Patent ID: 12194279

DETAILED DESCRIPTION

In the present application, the term “distal part/end” refers to the part/end of the device, or the parts/ends of the components or members thereof, which in accordance with the use of the device, is located the furthest away from a delivery/injection site of a patient. Correspondingly, the term “proximal part/end” refers to the part/end of the device, or the parts/ends of the members thereof, which in accordance with the use of the device is located closest to the delivery/injection site of the patient.

FIGS.1and2A and2Billustrate the two sections of a semi-disposable device1that when connected together (seeFIGS.3A-3D) form one possible complete reconstitution medicament delivery device of the present disclosure. By “semi-disposable” it is meant that the dose setting mechanism is reusable and the cartridge holder and/or the screw driven sleeve is designed and configured to be disposed of along with the empty cartridge after the medicament has been expelled. A “completely disposable” device is one where the sleeve is permanently connected to the dose setting housing and after the reconstitution process the sleeve is also permanently attached to the cartridge holder such that after the expulsion of the medicament, the entire device is disposed of.

The proximal section2of device1includes the dose setting mechanism. The distal section3includes cartridge holder50and screw driven sleeve16, where the cartridge holder includes a distal portion17and a proximal portion40. The dose setting mechanism2includes housing4, piston rod11, piston return ring12(i.e., part of a piston rod reset feature), dose knob5, button6, and window7to view dose settings8. At the proximal end of housing4is a first thread9and may include a radial stop10that works to clearly define the radial position of the cartridge holder in the ready-to-use state. The radial stop10is designed to interact and abut a cooperating stop51on the terminal distal end of distal portion17of the cartridge holder when the screw driven sleeve16is fully retracted into the cartridge holder and when snap arm32engages the proximal snap window30.

The cartridge holder50accepts and securely holds cartridge35, preferably through a snap fit connection between the bypass21and notch20located on the second observation window22(seeFIGS.2A and2B). The bypass21is part of cartridge35and allows the solvent37(seeFIGS.5A-5E) to flow from the second or distal chamber18into the first or proximal chamber19during the reconstitution process where the solvent solubilizes the lyophilized drug agent38. The lyophilized drug is typically prepared in a lyophilization process that generally involves three stages; freezing, primary drying, and secondary drying. Freezing takes place in a freeze dryer, however, a conventional freezer can also be instead. Freezing temperatures are around −40° C. and there is no thawing before the drying stages. The frozen product goes from frozen state to dry powder through the process of sublimation at reduced pressure to cause the frozen water to sublime directly from the solid phase to the gas phase leaving a dry powder. The solvent used to rehydrate the lyophilized drug agent is typically water or could be any liquid that solubilizes the lyophilized drug and is biocompatible as an injectable material.

The cartridge holder50has two observation windows22,23. Window23can be a cut-out in the distal portion17of the cartridge holder. This window23allows the user to observe the solvent37that is initially contained in chamber18when the device is in the starting configuration. As the reconstitution process begins window23will show the axial movement of sleeve16as it is screwed or retracted into cartridge holder50. Window22is located in the proximal portion40of the cartridge holder and can also be a cut-out. Window22may also have notch20that is designed to engage and secure bypass21of the cartridge35through, for example, a snap fit connection. This window also allows the user to view the lyophilized drug agent before, during and after the reconstitution process.

The exemplary multi-compartment cartridge35(seeFIGS.5A-5E) is shown as a dual chamber cartridge comprised of a first or proximal chamber19and a second or distal chamber18. These chambers are separated by a sliding piston or stopper, namely first stopper26, the proximal end of chamber19is sealed by pierceable membrane or septum37that is secured in place by a crimped metal cap36. The proximal end of cartridge35is sealed by a second sliding stopper25. Solvent37is contained between stoppers25,26. Lyophilizate38containing the drug agent is in first chamber19.FIGS.5A-5Eshow the movement and changing chamber configuration during the reconstitution process as the delivery device transforms from the initial or starting configuration (seeFIGS.3A-3D) and progresses to the delivery ready configuration shown inFIGS.6A-6D. The flow of solvent around the first stopper is also illustrated by arrows41.

