BRPI9610977A2 - multifunctional hematopoietic receptor agonists - Google Patents

Abstract

"multifunctional hematopoietic receptor agonists". novel multifunctional hematopoietic receptor agonist proteins, encoding multifunctional hematopoietic receptor agonist proteins, processes for making multifunctional hematopoietic receptor agonist proteins, and processes for using hematopoietic receptor agonist proteins are shown. multifunctional.

Description

Invention Patent Descriptive Report for AGONISTS

MULTIFUNCTIONAL HEMATOPOIETIC RECEPTORS ⁰ ,

The present patent application claims priority under 35 USC paragraph 119 (e) of patent application USS No. serial number 60 / 004,834 deposit5 issued on October 5, 1995.

Field of the Invention

The present invention relates to multifunctional hematopoietic receptor agonists.

Basics of the Invention iq Colony-stimulating factors (CSFs) that stimulate bone marrow cell differentiation and / or proliferation have generated much interest because of their therapeutic potential to restore lower levels of hematopoietic cells derived from embryonic cells. CSFs in both human and murine systems have been identified and differentiated according to their activities. For example, granulocyte-CSF (G-CSF) and macrophage-CSF (M-CSF) stimulate the in vitro formation of neutrophilic granulocyte and macrophage colonies, respectively, while GM-CSF and interleukin-3 (1L-3) they have broader activities and stimulate the formation of macrophage, neutrophilic and eosinophilic granuocyte colonies20. IL-3 also stimulates the formation of pure and megakaryocytic mast colonies and mixed erythroids.

U.S. 4,877,729 and U, S, 4,959,455 disclose human IL-3 and gibbon IL-3 cDNAs and the protein sequences they encode. The hlL ~ 3 disclosed has serine instead of proline at position 8 in the protein sequence.

International Patent Application (PCT) WO 88/00598 discloses gibbon and human-like IL-3. The hLL-3 contains a replacement Ser ⁸ -> Pro ⁸ . Suggestions are made to replace Cys with Ser, thus breaking the disulfide bridge and to replace one or more amino acids at glycosylation sites.

U.S. 4,810,643 discloses the DNA sequence encoding human GCSF.

WO 91/02754 discloses a fusion protein comprised of GM-CSF and IL-3 which has greater biological activity compared to GM-CSF or IL-3 only. Analogous IL-3 and non-glycosylated GM-CSF proteins are also disclosed as components of the multifunctional hematopoietic receptor 5 agonists.

WO 92/04455 discloses fusion proteins composed of IL-3 fused to a lymphokine selected from the group consisting of IL-3, IL-6, IL-7. IL-9, IL-11, EPO and G-CSF.

WO 95/21197 and WO 95/21254 disclose fusion proteins 10 capable of multifunctional hematopoietic properties.

GB 2 285,446 refers to the c-mpl (thrombopoietin) and various forms of thrombopoietin which are demonstrated, the influence on the replication, differentiation and maturation of megakaryocytes and megakaryocyte progenitors that can be used for the treatment of thrombocyte15 penia.

EP 675,201 A1 refers to the hgante c-mpl (Megakacaryocyte growth and development factor (MGDFj, allelic variations of Hgante c-mpl and hgante c-mpl linked to water-soluble polymers such as polyethylene glycol.

WO 95/21920 provides the murine and human Hgante c-mpl and polypeptide fragments thereof. The proteins are useful for in vivo and ex vivo therapy to stimulate platelet production.

Rearrangement of Sequences.of.Prgte.ina

In evolution, DNA sequence rearrangements play an important role in generating a diversity of protein structure and function. Gene duplication and exon shuffling provide an important mechanism to quickly generate diversity and thus provide organisms with a competitive advantage, especially since the basal mutation rate is low (Doolittle, Protein Science 1: 191-200, 30 1992).

The development of recombinant DNA methods has made it possible to study the effects of sequence transposition on protein folding, structure and function. The approach used in creating the new sequences looks like that of naturally occurring pairs of proteins that are related by linear reorganization their amino acid sequences (Cunningham et al., Proc. Naff Acad. Scí. USA, 5 76 3218-3222, 1979, leather & Erfle, J. SactenoZ 172. 3837-3841, 1990;

Schimming and others. Eor. J. Bloche / n. 204: 13-19, 1992; Yamiuchi and Minamikawa. FESS Lett. 260: 127-130, 1991, MacGregor et al. FEES Left 378: 263-266), The first in vitro application of this type of protein rearrangement was described by Goldenberg and Creighton (J. Mo /. B / of. 165: 407-413, 10 1983). A new N-terminus is selected at an internal site (breakpoint) of the original sequence, the new sequence having the same order of amino acids as the original from the breakpoint until it reaches an amino acid that is at or near the C-terminus original. At this point, the new sequence is associated, either directly or through an additional portion of sequence (ügante), to an amino acid that is in the self next to the original N-terminus and the new continuous sequence with the same sequence as the original until reach a point that is at or close to the original N-terminal amino acid at the site of the breakpoint of the original sequence, this residue forming the new C-terminal of the chain,

This approach has been applied to proteins ranging in size from 58 to 462 amino acids (Goldenberg and Creighton, J. Mal. Bibl, 165. 407-413, 1983; Li to Coffino, Mo /. Cell. Biol. 13: 2377 -2383). The examined proteins represented a wide range of structural ciases, including proteins that contain predominantly alpha-helix (interleukin25 4; Kreitman et al., Cytokine 7: 311-318, 1995), beta-leaf (interleukin-1;

Horlick et al., Protein Eng. 5: 427-431, 1992) or mixtures of the two (yeast phosphoribosyl anthranilate isomerase; Luger et al. Science 243. 206-210, 1989). Broad categories of protein function are represented in these sequence reorganization studies:

Enzymes

T4 lysozyme dihydrofolate reductase ribonuclease T1

Bacillus beta-giucanase aspartate transcarbamoylase phosphoribosyl anthranylate ispsase pepsin / pepsinogenic ghceraldehyde-34 phosphoglycerate omitine dehydrogenase

Zhang et al., FfiochemisYy 32: 12311-12318, 1993, Zhang et al., Struct / ature Struct. Biot. 1: 434438 (1995)

Buchwalder et al., Biochemistry 31: 16211630, 1994; Protasova and others, Prof. Eng, 7: 1373-1377. 1995)

Mullins et al., J, Am. Chem. Soo. 116. 55295533. 1994; Garret et al .. Profem Science 5: 204-211, 1996)

Hahn et al., Proc. Natl. Acad Sci U.S.A. 91; 1 () 417-1 () 421, 1994)

Yang & Schachman, Proc. Natl. Acad. Know. U.S.A .. 90: 11980-11984. 1993)

Luger et al., Science 243; 206-210 (1989; Luger et al., Prof. Eng, 3; 249-258, 1990)

Lin et al., Protein Science 4 159-166, 1995)

Vignaís et al., Protein Science 4: 994-1000,

1995)

Li & Coffino, Mo /. Ce //. Biof 13: 2377-2383) yeast dehydrogenase Ritco-Vonsovici et al., B / ochemisdy 34:

16543-16551, 1995)

Pancreatic trypsin inhibitor enzyme inhibitor basic

Cytokines

Goldenberg and Creighton, J. Mo / .. Bto /. 165: 407413, 1983) interleuGina1beta Horlick et al. Protein Eng. 5; 427-431, 1992) interleukin-4 Kreitman et al., Citokine 7: 311-318, 1995)

Tyrosine Kinase Recognition Domain alpha3pectrin domain SH3 Viguera et al., J. Mot 8ioi. 247: 6704581,

1995)

Transmembrane Protein ompA Koebnik to Kramer, J. Mo /. Bio. 250 617-626,

1995)

Chimeric protein interleukin-4Pseudo / nons-exotoxin Kreitman et al., Proc. Nati. Acnd. Know. U.S.A. 91: 6889-6893, 1994)

The results of these studies have been highly variable. In many cases substantially lower activity, solubility or stability have been observed (E. co / ι dihydrofluate reductase, aspartate transcarbamoylase, fostonbosyl isomerase anthranylate, glyceraldehyde-3 phosphate dashydrogenase, ornithine decarboxylase, omp A, phosphoglycerate de25). In other cases, the proiein rearranged in sequence appeared to have many almost identical properties as its natural counterpart (tnpsin-based pancromatic inhibitor. T4 lysozyme, TI ribonuclease, Bacillus beta-glucanase, myelucine-IBeta, domain of the alpha3 spectrin SH3, pepsinogen. -4). In exceptional cases, an unexpected improvement has been observed in relation to some natural properties, for example, the solubility and refolding rate for rearranged SH3 alpha-spectrin domain sequences and the affinity of receptor and fusion molecule anti-tumor activity of transposed interleukin-4-Pseudomonas exotoxin (Kreitman et al., Proc. / Vat /. Acad Set. USA 91: 6889-6893., 1994: Kreitman et al., Cancer Res. 55. 3357-3363, 1995),

S The primary motivation for these types of studies has been to study the role of short-range and long-range interactions in protein folding and stability. Sequence rearrangements of this type convert a subset of interactions that are long range in the original sequence into short range interactions in the new sequence and vice versa. The fact that 10 many of these sequence rearrangements are capable of achieving conformation with at least some activity is convincing evidence that protein folding occurs through multiple folding paths (Viguera et al., J. Mqí Bid. 247: 670-681 , 1995). In the case of the SH3 domain of alpha-spectrin, the fact that choosing new terminations at locations that correspond to beta-'grip turns resulted in proteins with slightly less stability, but which were nevertheless capable of folding.

The positions of the internal breaking points used in the studies cited here are found exclusively on the surface of proteins and are distributed throughout the linear sequence without any obvious deviation towards the ends or the middle (the variation in the relative distance from the N terminal original to the breaking point is about 10 to 80% of the total length of the sequence). The ligands that connect the original N and C terminals in these studies were in the range of 0 to 9 residues. In one case (Yang & Schachman. Proc. Natí. Acad. Sci. USA 90. 11986-11984, 1993), 25 a portion of the sequence was deleted from the original C-terminal segment and the connection made from the C terminal truncated to the terminus Original N. Flexible hydrophilic residues such as Gly and Ser are often used in binders. Viguera et al. (J. MoA Bid. 247 :, 670-681, 1995) compared the junction of the original N- and G- terminations with the 3- or 4-residue linkers;

the 3-residue binder was less thermodynamically stable. Protasova et al., (Prot. Eng. 7 1373-1377, 1994) used 3- or 4-residue ligands in the association of the original N-termini of dihydrotolate reductase from

E. co / Z only the 3-residue ligand produced protein in good yield.

Summary of the Invention

New homatopoietic proteins of this invention are represented by the formulas:

Ri 4.1¾ Rg-Li-Ri. Ri-R ₂ or R ₂ -R ₁ in which R and R ₂ are independently selected from the group consisting of, (1) A potipeptide comprising; or modified amino acid sequence of human G-CSF of the formula:

X&S xaa xaa G xy Pro Allah To be Know- Léu 10 Pro Gin To be Xaa Read your Xaa Xxiíà xaa G lu 2C Gin go Xaa Lys Xaa Gin Gly Xaa Gly Allah 30 Xaa Read Gin G, L u xaa Read Xaa There Τ: τχ · Tyr 40 Lys Read XaK Glu Xaa XH-â Go xaa xaa dly HY & To be Gly Xie S ^ XO Trp Aza 60 Pro Read To be X <aa Pre To be Xaa A.i.a. 70 Xaa Read Ale Gly Xaa Read Know Gin Read His 80 To be Gly Read Read ^ yr Gin Gly Read Read 90 Gin 4Ax Lsu Qlu Oly 11 and To be Pro GaL Read too Gly Fra Thr Read Xaa x * Read «Λ Xaa Asp 110 Go Allah Asp Fhe Allah Xaa Thr Xie Trp Gin Glt-Tl Met r * Ί »L2 3.U Xaa Xaa Gly Met Allah Pro Allah 130 Read Gin Pre Thr ^ # 2.44 Clv Allah Pru Allah 140 Phe Allah To be Shah Gin X> aa Xaa Allah Oxy 150 Gxy Go Read go Allah To be Xaa . «4 & U.-. Gin Xaa 160 Phe .uh X.aa X. & S

Being Tyr Arg Vai Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID N0: 1) on

Xaa «is the Xaa portion in the Xaa position η the Xaa position. p.3. position Xaa m position Xaa m position Xaa ns position Xü & a no position. Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position

Arg, Cys,

Xaa the position Trp, Glu Xaa in position Xaa in position Xaa. in position Xaa in position Xaa in position Xaa n »position Xaa ns position xaa in the sections Xaa «S position Xaa in position Xaa the position Xaa in position Xaa ns position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position Xaa in position

is Thr, Ser, Arg, Tyr Sly;

«Pro or Leu;

^it's Leu, Arg. Tyr »« Being;

is Phe, be. His, Thr Pro;

0 Lys, Pro. Ser, Thr co His;

-a Cys, Ser, Gly, Ala, Xie, Tyr ^or Arg;

® Leu, Thr, Pro, His. Xie au ’Cys;

® Arg, Tyr, Ser. Thr or Ala;

4 Xie, Pro, Tyr i Leu;

® Asp, * Gly;

. 3Q ® Ara, Xie, Leu or Gly · .;

«Lys $ er;

® Cys «ο Ser;

^{It is} Cys ου sex-

His, Thr, Gly, Val, Lys, Trp. Ala, ^or Leu;

4 Pro. Gly. Arg, Asp, Go. Ala, His, Thr;

and Glu, Arg, Phe, Arg, He ^or Ala;

0 Leu and Thr;

«Read, Phe. Arg ^ΰυ Ser?

