PATENT ABSTRACT
The invention relates to peptides having the general formula (I), or a salt or amide thereof, wherein R 1  and R 2  are either the same or different, wherein R 1  and R 2  are each selected from the group consisting of hydrogen and a saturated or unsaturated hydrocarbon residue, said residue having from 1 to 10 carbon atoms, wherein Z 1  is selected from the group consisting of histidine and proline, wherein Z 2  is selected from the group consisting of an arginine and a peptide comprising an initial arginine and having from 2 to 30 amino acids. The invention also relates to methods using the peptides of the present invention in the treatment of inflammation.

PATENT DESCRIPTION
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    The present application is a divisional of U.S. patent application Ser. No. 10/459,030, filed Jun. 11, 2003, which is a continuation of International Patent Application No. PCT/AT01/00387, filed Dec. 7, 2001, published in German on Jun. 20, 2002 as International Patent Publication No. WO02/248180, which claims priority to Austrian Application No. AT A 2063/2000, filed Dec. 12, 2000, all of which are incorporated in their entireties herein. 
     
    
     BACKGROUND 
       [0002]    The invention concerns peptides and/or proteins, their use for preparing a therapeutic and/or preventive pharmaceutical composition as well as a pharmaceutical composition. 
         [0003]    Substances for the inhibition or prevention of inflammatory reactions, so-called immunosuppressants, which so far have been used for prophylaxis and therapy, generally comprise two distinct groups. Firstly, derivatives of a hormone, i.e. cortisone, naturally occurring in the body, and secondly, exogenous immunosuppressants such as cyclosporin and its derivatives, azathioprine, cyclophosphamide etc. All those substances possess anti-inflammatory effects but they show substantial side reactions in long-term therapy. Those side reactions have a limiting effect on long-term therapy, which is why those substances are used alternately or in combination in order to keep side effects on a tolerable level or in order to be able to actually proceed with the therapy. As examples of side reactions, the pathological fractures associated with cortisone are to be mentioned, which fractures are caused by the osteoporotic effect of the cortisone, or the renal failure which may be caused by cyclosporin. Those side reactions are inevitable with both groups of compounds, and hence it is merely a question of the duration of the therapy and of the total dose at what point the therapy must be stopped. 
       SUMMARY OF THE INVENTION 
       [0004]    The present invention has as its object to provide new pharmaceutical products which are suitable for preventing or inhibiting inflammatory effects and which only show minor side effects. A further object consists in providing long-term therapy. 
         [0005]    In the following, the amino acids of the peptides according to the invention are referred to by the usual abbreviations, which denote the α-amino acids. 
         [0006]    By “analogues,” a peptide is understood which, by derivatisation, substitution, preferably homologous substitution, deletion and/or insertion, is derived from the sequence of the fibrin and in particular from the preferred sequences. 
         [0007]    The peptides or protein according to the invention exhibit the general formula I 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2 , being equal or different, denote hydrogen, a saturated or unsaturated hydrocarbon residue comprising from 1 to 3, in particular up to 10, carbon atoms,
       Z 1  denotes a histidine or proline residue,   Z 2  denotes an arginine residue, a peptide residue or a protein residue comprising an initial arginine residue, in particular comprising from 2 to 30 amino acids, as well as the salts thereof, and, f.i., also amides, or mixtures with each other and/or with at least one further substance for therapeutic and/or preventive use in human and/or veterinary medicine, whereby in particular only L-amino acids are provided. Sequences of formula I are listed in Table 1.       
 
         [0010]    It was completely surprising that the specified amino acid sequence prevents the adhesion of cells from the bloodstream to endothelial cells of the vascular wall and/or their subsequent transmigration from the blood into the tissue. 
         [0011]    The peptides or protein according to the invention exhibit the general formula II 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2 , being equal or different, denote hydrogen, a saturated or unsaturated hydrocarbon residue comprising from 1 to 3, in particular up to 10, carbon atoms,
       Z 1  denotes a histidine or proline residue,   Arg denotes an arginine,   Z 3  denotes a proline or valine residue,   Z 4  denotes a leucine or valine residue,   Z 5  denotes a protein residue or a peptide residue, in particular comprising from 2 to 30 amino acids, or an alcohol comprising from 1 to 3, in particular up to 10, carbon atoms, or an organic or inorganic base residue, as well as the salts thereof, and, f.i., also amides, or mixtures with each other and/or with at least one further substance for therapeutic and/or preventive use in human and/or veterinary medicine, whereby in particular only L-amino acids are provided. Sequences of formula II are listed in Table 2.       
 
         [0017]    It was completely surprising that parts of the sequence, peptides or fragments of the fibrinogen exhibit anti-inflammatory effects. Without being bound by such theoretical considerations, said effects might be based on the fact that the fibrin binds to endothelial cells via its neo-N-terminus of the Bbeta-chain and to cells in the bloodstream via the sequence of the Aalpha-chain, thereby leading to the adhesion and transmigration of cells into the tissue. Those bindings exhibit a side reaction in that the formation of fibrin is inhibited. However, said inhibition does not constitute a potential disadvantage to the patient since the blood coagulation is sufficient also in the absence of fibrin if slight injuries occur. Only in case of surgical treatment, it might optionally be suitable to stop such kind of therapy. Other side reactions may substantially be ruled out, since those substances only interact with natural ligands. Furthermore, the natural defence is not affected adversely by the leukocytes in the blood. Thus, the composition of the same, such as granulocytes, lymphocytes and monocytes, remains unaffected so that the natural defence process is maintained and the defence against infections in the blood remains unchanged. 
     