The screw driven sleeve16(seeFIGS.4A and4B) is tube-like cylinder having an internal thread14located on the inner proximal surface. The outside surface of sleeve16has a thread15configured to engage a cooperating thread55located inside the distal portion17of the cartridge holder (seeFIGS.2A and2B). In some designs, thread15can be a female thread, e.g., a helical groove, that will engage a nib located on the inside surface of distal portion17. The proximal end of sleeve16has at least one flexible or snap arm32that has a protrusion33that projects radially outward relative to the longitudinal axis45, which is also the axis of device1and cartridge35. This protrusion is designed to fit into both the proximal and distal snap windows30,31that are configured as cut-outs in proximal portion17of cartridge holder50. The flexible snap arm32is designed to flex radially inward as the cartridge holder is rotated relative to the screw driven sleeve16causing the sleeve to be retracted into the cartridge holder during the reconstitution procedure. Once the cartridge holder has been fully screwed to the sleeve, the protrusion33becomes aligned with snap window31and the snap arm flexes radially outward such that the protrusion fits into and engages window31. In the design where the cartridge holder and sleeve are disposable, this engagement is permanent such that a user will not be able to rotate the cartridge holder relative to the sleeve. This permanent locking engagement can be achieved by using an asymmetrically shaped protrusion, sometimes referred to as an irreversible snap lock.

FIGS.5A-5Eshown the position of stoppers25,26relative to bypass21after the reconstitution process is complete. As illustrated, chamber18is completely subsumed as stopper25has moved proximally and in abutment with stopper26. At this stage the device1is now ready to be primed and/or to perform an injection once a needle is attached to connection24.

The present disclosure is applicable with a number of injection device designs.FIGS.1to6Dillustrate just one possible type of pen-shaped injection design as being a semi-disposable device, where the only the dose setting mechanism is designed and configured for reuse. In such a device, after the reconstitution process is complete and after the medicament has been expelled from the cartridge, the user detaches the cartridge holder/screw driven sleeve assembly containing the empty cartridge from the reusable dose setting mechanism and discards the assembly. A new assembly, containing a fresh cartridge, can then be connected to the dose setting mechanism and the reconstitution process/medicament delivery sequence can be repeated. The used cartridge holder/screw driven sleeve assembly is characterized in that the screw driven sleeve is fully contained within (i.e., screwed into) the cartridge holder and no part of it is accessible by the user. Further, because the snap arm is in a permanent connection with the proximal snap window, even if the user tried to turn the screw driven sleeve the permanent connection would prohibit any relative rotational movement between the cartridge holder and screw driven sleeve.

For a device design where the either the cartridge holder or screw driven sleeve or both are to be reused, it is necessary to unscrew the screw driven sleeve from the inside of the cartridge holder. To that end, it is helpful to provide a user assist component.FIGS.7A to9Billustrate a device design where the screw driven sleeve and the cartridge holder is to be reused. In order to reuse the screw driven sleeve60, it is necessary to have a releasable or non-permanent engagement between the snap arm63and the proximal snap window such that the cartridge holder61can be rotated relative to the screw driven sleeve60along thread66. This will cause the screw driven sleeve60to extend outward of the inside of the cartridge holder and return to the starting position. This releasable engagement can be achieved by using a symmetrical protrusion64on snap arm63(seeFIGS.8A-8C). As explained above, once the medicament delivery is completed, the user will counter rotate the cartridge holder, which will also counter rotate the screw driven sleeve because of the snap fit of the proximal snap window with the protrusion on the snap arm. Once the assembly is disconnected from the reusable dose setting mechanism, the user must be able to counter rotate the screw driven sleeve to reset the sleeve to the starting position where the snap arm is releasably engaged with the distal snap window. One possible design to assist the user in this resetting of the screw driven sleeve is to include a knurled ring62on the distal end of the screw driven sleeve. This gripping surface will provide leverage, so the user can exert the needed torque to overcome the snap fit between protrusion64and the proximal snap window. Ring62could also be used to provide a user leverage to disconnect thread65from the dose setting mechanism. Cartridge holder61can also have a second or proximal window69with a reduced section68that allows an empty cartridge to be removed and new, full cartridge35to be slid into the cartridge holder61(seeFIGS.9A and9B).