SQ 4 Leu. He, His, Pro Tyr;

0 Leu ° ^u HiS;

4 Cys ^GU Ser;

it is Gin, Lys, Leu ^or Cys;

s Gin, Pro, Leu, Arg Ser;

® Cys or Ser;

104 is Asp, Gly ^or Val;

108 ® Leu, Ala. Val, Arg, Trp, Gin Gly;

115 4 Thr. His. ^ _su or Ala;

120 ® Gin, Gly, Arg, Lys His

123 θ Glu, Arg. Phe «« Thr

144 4 phe. His, Arg, Pro, Leu, Gin ^or Glu;

146 4 Ar _g or Gin;

147 0 Arg ^or Gin;

156 0 His, Gly au Ser;

15.9. is Ser. Arg. Thr. Tyr. Go 0 «Gly;

162 «Glu. read. Gly or Trp;

163 4 y _a x _x □ xy _j Arg Ala;

169 4 Arg, Ser, Leu. Arg »u Cys;

170 4 His, Arg © u Ser;

wherein optionally 1-11 amino acids from the N-terminus and 1-5 from the C-terminus can be deleted; and where the N-terminus is associated with the C-terminus directly or by means of a linker capable of associating the N-terminus with the C-terminus and having new G and N termini in the amino acids;

38-39 59-60 99-100 39-40 60-61 123-124 40-41 61-62 124-125 41-42 62-63 125-126 42-43 63-64 126-127 43-44 64-65 127-128 44-45 6t> -66 128-129 45-48 66-67 129-130 46-47 67-68 130-131 47-48 68-69 131-132 48-49 69-70 132-133 49-50 70-71 133-134 50-51 71-72 134-135 51-52 91-92 135-136 52-53 92-93 136-137 53-54 93-94 137-138 54-55 94-95 138-139 55-58 95-96 139-140 56-57 96-97 140-141 57-58 97-98 141-142 58-59 98-99 or 142-143

(H) A polypeptide comprising: a modified NL-3 amino acid sequence of the formula:

<1: 77777 Meo Thr Gin s Thr Thr To be Read Lys 10 Thr To be Trp Go Asm 15 Cy $ Xaa xaa Λ V Xaa Xaa Xaa Xaa xaa 25 Xaa XaaT Xaa Xaa Xaa 30 xaa Shah X && 3S Xaa Xaa Xaa Wing Xaa 40 Xaa Xaa Xaa Xaa Xaa 45

X-ta

Xââ x & «xaa

Xaa

Xaa

Xaa

Xas Xas

Xae

X & e xaa

Xaa xaa

Xaa

Xaa

Xaa x & a xaa

Xaa

Xás Xaa

Xaa bs

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa xaa §5

Xaa

100

Xaa

Xaa

Xaa

Xaa xaa

10S xaa toe

Xaa

Xaa xaa

Xaa

Xaa

Xaa

Xaa

Xaa xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Xaa

Sl.n

Gin

Thr

Thr

Read it.

To be

Read 13 0

Allah

Fhe

Xie tSEQ U> NO: 2);

wherein x «a in position

I?

Xan in the passion U ú Asn, Kis, Leu, Xaa in p & section XS á Mat, Pha, 21 «, Xaa in position $ 2 is 11 «, Cys, Gin. Xaa in position 21 <· Asp, Pha. Ly®, Thr, S®r or go 7 Xaa in position . 22 & Giii, Trp, ? ro, Read, Go OiJ Giy ·. Xaa .in position 23 is 11 *, Go, Allah, L * u, Sar, pu Ar < Xaa ns position a4 ê XX®, Giy, Go, 5U & , ns pn & içâ » 25 ê Thr, Mi. *, Cly, Xaa in position $ 2 is 8.1 «, Thr, Ph® Xaa ns position 27 is L «ü, Q1 y, Arg, Xaa ns position 23 is Lys> Arg, Lesu, Xaa in position 25 is Cl ', Asn, L «ü, Xaa the position 30 is Pre, Mia, Thr, Xaa in position 3i is Pr », Asp, wiy, Xaa in position 32 è L «u, Val < Arg,

is Sar, Ly®, Gly, Asp, Met

Arg

Allah

11 «, Phe, Arg, Gly, * <* iu, Arg,> Ar ^ _x Ala,

Be Wing

Gly, Trp

Arg. Ssr. Gin, Arg, Gly, Arg, Thr, & «

QX »

Pr © ..

Cly,

Xrg,

Allah

A®p,

Arg,

Gin

Wing <* lli, <JU · AX'g;

Gin;

Cj'S;

Allah;

Qly, Glu, Glzi, Astn

Pre

Mis

Ly®,

Fh®, or

Asp <As », Qla,

PX «.

or

L »u,

Pr *, or

A.U, or or Ala

AU,

Pr », Vai _or β« Vai;

Gin $ «r, Leu, or Ly»;

Lw,

Gly,

Ala, or qx _U;

1'1

Xaa π the position 3 3 is Pr®. Leu, Gin, Wing, Th-, OU ’G1U; Xaa _n3 position 34 ώ, Leu, Go, Gly, Ser, Lys, Giu, Gin. Thr, Arg, Ale, Ph®, lie o U Met; Xaa ns position 3 5 e Leu, Ala, Gly ,. Asn. Fm, Gin, _or Vai; Xaa in position 3 5 ώ Asp, Ford, p _u Go; Xaa position 37 _is Ph®, Ser, Fm, Trp, 0 «Ile: Xaa ns Possession 38 is Asn, 0 «Wing; Xaa * ta position 40 è Read it. Trp _{<ç} iJ} Arg; Xaa ss po-Síçâft 41 ê A.en, Cys, Arg, Leu, His, Her, βυ p.ro; Xaana position 42 is Gj.y, Asp, Ser, Cys, Asn, Lys, Thr, Lay, Go, Glu. Phe, Tyr, 11®, Met py Ala? Xaa.- _the position 43 is Glu í Asn, Tyr, Leu, Fh®, Asp, Ala, Cys, Gin, Arg, 3k. Gly o ^: s.i Ser $ Xaa in position 44 is Àsp, Ser, Lau, Àrg, Lys, Tht, Met, Tip, Glu, Am, Gin, Ala _or Pr®; Xaa _{;> 3} position 45 is Gin, Pro, Fh®, Go, Met, Lav, Thr, Lys, Trp, Asp, Wing, Arg, 5®r, Ala, Ile, GluOU His, - Xsjs. position 48 is Asp, Phe, Ser, Thr, Cy®, Glu, Asn, Gin, Lys. His, Allah, • ryr. 11 «, Vaiou Gly γ Xaa o the position 47 ê 11®, Gj.y and lai, Sar, Arg, Fro, 0 «His; Xaana position 45 is Leu, Ser, Cys, Arg, Ila, His, Fha, Gin, Lys, Vhr, Allah, Mat, Asq Asn; Xaa position 43 ό Met, Arg, Ala, Gly, Pro, Asn, Kis, 0 !. ₍ Asp

Atλλ at position SO s Gin, Leu, Thr. Asp, Tyt, Lys., A «h, ser.

Ala, lie. Go His, Phe, Met or u Gin; Xaa _na position 51 is Aan. Arg, M®t, Pm, Ser, Thx, or xis; Xftfins position 52 is The rs. Hi.s, Arg, Leu, Gly, Sei, q Thr; Xaa Ha position 53 is .Leu, Thr, Ala, Gly, Glu, Pm, Lys, Ser, cu Mat; Xaa position 54 _is Arg, Asp, Ile, Ser, Vai, Thr ,. GIn, Asn, Lys, Kis, Ala otí Lev Ϊ X & j & Π-3 position 5S Arg, Thr, Go, Ser, Lau, Gly - Xa.es n a position 58 is Pro, Gly, Cys, Ser, Gin, Glu, Arg, His,

Thx, Ala, Tyr, FH®, Leu, ValOU Lys;

Xaana ps & iection 57 Is Qjy,

Xaa ns position

Are

Leu, S'r, Asp, Arg, Gin, Val, OR Cys;

Xaa n «çosíçsp "% a Glu Tyr, Mis. Leu, Pro. <; i to Arg; Xaa in position 6C is Allah. S®, Pre Tyr, Asr .. Oli η · ψ. ~. Xaa in position 61 ê Phe, Asn, du Pr *, Lyr. Arg, OR Being; Xaa in position faith is Asn ,. His, Val, ÀT5. Pr *. Thr, Asp. oy llo; Xaa os position S3 v Arg. Tyr, Trp _t Ly «> To be. Hrs. Pro, or Vai; Xaa r> the position S4é Allah. Asn, m. To be, OR Lys. ' Xaa ^Physics »PosfÇà» £ S is Go., Thr. Pro. His, Read it. Phe, ^Ql! To be; Xaa rta position Sê ê Lys, Lie. Arg. Go. Asn, Stu. or Being; Xaa. in position S7 ό Illustration, phe. Go. Gly, Asn, 11 «, Pro. Or His Xaa ^! ' ^{: S} pa & Mo δ »® ⁵ Read, Trp. To be, 11 «, Phe, Thr.OU Hrs; Xaa in position fiS « Gin, £ ti7: φ Thr. J Arg, Trp, dy, ^βίί À0 & ¢ 3. Xea in position _7th Asn, Leu ,. Go. Trp. Pro, ÇU Aia; Xa & in position 71 Ô Allah. Ket. Leu, Pr «, Arg, Glu, Thr, Qin, Trp. OR As π; Xaa fia position 72 is S «r, Glu, Met, Allah. His. Asn, Arg, _or Asp;

Xxa f-S position 7 3 is Allah, Glu, Aep. Read it. To be, Gl>. Thr. <ju Arg; Xaa ns position 74 and 11 ». Met. Thr. <Pro, Arg, Gly _; , Wing: Xaa ns posttion 7¾ is Glu, Lys, Qly, Aap. Pro, 'Prp, Arg. To be, Gin., * U Xaa at position 7S $ To be, Go. Allah. Asn. Trp, Glu. Pro. Sly, OR Asp; Xaa Πά position 77 and XI ", Ser. Arg. Thr, 0 Leu; Xaa ns position 7P is Read it. Ala, Ser. 51 «. Phe. Gly, or Arg; Xaa SB position 79 is Lys. Thx. Asn, fciet .. · Arg, He. Gly, or Asp, Xaa fia position ONLY and Asn. Trp. Go, Gly. Thr. Read> Giu.uu Arg; Xaa no position 81 and Leu, Gin, Gly. Al *. Trp, Arg, Go.or Lye; Xaaoa position 82 and Leu, Gin, Lys, Trp. Arg Asp, Slu. Asn.

His. Thr, Ser, Ala, lyr, Ph®, lie. Μ _β «

Si é Pro, Ala, Thr, Trp, Arg. gg Met; 84 is Cys, Glu. Gly, Arg. Met. »U Go; 85 è Read, Asn, Go, o Gin; Pro. Cye. Arg. Allah. or Cys?

