of the refractivity, a measurement light source unit 164, a moving lens 162 and the moving lens 144 are moved. This movement of the measurement light source unit 164 and the moving lens 162 is to bring the shape of the measurement reflected light flux from the findus oculi on the image pickup element 136 closer to the standard size. That is because the measurement accuracy is deteriorated if the image of the measurement reflected light flux formed on the image pickup element 136 is too small or too large. The measurement light source unit 164 is comprised of the light source 153 for measuring ocular refractivity, the relay lens 154, the conical prism 155 and the measurement ring target 156. If this constitution is to be used, first, at the first measurement, the rough refractivity of the eye E to be examined is calculated and converted to a movement amount, the measurement light source unit 164 and the moving lens 162 are moved and measurement is made again. And at the second measurement, the value of ocular refractivity calculated based on the image of measurement reflected light flux formed on the image pickup element 136 and the refractivity obtained by the movement amount are added together to obtain the refractivity of the eye to be examined. When this measurement of the objective refractivity for the eye to be examined is finished, a subjective optometry will be carried out. The variable cross cylinders 147 and 148 are rotated around the optical axis according to the value of the refractivity, the moving lens 144 is moved along the optical axis, the rotating plate 152 is rotated, fixation markers required for subjective optometry, Landolt rings, for example, are set, the lamp 138 is lighted, and the fixation marker is presented to the eye E to be examined. And the subjective optometry is carried out. An example of the subjective examination is as previously explained. And when the subjective examination to obtain far dioptric power is finished, an examination to obtain near dioptric power is carried out. As shown in FIG. 31, the body portions 5l and 5r are rotated around the center of cycloduction Eg of the eye E to be examined. The center of cycloduction Eg is, for example, a point on the side of the findus oculi by about 12 mm from the top of the cornea. Also, the fixation markers of the right and the left optical systems are set to the Landolt rings for measuring near dioptric power, and the variable cross cylinders 147 and 148 and the moving lens 144 are set so that they are the far dioptric power of the eye E to be examined. Next, the moving lens 144 is moved to a position of, for example, the far dioptric power +(−1D), the body portions 5r and 51 are rotated around the center of cycloduction Eg so that the visual axes of both eyes accord to each other at the position of the far dioptric power +(−1D) and moved in the horizontal direction. Then, the lamp 138 is lighted, and the fixation marker is projected to the fundus oculi Ef of the right and the left eyes at the same time. By this, both of the eyes E to be examined are brought into the state the projected target is gazed. At this time, in the same way as the objective measurement of far dioptric power, the light source 153 for measuring ocular refractivity is lighted so as to obtain the refractivity of both eyes E to be examined. When the eye E to be examined is correctly adjusted, a value with +(−1D) of the far dioptric power of the eye E to be examined should be obtained. That is because the set value of the far dioptric power +(−1D) is made to be gazed. When the value of +(−1D) is obtained, the moving lens 144 is set to the position of +(−2D), and the body portions 5r and 51 are rotated around the center of cycloduction Eg so that the visual axes of both eyes accord to each other at the position of the far dioptric power +(−2D) and also moved in the horizontal direction. Next, the lamp 138 is lighted, and the both eyes E to be examined are made to gaze the projection target. And the refractivity of the both eyes E to be examined is obtained. If there is a difference between a value added to the far dioptric power and a measured value and the measured value is larger than the value obtained by addition, it is assumed that accommodation was not proper, and the near dioptric power is used as a value measured immediately before. That is, as shown in the flowchart in FIG. 33, the far dioptric power is measured (S. 1), a predetermined value a is added to the far dioptric power (S. 2), the body portions 5r and 51 are moved (S. 3), the target is presented (S. 4), the objective measurement is executed (S. 5), and if the difference between the measured value obtained by objective measurement and the set value is less than 0, the measurement is repeated in steps (S. 6), and the measurement is stopped when the difference becomes larger than 0 so as to determine the near dioptric power (S. 7). The value of near dioptric power is, where the number of repeated steps is N: Near dioptric power=Far dioptric power+α×(N−1)−Near position For example, when α is (−1D), the near position is −3D, the far diptric power is 0D and the number of repeated steps is N=2, Near dioptric power=Far dioptric power+α×(N−1)−Near position=0+(−1)×1−(−3)=2 Therefore, according to this variation 2, the near dioptric power can be objectively measured for both eyes quantitatively and at the same time, not depending on the eye to be examined. Also, based on a response of the direction of the cut in the presented Landolt ring by tilting the lever 6h, it can be checked whether the eye E to be examined gazes the Landolt ring or not. Also, if the objective measurement is carried out when the direction of the cut of the Landolt ring matches the direction where the lever 6h is tilted, the objective measurement can be made when the examinee is gazing, and measurement accuracy is improved. Also, when the objective measurement is made several times and its average value is obtained, by presenting different Landolt rings such as Landolt rings with cuts in the different directions are presented to an examinee at every measurement, the accommodation state of the eye to be examined is maintained, and measurement accuracy is further improved. INDUSTRIAL APPLICABILITY According to the invention in claims 1 and 2, the examinee himself/herself can carry out optometry for both eyes at the same time. According to the invention in claim 3, the success probability of auto-alignment for both eyes of the examinee for the optometric apparatus body can be improved. According to the invention in claim 4, without hindering operation of the optometric apparatus by the examinee, an optometric assistant can check the operating state and give appropriate advice, which is convenient. According to the invention in claim 5, without detailed explanation by optometrists or optometric assistants, the examinee can obtain how to operate the optometric apparatus. According to the invention in claim 6, since comparison can be made between previous vision and the current vision, judgment can be made easily on whether new spectacles are required or not. According to the invention in claims 7 through 11, the success probability of auto-alignment in a short time can be improved. According to the invention in claim 12, without using a polarizing plate or polarized spectacles, binocular vision is enabled. According to the invention in claim 13, accurate measurement is possible for examinees who have heterophoria but have no trouble in daily life. According to the invention in claim 14, optometry using publicly known optotypes examining device can be made. According to the invention in claims 16 and 17, relation between accommodation and convergence can be easily measured. Especially, it has an effect that the near refractivity of an examinee can be measured quantitatively for both eyes at the same time without relying on response of the examinee.

<SOH> BACKGROUND ART <EOH>There is known an optometric apparatus constituted so that ocular refractivity of the right and left eyes of an examinee can be measured at the same time subjectively and objectively (See Japanese Patent Laid-Open No. 2000-83900). This conventional optometric apparatus is so constituted that the examinee takes optometry following instructions of an optometrist. However, optometric measurement of the examinee by the optometrist is not favorable in view of efficient management and cost reduction. Also, recently, in the case of accommodative functional disorder such as near-vision disorder, asthenopia, sense of blear, etc. or in the case that abnormality of convergence and accommodation systems are suspected, when carrying out prescription of spectacles for reading or health management of VDT (video display terminal) workers and so on, accommodative functions such as accommodative near point, accommodative ability and accommodative dynamics are measured. For measurement of accommodative functions, subjective methods such as Ishihara's near point meter and accommodo-poly-recorder and objective methods such as infrared optometer and front-open type infrared optometer are used. For measurement of subjective accommodative near point, 0.6 Landolt-ring targets and bar targets on near-distance optotypes are usually made to approach from the distance where an examinee can see the clearest at a constant rate of a target moving speed of 2.5 cm/sec to 5 cm/sec, and the distance where occurrence of even a slight blur is sensed is recorded as a near point. The infrared optometer of the objective method has renovated a normal autorefractometer, in which an ocular refractive state of horizontal meridians when a target is moved at a constant speed is continuously measured so as to record dynamic characteristics of accommodation. The front-open type optometer records accommodation change of both eyes by moving a real space in front of the eyes with the target as an external target in the state close to natural vision. However, in the subjective measurement of accommodative near point, after an examinee has learned blur of targets and subjective sensing standard of clear vision by practice, a distance where blur is sensed when a target is moved from a long distance to a short distance (disappearance threshold) and a distance where clear vision is enabled when the target is moved from the short distance to the long distance on the contrary (appearance threshold) are measured 3 times, respectively, and an average value of the both is set as a near point. The measurement depends on subjective response and is subject to large fluctuation due to instability in subjective sensing standard between blur and clear visions of targets and uncertainty in target following motion and response of the examinee, which is particularly unsuitable for measurement of infants. The measurement by the infrared optometer is carried out with one eye shielded and a target moved on the optical axis of one eye as accommodation stimulation, and it is different from daily relations between convergence and accommodation. Accommodation and convergence are increased/decreased together in the daily life and in an unseparable relation with each other. Accommodation measurement with one eye shielded has a problem that accurate measurement of accommodative near point and accommodative ability is not possible. With the measurement by the front-open type infrared optometer, external targets are utilized to present targets in the state closer to the natural vision, but it has a problem that a range of target movement is restricted and accommodative near point including far point can not be measured. The present invention has been made in view of the above circumstances and its object is to provide an optometric apparatus which enables optometric measurement by an examinee himself/herself or an optometric assistant with less experience. Also, an object of the present invention is to provide an optometric apparatus which presents targets to both eyes while maintaining the relation between accommodation and convergence, capable of measurement of accommodative functions in a wide target moving range, maintains the relation between accommodation stimulation and convergence constant, capable of easy measurement of accommodation regardless of refraction error of an examinee, and is suitable for diagnosis of cases such as near-vision disorder, asthenopia, blear, etc. and suspected abnormality in convergence and accommodation systems in the clinical ophthalmology as well as judgment when carrying out prescription of spectacles for reading and health management of VDT (video display terminal) workers, especially an optometric apparatus which can easily measure the relation between accommodation and convergence.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is an explanatory view showing an outline of an optometric apparatus according to the present invention. FIG. 2 is an appearance drawing of the optometric apparatus shown in FIG. 1 . FIG. 3 is a view showing an optical system of the optometric apparatus shown in FIG. 1 . FIG. 4 is a view showing the optical system for the left eye shown in FIG. 3 in the enlarged manner. FIG. 5 is a plan view of the optical system for the left eye shown in FIG. 4 . FIG. 6 is a view showing the optical system for the right eye shown in FIG. 3 in the enlarged manner. FIG. 7 is a plan view of the optical system for the right eye shown in FIG. 6 . FIG. 8 is a block diagram of a control system of the optometric apparatus according to the present invention. FIG. 9 is a view showing a connection form between the optometric apparatus and a lens meter, in which (a) is an explanatory view showing the state where the lens meter is disposed in the neighborhood of the optometric apparatus and connected to a monitor device through an RS232C cable, (b) is a view showing the state where the lens meter is disposed far from the optometric apparatus and the lens meter and the optometric apparatus are connected to the monitor device through the RS232C cable, and (c) is a view showing the state where a plurality of the optometric apparatuses and the monitor devices are arranged and the lens meter is connected to the monitor device through LAN. FIG. 10 is an appearance view of the lens meter shown in FIG. 9 . FIG. 11 is a flowchart showing an example of optometric procedures of the optometric apparatus according to the present invention, in which (a) is a flowchart for those who have not worn spectacle glasses or contact lenses, (b) is a flowchart for those who wear spectacle glasses, and (c) is a flowchart for those who wear contact lenses. FIG. 12 is a view showing a landscape chart to be displayed on a liquid crystal display of the optical system shown in FIGS. 5 and 7 . FIG. 13 is an explanatory view of an anterior ocular segment image displayed on a display screen of the liquid crystal display shown in FIG. 2 , in which (a) is a view showing an anterior ocular segment image displayed on the display screen for the left eye and (b) is a view showing an anterior ocular segment image displayed on the display screen for the right eye. FIG. 14 is an explanatory view showing an example of auto-alignment, in which (a) shows the state where alignment is not gained, (b) shows the state where alignment is being gained and (c) shows the state where alignment is gained. FIG. 15 is an explanatory view showing another example of auto-alignment, in which (a) shows the state where alignment is not gained, (b) shows the state where alignment is gained for the left eye, (c) shows the relation between the body portion and the eye to be examined when gaining alignment for the right eye using the data when the alignment is gained for the left eye and (d) shows the state where alignment is gained for both eyes. FIG. 16 is a view showing an example of a red and green chart, in which (a) shows the red and green chart for the left eye, (b) shows the red and green chart for the right eye and (c) shows how a target is seen when the right and the left red and green charts are seen with both eyes with emmetropia. FIG. 17 is a view showing an example of an astigmatic chart. FIG. 18 is a view showing an example of a cross-cylinder chart. FIG. 19 is a view showing an example of cross heterophoria chart, in which (a) shows the cross heterophoria chart for the left eye, (b) shows the cross heterophoria chart for the right eye and (c) shows how a target is seen when both cross heterophoria charts are seen with emmetropic both eyes. FIG. 20 is a view showing an example of a stereoscopic vision chart, in which (a) shows the stereoscopic vision chart for the left eye, (b) shows the stereoscopic vision chart for the right eye, (c) shows how a target is seen when the stereoscopic vision chart is seen by emmetropic both eyes and (d) shows the state where a fusion frame is presented. FIG. 21 is a view showing an example of a near chart. FIG. 22 is a view showing an example of a Landolt ring. FIG. 23 is a perspective view showing an example of a cross cylinder lens. FIG. 24 is a view showing an example of a fusion frame chart. FIG. 25 is a view showing a variation of the optometric apparatus of the present invention and explanatory view with an optotypes device provided behind the optometric apparatus. FIG. 26 is an explanatory view showing an internal constitution of the optotypes examining device. FIG. 27 is a perspective view showing an example of polarized glasses. FIG. 28 is an explanatory view of a polarization axis of a polarization plate. FIG. 29 is a view showing an example of display of a measurement result. FIG. 30 is a perspective view showing an example of a rotary prism. FIG. 31 is a block diagram showing an outline constitution of the optical system of a variation 2 of the optometric apparatus according to the present invention. FIG. 32 is a view showing a detailed constitution of the optical system for the right eye shown in FIG. 31 . FIG. 33 is a flowchart for explaining action of the variation 2 of the optometric apparatus of the present invention. detailed-description description="Detailed Description" end="lead"?

20040513

20071002

20050127

60498.0

HASAN, MOHAMMED A

OPTOMETRIC DEVICE

UNDISCOUNTED

ACCEPTED

ACCEPTED

System and method for generating policies for a communication network

According to a broad aspect of a preferred embodiment of the invention, a network optimization method is provided. First, a set of input parameters describing a network and the users accessing it is analyzed. Input parameters may include such network-related information as network element inventory and topography, bandwidth capacity, routing information, etc. Customer-related inputs may include contact revenue, cost of service, non-performance penalties, and pattern-based customer importance profile and customer relationship management. Other inputs may include additional complex network and customer related business rules. Demands are estimated (530), graphed (530), and then the graph is pruned (580).

1. A method of adjusting one or more policies on a communication network comprising; ranking a set of network users for a given interval of time based on each user's score graph and producing a set of network policies correlated to the ranking. 2. The method according to clam 1, wherein the produced network policies provide a user a level of access to the network in substantial positive relation to the user's ranking. 3. The method according to claim 2, further comprising producing a symbolic network representation. 4. The method according to claim 3, further comprising pruning the symbolic network representation. 5. The method according to claim 4, further comprising clustering elements of the symbolic network representation. 6. The method according to claim 5, further comprising determining an optimization problem based on the symbolic network representation. 7. The method according to claim 5, further comprising determining a set semi-independent optimization sub-problems. 8. The method according to claim 6, wherein the optimization problem is evaluated by a set of algorithms. 9. The method according to claim 8, wherein an algorithm produces a possible solution for the optimization problem conforming to a set of business or operational constraints. 10. The method according to claim 9, further comprising selecting a solution provided by one of the algorithms. 11. The method according to claim 10, further comprising comparing each of a set of contract articles against a selected solution to determine whether each contract article may be fulfilled by the given solution.