    
     DETAILED DESCRIPTION 
       [0018]    Fibrinogen is produced in the liver and, in this form, is biologically inactive and normally is provided in the blood at concentrations of around 3 g/l. By proteolytic cleavage of the proenzyme prothrombin, thrombin is formed which cleaves off the fibrinopeptides A and B from the fibrinogen. In doing so, fibrinogen is transformed into its biologically active form. Fibrin and fibrin cleavage products are generated. 
         [0019]    Thrombin is formed during each activation of the blood coagulation, i.e. with each damage to the tissue, be it of inflammatory, traumatic or degenerative genesis. The formation of fibrin as mediated by thrombin is basically a protective process with the purpose of quickly sealing any defects caused to the vascular system. However, the formation of fibrin is also a pathogenic process. The appearance of a fibrin thrombus as the triggering cause of cardiac infarction is one of the most prominent problems in human medicine. 
         [0020]    The role which fibrin plays during the extravastation of inflammatory cells from the bloodstream into the tissue, which, on the one hand, is a desired process of the defence against pathogenic microorganisms or tumour cells occurring in the tissue, but, on the other hand, is a process which, by itself, induces or prolongues damage done to the tissue, has so far not been examined at all or not to a sufficient extent. Fibrin binds to endothelial cells via its neo-N-terminus of Bbeta by means of the sequence to Bbeta and to cells in the bloodstream by means of the sequence Aalpha, thereby leading to the adhesion and transmigration of cells into the tissue. 
         [0021]    The peptides or proteins according to the invention may prevent the adhesion of cells from the bloodstream to endothelial cells of the vascular wall and/or their subsequent transmigration from the blood into the tissue. 
         [0022]    A peptide or protein according to the invention of the general formula II, wherein Z 5  denotes a peptide residue comprising the following amino acid sequence (SEQ ID NO 291): 
         [0000]                        Asp Lys Lys Arg Glu Glu Ala Pro Ser Leu Arg Pro                   Ala Pro Pro Pro Ile Ser Gly Gly Gly Tyr Arg            
and Z 1  denotes a histidine residue,
 
         [0023]    Arg denotes an arginine residue, 
         [0024]    Z 3  denotes a proline residue, 
         [0025]    Z 4  denotes a leucine residue, 
         [0000]    prevents fibrin fragments from depositing on or adhering to the vascular wall. Thus, it is rendered impossible that inflammatory cells are retained at the endothelial cells of the vascular walls of arteries and veins, and such cells are prevented from remaining at the vascular walls, thus being prevented from infiltrating the tissue any further. 
         [0026]    A peptide or protein of the general formula II, wherein Z 5  denotes a peptide residue comprising the following amino acid sequence (SEQ ID NO 292): 
         [0000]                        Glu Arg His Gln Ser Ala Cys Lys Asp Ser Asp Trp                   Pro Phe Cys Ser Asp Glu Asp Trp Asn Tyr Lys            
and Z 1  denotes a proline residue,
 