Xea ne paaiçâe

X «iw position

Xaa * the position

Xaa «Psasçao

Xsa in position 87 £ Leu, Ser.- T’rp, o Gly; Xaans position «8 and Ala, Lys, Arg, Go. u Trp; Xaaoa pfSiçàn S9 & ’Thr, Asp, Cys, Read, Go, Glu. His. Asn.or Be Xa.a in position POWDER and Allah. Pro. Be, Thr. Gly, A & p, lie. oy Met;

Xoa ΐΊ3 CCI & TÇ ^ O 91 is Oh, Pro, To be Thx, Phe, Usu. Àsp. Oli His; Xaa f> Ã ttosJção $ 2 is Pro, Phe. Ar®, To be, i »ys. His j A1 &, Gly, Xle üftU; Xãã at ^ ÍÇ3Q . S3 ^is . Thr, Astp, Asv. Pro. ΑΙλ ^ Leu, or Arç; Xsss. at í> £ & (Ç BÍ3 .. 94 is Axg, lie. To be, G1 u, Leu, Go, Gl.n, Lys, H1 &.

AU, od Pro;

Xaa n. $ position s His, Gin, Pro, Val. £ xfô &.>. Gly. Thr, Asn, lys, Ser, Allah, . Trp, Phe, XX®, or Tyr; Shah& r> the position 9 s - Pro, Lys, Tyr, Gly, X.X & «, OG -t-h Aaa rss prsíçss 97 is XI®, Vai, Lys, Allah, OG Astj; Xaa to position $ S á > H.1S, Ile, Asn, A «p, Ά1 &, Thr. Glu, Gin, To be. Phe, Mar., Go, Lys, Arg, Tyr o « Pro; Xaa in the country $ c ê Xie, Lew, Arg, Asp, Go, Pro, * 31 n. Giyah, Ph®. OR 'Hís; Xaa in position IGÍí is Lys, Tyr, Leu , His , ÀX®, 11® ,, Be < Gin, 3® Pro Xátâ to position 191 is Asp ,. Pro, Measure Lys > Pis. Thr, Go, Tyr. hello. Asn, Ser, Ala, Gly ,. lie. Read, the v Gin * Xaa in the pasture 192 υ Gly, Leu, Giu , Lys , To be, iyr. or Pr '; Xaa in position 103 4 Asp, o® Ser, · Xaa in position 194 è Trp, Vai, Cys <Tyr , Thr, Met, Pro, Read it. Gin, Lys, Allah. Phs, õu Gly; Xaa -in position 105 is Asn, Pro, Ala , Phe , Sar, Trp, Gin, Tyt ,. Read, Lys, 118., Asp, or His; Xaa in position is Glu, Ser, Ala , Lys , Thx Ile, Sly, or Pro; Xaa to position 103 X Arg, Lys, Asp . Thr, 11®, Glr, & Í. &, Ί3 · όΓΐ

Ai * Pro;

Xaa Xaa in position 10 $ in position 11C Ser, or Trp; is Arg, is Ly ', Thr. Ow, Pro, Asrs, Cílti. _{ Thr, Tyr, Leu, Leu, Arg, To be, Gin, or Gly; His, Glu, Xaa to pos-tion UI to Leu, 11 «% & rg, Asp. o® Met; Xaa in position : <í Thr, Go, Gin, Τ '/ χ ₍ Glu. His, To be. ^or Pha; Xae in position 113 ê Phs, To be, Cys, more, Gly, Trp, Tyx, Asp, Lye, Leu, lie. Val. « ^U Asn; Xaa in position ^ 14 is Tyr, Cys, His, X 'rp, Ax®, ου L®u; Xaa at PQ £: CBO is L «u, Asri, Go, Pro, Axg, Ala, H1S, Thr,

Or men;

Its is Lye, Leu, Pre. Thr, ®t. Asp, V «l, Olu, To be . Asn <Ki *, Ala, Tyr, Phe, Gi In, or lie; in position 117 and Thr, S * r, Asn, lie, Trp, Lys, OR Pr »; Xa.a in position 11S is Leu, Ser, Pro, Ala, Glu, Oys, Asp, OR Tyr; Xaa in position 119 is Glu, Ser, Lys,? Ϊ́χ> <! Λ «< Tyr, OR Arg; in position 120 and Àen, Ala, Pro ,. Read, His. Go, or Gin; in position 121 is Ale, Ser, Xie, Asn, Pre, Lys, Ass * _f OR Cly; Shah in position -> - 2 ^ is Gin, Ser, Met, Three, Arg < Phe, Pr *, His, rie, - Tyr, OR Cys. in position 123 & A1 &, Mst, Glu, Pis, Ssr, Pr * » Tyr, OR L®u;

wherein optionally from 1 to '14 amino acids can be deleted from the N-terminus and / or from 1 to 15 amino acids can be deleted from the C-terminus; and wherein 0 to 44 of the amino acids called Xaa are different from the corresponding 5 native amino acids (1-133) of human interleukin-3; and where the N-terminus is associated with the C-terminus directly or through a linker (L2) capable of associating the N-terminus with the C-terminus and having new C and N termini on the amino acids;

26-27 50-51 85-86 27-28 51-52 86-87 28-29 52-53 87-88 29-30 53-54 88-89 30-31 54-55 89-90 31-32 64-65 90-91 32-33 65-66 91-92 33-34 66-67 92-93 34-35 67-68 97-98 35-36 68-69 98-99 36-37 69-70 99-100 37-38 70-71 100-101 od-39 71-72 101-102 39-40 72-73 102-103 40-41 82-83 eu 103-104; 41 -42 83-84 49-50 84-85

b (Hi) A popepeptide that comprises; a modified human c-mpl ligand amino acid sequence of the formula:

Be Prm ^ aPrc /? RoA.ra Cyra AspLeuArgV & lLeuSerLycLeuLeuArgAspS er

5 1015

HxsV & lL & ultiessrArgLsuSerGlcCysProGluyalRispruLeuPraThrmrc:

2D 25 3035

V alX »euL.euPraAl aValAspPheSerXd & uG lyGluTrpLys ThrGl nMetGluGlu

45 5055

T hr Ly s A1 a G j, nAsp I x eLeu 01 y A1 aV a 1 Th r LeuL euLeuG 1 uG lyv a iJKe t. A1 to € 0 S5 7075

WingArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGiyGlnLeuSerGly

S0 85 93§5

GlmvalArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnXaaXaa> tes • 100 105no

XaaGlyArgThrThrAlaHisLysAspProÀ.

aPheLeuGer PheGlnH i.s

130

LeuLeuAr g-G lyLysva I ArgPheLeuMet Leu 'Va 1G lyGlySezThrLeuCy s Va.l 135 140 145150

Ar gArg a Pro Pr cT hr T hrAl a V a .1 Pr o S er Ar gThr S er Leu v & iLeuThr 1 eu

160 les17

AsaGluLeuProAsuArgThrSerGlyLeuLeuGiuThrAsilPheThrAlaSerAls * 75 18Q IB5190

ArgThxThxGiy SexGiyLeuLeuLysTrpGlftGloGlyPhgArgAla.LysjX lePxo IS 5 2GO205

G lyLeaL euA sn Q1 nThrSerArg »exLe uAspGlnx 1 e PxoG lyiy r LeuAsnArg 21G -215 220225 .w vt. eH j. t u ** uL eu Le uAs tic u. yOtxr Ax gu ly t eti P x, e p r oG 2. vP x os e r A x g Ax g3? q x 230 235 240245

L®uG IvAlaProAsplX e S e rSer GlyThr SerAspThrGly SerLeuProPro Asn

250 2SS 2602§g

LeuGlnProGlyTyrSerPrcjSerPraThrHlsPrcProThrGlyGlnTxírOhrLeu

270 275 250285

PheProLeuProProThrLeuProThrProValValG IxiLeuM isPr oLeuLeuPr o

290 295300

AspProSexAl-aPrc’rhrPreThxProZhrserPrayeuLeuAixnThrseriyrThx 305 310 315320

HisSerGlnAsnLeuSerGInGluGly i £ EQ ra NO; 3}

325 33033'2

153 where

Xaa in position Phe, Trp, 112 is deieted or ; Met; Leu, Allah, Go, XI and, Pro. xaa in position 113 is daletadQ or 'Pro, Phe, Allah, Go, Leu, Xie, Trp, Met .; Xaa in position 11 ^ is detected or  Pro, Phe, Allah, Go, Leu, lie, Trp, Met; Xaa ns position 115 Gin, Gly, To be, Thr, Tyr,

ÃSH, where α termini N is associated with the C-terminus either directly or through a linker (L2) capable of associating the N-terminus to the C-terminus and having new C and N termini in the amino acids;

26- 27 28-29 30-31

27- 28 29-30 32-33

26-27 51-52 109-110 27-28 52-53 110-111 28-29 53-54 111-112 29-30 54-55 112-113 30-31 55-56 113-114 32-33 56-57 114-115 33-34 57-58 115-116 34-35 58-59 116-117 36-37 59-60 117-118 37-38 78-79 118-119 38-39 79-80 119-120 39-40 80-81 120-121 40-41 81-82 121-122 41-42 82-83 122-123 42-43 83-84 123-124 43-44 84-85 124-125 44-45 85-86 125-126 46-47 86-87 126-127 47-48 87-88 or 127-128: 48-49 88-89 50-51 108-409

(IV) A polypeptide comprising: a modified hlL-3 amino acid sequence of the formula:

Allah 1 Fru Met Thr Gin 5 Thr Thr Know' Read Lys 10 Th.r To be Trp Go Asn 15 Cys Xaa Xaa Xaa Aa? *> «6 .M. Xaa Xaa Xaa Xaa xaa 25 Xaa Xaa xaa xaa Xaa 30 Shah& Xaa Xaa. Xaa 35 Xaa Xaa Xaa Asn Xaa 40 Xaa Xaa xaa Xaa 45

Ϊ8

Χ && Xae Xsi & Xaa xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xsa xaa Xaa £ 0 Xaa , xaa xaa X ^A .a xaa Xaa Xaa Xaa Xaa Xaa 70 Xaa X && Xaa Xaa 75 Xaa Xãã X and SHAH xaa. S3 xaa Xaa Xaa xaa Xaa 85 Xaa Xaa xaa Xaa 90 xaa X3. & Xaa Xaa xaa & 5 Xaa Xaa Xaa xaa Xaa 100 Xaa X & sSt Xaa Xa * i Xaa 105 Xaa Phs Xact Xaa Xaa 110 Xaa Xaa Xaa xaa Xaa 115 Xaa Xaa Xaa Xaxâ Xaa 120 Xaa X && Xaa ΚΪΙΠ Gin 125 Thr Read To be Read 130 Allah (S £ Q Ila 'AD Hie »0: 2 5

ίμϊ « ‘Xaa ns JSOSiOBü 17 is s «y, Lyss, C ^: ly, Ajsp, Hex, «In, O> J Arg Shah" pOStÇBÍJ 1δ is Ito, Hís, Leu, 11 «, FM, Arjj, Li win; Xsa 83 position 19 is Meo < Pr. », He, Asg. djL Ala, OR Cys; Xaa 83 position 2δ is li®. Cy «, Cln _x Oiu, Arp, Pr ', _QU AU; Aaa at position 21 è Aap, Ph «<Lys, Arç, Ala, «ly, clu,« In , A®n, rhr, Ser ^{0 ü} Go; Xns at pssition 21 ^è I **> Ίΐρ,? £ <> ,, g «r, Wing, Pis, Assp, Asn , win. Read, Go Qçi Gly; Xaa 83 position 23 is 31 «> Go, Ala, Sly, Txp. Lyss, PM.