Device1has a dose dial sleeve that translates in a longitudinal direction during dose setting, dose correction and dose delivery. A dose is set through rotation of dose knob5, which causes the dose dial sleeve to move linearly in the distal direction. A dose is delivered by pushing button6on the end of the dose knob5in the opposite or proximal direction. This in turn causes the dose dial sleeve to move linearly back (proximally) into the dose setting mechanism2. One exemplary sequence of a possible dose setting mechanism is illustrated inFIGS.10A-10D, where the dose setting mechanism is shown in the zero-set dose position (“0” on scale8), when the dose is set, that start of the injection when button6is pressed, and the end of injection where the piston rod has moved proximally an axial distance proportional to the set dose of medicament. The dose setting mechanism shown inFIGS.10A-10Dis designed and configured to only allow setting of a fixed, single predetermined dose that is signified by “GO” on scale8.

The pen-type injector design shown in the figures will now be described with more detail as to the component parts and their operation. The complete injection device1is illustrated in the zero-dose state as indicated by scale8showing a zero through the window7of housing4(seeFIGS.7A-7E).FIGS.3A-3Dshow the device1with a protective cap removed to expose the cartridge holder50having a proximal needle connector24at the proximal end. A double-ended pen needle is typically attached to the needle connector24through a snap fit, thread, Luer-Lok, or other secure attachment with that the double ended needle cannula can achieve fluid communication with reconstituted medicament39within chamber19of cartridge35positioned within cartridge holder50. The cartridge35is sealed at the proximal end by septum37(seeFIGS.5A-5E).

As mentioned, the dose setting mechanism can be designed and configured as a fixed dose device. Alternatively, the dose setting mechanism could allow for setting of one or more user selected doses through the rotation of the dose knob5relative to housing4. Part of the dose setting mechanism of most pen-type injectors is a piston rod11as illustrated inFIGS.1,5A-5E and10A-10D. Such piston rods usually have a non-circular cross-section and have two flat surfaces that are designed to prevent the piston rod from rotating but allowing it to move linearly in the proximal direction. As the piston rod moves proximally it pushes stoppers25,26proximally to expel medicament39. The piston rod11is held in a non-rotational state relative to housing4during both dose setting and dose delivery because it is arranged within a non-circular pass through hole in the center of a piston rod guide. The piston rod guide is both rotationally and axially fixed to housing4. This fixation can be achieved when the piston rod guide is a separate component from the housing4or the piston rod guide could be made integral with the housing.

If the device is not pre-primed during the device assembly or does not have an automatic or forced priming feature, then the user will need to manually prime the device as follows. The dose knob5is rotated such that an amount of medicament39will be expelled from cartridge35. The injection device1of this disclosure can also have a so-called forced or automatic priming feature where prior to using the dose setting mechanism, i.e., before a user could dial a dose, a sliding lock or other mechanism would necessarily need to be activated such that an amount of medicament is expelled.

In some instances, the user may need to cancel the priming procedure or a previously set dose. This achieved through a dose canceling procedure. Dose cancellation is accomplished by turning the dose knob in the opposite direction used to set a dose. During dose cancellation, certain components in the dose setting mechanism rotate and translate axially in the opposite or proximal direction compared to the dose setting procedure.

During dose setting, the dose knob5translates out and away from the distal end of housing4. As the dose dial sleeve rotates and translates distally, the progress of the dose setting (or dose cancellation) is observed in window7as printed indicia on the dose dial sleeve moves past the window. When a desired dose setting is reached the indicia8for that dose will appear in the window. At this point the injection device1is ready for a priming procedure or, if already primed, the delivery of the medicament to an injection site. In either the case, the user will push button6on the dose knob in the proximal direction until the zero-dose hard stop is reached and a zero-dose indicia is observed in the window. During a priming step the user will observe whether medicament is expelled out of the cannula of a pen needle. If no medicament is expelled this means the piston rod is not in abutment with the distal face of sliding piston or stopper25. The priming step is then repeated until medicament is observed exiting the cannula.

The dose setting mechanism of the present disclosure can also have a maximum dose hard stop feature that prevents a user from setting a dose greater than the highest predetermined dose setting.

Once a dose has been dialed on the dose setting mechanism, the user can then exert an axial force in the proximal direction on button6to initiate the dose delivery procedure. The axial force exerted by the user overcomes a distally directed force exerted by a biasing member causing the piston rod11to move axially in the proximal direction. Axial movement of the piston rod causes the sliding stoppers to also move axially relative to the inside walls of chamber19of the stationary cartridge35forcing an amount of medicament39out of the needle cannula6that is equivalent to the dose that was set by the user during the dose setting procedure.