FIELD OF THE INVENTION The present invention relates to the field of communication. More specifically, the present invention relates to the field of adjusting communication networks to improve the operation of the network. BACKGROUND OF INVENTION A communication network accessed and used by multiple users or customers may include a huge number of communication and computing devices (e.g. computers, routers, switches, etc . . . ) also referred to as network elements. Each device or network element may support different operations and may follow different policies. At any given moment, large numbers of users may attempt to access the network and may cause vast amounts of communication traffic to traverse the network. In some cases, the amount of data traffic attempting to pass through a network element may exceed the maximum capacity of that network element, and a condition known as a bottleneck may result. In a network operated by a network operator for access by a group of customers, each customer may have different and complex needs, which needs may be stated in a contract (e.g. Service Level Agreement (“SLA”)) with the network operator. An SLA between a customer and a network operator may contain provisions guaranteeing minimum Quality of Service (“QOS”) for the given customer and for one or more given applications of the specific customer. QOS is defined, in part, by the ability of a network to carry data traffic that complies with cervix minimal resources and service requirements (e.g., bandwidth, delay, jitter, etc.). A user's QOS may be guaranteed within their SLA with the network operator, and certain SLAs may impose penalties on a network operator if a customer's QOS fans below a threshold level. Many techniques and methodologies are known for establishing and maintaining QOS levels across a network and within specific network elements or devices. Methods including Weighted Fair Queuing (WFQ), Differentiated Services (Diffserv), Multiprotocol Label Switching (MPLS), Resource Reservation Protocol (RSVP), and others are used to define network policies which attempt to avoid network congestion or bottlenecks. However, when a communication network experiences a surge in traffics or a reduction in the network capacities (e.g., caused by faults), fixed network policies may not be able to compensate for this surge or reduction of capacities, and certain network elements may become congested. Operating at or above capacity along certain data paths, the network may experience bottlenecks and an overall QOS degradation for one or a group of its users. One method of preventing a user's QOS from falling below a predefined level due to congestion caused by data traffic of a new user is to limit or deny access to the network to new users or new applications. This method involving denial of service requires either that s a new user or new application be denied a request for access, or that a session of a user or application currently using the network be terminated. In this manner, the total number of users or applications using the network may be kept to a number sufficiently low such that the QOS of the majority of existing communication sessions is not degraded. However, refusal of service may translate into lost revenues and in other instances may mean the loss of highly valued customers. In order to avoid the above-mentioned conditions and commercial results, extensive work has been done to optimize the throughput and QOS compliance of communication networks. Traditionally, however, optimization has emphasized physical network design, selection and topology of network elements (e.g. which components are needed and how to connect them) and routing architecture. Some methods of the prior art use a combination of admission control and dynamic routing to optimize a network. Some methods of the prior art have attempted to optimize a network with respect to revenues or profits related to the operation of the network. These methods, however, all use simplistic revenue models which do not take into consideration factors such as customer usage over time, customer payment patterns, customer value to the operator, etc. Network optimization methods of the prior art are thus lacking in many respects. SUMMARY OF THE INVENTION The present invention is a system and method for adjusting policies in a communication network. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that the network's profitability is improved. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that other parameters in the network are improved (e.g. average QOS for all customers). As part of the present invention, a symbolic network representation (e.g. a node graph) may be formed. The symbolic network representation may be formed by abstracting and pruning an actual representation of the network. As part of the abstracting step, network elements, resources, applications, and users may be clustered based on a predefined set of rules. Pruning may be accomplished by removing those elements of the symbolic representation which would not limit the performance of the overall network under foreseeable conditions. As a further part of the present invention a symbolic representation of a network to be adjusted may be converted into one or a set of optimization problems. In some embodiments of the present invention, a symbolic representation may be converted into two or more problems or multi-variable functions, where each problem may be semi-independent from the other and may represent a separate portion of the overall network. A set of different algorithms may be used to estimate possible solutions for each optimization problem. In some embodiments, the algorithms may attempt to estimate a solution comprised of a group of network policies intended to optimize the network with respect profitability. The algorithms used may include Greedy Algorithms, Genetic Algorithms, Simulated Annealing, Taboo Search, Branch and Bound, Integer-Programming, Constraint-Programming. Each of the algorithms mentioned above represents a large family of algorithms and each of the specific algorithms may be used with different parameters. For different problem instances, algorithm behavior may change radically. One way of reducing the risk of using an inappropriate algorithm while trying to solve new problems is by combining several algorithms and letting them cooperate and compete through a blackboard system. Different algorithms may compete with one another to produce an estimate of the most optimal solution for a given problem. The possible solution for each problem may be in the form of policies to be implements on a portion of the network represented by the particular problem analyzed. In some embodiments of the present invention, network policies may be adjusted automatically by the present invention. BRIEF DESCRIPTION OF THE DRAWINGS The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to or ion and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which: FIG. 1 is a flow diagram showing three basic stages of an optimize on method or process according to the present invention; FIG. 2 is a flow diagram showing the steps of one possible pre-processing stage according to the present invention; FIG. 3 is a network diagram of an exemplary communication network which may be adjusted or tuned according to a system or method of the present invention; FIG. 4 is a symbolic network representation of the network diagram in FIG. 3; FIG. 5 is a flow diagram showing the steps of a process or method by which preliminary pruning may be performed according to the present invention; FIG. 6 is flow diagram showing further steps of a process or method by which preliminary pruning may be performed according to the present invention; FIG. 7 is a flow diagram showing the steps of a process or method of formulating a set of semi-independent sub-problems according to the present invention; FIG. 8 is a flow diagram showing three possible steps of a process or method by which abstraction of a network representation may be performed according to the present invention; FIG. 9 is a block diagram shoving relationships and interaction between a set of optimization algorithms through a blackboard and under the control of a control unit; FIG. 10 is a block diagram depicting multiple instance of a the same algorithms running in parallel; FIG. 11 is flow diagram showing the steps of a process or method by which a list of network user contracts may be evaluated according to the present invention; FIG. 12 is a flow diagram showing the steps of a post-processing stage according to the present invention; FIG. 13 is a flow diagram showing the steps of a process or method by which a contract my be tested according to the present invention; FIG. 14 is a flow diagram showing the steps of a possible algorithm interaction process or method according to the present invention; FIG. 15 is a flow diagram showing the steps of a possible algorithm interaction process or met hod according to the preset invention where CPU is a shred resource; FIG. 16 is a flow diagram showing steps of a possible process or method for generating pattern based store cards according to the present invention; FIG. 17 is a flow diagram showing the steps of a process or method of calculating volume of a single discrete dimension of a pattern based scorecard according to the present invention; FIG. 18 is a flow diagram showing the steps of one possible process or method of calculating volume of a multiple discrete dimensions of a pattern based scorecard according to the present invention; and FIG. 19 is a flow diagram showing the steps of one possible process or method of calculating a pattern based scorecard according to the present invention. It will be appreciated that for simplicity and clarity of illustration, elements shown in the Fig.s have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the Fig.s to indicate corresponding or analogous elements. DETAILED DESCRIPTION Unless specifically stated otherwise, as apparent from the following discussions, it is appreciated that throughout the specification discussions utilizing terms such as “processing,” “computing,” “calculating,” “determining,” or the like, refer to the action and/or processes of a computer or computing system, or similar electronic computing device, that manipulate and/or transform data represented as physical, such as electronic, quantities within the computing system's registers and/or memories into other data similarly represented as physical quantities within the computing system's memories, registers or other such information storage, transmission or display devices. Embodiments of the present invention may include apparatuses for performing the operations herein. This apparatus may be specially constructed for the desired purposes, or it may comprise a general purpose computer selectively activated or preconfigured by a computer program stored in the computer. Such a computer program may be stored in a computer readable storage medium, such as, but is not limited to, any type of disk including floppy disks, optical disks, CD-ROMs magnetic-optical disks, read-only memories (ROMs), random access memories (RAMs), electrically programmable read-only memories (EPROMs), electrically erasable and programmable read only memories (EEPROMs), magnetic or optical cards, or any other type of media suitable for storing electronic instructions and capable of being coupled to a computer system bus. The processes and displays presented herein are not inherently related to any particular computer or other apparatus. Various general purpose systems may be used with programs in accordance with the teachings herein, or it may prove convenient to construct a more specialized apparatus to perform the desired method. The desired structure for a variety of these systems will appear from the description below. In addition, embodiments of the present invention are not described with reference to any particular programming language. It will be appreciated that a variety of programming languages may be used to implement the teachings of the invention as described herein. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, components and circuits have not been described in detail so as not to obscure the present invention. The present invention is a system and method for adjusting policies in a communication network. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that the networks profitability is improved. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that other parameters in the network are improved (e.g. average QOS for all customers). As part of the present invention, a symbolic network representation (e.g. a node graph) may be formed. The symbolic network representation may be formed by abstracting and pruning an actual representation of the network. As part of the abstracting step, network elements, resources, applications, and users may be clustered based on a predefined set of rules. Pruning may be accomplished by removing those elements of the symbolic representation which would not limit the performance of the overall network under foreseeable conditions. As a further part of the present invention, a symbolic representation of a network to be adjusted may be converted into one or a set of optimization problems. In some embodiments of the present invention, a symbolic representation may be converted into two or more problems or multi-variable functions, where each problem may be semi-independent from the other and may represent a separate portion of the overall network. A set of different algorithms may be used to estimate possible solutions for each optimization problem. In some embodiments, the algorithms may attempt to estimate a solution comprised of a group of network policies intended to optimize the network with respect profitability. Although the solutions may not exactly “optimize” the network, they may serve to adjust or tune the network so as to improve the network with respect to profitability. The algorithms used may include Greedy Algorithms, Genetic Algorithms, Simulated Annealing, Taboo Search, Branch and Bound, Integer-Programming, and Constraint-Programming. Each of the algorithms mentioned above represents a large family of algorithms and each of the specific algorithms may be used with different parameters. For different problem instances, algorithm behavior may change radically. One way of reducing the risk of using an inappropriate algorithm while trying to solve new problems is by combining several algorithms and letting them cooperate and compete through a blackboard system. Different algorithms may compete with one another to produce an estimate of the most optimal solution far a given problem. The possible solution for each problem may be in the form of policies to be implements on a portion of the network represented by the particular problem analyzed. In some embodiments of the present invention, network policies may be adjusted automatically by the present invention. The present invention may permit network adjustment or tuning with respect to complex realistic inputs that may include economical revenue models, multipart contractual agreements, actual network-specific and contract-specific traffic volume and patterns, billing data, and customer relationship agent (“CRM”) data. The present invention may support a rich representation of contracts and SLAs where a contract can consist of multiple subcontracts, each with a set of unique QOS requirements. Penalties and revenues may be related separately to each sub-contract or the entire contract where revenue is obtained only if the full contract, including all its subcontracts is fulfilled. Additionally, the present invention may permit the use of plug-in business rules, which makes it adaptable to various environments without having to change the optimization algorithms. The present invention may also include an abstract network representation that allows using the same algorithms to optimize different types of network, including but not limited to ATM and IP networks. Unlike existing network optimization tools that rely on network re-engineering (adding components or changing topology) or on changing the routing, the present invention may use different QOS policing techniques to adjust or tune the overall profitability of a network. For example, in a network that uses Diffserv, the present inventing may adjust or tune the network either by changing the Differv definitions or by changing the coloring rules. According to some embodiments of the present invention, near-real time tuning of an entire network is possible, as compared to existing systems that perform either a “batch optimization” of the whole network or a limited optimization, e.g., acceptance control applied only to new communications entering the network. Furthermore, the present invention may use an abstraction and clustering layer that enables an “optimization process” (the term “optimization” as used in this specification may also include “adjusting or tuning such take a particular parameter or characteristic of a network is improved”) to focus on the most relevant elements of a network, thus allowing near-real time optimization even for very large networks. Optimization may be performed for a specific interval of time during which contractual provisions, SLAs and network status may change. A component of network profitability optimization may be the ability to rank network users based on their value to the network operator. For example, two customers may have similar contracts and SLAs, yet the first customer may pay on time, while the other has not paid in months. Moreover, the first customer may use only a fraction of the bandwidth assured by his SLA, while the other may over-utilizes his allowance of bandwidth. Thus, the first customer's contract may be of more value to the network owner than that of the second customer. Yet a simple look at each contact's revenue figure may not reveal this distinction. In order to highlight the difference in value of the two customers, a traditional scorecard may be used. But often, just assigning a score to a customer is not enough. For example, even of the two customers have the same score, and both bought contracts that give them the same amount of bandwidth, the first customer may do most of his important transactions in the morning, while the second customer may do his most important transactions in the evening. Obviously, assigning a simple score per customer is not enough to determine which customer is more important at a particular time. It is essential to use a score profile that reflects change in customer's score across time. Such profile can be best described as the customer's score graph. Therefore, as part of the present invention, a traditional scorecard model may be extended into a pattern-based scorecard that allows for estimation of the value of each contract at a specific time or over a specific interval of time. A two-dimensional patter-based graph may be used, in which one dimension is the time and the other is a customer's score. A major benefit of using a patter-based scorecard is that it enables optimization decisions to be taken with respect to the whole graph instead of just a single score. It may provide the flexibility to perform optimization either for a single point or for an entire interval on the graph. The method of utilizing a pattern-based scorecard is applicable to many areas, and extends to the use of multidimensional pattern-based graphs. Profit Optimization Defined The goal of the network profit optimization is to select a set of contracts that can be fulfilled according to the network and business constraints, so that the sum of the value to the operator of all the fulfilled contracts is maximized. The optimization identifies the set of contracts that should be fulfilled and a set of operations (e.g. set of policies which should be set) that should be performed in the network in order to fulfill the contracts. In order to fulfill the contracts, the present invention may use different policy mechanisms found in networks, including but not limited to: weighted fair queuing (WFQ), Diffserv, MPLS and RSVP. The operations used by the present invention may not need to include physical changes to the network (e.g., adding lines or routers), directly changing routing tables (routing tables may be changed indirectly as result of the changes in the policies, or the usage of RSVP). The present invention may have an internal representation of the different technologies, and the policies applicable to each of them. An optimizer application can be adapted to work with more technologies by entering their descriptions. For example, an optimization application according to the present invention may be operate with a variety of network technologies and protocols, including but not limited to wire, wireless, IP and ATM networks. Network Optimization Inputs The inputs to a network optimizer according to the present invention may comprise three basic groups of data elements: (1) data that provides network description; (2) data that describes network customers and business arrangements in place with each customer; and (3) data that defines optimization criteria to be satisfied by the optimization process. Network description data may comprise information such as inventory, topology and condition of network elements. For example, the information may contain a listing of all network elements, their locations, corresponding network ports and connections with their respective bandwidth capacities. Other inputs may include network routing and malfunctions data, information on supported policies (e.g., if Diffserv is supported), applied policies (e.g., if Diffserv is in use with network elements), as well as limits that could be placed on policies (e.g., if a network elements can not support more than three policies). The optimizer can also work with partial network data (e.g., without muting information). Data describing network customers may include their historical usage patterns, pattern-based scorecards, actual current usage, billing data, and both business and network practices. It may also include contract-specific financial data, operational and legal information. For example, a contact article may require a network operator to provide service to a specific customer over a certain time interval with certain QOS specifications. Since a typical contract is a set of many individual contract articles, the overall value derived from the entire contract will be based on the performance against all the articles in the contract. This value will aggregate factors including, but not limited to: (1) face value of the entire contract, (2) cost associated with fulfilling articles of the contract, and (3) penalties associated with violating QOS or other contract provisions contained in various contract articles. Additional customer information may specify level of importance assigned by the network operator to each customer contract. This data may be represented with a pattern-based scorecard as will be further describer below. The optimization criteria may include such requirements as performing optimization (e.g. specifying network policies) for a specific time interval, where such an interval can be comprised of several sub-intervals, each with unique service requirements and network status. For example, an interval from 8 AM to 11 AM may include three sub-intervals: 8 AM to 9 AM, 9 AM to 10 AM and 10 AM to 11 AM. A contact may specify that a customer should receive service from 8 AM to 10 AM and no service from 10 AM to 11 AM, because of scheduled router maintenance. The selection of sub-intervals thus depends on business practices of the network's owner and may constitute a critical input that enables the present invention to perform a set of actions at the beginning of the specified interval that will yield a solution considering the changes in the demands and resources across multiple sub-intervals. It is possible to have different policies set per each sub-interval, which may require solutions to several optimization problems, one solution per each sub-interval. Turning now to FIG. 1, there is shown a block diagram indicating three stages of a method of adjusting a network according to present invention. The three steps are pre-processing 100, optimization 110, and post-processing 120. The output 130 of the method is one or a set of policies to be implemented an various network elements. Pre-Processing Turning now to FIG. 2, there is shown a block diagram depicting an example of a pre-processing stage according to the present invention. The pre-processing stage according to the example of FIG. 2 may include five steps: (1) Representation Transformation 200, (2) Preliminary Pruning 210, (3) Abstraction 220, (4) Division into Semi-Independent Subproblems 230, and (5) Pruning 240. Representation Transformation During the process of representation transformation, a description of the network, which may either be provided in a network manager application or may be derived using a pinging and mapping routine or by other methods, is translated into a symbolic network representation, such as a directed graph representation, where network elements and their connections and ports may be represented by nodes. For example, turning now to FIG. 3, we can see an example of a simple network representation where the information in the parentheses represents the bandwidth capacities with the first number informing the upstream limit, and the second the downstream limit. All the connections are bi-lateral. The numbers in the network elements' parentheses apply to all the ports for the network elements. Turning now to FIG. 4, there is shown an example of a symbolic network representation which is a directed graph representation of the network of FIG. 3. A pair of nodes represents bi-directional connections or ports connected to bi-directional connections. Each node that represents a port (or half of a bi-directional port) is connected by a directed edge to the node that represents the connection (or the corresponding half of a bi-directional connection). The direction of the edge corresponds to the direction in which the connection was oriented in the original network. Each network elements is represented by a node, which are linked by edges to all the nodes that represent that network elements ports. All the relevant attributes of network elements, ports, and connections are associated with the correspondent nodes. For example, if a give connection has a bandwidth limit the same bandwidth limit will apply to the nodes that represent it. Preliminary Pruning During one example of a preliminary pruning stage according to the present invention, elements that do not constrain contact fulfillment may be removed from the symbolic network representation. For example, a port that possesses more bandwidth capacity than required to satisfy any foreseeable demands will be pruned. Network requirements that correspond to the level of performance desired within the time interval for which the optimization is performed may be estimated as part of the preliminary pruning process. The requirements are calculated per each sub-interval within the specified interval. Information inputs used for estimating the expected network requirements, including minimum QOS levels for clients, may include data from forecasting systems, historical data, usage patterns, and data from ordering and provisioning systems. As a further sub-step of a preliminary pruning process, calculated or estimated requirements may be mapped to the elements of the symbolic network representation (e.g. directed graph representation). For each expected network requirement, the present invention may calculate its probability to demand the use of one or more network elements, ports, and connections. The probability calculation may be derived from some or all the following information sources: (1) routing tables, (2) routing algorithms, (3) historical data, (4) network management systems network status (e.g., malfunctioning elements), provisioning systems. The calculation may be performed for each criterion that is used as a constraint in the optimization. Such criteria may include: (1) bandwidth requirements. (2) delay, (3) jitter and (4) packet drop rates. For example, for the bandwidth criterion, if the bandwidth requirement of a certain request is k, and the probability of that bandwidth resource being requested is p, then the expected resource consumption is k*p*t, where t is a factor, that is used to account for over or under provisioning. t>1 will result in bandwidth over-provisioning and 0<t<1 will results in under-provisioning. Thus, t can be interpreted as a safety/risk factor. The probability calculation method can be adapted for any similar criterion. After performing the calculations or estimations relating to all the possible network requirements, a verification of each node's resources may be performed. A check may be performed to assess whether each element's resources are sufficient to satisfy each element's probable requirements. FIG. 5 is a flow diagram depicting the flow of an example of a process by which such a check may be performed. The process of FIG. 5 begins with an empty solution set 500. Step 510 selects the first sub-interval for examination. Step 520 performs requirements estimation for the selected sub-interval. Step 530 maps calculated requirements to the graphical representation of the network. Step 540 identifies nodes that lack resources and step 550 adds such nodes to the collection intended to identify all the “problematic” nodes. If the current sub-interval is not the last one to be analyzed, steps 570 and 560 iterate the process to perform steps 520 through 560 for another sub-interval. In case there are no more sub-intervals to analyze, the process may advance to step 580 where “non-problematic” nodes are pruned or removed from the symbolic network representation. An example of one possible method for performing the actual pruning is depicted in FIG. 6. Each node whose resources are sufficient to satisfy any foreseeable requirements are removed from the network representation or graph and all the edges that connected that node to other nodes are removed form the network graph. Specifically, step 600 defines N as a set of all the nodes representing network elements and ports in the network. Step 610 defines E as a set of all the edges on the graph. Step 620 defines NewN as a set of all the nodes that are problematic in at least one sub-interval (NewN is equal to S found in FIG. 5). Step 630 defines NewE as a set that is initially empty and represents the universe of edges that belong to the pruned Graph. Step 680 examines contents of E and, if E is not empty, iterates the process to step 640 where the process selects an edge e form the set E. Step 650 performs negative process iteration by removing e from E. Step 660 checks if the two nodes in set N that are connected by e, also belong to set NewN. If the outcome of this step is positive, step 670 of the process adds e to the set NewE. Next step, 680, check if there are no more connections e left in the set E to be analyzed by the process. Positive outcome brings the process to its final step 690 where new directed graph representation of the network is defined on the basis of sets NewN and NewE and where every node is resource-deficient with respect to at least one criterion in at least one sub-interval. Abstraction The abstraction of the symbolic representation of the network and thus the optimization problem to be solved may be achieved by generating clusters of similar customers, similar nodes, similar services, similar contracts, and referring to each such cluster as a single representative entity. The clustering can be accomplished according to specific business rules defined by the network operator. For example, an operator may define that all home users are similar, even if in reality their usage pattern differs greatly, and that all the banks should be treated individually, despite their degree of similarity. The quality of the possible optimization may increases with increased granularity of clustering, which in turn may increase the amount of computational resources required by the present invention. Clustering may be accomplished with a process that may use a standard clustering algorithm. Existing algorithms can be used to execute any of the several alternative methods. An example of one such method may define the parameters of the similarity criteria, which in turn may define the size and granularity of the clusters. For example, assuming that the only criterion is the average required bandwidth, it is possible to classify two clients as belonging to the same cluster if their average bandwidth requirement divided by 10 is equal. This method should result in an arbitrary number of clusters. Another example of clustering may pre-define the desired size an granularity of the clusters, which in turn defines the similarity parameters. For example, assuming that the only criterion is the average required bandwidth, in order to get exactly 4 clusters, it is possible to obtain a number n such that will yield exactly 4 clusters if two clients will belong to the same cluster if their average required bandwidth divided by n is substantially equal. A first step in an abstraction process which may be used with the present invention may cluster network nodes by measuring their similarity based upon criteria that may include such inputs as: (1) network topology; (2) node-specific information about customer and service usage patterns; and (3) pre-defined classification and custom rules specified by the network operator. Next, the process may cluster services by measuring their similarity based upon criteria that may include such inputs as: (1) service location on the network; (2) pre-defined service classification (e.g. Video vs. E-mail); (3) service usage patterns including pattern-based scorecards; (4) service-specific QOS requirements (e.g. VoIP is sensitive to jittering, while Video Steaming with buffers is not); (5) customer-specific information (e.g. home users vs. business users); (6) historical data; and (7) custom rules specified by the network operator. Service clustering may also use the result of node clustering. For example, if two diffident services use two different POPs represented by two different nodes, and these nodes were placed into the same cluster, then in abstraction, the two services may be considered to use the same POP. During an abstraction step, customers may be clustered by measuring their similarity based upon criteria that may include such inputs as: (1) geographical location; (2) access point classification (e.g., the POP); (3) access method (e.g. ASDL, ISDN, etc.); (4) customer usage patterns including pattern-based scorecard; (5) customer classification (e.g. business users vs. home users); (6) contract and SLA information; (7) historical and CRM data; and (8) custom rules specified by the network operator. Customer clustering may also use the result of node clustering. For example, if two different customers use two different POPs represented by two different nodes, and these nodes were placed into the same cluster, then in abstraction, the two services may be considered as using the same POP. In a similar manner, customer clustering may also utilize the result of service clustering. The clustering process is repeated until the reduction in number of clusters obtained by repeating the process is less than a pre-defined limit. In the repetition, the similarity fiction uses clusters found in the previous iterations. The result of the abstraction stage is a representation of the network that has fewer nodes, services and clients. For example, a single new user may be used to represent all the home users. Division into Independent and Semi-Independent Sub-Problems Once a symbolic network representation, and the optimization problem it defines, is abstracted according to the present invention, the symbolic representation and the optimization problem it represents may be divided into independent and semi-independent sub-problems. Two sub-problems are considered independent if they do not contain common network elements and if none of the same customers or services use any of the network elements that belong to the two different independent sub-problems. The concept of Distance is key to understanding what constitutes an independent sub-problem. Distance is a function which defines the distance between a given network node and a sub-problem with given customers and services. The distance for two independent sub-problems, P1 and P2, is equal to infinity if, for each element e1 in P1, the distance between e1 and P2 is equal to infinity and if, for each element e2 in P2, the distance between e2 and P1 is equal to infinity. Similarly, two sub-problems can be considered semi-independent, given a certain distance function D and a threshold T, if for each element e1 in P1, the distance between e1 and P2 is greater than or equal to T and if, for each element e2 in P2, the distance between e2 and P1 is greater than or equal to T. Each sub-problem for a particular portion of the network is party defined or derived from a corresponding portion of the symbolic representation of the network. The division of the optimization problem into independent sub-problems makes it easier to obtain a solution. While many problems do not include fully independent sub-problems, disaggregating the problem into the semi-independent problems may result in a set of problems that can be optimized more easily than the full problem. Even though solving these problems may not provide the “optimal solution” to the full problem, it provides an approximation of an optimal solution, if one exists. The network optimization method does not place restrictions on the distance function and the threshold. Several functions are built into the system and other functions may be easily integrated using technologies such as, for example, COM or Dynamic Link Libraries (DLLs). Turning to FIG. 7, there is shown a detailed flow diagram of the step of one possible method by which an optimization problem (e.g. derived from a symbolic network representation) according to the present invention may be divided into several semi-independent sub-problems. First in step 700, N is defined as a set of nodes in the network representation. Next, in step 705, C is defined as a set of customers in the network representations. Following that, in step 710, S is defined as a set of services in the network representation. Then, in step 715, T is defined as the threshold criteria used to determine problem semi-independence. Next, in step 720 a set of possible sub-problems P1 . . . Pn is defined. In the step 725, a sub-problem counter i to zero is set. Next, step 730 checks if N contains any un-analyzed nodes. Step 745 sub-problem counter is iterated by one, which ensures that for each sub-problem Pi the process will loop through all the nodes contained in N. As part of step 735, a network element is selected and entered into the current semi-independent sub-problem being analyzed while the process performs a negative iteration that reflects the fact that there is one less node in the set N to be analyzed in the next process cycle. In the step 740, the process defines a new set K, which contains the current universe of un-analyzed network nodes. Further, step 750 checks if K is equal to zero. Positive outcome indicates that all network nodes have been analyzed for the current sub-problem i, which forces the process to return step 730, where it is advanced to the next sub-problem with counter i being iterated by 1. Negative outcome of check 750 implies that there remain nodes that have not yet been analyzed in conjunction with the current sub-problem. Next, the process moves on to step 755, where node g is picked out from the set K, after which K is left with one fewer node to be analyzed in the next iteration. After this, in the step 760, the distance function is calculated for the current node g. The same step, 760, checks that the value of the distance function does not exceed pre-determined threshold T. A negative outcome means that the condition of semi-independence has not been satisfied for the node g and the process is advanced to step 750. A positive outcome means that g should be added to the current semi-independent problem and removed from the set N. Following this step, the process returns to 740. It is evident that the process depicted in FIG. 7 continues until all the network elements in the original problem are associated with a sub-problem. Pruning After the clustering and the division into semi-independent sub-problems, the present invention may attempt again to prune from the network representation network elements that do not constrain contract fulfillment. Even though many non-constraining network elements may have been pruned in the initial pruning stage, the abstraction and problem disaggregation into sub-independent problems make it possible to identify more such elements. Additional pruning is performed per each sub-problem using the same method that was employed in the preliminary pruning. Optimization Following the initial pruning, abstraction, problem disaggregation and another round of pruning, optimization may be attempted separately on each of the semi-independent sub-problems created in the pre-processing stage. The optimization may be performed or attempted by using various algorithms that run simultaneously and use a blackboard-based architecture to cooperate and compete. Turning now to FIG. 9, there is presented an example of a basic blackboard architecture where three algorithms, in this example a (1) Generic Algorithm 910, a (2) Greedy Algorithm 920 and (3) a Simulated Annealing algorithm 930 “share” a common blackboard 940 that contains a common representation of the problem and of the solutions. The algorithms may exchange their selected solutions 950 trough the blackboard. Additionally, algorithms may post to the blackboard their operational statistics 960. An example of such statistic is the number of evaluations completed by an algorithm by a certain point in time. A controller or control unit 900 may be responsible for managing the optimization process. The control unit 900 may calculate control parameters that may include the following (1) the absolute quality of the solutions found by one instance, (2) the relative quality of the solutions found by one instance compared to solutions found by other instances, (3) the absolute advance rate of one instance (e.g. the amount of resources the instance used in order to improve its last solution) and (4) the relative advance rate of one instance compared to other instances (e.g. the amount of resources the instance used in order to improve its last solution compared to other instances). Controller 900 may use parameters it calculates to estimate the potential of the different algorithms to find improved solutions. According to its estimations, the controller 900 may decide on the amount of computing resources to be allocated to the different instances of the algorithms. The controller 900 may increase or decrease the resources assigned to an instance of an algorithm, halt an instance of an algorithm, create a new instance of an algorithm from a certain family and supply the values of the parameters to be used in the new instance. The use of competing and cooperating algorithms on a blackboard to solve optimization problems are well known. Any processing known today or to be derived in the future is applicable to the present invention. In addition to the algorithm depicted in FIG. 9, the algorithms known as “Taboo Search” and “Branch and Bound” may be used. Any family of optimization algorithms known today to be devised in the future is applicable to the present invention. Turning now to FIG. 10, there is shown a diagram depicting more than one algorithm of each type being used in as part of an optimization according to the present invention. Either with different paramours, or with the same parameters, multiple instances of the same algorithm may be used. The latter option is valuable due to the stochastic nature of some of the algorithms such as, for example, Simulated Annealing. Specifically, FIG. 10 shows how Three Genetic Algorithms (1010, 1040, 1060), three Simulated Annealing Algorithms (1030, 1050, 1070) and one Greedy Algorithm may be used as part of an optimization process according to the present invention. One possible interaction flow of various algorithms and the controller/blackboard 1460 according to the present invention is depicted in FIG. 14. In the first step, the controller 1460 starts a new instance of an algorithm and passes to it an allowance of resources. The allowance defines the number of solutions that the algorithm is allowed to evaluate. This value is expressed by the variable steps used in the step 1420. Next, in the step 1400, the algorithm instance starts to run. In the step 1410, the instance generates a solution. In the following step, 1420, the solution is evaluated, and the number of allowed solution steps is decreased by one. Next, in the step 1430, the controller checks if the new solution is the best found so far by this instance of the algorithm. If so, the algorithm reports the solution and steps used to obtain it to the controller, otherwise step 1440 verifies if the instance has the resources to perform additional evaluations. If the outcome is positive, the instance returns to step 1410 to generate another solution, otherwise the instance reports the solution and steps used to obtain it to the controller and indicates that it is out of resources (e.g. it has exhausted the number of evaluations initially granted to it). Next, the controller may use information stored in the blackboard to determine the amount of resources to assign to the algorithm and returns this allowance to the algorithm. In a similar way, the allowance of resources can take the form of CPU time allocated to an algorithm. FIG. 15 illustrates such a scenario. Contract Value Evaluation Now turning to FIG. 11, we can examine the process by which one possible optimization method according to the present invention may calculate the value of an ordered list of contracts C. Fist, in the step 1100, the process defines a list of contracts. Next, in the step 1110, the process sets value variable to zero and the process counter i to 1. Further, in the step 1120, the process checks whether there are still contracts that have not been evaluated. If no, then all the contracts have been analyzed and the process halts on step 1170. If yes, then the next step, 1130, will test if the current contract Ci can be fulfilled, and if so, the next step, 1140, will guaranty that contract by setting the appropriate policies. Further, step 1150 will calculate the value of the current contract and increment it to the running sum that represent total value of all contracts. Step 1160 will increment process counter by 1 thus advancing the process to the next cycle. The evaluation process described above, implies that fulfilling a contract requires fulfilling all of its articles, where the criteria for fulfilling a contact in respect to each article depends on the QOS requirements and a set of rules that define the applicable network and business constraints. The algorithms may not calculate values associated with the solution they provide. Instead, they may use an evaluator that assesses the solutions by, among other things, examining if the performance criteria applied to the contracts and sub-contracts is satisfied. An evaluator according to the present invention may not contain rigid business and network constraints, but rather constraint templates that can be used to create constraint instances. The process can seamlessly integrate built-in constraint templates and rule constraints provided as COM objects or as DLLs, so that a single template may be used to define several constraints by invoking the rule templates with different parameters. For example, a rule template may limit the total assigned bandwidth to a pre-defined fraction of the available bandwidth in certain connections, place a limit on the number of policies in a given network port, or limit the number of data flows in a given network element. Each algorithm may use its own copy of the evaluator, or even several copies of it, which permits evaluating multiple solutions in parallel. This may be especially be useful for genetic algorithms. At the same time, several algorithms may use a single evaluator. All the copies of an evaluator in a single optimization process may use the same constraints, more specifically, the same rule templates and parameters. FIG. 13 illustrates the flow of a process by which a list of contracts can be that evaluates whether as to whether they may be fulfilled. Here, the first step 1300 initiates the process by specifying a set of n articles which may constitute a single contract to be analyzed. Step 1310 initializes the process counter. Step 1320, which is performed for all iterations in the process cycle, checks if there is another un-analyzed contract that requires processing. A negative outcome results in the process being halted and returning a “TRUE” value in step 1360. Otherwise, step 1330 checks if the current contract article can be performed given the network conditions. A negative outcome indicates that the entire contract cannot be performed and step 1360 of the process will cancel all the policies and changes relating to that particular contact that might have been guaranteed in the course of the process. Next, the process is halted in the step 1370 retuning a “FALSE” value. If the outcome of step 1330 is positive, the process moves to step 1340 where it sets the policies required to guarantee fulfillment of the current contract. Step 1350 iterates the process to the next cycle, in which another contact is evaluated. The steps 1320-1370 are repeated until the condition in step 1320 indicates that all articles of the contract have been analyzed and could be fulfilled and have been guaranteed. Post-Processing FIG. 12 describes a possible post-processing stage according to the present invention. Step 1200 initiates the process by defining a set of k contracts selected for fulfillment by the optimization process. Each of the contracts in this set can represent multiple contracts that were clustered together in the pre-processing stage. Next, step 1210 may initialize the process counter i. Further, step 1220 checks if the process counter exceeds k, which would indicate absence of un-analyzed contact. If no, the process may be advanced to step 1230 that selects the n original contracts making up the current contact. Next, in the step 1240, the process sets j as a counter that defines a loop designed to process all the original contracts. Step 1250 checks if all the original contracts have gone through the loop. If no, step 1260 will define how to fulfill the current original contract based on the results of the optimization stage. Specifically, it will be determined which policies needed to be set. Network and business specific rules may be ignored at this juncture. Step 1270 may iterate the loop to evaluate the next original contract. This process is repeated until the check performed in step 1250 will determine that all original contacts have been analyzed and will advance the process to step 1280, which may iterate it to the next cycle that will select another aggregated contract. This process may be repeated for every aggregated contract until the check performed in step 1220 determines that all the contracts have been analyzed, which may bring the process to step 1290. In this step, for each network element and port, the process will consider all the policies defined in the proceeding steps. If these policies satisfy such limitations of network element's and parts as the umber of flows and policies permitted, then the process may recommend applying the associated policies. If the policies do not satisfy existing limitations, the process may use network masks to group them together in order to obtain a reduced number of flows and policies which to would satisfy network element and port constraints. Thus network policies are compiled. Pattern-Based Scorecard Any method known today or to be developed in the future for compiling a score card or score graph may be applicable to the present invention, FIG. 16 depicts one method according to the present invention to calculate the pattern based scorecard or score graph. Calculating a pattern-based scorecard according to some embodiments of the present invention may include five steps. As seen in FIG. 16, Preliminary step 1600 may perform selection of problem dimensions, for example, by specifying a time interval defined by specific days of the week and hours of the day. The dimension may be continuous or discrete. Next step 1610 may perform discovery of the patterns across specified dimensions. For example, if the dimension is a time interval defined as a specific hour of a specific day, and the pattern is usage volume, then for each minute in the specified hour, the process may calculate the amount of service used by the entity whose score is being calculated. The pattern may reflect such characteristics as service usage, revenue, expenses, etc. Further, step 1620 may calculate the flat (regular) score by employing various methods that may include mathematical calculations, rule-based systems, expert systems, and neural networks. The result of the calculations may be a single score given to the entity. Next, step 1630 may calculate the volume. As FIG. 17 illustrates, for a single discrete dimension, the volume may be the sum of all the points in the pattern. For a single continuous dimension, the volume may be the integral of the pattern. Finally, step 1640 may calculate the pattern-based scorecard, where for a single discrete dimension, the pattern-based scorecard may be a discrete graph in which each point is the flat-score multiplied by the value of the pattern in that point and divided by the volume. For a single continuous dimension, the pattern-based scorecard may be a continuous graph in which each point is a flat score multiplied by the value of the pattern in that point and divided by the volume. When more than one dimension is used, there may be three methods for calculating the volume. The first method may set all the dimensions on the same level and calculate an integral or sum of all the points in all the dimensions at the same time. FIG. 18 describes a process of calculating the volume using the first method when all the involved dimensions are discrete. Step 1800 sets the Volume to 0. Next, step 1810 sets K to the number of dimensions. Step 1810, initializes i1, which sets the number of processed intervals in the first dimension to 0. Step 1820 initializes i2, which sets the number of processed intervals in the second dimension to 0. This is done for all the K dimensions, and step 1820, does it for the kth dimension. Each of the Steps 1810, to 1820 is the starting point for an iterative loop over the correspondent dimension. Step 1825 adds to the volume the volume at the point P(i1, i2, . . . ik). Step 1830 checks if all the points in the loop for the kth dimension were processed, if not, ik is incremented in step 1835, and the loop continues to step 1825 to process the next interval in the kth dimension. Similar steps are done for all the dimensions, and step 1840 checks if the all the points in the loop for the second dimension were processed. If not, i2 is incremented in step 1845, and the loop continues to step 1820 to process the next interval in the second dimension. Step 1850 checks if the all the points in the loop for the first dimension were processed, and if not, i1 is incremented in step 1855, and the loop continues to step 1815 to process the next interval in the first dimension. When step 1860 is reached, the calculation ends and the Volume value is considered to be the cumulative volume. The second method for calculating the volume may require building of a hierarchy of dimensions, calculating the value of every point in every dimension, and setting the volume of the specific point in a sub-dimension to the value of the pattern in that point. Another method may combine elements of the above described two methods, where a different method is used for each dimension. Regardless of the method, a multidimensional pattern-based scorecard may be calculated similarly to a single-dimension scorecard, with the exception that the volume used at different points may be different. Turning now to FIG. 19, there is described the process of calculating a pattern based scorecard when all the involved dimensions are discrete. Step 1900 sets the sets K to the number of dimensions. Step 1905, initializes i1, setting the number of processed intervals in the first dimension to 0. Next step 1910 initializes i2, which sets the number of processed intervals in the second dimension to 0. This is done for all the K dimensions, step 1915, does it for the kth dimension. Each of tie Steps 1905, to 1915 is the staring point for an iterative loop over the correspondent dimension. Step 1920 sets the score on the point i1, i2, . . . ik, to be the flatten score multiplied by the volume at the point, denoted by P(i1, i2, . . . ik), divided by the total volume. Step 1925 checks if the all the points in the loop for the kth dimension were processed, if not, ik is incremented in step 1930, and the loop continues to step 1920 to process the next interval in the kth dimension. Similar or steps are done for all the dimensions, step 1935 checks if the all the points in the loop for the second dimension were processed if not, i2 is incremented in step 1940, and the loop continues to step 1915 to process the next interval in the second dimension. Step 1945 checks if the all the points in the loop for the first dimension were processed, if not, ii is incremented in step 1950, and the loop continues to step 1910 to process the next interval in the first dimension. When step 1955 is reached, the calculation ends and the scare for each point in the multidimensional graph has been calculated.