Lí © Lí _x ,

Xaar.a position i 24 £ n «. «Iy. Go, Arg, S «r„ FM, Read; Xaa in position 25 is Thr, Hi a. Sly, Cln, Arp, Pí o, _oü Ale Xaa in position 1'6 s HU, Thr, Phe, «Ay, Asg, Wing, _or ΊΧρ; Xa & in position 2 is L®u, Cly < ÂX · ^^ Thr, Ser, or Ala? Xan in position 2S The Lys, Gin, Gly, Pro, Go OR Xaa in position 2S and Gift, Asn, Leu, Pro. Arg, Or go;

position

Xaa è

ΠΒ δ

Thy

Giy,

8i «

Asp, Gin, Ser, Leu, oii I, ys, ·

Xaa 03 POSITION 31 is ? **, A $ P, Gry, A1 &, Arg, Leu, py <51r> .- Xaa in position 32 έ Read, Go, Arg, Gin, Acen, Cxy. Ale, _or Glu Xea in position 3.3 ^is Fro. Iau, Gin, Ala, Thr, _or Glu; Xaa rss possibility 34 è Read, Go, Gly, Ser, Lys, Qlu, Gin, Thr, Arg, Ala, Pm, XI * OLÍ -: M «t-í Xaa in pn & i ation 35 is Leu, Ala, Gly, Asn, Pro, G.ln, Val; Xaa in position 3g Asp, Leu, W will; Ass in position 3? is Fm, Ser. Pro, Trp, Ile; Xaa in position 38 ê As.tX, Ala; X «i in position 4S is Leu, Trp, or Arg; Xaa pa position 41 is Asrs, Cys. Arg, Leu, His, Met, qi.i Pre; Xaa in position 42 « Gly, Asp, Ser, Cys, Asn, Ly ', Thr. Leu, Go, <51 u, Fh®, lyr, 11 ', Pier Ala; Aaa in position 43 @ Glu, Asn, lyr. Leu, Fhê, Asp, Ala, Cys, Gin, Arg, Thr, Sly I Ser1 Wing ns position 44 s Asp, Ser, Leu, Arg, Lys, Thr, Mer, Trp, Glu, Aar *, Cl », Ale or Pre; Xaa, in position 45 is Gift, Pr », Phe, Go, Sea, Leu, Thr, Lys,

Txp, Arp,

Asfc «

in position

Arg- Set, Ale, Xie

Uys>

Hi. A.

A »p, Phe, Ser, Thr, Cy® _;

Tyr, Tie, Val or Sly;

Xaa r> the position 4T < XX », Gly, Vai, fri. Arg, Pre, or Hi.s; Xaa rus position 4 S © Read, Ser, Cys. Arg, XX®, Hie, Fh®, Glu, uy s, VAr, Ada, Met, Val or Asn; Shah in position 4S is Met, Arg, Ala, Gy, Pre, A »n, His, _oy As; Xee o the position Sfi is Glu, Leu, Thr, Asp., Tyr, Lye, Asn, Ser, A - *. A, are .. go, Hrs, Phe, Met or Gin; Xaa in position si 4 Asp. Arg ·, Met, Pro, set, Thr, or H £ _Sj! Xae P3 position 52 is Asn, His, Arg, Leu, Gly, Ser, oil Tltr * Xaa 03 position S3 ã Leu, Thr, A; a, Gly, Glu, Pre, Lyss, Ser, o ^: Xaa in position 54 is Arg, Asp. XI®, Fri, Vai, l ^ r, Gin, As », Lys, His, Hai La Ward '; Wing in position 55 P Arg, Thr. Go, Fri, Leu, _or sx _y? Xea in po & ation 55 ê i’TOrf i * Xy> Cys, ÍlltVf <j! u. Hi #, Thr. Allah. Tyx, <3V Lys;

Met, 20

Xaa ns position 5? is Asr »nu Gly; Xaa in position 58 <ã Leu, Ser, As », Arg, 01«, Vai, or Cya; Xaa os position $ 5 and Glu lyr, His, Loti, Pr ', or Arg; Kaa in position 60 THE Al », Ser, Pro, Tyr, Asrs. or 'Thr; Kaa o the position 81 is Ph®, Asn, Giu, Pr®, Lys, Àrg, <w S®r; Xaa o the position is Asn, Bi®, Val, Arg, Fr =>, Thr, Asp, _or He; > iaa in position §3 is Arg, Tyr, Trp, Ly®, s »r, g £ _{& í Ργ} ®, _{or Va1} , Xaa os position i-i and Ala, Asn, Pro, Ssr, or Lys; Xaa at pos-çâs 6th is V.A1, Ifer, Fro, His, Leu, Pho, _C1 j Set; Xaa ns position SS and Lys, 1'le, Arg, Val, Asn, Giu, or Ser; Xaa in position 67 and Ser, Ala, Fha. Go, Gly, As », ü®, _{PrO (0 {j aii?} Xaa in position € 8 is Lau, Val, Trp, Ser, n ', Ph®, Thr, or Hxs; Χαλ in position δ * * Gin, Ala, Pro, Thx, Giu, Arv, Trp, Gly, _íu Leu X «a in position 70 is Asn, Leu, Vai, Trp, prs>. οι, ι Ala; Xaa in position 71 is Ala, Mar, Lau, Pr », Arç, Glu, Thr, Gin,

Trp, or As';

Xaa naposiçes 72 is Ser, Glu, Het, Alã. Sis, Asn, Arg, _ÔL | Asp;

Xaa at position 71 is Ala, Glu, Asg>, Leu, Ser, Sly, Thx, «u Axg;

^Xaat at positions 4 is Jl »t, 'Thr, Pr», Arg, Gly, Ala;

Xa »in position 7 $ è« 1 », Lys, Gly, Asp, _Pro , _ττρ ^

S1A, OR Leu ;.

Shah" in position $ 7 and To be, Go, Allah, Asn, Trp, .Glu.x Pros, ciy, PU Asp Xaa in position 7 ^ and Ile, To be, Axs Thr, 0 U L «u; Xaa in position 7§ ά Read Allah, To be. Glu, Phs, y t Arg; Xaa in position £ Lys, Thr, At" Sea, Arg. Xl ^ _x «Ly. 00 Asp; Xaa in position 8P and Asn, Trp, Go, Gly. Thr, L> me 01 », 0U Arg; Xaa ns position 81 is Leu, Gin, Giy, Allah, Trp, Arg, saw.. 00 Lys; Xaa in position S2 Leu, Gin, Lya, Trp, Axg, Asp, GXu, Asn, His, Thr, To be, Allah, Tyr, Ph®, Ile, H «t o u Go; Xaa in position S3 is £ r <3. < Allah, Thr Trp, Ary, CU Met; Xa® in position 84 15 Cys. Giu, eiy. Arg Met, Or go; X »3t ns position SS is Read Asn, Go, <3 ^ Q 1"; Xaa in position $ 8 is Pr », Cys, Arg, Allah u Lys; Shah" in position 87 is L ®U ₄ To be, Trp _f OU 01y; Xaa in position 8S is Allah, Lys, Axg, Go OR 'Prp;

Xaa in position §9 and Thr, Asp, Oys, Leu, Vai, G2u. Hi®, Wing Xai in position 30 è Allah, Pro, Ser, Thr, Gly, Asp, He, Met; Xa < in position 81 è Allah, Pro, Ser, Thr, Fhe, Read, '2ίί &; Shah* in position §2 is Pre, Pha, Ara, Ser, Lys, His, Ala, Giy, ιι® Yours 1 Xaa in position S3 is Thr, Asp, Ser, Asn, Pr®, A & a, Leu, Arg? Xaa in position 94 è Arg, Ile, Ser, Glu, Leu, Go, Gin, tys. Mis Allah. Frm, Xaa in position 95 is His, Gin, Pro, Ara, Go, Read, Gly, Thr, Asn, Ly® :, Sar , Wing, Trp, Fh®, 11®, Ty _x; Xaa in position 96 is Fro, Lya, Tyr, aiy, iu, 'fti; Xaa in position 97 is lie, Go, Lys, Ala, A »n? Xaa in position 98 è Hís, He, Asn, Leu, Asp, Ala, Thr, Glu, Gin , To be, She, Met, Val, Lys, Arg, Tyr Pro; Xaa in position 99 is X1 <£ ♦ Vi®..1> Frc, Gin, Gly, Ser . Fhe, Hi®; Xaa in position 13C á ky ». Tyr, Leu, Hei, Arg, IIe. To be, Gin, Xaa in position 1QI is Asp Fro, Hat, Ly®, Mis, Thr, Go,

Pro,

Tyr, Glu

Gin,

A »n, Ser, Ala, Gly, 12«, Leu

Xaa ng position 292 è Gly, Leu _f Glu, Lys, To be. Tyr, Pro? xaa ns position 193 Ò Asp, Ser; Xaa in position 1H4 is Trp, Go, cye. Tyr. Thr, Met, Pro, Leu, Gin, Lys, Ala, Ph®, Glyj Xaa in position 105 is Asn, Fro, Ala, Phe, To be, Trp, Gin, Tyr, Leu, Lys ·, lie, Asp, His; Xaa PG POSITION m is Glu, Ser, Aia, Lys, Thr, lie, Cly, p _£ -O; Xaa in position 108 ê Arg, Lys, Asp, Uu, Thr, 11®, Gl®, His, ser, Wing or Pro; xaa in position .199 ό Arg, Thr, Pro, Qlu, Tyr < . Leu, Ser, ciy? X & ns position lie _is Lys, Ala, Aen, Thr, Leü, Arg, Gin. Hi®, Qlu, Ser, or Trp? xaa in position 121 is. L®u, Ile _t Arg, ÂSp, er Met; Xaa in position 312 is Thr, Go, Gin. Tyr, Glu, His, Ser, Phe? xaa in position 115 «is Phe. Ser, Cys, Mis, «Ay. Trp, Tyr, Asp, Lys, Leu, Ils, Vai A®n?

X & 3 in position is lyr, cys. Hrs, S®r, Trp, Ar§, OR LfiU; in position 115 & Read As n Go. Pro, Arg, Ala, His. Thr, Trp, Met; Shah in position 11 « O Lys. Read it. Pr », Thr, Met, Asp, Go, Glu, Arg, ’Lrp. To be , Asn, His, Ala, Tyr, Phe, Gin, or lie; in position 117 is thx. To be, Asn, He, Trp, Lys, OR Pro; Xes in position 118 and Read it. To be, Pro, Allah, look, eye, Asp, OR Tyr; Shah" in position 119 is . Olu, To be. Uys, Pro, Leu, Thr, Tyr. OR Arg; Xaa in position 12 S and Asn, Allah, Pro. Leu, His, Vai, or Gin; x * a in position 121 is Allah. To be, Xie, Asn, Pro, Uys, Asp, <ju Gly; Xaa in position 122 and Gin, Be> Met, Txps Arg, Phe, Pro, His, ii «, Tyr, OR < ys at position 123 and AX &> Het. GlU; Ser, Pro. Tyr, OR Leu;

wherein optionally from 1 to 14 amino acids can be deleted from the N-terminus and / or from 1 to 15 amino acids can be deleted from the C-terminus; and wherein 1 to 44 of the amino acids called Xaa are different from the corresponding amino acids of native human mtedeucin-3 (1-133);

or (V) a colony stimulating factor; and where L-j is a linker capable of binding R- | the Rg;

with the proviso that at least or R ^ is selected from the polypeptide of formula (I), (H) or (111); and said hematopoietic protein may optionally be immediately preceded by (methionine ^). (alanine '·) or (methionine ‘^ <alaruna' I):

The most preferred breakpoints at which the new C and the new N-terminus in the above polypeptide (I) can be obtained are; 38-39, 39-40. 40-41, 41-42, 48-49, 53-54, 54-55, 55-56, 56-57, 57-58, 58-59, 59-60, 60-61. 61-62, 62-63, 64-65, 65-66, 66-67, 67-68, 68-69, 69-70, 96-97, 125-126, 126-127. 127-128, 128-129, 129-130, 130-131, 131-132, 132-133. 133-134, 134-135, 135-136, 136-137, 137-138. 138-139, 139-140, 140-141 and 141-142.

The most preferred breakpoints at which the new C terminus and the new N terminus in the above polypeptide (1) can be obtained are;

38-39, 48-49, 96-97, 125-126, 132-133 δ 141-142.

The most preferred breakpoints at which the new C-terminus and N-terminus in the above polypeptide (II) can be obtained are;

28-29, 29-30, 30-31, 31-32, 32-33, 33-34, 34-35, 35-36, 36-37, 37-38. 38-39,

39- 40, 66-67, 67-68, 68-69, 69-70, 70-71, 84-85, 85-86, 86-87, 87-88, 88-89, 89-90, 90- 91, 98-99, 99-100, 100-101, and 101-102.