If the device is configured as a disposable injection device, then the cartridge35is not replaceable because the connection between the cartridge holder50and the housing4of the dose setting mechanism2is permanent. Only through breaking or deformation of this connection can the cartridge be removed from the injection device. Such a disposable device is designed to be thrown out once the medicament has been expelled from the cartridge.

In an alternate embodiment,FIG.11andFIGS.13A-13Cillustrate the two sections of a semi-disposable device1that when connected together (seeFIGS.15A and15B) form another possible complete reconstitution medicament delivery device of the present disclosure. As described above, this embodiment can be designed as a “semi-disposable” or “completely disposable” device.

The distal part of device1includes the dose setting mechanism2. The proximal part3includes cartridge holder50, where the cartridge holder includes a distal portion50band a proximal portion50a. The dose setting mechanism2includes housing4, piston rod11, piston return ring12(i.e., part of a piston rod reset feature), dose knob5, button6, and window7to view dose settings8. At the proximal end of housing4is a thread9and may include a radial stop9aor snap fit that works to clearly define the radial position of the cartridge holder relative to the dose setting mechanism after the reconstitution procedure when the device is in the ready-to-use state. The radial stop9ais designed to interact and abut a cooperating stop of snap fit feature on the terminal distal end of distal portion50bof the cartridge holder when the cartridge holder and dose setting mechanism have been screwed together and abut one another.

FIGS.12A-12Dillustrates a close-up of the return ring12removed and separated from the dose setting mechanism2for clarity purposes. The outside surface12aof the return ring can contain a plurality of longitudinal splines12b. These splines function as a gripping surface for the user to facilitate gripping and rotating the return ring in the counter-clockwise direction (relative to the dose setting mechanism2) when it becomes necessary to reset (retract) the piston rob back into the dose setting mechanism to a starting position. These splines12balso function as an engagement surface for one or more guide elements170(seeFIGS.13A-13C). The return ring12has an inner surface that may be non-circular and having a shape310that conforms to the piston rod such that the return ring and the piston rod are axially fixed to each other.

Guide elements170can be positioned on the inside surface50cof cartridge holder50and configured with a plurality of longitudinal splines170athat are designed to cooperate and engage with splines12b. Guide elements170are rotationally fixed to the inside surface50cof the cartridge holder50and can be separate components that are fixedly attached to the inside surface or the guide elements can be fabricated as integral parts of the inside surface, for example, through a molding process. When the cartridge holder and the dose setting mechanism are axially aligned with each other and then brought together, splines170aand12bwill engage and axially slide relative to each other forming a rotationally fixed engagement such that clockwise rotation of the cartridge holder (relative to the dose setting mechanism) will cause clockwise rotation of the return ring12. This rotation of the return ring will cause rotation of the piston rod11, which in turn will cause it to translate axially out of the dose setting mechanism in the proximal direction. The inner surface12cof the distal end of return ring12is configured to engage the piston rod11in a rotationally fixed manner, for example, by having a non-circular cross-section310as illustrated inFIGS.12A-12D.

FIGS.18A-18Fpresent alternative design of the above described interaction between a cartridge holder100and a dose setting mechanism (not shown), where both assemblies are fully disposable. In this design, there is no return ring. Instead there is a piston rod guide150axially fixed within the dose setting mechanism and having two longitudinally extending fingers152projecting proximally from a guide153having non-circular inner portion154that prevents relative rotation of the piston rod. The fingers152are separated by a slit or gap151that is designed to slidably accept corresponding radial projections101fixedly attached (both axially and rotationally) to the inside surface102of cartridge holder100. The dimension of the gaps151and/or projections101are selected such that projections101fit within the gaps151abutting the sides of the fingers152when the cartridge holder100is aligned with the dose setting mechanism. As the cartridge holder is screwed into/onto the dose setting mechanism, the rotating projections101engage the fingers152causing the piston rod guide150to engage and rotate. Rotation of the piston rod guide150also rotates the guide153and non-circular portion154, which engages and rotates the piston rod. This causes the piston rod to translate axially forward in the proximal direction initiating the reconstitution process. Once the cartridge holder100has been fully assembled with the dose setting mechanism the piston rod guide150is locked rotationally relative to the dose setting mechanism housing and therefore prevents rotation of the piston rod during dose setting and dose delivery.