         [0027]    Arg denotes an arginine residue, 
         [0028]    Z 3  denotes a valine residue, 
         [0029]    Z 4  denotes a valine residue, 
         [0000]    has the effect of preventing the cells of the peripheral blood from adhering to fibrin or fibrin fragments, hence prohibiting their migration in the tissue. 
         [0030]    The described cleavage products are also known in the literature as peptide Bbeta and peptide Aalpha. Said above mentioned proadhesive and promigratory path is a completely new one for the system of controlling the migration of cells from the blood into the tissue. This function of the fibrin may be blocked by peptide Bbeta and also by peptide Aalpha. 
         [0031]    Therefore, said peptides according to the invention are suitable as therapeutic agents for humans and animals in order to block the migration of cells from the blood into the tissue. Since fibrin or other fibrinogen products produced by proteolytic cleavage, such as, f.i., fibrinogen cleaved by an urokinase-plasminogen-activator, are generated only to a specific and regionally limited extent, i.e. at sites of inflammation, disturbed coagulation, arterial sclerosis, thrombosis and/or tumour growth, the effect of said therapeutic agent is regionally limited, which means that pathological side effects occurring in other places are not to be expected or only to a limited extent. 
         [0032]    Preferable and completely unexpected fields of application for the peptides and/or proteins according to the invention consist in the preparation of pharmaceutical compositions for the therapy or prevention of local and/or generalized inflammations in the body in case of infectious genesis, based upon an auto-immune reaction, based upon a rheumatic disease, based upon a disorder in the immune system, based upon a genetic disease, for the prevention and/or therapy of the rejection occurring after organ transplants, of arterial sclerosis, of a reperfusion trauma, based upon arteriosclerotic and/or thrombotic diseases and an increased fibrin deposition. Such a peptide, in particular Bbeta, is also excellently suitable for the preparation of a pharmaceutical composition which accomplishes the transportation of a further drug substance to human or animal endothelial cells. In doing so, the drug substance to be transported is coupled to the peptide at one end and then, via VE-cadherin, deposits on a free spot of the vascular wall, i.e. on an endothelial cell. 
         [0033]    In the following, the invention is explained in further detail by way of examples. 
       EXAMPLES 
     Example 1 
     Preparation of the Fibrinogen Cleavage Products 
       [0034]    Non-polymerizing degradation products of fibrinogen were obtained by means of a decomposition involving cyanogen bromide according to Blombäck et al. (Nature 1968, 218; 130-134). The fibrinogen thus degraded largely consists of a 63 kD fragment, i.e. the N-terminal disulfide knot, NDSK, and comprises Aalpha-chain 1-51, Bbeta-chain 1-118 and gamma-chain 1-78. In order to obtain NDSK-II (NDSK minus fibrinopeptides A and B), the N-terminal amino acids of the Aalpha- and Bbeta-chains were cleaved off with thrombin (20 units/1 μg NDSK) in three hours at room temperature and subsequently were treated with diisopropylfluorophosphate in order to block thrombin activity. The NDSK-II thus obtained consisted of Aalpha-chain 17-51, Bbeta-chain 15-118 and gamma-chain 1-78. 
         [0035]    In order to obtain NDSK-uPA, 500 μg of NDSK was treated with 200 units of urokinase-plasminogen-activator (uPA) of Messrs. Technoclone, Vienna, Austria, for one hour at 37° C. The reaction was stopped with 5 mM phenylmethylsulfonyl fluoride. The NDSK-uPA thus obtained is a NDSK and has no fibrinopeptide B. 
         [0036]    As a negative control, a second fraction was obtained from the fibrinogen cleavage products referred to as FCB-2 according to Nieuwenhuizen et al. (Biochem Biophys Acta 1983, 755; 531-533), which cleavage products were produced by being treated with cyanogen bromide. FCB-2 is a protein having a size of 43 kD and consists of Aalpha-chain 148-208, Bbeta-chain 191-305 and gamma-chain 95-265. For control purposes, thrombin and diisopropylfluorophosphate were added to said protein. That, however, did not result in any change to the protein (in the following, referred to as FCB-2-thr). 
         [0037]    For the purpose of further negative controls, culture medium (RPMI of Messrs. Life techn. Inc., Paisky, UK) was treated with thrombin as above and, subsequently, was inactivated (RPMI-thr) or was treated with uPA as above and was inactivated (RPMI-uPA). 
       Example 2 
       [0038]    Peptide Aalpha (SEQ ID NO 293) corresponds to amino acids 1 to 28 of the alpha-chain of the fibrin and is identical to amino acids 17 to 45 of the Aalpha-chain of the fibrinogen: 
         [0000]    
       
         
               
               
             
           
               
                 Gly Pro Arg Val Val Glu Arg His Gln Ser Ala Cys 
                   
               
               
                   
               
               
                 Lys Asp Ser Asp Trp Pro Phe Cys Ser Asp Glu Asp 
               
               
                   
               
               
                 Trp Asn Tyr Lys 
               
             
          
         
       
     
         [0039]    Peptide Bbeta (SEQ IN NO 294) corresponds to amino acids 1 to 28 of the beta-chain of the fibrin, which is identical to amino acids 15 to 43 of the Bbeta-chain of the fibrinogen, which exhibits the following sequence: 
         [0000]    
       
         
               
               
             
           
               
                 Gly His Arg Pro Leu Asp Lys Lys Arg Glu Glu Ala 
                   
               
               
                   
               
               
                 Pro Ser Leu Arg Pro Ala Pro Pro Pro Ile Ser Gly 
               
               
                   
               
               
                 Gly Gly Tyr Arg 
               
             
          
         
       
     
         [0040]    By applying a fluorenylmethyloxycarbonyl (FMOC)-protective group strategy according to Carpino L. A. and Han. G Y, J. Amer. Chem. Soc. 1981; 37; 3404-3409, both peptides were synthesized by means of a solid-phase peptide synthesis according to Merrifield R. B., J. Amer. Chem. Soc. 1963; 85, 2149-2154, using a multiple peptide synthesizer. The crude peptides were purified by preparative reversed-phase HPLC via a Nucleosil 100-10, C18-column according to Engelhart H. and Müller H. Chromatography 1984 19:77 as well as Henschen A., Hupe K. P. and Lottspeich F. High Performance Liquid Chromatography VCH 1985. As control peptides, peptides of the same length but comprising a randomized amino acid sequence were used. 
       Example 3 
     HU-SCID Mouse-Model 
       [0041]    Human skin was transplanted onto the backs of SCID mice, and two weeks later human lymphocytes were injected into the peritoneum. The proceedings were according to Petzelbauer et al. (J. Invest. Dermatol. 1996, 107; 576-581). Then, fifteen mice thus prepared were injected in their tail veins with the following: 
         [0000]    a) 100 μg of human NDSK-II
 
b) 100 μg of human FCB-2
 
c) 100 μg of peptide Aalpha
 
d) 100 μg of peptide Bbeta
 
e) 100 μg of randomized Aalpha
 
f) 100 μg of randomized Bbeta
 
Twenty-four hours later, the human skin was removed and the number of inflammatory sites, expressed in cells per 0.3 mm 2 , was evaluated and the mean value was determined with a standard deviation.
 