<SOH> BACKGROUND OF INVENTION <EOH>A communication network accessed and used by multiple users or customers may include a huge number of communication and computing devices (e.g. computers, routers, switches, etc . . . ) also referred to as network elements. Each device or network element may support different operations and may follow different policies. At any given moment, large numbers of users may attempt to access the network and may cause vast amounts of communication traffic to traverse the network. In some cases, the amount of data traffic attempting to pass through a network element may exceed the maximum capacity of that network element, and a condition known as a bottleneck may result. In a network operated by a network operator for access by a group of customers, each customer may have different and complex needs, which needs may be stated in a contract (e.g. Service Level Agreement (“SLA”)) with the network operator. An SLA between a customer and a network operator may contain provisions guaranteeing minimum Quality of Service (“QOS”) for the given customer and for one or more given applications of the specific customer. QOS is defined, in part, by the ability of a network to carry data traffic that complies with cervix minimal resources and service requirements (e.g., bandwidth, delay, jitter, etc.). A user's QOS may be guaranteed within their SLA with the network operator, and certain SLAs may impose penalties on a network operator if a customer's QOS fans below a threshold level. Many techniques and methodologies are known for establishing and maintaining QOS levels across a network and within specific network elements or devices. Methods including Weighted Fair Queuing (WFQ), Differentiated Services (Diffserv), Multiprotocol Label Switching (MPLS), Resource Reservation Protocol (RSVP), and others are used to define network policies which attempt to avoid network congestion or bottlenecks. However, when a communication network experiences a surge in traffics or a reduction in the network capacities (e.g., caused by faults), fixed network policies may not be able to compensate for this surge or reduction of capacities, and certain network elements may become congested. Operating at or above capacity along certain data paths, the network may experience bottlenecks and an overall QOS degradation for one or a group of its users. One method of preventing a user's QOS from falling below a predefined level due to congestion caused by data traffic of a new user is to limit or deny access to the network to new users or new applications. This method involving denial of service requires either that s a new user or new application be denied a request for access, or that a session of a user or application currently using the network be terminated. In this manner, the total number of users or applications using the network may be kept to a number sufficiently low such that the QOS of the majority of existing communication sessions is not degraded. However, refusal of service may translate into lost revenues and in other instances may mean the loss of highly valued customers. In order to avoid the above-mentioned conditions and commercial results, extensive work has been done to optimize the throughput and QOS compliance of communication networks. Traditionally, however, optimization has emphasized physical network design, selection and topology of network elements (e.g. which components are needed and how to connect them) and routing architecture. Some methods of the prior art use a combination of admission control and dynamic routing to optimize a network. Some methods of the prior art have attempted to optimize a network with respect to revenues or profits related to the operation of the network. These methods, however, all use simplistic revenue models which do not take into consideration factors such as customer usage over time, customer payment patterns, customer value to the operator, etc. Network optimization methods of the prior art are thus lacking in many respects.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is a system and method for adjusting policies in a communication network. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that the network's profitability is improved. The system and method according to the present invention may produce one or a set of policies for network elements on the network such that other parameters in the network are improved (e.g. average QOS for all customers). As part of the present invention, a symbolic network representation (e.g. a node graph) may be formed. The symbolic network representation may be formed by abstracting and pruning an actual representation of the network. As part of the abstracting step, network elements, resources, applications, and users may be clustered based on a predefined set of rules. Pruning may be accomplished by removing those elements of the symbolic representation which would not limit the performance of the overall network under foreseeable conditions. As a further part of the present invention a symbolic representation of a network to be adjusted may be converted into one or a set of optimization problems. In some embodiments of the present invention, a symbolic representation may be converted into two or more problems or multi-variable functions, where each problem may be semi-independent from the other and may represent a separate portion of the overall network. A set of different algorithms may be used to estimate possible solutions for each optimization problem. In some embodiments, the algorithms may attempt to estimate a solution comprised of a group of network policies intended to optimize the network with respect profitability. The algorithms used may include Greedy Algorithms, Genetic Algorithms, Simulated Annealing, Taboo Search, Branch and Bound, Integer-Programming, Constraint-Programming. Each of the algorithms mentioned above represents a large family of algorithms and each of the specific algorithms may be used with different parameters. For different problem instances, algorithm behavior may change radically. One way of reducing the risk of using an inappropriate algorithm while trying to solve new problems is by combining several algorithms and letting them cooperate and compete through a blackboard system. Different algorithms may compete with one another to produce an estimate of the most optimal solution for a given problem. The possible solution for each problem may be in the form of policies to be implements on a portion of the network represented by the particular problem analyzed. In some embodiments of the present invention, network policies may be adjusted automatically by the present invention.

20040513

20140708

20050113

68680.0

KEEHN, RICHARD G

System and method for generating policies for a communication network

UNDISCOUNTED

ACCEPTED

ACCEPTED

Receivers for television signals

A television signals receiver for receives and stores television signals encoded at a variable data rate. Time information is generated based on the time of receipt of the signals that defines the duration of the television signals when output in decompressed form at a substantially constant data rate. The received signals are then written to a file on a hard disk (13) in received order together with the time information. The time information of signals stored in the file is monitored and old signals are deleted from the file such that the file stores signals corresponding to a predetermined period of time.

1. A method of storing data comprising: receiving data at a variable data rate that represents an information stream; storing the received data; determining the expected duration of the information stream represented by the stored data should the information stream be reproduced as intended; and deleting the oldest stored data when the determined duration reaches a given period such that the determined duration does not exceed the given period. 2. The method of claim 1, wherein the information stream is intended to be reproduced at a substantially constant rate. 3. The method of claim 1, wherein the data represents a video stream. 4. The method of claim 1, wherein the expected duration of the information stream represented by the stored data is determined as the period during which the stored data was received. 5. The method of claim 1, wherein the given period is a default period that may be varied by a user. 6. The method of claim 1, wherein: receiving the data comprises receiving a data stream of compressed video data delivered at a variable data rate; the determination comprises generating time information based on the time of receipt of the data and relating to the duration of the data when output in decompressed form at a substantially constant data rate; storing the data comprises writing the received data to a file in a store in received order together with the time information; and the deletion comprises monitoring the time information of data written to the file and deleting data from the file when the total amount of data in the file corresponds to a period of time greater than a predetermined period so that at any instant in time the amount of data in the file is of a duration no greater than the predetermined period. 7. The method of any one of claims 1, wherein the data is stored as a data file in a memory and the oldest stored data is deleted by moving the start of the data file to data representing information later in the information stream. 8. A method of storing data, comprising storing a data stream as a data file in a memory such that the data file does not exceed a specified size by deleting the oldest stored data from the data file whilst storing new data at the end of the data file, wherein the oldest data is deleted by moving the start of the data file to later in the stored data stream. 9. The method of claim 7, wherein the memory is formatted as plural storage sectors and the data file occupies a series of the storage sectors. 10. The method of claim 9, wherein the start of the data file is identified as at a particular storage sector. 11. The method of claim 10, wherein the start of the file is moved by identifying another particular storage sector later in the series of storage sectors such that the preceding storage sectors in the series are removed from the data file. 12. A method of recording data representing a programme for subsequent playback of the programme, the method comprising: storing one set of received data for one programme in a store while simultaneously outputting the same data for display of the programme represented thereby, the one set of received data being stored in accordance with the method of claim 1; and simultaneously recording another set of received data for another programme in the store. 13. A method of recording television programmes, the method comprising storing times that programmes are to be recorded and revising the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority to the programme having programme type with higher priority on a stored programme type priority list. 14. The method of claim 13, comprising revising the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority in turn to programmes having respective programme types with higher respective priorities on a stored programme type priority list 15. A method of making recordings of plural programmes, the method comprising: generating a priority list identifying types of programmes to be recorded and their relative priorities; storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. 16. A method of controlling a recorder to record programmes, the method comprising: storing a priority list identifying types of programmes to be recorded and their relative priorities; storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; receiving a data stream including data representing programme content, programme identity data and data identifying the broadcast times of programmes; comparing the stored timing information with the received data identifying the broadcast times of programmes; adjusting the stored timing information in the event of a change as determined from the received data identifying the broadcast times of programmes; comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. 17. An apparatus for storing data comprising: a receiver for receiving data at a variable data rate that represents and information stream; a storage device for storing the data; and a processor for determining the expected duration of the information stream represented by the stored data should the information stream be reproduced as intended; wherein the storage device deletes the oldest stored data when the determined duration reaches a given period such that the determined duration does not exceed the given period. 18. The apparatus of claim 17, wherein the information stream is intended to be reproduced at a substantially constant rate. 19. The apparatus of claim 17, wherein the data represents a video stream. 20. The apparatus of claim 17, wherein the processor determines the expected duration of the information stream represented by the stored data as the period during which the stored data was received. 21. The apparatus of claim 17, wherein the given period is a default period and the apparatus comprises means by which a user can vary the default period. 22. The apparatus of claim 17, wherein the storage device is a hard disk. 23. The apparatus of claim 17, wherein: the receiver comprises means for receiving a data stream of compressed video data delivered at a variable data rate; the processor comprises means for generating time information based on the time of receipt of the data and relating to the duration of the data when output in decompressed form at a substantially constant data rate; the storage device comprises means for writing the received data to a file in a store in received order together with the time information; and the processor further comprises means for monitoring the time information of data written to the file and means for deleting data from the file from the file when the total amount of data in the file corresponds to a period of time greater than a predetermined period so that at any instant in time the amount of data in the file is of a duration no greater than the predetermined period. 24. The apparatus of claim 17, wherein the storage device stores the data as a data file in a memory and deletes the oldest stored data by moving the start of the data file to data representing information later in the information stream. 25. An apparatus for storing data, comprising means for storing a data stream as a data file in a memory and a file manager for managing the size of the data file such that it does not exceed a specified size by deleting the oldest data stored in the data file whilst new data is stored at the end of the data file, wherein the file manager deletes the old data by moving the start of the data file to later in the stored data stream. 26. The apparatus of claim 24, wherein the memory is formatted as plural storage sectors and the data file occupies a series of the storage sectors. 27. The apparatus of claim 26, wherein the file manager identifies the start of the data file as at a particular storage sector. 28. The apparatus of claim 27, wherein the file manager moves the start of the file by identifying another particular storage sector later in the series of storage sectors such that the preceding storage sectors in the series are removed from the data file. 29. An apparatus for recording data representing a programme for subsequent playback of the programme, the apparatus comprising: means for storing one set of received data for one programme in a store while simultaneously outputting the same data for display of the programme represented thereby, the one set of received data being stored by the apparatus of claim 17; and means for recording another set of received data for another programme in the store. 30. An apparatus for recording television programmes, the apparatus comprising means for storing times that programmes are to be recorded and means for revising the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority to the programme having programme type with higher priority on a stored programme type priority list. 31. The apparatus of claim 30, wherein the revising means revises the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority in turn to programmes having respective programme types with higher respective priorities on a stored programme type priority list 32. An apparatus for making recordings of plural programmes, the apparatus comprising: means for generating a priority list identifying types of programmes to be recorded and their relative priorities; means for storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; means for comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and means for revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. 33. An apparatus for controlling a recorder to record programmes, the apparatus comprising: means for storing a priority list identifying types of programmes to be recorded and their relative priorities; means for storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; means for receiving a data stream including data representing programme content, programme identity data and data identifying the broadcast times of programmes; means for comparing the stored timing information with the received data identifying the broadcast times of programmes; means for adjusting the stored timing information in the event of a change as determined from the received data identifying the broadcast times of programmes; means for comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and means for revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. 34. A method of recording television programmes comprising: buffering a television signal currently being displayed on a television screen; and responding to a request to record a television programme included in the television signal by saving the buffered television signal along with subsequent television signals to record the programme 35. The method of claim 34, wherein the request to record the television programme comprises pausing display of the television programme. 36. The method of claim 34, wherein the request to record the television programme comprises display of the buffered television signal. 37. The method of claim 34, wherein the saved buffered television signal is truncated to the start of the television programme. 38. A method of displaying a recorded television programme comprising progressively deleting data representing the recorded programme at a given interval behind the programme as it is displayed. 39. An apparatus for recording television programmes comprising: a memory for buffering a television signal currently being displayed on a television screen; and a processor for responding to a request to record a television programme included in the television signal by saving the buffered television signal along with subsequent television signals to record the programme 40. The apparatus of claim 39, wherein the request to record the television programme comprises pausing display of the television programme. 41. The apparatus of claim 39, wherein the request to record the television programme comprises display of the buffered television signal. 42. The apparatus of claim 39, wherein the processor truncates the saved buffered television signal to the start of the television programme. 43. An apparatus for displaying a recorded television programme comprising a processor progressively deleting data representing the recorded programme at a given interval behind the programme as it is displayed. 44. A television signal receiver including the apparatus of claim 17. 45. (canceled) 46. The method of claim 8, wherein the memory is formatted as plural storage sectors and the data file occupies a series of the storage sectors. 47. The method of claim 46, wherein the start of the data file is identified as at a particular storage sector. 48. The method of claim 47, wherein the start of the file is moved by identifying another particular storage sector later in the series of storage sectors such that the preceding storage sectors in the series are removed from the data file. 49. The apparatus of claim 25, wherein the memory is formatted as plural storage sectors and the data file occupies a series of the storage sectors. 50. The apparatus of claim 49, wherein the file manager identifies the start of the data file as at a particular storage sector. 51. The apparatus of claim 50, wherein the file manager moves the start of the file by identifying another particular storage sector later in the series of storage sectors such that the preceding storage sectors in the series are removed from the data file.