The cartridge holder50accepts and securely holds cartridge35, preferably through a snap fit connection between the bypass21and a notch or other secure connector located on or near the second observation window22(seeFIGS.13A-13C). The bypass21is part of cartridge35and allows the solvent37(seeFIGS.16A-16E) to flow from the second or distal chamber18into the first or proximal chamber19during the reconstitution process where the solvent solubilizes the lyophilized drug agent38. The lyophilized drug is typically prepared as described above.

The cartridge holder50has two observation windows22,23(seeFIGS.18A-18F). Window23can be a cut-out in the cartridge holder that allows the user to observe the solvent37that is initially contained in chamber18when the device is in the starting configuration. As the reconstitution process begins, window23will show the axial movement of return ring12in the proximal direction as the cartridge holder is screwed onto the dose setting mechanism via the engagement of threads9and300. Window22is also located in the cartridge holder50and can also be a cut-out. Window22may also have notch that is designed to engage and secure bypass21of the cartridge35through, for example, a snap fit connection. This window22also enables the user to view the lyophilized drug agent before, during and after the reconstitution process.

The exemplary multi-compartment cartridge35(seeFIGS.16A-16E) is shown as a dual chamber cartridge comprised of a first or proximal chamber19and a second or distal chamber18. These chambers are separated by a sliding piston or stopper, namely first stopper26, the proximal end of chamber19is sealed by pierceable membrane or septum37that is secured in place by a crimped metal cap36. The proximal end of cartridge35is sealed by a second sliding stopper25. Solvent37is contained between stoppers25,26. Lyophilizate38containing the drug agent is in first chamber19.FIGS.16A-16Eshow the movement and changing chamber configuration during the reconstitution process as the delivery device transforms from the initial or starting configuration (seeFIGS.14A-14F) and progresses to the delivery ready configuration, the right-hand illustration inFIGS.16A-16E. The flow of solvent around the first stopper is also illustrated by arrows41.

FIG.11shows the threaded tube-like cylinder having external threads9located on an outer proximal surface of the dose setting mechanism2. This threaded outside surface is configured to engage a cooperating thread300located inside the distal portion of the cartridge holder (seeFIGS.13A-13C). In some designs, thread300can be a female thread, e.g., a helical groove, that will engage a nib located on the inside surface of distal portion17. A radial stop or snap feature9acan be included on thread300such that when the cartridge holder has been fully screwed onto the dose setting mechanism the hard stop or snap feature will engage a corresponding feature on the inside surface of the cartridge holder to provide a tactile feedback to the user that the two parts are securely connected. In a design where the delivery device is completely disposable, this engagement is permanent such that a user will not be able to reverse the rotation of the cartridge holder relative to the dose setting sleeve. This permanent locking engagement can be achieved by using an asymmetrically shaped protrusion, sometimes referred to as an irreversible snap lock.

FIGS.15A and15Bshow the position of stoppers25,26relative to bypass21after the reconstitution process is complete. As illustrated, chamber18is completely subsumed as stopper25has moved proximally and in abutment with stopper26. At this stage the device1is now ready to be primed and/or to perform an injection once a needle200is attached to connection24.

As with the embodiments described above, this embodiment is applicable with a number of injection device designs. The pen-type injection device ofFIGS.11to16Eis just one possible design of an injection device, one that is either completely reusable or a semi-disposable device, where after the reconstitution process is complete and after the medicament has been expelled from the cartridge through one more injections, the user detaches the cartridge holder containing the empty cartridge from the reusable dose setting mechanism and discards the assembly. A new assembly, containing a fresh cartridge, can then be connected to the reusable dose setting mechanism and the reconstitution process/medicament delivery sequence can be repeated. Alternatively, the device could be completely reusable, where the cartridge holder is designed for reuse as well and where the empty used cartridge is removed and replaced with a full cartridge.