       For a: 22+/−2.8 
       [0042]    for b: 9+/−2.1
 
for c: 4+/−1.1
 
for d: 6+/−1.1
 
for e: 5+/−1.2
 
for f: 7+/−1.3
 
That allows the conclusion that NDSK-II causes inflammations, and hence said protein was used as a pathogenic substance. The other compounds per se do not exhibit any significant increase in the amount of inflammatory cells.
 
       Comparative Example 4 
       [0043]    Fifteen mice according to Example 3 were injected in their tail veins with
 
100 μg of human NDSK-II and
 
100 μg of randomized peptide Aalpha.
 
Further proceedings were according to Example 3. Per 0.3 mm 2 , 23+/−3.5 inflammatory sites could be determined.
 
       Comparative Example 5 
       [0044]    Fifteen mice according to Example 3 were injected in their tail veins with
 
100 μg of human NDSK-II according to Example 1 and
 
100 μg of randomized peptide Bbeta.
 
Further proceedings were according to Example 3. Per 0.3 mm 2 , 24+/−2 inflammatory sites could be determined.
 
       Example 6 
       [0045]    Fifteen mice according to Example 3 were injected with
 
100 μg of human NDSK-II and
 
100 μg of synthesized peptide Aalpha.
 
Further proceedings were according to Example 3. Per 0.3 mm 2 , 21+−2.2 inflammatory sites could be determined.
 
       Example 7 
       [0046]    Fifteen mice according to Example 3 were injected in their tail veins with
 
100 μg of human NDSK-II and
 
100 μg of synthesized peptide Bbeta.
 
Further proceedings were according to Example 3. Per 0.3 mm 2 , 14+/−2 inflammatory sites could be determined.
 
Examples 4 to 7 show that peptide Bbeta blocks lymphocytic inflammation.
 
       Comparative Example 8 
       [0047]    Endothelial cells from human umbilical veins (HUVEC) were marked with a red fluorescent dye (Cell Tracker Orange, 1 μl/ml, Molecular Probes, Eugene, Oreg.) and were dispersed on a collagen matrix (Collaborative Biomedical Products, Bedford, Mass.). Upon confluence of the endothelial cells, peripheral mononuclear blood cells (PBMC) (10 5  cells per 25 mm 2 ) marked with a green fluorescent dye (Cell Tracker Green, 1 μl/ml, Molecular Probes of Messrs. Eugene, Oreg.) were superimposed. Thereafter, the cells were incubated at 37° C. for twelve hours. 
         [0048]    Adhering cells that had transmigrated into the gel were photographed with a laser-scan microscope, were converted into pixels and were evaluated by means of an ‘NIH image” according to Gröger et al. (J. Immunol. Method 1999; 222: 101-109). 
         [0049]    It was feasible to determine the number of adherent cells per 0.1 mm 2  such as mentioned under “adhesion.” It was feasible to determine the number of migrated cells per 0.04 mm 3  such as mentioned under “migration.” The mean value of three times three trials was evaluated together with the standard deviation. 
         [0000]                                                                      adhesion   migration                                        a) RPMI-uPA   0.1   μg/ml   40 +/− 4    4 +/− 3               1.0   μg/ml   38 +/− 2    5 +/− 2               10.0   μg/ml   32 +/− 4    5 +/− 1           b) NDSK   0.1   μg/ml   31 +/− 18   6 +/− 3               1.0   μg/ml   35 +/− 18   5 +/− 2               10.0   μg/ml   36 +/− 24   6 +/− 3           c) NDSK-II   0.1   μg/ml   55 +/− 21   12 +/− 5                1.0   μg/ml   67 +/− 31   19 +/− 12               10.0   μg/ml   65 +/− 31   19 +/− 10           d) NDSK-uPA   0.1   μg/ml   58 +/− 3    10 +/− 2                1.0   μg/ml    60 +/− 3.5   14 +/− 3                10.0   μg/ml   65 +/− 3     18 +/− 1.5           e) FCB2   0.1   μg/ml   30 +/− 26   6 +/− 4               1.0   μg/ml   10 +/− 10   3 +/− 2               10.0   μg/ml   21 +/− 7    5 +/− 4           f) FCB-2-thr   0.1   μg/ml   20 +/− 12   6 +/− 5               1.0   μg/ml   23 +/− 13   7 +/− 5               10.0   μg/ml   26 +/− 11   4 +/− 2           g) RPMI-thr   0.1   μg/ml   29 +/− 15   4 +/− 5               1.0   μg/ml   26 +/− 14   5 +/− 5               10.0   μg/ml   41 +/− 20   5 +/− 4                        
That allows the conclusion that NDSK-II results in significant migrations of peripheral blood-monocellular cells (PBMC) to a greater extent than NDSK-uPA and hence exhibits pathogenic activity. None of the controls a), b), e), f) and g) resulted in any significant migration.
 