This invention relates to methods and apparatus for recording television signals for subsequent playback and, more specifically, to improvements in the storage of data representing television signals and such like and improvements in the control of recording and playback. In recent years there has been a move towards broadcasting television signals in digital form. Suitable receivers/recorders (also known as ‘set top boxes’, but generally referred to herein as ‘receivers’) have been developed to take advantage of the digital format to allow the viewer, among other things, to record one television programme while watching another. An example of such a receiver is described in our International patent application published as WO-A-01/11865, the teachings of which are incorporated in this document by reference. The receiver described in that International patent application is arranged to receive signals representing television programmes and television programme schedule data and has a recorder comprising a “hard disk” for recording received television programmes. The receiver constantly receives updated programme schedule data in a dedicated programme schedule data channel and is arranged to output the programme schedule data for display on a television screen. A user can use the displayed programme schedule data to select programmes for recordal. The receiver is also arranged to receive additional programme schedule information included in each received television channel, which information is used to control the hard disk to record user-selected pre-programmed television programmes. The hard disk is operable to record simultaneously two different television programmes received in different channels. Also, the receiver is operable to replay a currently broadcast programme offset in time. The time offset can be overcome by playing back the part of the programme inside the time offset at an increased frame rate. Furthermore, the receiver is arranged to receive transition signals indicating transitions between parts of programmes. Transitions might be between different items in a magazine format programme, for example a sports magazine programme or music video programme. The recorder is operable to use these transition signals, for example, to skip between parts of recorded programmes replayed from the hard disk. Some receivers include a facility for recording a programme while it is being viewed to enable “instant” playback of a portion of the programme while it is still being broadcast. Instant playback recording might begin automatically when the viewer first switches to a channel and might continue until such time as the viewer switches from the channel or until an allotted memory space is full up. Recording can be automatic as it can be done without any intervention by the viewer. Instant playback recording may be implemented by recording a programme as data in a so-called cyclic file, such as described in EP1185095. A cyclic file is generally a data file of fixed size, e.g. a certain number of bytes such as 2 gigabytes. Data may be recorded in a cyclic file as it is received until the file is full of data. At that point the recording continues from the beginning of the file, writing over the data previously recorded in the file. Thus, the cyclic file always contains the most recent viewed portion of a programme as far as the size of the cyclic file allows. The size of a cyclic file used by a receiver is typically selected such that it can store a length of program likely to be useful to a viewer whilst bearing cost considerations in mind. As memory costs have fallen and sizes of, for example, hard disk memories have increased, the amount of time that can be recorded in cyclic files has increased. At present, a cyclic file may typically be expected to store received video data of approximately 30 minutes to one hour in length, thus giving the viewer the option of instant playback of any portion of a programme from up to one hour previously. Compression techniques are used to compress digital television data before it is transmitted. A frame of video showing, say, a crowd scene is generally much more complex than a frame of video showing, say, a commentator in front of a plain background and thus will be more difficult to compress without introducing unwanted artefacts. Similarly, video including significant changes between frames, such as video of fast moving scenes, is generally more complex than slower changing video. Less compression can therefore be applied to some video, such as the crowd scene, than to other video, such as the commentator, in order to maintain the same level of perceived quality. To try to maintain the same level of perceived quality, but at the same time compress the video data as much as possible, the rate at which video data is transmitted can therefore be varied depending on content. This is known as Variable Bit Rate (VBR) encoding. For example, during transmission of the crowd scene a data rate of 6 megabits per second may be used, while during transmission of the commentator, only 3 megabits per second may be used. It is therefore not possible to know in advance how much disk space will be required to store data for 30 minutes (say) of a programme when VBR encoding is used. Furthermore, it is common for broadcasters to vary the bandwidth allocated to a channel in order to accommodate demands on their networks. For example, a particular uplink to a satellite of a satellite network may have a fixed bandwidth, i.e. data rate, of (say) 20 megabits per second available to transmit data to a given satellite. This bandwidth may be divided between the channels broadcast via the satellite, generally such that the full available bandwidth is exploited, i.e. such that there is little or no spare bandwidth. However, the bandwidth required by each channel may vary from time to time. Furthermore, the number of channels to be transmitted on the uplink may change from time to time, e.g. during the course of a day. The bandwidth allocated to a channel and hence the data rate at which particular programmes are received at a receiver may therefore vary. Again, it is therefore very difficult to determine, in advance, the size of a cyclic file that will be required to store 30 minutes (say) of a given programme. To ensure that a user always has at least 30 minutes (say) of content on the disk, cyclic files have therefore been made as large as may be necessary to cover the worst case, e.g. to make the file large enough to store 30 minutes (say) of video data transmitted with the lowest compression, i.e. at the highest data rate. This is wasteful of disk space. Having to dedicate memory for the greatest possible memory requirement for the cyclic file also limits the user's choice. It may also be unpredictable for a user, as the user is not certain whether the cyclic file contains 30 minutes (say) of a programme, more or less. According to the present invention, there is therefore provided a method of storing data comprising: receiving data at a variable data rate that represents an information stream; storing the data; determining the expected duration of the information stream represented by the stored data should the information stream be reproduced as intended; and deleting the oldest stored data when the determined duration reaches a given period such that the determined duration does not exceed the given period. Also according to the present invention there is provided an apparatus for storing data comprising: a receiver for receiving data at a variable data rate that represents an information stream; a storage device for storing the data; and a processor for determining the expected duration of the information stream represented by the stored data should the information stream be reproduced as intended; wherein the storage device deletes the oldest stored data when the determined duration is greater than a given period such the determined duration does not exceed the given period. Thus, the amount of stored data is determined by the duration of the information the data represents, e.g. by the length of stored video or stored television signals when viewed as normal. This has the advantage of being able to provide a buffer, e.g. for a television signal, that has a maximum capacity defined by the duration of the information it is intended to contain, e.g. a television programme of say 30 minutes, rather than the amount of data that can be stored in the buffer, e.g. 2 gigabytes. This is far more predictable for a user as the user can be more certain of the length of the stored information stream. Provided enough data has been received and stored to reach the given period, the storage device, memory or buffer will always store data representing substantially the given period of the information stream. The information stream is typically a continuous signal intended to be reproduced at a known or predictable rate. For example, the information stream may be a video steam or an audio stream, such as a television or radio signal. In particular it may be a satellite television broadcast using, for example, the Digital Video Broadcast/Moving Picture Experts Group 2 (DVB/MPEG 2) standard. Television signals are normally reproduced at a known number of frames per second. In particular, the information stream may therefore be intended to be reproduced at a substantially constant rate, e.g. a constant frame rate. The expected duration of the stream of information represented by the data can be determined in a variety of ways. For example, the data may contain headers or markers providing timing information for reproduction of the information that can be read to determine the expected duration. The so-called “I-frames” of the MPEG standard may be produced at known intervals and therefore provide such markers. Alternatively, knowledge of the amount of data received, along with it's compression rate where appropriate, may be used to determine expected duration. However, it is particularly preferred that the expected duration of the stream of information represented by the data is determined as the length of the period during which the stored data was received. This exploits the knowledge that for certain signals, such as DVB/MPEG 2 broadcasts, data representing information to be displayed in a particular time period is transmitted over a time period of the substantially same length (although the amount of data in respective periods may vary, e.g. according to the amount of compression applied). In other words, for certain signals, the data received in a one second interval relates to information to be reproduced in a one second interval so that logging the time it takes to receive the data logs the expected duration of the information stream when it is reproduced as intended. The preferred method is particularly straightforward and convenient as it requires minimum processing to implement. The given period is typically a default period, for example stored in software used to implement the method or apparatus. However, it is beneficial for a user to be able to vary the given period. This may allow a user to choose how memory resources are allocated. The apparatus might therefore comprise means, such as a controller, by which the user may vary the given period. Typically, the given period might have a default of 30 minutes and be varied by the user to one of 0 minutes (i.e. turned off), 5 minutes, 15 minutes, 30 minutes or 1 hour, or any other convenient period subject to the maximum memory space available. The storage device may be any of a variety of suitable memory units, such as computer RAM (Random Access Memory), CD-RW (Compact Disc—Re-Writable) drive, DVD-RW (Digital Video/Versatile Disc Re-Writable) drive or Flash memory. However, it is particularly preferred that the storage device is a hard disk drive, such as a conventional computer hard disk. Hard disks have large capacity, are robust and have fast read and write rates. They are therefore suited to this invention, particularly when video data is stored, which has a relatively high data rate. Typically, the received data is therefore stored in a file in a memory. In other words, the storage device stores the data as a file in a memory. The remainder of the memory may be used by other applications or to store other data. To facilitate this, the size of the file may be dynamically adapted to equal the amount of stored data. Whilst the duration of the stream of information represented by the stored data may remain substantially constant, the size of the file in which the data is stored varies according to the amount of stored data, which in turn depends on the rate at which data is received. As it was always necessary for the cyclic files of the prior art to be large enough to cover the worst case, i.e. to store (say) 30 minutes of data received at the maximum data rate, these cyclic files took up a large amount of memory space. However, memory space can be allocated to the stored data of the invention dynamically, as the amount of stored data is monitored according to the duration of the information it represents. Thus, during periods of low received data rate, the file in which the data is stored can be smaller than during periods of high received data rate. Memory space can therefore be allocated to the file and to other applications or other stored data more efficiently. In other words, the need in the prior art to reserve memory space which is surplus to requirements during periods of low received data rate is obviated by the invention. Other applications or stored data might include recordal of entire programmes, or a particular broadcast, between fixed start and end times as facilitated by Personal Video Recorders (PVRs) and such like. Data files for such recordings may be regarded as ‘linear’ in that there is not usually any deletion of the start of the file that limits the size of the file, such as the prior art cycling back to overwrite earlier data with new data Rather, linear files are usually of indeterminate length. An example of how broadcast data is processed for storage in linear files on a hard disk is described in International patent application published as WO-A-01/35669. Broadcast data is transmitted in scrambled form to protect the content from unauthorised viewing. The published patent document describes an apparatus and method for processing scrambled data streams, in which the scrambled data is recorded in its scrambled state and is only descrambled at the time of playback. When a receiver provides instant playback recording of received television programmes as discussed above, it may be desirable to allow a user to save the instant playback recording. A user can then, for example, choose to save an entire programme after it has started by saving the instant playback recording along with the remainder of the programme. However, recordings of entire programmes are usually made in linear files and the instant playback recording is usually made in a cyclic file. The cyclic files and the linear files of the prior art are incompatible with one another. It is not therefore a simple task to convert between a cyclic file structure and a linear file structure. For example, when a cyclic file is stored on a hard disk, a given space on the hard disk, of the predetermined size, is generally permanently allocated to the cyclic file. This can reduce choice and usability for the user by committing memory space that could be allocated to other uses. Furthermore, if, at some stage, it is desirable to store in a linear file the data stored in such a cyclic file, it is necessary to copy the data from the cyclic file into a new linear file. This operation is generally inefficient, for example, in use of processing and memory resources, and undesirable. A preferred feature of the invention is therefore that the data is stored as a data file and that the oldest stored data is deleted by moving the start of the data file to data representing information later in the stream of information. The data can then be stored in effectively the same way as data is stored in a linear file, except that the start of the file can be moved to delete the earliest or oldest data from the file and limit the size of the file. Should it be desired to convert the file to a linear file, movement of the start of the file is simply stopped. This is clearly more efficient than the prior art. The applicants consider this to be new in itself and, according to another aspect of the present invention there is therefore provided a method of storing data, comprising storing a data stream as a data file in a memory such that it does not exceed a specified size by deleting the oldest data from the data file whilst storing new data at the end of the data file, wherein the oldest data is deleted by moving the start of the data file to later in the stored data stream. According to another aspect of the present invention there is provided an apparatus for storing data, comprising means for storing a data stream as a data file in a memory and a file manager for ensuring that the data file does not exceed a specified size by deleting the oldest data from the data file whilst new data is stored at the end of the data file, wherein the file manager deletes the oldest data by moving the start of the data file to later in the file. Unlike the prior art, the oldest data is not simply overwritten. Rather new data is added to the end of the data file as if it were a linear file. The start of the data file is redefined to maintain the size of the file and as the start of the file is moved, the memory used by the oldest data is returned to the memory for general use. Thus, at any particular time, the data file actually resembles a linear file, and can therefore be converted to such simply by stopping the deletion process. Thus, conversion of the file from a “buffer” to a linear file is straightforward. As mentioned above, the memory is typically a hard disk or such like. More generally, the memory may therefore be formatted as plural storage sectors and the data file may occupy a series of the storage sectors. The start of the data file may be identified as at a particular storage sector The start of the data file may be moved by identifying another particular storage sector later in the series of storage sectors such that the preceding storage sectors in the series are removed from the data file. This implementation is particularly convenient. Overall, according to another aspect of the invention there is provided a method of storing data, the method comprising: receiving data in a data stream comprising compressed video data delivered at a variable data rate; generating time information based on the time of receipt of the data and relating to the duration of the data when output in decompressed form at a substantially constant data rate; writing the received data to a file in a store in received order together with the time information; monitoring the time information of data written to the file; and deleting data from the file from the file when the total amount of data in the file corresponds to a period of time greater than a predetermined period so that at any instant in time the amount of data in the file is of a duration equal to or not substantially greater than the predetermined period. According to another aspect of the present invention, there is provided an apparatus for storing data, the apparatus comprising: means for receiving data in a data stream comprising compressed video data delivered at a variable data rate; means for generating time information based on the time of receipt of the data and relating to the duration of the data when output in decompressed form at a substantially constant data rate; means for writing the received data to a file in a store in received order together with the time information; mean for monitoring the time information written to the file; and means for deleting data from the file when the total amount of data in the file corresponds to a period of time greater than a predetermined period so that at any instant in time the amount of data in the file is of a duration equal to or not substantially greater than the predetermined period. According to another aspect of the invention there is provided a method of recording data representing programmes for subsequent playback of the programmes, the method comprising: storing one set of received data for one programme in a store while simultaneously outputting the same data for display of the programme represented thereby, the one set of received data being stored in accordance with the above method; and recording another set of received data for another programme in the store. The invention also provides an apparatus for recording data representing programmes for subsequent playback of the programmes, the apparatus comprising: means for storing one set of received data for one programme in a store while simultaneously outputting the same data for display of the programme represented thereby, the one set of received data being stored by the above apparatus; and means for recording another set of received data for another programme in the store. The invention also provides a method of recording television programmes, the method comprising storing times that programmes are to be recorded and revising the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority to the programme having programme type with higher priority on a stored programme type priority list. The invention also provides an apparatus for recording television programmes, the apparatus comprising means for storing times that programmes are to be recorded and means for revising the stored times if there is a overlap in the time that two or more programmes are to be recorded to give priority to the programme having programme type with higher priority on a stored programme type priority list. The invention also provides a method of making recordings of plural programmes, the method comprising: generating a priority list identifying types of programmes to be recorded and their relative priorities; storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. The invention also provides an apparatus for making recordings of plural programmes, the apparatus comprising: means for generating a priority list identifying types of programmes to be recorded and their relative priorities; means for storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; means for comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and means for revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. The invention further provides a method of controlling a recorder to record programmes, the method comprising: storing a priority list identifying types of programmes to be recorded and their relative priorities; storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; receiving a data stream including data representing programme content, programme identity data and data identifying the broadcast times of programmes; comparing the stored timing information with the received data identifying the broadcast times of programmes; adjusting the stored timing information in the event of a change as determined from the received data identifying the broadcast times of programmes; comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. The invention further provides an apparatus for controlling a recorder to record programmes, the apparatus comprising: means for storing a priority list identifying types of programmes to be recorded and their relative priorities; means for storing timing information relating to one or more programmes to be recorded together with information identifying the type of programme to be recorded; means for receiving a data stream including data representing programme content, programme identity data and data identifying the broadcast times of programmes; means for comparing the stored timing information with the received data identifying the broadcast times of programmes; means for adjusting the stored timing information in the event of a change as determined from the received data identifying the broadcast times of programmes; means for comparing entries on the priority list with the stored timing and type information for each programme to be recorded; and means for revising the stored timing information in the event of a conflict between timing information for two or more programmes to be recorded, depending on the relative priorities of the conflicting programmes. Examples of the invention are now described with reference to the accompanying drawings, in which: FIG. 1 is a schematic functional block diagram of a television receiver; FIG. 2 is a schematic functional block diagram of a hard disk of the television receiver of FIG. 1; FIG. 3 is a schematic representation of a first recording timeline; FIG. 4 is a schematic representation of a second recording timeline; FIG. 5 is a schematic representation of a third recording timeline; FIG. 6 is a schematic representation of a fourth recording timeline; FIG. 7 is a schematic representation of a first conflict screen; FIG. 8 is a schematic representation of a second conflict screen; FIG. 9 is a schematic representation of a third conflict screen; FIG. 10 is a schematic representation of a fourth conflict screen; and FIG. 11 is a schematic representation of a fifth conflict screen. FIG. 1 of the accompanying drawings shows a “set top box” or receiver 3 for receiving television signals from a satellite television broadcast network. In this example, received signals are input to first and second tuners 10a and 10b but any plural number of tuners may be used in the receiver 3. The tuners 10a and 10b are tuneable into the same or different channels of the satellite television broadcast network for simultaneous reception of the same or different television programmes. Signals from the first and second tuners 10a and 10b are passed to a Quadrature Phase Shift Key (QPSK) demodulator 11. Demodulated signals are error-corrected by way of a forward error corrector circuit 12. The receiver 3 has a hard disk 13 which receives from the forward error corrector circuit 12 compressed video and audio data representing received television programmes for recording and subsequent playback, as described in greater detail below. The received signals comprise digitally encoded data. In this example, the data is compressed using the Digital Video Broadcast/Moving Pictures Expert Group 2 (DVB/MPEG 2) standard which permits both programme data and additional data (for example interactive service data) to be transmitted in a single channel. DVB/MPEG 2 enables high compression ratios to be achieved. The hard disk 13 receives and stores compressed data. The data is decompressed only after retrieval from the hard disk 13. Satellite (and indeed cable) programmes are usually scrambled to prevent unauthorised access by non-authorised subscribers. The receiver 3 therefore has a conditional access control circuit 14 which co-operates with a smart card 14a to determine whether the viewer has subscribed to a particular channel and is therefore authorised to access the channel. Parental control over channel access is also provided, at least in part, by the access control circuit 14. The receiver 3 further comprises a descrambling circuit 15 which is controlled by the access control circuit 14 to enable the descrambling of the signal by authorised subscribers. Descrambled data is supplied to a transport/demultiplexer 16 which separates the data into video data, audio data, user services data, programme scheduling data, etc. for distribution to various locations within the receiver 3. The receiver 3 also comprises a video decompression and processing circuit 18 utilizing a dedicated video Random Access Memory (RAM) 17, and an audio decompression and processing circuit 19, operating according to the MPEG 2 standard, for example. The video and audio decompression and processing circuits 18 and 19 receive demultiplexed signals directly from the transport/demultiplexer 16, or from the hard disk 13. Decompressed video signals are input to a Syndicat des Constructions d'Appareits Radiorecepteurs et Television (SCART) interface 20 for direct input to the television (TV) 2 and to a Phase Alternation Line (PAL) encoder 21 where they are encoded into the PAL format for modulation by a Ultra High Frequency (UHF) modulator 22 for output to the UHF input of the TV 2 if so desired. The receiver 3 is controlled by a processor 23 which communicates with the various units of the receiver via a bus 24. The processor 23 has associated with it Read Only Memory (ROM) 25 (optionally including a Compact Disc—Read Only Memory (CD-ROM) drive 25a), Random Access Memory (RAM 26) and a flash (non-volatile and writable) memory 27. The processor 23 controls operation of the receiver 3 by tuning the tuners 10a and 10b to receive signals for the desired channels by controlling the demultiplexing, descrambling and decompression so that the desired programme and/or interactive service data is displayed on the screen of the TV 2, and by controlling the hard disk 13 to record desired television programmes or to play back previously recorded television programmes. Viewer selection of desired programmes and customer services is controlled by viewer manipulation of a remote control unit 28, which in response to such viewer manipulation transmits control signals to a receiver 29 for input to the processor 23. The remote control unit 28 also allows the viewer to control of the operation of the hard disk 13 to record television programmes, to play back recorded television programmes and to program the recording of television programmes, etc. The receiver 3 further comprises a high-speed data interface 30 and a Recommended Standard 232 (RS232) interface 31 providing a serial link. The high-speed data interface 30 and the RS232 interface 31 may be connected to a Personal Computer (PC) and/or a games console and/or other digital equipment (not shown). The high speed data interface 30 enables the receiver 3 to be connected to other devices (not shown), for example to enable reception of services transmitted via other media such as broadband cable, external storage media or digital terrestrial broadcast. The receiver 3 further comprises a modem interface 32 for connecting a telephone network. Operation of the receiver 3 is controlled by software that makes the processor 23 responsive to control signals from the remote control unit 28, additional data in the received signals and/or data stored in the memory units 25 to 27. Interaction between hardware and software in the receiver 3 is described in detail in our international patent application published as WO-A-01/11865. Operation of the receiver 3 in receiving and decoding data representing television programmes and data defining scheduling and other information related to the programmes is described in detail in our international patent application published as WO 96/37996. Operation of the receiver 3 in providing interactive services is described in our international patent application published as WO 97/23997. Within the Digital Video Broadcasting (DVB) standard for digital television broadcast there exists a standard for the transmission of schedule information such that it can be decoded and presented correctly to subscribers in the form of an Electronic Programme Guide (EPG). This DVB standard is known generally as the SI standard and can be found in the specification: ETS 300 468, ETSI Digital Broadcasting Systems for Television, Sound and Data Services; Specification for Service Information (SI) in Digital Video Broadcasting (DVB) Systems 2nd edition. Guidelines for using the specification are given in ETSI ETR 211—DVB SI Guidelines. The receiver 3 is designed to support the SI specification. In addition to operating data for use in controlling access to channels, additional data in a channel can include brief programme schedule data representative of so-called event information tables (EITs) defining the scheduling of programmes in each channel. The programme schedule data is used by the receiver 3 to control the operation of the hard disk 13. When the receiver 3 is programmed to record a selected television programme, the receiver 3 operates the hard disk 13 to start and to stop the recording in accordance with the programme schedule data which comprises the start and the end time of the selected television programme. Since the programme schedule data is updated regularly, the recording is started and stopped in accordance with the updated programme schedule, thus guaranteeing that a selected television programme is actually recorded even in case of a change of programme schedule, because such change is reflected in the programme schedule data in each channel. The programme schedule data may be stored in the RAM 26 and, once stored, the scheduling information is available effectively instantaneously for controlling the operation of the hard disk 13. As discussed above, the programme schedule data is transmitted regularly so that the receiver 3 will be updated substantially continuously. The information is brief to enable each channel to carry the programme schedule data without excessive overheads in terms of bandwidth requirements in each channel and memory requirements in the receiver. In addition, a dedicated EPG channel transmits more detailed programme scheduling information. The information transmitted via this dedicated channel is updated more frequently and covers a longer period of time (e.g. one week). As a consequence, an up-to-date television programme schedule of a complete week will always be available. As explained in greater detail below, the receiver 3 is arranged to display the programme scheduling information on the TV 2. Also, a viewer can interact with the receiver 3 to program recordings of television programmes, view a desired part of the available programme schedule, etc., on the basis of the information received via the dedicated EPG channel. Accordingly, while the programme schedule data in each channel is used by the receiver 3 to operate the hard disk 13 to record a selected television programme in a selected channel at the correct up-to-date time, the programme scheduling information in the dedicated EPG channel is used to display the programme schedule for several of the channels over a predetermined period of time (which in turn is used for programming the receiver 3 as described below). Since the tuners 10a and 10b can be tuned to receive different channels, it is possible for a first television programme in one channel to be displayed on a TV and recorded on the hard disk 13, while at the same time a second television programme in another channel is also recorded on the hard disk 13. The hard disk 13 of the receiver 3 is similar to conventional hard disks used in computer systems for storing large amounts of data. The hard disk 13 has a capacity of many gigabytes (e.g. 40 gigabytes) and receives video and audio data for storage in the compressed form in which it is received, for example, in accordance with the DVB/MPEG 2 standards as discussed above. This allows for the storage of several hours of television programmes (e.g. 20+ hours) on the hard disk 13. The hard disk 13 comprises two storage areas, one for the storage of television programme data, and the other for storing “metadata” which is used to control the hard disk 13, as discussed in greater detail in our earlier patent publications mentioned above. The processor 23 controls the operation of the hard disk 13. More-specifically, the processor 23 controls the recording and playback of television programmes to and from the hard disk 13. Other processors (not shown) can be used to control the hard disk 13 as appropriate, but the control is described in this document with reference to only processor 23 to facilitate understanding. Referring to FIG. 2, a schematic block diagram of the arrangement of the hard disk 13 is shown. In this example, the hard disk 13 has three data channels, through two of which data is received for storage on the hard disk 13 and through one of which data is output for subsequent displaying of television pictures. The three data channels consist of two data input channels 54 and 55 and one data output channel 56. Each of the data channels has associated with it a data buffer 57, 58 and 59, respectively. Each of the data buffers 57, 58 and 59 comprises a RAM of sufficient size to store several seconds of data (e.g. 8 megabytes). The operation of the data buffers 57, 58 and 59, as well as that of the hard disk 13, is controlled by the processor 23. The hard disk 13 is operable to manage simultaneous reception of data through the data channels 54 and 55 and output of data through the data channel 56. Data received through the data channels 54 and 55 is not stored directly on the hard disk 13 as it is received but is buffered by the buffers 57 and 58, respectively. Likewise, data to be output through the data channel 56 is not output directly as it is read from the hard disk 13 but is buffered in the buffer 59. The hard disk 13 is capable of managing a data rate that is higher than the rate at which data can be transferred through at least two of the three channels 54, 55 and 56. Indeed, in this example, the hard disk 13 is capable of managing a data rate at least as high as the rate of data transmitted through all three channels 54, 55 and 56 combined. The hard disk 13 is therefore capable of simultaneously storing data received through both the input channels 54 and 55 and outputting data through the output channel 56. This is achieved by buffering the received data and the data to be output in the buffers 57, 58 and 59, and by switching between them in order to transfer data from the input buffers 57 and 58 to the hard disk 13, or to transfer data from the hard disk 13 to the buffer 59. Although hard disks comprising separate heads for writing and reading are available, in the interest of cost, in this example, the hard disk 13 comprises one single head for both writing onto and reading from the hard disk 13. Therefore, while the hard disk 13 at any point in time stores/reads data associated with only one of the three data channels 54, 55 and 56, it sequentially stores/reads data associated with the three channels 54, 55 and 56, thereby “virtually” dealing with the three data channels 54, 55 and 56 simultaneously. The switching is controlled by the processor 23 by arbitrating between any three of the buffers 57, 58 and 59 at a frequency which is in accordance with their buffer size so as to prevent a data overflow and thereby data loss. For example, if the buffers 57, 58 and 59 are capable of storing 8 megabytes of received data each, and the receiver 3 is operated to record two simultaneous television programmes received through the channels 54 and 55 at an average data rate of approximately 2 megabytes per second, then the hard disk 13 is operated to receive alternately data from the buffers 57 and 58 at an alternation cycle of 4 seconds or preferably less, transferring the buffer content to the hard disk 13 each time the processor switches from one of the buffers 57, 58 to the other. Accordingly, it is possible to record simultaneous/overlapping television programmes received by the first and second tuners 10a, 10b in different channels. The buffering of incoming as well as outgoing data by the data buffers 57, 58 and 59 means that the hard disk 13 does not need to be synchronised to a particular input or output data rate. Instead, the hard disk 13 always reads and stores data at the same constant data rate. The amount of data stored on or read from the hard disk 13 is determined by the duration for which the hard disk 13 is switched for data transfer to the respective one of the data buffers 57, 58 or 59. During such time data is transferred from or to the respective data buffer 57, 58 or 59 at the constant data rate. While the reception data rate through the channels 54 and 55 or the output data rate through the channel 56 may vary (for example depending on the bandwidth of received television signals, or depending on the playback mode), the intermittent rate of data transfer between any of the buffers 57, 58 and 59 and the hard disk 13 is constant and determined by the data rate at which the hard disk 13 works. The hard disk 13 is substantially the same as a hard disk from a conventional personal computer. As for computer data file systems, data is stored on the hard disk 13 in sectors, which might each store say 512 kilobytes of data and may or may not be contiguous on the hard disk 13. The processor 23 uses file system software to manage the storing of data on the hard disk 13 such that, regardless of how data is actually stored on the hard disk 13, it appears to be input and output as contiguous stream of data. More specifically, the processor 23 maintains a file allocation table. When data is to be written on the hard disk 13, the processor 23 allocates sectors of the hard disk 13 to a new file. The file allocation table effectively links sectors of the hard disk 13 together to form individual files as necessary, despite the individual sectors not neccessarily being contiguous. A time counter 23a for maintaining a record of the playback duration of the programme data recorded on the hard disk 13 is associated with the processor 23. The counter 23a is shown as a separate unit from the processor 23 to facilitate understanding. It will however be appreciated from the following that the counting function of the counter 23a may in practice be performed by registers within, or software running on, the processor 23. In this example, there is a close correlation between the relative timing of different portions of the data received at the receiver 3 (the arrival time) and the relative timing of the portions when they are intended to be displayed (the presentation time). This correlation exists despite the fact that the rate at which data is transmitted (i.e. the amount of data transmitted during a period), and therefore received, varies depending on content because, regardless of content, it takes approximately one second to broadcast data for one second of a programme. The processor 23 and the counter 23a take advantage of this to ‘count’ time in the incoming programme data. In this example, the counter does not simply count time from the beginning of programme data to be stored in a file as this can be complex if old data at the beginning of the file is deleted. Instead, the counter counts an absolute time (GMT or UTC for example). The count data is appended to the programme data as it is written to the disk 13 in this example. In another example, the count data is written to a separate index register file on the disk 13, for example in the metadata area of the disk 13 mentioned above. As programme data is received by the receiver 3, it can be written to a file on the hard disk 13. More specifically, the received programme data can be stored on the hard disk 13 as a linear file or in a so-called “review buffer”. A linear file has a defined start and programme data is added to the file from the start until a defined end is reached. In contrast, the review buffer has a defined start, but once the file contains programme data of a specified duration, the processor 23 deletes the beginning of the file and continues to record received programme data in the file in new sectors of the hard disk 13. (In practice, the new sectors might include some or all of those sectors that contained the data deleted from the beginning of the file, but only if the processor happens to allocate those new sectors to the file. This is not the same as simply overwriting sectors already permanently allocated to the file.) The count data is most useful for the review buffer. For example, the processor 23 can monitor the count data for the programme data as it is written to a file on the hard disk 13. When the processor determines that the programme data in the file has a specified duration, the processor 23 can delete the beginning of the file whilst new programme data is written at the end of the file such that the programme data stored in the file does not exceed the specified duration. More specifically, the processor 23 can move the start of the file. For example, the processor 23 can identify the sector in which the file starts and then locate a subsequent sector of the file from the file allocation table to which to move the start of the file, such that the sectors preceding the new start of the file are deleted from the file. The count data can be used to control movement of the start of the file, i.e. to locate the subsequent sector to which to move the start of the file. When the count data is appended to the programme data as it is written to the data file, the processor 23 reads the count data from the file. When the count data indicates that (say) 30 seconds of programme data has elapsed from the start of the file, the start of the file is moved to the sector storing data including that point in the file. When the counter 23a and processor 23 subsequently indicate that (say) 30 seconds of new programme data has been written at the end of the file, the start of the file is then moved again and so on. If the count data is stored in the separate index register, the processor 23 operates in the same manner, except that data in the index register is read to identify a point in the file at which (say) 30 seconds of the programme has elapsed. In one example, the index register may store the number of bytes of data periodically received and the new start of the file can be identified by summing the number of bytes for the desired period (e.g. 30 seconds). This method of storing data provides the receiver 3 with greater flexibility than has previously been possible. In particular, the receiver 3 can change from recording just the last 30 minutes (say) of the programme in a review buffer, to recording the programme in its entirety in a linear file straightforwardly, as long as the viewer selects ‘record’ for the programme within 30 minutes (say) from the start of the programme. This is achieved by stopping moving the start of the review buffer. As soon as this is done, the review buffer is effectively converted to a linear file. A new review buffer can then be straightforwardly created by starting a new file if desired. FIG. 3 of the accompanying drawings illustrates one way in which the hard disk 13 is controlled to store data during the recording of a programme. The hard disk 13 is arranged to record by default the programme currently being viewed by the viewer in a file on the hard disk 13. This file is referred to as a “review buffer” as mentioned above. Under this default condition, which is depicted by time line A in FIG. 3, the hard disk 13 will store up to 30 minutes (say) of the current programme. Typically, this length of time is preset as a default time of 30 minutes during manufacture or configuration of the receiver 3, but it may be user selected to be 0 minutes (i.e. turned off), 5 minutes, 15 minutes, 30 minutes or 1 hour for example. Generally, any period up to an hour could be chosen by a user. The recording begins when the user switches on the receiver 3 or when he switches to a new channel. Recording continues until the designated period of time has been recorded and thereafter continues with the oldest or earliest parts of the recording being deleted such that only the selected length of the programme is retained. This default recording operation is a background operation and requires no user interaction. Time line B shows progression of the recording shown in time line A during the broadcast of a programme. In time line B, the length of the current programme stored in the review buffer is at it's maximum and does not include all of the programme from the time when the user switched on the receiver 3 or switched channels. The same time line is also shown as time line C of FIG. 3 at a later time when the review buffer includes the end of the previous current programme and the beginning of a succeeding programme, i.e. extends on both sides of a programme start. In the event that the user presses a “pause” button on the receiver 3 or the remote control unit 28 during normal viewing of a broadcast programme, the receiver 3 enters a “live pause” mode. In this mode a paused frame of video is displayed on the TV 2, but the programme continues to be recorded. More specifically, if, as shown in time line C, the review buffer includes the start of a programme when the live pause mode is entered, the content of the review buffer is truncated to the start time of the current programme as shown in time line D. In other words, all data stored in the review buffer that is older than the start of the current programme is deleted. If the start time is not included in the review buffer when the live pause mode is entered, the entire programme recorded so far, i.e. all the data in the review buffer, is retained. Thereafter, as shown in time line D, recording continues with all data being held in the file. More specifically, the review buffer is converted to a linear file by the deletion of data from the file being suspended. At the programme boundary, e.g. when the start of the next programme is received, the recordal of data in the linear file is stopped and the next programme starts to be recorded in a new review buffer, as shown in time lines D, E and F. The linear file therefore includes the recorded programme, either in its entirety, or from the (say) 30 minutes (or whatever period is set by the user) from before the instant when the pause button was pressed until the end of the programme. The new review buffer contains the succeeding programme from the start. In time line D, the viewer has commenced navigation within the recorded file by pressing the “play” button or the “fast forward” button on remote control 28 and the receiver 3 is displaying the programme stored in the linear file. At the point shown in time line E, the receiver 3 has reached the end of the programme stored in the linear file. In the meantime, the new review buffer has recorded the next succeeding programme for the default or selected period of time and is continuing to record the programme by deleting the earliest part of the recorded programme from the buffer. As the viewer cannot therefore view the start of the next succeeding programme (as it has already been deleted from the new review buffer), the receiver 3 returns the viewed to normal viewing by displaying the live broadcast as illustrated in time line F. The receiver is therefore effectively in the same state as in time line B, but with the viewer watching, and the review buffer recording, a later broadcast programme. Time lines A, B and C of FIG. 4 are identical to time lines A, B and C of FIG. 3. Time line D of FIG. 4 illustrates recordal of the current programme in live pause mode before the next succeeding programme starts to be recorded in a new review buffer. In time line E of FIG. 4, the viewer has pressed the “fast forward” button on the remote control 28 and the receiver 3 is displaying the programme recorded in the linear file at an increased rate. In time line F of FIG. 4, the receiver 3 has displayed all of the programme recorded in the linear file and, in this example, is displaying the next succeeding programme as recorded in the new review buffer. As can be seen from time lines E and F, the new review buffer has not reached its maximum capacity and still contains the start of the next programme when all of the programme stored in the linear file has been displayed. The receiver 3 can therefore seamlessly catch up with the live broadcast by displaying the contents of the linear file and the new review buffer at an increased rate. In another example, even when the review buffer includes the start of the next programme, the viewer is returned to, i.e. the receiver 3 displays, the live broadcast. Typically, the user is given a choice between these two examples, e.g. by display of an appropriate message. In the above example, the live pause mode causes the entire review buffer (subject to truncation) to be retained (as linear file) until the recorded programme has been viewed to the end. Thus, the viewer can rewind to beginning of the programme or to the length of the review buffer before live pause mode was entered at any time until entire programme has been viewed. In another example, as soon as the viewer starts to view the recorded programme, e.g. by pressing the “play” or “fast forward” buttons on the remote control 28, deletion of the start of the file recommences. More specifically, programme data before the default time of (say) 30 minutes or the selected time mentioned above from the point in the recorded programme being viewed is deleted from the file. (In the event that the selected time is 0 minutes, programme data before 5 minutes from the point in the recorded programme being viewed is deleted from the file.) Memory space is therefore made freely available more quickly than in the previous example. Time lines A and B of FIG. 5 are the same as time lines A and B of FIG. 3. However, in time line C of FIG. 5, the viewer presses a save button on the remote control 28 instead of the pause button as in time line C of FIG. 3. Whilst the receiver therefore truncates the review buffer to the start of the programme being recorded in the review buffer and converts the review buffer to a linear file as in time line D of FIG. 3, in time lines D and E of FIG. 5, the receiver 3 saves the linear file. In particular, the title of the recorded programme is added to the user's personal planner. The saving is actually carried out at the end of the recorded programme. In addition, if the user changes channel after pressing the save button, the receiver continues to record the programme and the programme received in the new channel is recorded in a new review buffer. Time lines A to D of FIG. 6 are the same as time lines A to D of FIG. 3. However, in time line E, whilst the viewer is fast forwarding through the stored programme, the viewer decides to save the programme and presses the save key on the remote control 28. The receiver 3 therefore saves the linear file at the end of the programme by adding the programme name to the viewer's personal planner and returns the viewer to the live broadcast in a similar manner to time lines E and F of FIG. 3. The receiver 3 is able to record one programme, while another programme is being both viewed and recorded. The receiver also automatically records programmes in a review buffer or in a linear file without specific input from a user. This greater flexibility and automation in recording brings with it the possibility of conflict between demands for memory space of the hard disk 13. For example, allowing two programmes to be recorded simultaneously increases the likelihood of a conflict occurring between programmes selected to be recorded and programmes already recorded. In order to deal with this problem, the receiver 13 includes a priority table, that may be user defined, but is normally defined on configuration of the receiver 13. One way in which existing recordings can be prioritised is to allow the viewer to select recordings that should never be automatically deleted (“keep events”) and to make decisions based on that selection. Keep events take priority over any other recording and, if the hard disk is already full of keep events, other recordings including automatic recordings in the review buffer are abandoned in order to preserve the keep events. The next highest priority is given to pay-per-view (PPV) programmes. These programmes are paid for and the viewer would therefore be unhappy if a PPV recording was erased before being viewed. Next is other recorded but not yet viewed programmes, followed by recordings already viewed and recordings made while a programme was being viewed (e.g. the review buffer). Part-recorded programmes have lower priority than full recordings. Thus, if there is a disk space conflict, the first recordings to be deleted are the recordings made while a programme was being viewed followed by recordings that have already been viewed, then other recorded programmes and so on up to PPV programmes. Keep events are not usually automatically deleted. Conflicts can also occur between programmes identified for recording. These conflicts can be dealt with in a similar manner by prioritising the programmes to be recorded. In this example, the highest priority is given to keep events, then PPV programmes, then scheduled programmes that are series linked (e.g. an ongoing soap opera or series) and then other scheduled programmes. The review buffer has lowest priority since it is a record of what the viewer has just seen. If two programmes were to fall into the same priority group or category then the shorter programme is recorded in favour of the longer programme in the absence of any other input from the viewer. The receiver 3 may include the facility for extra-time recording in which a recording begins early or ends late in order to accommodate slight slippage in the broadcasting schedule. This extra time recording can cause conflicts with a start time for one programme being earlier than a finish time for another programme. In this example, this conflict is dealt with by providing the end of one programme with priority over the start of another and by giving a real end time priority over an extended end time. This automatic prioritising of recordings need only be applied in the absence of further input from the viewer. Conflicts can develop after the receiver 3 has been programmed because of a slip or other change in the scheduled broadcast time of thee programme. In the event that a conflict develops, the receiver 3 is arranged to display a warning when the viewer turns on the receiver 3, inviting the viewer to adjust the programmed recordings. If the viewer does not turn on the receiver 3 before the conflicting programmes are broadcast, then the prioritising rules will be applied. Conflicts can, of course, also occur when the viewer is programming the receiver 3 to record programmes. In either case, the receiver 3 will output display screens identifying the conflict and suggesting changes to the programmed recording in order to resolve the conflict. The suggested changes are made based on the defined priority rules. An example of a warning display screen is shown in FIG. 7 of the drawings. Here the viewer is watching channel 310 Sky Premier and the receiver is programmed to record both Enemy of the State and Shark Files. There are only two tuners 10a, 10b and so one of the recordings will have to be sacrificed if the viewer is to continue watching channel 310 Sky Premier. The viewer can interact with the display screen to cancel the recording of either Enemy of the State or Shark Files, or can leave the programming as is, to end his viewing of channel 310 Sky Premier. An example of a recording clash warning screen is shown in FIG. 8 of the drawings. Here the viewer has previously programmed the receiver to record Enemy of the State and Shark Files at times that overlap. The viewer has then attempted to record The X Files at a time that conflicts with the broadcast (and recording) time of the other two programmes. A message, similar to that displayed on the screen of FIG. 7, is displayed advising the viewer on how to resolve the conflict. Another example of a recording clash warning screen is shown in FIG. 9 of the drawings. Here the receiver 3 has been programmed to record Simpsons and Charmed through one receiver 10a and The Matrix and Weakest Link through the other receiver 10b. Simpsons and The Matrix both end at 7.30 pm, and Charmed and Weakest Link both start at 7.30 pm. When Heartbeat is added to the recording schedule a conflict occurs. The receiver 3 generates the display screen as shown, identifying the conflict with a highlight 300 and suggesting changes by highlighting a programme 302 (in this case Simpsons) that should be deleted. Viewer interaction will result in the screen being changed to that shown in FIG. 10, in which programme 302 is no longer shown and programme 304 (Weakest Link) is highlighted as the suggested deletion. Further interaction will result in the screen shown in FIG. 11 being displayed, in which Heartbeat is programmed to be recorded via one receiver 10a, and The Matrix and Charmed are programmed to be recorded via the other receiver 10b. Other screens are of course possible depending on the number of tuners 10a, 10b, the priority rules and other features of the system. Modifications and variations such as will occur to those possessed of appropriate knowledge and skills may be made to the above examples without departure from the spirit and scope of the invention as set out in the appended claims and equivalents thereof.