The most preferred breakpoints at which the new C-terminus and N-terminus in the above polypeptide (H) can be obtained are; 34-35, 69-70 and 90-81.

The most preferred breakpoints at which the new C-terminus and N-terminus in the above polypeptide (III) or the amino acid sequence of (SEQ. ID No. 256) can be obtained are;

80- 81, 81-82, 82-83, 83-84, 84-85, 85-86, 86-87, 108-109, 109-110, 110111, 111-112, 112-113, 113-114, 114-115, 115-116, 116-117, 117-118, 1181.19, 119-120, 120-121, 121-122, 122-123, 123-124, 124-125, 125-126, and 126-127 .

The most preferred breakpoints at which the new C-terminus and N-terminus in the above polypeptide (III) or the amino acid sequence of (SEQ. ID No. 256) can be obtained are;

81-82, 108-109, 115-116, 119,120, 1.22,123 and 125,126.

The multifunctional receptor agonist of the present invention can also be represented by the following formula:

(T '), - (L') _b -X '- (L' _fc -X ^J -ÍL ² ) a- (T ² ) and XMLVX ² -a.) - Y '- (L) eY ² where :

χ1 is a peptide that comprises an amino acid sequence that corresponds to the sequence of residues n + 1 to J of the original protein dp • 20 that has amino acid residues numbered sequentially 1 to J with an amino terminus at residue 1:

L is an optional binder;

X ² is a peptide comprising an amino acid sequence of residues 1 an from the original protein;

Y ^ is a peptide comprising an amino acid sequence corresponding to the sequence of residues n + 1 to K of the original protein which has amino acid residues sequentially numbered 1 to K with an amino terminus at residue 1;

is a peptide that comprises an amino acid sequence that corresponds to the 1 to n residue sequence of the original protein;

dei ² are optional peptide spacers:

n is an integer in the range 1 to J - 1;

b, c and d are each independently 0 or 1, aes are 0 or 1, as long as both a and e cannot both be 0; and

Τ '* and are proteins.

In addition, the present invention relates to recombinant expression vectors comprising nucleotide sequences that encode multifunctional hematopoietic receptor agonists, related microbial expulsion systems and processes for obtaining multifunctional hematopoietic receptor agonists. The invention also relates to pharmaceutical compositions containing multifunctional hematopoietic receptor agonists and methods for using multifunctional hematopoietic receptor agonists.

In addition to the use of the multifunctional hematopoietic receptor agonists of the present invention in vivo, it is considered that in vivo uses would include the ability to stimulate bone marrow and blood cell activation and growth prior to infusion in patients.

Brief Description of the Figures

Figure 1 schematically illustrates the sequence rearrangement of a protein The N (N) termination and the C (C) termination of the native protein are • ²⁰ associated via a ligand or directly associated. The protein is opened to a breaking point that creates a new N-terminus (new N) and a new C-terminus (new C) that results in a protein with a new linear amino acid sequence. A rearranged molecule can be synthesized again as a linear molecule and not through the original N-termination and C-termination stages and opening the protein at the breaking point.

Figure 2 presents a scheme of Method I, to create new proteins in which the native protein's N-terminus and C-terminus are associated with a linker and a different N-terminus and C-terminus are created than the protein. In the example shown, the sequence rearrangement results in a new gene that encodes a protein with a new N-terminus created at amino acid 97 of the original protein, the original C-terminus (aa 174) associated with amino acid 11 (aa 1 -10 are eliminated) through a ligand region and a new C-terminus created at amino acid 98 of the original sequence.

Figure 3 presents a scheme of Method II, to create new proteins in which the original N-terminus and C-terminus of the native protein are associated with a linker and a different N-terminus and C-terminus are created than the protein. In the example shown, the sequence rearrangement results in a new gene that encodes a protein with a new N-terminus created at amino acid 97 of the original protein, the original C-terminus (aa 174) associated with the original N-terminus and a new C-terminus created at amino acid 96 of the original sequence.

Figure 4 presents a scheme of Method III, to create new proteins in which the native protein's N-terminus and C-terminus are associated with a linker and a different N-terminus and C-terminus are created than the protein. In the example presented, the sequence rearrangement results in a new gene encoding, a protein with a new N-terminus created at amino acid 97 of the original protein, the original C-terminus (aa 174) associated with amino acid 1 through a ligand region and a new terminus C created at amino acid 96 of the original sequence.

Detailed Description of the Invention

The present invention encompasses multifunctional hematopoietic receptor agonists formed from covatively linked polypeptides. each of which can act through a different and specific cell receptor to initiate complementary biological activities. Hematopoiesis requires a complex series of cellular events in which embryonic cells continuously generate large populations of maturation cells in all major strains. There are usually 20 less known skin regulators with proliferative hematopoietic activity. Since most of these proliferations can only stimulate one or another type of colony formation in vitro, the precise pattern of colony formation stimulated by each regulator is quite characteristic. Two regulators do not stimulate exactly the same pattern of colony formation, as assessed by colony numbers or. most notably, due to the pattern of lineage and maturation of the cells that constitute the developing colonies. Proliferative responses can be more easily analyzed in simplified in vitro culture systems. Three quite different parameters can be distinguished: change in colony size, change in number of colonies and cell line. Two or more factors can act on the progenitor cell, inducing the formation of a larger number of progenies thereby increasing the size of the colony. Two or more factors may allow the proliferation of a larger number of progenitor cells either because of the distinct subsets of existing progenitor cells that respond exclusively to one factor or because some progenitors require stimulation by two or more factors before being able to respond. Activation of additional receptors in a cell by the use of two or more factors is likely to improve the mythic signal because of the coalescence of initially different signal pathways in a common final path that reaches the nucleus (Metcalf, Nature 339: 27, 1989 ). Another 30 mechanisms could explain synergy. For example, if a signaling path is limited by an intermediate activation of an additional signaling path that is caused by a second factor, then this can result in an additive super response. In some cases, activation of one type of receptor can induce improved expression of other receptors (Metcalf, B / ood 82; 3515-3523. 1993). Two or more factors can result in a different pattern of cell lines than from a single S factor. The use of multifunctional hematopoietic receptor agonists may have a potential clinical advantage that results from a proliferative response that is not possible by any single factor.

Hematopoietic growth factor receptors and others can be grouped into two distinct families of related proteins10; (1) iirosin kinase receptors, including those for epidermal growth factor, M-CSF (Shern Blood 75: 1. 1990} and SCF (Yarden et al., EMBO J. 6: 3341. 1987); and (2) receptors hematopoietic, which do not contain an iirosin kinase domain, but which exhibit obvious homology in their extraceous domain (Bazan, PNAS USA 87: 6934-6938, 1990). In15 included in this latter group are entropoietin (EPO) (D'Andrea and others , Ce // 57: 277, 1989), GM-CSF (Gearing et al., M) J. & 3667, 1989), IL-3 Kitamura et al, Ce // 86: 1165, 1991), G-CSF ( Fukunaga et al., J. Bto. Ctiem. 285: 14008-15, 1990), IL-4 (Harada et al., PUAS USA 87 857.1990), IL-5 (Takaki et al., EMBO J. 9: 4367, 1990), IL-6 (Yamasaki and 20 others. Science 241: 825, 1988). IL-7 (Goodwin et al., Ce // 60: 941-51, 1990), LIF (Gearing et al., EMBQ J. 10: 2839, 1991) and IL-2 (Cosman et al., MoMmmunol.. 23: 935 -94, 1986). The majority of the latter group of receptors exists in a form with high affinity as heterodimers. After binding with Hgante, specific alpha-chains become associated with at least one other receptor chain (beta-chain, gamma-chain). Many of these factors share a common receptor subunit. Legacies for GM-CSF, IL-3 and IL-5 share the same beta-chain (Kitamura et al., Ce // 66; 1165. 1991). Takaki et al., O4B0 J. 10: 2833-8, 1991) and receptor complexes for IL-6, LlF and IL-11 share a common beta-chain (gp130) (Taga. Et al., Ce // 58: 573 -81, 1989; Gearing et al. Science 255: 1434-7, 1992). The II2 receptor complexes. IL-4, IL-7, IL-9 and IL-15 share a common gamma-chain (Kondo et al., Science 262. 1874, 1993: Russell et al., Science 266: 1042-1045, 1993; Noguchi θ others, Sc / ence 262: 1877. 1993; Giri et al. EA4BO J. 13: 2822-2830, 1994).

The use of a multiple-action hematopoietic factor may also have a potential advantage in reducing the demands placed on factor-producing cells and their induction systems. If there are limitations on a tula's ability to produce a factor, then decreasing the required concentrations of each of the factors and using them in combination can usefully reduce the demands for factor-producing cells. The use of a multiple-action hematopoietic factor can decrease the number of factors that would be needed, probably reducing the likelihood of adverse side effects.

The new compounds of this invention are represented by a formula selected from the group consisting of:

R-lq -Rg. 1 ^ 1 “^ 2 θ 1

Where Rq and R2 are as defined above.

Rg is preferably a colony stimulating factor with a different but complementary activity to Rj. Complementary activity means activity that improves or varies the response to another cell modulator.

The polypeptide is associated directly or through a linker segment to the term Rç θ polypeptide directly defines multifunctional hematopoietic receptor agonists in which the polypeptides are associated without a peptide linker. Thus lq represents a chemical bond or polypeptide segment to which both Rj and R2 are associated in frame, most commonly Lq is a linear peptide to which Rq and Rg are associated by amide bonds linking the carboxy terminus of Rq to the amino terminus of Li and the carboxy terminus of Lq to the amino terminus of Rg. By frame members, it is understood that there is no translation or interruption termination between the frames for reading the DNA encoding Ri and Rg30 A non-exclusive list of other growth factors, that is, colony-stimulating factors (CSFs), is that of cilocins, lymphokines, interleukins, hematopoietic growth factors that may be associated with (I), (II) or (III) include GM-CSF, G-CSF, ligating c-mpl (also known as TPO or MGDF), M-CSF, erythropoietin (EPO), IL-1. IL-4. 9L-2, IL-3, IL-5, IL-6, IL-7, IL-8, IL-9, 11-10, IL-11, IL-12. IL-13, 11.-15, LIF. hgando flt3 / flk2, human growth hormone, B-cell growth factor, 5 eosinophil differentiation factor and embryonic cell factor (SCF) also known as steel factor or c-kii ligand. In addition, this invention encompasses the use of modified or changed R R or Rg molecules or modified DNA sequences encoding these or Rg molecules. The present invention also includes multifunctional he10 matopoietic receptor agonists in which R1 or R9 is a variant of hll-3, a variant of c-mpl ligand or a variant of G-CSF. A “hlL-3 variant is defined as a hlL-3 molecule that has amino acid substitutions and / or portions of hlL-3 eliminated as disclosed in WO 94/12638, WO 94/12639 and WO 95/00646, as well as other variants known in the art. A variant of c-mpl * ligand is defined as a c-mpl ligand molecule that has deleted amino acid substitutions and / or portions of c-mpl ligand, disclosed in USS Patent Application Number 08 / 383,035 as well as other known variants in the technique. A variant of G-CSF is defined as a G-CSF molecule that has 20 amino acid substitutions and / or portions of G-CSF deleted, as disclosed herein, as well as other variants known in the art.

The linking group (Ly) is generally a polypeptide with a length between 1 and 500 amino acids. The ligands that associate the two molecules are preferably designed to (1) allow the two molecules to fold and act independently of each other, (2) do not have a propensity to reveal an ordered secondary structure that could interfere with the functional domains of the two proteins, (3) have minimal hydrophobic characteristics that could interact with the functional domains of protein and (4) provide spherical separation of R ^ and Rg such that R ^ and Rg ask to interact simultaneously with their corresponding receptors in an isolated cell . Typically surface amino acids in flexible protein regions include Gly „Asn and Ser. Virtually any permutation of Gly-containing amino acid sequences would be expected _; Asn and Ser meet the above criteria for a sequential sequence. Other neutral amino acids, such as Thr and Ala _: can also be used in the sequence. Additional amino acids can also be included in the linkers by virtue of the addition of unique restriction sites in the sequence to facilitate the construction of the multifunctional hematocrit receptor agonists.