       Example 9 
       [0050]    100 μg of NDSK-II and Bbeta or Bbeta randomized were added to the collagen matrix according to Example 8 comprising the suspension of PBMC, and further proceedings were in accordance with Example 8. 
         [0000]                                                              adhesion   migration                                    a)   no addition of NDSK-II   38 +/− 15    6 +/− 4       b)   only 100 μg of NDSK-II   73 +/− 29   16 +/− 7       c)   10 μg of Bbeta + NDSK-II   63 +/− 33    7 +/− 4       d)   100 μg of Bbeta + NDSK-II   47 +/− 34    5 +/− 4       e)   1000 μg of Bbeta + NDSK-II   52 +/− 27   10 +/− 6       f)   10 μg of Bbeta randomized + NDSK-II   77 +/− 33   16 +/− 6       g)   100 μg of Bbeta randomized + NDSK-II   86 +/− 35   15 +/− 6       h)   1000 μg of Bbeta randomized + NDSK-II   78 +/− 31   13 +/− 8                    
As can be gathered from those test results, peptide Bbeta blocks inflammations.
 
       Example 10 
       [0051]    100 μg of NDSK-II and Aalpha or Aalpha randomized were added to the collagen matrix according to Example 8 comprising the suspension of PBMC, and further proceedings were in accordance with Example 8. 
         [0000]                                                              adhesion   migration                                    a)   no addition of NDSK-II   42 +/− 6    10 +/− 1       b)   only NDSK-II   96 +/− 11   24 +/− 3       c)   10 μg of Aalpha + NDSK-II   69 +/− 12   21 +/− 4       d)   100 μg of Aalpha + NDSK-II   73 +/− 13   15 +/− 6       e)   1000 μg of Aalpha + NDSK-II   70 +/− 6    13 +/− 5       f)   10 μg of Aalpha randomized + NDSK-II   70 +/− 6    25 +/− 2       g)   100 μg of Aalpha randomized + NDSK-II   65 +/− 16   24 +/− 3       h)   1000 μg of Aalpha randomized + NDSK-II   70 +/− 12   26 +/− 3                    
As can be gathered from the test results, peptide Aalpha blocks the migration of PBMC only partially.
 
       Example 11 
       [0052]    Since PBMC substantially consists of a mixture of lymphocytes and monocytes, pure lymphocytes instead of PBMC (as in Examples 8-10) were used in Example 11. 
         [0053]    100 μg of NDSK-uPA or 100 μg of NDSK-II, respectively, and Aalpha or Bbeta, respectively, were added to the collagen matrix according to Example 8 comprising endothelial cells and lymphocytes. 
         [0000]                                                              adhesion   migration                                    a)   no addition   68 +/− 8   16 +/− 3       b)   NDSK-uPA   143 +/− 11   53 +/− 5       c)   NDSK-II   119 +/− 11   43 +/− 4       d)   only 100 μg of Bbeta    58 +/− 18   14 +/− 1       e)   NDSK-uPA + 100 μg of Bbeta   74 +/− 8   19 +/− 2       f)   NDSK-II + 100 μg of Bbeta   74 +/− 8   17 +/− 3       g)   only 100 μg of Aalpha   77 +/− 4   18 +/− 1       h)   NDSK-uPA + 100 μg of Aalpha   131 +/− 4    40 +/− 3       i)   NDSK-II + 100 μg of Aalpha   131 +/− 4    44 +/− 4       j)   only 100 μg of Bbeta randomized   75 +/− 5   19 +/− 1       k)   NDSK-uPA + 100 μg of Bbeta   134 +/− 13   46 +/− 4           randomized       l)   NDSK-II + 100 μg of Bbeta   120 +/− 12   42 +/− 4           randomized                    
Those test results show
 
1) that both NDSK-II and NDSK-uPA promote lymphocytic inflammation,
 
2) that peptide Bbeta completely blocks the lymphocytic adhesion and migration induced by NDSK-II and NDSK-uPA, whereas peptide Aalpha exhibits no blocking activity, which suggests that the free alpha-chain is not required for inducing the adhesion and migration of the lymphocytes.
 