20041207

20150901

20060810

88315.0

H04N7173

CHEN, CAI Y

RECEIVERS FOR TELEVISION SIGNALS

UNDISCOUNTED

ACCEPTED

H04N

ACCEPTED

2-(3-Sulfonylamino-2-oxopyrrolidin-1-yl)propanamides as factor xa inhibitors

The invention relates to compounds of formula (I) pharmaceutical compositions containing the same as well as methods of treating patients suffering from a condition susceptible to amelioration by a Factor Xa inhibitor using the same.

1. A compound of formula (I) (I) wherein: R1 represents hydrogen or —C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents hydrogen, —C1-4alkyl, —C3-4alkenyl, —C2-4alkylOH, —C2-4alkylOC1-4alkyl, —C1-4alkylCN or —C0-4alkylC3-6cycloalkyl; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-4alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y; X represents —C1-4alkylene- optionally substitued by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached; Y represents —C3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing at least one heteroatom selected from O, N or S and optionally substituted at C and/or N atoms by —C1-3alkyl, C1-3alkoxy, C1-3alkylOH, halogen, —CN, —CF3, —NH2, —CO2H and —OH; Ra and Rb independently represent hydrogen or —C1-4alkyl; Rc and Rd independently represent hydrogen or —C1-4alkyl or together with the N atom to which they are attached form a non-aromatic 5-, 6- or 7-membered heterocyclic group optionally substituted by a heteroatom selected from O, N or S; Re represents —C1-4alkyl or —CF3; Rf represents NO2 or CN; R6 represents a group selected from: Z represents an optional substituent halogen, alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; and pharmaceutically acceptable derivatives thereof. 2. A compound of formula (I) as claimed in claim 1 wherein: R1 represents hydrogen or —C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents —C1-4alkyl, —C2-4alkylOH, —C1-4alkylCN, —C3-6cycloalkyl; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-4alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or —C1-3alkyl; R6 represents a group selected from: Z represents an optional substituent halogen, alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; and pharmaceutically acceptable salts and solvates thereof. 3. A compound as claimed in claim 1 wherein R1 represents hydrogen or —CH2CONH2. 4. A compound as claimed in claim 1 wherein one of R2 and R3 represents methyl and the other represents hydrogen. 5. A compound as claimed in claim 1 wherein R4 represents —C1-4alkyl, —C3-4alkenyl, —C2-4alkylOH, —C2-4alkylOC1-4alkyl, —C1-4alkylCN or —C0-4alkylC3-6cycloalkyl. 6. A compound as claimed in claim 1 wherein R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-4alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y. X represents —C1-3alkylene- optionally substituted by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached; Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl. 7. A compound as claimed in claim 6 wherein R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHC(NH2)═NRf, or a group X—Y; X represents —C1-3alkylene-; Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl. 8. A compound as claimed in claim 1 wherein R6 represents a group selected from: chloronaphthylene, chlorobenzothiophene, chlorobithiophene, chlorophenylethene or (chlorothienyl)ethene. 9. A compounds as claimed in claim 1 selected from: (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-3-ylmethyl)propanamide (2S)-N-(2-Azepan-1-ylethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl)-N-isopropyl-beta-alaninamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N ,N-dimethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N ,N-dipropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclobutylpropanamide (2S)-2-((3S)-3-(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-N-[2-(Aminosulfonyl)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(1H-pyrazol-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[3-(4-methylpiperazin-1-yl)propyl]propanamide formate tert-Butyl 2-[[(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate tert-Butyl 3-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]propylcarbamate tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](cyclopropylmethyl)amino]ethylcarbamate (2S)-N-(2-Aminoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(3-Aminopropyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{3-[(methylsulfonyl)amino]propyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[3-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)propyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[2-(methylamino)ethyl]propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide (2S)-N-{3-[(Aminocarbonyl)amino]propyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(E)-2-(5-chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(6-chloro-1-benzothien-2-yl)sulfonyl]amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide. 10. (Cancelled). 11. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutical carrier and/or excipient. 12. (Cancelled). 13. A method of treating a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor comprising administering a therapeutically effective amount of a compound according to claim 1. 14. A process for preparing a compound of formula (I) which comprises: reacting a compound of formula (II) with a compound of formula (III): OR: reacting a compound of formula (XIV) with a compound of formula (VI): OR: reacting a compound of formula (XV) with a compound of formula (VIII):