The preferred L-j linkers of the present invention include the sequences selected from the group of formulas:

(Giy'Serf (SEQ ID NQ4), (Gl / Serf (SEQ ID NO: 5) _i {Gl / Serf (SEQ ID NO: 6). (Gíy ⁴ Ser) ^p (SEQ ID NO.7) _: (AlaGlySerf (SEQ ID NO.8).

An example of a flexible amino acid ligand is the gypsy and senna-rich spacer region present within the plll protein of filamentous bacteriophages15, for example, MT3 or id bacteriophages (Schaller et al., PA / AS USA 72: 737-741. 1975 ). This region provides a long, flexible spacer region between two domains of the superficial pill protein. The spacer region consists of the amino acid sequence:

GíyGiyGiySerGiyGiyGlySerGIyGlyGlySerGIuGlyGlyGlySerGIuGtyGlyGlySer 20 GiuGlyGlyGíySerGiuGiyGlyGlySerGlyGlyGlySer (SEQ ID N0.9)

The present invention also includes linkers in which an endopeptidase recognition sequence is included. Such a dividing site can be valuable in separating the individual components of the multifunctional hematopoietic receptor agonist to determine whether they are properly folded and active in vitro. Examples of various endopeptidases include, but are not limited to, plasmin, enterokinase. kallikrein, urokinase. tissue plasminogen activator, clostripain, chymosin, coagenase, Russell's viper venom protease, post-proline divination enzyme _,; protease V8. Thrombin and factor Xa.

Paptide ligand segments from the hinge region of heavy chain immunoglobulins IgG, IgA, IgM IgD or IgE provide an angular relationship between the bound polypeptides. Especially useful are those hinge regions where cysteines are replaced with sarinas. Preferred linkers of the present invention include sequences derived from murine IgG gamma 1b hinge region in which the cysteines have been changed to serines. These linkers also include an endopeptidase dividing site. Examples of such linkers include the following sequences:

IleSerGluProSerGIyProlleSefThrlIeAsnProSerProProSerlysGluSerHísUyusS erPro (SEQIDNO: 10) and

IteGiuGiyArglleSerGlyProSerGiyProlleSerThrlleAsnProSerProProSerLysGlu SerHisLysSerPro (SEQIDNO: 11)

The present invention, however, is not limited in form, by the size or by the number of sequences used, and the only requirement of the ligand is that the functionality does not interfere with the folding and function of the individual molecules of the multifunctional hematopoietic receptor agonists.

Determination of Lp Lioante

The component of the amino acid sequence of the hg Lg to be used in R-j and / or Rg can be selected empirically or with direction from structural information or by using a combination of the two approaches.

When structural information is not available · a small series of binders can be prepared for testing using a design whose length is varied in order to investigate a range from 0 to 50 Å and whose sequence is chosen to be consistent with surface exposure (hydrafilicity) Hopp & Woods, Mo / Immuno 2Q: 483-489, 1983), Kyte & Doolittle, J. Mo /. Only/. 157: 105-132; surface area exposed to solvent, Lee & Richards, J. Mo /. Biot 55: 379-400, 1981) and the ability to adopt the necessary conformation without messing up the conformation of R ^ or R ² (conformationally flexible; Karplus & Schulz, A / atorvvfosenscòaffen 72: 212-213, 1985}. of translation from 2.0 to 3.8 A per residue, this would mean that the conformation to be tested was between 0 and residues, with 0 to 15 residues being and preferred beam. Examples of an empirical series would be to build ligands using a sequence cassette such as Gly-Gly-Gly-Ser (SEQ. ID NE 12) repeated n times, where n is 1, 2, 3 or

4. Those skilled in the art will recognize that there are many sequences that vary in length or composition that can serve as binders with the primary consideration being that they are not excessively long or short (cf., Sandhu. Cnfica / Rev. Bfotech. 12: 437-462, 1992); if they are too long, the effects of entropy will likely destabilize the three-dimensional fold and can also make the fold10 kinetically impractical and if they are too short, they will likely destabilize the molecule because of torsional or spherical tension

Those skilled in the analysis of structural protein information will recognize that the use of the distance between the ends of the chain, defined as the distance between the c-atfa carbons. can be used to define the length of the sequence to be used or at least to limit the number of possibilities that must be tested in an empirical selection of ligands. They will also recognize that it is sometimes the case that the positions of the ends of the chain polypeptides are poorly defined in 20 structural models derived from X-ray diffraction data or from nuclear magnetic resonance spectroscopy, and that when true, this situation will therefore need to be taken into account in order to properly assess the length of the necessary ligand. From those residues whose positions are well defined, two residues are selected that are close to the ends of the chain and the distance between their c-alpha carbonds is used to calculate an approximate length for a ligand between them. Using a calculated length as a guide, binders are then selected with a residue number range (calculated using 2 to 3.8 A per residue). These binders can be made up of the original sequence, abbreviated or extended if necessary and when extended the additional residues can be chosen as being flexible and hydrophilic as described above; or optionally the original sequence can be replaced using a series of linkers, an example being the Gly-Giy-Gly-Ser cassette approach (SEQ. ID No. 12) mentioned above: or optionally a combination of the original sequence and new sequence that has an appropriate total length.

Determination of the Amino and Carboxyl Terminations of Ri and Rq

Ri and Rq sequences capable of doubling to biologically active states can be prepared by appropriate selection of the initial (amino terminus) and final (carboxyl terminus) positions from within the original polypeptide chain while using the Lq ligand sequence as desired. before. The amino and carboxyl termini are selected from within a common stretch of the sequence, referred to as the breaking point region, using the direction lines described below. A new amino acid sequence is thus generated by selecting 15 amino and carboxyl termini from within the same breaking point region. In many cases, the selection of new terms will be such that the original position of the carboxyl term immediately before the amino term. However, those skilled in the art will recognize that termination selections at any location within the region may work and that these will effectively lead to deletions or additions to the amino or carboxyl moieties of the new sequence /

It is a dogma of molecular biology that the primary amino acid sequence of a protein dictates the fold to the td-dimensional structure necessary for expression of its biological function. Those skilled in the art know methods for obtaining and interpreting three-dimensional structural information using X-ray diffraction of isolated protein crystals or spectroscopy in nuclear magnetic resonance of protein solutions. Examples of structural information that are pertinent to the identification of breakpoint regions include the location and type of structure secun3Q protein daily (alpha and 3-10 helices, beta parallel and anti-parallel washes, reversals and chain loops and circuits closed; Kabsch & Sander, Biopofymers 22: 2577-2637, 1983), the degree of solvent exposure of amino acid residues, the extent and type of interactions of residues with each other (Chothia. Ann Rev: Siochem. 53: 537-572, 1984) and the static and dynamic distribution of conformations along the poüpeptide chain (Aider & Mathews, Methods Enzyme /. 154: 511-533, 1987). In some cases, additional information regarding exposure of residues to solvent is known; an example is a post-translational carbohydrate binding site that is necessarily on the surface of the protein. When experimental structural information is not available or cannot be obtained, methods are also available to analyze the primary amino acid sequence in order to make predictions of tertiary and secondary protein structure, solvent accessibility and the occurrence of of closed circuits. Biochemical methods are also sometimes applicable to empirically determine surface exposure when direct structural methods are not possible; for example, using the identification of chain-splitting sites after limited proteolysis to indicate surface exposure (Gentile & Salvatore, Eur. J, Siochem 218. 603-621, 1993) So using structurally derived structural information or prophetic methods (eg Snnivisan & Rose Profe / ns: Sfrucri. Funct & Genetics, 22: 81-89, 1995) the parental amino acid sequence is inspected to classify regions whether or not they are integral for maintaining secondary and tertiary structure . The occurrence of sequences within the regions known to be involved in periodic secondary structure (alpha and beta leaves 3-10 helices, parallel and aniparallel) are regions that should be avoided. Similarly, it is more likely that the regions of the amino acid sequence that are observed or expected to have a low degree of solvent exposure are part of the so-called hydrophobic nucleus of the protein and should also be avoided for selection of amino and carboxyl termini. In contrast, those regions which are known or expected to be in surface loops or closed circuits and especially those regions which are known to be unnecessary for biological activity, are the preferred sites for locating the ends of the polypeptide, Continuous stretches of amino acid sequence that are preferred based on the above criteria are cited as a breaking point region.

Non-covalent multifunctional hematopoietic growth factors

An alternative method for linking two hematopoietic growth factors is through a non-covalent interaction. Such complexed proteins can be described by one of the formulas Rj-Ci 4 R2 ^ 2 ^; or Cq ~ Rl * ^ 2 ~ ^ 2i C'f-R'j + Rg-Cg: C1-R1 ^{+ +} ^ 2 * & 2 ·

R-Ι and Rg as defined above. The Cq and Cg domains are identical or non-identical chemical structures, typically proteinaceous, that can form a specific non-covalent association. The complexes between C1 and Cg result in a one-to-one stoichiometric relationship between R-s and Rg for each complex. Examples of associating domains are leucine closure domains or transcription factors, dimerization domains of Baclerian transcriptional repressors and immunoglobulin constant domains. Covalent bonds connect R- | and C-j and Rg θ Cg, respectively. As indicated in the formulas, the C-j and Cg domains may be present at the N-terminus or at the C-terminus of their corresponding hematopoietic growth factor (R). These multi-domains (Cj and Cg) include those derived from the bZíP family of proteins (Abela et al., 20 Nature 341: 24-25, 1989, Landshulz et al., Sc / ence 240: 1759-1764, 1988: Pu et al. , Nuc. Add Res. 21. 4348-4355, 1993: Kozarides et al.,

Nature 336. 646-651 ,. 1988), as well as multimerization domains of the helix-closed-helix protein family (Abel et al., Nature 341: 24-25, 1989: Murre et al., Ce / f 56; 777-783, 1989; Tapscott et al. , 25 Science 242: 405-411, 1988; Fisher et al., Genes & Dev. 5: 2342-2352,

1991). The preferred multifunctional hematopoietic receptor agonists of the present invention include dimerized colony stimulating factors by virtue of their incorporation as translational multifunctional hematopoietic receptor agonists with the leucine closing dimerization domains of the BZIP Fos and Jun family proteins. Jun's leucine is able to interact with identical domains. On the other hand, the Fos leucine zipper domain interacts with Jun's leucine zipper domain, but it does not interact with other Fos leucine zipper domains. Mixtures of Fos and Jun predominantly result in the formation of Fos-Jun heterodimers. Consequently, when associated with colony stimulating factors, the Jun domain can be used to direct the formation of homo- or heterodimers. The preferential formation of heterodimers can be achieved if one of the partners of the colony stimulating factor is engineered to possess Jun's teucin closure domain while the other is engineered to possess the Fos closure.

Additional peptide sequences can also be added to facilitate purification or identification of multifunctional hematopoietic receptor agonist proteins (e.g., poly-His). A highly antigenic peptide can also be added that allows quick and easy dosing of the multifunctional hematopoietic receptor agonist protein by a specific monoclonal antibody.

Mutant amino acid sequence / * “mutant protein, variant protein, mutein or mutant polypeptide refers to a polypeptide that has an amino acid sequence that varies from a native sequence as a result of deletions, amino acid substitutions, or both, or is encoded by a nucleotide sequence obtained intentionally variant of a native sequence, Native sequence refers to an amino acid or nucleic acid sequence that is identical to a wild-type or native form of a gene or protein.

Hematopoietic growth factors can be characterized by their ability to stimulate colony formation by human hematopoietic progenitor cells. The colonies formed include erythroid, granulocyte, megakaryocyte, mixtures of granulocyte and the same. Many of the hematopoietic growth factors have demonstrated the ability to restore bone marrow function and peripheral blood cell populations to therapeutically advantageous levels in studies initially performed in primates and subsequently in humans. Many or all of these hematopoietic growth factor biological activities involve signal transduction and high affinity receptor binding. The multifunctional hematopoietic receptor agonists of the present invention may exhibit useful properties such as having similar or greater biological activity when compared to an isolated factor or having improved half-life or decreased adverse side effects or a combination of these properties.