       Example 12 
       [0054]    The proceedings were in accordance with Example 11, except for pure monocytes being used instead of lymphocytes. 100 μg of NDSK-uPA or 100 μg of NDSK-II, respectively, was added to peptide Aalpha, randomized Aalpha, Bbeta or randomized Bbeta. 
         [0000]                                                              adhesion   migration                                    a)   no addition   43 +/− 8   7 +/− 1       b)   NDSK-uPA    48 +/− 10   10 +/− 2        c)   NDSK-II    90 +/− 11   19 +/− 6        d)   100 μg of Bbeta   59 +/− 7   5 +/− 1       e)   NDSK-uPA + 100 μg of Bbeta    61 +/− 11   8 +/− 3       f)   NDSK-II + 100 μg of Bbeta   70 +/− 7   7 +/− 5       g)   100 μg of Bbeta randomized   40 +/− 7   6 +/− 1       h)   NDSK-uPA + 100 μg of Bbeta   45 +/− 5   8 +/− 3           randomized       g)   NDSK-II + 100 μg of Bbeta    92 +/− 10   20 +/− 7            randomized       j)   100 μg of Aalpha   59 +/− 6   5 +/− 1       k)   NDSK-uPA + 100 μg of Aalpha   62 +/− 4   8 +/− 5       l)   NDSK-II + 100 μg of Aalpha    68 +/− 10   9 +/− 6       m)   100 μg of Aalpha randomized   58 +/− 7   6 +/− 1       n)   NDSK-uPA + 100 μg of Aalpha    50 +/− 10   10 +/− 4            randomized       o)   NDSK-II + 100 μg of Aalpha   108 +/− 8    21 +/− 5            randomized                    
Those test results show that only NDSK-II and not NDSK-uPA promotes the migration of monocytes, which means that both the alpha-chain and the beta-chain have to exhibit a free N-terminal end and block the migration of the monocytes.
 
       Example 13 
       [0055]    The proceedings were in accordance with Example 11, with pure lymphocytes being used. 100 μg of NDSK-uPA or 100 μg of NDSK-II, respectively, was added to the short peptide salts derived from Aalpha Gly Pro Arg (Pro)-NH 2  acetate (Aalpha derivative) or derived from Bbeta Gly His Arg Pro-OH acetate (Bbeta derivative). 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 adhesion 
                 migration 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 a) 
                 no addition 
                 60 +/− 8 
                 14 +/− 1 
               
               
                 b) 
                 NDSK-uPA 
                 149 +/− 12 
                 57 +/− 5 
               
               
                 c) 
                 NDSK-II 
                 121 +/− 11 
                 48 +/− 7 
               
               
                 d) 
                 only 100 μg of Bbeta derivative 
                  58 +/− 10 
                 12 +/− 9 
               
               
                 e) 
                 NDSK-uPA + 100 μg of Bbeta derivative 
                 70 +/− 8 
                 16 +/− 3 
               
               
                 f) 
                 NDSK-II + 100 μg of Bbeta derivative 
                 69 +/− 7 
                 14 +/− 5 
               
               
                 g) 
                 only 100 μg of Aalpha derivative 
                 77 +/− 4 
                 18 +/− 1 
               
               
                 h) 
                 NDSK-uPA + 100 μg of Aalpha derivative 
                 134 +/− 4  
                 48 +/− 5 
               
               
                 i) 
                 NDSK-II + 100 μg of Aalpha derivative 
                 131 +/− 7  
                 49 +/− 6 
               
               
                 j) 
                 only 100 μg of Bbeta derivative 
                 70 +/− 5 
                 14 +/− 7 
               
               
                   
                 randomized 
               
               
                 k) 
                 NDSK-uPA + 100 μg of Bbeta derivative 
                 130 +/− 12 
                 49 +/− 6 
               
               
                   
                 randomized 
               
               
                 l) 
                 NDSK-II + 100 μg of Bbeta derivative 
                 120 +/− 10 
                 55 +/− 8 
               
               
                   
                 randomized 
               
               
                   
               
             
          
         
       
     
         [0056]    Said experiment allows the conclusion that, if lymphocytic migration is inhibited, those short peptides, added continuously in an appropriate manner, exhibit the same activity as do the long peptides. 
       Example 14 
       [0057]    The proceedings were in accordance with Example 12, with pure monocytes being used. 100 mg of NDSK-uPA or 100 μg of NDSK-II, respectively, was added to the short peptide salts Aalpha Gly Pro Arg (Pro)-NH 2  acetate (Aalpha derivative) or Bbeta Gly His Arg Pro-OH acetate (Bbeta derivative). 
         [0000]                                                              adhesion   migration                                    a)   no addition   40 +/− 8   5 +/− 1       b)   NDSK-uPA   54 +/− 9   7 +/− 2       c)   NDSK-II    85 +/− 11   22 +/− 6        d)   100 μg of Bbeta derivative   52 +/− 7   6 +/− 1       e)   NDSK-uPA + 100 μg of Bbeta derivative    61 +/− 11   8 +/− 3       f)   NDSK-II + 100 μg of Bbeta derivative   68 +/− 7   8 +/− 4       g)   100 μg of Bbeta derivative randomized   40 +/− 7   6 +/− 1       h)   NDSK-uPA + 100 μg of Bbeta derivative   44 +/− 6   8 +/− 2           randomized       i)   NDSK-II + 100 μg of Bbeta derivative    92 +/− 10   23 +/− 7            randomized       j)   100 μg of Aalpha derivative   50 +/− 5   4 +/− 4       k)   NDSK-uPA + 100 μg of Aalpha derivative   60 +/− 5   7 +/− 6       l)   NDSK-II + 100 μg of Aalpha derivative    64 +/− 11   8 +/− 2       m)   100 μg of Aalpha derivative randomized    54 +/− 10   6 +/− 3       n)   NDSK-uPA + 100 μg of Aalpha derivative    50 +/− 10   10 +/− 4            randomized       o)   NDSK-II + 100 μg of Aalpha derivative   99 +/− 8   21 +/− 7            randomized                    
Said experiment allows the conclusion that, if monocytic migration is inhibited, those short peptides, added continuously in an appropriate manner, exhibit the same activity as do the long peptides.
 