FIELD OF THE INVENTION The present invention relates to a novel class of chemical compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly use in the amelioration of a clinical condition for which a Factor Xa inhibitor is indicated. BACKGROUND OF THE INVENTION Factor Xa is a member of the trypsin-like serine protease class of enzymes. It is a key enzyme in the coagulation cascade. A one-to-one binding of Factors Xa and Va with calcium ions and phospholipid converts prothrombin into thrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina. Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a pre-disposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure. Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M. A., Ann. NY Acad. Sci., 405: 349 (1986)). A Factor Xa inhibitor may be useful in the treatment of acute vascular diseases such as coronary thrombosis (for example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke. They may also have utility as anticoagulant agents both in-vivo and ex-vivo, and in oedema and inflammation. Thrombin has been reported to contribute to lung fibroblast proliferation, thus, Factor Xa inhibitors could be useful for the treatment of some pulmonary fibrotic diseases. Factor Xa inhibitors could also be useful in the treatment of tumour metastasis, preventing the fibrin deposition and metastasis caused by the inappropriate activation of Factor Xa by cysteine proteinases produced by certain tumour cells. Thrombin can induce neurite retraction and thus Factor Xa inhibitors may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. They have also been reported for use in conjunction with thrombolytic agents, thus permitting the use of a lower dose of thrombolytic agent. DESCRIPTION OF THE INVENTION The present invention provides compounds of formula (I): wherein: R1 represents hydrogen or —C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents hydrogen, —C1-4alkyl, —C3-4alkenyl, —C2-4alkylOH, —C2-4allkylOC1-4alkyl, —C1-4alkylCN or —C0-4alkylC3-6cycloalkyl; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-4alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y; X represents —C1-4alkylene- optionally substituted by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached; Y represents —C3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing at least one heteroatom selected from O, N or S and optionally substituted at C and/or N atoms by —C1-3alkyl, C1-3alkoxy, C1-3alkylOH, halogen, —CN, —CF3, —NH2, —CO2H and —OH; Ra and Rb independently represent hydrogen or —C1-4alkyl; Rc and Rd independently represent hydrogen or —C1-4alkyl or together with the N atom to which they are attached form a non-aromatic 5-, 6- or 7-membered heterocyclic group optionally substituted by a heteroatom selected from O, N or S; Re represents —C1-4alkyl or CF3; Rf represents NO2 or CN; R6 represents a group selected from: Z represents an optional substituent halogen, alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; and pharmaceutically acceptable derivatives thereof. Further aspects of the invention are: A pharmaceutical composition comprising a compound of the invention together with a pharmaceutical carrier and/or excipient. A compound of the invention for use in therapy. Use of a compound of the invention for the manufacture of a medicament for the treatment of a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor. A method of treating a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor comprising administering a therapeutically effective amount of a compound of the invention. The compounds of formula (I) contain chiral (asymmetric) centres. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these arc within the scope of the present invention. The present invention also provides certain compounds of formula (I) which are represented by formula (IA): wherein: R1 represents hydrogen or —C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents —C1-4alkyl, —C2-4alkylOH, —C1-4alkylCN, —C3-6cycloalkyl; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-4alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or —C1-3alkyl; R6 represents a group selected from: Z represents an optional substituent halogen, alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; and pharmaceutically acceptable salts and solvates thereof. Preferably R1 represents hydrogen or —C1-3alkylCONH2. More preferably R1 represents hydrogen or —CH2CONH2. Preferably, one of R2 and R3 represents methyl and the other represents hydrogen. Preferably, R4 represents —C1-4alkyl, —C3-4alkenyl, —C2-4alkylOH, —C2-4alkylOC1-4alkyl, —C1-4alkylCN or —C0-4alkylC3-6cycloalkyl. More preferably, R4 represents —C1-3alkyl, —C1-3alkylCN or —C0-4alkylC3-6cycloalkyl. Even more preferably, R4 represents —C1-3alkyl, —CH2CH2CN, —CH2cyclopropyl or —C3-5cycloalkyl. In another preferred aspect, R4 represents —C1-4alkyl, —C2-4alkylOH or —C1-4alkylCN. Preferably R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-4alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, —C2-4alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y. X represents —C1-4alkylene- optionally substituted by —OH, or a direct link, with the proviso that when X is substituted by —OH, X represents C2-4alkylene and the —OH group is not alpha with respect to the amide N atom to which the group X is attached; Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl. More preferably, R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y; X represents —C1-3alkylene-; Y represents phenyl, or an aromatic or non-aromatic 5-, 6- or 7-membered heterocyclic group containing one or two heteroatoms selected from O, N or S atoms and optionally substituted at C and/or N atoms by —C1-3alkyl. Even more preferably, R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-3alkylCN, —C1-4alkylCONRcRd, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-3alkylNHCONRaRb, —C2-3alkylNHSO2Re, —C2-4alkylSO2NRaRb, —C2-4alkylNHCO2C1-4alkyl, —C2-4alkylNHC(NH2)═NRf, or a group X—Y; X represents —C1-3alkylene-; Y represents phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine. Most preferably, R5 represents —C1-3alkyl, —C2-3alkylOH, —C1-2alkylCN, —C2-3alkylOCH3, —C2-3alkylNRaRb, —C1-2alkylCONH2, —CH2CH2NHCOCH3, —C2-3alkylNHSO2CH3, —CH2CH2SO2NH2, —C2-3alkylNHCONH2, —C2-3alkylNHCO2C4alkyl, —C2-3alkylNHC(NH2)═NNO2, or —C1-3alkylW wherein W represents thiophene, pyridine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine. In another preferred aspect, R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethylencimine and optionally substituted at C and/or N atoms by —C1-3alkyl. When Y is a heterocycle selected from thiophene, tetrahydrofuran or pyridine, the heterocyclic ring is C-linked to X. When Y represents a heterocycle selected from imidazole, pyrrolidine, piperidine, morpholine, piperazine, pyrazole or hexamethyleneimine, the heterocyclic ring is C-linked or N-linked to X. Preferably, when Y represents a heterocyclic ring selected from pyrrolidine, piperazine, morpholine or hexamethyleneimine, the heterocyclic ring is N-linked to X. Preferably, R6 represents a group selected from: chloronaphthylene, chlorobenzothiophene, chlorobithiophene, chlorophenylethene or (chlorothienyl)ethene. More preferably, R6 represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, or 5′-(chlorothienyl)ethene. Most preferably, R6 represents 6-chloro-1-benzothiophene, 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene or (4-chlorophenyl)ethene. Preferably, Ra and Rb independently represent hydrogen or methyl. Preferably, Rc and Rd independently represent hydrogen or —C1-3alkyl; Preferably, Rf represents NO2, It is to be understood that the present invention covers all combinations of preferred, more preferred, even more prefered and most preferred groups described herein above. The present invention also provides compounds of formula (I) wherein: R1 represents H or C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethyleneimine and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, 5chloro-1-benzothiophene, 6-chloro-1-benzothiophene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethyleneimine and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-3alkylOH, —C1-4alkyl, —C2-3alkylOCH3, —C1-3alkylCN, —C1-3alkylCONH2, —C2-3alkylN(CH3)(CH3), —C2-3alkylNHCOCH3, —C2-3alkylNHCONRaRb, —C2-3alkylNHSO2Ra, —C1-3alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, pyrrolidine, pyridine, piperidine or hexamethyleneimine; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, 5-chloro-1-benzothiophene, 6-chloro-1-benzothiophene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or C1-3alkylCONRaRb; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-3alkylOH, —C1-4alkyl, —C2-3alkylOCH3, —C1-3alkylCN, —C1-3alkylCONH2, —C2-3alkylN(CH3)(CH3), —C2-3alkylNHCOCH3, —C2-3alkylNHCONRaRb, —C2-3alkylNHSO2Ra, —C1-3alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, pyrrolidine, pyridine, piperidine or hexamethyleneimine; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or CH2CONH2; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethyleneimine and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, 5-chloro-1-benzothiophene, 6-chloro-1-benzothiophene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or CH2CONH2; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-4alkylOH, —C1-4alkyl, —C2-4alkylOC1-3alkyl, —C1-4alkylCN, —C1-4alkylCONRaRb, —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, —C2-4alkylNHCONRaRb, C2-4alkylNHSO2Ra, —C1-4alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, tetrahydrofuran, pyrrolidine, imidazole, pyridine, piperidine, morpholine or hexamethyleneimine and optionally substituted at C and/or N atoms by —C1-3alkyl; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or CH2CONH2; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-3alkylOH, —C1-4alkyl, —C2-3alkylOCH3, —C1-3alkylCN, —C1-3alkylCONH2, —C2-3alkylN(CH3)(CH3), —C2-3alkylNHCOCH3, —C2-3alkylNHCONRaRb, —C2-3alkylNHSO2Ra, —C2-3alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, pyrrolidine, pyridine, piperidine or hexamethyleneimine; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene, 5′-chloro-2,2′-bithiophene, (4-chlorophenyl)ethene, 5-chloro-1-benzothiophene, 6-chloro-1-benzothiophene; and pharmaceutically acceptable salts and solvates thereof. The present invention also provides compounds of formula (I) wherein: R1 represents H or CH2CONH2; One of R2 and R3 represents —C1-3alkyl and the other represents hydrogen; R4 represents C1-4alkyl, C2-4alkylOH or C1-4alkylCN; R5 represents —C2-3alkylOH, —C1-4alkyl, —C2-3alkylOCH3, —C1-3alkylCN, —C1-3alkylCONH2, —C2-3alkylN(CH3)(CH3), —C2-3alkylNHCOCH3, —C2-3alkylNHCONRaRb, —C2-3alkylNHSO2Ra, —C1-3alkylSO2NRaRb, or a group X—Y; X represents —C1-3alkylene- or a direct link; Y represents —C3-6cycloalkyl, phenyl, or a heterocyclic group selected from thiophene, pyrrolidine, pyridine, piperidine or hexamethyleneimine; Ra and Rb independently represent hydrogen or C1-3alkyl; R6 represents 6-chloronaphthylene; and pharmaceutically acceptable salts and solvates thereof. As used herein, the terms “alkyl” and “alkoxy” mean both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl (—CH3), ethyl (—C2H5), propyl (—C3H7) and butyl (—C4H9). Examples of alkoxy groups include methoxy (—OCH3) and ethoxy (—OC2H5). As used herein, the term “alkylene” means both straight and branched chain saturated hydrocarbon linker groups. Examples of alkylene groups include methylene (—CH2—), ethylene (—CH2CH2—) and propylene (—CH2CH2CH2—). As used herein, the term “alkenylene” means both straight and branched chain unsaturated hydrocarbon linker groups, wherein the unsaturation is present only as double bonds. Examples of alkenylene groups includes ethenylene (—CH═CH—) and propenylene (—CH2—CH═CH—). As used herein, the term “halogen” includes fluorine, chlorine, bromine and iodine. As used herein, the term “cycloalkyl group” means an aliphatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. As used herein, the term “heterocyclic group” means rings containing one or more heteroatoms selected from: nitrogen, sulphur and oxygen atoms. The heterocycle may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Examples of 5-membered groups include thienyl, furanyl, pyrrolidinyl and imidazolyl. Examples of 6-membered groups include pyridyl, piperidinyl, morpholinyl, piperazinyl, pyrazinyl. Examples of 7-membered groups include hexamethyleneiminyl. As used herein, the term “pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. As used herein, the term “pharmaceutically acceptable derivative”, means any pharmaceutically acceptable salt, solvate, or prodrug e.g. ester or carbamate, or salt or solvate of such a prodrug, of a compound of formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof. Preferred pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters. Particularly preferred pharmaceutically acceptable derivatives are salts, solvates and esters. Most preferred pharmaceutically acceptable derivatives are salts and solvates. Suitable salts according to the invention include those formed with both organic and inorganic acids and bases. Pharmaceutically acceptable acid addition salts include those (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin -2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrtolidin-1-yl)-N-isopropylpropanamide (2S)-N-Benzyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-cyanoethyl)-N(tetrahydrofuran-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(H-imidazol-4-yl)ethyl]-N-methylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphthyl-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrtolidin-1-yl)-N,N-dipropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopentyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclohexylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyanoethyl)-N-cyclobutylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-N-[2-(Aminosulfonyl)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-bis(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl-isopropyl-N-(1H-pyrazol-3-ylmethyl)propanamide (2S)-N-Allyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[3-(4-methylpiperazin-1-yl)propyl]propanamide formate tert-Butyl 2-[[(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate tert-Butyl 3-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)aminopropylcarbamate tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](cyclopropylmethyl)amino]ethylcarbamate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-tert-Butoxyethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(pyridin-4-ylmethyl)propanamide formate (2S)-N-(2-Aminoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(3-Aminopropyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide hydrochloride (2S)-N-(2-Aminocthyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-[(methylsulfonyl)amino]ethyl}) propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl)}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{3-[(methylsulfonyl)amino]propyl)}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[3-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)propyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamirde (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[2-(methylamino)ethyl]propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide (2S)-N-{3-[(Aminocarbonyl)amino]propyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-({[(E)-2-(5-Chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-({[(E)-2-(4-Chloropbenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide tert-Butyl 2-{[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]amino}ethylcarbamate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-piperidin-1-ylethyl)propanamide (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanamide hydrochloride (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(E)-2-(5-chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(6-chloro-1-benzothien-2-yl)sulfonyl]amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide. More preferred compounds of the invention include: (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isobutyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-propyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-3-ylmethyl)propanamide (2S)-N-(2-Azepan-1-ylethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl)-N-isopropyl-beta-alainamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-Benzyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(tetrahydrofuran-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-y)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopentyl-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl-cyclohexyl-N-ethylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)propanamide formate (2S)-2-((3S)-3-{([(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide (2S)-2{(3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclohexylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclobutylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-N-[2-(Aminosulfonyl)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(1H-pyrazol-3-ylmethyl)propanamide (2S)-N-Allyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[3-(4-methylpiperazin-1-yl)propyl]propanamide formate tert-Butyl 2-[[(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate tert-Butyl 3-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]propylcarbamate tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](cyclopropylmethyl)amino]ethylcarbamate (2S)-N-(2-tert-Butoxyethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(pyridin-4-ylmethyl)propanamide formate (2S)-N-(2-Aminoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(3-Aminopropyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{3-[(methylsulfonyl)amino]propyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[3-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)propyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[2-(methylamino)ethyl]propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-[(Aminocarbonyl)amino]ethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide (2S)-N-{3-[(Aminocarbonyl)amino]propyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-({[(E)-2-(5-Chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-yl]-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-({[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(E)-2-(5-chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(6-chloro-1-benzothien-2-yl)sulfonyl]amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide. Even more preferred compounds of the invention include: (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-3-ylmethyl)propanamide (2S)-N-(2-Azepan-1-ylethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl)-N-isopropyl-beta-alaninamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropylpropanamide formate (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate (2S)-N-[2Acetylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclobutylpropanamide (2S)-2-((3S)-3-(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide (2S)-N-[2-(Aminosulfonyl)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(1H-pyrazol-3-ylmethyl)propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[3-(4-methylpiperazin-1-yl)propyl]propanamide formate tert-Butyl 2-[[(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate tert-Butyl 3-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]propylcarbamate tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](cyclopropylmethyl)amino]ethylcarbamate (2S)-N-(2-Aminoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(3-Aminopropyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide hydrochloride (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{3-[(methylsulfonyl)amino]propyl}propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-[3-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)propyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[2-(methylamino)ethyl]propanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide (2S)-N-{3-[(Aminocarbonyl)amino]propyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-(2-hydroxyethyl)propanamide (2S)-2-((3S)-3-{[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-[(3S)-3-({[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(E)-2-(5-Chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(6-chloro-1-benzothien-2-yl)sulfonyl]amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide. In another aspect, preferred compounds of the invention include: (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isobutyl-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-propyl-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-3-ylmethyl)propanamide; (2S)-N-(2-Azepan-1-ylethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl)-N-isopropyl-beta-alaninamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide; (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropylpropanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide; (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide; (2S)-N-Benzyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-3-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(tetrahydrofuran-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2cyanoethyl)-N-methylpropanamide; (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2dimethylamino)ethyl]-N-ethylpropanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-bydroxyethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(2-morpholin-4-ylethyl)propanamide formate; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethyl)propanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate; (2S)-N-[2-(Acylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopentyl-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)propanamide formate; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclohexylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide; (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclobutylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-2-((3S)-3-(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide; (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide; (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide; (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide The compounds of formula (I) are Factor Xa inhibitors and as such are useful in the treatment of clinical conditions susceptible to amelioration by administration of a Factor Xa inhibitor. Such conditions include acute vascular diseases such as coronary thrombosis (for example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke; in oedema and PAF mediated inflammatory diseases such as adult respiratory shock syndrome, septic shock and reperfusion damage; the treatment of pulmonary fibrosis; the treatment of tumour metastasis; neurogenerative disease such as Parkinson's and Alzheimer's diseases; viral infection; Kasabach Merritt Syndrome; Haemolytic uremic syndrome; arthritis; osteoporosis; as anti-coagulants for extracorporeal blood in for example, dialysis, blood filtration, bypass, and blood product storage; and in the coating of invasive devices such as prostheses, artificial valves and catheters in reducing the risk of thrombus formation. Accordingly, one aspect of present invention provides a compound of formula (I) or a physiologically acceptable derivative thereof for use in medical therapy, particularly for use in the amelioration of a clinical condition in a mammal, including a human, for which a Factor Xa inhibitor is indicated. In another aspect, the invention provides a method for the treatment and/or prophylaxis of a mammal, including a human, suffering from a condition susceptible to amelioration by a Factor Xa inhibitor which method comprises administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of a condition susceptible to amelioration by a Factor Xa inhibitor. Preferably, the condition susceptible to amelioration by a Factor Xa inhibitor is selected from coronary thrombosis (for example myocardial infarction and unstable angina), pulmonary embolism, deep vein thrombosis and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke; It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms. While it is possible that, for use in therapy, a compound of the present invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. In a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deletrious to the receipient thereof. Accordingly, the present invention further provides a pharmaceutical formulation comprising at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, thereof in association with a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deletrious to the receipient thereof. In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof in association with a pharmaceutically acceptable carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by a Factor Xa inhibitor. There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula (I) or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable carrier and/or excipient. The compounds for use according to the present invention may be formulated for oral, buccal, parenteral, topical, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner. The compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compounds according to the present invention may be formulated for topical administration by insufflation and inhalation. Examples of types of preparation for topical administration include sprays and aerosols for use in an inhaler or insufflator. Powders for external application may be formed with the aid of any suitable powder base, for example, lactose, talc or starch. Spray compositions may be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as metered dose inhalers, with the use of a suitable propellant. The compounds according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A proposed dose of the compounds according to the present invention for administration to a human (of approximately 70 kg body weight) is 0.1 mg to 1 g, preferably to 1 mg to 500 mg of the active ingredient per unit dose, expressed as the weight of free base. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The dosage will also depend on the route of administration. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian. The compounds of formula (I) may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. The compounds of the present invention may be used in combination with other antithrombotic drugs such as thrombin inhibitors, thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic drugs such as tissue plaminogen activator and streptokinase, non-steroidal anti-inflammatory drugs such as aspirin, and the like. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the Factor Xa inhibitor or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. The compounds of formula (I) and pharmaceutically acceptable derivative thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups are as defined above for compounds of formula (I) unless otherwise stated. According to a further aspect of the present invention, there is provided a process (A) for preparing a compound of formula (I) which process comprises reacting a compound of formula (II) with a compound of formula (III). Suitably, the reaction may be carried out in the presence of a coupling agent, for example 1-[3-(dimethylamino)propyl]-3-ethyl carbodimide hydrochloride, HOBt (1-hydroxybenzotriazole), a base, e.g. Et3N (triethylamine), and an organic solvent, e.g. DCM (dichloromethane), suitably at room temperature. It will be appreciated by persons skilled in the art that compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) which are optionally protected by standard protecting groups, as precursors. For instance, compounds of formula (I) where R5 is C1-3alkylNH2, may be converted into compounds of formula (I) possessing alternative substituents at R5, e.g. —C2-4alkylNRaRb, —C2-4alkylNHCOC1-3alkyl, C2-4alkylNHCONRaRb, C2-4alkylNHSO2Re, by methods well known in the art (see for example March, J., Advanced Organic Chemistry, 4th Edition 1992, John Wiley & Sons). Compounds of formula (II) may be prepared from compounds of formula (IV): wherein P1 is a suitable carboxylic acid protecting group, e.g. t-Butyl, by removal of the protecting group under standard conditions. For example, when P1 represents t-Butyl, removal of the protecting group may be effected under acidic conditions, using for example TFA (trifluoroacetic acid) in a solvent such as DCM. A compound of formula (IV) may be prepared by reacting a compound of formula (V) with a compound of formula (VI) where P1 is as described above: Suitably, where X is a leaving group such as a halogen atom, e.g. bromine, the reaction is carried out in the presence of a base, e.g. potassium carbonate. Preferably, the reaction is effected in a suitable solvent, e.g. DMF, suitably at room temperature. A compound of formula (V) may be prepared by reacting a compound of formula (VII) with a compound of formula (VIII): wherein T is a reactive group, such as a halide, preferably chloride, and P1 is as described above. The reaction is conveniently carried out in the presence of a base, e.g. pyridine, and in a suitable solvent, e.g. DCM, suitably at room temperature. A compound of formula (VII) may be prepared from a compound of formula (IX) where P1 is as described above and P2 represents a suitable amine protecting group, e.g. Cbz (benzyloxycarbonyl), by removal of the protecting group under standard conditions. For example, the protecting group may be removed by reaction with hydrogen in the presence of a metal catalyst, e.g. palladium/C. Suitably, the reaction is carried out in an alcoholic solvent, e.g. ethanol, suitably at room temperature. A compound of formula (D) may be prepared from a compound of formula (X) by cyclisation, wherein P1 and P2 are as described above and L represents a leaving group, e.g. SMeRX. The ring closure may be performed by treatment with Dowex 2×8 400 mesh OH− resin in a suitable solvent, e.g. MeCN (acetonitrile). Alternatively, the ring closure may be performed by treatment with potassium carbonate in a suitable solvent, e.g. MeCN. Generally R will represent alkyl or aralkyl and X will represent halide, especially iodide or sulphate. A compound of formula (X) in which L represents SMeRX may be formed from a compound of formula (XI) by treatment with RX, where P1 and P2 are as described above and RX is a compound (e.g. MeI, benzyl iodide or Me2SO4) capable of converting sulphur in the SMe moiety to a sulfonium salt, in a suitable solvent, e.g. propanone or acetonitrile. Protection of the amine is convenient, although not essential, for this reaction. A compound of formula (XI) may be prepared by reacting a compound of formula (XII) with a compound of formula (XIII): Suitably, the reaction may be carried out in the presence of a coupling agent, for example 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride, HOBt, a base, e.g. Et3N, and an organic solvent, e.g. DCM, suitably at room temperature. Compounds of formulae (III), (VI), (VIII), (X), (XI), (XII) and (XIII) are known compounds and/or can be prepared by processes well known in the art. The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product. For example, those skilled in the art will appreciate that, with the use of appropriate protecting groups, the coupling to any of groups —R1, —SO2R6 or —NR4R5 can be the final step in the preparation of a compound of formula (I). Hence, in another aspect of the invention, the final step in the preparation of a compound of formula (I) may comprise the coupling to group —R1 by reacting a compound of formula (XIV) with a compound of formula (VI) under the conditions described above: Suitably, where X is a leaving group such as a halogen atom, e.g. bromine, the reaction is carried out in the presence of a base, e.g. potassium carbonate. Preferably, the reaction is effected in a suitable solvent, e.g. DMF, suitably at room temperature. A compound of formula (XIV) may be prepared by reacting a compound of formula (V) wherein P1 is hydrogen with a compound of formula (III) under the conditions described above. In a further aspect of the present invention, the final step in the preparation of a compound of formula (I) may comprise the coupling to group —SO2R6 by reacting a compound of formula (XV) with a compound of formula (VIII) under the conditions described above: The reaction is conveniently carried out in the presence of a base, e.g. pyridine, and in a suitable solvent, e.g. DCM, suitably at room temperature. A compound of formula (XV) may be prepared by reacting a compound of formula (VII) with a compound of formula (VI) followed by deprotection and reaction with a compound of formula (III) under the conditions described above. Those skilled in the art will appreciate that in the preparation of the compound of formula (I) or a solvate thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, “Protective groups in organic synthesis” by T. W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl or aralkyl type protecting groups (e.g. benayl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include for example alkyl silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate. Various intermediate compounds used in the above-mentioned process, including but not limited to certain compounds of formulae formulae (II), (IV), (V), (VII), (IX), (XIV) and (XV) are novel and accordingly constitute a further aspect of the present invention. The present invention will now be further illustrated by the accompanying examples which should not be construed as limiting the scope of the invention in any way. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. EXAMPLES Abbreviations BOC t-Butyloxycarbonyl Cbz or Z Benzyloxycarbonyl THF Tetrahydrofuran DCM Dichloromethane HOBT 1-Hydroxybenzotriazole br broad m multiplet q quartet s singlet t triplet Example 1 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.015 g) in DMF (1 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.015 g), HOBT (0.01 g) and triethylamine (0.007 ml) and the mixture was stirred at room temperature for 30 min. Diethylamine (0.007 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a colourless oil. Mass spectrum: Found: MH+452 H.p.l.c. (1) Rt 3.21 min Using similar chemistry, the following were prepared: Example 2 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+515 H.p.l.c. (1) Rt 2.75 min Example 3 (2S)-2-((3S)-3-}[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide Mass spectrum: Found: MH+438 H.p.l.c. (1) Rt 2.98 min Example 4 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide Mass spectrum: Found: MH+ 514 H.p.l.c. (1) Rt 3.48 min Example 5 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide Mass spectrum: Found: MH+ 528 H.p.l.c. (1) Rt 3.59 min Example 6 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide Mass spectrum: Found: MH+ 480 H.p.l.c.