Multifunctional hematopoietic receptor agonists that have little or no agonistic activity can be useful as antagonists, as antigens for the production of antibodies for use in immune therapy or immunotherapy, as genetic probes or as intermediates used to build other useful hlL-3 muteins.

The biological activity of the multifunctional hematopoietic receptor agonist proteins of the present invention can be determined by DNA synthesis in faton-dependent cell lines or by counting the colony-forming units in an in vitro bone marrow dosage.

The multifunctional hematopoietic receptor agonists of the present invention may have an improved therapeutic profile compared to single-acting hematopoietic agonists. For example, some multifunctional hematopoietic receptor agonists of the present invention may have similar or more potent growth factor activity relative to other hematopoietic agonists without have a similar or corresponding increase in side effects,

The present invention also includes DNA sequences that code for multifunctional hematopoietic receptor agonist proteins, DNA sequences that are substantially similar and function in substantially the same way, and DNA sequences that differ from the DNAs that encode the multifunctional hematopoietic receptor agonists of the invention. only because of the degeneracy of the genetic code. Also included in the present invention are oigonucleotide intermediates used to construct the mutant ÜNAs of the polypeptides encoded by these oligonucleotides.

Genetic engineering techniques now standardized in the art (U.S. Pat. 4,935,233 and Sambrook et al. Molecular Cloning A Laboratory Manual ”, Cold Spring Harbor Laboratory, 1989) can be used in the construction of the DNA sequences of the present invention. One such method is cassette mutagenesis (Wells et al. Gene 34: 315-323, 1985) in which a portion of the coding sequence on a plasmid is replaced with synthetic oligonucleotides that encode the desired amino acid substitutions in one part of the gene between two restriction sites,

Pairs of complementary synthetic oligonucleotides that co-hinder the desired gene can be obtained and annealed with one another. The oigonucleotide UNA sequence would encode the sequence for desired gene amino acids with the exception of those substituted and / or deleted from the sequence.

Plasmid DNA can be treated with the chosen restriction endonucleases then linked to the annealed oligonucleotides. Bound mixtures can be used to transform JM101 cells into resistance to an appropriate antibiotic. Isolated colonies can be chosen and the plasmid DNA examined by restriction analysis and / or DNA sequencing to identify plasmids with the desired genes.

The cloning of the DNA sequences of the new multifunctional hematopoietic agonists in which at least one of which can be performed the DNA sequence of the other stimulating factor of oolonia using intermediate vectors. Alternatively, one gene can be directly cloned into a vector containing the other gene. Linkers and adapters can be used to associate the DNA sequences, as well as to replace the lost sequences, when a restriction site was internal to the region of interest. Thus the genetic material (DNA) encoding a polypeptide, peptide linker and the other polypeptide is inserted into a suitable expression vector that is used to transform bacteria, yeast, insect cells or mammalian cells. The transformed organism is cultured and the protein isolated by standard techniques. The resulting product is therefore a new protein that has a colony stimulating factor associated by a region of ligand with a second colony stimulating factor.

Another aspect of the present invention provides plasmid DNA vectors for use in the expression of these new multifunctional hematopoietic receptor agonists. These vectors contain the new DNA sequences described above which code for the new pohpeptides of the invention. Suitable vectors that can transform microorganisms capable of expressing multiple multifunctional hematopoietic receptor agonists include expression vectors that comprise nucleotide sequences that code for multifunctional hematopoietic receptor agonists associated with transcriptional and transiaconal regulatory sequences that are selected according to the host cells used .

Vectors incorporating modified sequences as described above are included in the present invention and are useful in the production of multifunctional hematopoietic receptor agonist polypeptides. The vector employed in the method also contains regulatory sequences selected in operative association with the DNA encoding sequences of the invention and which are capable of directing its replication and expression in selected host cells.

As another aspect of the present invention provides a process for producing the new multifunctional hematopoietic receptor agonists. The method of the present invention involves culturing cells or 25 suitable cell lines, which have been transformed with a vector containing a DNA sequence that encodes for the expression of a new multifunctional hematopoietic receptor agonist. Suitable cells or cell lines can be bacterial cells. For example, the various strains of E co / i are well known as host cells in field 30 of biotechnology. Examples of such strains include E, with strains JM101 (Yanish-Perron et al., Gene 33: 103-119,1985) and MON105 (Obukowicz et al., Applied Environmental Microbiology 58 1511-1523, 1992). Also molten in the present invention is the expression of the multifunctional hematopoietic receptor agonists protein that uses an oromosomal expression vector for E, based on the bacieriophage Mu (Weinberg et al., Gene 126: 25-33, 1993). Various strains of 8. soap / is can also be used in this method. Many strains of yeast cells known to those skilled in the art are also available as host cells for expression of the polypeptides of the present invention. When expressed in the cytoplasm of E .. ooE, the gene encoding the multifunctional hematopoietic receptor agonists of the present invention can also be constructed in such a way that at the 5 'end of the gene, codons are added to encode Mef - ^ - AísH- or Met' ⁵ at the N-terminus of the protein. The N-termini of proteins obtained in the cytoplasm of E. co / f are affected by post-trans-anionic processing by methionine aminopeptidase (Ben Basset et al. J. Bac. 169: 751-757, 1987) and possibly by other peptid15 doses so that after expression methionine is separated by dividing the N-terminus. The multifunctional hematopoietic receptor agonists of the present invention may include multifunctional hematopoietic receptor agonists that have MeH, Alar ¹ or Met ^ -Ala ¹ - at the end N. These hematopoietic receptor agonists multifunctional mutants 20 can also be expressed in E by fusing a secretion signal peptide to the N terminus. This signal peptide is cleaved from the polypeptide as part of the secretion process.

Also suitable for use in the present invention are mammalian cells, such as Chinese hamster ovary (CHO) cells.

The general methods for expression of foreign genes in mammalian cells are reviewed in Kaufman, R. J., 1987) Genetic Engineering.

Principles and Methods, Vol. 9, J. K. Setlow, editor. Plenum Press, New York. An expression vector is constructed in which a strong promoter capable of functioning in mammalian cells triggers the transcription of a eukaryotic secretion signal peptide encoding region. which is translationally associated with the coding region for the multifunctional hematopoietic receptor agonist. For example, sinks can be used

4'1 mids such as pcDNA, l / Neo, pRc / RSV and pRc / CMV (obtained from Invdrogen Corp, San Diego, California). The eukaryotic secretion signal peptide coding region may be from the gene itself or may be from another secreted mammalian protein (Bayne, M. L.

and others, Proc. W Acad. Know. U.S.A. 84 2638-2642, 1987). After the construction of the vector containing the gene, the vector DNA is transfected into mammalian cells. Such cells can be, for example, the COS7 patterns. HeLa, BHK, CHO or mouse L. The cells can be cultured, for example, in DMEM media (JRH Scientific). The polypeptide secreted 10 in the media can be recovered by standard biochemical approaches after transient expression for 24 - 72 hours after transfection of the cells or after establishment of stable cell lines after selection for antibiotic resistance. The selection of suitable mammalian host cells and methods for transformation, culture, amplification, product selection and production and purification are known in the art.

See, for example, Gethíng and Sambrook, Nature, 293 620-625, 1981) or alternatively, Kaufman et al., MoL Cell, Bioí, 5 (7); 1750-1759, 1985) or Howley et al., U.S. Pat. 4,419,446. Another suitable mammalian cell line is the monkey CQS-1 cell line. A similarly useful mammalian cell line is the CV1 cell line

When desired, insect cells can be used as host cells in the method of the present invention. See, for example, Milter et al., Geneéc Engineering, 8. 277-298 (Plenum Press 1986) and references cited therein. In addition, general methods for expressing foreign genes in insect cells using Baculovirus vectors are described in :. Summers, M. D, and Smith ,. E., 1987) - A manual of methods for Baculovirus vectors and insect cell culture procedures, Texas Agricultural. Experiment Station Bulletin N ⁰ 1555. An expression vector 30 is constructed that comprises a Baculovirus transfer vector, in which a strong Baculovirus promoter (such as the polyhedron promoter) triggers the transcription of a signal peptide coding region. eukaryotic secretion, which is translaciously associated with the coding region for the multifunctional hematopoietic receptor agonist polypeptide. For example, plasmid pVL1392 (obtained from Invitrogen Corp., San Diego, California) can be used. After the construction of the vector that contains the gene encoding the multifunctional hematopoietic receptor agonists polypeptide, two micrograms of this DNA are co-transfected with a micrograms of Baoulovirus DNA (see Summers & Smith, 1987) in insect cells, oepa SF9. The pure Baoulovirus recombinants containing the multifunctional hematopoietic receptor agonists are used to infect cultured cells, for example, in serum-free Excell 401 medium (JRH Bioscienes, Lenexa, Kansas). The multifunctional hematopoietic receptor agonist secreted into the medium can be recovered by standard biochemical approaches. Supernatants from mammalian or insect cells expressing the multifunctional hematopoietic receptor agonist protein can first be concentrated using any of some commercial concentration units.

The multifunctional hematopoietic receptor agonists of the present invention may be useful in the treatment of diseases characterized by increasingly lower levels of myeloid, erythroid, lymphoid cells or megakaryocytes in the hematopoietic system or combinations thereof. In addition, they can be used to activate mature myeloid and / or lymphoid cells. Among the conditions susceptible to treatment with the polypeptides of the present invention is leukopenia, a reduction in the number of circulating leukocytes (white cells) in peripheral blood. Leukopenia can be induced by exposure to certain viruses or radiation. Ba is often a side effect of various forms of cancer therapy, for example, exposure to chemotherapeutic drugs. radiation and from infection or hemorrhage. Therapeutic treatment of leukopenia with these multifunctional hematopoietic receptor agonists of the present invention can prevent undesirable side effects caused by treatment with currently available drugs.

The multifunctional hematopoietic receptor agonists of the present invention may be useful in the treatment of neutropenia and, for example, in the treatment of such conditions as aplastic anemia, cyclic neutropenia, idiopathic neutropenia. Chédiak-Higashi syndrome, systemic tomato lupus eri5 (SLE), leukemia, myelodysplastic syndrome and myelofibrosis.

The multifunctional hematopoietic receptor agonist of the present invention may be useful in the treatment or prevention of thrombocytopenia. Usually the only therapy for thrombocytopenia is the transfusion of a cupreta10, which is costly and carries significant risks of infection (HIV.

H8V) and alloimmunization. Multifunctional hemaopoietic receptor agonists can alleviate or decrease the need for platelet transfusion. Severe thrombocytopenia can result from genetic defects such as Fanconi Anemia, Wiscott-Aldrich or May Hegglin syndromes. Acquired thrombocytopenia 15 can result from auto- or allo-antibodies such as in Immune Purple Thrombocytopenia, Systemic Lupus Erythematosus, hemoitic anemia or fetal maternal incompatibility. may result in thrombocytopenia. 20 Severe thrombocytopenia can also result from chemotherapy and / or radiation or cancer therapy. Thrombocytopenia can also result from spinal cord invasion due to carcinoma, lymphoma, leukemia or fibrosis.

The multifunctional hematopoietic receptor agonists of the present invention may be useful in the mobilization of poetic hemafo25 progenitors and embryonic cells in peripheral blood. Peripheral blood-derived parents have been shown to be effective in reconstituting patients in adjusting autologous bone marrow transplantation. Hematoporetic growth factors including G-CSF and GM-CSF have been shown to improve the number of circulating parents and 30 embryonic cells in peripheral blood. This simplified the procedure for the collection of peripheral embryonic cells and drastically reduced the cost of the procedure by decreasing the number of feresis needed. The multifunctional hematopoietic receptor agonists may be useful in mobilizing embryonic cells and to further improve the effectiveness of peripheral embryonic cell transplantation.

The multifunctional hematopoietic receptor agonists of the present invention may also be useful in the ex vivo expansion of hematopoietic progenitors and embryonic cells. Colony stimulating factors (CSFs), such as htL-3, were administered alone, administered with other CSFs or in combination with bone marrow transplants following high-dose chemotherapy to treat neutropenia and thrombocytopenia which are often the result such treatment. However, the period of severe neutropenia and thrombocytopenia may not be completely eliminated, the myeloid lineage, which is comprised of monocytes (macrophages), granulocytes (including neutrophils) and megakaryocytes, is fundamental in preventing infections and bleeding that can become 15 a danger to life. Neutropenia and thrombocytopenia can also be the result of disease, genetic disorders, drugs, toxins, radiation and many therapeutic treatments such as conventional therapy against oncology.