       Example 15 
       [0058]    The tests were carried out on male wistar rats weighing between 220 g and 280 g. The rats were given standard food and water. For carrying out the test, the rats were anaesthetized and artifically respirated with a frequency of 70 pulses per minute, whereby from 8 ml to 10 ml per kilogram of a gas containing 30% by volume of oxygen and having an overpressure of from 1 mm to 2 mm mercury was emitted. The cardiac artery on the right hand side was equipped with a measuring cannula, and the blood pressure in the artery as well as the heartbeats were determined. The pressure rate was determined as a product of the blood pressure in the artery and of the heartbeat rate with the dimension mm mercury/minute/10 3 . The vein on the right hand side was equipped with a measuring cannula for doping the test substances. After carrying out the surgical treatment, 2 ml of rat blood was supplied to the heart. Thirty minutes later, the cardiac artery on the left hand side was occluded. Another twenty-five minutes later, the occlusion was released in order to resupply the ischaemic area with blood. At that point of time, 800 μg/kg of peptide Bbeta or peptide Bbeta randomized, respectively, was intravenously administered to half of the animals, and then two hours were allowed to pass. 
         [0059]    In order to distinguish between damaged and undamaged cardiac tissue, the cardiac artery on the left hand side was then supplied with evans blue dye at a concentration of 2% by weight. Thereupon, the removed heart was dissected by five horizontal cuts, the right hand wall of the vein was removed and the sections were treated with triphenyltetratolchloride (1% by weight) for twenty minutes at 37° C. so as to be able to distinguish between normal tissue and infarct tissue. The sections were evaluated by computer-sustained planimetry. 
         [0060]    Because of the vascular occlusion, 62.5% of the cardiac muscle in the hearts of the reference rats was threatened, as opposed to 60% in the hearts of the test rats. In the hearts of the reference rats, 46% of the endangered tissue was dead, as opposed to 29% in the hearts of the test rats. That corresponds to a 37% reduction of dead tissue (p&lt;0.05). 
         [0061]    The substances according to the invention as well as the use of the substances according to the invention for preparing a pharmaceutical composition are of special significance: 
         [0062]    For a pharmaceutical composition used in the therapy of diseases caused by the tissue-damaging effect of autoreactive lymphocytes. 
         [0063]    Among those are diseases fitting into the sphere of autoimmunity, such as collagenoses, rheumatic diseases, psoriasis and post-/parainfectious diseases and diseases caused by a graft versus host reaction. A healing effect occurs, since said pharmaceutical composition blocks the migration of lymphocytes into the tissue. Thus, the lymphocytes remain in the bloodstream and are incapable of producing an autoreactive tissue-damaging effect. 
         [0064]    A healing effect occurs with a drug for the therapy and/or prevention of the rejection occurring after organ transplants, since said drug prevents the migration of lymphocytes from the bloodstream into the foreign organ and hence the foreign organ cannot be destroyed by autoreactive lymphocytes. 
         [0065]    A healing effect occurs with a drug for the therapy and/or prevention of arterial sclerosis after organ transplants, since said drug prohibits the migration of lymphocytes and monocytes into the vascular wall and hence prevents the activation of the cells of the vascular wall. In doing so, the occurrence of arterial sclerosis following organ transplants is minimized or prevented. 
         [0066]    A healing effect occurs with a drug for the therapy and/or prevention of a reperfusion trauma following a surgically or pharmaceutically induced restoration of the blood flow such as, f.i. after cardiac infarction, apoplectic stroke, after vascular surgery, bypass surgery and organ transplants, since said drug inhibits the migration of lymphocytes and monocytes into the vascular wall. The reperfusion trauma is caused by oxygen deficiency/acidosis occurring in the cells of the vessel during the restoration of the blood flow and leads to their activation. Thereby, lymphocytes and monocytes adhere to the vascular wall and migrate into the same. The fact that lymphocytes and monocytes are prevented from adhering to and migrating into the vascular wall brings about a decrease in the hypoxia/acidosis-induced damage, without any permanent vascular damage being caused by the subsequent inflammatory reaction. 
         [0067]    A healing effect occurs with a drug for the therapy and/or prevention of arterial sclerosis following metabolic diseases or ageing processes, since said drug inhibits the migration of lymphocytes and monocytes into the vascular wall and hence inhibits the progredience of the arteriosclerotic plaque resulting therefrom. 
         [0068]    The pharmaceutical composition according to the invention may also be used for transporting a further drug substance. The pharmaceutical composition according to the invention specifically binds a surface molecule to endothelial cells. Thus, drug substances coupled thereto may be contacted with endothelial cells at high concentrations, without them being able to trigger side reactions in other places. The use of substances inhibiting cell division may be mentioned as an example, which substances may exhibit an antiangiogenetic effect after having been adducted specifically to endothelial cells. In that case, tumour patients experience a healing effect, since the growth of the tumour is blocked by preventing the proliferation of endothelial cells and hence by avoiding neoangiogenesis. 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Peptides of Formula I: 
                   