Device1has a dose dial sleeve that translates in a longitudinal direction during dose setting, dose correction mid dose delivery. A dose is set through rotation of dose knob5, which causes the dose dial sleeve to move linearly in the distal direction. A dose is delivered by pushing button6on the end of the dose knob5in the opposite or proximal direction. This in turn causes the dose dial sleeve to move linearly back (proximally) into the dose setting mechanism2. One exemplary sequence of a possible dose setting mechanism is illustrated in17A-17C, where the dose setting mechanism is shown in the zero-set dose position (“0” on scale8), when the dose is set, that start of the injection when button6is pressed, and the end of injection where the piston rod has moved proximally an axial distance proportional to the set dose of medicament. The dose setting mechanism shown inFIGS.7A-7Eis designed and configured to only allow setting of a fixed predetermined dose that is signified by “GO” on scale8.

The pen-type injector design shown inFIGS.11to18Fwill now be described with more detail as to the component parts and their operation. The complete injection device1is illustrated in the zero-dose state as indicated by scale8showing a zero through the window7of housing4.FIGS.15A and15Bshow the device t with a protective cap removed to expose the cartridge holder50having a pen needle200connected to a needle connector24at the proximal end (seeFIGS.13A-13C). A double-ended pen needle is typically used mounted in a hub and attached to needle connector24through a snap fit, thread. Luer-Lok, or other secure attachment with that the double ended needle cannula can achieve fluid communication with reconstituted medicament39within chamber19of cartridge35positioned within cartridge holder50. The cartridge35is sealed at the proximal end by septum37(seeFIGS.16A-16E).

As mentioned, the dose setting mechanism can be designed and configured as a fixed dose device. Alternatively, the dose setting mechanism could allow for setting of one or more user selected doses through the rotation of the dose knob5relative to housing4. Part of the dose setting mechanism of most pen-type injectors is a piston rod11that in some cases has a non-circular cross-section with two flat surfaces that are designed to prevent the piston rod from rotating, but allows it to move linearly in the proximal direction. As the piston rod moves proximally it pushes stoppers25,26proximally to expel medicament39. The piston rod11is held in a non-rotational state relative to housing4during both dose setting and dose delivery because it is arranged within a non-circular pass through hole in the center of a piston rod guide in the case of a fully disposable device or in the piston rod return ring when the device is design as a rescuable device. In either design, during dose setting and dose delivery the piston rod guide or return ring is both rotationally and axially fixed to housing4. This fixation can be achieved when the piston rod guide is a separate component from the housing4. The return ring becomes rotational fixed relative to the housing when the cartridge holder is fully attached to the dose setting mechanism.

The priming features described above are applicable to the embodiments shown inFIGS.11to18F. The same is true of the dose canceling procedure.

During dose setting, the dose knob5translates out and away from the distal end of housing4. As the dose dial sleeve rotates and translates distally, the progress of the dose setting (or dose cancellation) is observed in window7as printed indicia on the dose dial sleeve moves past the window. When a desired dose setting is reached the indicia for that dose will appear in the window. At this point the injection device1is ready for a priming procedure or, if already primed, the delivery of the medicament to an injection site. In either the case, the user will push button6on the dose knob in the proximal direction until the zero-dose hard stop is reached and a zero-dose indicia is observed in the window. During a priming step the user will observe whether medicament is expelled out of the cannula of a pen needle. If no medicament is expelled this means the piston rod is not in abutment with the distal face of sliding piston or stopper25. The priming step is then repeated until medicament is observed exiting the cannula.

The dose setting mechanism of the present disclosure can also have a maximum dose hard stop feature that prevents a user from setting a dose greater than the highest predetermined dose setting.

Once a dose has been dialed on the dose setting mechanism, the user can then exert an axial force in the proximal direction on button6to initiate the dose delivery procedure. The axial force exerted by the user overcomes a distally directed force exerted by a biasing member causing the piston rod11to move axially in the proximal direction. Axial movement of the piston rod causes the sliding stoppers to also move axially relative to the inside walls of chamber19of the stationary cartridge35forcing an amount of medicament39out of the needle cannula6that is equivalent to the dose that was set by the user during the dose setting procedure.

If the device is configured as a disposable injection device, then the cartridge35is not replaceable because the connection between the cartridge holder50and the housing4is permanent. Only through breaking or deformation of this connection can the cartridge be removed from the injection device. Such a disposable device is designed to be thrown out once the medicament has been expelled from the cartridge.

It is to be understood that the embodiments described above and shown in the drawings are to be regarded only as non-limiting examples of the possible designs of the safety assembly and such designs may be modified in many ways within the scope of the patent claims.