(1) Rt 3.48 min Example 7 (2S)-2-((3S)-3-{[(6-Chloro-2-naghthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-thyl-N-isopropylpropanamide Mass spectrum; Found: MH+ 464 H.p.l.c. (1) Rt 3.32 min Example 8 (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl propanamide Mass spectrum: Found: MH+ 515 H.p.l.c. (1) Rt 2.77 min Example 9 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 501 H.p.l.c. (1) Rt 2.81 min Example 10 (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopurrolidin-1-yl)-N-isopropyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 2.75 min Example 11 (2S)-2-((3S)-3-{[(6-Chloro-2-nanhthyl1sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isobutyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 543 H.p.l.c. (1) Rt 3.35 min Example 12 (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-propyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 3.22 min Example 13 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-3-ylmethyl)pronanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 2.90 min Example 14 (2S)-N-(2-Azepan-1-ylethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isoproplproyanamide formate Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt 2.83 min Example 15 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isoproipelropanamide Mass spectrum: Found: MH+ 491 H.p.l.c. (1) Rt 3.23 min Example 16 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxoparrolidin-1-yl)propanoyl)-N-isopropyl-beta-alaninamide Mass spectrum: Found: MH+ 509 H.p.l.c. (1) Rt 2.97 min Example 17 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 482 H.p.l.c. (1) Rt 3.05 min Example 18 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide Mass spectrum: Found: MH+ 503 H.p.l.c. (1) Rt 3.30 min Example 19 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxoprrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide Mass spectrum: Found: MH+ 505 H.p.l.c. (1) Rt 3.37 min Example 20 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide Mass spectrum: Found: MH+ 424 H.p.l.c. (1) Rt 2.89 min Example 21 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl-N-isopropyl-N-methylpropanamide Mass spectrum: Found: MH+ 452 H.p.l.c. (1) Rt 3.08 min Example 22 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 454 H.p.l.c. (1) Rt 2.78 min Example 23 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 463 H.p.l.c. (1) Rt 2.95 min Example 24 (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide Mass spectrum: Found: MH+ 467 H.p.l.c. (1) Rt 2.73 min Example 25 (2S)-2(3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide Mass spectrum: Found: MH+ 495 H.p.l.c. (1) Rt 2.84 min Example 26 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide Mass spectrum: Found: MH+ 507 H.p.l.c. (1) Rt 2.32 min Example 27 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate Mass spectrum: Found: MH+ 523 H.p.l.c. (1) Rt 2.30 min Example 28 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate Mass spectrum: Found: MH+ 537 H.p.l.c. (1) Rt 2.33 min Example 29 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate Mass spectrum: Found: MH+ 536 H.p.l.c. (1) Rt 2.33 min Example 30 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate Mass spectrum: Found: MH+ 495 H.p.l.c. (1) Rt 2.32 min Example 31 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 3.17 min Example 32 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 2.92 min Example 33 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 501 H.p.l.c. (1) Rt 3.06 min Example 34 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide Mass spectrum: Found: MH+ 515 H.p.l.c. (1) Rt 2.69 min Example 35 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 501 H.p.l.c. (1) Rt 2.75 min Example 36 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1yl)-N-[2-(1 H-imidazol4-yl)ethyl]-N-methylpropanamide formate Mass spectrum: Found: MH+ 504 H.p.l.c. (1) Rt 2.61 min Example 37 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 541 H.p.l.c. (1) Rt2.51 min Example 38 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide Mass spectrum: Found: MH+ 469 H.p.l.c. (1) Rt 2.86 min Example 39 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl-N-(2-methoxyethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 469 H.p.l.c. (1) Rt 2.94 min Example 40 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate Mass spectrum: Found: MH+ 536 H.p.l.c. (1) Rt 2.38 min Example 41 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-pyridin-2-ylethyl)propanamide Mass spectrum: Found: MH+ 543 H.p.l.c. (1) Rt 2.48 min Example 42 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxypropyl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 496 H.p.l.c. (1) Rt 3.07 min Example 43 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyanomethyl)-N-isopropyltpropanamide formate Mass spectrum: Found: MH+ 477 H.p.l.c. (1) Rt 3.1 min Example 44 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(3-methoxypropyl)propanamide Mass spectrum: Found: MH+ 510 H.p.l.c. (1) Rt 3.16 min Example 45 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-methoxyethyl)propanamide Mass spectrum: Found: MH+ 496 H.p.l.c. (1) Rt 3.13 min Example 46 (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 523 H.p.l.c. (1) Rt 2.9 min Example 47 (2S)-N-Benzyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 528 H.p.l.c. (1) Rt 3.47 min Example 48 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopprrolidin-1-yl)-N-isopropyl-N-(thien-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 534 H.p.l.c. (1) Rt 3.43 min Example 49 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 496 H.p.l.c. (1) Rt 2.95 min Example 50 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 482 H.p.l.c. (1) Rt 2.93 min Example 51 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 545 H.p.l.c. (1) Rt 2.30 min Example 52 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 545 H.p.l.c. (1) Rt 2.37 min Example 53 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(3-hydroxypropyl)-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 545 H.p.l.c. (1) Rt 2.59 min Example 54 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(tetrahydrofuran-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 503 H.p.l.c. (1) Rt 3.18 min Example 55 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(cyclopropylmethyl)propanamide Mass spectrum: Found: MH+ 502 H.p.l.c. (1) Rt 3.19 min Example 56 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(2-pyridin-2-ylethyl)propanamide Mass spectrum: Found: MH+ 554 H.p.l.c. (1) Rt 2.53 min Example 57 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isobutylpropanamide Mass spectrum: Found: MH+ 505 H.p.l.c. (1) Rt 3.25 min Example 58 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 572 H.p.l.c. (2) Rt 10.8 min Example 59 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-nehthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-pyridin-2-ylethyl)propanamide Mass spectrum: Found: MH+ 586 H.p.l.c. (2) Rt 10.96 min Example 60 (2S)-2-((3S)-3-{(2-amino-2oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide Mass spectrum: Found: MH+ 525 H.p.l.c. (2) Rt 10.5 min Example 61 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 586 H.p.l.c. (1) Rt 3.05 min Example 62 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-2-ylmethyl)propanamide Mass spectrum: Found: MH+ 558 H.p.l.c. (1) Rt 2.94 min Example 63 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pyridin-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 558 H.p.l.c. (1) Rt 2.78 min Example 64 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-4-ylethyl)propanamide Mass spectrum: Found: MH+ 572 H.p.l.c. (1) Rt 2.64 min Example 65 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(pridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 558 H.p.l.c. (1) Rt 2.68 min Example 66 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(1H-imidazol-4-yl)ethyl]-N-methylpropanamide formate Mass spectrum: Found: MH+ 561 H.p.l.c. (1) Rt 2.57 min Example 67 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-pyridin-2-ylethyl)propanamide Mass spectrum: Found: MH+ 572 H.p.l.c. (1) Rt 2.73 min Example 68 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-phenylethyl)propanamide Mass spectrum: Found: MH+ 571 H.p.l.c. (1) Rt 3.34 min Example 69 (2s)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-phenylethyl)propanamide Mass spectrum: Found: MH+ 585 H.p.l.c. (1) Rt 3.44 min Example 70 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dimethylpropanamide Mass spectrum: Found: MH+ 481 H.p.l.c. (1) Rt 2.78 min Example 71 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-methylpropanamide Mass spectrum: Found: MH+ 509 H.p.l.c. (1) Rt 2.95 min Example 72 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 511 H.p.l.c. (1) Rt 2.70 min Example 73 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 539 H.p.l.c. (1) Rt 2.83 min Example 74 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 520 H.p.l.c. (1) Rt 2.83 min Example 75 (2S)-N2-Amino-2-oxoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methylpropanamide Mass spectrum: Found: MH+ 524 H.p.l.c. (1) Rt 2.66 min Example 76 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)-2-oxoethyl]-N-methylpropanamide Mass spectrum: Found: MH+ 552 H.p.l.c. (1) Rt 2.74 min Example 77 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(3-hydroxypropyl)propanamide Mass spectrum: Found: MH+ 539 H.p.l.c. (1) Rt 2.79 min Example 78 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-y)-N-methyl-N-(2-pyrrolidin-1-ylethyl)propanamide formate Mass spectrum: Found: MH+ 564 H.p.l.c. (1) Rt 2.27 min Example 79 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthal)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(2-morpholin-4-ylethyl)propanamide formate Mass spectrum: Found: MH+ 580 H.p.l.c. (1) Rt 2.25 min Example 80 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxogprrolidin-1-yl)-N-ethyl-N-(2-morpholin-4-ylethyl)propanamide formate Mass spectrum: Found: MH+ 594 H.p.l.c. (1) Rt 2.29 min Example 81 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-ethylpropanamide formate Mass spectrum: Found: MH+ 552 H.p.l.c. (1) Rt 2.28 min Example 82 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-(pyridin-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 598 H.p.l.c. (1) Rt 2.38 min Example 83 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-hydroxyethyl)propanamide Mass spectrum: Found: MH+ 526 H.p.l.c. (1) Rt 2.76 min Example 84 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-methoxyethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 526 H.p.l.c. (1) Rt 2.83 min Example 85 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-(2-piperidin-1-ylethyl)propanamide formate Mass spectrum: Found: MH+ 593 H.p.l.c. (1) Rt 2.33 min Example 86 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(2-morpholin-4-ylethyl)propanamide formate Mass spectrum: Found: MH+ 610 H.p.l.c. (2) Rt 10.35 min Example 87 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-methylpropanamide Mass spectrum: Found: MH+ 495 H.p.l.c. (1) Rt 2.96 min Example 88 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-diethylpropanamide Mass spectrum: Found: MH+ 509 H.p.l.c. (1) Rt 3.08 min Example 89 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-dipropylpropanamide Mass spectrum: Found: MH+ 537 H.p.l.c. (1) Rt 3.22 min Example 90 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamirde Mass spectrum: Found: MH+ 523 H.p.l.c. (1) Rt 3.17 min Example 91 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(pyrid-4-ylmethylpropanamide Mass spectrum: Found: MH+ 586 H.p.l.c. (1) Rt 2.67 min Example 92 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-isopropylropanamide Mass spectrum: Found: MH+ 548 H.p.l.c. (1) Rt 3.07 min Example 93 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-azepan-1-ylethyl)-N-isopropylpropanamide formate Mass spectrum: Found: MH+ 620 H.p.l.c. (1) Rt 2.65 min Example 94 (2S)-N-[2-(Acetylamino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloronaphth-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 580 H.p.l.c. (1) Rt 2.87 min Example 95 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopentyl-N-methylpropanamide Mass spectrum: Found: MH+ 478 H.p.l.c. (1) Rt 3.23 min Example 96 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide Mass spectrum: Found: MH+ 506 H.p.l.c. (1) Rt 3.45 min Example 97 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide Mass spectrum: Found: MH+ 492 H.p.l.c. (1) Rt 3.34 min Example 98 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide Mass spectrum: Found: MH+ 517 H.p.l.c. (1) Rt 3.25 min Example 99 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide Mass spectrum: Found: MH+ 489 H.p.l.c. (1) Rt 3.09 min Example 100 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)propanamide formate Mass spectrum: Found: MH+ 564 H.p.l.c. (1) Rt 2.40 min Example 101 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide Mass spectrum: Found: MH+ 501 H.p.l.c. (1) Rt 3.34 min Example 102 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopentylpropanamide Mass spectrum: Found: MH+ 574 H.p.l.c. (1) Rt 3.11 min Example 103 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclohexylpropanamide Mass spectrum: Found: MH+ 531 H.p.l.c. (1) Rt 3.34 min Example 104 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-methylpropanamide Mass spectrum: Found: MH+ 549 H.p.l.c. (1) Rt 3.19 min Example 105 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclopropylpropanamide Mass spectrum: Found: MH+ 546 H.p.l.c. (1) Rt2.96 min Example 106 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-cyanoethyl)-N-cyclobutylpropanamide Mass spectrum: Found: MH+ 503 H.p.l.c. (1) Rt 3.18 min Example 107 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 527 H.p.l.c. (1) Rt 2.79 min Example 108 (2S)-2-((3S)-3-(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclopropyl-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 584 H.p.l.c. (1) Rt 2.70 min Example 109 (2S)-N-[2-(Aminosulfonyl)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 545 H.p.l.c. (1) Rt 3.06 min Example 110 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide Mass spectrum: Found: MH+ 606 H.p.l.c. (1) Rt 2.6 min Example 111 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide Mass spectrum: Found: MH+ 608 H.p.l.c. (1) Rt 2.55 min Example 112 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrolidin-1-yl)-N-isopropyl-N-(2-piperidin-1-ylethyl)propanamide Mass spectrum: Found: MH+ 549 H.p.l.c. (1) Rt 2.64 min Example 113 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(2-morpholin-4-ylethyl)propanamide Mass spectrum: Found: MH+ 551 H.p.l.c. (1) Rt 2.57 min Example 114 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-cyclohexyl-N-ethylpropanamide Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt 3.29 min Example 115 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 587 H.p.l.c. (1) Rt 3.01 min Example 116 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-phenylpropanamide Mass spectrum: Found: MH+ 557 H.p.l.c. (1) Rt 3.16 min Example 117 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxy-2-phenylethyl)-N-methylpropanamide Mass spectrum: Found: MH+ 530 H.p.l.c. (1) Rt 3.16 min Example 118 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N,N-bis(2-hydroxyethyl)propanamide Mass spectrum: Found: MH+ 484 H.p.l.c. (1) Rt 2.79 min Example 119 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-(1H-pyrazol-3-ylmethyl)propanamide Mass spectrum: Found: MH+ 518 H.p.l.c. (1) Rt 3.1 min Example 120 (2S)-N-Allyl-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 527 H.p.l.c. (1) Rt 2.86 min Example 121 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[3-(4-methylpiperazin-1-yl)propyl]propanamide formate Mass spectrum: Found: MH+ 578 H.p.l.c. (1) Rt 2.53 min Example 122 tert-Butyl 2-[[(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxoprrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate Mass spectrum: Found: MH+ 638 H.p.l.c. (1) Rt 3.28 min Example 123 tert-Butyl 3-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]propylcarbamate Mass spectrum: Found: MH+ 595 H.p.l.c. (1) Rt 3.47 min Example 124 tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](cyclopropylmethyl)amino]ethylcarbamate Mass spectrum: Found: MH+ 592 H.p.l.c. (1) Rt 3.53 min Example 125 (2S)-2-((3S)-3-{(2-Amino-2oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 495 H.p.l.c. (1) Rt 3.01 min Example 126 (2S)-N42-tert-Butoxyethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(pyridin-4-ylmethyl)propanamide Mass spectrum: Found: MH+ 587 H.p.l.c. (1) Rt 3.08 min Example 127 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-hydroxyethyl)-N-(pyridin-4-ylmethyl)propanamide formate Example 126 (0.058 g) was dissolved in DCM (2 ml) and trifluoroacetic acid (3 ml) was added. After stirring for 4 h at room temperature, the mixture was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.003 g) as a white solid. Mass spectrum: Found: MH+ 531 H.p.l.c. (1) Rt 2.54 min Example 128 (2S)-N2-Aminoethyl)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylropanamide hydrochloride Example 124 (0.12 g) was dissolved in 4N hydrochloric acid:dioxane (1:1, 5 ml) and stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure to give the title compound (0.9 g) as a beige solid. Mass spectrum: Found: MH+ 538 H.p.l.c. (1) Rt 2.5 min Using similar chemistry and Example 125, the following was prepared: Example 129 (2S)-N3-Aminopropyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide hydrochloride Mass spectrum: Found: MH+ 495 H.p.l.c. (1) Rt 2.56 min Example 130 (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro -2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide hydrochloride Mass spectrum: Found: MH+ 493 H.p.l.c. (1) Rt 2.54 min Example 131 (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]ethylcarbamate (0.21 g) was dissolved in DCM (4 ml), and trifluoroacetic acid (4 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and DCM, and the organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate, methanol and methanol:10% aqueous ammonia) to live the title compound (0.124 g) as a white solid. Mass spectrum: Found: MH+ 481 H.p.l.c. (1) Rt 2.5 min Example 133 (2S)-N-(2-Amino-2-oxoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Using Intermediate 26 and ammonium chloride, and the synthetic procedure described for Example 1, the title compound was prepared. Mass spectrum: Found: MH+ 493 H.p.l.c. (1) Rt 2.94 min Example 134 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.04 g) was dissolved in DCM (3 ml) at 0° C. and was treated with pyridine (0.027 ml) and mesyl chloride (0.03 ml). The reaction mixture was allowed to reach room temperature and then stirred at room temperature for 3 h. Additional DCM (3 ml) followed by hydrochloric acid (5 ml) was added. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM, diethyl ether, ethyl acetate: 10% aqueous NH3) to give the title compound (0.024 g) as gum. Mass spectrum: Found: MH+ 559 H.p.l.c. (1) Rt 3.08 min Using similar chemistry, the following was prepared: Example 135 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{2-[(methylsulfonyl)amino]ethyl}propanamide Mass spectrum: Found: MH+ 616 H.p.l.c. (1) Rt2.98 min Example 136 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-{3-[(methylsulfonyl)amino]propyl}propanamide Mass spectrum: Found: MH+ 573 H.p.l.c. (1) Rt 3.12 min Example 137 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-{2-[(methylsulfonyl)amino]ethyl}propanamide Mass spectrum: Found: MH+ 571 H.p.l.c. (1) Rt 3.15 min Example 138 (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopromylpropanamide (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.035 g) was dissolved in ethanol (2 ml), treated with S-methyl-nitro-isothiourea (0.022 g) and stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.019 g) as a white solid. Mass spectrum: Found: MH+ 568 H.p.l.c. (1) Rt 3.07 min Using similar chemistry, the following was prepared: Example 139 (2S)-N-[2-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)ethyl]-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopromylpropanamide Mass spectrum: Found: MH+ 625 H.p.l.c. (1) Rt 2.97 min Example 140 (2S)-N-[3-({(E)-Amino[oxido(oxo)hydrazono]methyl}amino)propyl]-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopurrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 582 H.p.l.c. (1) Rt 3.06 min Example 141 and Example 142 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropyl-N-[2-(methylamino)ethyl]propanamide and (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-[2-(dimethylamino)ethyl]-N-isopromylpropanamide (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.06 g) was dissolved in formic acid (2 ml), cooled to 0° C. and treated slowly with formaldehyde (2 ml). The mixture was heated to 50° C. for 18 h, cooled to room temperature and then basified to pH8 with sodium bicarbonate solution. The aqueous mixture was extracted with DCM, and the combined, dried (over magnesium sulphate) organic extracts concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM: methanol aqueous ammonia 200:5:2) to give Example 143 (0.027 g) and Example 144 (0.017 g), both as colourless gums. Example 141 Mass spectrum: Found: MH+ 494 H.p.l.c. (1) Rt 2.61 min Example 142 Mass spectrum: Found: MH+ 508 H.p.l.c. (1) Rt 2.62 min Example 143 (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naghthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (2S)-N-(2-Aminoethyl)-2(3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide (0.02 g) was dissolved in THF (2 ml) and treated with N-methyl morpholine (0.183 ml) followed by phenyl carbamate (0.034 g), and the resultant mixture heated under reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with methanol. The resultant suspension was filtered and the filtrate was separated using SPE (silica, eluting with DCM, ethyl acetate, methanol, methanol:10% aqueous NH3) to give an impure sample of the title compound, which was further purified using mass directed preparative h.p.l.c. to give the title compound (0.01 g) as an oil. Mass spectrum: Found: MH+ 522 H.p.l.c. (1) Rt 2.90 min Using similar chemistry, the following was prepared: Example 144 (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopropylpropanamide Mass spectrum: Found: MH+ 581 H.p.l.c. (1) Rt 2.78 min Example 145 (2S)-N-{2-[(Aminocarbonyl)amino]ethyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide Mass spectrum: Found: MH+ 536 H.p.l.c. (1) Rt 2.96 min Example 146 (2S)-N-{3-[(Aminocarbonyl)amino]propyl}-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-isopromylpropanamide Example 131 (0.03 g) was dissolved in dry THF (3 ml) and treated with N,N-diisopropylethlamine (0.039 ml) and phenyl carbamate (0.047 g) and then heated under reflux for 4 h. The cooled reaction mixture was concentrated under reduced pressure and the residue purified using mass directed preparative h.p.l.c. to give the title compound (0.014 g) as a pale yellow solid. Mass spectrum: Found: MH+ 535 H.p.l.c. (1) Rt 2.95 min Example 147 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)-N-(2-hydroxyethyl)propanamide Intermediate 20 (0.05 g) was dissolved in dry THF (5 ml) and tetrabutylammonium fluoride (0.028 g) was added. After stirring at room temperature for 4 h, a further quantity of tetrabutylammonium fluoride (0.014 g) was added. After 1 h, the mixture was concentrated under reduced pressure and the residue was partitioned between DCM and water. The separated organic component was dried (over magnesium sulphate), filtered and concentrated under reduced pressure. The residue was partially purified using SPE (silica, eluting with cyclohexane:ethyl acetate, 20:1 to 1:1) to give an impure sample of the title compound. Further purification using mass directed preparative h.p.l.c. provided the title compound (0.014 g) as a colourless gum. Mass spectrum: Found: MH+ 494 H.p.l.c. (1) Rt 3.06 min Example 148 (2S)-2-((3S)-3-{[(5′-Chloro-2,2′-bithien-5-ylsulfonyl]amino}-2-oxopyrolidin-1-yl)-N-ethyl-N-isopropylpropanamide Using Intermediate 25 and 5′-chloro-2,2′-bithiophene-5-sulfonyl chloride, and the chemistry described for the preparation of Intermediate 4, the title compound was prepared. Mass spectrum: Found: MH+ 504 H.p.l.c. (1) Rt 3.41 min Using similar chemistry, the following were prepared: Example 149 (2S)-2-((3S)-3-{[(6-Chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide Mass spectrum: Found: MH+ 472 H.p.l.c. (1) Rt 3.21 min Example 150 (2S)-2-[(3S)-3-({[(E)-2-(5-Chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1yl]-N-ethyl-N-isopropylpropanamide Mass spectrum: Found: MH+ 448 H.p.l.c. (1) Rt 3.05 min Example 151 (2S)-2-[(3S)-3-({[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide Mass spectrum: Found: MH+ 442 H.p.l.c. (1) Rt 3.09 min Example 152 tert-Butyl 2-{[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]amino}ethylcarbamate Using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, and the synthetic procedure described for Example 1, the title compound was prepared. Mass spectrum: Found: MH+ 539 H.p.l.c. (1) Rt 3.15 min Using similar chemistry, the following was prepared: Example 153 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(2-piperidin-1-ylethyl)propanamide Mass spectrum: Found: MH+ 507 H.p.l.c. (1) Rt 2.42 min Example 154 (2S)-N-(2-Aminoethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanamide hydrochloride Example 152 (0.281 g) was dissolved in DCM (3 ml), and 4M HCI in dioxane (3 ml) was added. The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure to give the title compound (0.247 g) as a white solid. Mass spectrum: Found: MH+ 439 H.p.l.c. (1) Rt 2.35 min Example 155 (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(E)-2-(5-chlorothien-2-yl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide Using Example 150, and the synthetic procedure described for Intermediate 6, the title compound was prepared. Mass spectrum: Found: MH+ 505 H.p.l.c. (1) Rt 2.92 min Using similar chemistry and Example 149, the following was prepared: Example 156 (2S)-2-((3S)-{(2-Amino-2-oxoethyl)-3-({[(6-chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-ethyl-N-isopropylpropanamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1) Rt 3.09 min Intermediate 1 tert-Butyl N-[(benzyloxy)carbonyl]-L-methionyl-D-alaninate Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and 1-[3-(diemthylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13 g) was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). The mixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) was added and stirring continued for 18 h. The mixture was evaporated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9 g) as an orange oil which crystallised on standing. Mass spectrum: Found: MH+ 411 Intermediate 2 tert-Butyl (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate A solution of tert-butyl N-[(benzyloxy)carbonyl]-1-methionyl-D-alaninate (11.9 g) in acetone (75 ml) was treated with methyl iodide (18 ml) and stirred at room temperature for 72 h. The reaction mixture was then concentrated under reduced pressure to give an orange solid which was dissolved in acetonitrile (200 ml). Dowex (OH− form) resin (19.42 g) was added and the mixture stirred for 18 h at room temperature. The mixture was filtered and the resin washed with ethyl acetate. The filtrate was evaporated under reduced pressure to afford a yellow oil which was purified by Biotage™ chromatography (eluting with cyclohexane/ethyl acetate 3:2) to give the title compound (2.92 g) as a colourless oil. Mass spectrum: Found: MH+ 363 Intermediate 3 tert-Butyl (2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate A mixture of tert-butyl (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (2.82 g), 10% palladium on carbon (0.300 g) and ethanol (150 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g) as a pale yellow oil. 1H NMR (D4MeOD): δ4.56(1H, q), 3.57(1H, dd), 3.49-3.35(2H, 2×m), 2.48-2.39(1H, m), 1.88-1.77(1H, m), 1.47(9H, s), 1.40 (3H, d) ppm. Intermediate 4 tert-Butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate A solution of tert-butyl (2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate (1.8 g) in DCM (75 ml) was treated with 6-chloronaphthylsulphonyl chloride1 (2.28 g) and pyridine (0.705 ml) and stirred at room temperature for 72 h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was purified by Biotage™ chromatography (eluting with cyclohexane/ethyl acetate 3:1) to give the title compound (2.31), as a white solid. Mass spectrum: Found: MH+ 453 Intermediate 5 (2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid tert-Butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.643 g) was dissolved in DCM (19 ml), and trifluoroacetic acid (19 ml) was added. The mixture was stirred at room temperature for 2.5 h and then concentrated under reduced pressure. Anhydrous DCM (4 ml) was added and the solution evaporated under reduced pressure. Repetitive addition of DCM and concentration under reduced pressure provided the title compound (0.56 g) as a white foam. Mass spectrum: Found: MH+ 397 Intermediate 6 tert-Butyl (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate A solution of tert-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.31 g) in DMF (22 ml) was treated with potassium carbonate (0.786 g) followed by 2-bromoacetamide (0.48 g) and the resultant mixture stirred at room temperature for 22 h. Additional 2-bromoacetamide (0.4 g) and potassium carbonate (0.4 g) were added and the mixture was stirred at room temperature for 24 h. The reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The separated organic layer was washed with water, dried (over magnesium sulphate) and evaporated under reduced pressure to give the title compound (1.4 g) as a white foam. Mass spectrum: Found: MH+ 510 Intermediate 7 (2S)-2-((3S)-3-{(2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid tert-Butyl (2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1.4 g) was dissolved in DCM (35 ml), and trifluoroacetic acid (35 ml) was added. The mixture was stirred at room temperature for 2 h and then evaporated under reduced pressure. The residue was azeotroped with anhydrous dichloromethane and then dried under high vacuum. The residual viscous oil was triturated with diethyl ether to give the title compound (1.23 g) as a white solid. Mass spectrum: Found: MH+ 454 Intermediate 8 tert-Butyl 2-(isopropylamino)ethylcarbamate N-Isopropylethylene diamine (1.25 ml) was dissolved in dry DCM (50 ml), cooled to 0° C. and treated with di-tert-butyl dicarbonate (1.09 g) and triethylamine (1.39 ml). The resultant mixture was stirred at room temperature for 90 min and then evaporated under reduced pressure. The residue was purified using SPE (silica, eluting with DCM:MeOH:aqueous NH3, 100:8:1) to give the title compound (0.85 g) as a pale yellow oil. T.l.c. (DCM:MeOH:aqueous NH3, 200:5:2) Rf 0.2 Using similar chemistry, the following was prepared: Intermediate 9 tert-Butyl 3-(isopropylamino)propylcarbamate T.l.c. (DCM:MeOH:aqueous NH3, 200:5:2) Rf 0.25 Intermediate 10 tert-Butyl 2-[[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopronyl)amino]ethylcarbamate To a solution of (2S)-2-((35)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.198 g) in DMF (10 ml) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.321 g) and diisopropylethylamine (0.174 ml) and the mixture was stirred at room temperature for 30 min. tert-Butyl 2-(isopropylamino)ethylcarbamate (0.202 g) was added and the resultant mixture stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM and saturated sodium bicarbonate. The organic layer was separated, dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give an oil which was purified using SPE (silica, eluting with cyclohexane:ethyl acetate, 20:1 to 1:2) to give the title compound (0.210 g) as a colourless gum. Mass spectrum: Found: MH+ 581 Intermediate 11 3-(Cyclopropylmethyl-amino)-propionitrile With stirring and cooling in an ice-bath to maintain a temperature of 8-10° C., acrylonitrile (0.614 ml) was added to aminomethylcyclopropane (0.651 g). The resultant mixture was stirred at room temperature for 15 h to give the title compound (1.02 g) as a yellow oil. Mass spectrum: Found: MH+ 125 Intermediate 12 N-(pyridin-4-ylmethyl)propan-2-amine 4-Bromomethylpyridine (1 g) was suspended in THF:ethanol (5:1) and cooled to 0-5° C. Isopropylamine (1.01 ml) was added and the resultant mixture allowed to reach room temperature. After 24 h, the mixture was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with DCM:methanol 1:1, 3:7, 1:4 and methanol) to give an impure sample of the title compound. Further purification using SPE (silica, eluting with DCM, ethyl acetate, acetonitrile, methanol) gave the title compound (0.25 g) as a white solid. Mass spectrum: Found: MH+ 151 Intermediate 13 Hexamethyleneimineacetonitrile To a solution of chloroacetonitrile (73 g) in benzene (500 ml) was added anhydrous sodium carbonate (52 g) followed by a solution of hexamethyleneimine (96 g) in benzene (250 ml). The mixture was stirred and heated under reflux for 4 h, cooled in an ice-bath and filtered. The filtrate was concentrated under reduced pressure and the residue purified by distillation to give the title compound (117 g) as an oil. B.p. 108-112° C., 17 mm Hg Intermediate 14 1-Amino-2-hexamethyleneiminoethane A solution of hexamethyleneimineacetonitrile (60 g) in dry diethyl ether (200 ml) was slowly added to a stirred suspension of lithium aluminium hydride (16.5 g) in dry diethyl ether (200 ml) at a rate to maintain a steady reflux. Addition was completed in 1.5 h, and then the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled in an ice-bath and treated with methanol (10 ml), sodium hydroxide solution (10N, 10 ml) and water (40 ml), and left to stand at room temperature for 18 h. The organic layer was separated, and stirred with potassium hydroxide pellets, filtered and concentrated under reduced pressure. The residue was purified by distillation to give the title compound (44.4 g) as an oil. B.p. 86-90° C., 17 mm Hg Intermediate 15 N-(2-Hexamethyleneiminoethyl)-N-isopronylamine A mixture of 1-amino-2-hexamethyleneiminoethane (14.2 g), acetone (7 g) and platinium oxide (0.4 g) in ethanol (50 ml) was hydrogenated at room temperature and pressure for 24 h. The solution was filtered over Celite™ and the filtrate concentrated under reduced pressure. The residue was distilled to give the title compound (13.85 g) as an oil B.p. 102-106° C., 17 mm Hg Intermediate 16 N-(1H-pyrazol-3-ylmethyl)propan-2-amine To a mixture of pyrazolyl-3-carboxaldehyde (0.06 g), isopropylamine (0.081 ml) and acetic acid (0.072 ml) in dry DCM (4 ml), sodium triacetoxyborohydride (0.2 g) was added at 0° C. and the resultant solution sturred at room temperature for 72 h. Sodium hydroxide solution (2M) was added and the solution was extracted with DCM. The combined organic extracts were filtered through a hydrophobic frit and the filtrate concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with methanol and methanol: 10% aqueous ammonia) to give the title compound (0.074 g) as a gum. GCMS: MH+ 151 Using similar chemistry, the following was prepared; Intermediate 17 N-(pyridin-4-ylmethyl)prop-2-en-1-amine GCMS: MH+ 149 Intermediate 18 tert-Butyl 2-[(cyclopropylmethyl)amino]ethylcarbamate tert-Butyl N-(2-oxoethyl)carbamate (1 g) was dissolved in dry methanol (40 ml) and treated with cyclopropane methylamine (0.709 ml) and 4A° molecular sieves (1 g) and the resultant mixture stirred at room temperature for 5 h. Sodium borohydride (0.38 g) was added and the reaction stirred for a further 18 h at room temperature. Sodium hydroxide (2N, 3 ml) was added, the mixture filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide solution (2N) and ethyl acetate. The separated organic layer was dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (1 g) as a colourless oil 1H NMR (CDCl3): δ4.95(1H, br.s), 3.23(2H, dt), 2.75(2H, t), 2.47(2H, d), 1.45(9H, s), 0.95(1H, m), 0.47(2H, m), 0.12(2H, m) ppm. Intermediate 19 2-{[tert-Butyl(dimethyl)silyl]oxy}-N-(cyclopropylmethyl)ethanamine (tert-Butyldimethylsilyloxy)acetaldehyde (0.98 g) was dissolved in dry methanol (40 ml) and then treated with cyclopropane methylamine (0.634 ml) followed by 4A° molecular sieves (1 g). The resultant mixture was stirred for 5 h at room temperature and then sodium borohydride (0.340 g) was added. After stirring for a further 18 h at room temperature, sodium hydroxide (2N) was added, the mixture was filtered and the filtrate concentrated under reduced pressure. The residue was partitioned between sodium hydroxide (2N) and ethyl acetate. The separated aqueous layer was washed further with ethyl acetate. The combined organic components were dried (over magnesium sulphate), filtered and concentrated under reduced pressure to give the title compound (0.78 g) as a yellow oil. 1H NMR (CDCl3): δ3.70(2H, t), 2.70(2H, t), 2.75(2H, t), 2.47(2H, d), 0.95(1H, m), 0.88(9H, s), 0.47(2H, m), 0.10(2H, m), 0.05(6H, s) ppm. Intermediate 20 (2S)-N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)-N-(cyclopropylmethyl)propanamide Using Intermediates 5 and 19, and similar chemistry to that described for the preparation of Example 1, the title compound was prepared. Mass spectrum: Found: MH+ 609 Intermediate 21 tert-Butyl [[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]acetate Using tert-butyl (isopropylamino)acetate and Intermediate 5, and similar chemistry to that described for the preparation of Example 1, the title compound was prepared. Mass spectrum: Found: MH+ 553 Intermediate 22 2-tert-Butoxy-N-(pyridin-4-ylmethyl)ethanamine Using 4-pyridine carboxaldehyde and O-tert butyl ethanolamine, and the synthetic procedure described for Intermediate 16, a crude sample of the title compound was prepared, which was used directly in the next stage of the synthetic sequence. Intermediate 23 (2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid Using Intermediate 2 and the procedure described for Intermediate 5, the title compound was prepared. Mass spectrum: Found: MH+ 307 Intermediate 24 Benzyl (3S)-1-{(1S)-2-[ethyl(isopropyl)amino]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-ylcarbamate Using the Intermediate 23 and ethylisopropylamine, and similar chemistry to that described for the preparation of Example 1, the title compound was prepared. Mass spectrum: Found: MH+ 376 Intermediate 25 (2S)-2-[(3S)-3-Amino-2-oxopyrrolidin-1-yl]-N-ethyl-N-isopropylpropanamide Using Intermediate 24 and the synthetic procedure described for Intermediate 3, the title compound was prepared. Mass spectrum: Found: MH+ 242 Intermediate 26 [[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl](isopropyl)amino]acetic acid Using Intermediate 21, and the chemistry described to prepare Example 131, the title compound was prepared: Mass spectrum: Found: MH+ 496 References 1. Klimkowski, Valentine Joseph; Kyle, Jeffrey Alan; Masters, John Joseph; Wiley, Michael Robert. PCT Int. Appl. (2000), WO 0039092. In vitro Assay for Inhibition of Factor Xa (1) Compounds of the present invention (Examples 1-147) were tested for their Factor Xa inhibitory activity as determined in vitro by their ability to inhibit human Factor Xa in a chromogenic assay, using N-α-benzyloxycarbonyl-D-Arg-Gly-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10 mM stock solution in dimethylsulfoxide at appropriate concentrations. Assay was performed at room temperature using buffer consisting of: 50 mM Tris-HCl, 150 mM NaCl, 5 mM CaCl2, pH 7.4. containing human Factor Xa (final conc. Of 0.0015 U.ml−1). Compound and enzyme were preincubated for 15 min prior to addition of the substrate (final conc. of 200 μM). The reaction was stopped after 30 min with the addition of soybean trypsin inhibitor or H-D-PHE-PRO-ARG-Chloromethylketone. BioTek EL340 or Tecan SpectraFluor Plus plate readers were used to monitor the absorbance at 405 nm. To obtain IC50 values the data were analysed using ActivityBase® and XLfit®. Calculation of Ki values: Ki=IC50/(1+[Substrate]/Km) The Ki value for the above assay can be obtained by dividing the IC50value by 7. In vitro Assay for Inhibition of Factor Xa (2) Compounds of the present invention (Examples 148-156) were tested for their Factor Xa inhibitory activity as determined in vitro by their ability to inhibit human Factor Xa in a fluorogenic assay, using Rhodamine 110, bis-(CBZ-glycylglycyl-L-arginine amide as the fluorogenic substrate. Compounds were diluted from a 10 mM stock solution in dimethylsulfoxide at appropriate concentrations. Assay was performed at room temperature using buffer consisting of: 50 mM Tris-HCl, 150 mM NaCl, 5 mM CaCl2, pH 7.4. containing human Factor Xa (final conc. Of 0.0003 U.ml−1). Compound and enzyme were preincubated for 15 min prior to addition of the substrate (final conc. of 10 μM). The reaction was stopped after 3 hrs with the addition of H-D-PHE-PRO-ARG-Chloromethylketone. An LJL-Analyst fluorimeter was used to monitor fluorescence with 485 nm excitation/535 nm emission. To obtain IC50 values the data were analysed using ActivityBase® and XLfit®. Calculation of Ki values: Ki=IC50/(1+[Substrate]/Km) The Ki value for the above assay can be obtained by dividing the IC50 value by 1.6. All of the synthetic Example compounds tested (Examples 1-156) by one of the above described in vitro assays for Factor Xa exhibited IC50 values of less than 4 μM. Preferably compounds have a Ki value of less than 1 μM, more preferably compounds have an Ki value of less than 200 nM, most preferably compounds have a Ki value of less than 20 nM. Method for Measurement of Prothrombin Time (PT) Blood is collected into a sodium citrate solution (ratio 9:1) to give a final concentration of 0.38% citrate. Plasma is generated by centrifugation of citrated blood samples at 1200×g for 20 min at 4° C. The PT test is performed at 37° C. in plastic cuvettes containing a magnetic ball bearing. 50 μL of citrated plasma and either 25 μL of 2.8% DMSO for control or 25 μL of test compound (dissolved in DMSO and diluted in water and 2.8% DMSO to give 0.4% DMSO final in assay) at a concentration of 7-times the final desired concentration is pippetted into each cuvette. This mixture is incubated for 1 mm at 37° C. before adding 100 μL of thromboplastin mixture (comprising lyophilised rabbit thromboplastin and calcium chloride which is reconstituted in distilled water as per manufacturer's [Sigma] instructions). On addition of the thromboplastin mixture, the timer is automatically started and continued until the plasma clotted. The time to clotting was recorded (normal range for human plasma is 10-13seconds). Method for Measurement of Prothrombin Time (PT)-Test 2 Blood is collected into a sodium citrate solution (ratio 9:1) to give a final concentration of 0.38% citrate. Plasma is generated by centrifugation of citrated blood samples at 1200×g for 20 min at 4° C. The PT test is preformed at 37° C. in plastic cassettes and using a MCA210 Microsample Coagulation Analyzer (Bio/Data Corporation). For assay, 25 ul of plasma containing test compound at concentrations ranging from 0.1 to 100 uM (made from a 1 mM stock solution in 10% DMSO and plasma) and 25 ul of Thromboplastin C Plus (Dade Berhing) are automatically injected into the cassette. Upon addition of the Thromboplastin C Plus, the instrument determines and records the time to clot (normal range for human plasma is 10-13seconds). General Purification and Analytical Methods LC/MS Method (1) Analytical HPI,C was conducted on a Supelcosil LCABZ+PLUS column (3 μm, 3.3 cm×4.6 mm ID) eluting with 0.1% HCO2H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HCO2H in water (solvent B), using the following elution gradient 0-0.7 minutes 0% B, 0.7-4.2 minutes 0→100% B, 4.2-5.3 minutes 100% B, 5.3-5.5 minutes 100→0% B at a flow rate of 3 ml/minutes (System 1). The mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation [(ES+ve to give MH+ and M(NH4)+ molecular ions] or electrospray negative ionisation [(ES−ve to give (M−H)− molecular ion] modes. LC/MS Method (2) Method 2 was conducted on a Waters Xtera RP18 column (3 μm, 15 cm×2.1 mm ID) eluting with solvent A (0.1% HCO2H and water) and solvent B (100% acetonitrile, 0.1% HCO2H and reserpine 2.5 μgml−1) at 20° C. The following elution gradient was ran: 0-2.0 minutes 0% B; 2.0-18.0 minutes 0-100% B; 18.0-20.0 minutes 100% B; 20.0-22.0 minutes 100-0% B; 22.0-30.0 minutes 0% B, at a flow rate of 0.4 ml/minutes. The mass spectra (MS) were recorded on a Micromass QTOF 2spectrometer using electrospray positive ionisation [ES+ve to give MH+]. Note: The number given in brackets in the Examples and Intermediates above, c.g. H.p.l.c. (1), specifies the LCIMS method used. 1H mr spectra were recorded using a Bruker DPX 400 MHz spectrometer using tetramethylsilane as the external standard. Biotage™ chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KPSil. Mass directed autoprep refers to methods where the material was purified by high performance liquid chromatography on a HPLCABZ+5 μm column (5 cm×10 mm i.d.) with 0.1% HCO2H in water and 95% MECN, 5% water (0.5% HCO2H) utilising the following gradient elution conditions: 0-1.0 minutes 5% B, 1.0-8.0 minutes 5→30% B, 8.0-8.9 minutes 30% B, 8.9-9.0 minutes 30→95%B, 9.0-9.9 minutes 95% B, 9.9-10 minutes 95→0% B at a flow rate of 8 ml minutes−1 (System 2). The Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest. Hydrpophobic frits refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd. TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with silica gel 60 F254.