               
               
                 Gly-His/Pro-Arg-Xaa 2 -Xaa 29   
               
             
          
           
               
                   
                 SEQ ID 
                   
               
               
                 SEQUENCE 
                 NO 
               
               
                   
               
             
          
           
               
                 Gly His Arg 
                 1 
                   
               
               
                   
               
               
                 Gly Pro Arg 
                 2 
               
               
                   
               
               
                 Gly His Arg Xaa 
                 3 
               
               
                   
               
               
                 Gly Pro Arg Xaa 
                 4 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa 
                 5 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa 
                 6 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa 
                 7 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa 
                 8 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa 
                 9 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa 
                 10 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa 
                 11 
               
               
                   
               
               
                 Gly Pro Mg Xaa Xaa Xaa Xaa Xaa 
                 12 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa 
                 13 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa 
                 14 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 15 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 16 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 17 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 18 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 19 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 20 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 21 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 22 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 23 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 24 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 25 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 26 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 27 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 28 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 29 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 30 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 31 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 32 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 33 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 34 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 295 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 296 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 35 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 36 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 37 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 38 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 39 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 40 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 41 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 42 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 43 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 44 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 45 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 46 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 47 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 48 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 49 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 50 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 51 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 52 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 53 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 54 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 55 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 56 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 57 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
                 58 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Peptides of Formula II: 
                   
               
               
                 Gly-His/Pro-Arg-Pro/Val-Leu/Val-Xaa 2 -Xaa 30   
               
             
          
           
               
                   
                 SEQ ID 
                   
               
               
                 SEQUENCE 
                 NO 
               
               
                   
               
             
          
           
               
                 Gly His Arg Pro Leu Xaa Xaa 
                 59 
                   
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa 
                 60 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa 
                 61 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa 
                 62 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa 
                 63 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa 
                 64 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa 
                 65 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa 
                 66 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa 
                 67 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa 
                 68 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa 
                 69 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa 
                 70 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa 
                 71 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa 
                 72 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa 
                 73 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa 
                 74 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa 
                 75 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa 
                 76 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa 
                 77 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa 
                 78 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa 
                 79 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa 
                 80 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa 
                 81 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa 
                 82 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa 
                 83 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa 
                 84 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa 
                 85 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa 
                 87 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa 
                 88 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa 
                 89 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa 
                 90 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 91 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 92 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 93 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 94 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 95 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 96 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 97 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 98 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 99 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 100 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 101 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 102 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 103 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 104 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 105 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 106 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 107 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 108 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 109 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 110 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 111 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 112 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 113 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 114 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 115 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 116 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 117 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 118 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 119 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 120 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 121 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 122 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 123 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 124 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 125 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 126 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 127 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 128 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 129 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 130 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 131 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 132 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 133 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 134 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 135 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 136 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 137 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 138 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 139 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 140 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 141 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 142 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 143 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 144 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 145 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 146 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 147 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 148 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 149 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 150 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 151 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 152 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 153 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 154 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 155 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 156 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 157 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 158 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 159 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 160 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 161 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 162 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 163 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 164 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 165 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 166 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 167 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 168 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 169 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 170 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 171 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 172 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 173 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 174 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 175 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 176 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 177 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 178 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 179 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 180 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 181 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 182 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 183 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 184 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 185 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 186 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 187 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 188 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 189 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 190 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 191 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 192 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 193 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 194 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 195 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 196 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 197 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 198 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 199 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 200 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 201 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 202 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 203 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 204 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 205 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 206 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 207 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 208 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 209 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 210 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 211 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 212 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 213 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 214 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 215 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 216 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 217 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 218 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 219 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 220 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 221 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 222 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 223 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 224 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 225 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 226 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 227 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 228 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 229 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 230 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 231 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 232 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 233 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 234 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 235 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 236 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 237 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 238 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 239 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 240 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 241 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 242 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 243 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 244 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 245 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 246 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 247 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 248 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 249 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 250 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 251 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 252 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 253 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 254 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 255 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 256 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 257 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 258 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 259 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 260 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 261 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 262 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 263 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 264 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 265 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 266 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 267 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 268 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 269 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 270 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 271 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 272 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 273 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 274 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 275 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 276 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 277 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 278 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 279 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 280 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 281 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 282 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 283 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 284 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 285 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Leu Xaa Xaa Xaa Xaa Xaa Xaa 
                 286 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 287 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Pro Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 288 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly His Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 289 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa 
               
               
                   
               
               
                 Gly Pro Arg Val Val Xaa Xaa Xaa Xaa Xaa Xaa 
                 290 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 
               
               
                 Xaa Xaa