<SOH> BACKGROUND OF THE INVENTION <EOH>Factor Xa is a member of the trypsin-like serine protease class of enzymes. It is a key enzyme in the coagulation cascade. A one-to-one binding of Factors Xa and Va with calcium ions and phospholipid converts prothrombin into thrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction and unstable angina. Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the venous vasculature which can result in reduced blood flow to the affected extremity and a pre-disposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the vasculature leading to widespread organ failure. Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M. A., Ann. NY Acad. Sci., 405: 349 (1986)). A Factor Xa inhibitor may be useful in the treatment of acute vascular diseases such as coronary thrombosis (for example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke. They may also have utility as anticoagulant agents both in-vivo and ex-vivo, and in oedema and inflammation. Thrombin has been reported to contribute to lung fibroblast proliferation, thus, Factor Xa inhibitors could be useful for the treatment of some pulmonary fibrotic diseases. Factor Xa inhibitors could also be useful in the treatment of tumour metastasis, preventing the fibrin deposition and metastasis caused by the inappropriate activation of Factor Xa by cysteine proteinases produced by certain tumour cells. Thrombin can induce neurite retraction and thus Factor Xa inhibitors may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. They have also been reported for use in conjunction with thrombolytic agents, thus permitting the use of a lower dose of thrombolytic agent.

20040514

20070220

20050106

89061.0

FREISTEIN, ANDREW B

2-(3-SULFONYLAMINO-2-OXOPYRROLIDIN-1-YL)PROPANAMIDES AS FACTOR XA INHIBITORS

UNDISCOUNTED

ACCEPTED