Bone marrow transplants were used to treat this patient population. However, several problems are associated with the use of bone marrow to reconstruct a compromised hematopoietic system, including; 1) the number of embryonic cells in the bone marrow, spleen or peripheral blood is limited, 2) Graft Versus Host Disease. 3) graft rejection and 4) possible contamination with tumor cells. Embryonic cells make up a very small percentage of the nucleated cells in the bone marrow, spleen or peripheral blood. It is evident that there is a dose response such that more embryonic cells will improve hematopoietic recovery. Therefore, in vitro expansion of embryonic cells would improve hematopoietic recovery and patient survival. Bone marrow from an allogeneic donor was used to provide bone marrow for transplantation. However, Graft Versus Host Disease and rejection

4ο of the graft limit bone marrow transplantation even in people who receive the transplant with related HLA-combined donors. An alternative to allogeneic bone marrow transplants is autologous bone marrow transplants. In autologous bone marrow transplants, part of the patient's own marrow is harvested before myeloblative therapy, for example, high-dose chemotherapy and is transplanted back to the patient later. Autologous transplants eliminate graft versus host disease and graft rejection. However, autologous bone marrow transplants still present problems in terms of the limited number of embryonic cells in the marrow and possible contamination with tumor cells. The limited number of embryonic cells can be prevented by the ex vivo expansion of embryonic cells. In addition, embryonic cells can be specifically isolated. based on the presence of specific surface antigens such as 15 CD34 + in order to decrease contamination of the bone marrow graft tumor cell;

The following patents contain further details on the separation of embryonic cells, CD34 * cells, cell culture with hematopoietic factors, the use of cells for the treatment of patients with 20 hematopoietic disorders and the use of hematopoietic factors for cell expansion and therapy of gene.

5,061,620 refers to compositions comprising human hematopoietic embryonic cells provided by separating the embryonic cells from dedicated cells

5,199,942 describes a method for autologous hematopoietic cell transplantation comprising: (1) obtaining hematopoietic progenitor cells from a patient; (2) ex-vivo expansion of cells with a growth factor selected from the group consisting of β3, fluffy 3, fluffy kit. GM-CSF. IL-1, GM-CSF / IL-3 fusion protein and 30 combinations thereof; (3) administration of cell preparation to a patient.

5,240,856 refers to a cell separator that includes an apparatus to automatically control the cell separation process,

WO 91/16116 describes devices and methods for selectively isolating and separating target cells from a mixture of cells.

WO 91/18972 describes processes for the in vitro culture of bone marrow, by bone marrow cell incubator suspension, using a hollow fiber bioreactor,

WO 92/18615 relates to a process for maintaining and expanding bone marrow cells, in a culture medium containing specific mixtures of cytokines, for use in transplants,

WO / 08266 describes a method for selectively expanding embryonic cells, comprising the steps of (a) separating CD34 + embryonic cells from other cells and (b) incubating the separated cells in a selective medium, such that the embryonic cells are selectively expanded .

WO 93/18136 describes a process for in vitro support of mammalian cells derived from peripheral blood,

WO 93/18648 relates to a composition comprising 20 human neutrophil precursor cells with a high content of myeloblasts and promyelocytes for the treatment of genetic or acquired neutropenia.

WO 94/08039 describes a method of enriching embryonic human hematopoietic cells by selecting cells that express the kit-c protein.

WO 94/11493 describes a population of embryonic cells that are small size CD34 +, which are isolated using a counterflow elutriation method.

WO 94/27698 relates to a method that combines immunoaffinity separation and continuous flow centrifugal separation for the selective separation of a population of heterogeneous cells from a mixture of heterogeneous cells.

WO 94/25848 describes a cell separation apparatus for the accumulation and manipulation of target cells.

The long-term culture of CD34 + precursors enriched with human bone marrow hematopoietic progenitor cells in cultures comprises IL-la, IL-3, IL-6, or GM-CSF is discussed in Brandt and others J. Clin. Invest. 86. 932-941, 1990).

Another aspect of the present invention provides a method for selective ex vivo expansion of embryonic cells. The term "embryonic cells" refers to tucullen hematopoietic embryonic cells as well as primitive precursors and progenitor cells that can be isolated from bone marrow, spleen or peripheral blood. The term "expansion" refers to the differentiation and proliferation of cells. The present invention provides a method for selective ex-vivo expansion of embryonic cells, comprising the steps of: (a) separation of embryonic cells from other cells, (b) culturing said embryonic cells separated with a selective medium containing multifunctional hematopoietic receptor agonizing protein (s), and (c) harvesting said embryonic cells. Embryonic cells, as well as compromised progenitor cells destined to become neutrophils, erythrocytes, platelets, etc. can be distinguished from most other cells by the presence or absence of particular progenitor marker antigens. such as CD34, which are present on the surface of these cells and / or by morphological characteristics. The phenotype for a highly enriched human embryonic cell fraction is reported as CD34 +, Thy-1 _: and it should be understood that the present invention is not limited to the expansion of this embryonic cell population. The CD34 + enriched human embryonic cell fraction can be separated by a number of reported methods, including affinity columns or beads, magnetic beads, or flow cytometry using antibodies directed to surface antigens such as CD34 +, in addition to physical separation methods such as counter-flow elutrimentation can be used to enrich hematopoietic progenitors. The CD34 * progenitors are heterogeneous and can be divided into several subpopulations characterized by the presence or absence of co-expression of molecules associated with the cell surface associated with the different lineage. Most immature progenitor cells do not express any known lineage associated markers, such as HLA-DR or CD38, but they can express CD90 (lhy-1). Other surface antigens such as CD33, CO38, CD41, CD71, HLA-DR or kit-c can also be employed to selectively isolate hematopoietic progenitors. The separated cells can be incubated in selected medium in a culture flask, sterile bag or hollow fibers.

Various colony-stimulating factors can be employed to selectively expand cells. Representative factors that have been used for ex vivo bone marrow expansion include kit-c g, IL-3, G-CSF, GM-CSF, IL-1, IL-6, IL-11, flt- 3 or their combinations. The proliferation of embryonic cells can be monitored by enumerating the number of embryonic cells and other cells, by standard techniques (for example hemacymeter, CFU, LTCIC) or by flow cytometry before and after incubation.

Several processes for ex vivo embryonic cell expansion have been reported using a number of selection and expansion methods employing various colony stimulating factors including ligand kit c (Brandt et al., Blood 83: 1507-1514 [1994] , McKenna et al., Blood 86. 3413-3420 [1995]). IL-3 (Brandt et al., Blood 83. 15071514, Sato et al., Blood 82: 3600-3609 [1993]), G-CSF (Sato et al., 25 Blood 82: 3600-3609 [1993], GM-CSF (Sato et al., Blood 2. 3600-3609 [1993]), IL-6 (Sato et al., Blood 82: 3600-3609 [19931, IL-11 (Lemoli et al., Exp. Hem. 21: 1668-1672 [1993], Sato et al., Blood 82: 3600-3609 [1993], ligand flt-3 (McKenna et al., Blood 86: 3413 3420 [1995]) and / or their combinations (Brandt et al., Blood 83: 1507 1514 [1994], Haylock and 30 others, B / oODSO 1405-1412 [1992], Koller et al., Biotechnology 11: 358363 [1993], (Lemoli et al., Exp, Hem. 21: 1668-1672 [1993] _ , Mackenna et al., Blood 81: 3463-3420 [1995], Muench et al., Blood 81, 3483-3473 [1993], Patehen et al., Btedwapy 7: 13-26 [1994], Sato et al., Eteoo '

82: 3600-3609 [1993) ,. Smith to others, [19931. Exp. Hem 21 870-877 [1993], Steen et al. Stem Ce // s 12 214-224 [1994], Tsuiino et al., Exp. Hem.21: 1379-1386 [1993]). Among the individual colony stimulating factors5, NL-3 has been shown to be the most potent in expanding peripheral blood 0034+ cells (Sedo et al., Blood 82: 3600-3609 [1993], Kobayashi et al., Blood 73: 1836 -1841 [1989]). However, no single factor has been shown to be so effective as a combination of multiple factors. The present invention provides methods for ex vivo expansion using multiple multifunctional hematopoietic receptors that are more effective than a single factor alone.

Another aspect of the invention provides methods for sustaining and / or expanding hematopoietic precursor cells that include coination of cells in a culture vessel containing a culture medium that has been conditioned by exposure to a stromal cell line such as HS5 (WO 96/02662. Roeoklem and Torok-Strob, 8 / ood 85: 997-1105, 1995) which was supplemented with a multifunctional hematopathic receptor agonist of the present invention.

Another projected clinical use of growth factors has been the in vitro activation of hematopoietic progenitors and embryonic cells for gene therapy. Due to the long lifespan of hematopoietic progenitor cells and the distribution of their daughter cells throughout the body, hematopoietic progenitor cells are good candidates for transfection of an ex vivo gene. To have the gene of interest incorporated into the genome of the hematopoietic parent or embryonic cell, it is necessary to stimulate cell division and DNA replication. Hematopoietic embryonic cells cycle at a very low frequency, which means that growth factors can be useful to promote gene transduction and thus increase the clinical perspective for gene therapy. Potential applications of gene therapy (Crystal journal, Science 270 404-410 [1095]) include, 1) the treatment of many similar metabolic disorders and immunodeficiencies (Kay and Woo, Trends Genef. 10 253-257 [1994]), 2 ) neurological disorders (Friedmann, Trends Genet. 10: 210-214 (1994]), 3) cancer (Culver and Blaese, Trends Genet 10: 174-178 [1994]) e4) infectious diseases (Gilboa and Smith, Trends Genet. 10: 139-144 [1994]).

There are a variety of methods, known to those skilled in the art, for introducing genetic material into a host cell. A number of vectors, both viral and non-viral, have been developed to transfer therapeutic genes into primary cells. Virus-based vectors include; 1) replication of deficient recombinant retrovirus (Boris-Lawrie and Temin, Cun '. Opin. Genet Dev. 3- 102-109 [1993], Boris-Laurie and Temin, Anars from Acadern / a de Crénc / as de / Vova torque 716: 5971 [1994], Miller, Current Top. Microbiol. Immunol 158 1-24 (1992]) and recombinant adenovirus © difficult to replicate (Berkner, BioTechniques 6: 616-629 [1988], Berkner, Current. Top Immunol Microbiol 158 15: 39-66 [1922], Brody and Crystal, Proceedings of the Academy of Sciences of

New torque 716: 90-103 [1994]). Non-virus-based vectors include protein / DNA complexes (Cristiano et al., PNAS USA 90: 2122-2126 [1993], Curiel et al., PNA.S USA 88; 8850-8854 [1991]., Curiel, Anais da New Torque Academy of Sciences 716: 36-58 20 [1994]), electroporation and delivery mediated by liposomes such as Abatonic liposomes (Farhood and other Annals of the New York Academy of Sciences 716; 23-35 [1994]).

The present invention provides an enhancement to existing methods for expanding hematopoietic cells, into which new genetic material has been introduced, in that it provides methods using multifunctional hematopoietic receptor agonistic proteins that have enhanced biological activity including an activity not seen by any factor. colony stimulation.

Many drugs can cause bone marrow suppression or hematopoietic deficiencies. Examples of such drugs are AZT, DDI, alkylating agents and antimetabolites used in chemotherapy, antibiotics such as chloramphenicol, penicillin, ganciclovir, daunomycin and dro gas cam sulfa, phenothiazones, tranquilizers such as meprobamate, analgesics such as aminopyrine and dipyrone anti-depressants. such as phenitolna or carbamazepine, antithyroids such as propylthiouracil and methimazole and diuretios. The multifunctional hematopolytic receptor agonists of the present invention may be useful in preventing or treating bone marrow suppression or hematopoietic deficiencies that frequently occur in patients treated with these drugs.

Hematopoietic deficiencies can also occur as a result of viral, microbial or parasitic infections and as a result of treatment for kidney disease or kidney failure, for example, dialysis. The multifunctional hematopoietic receptor agonists of the present invention may be useful in the treatment of such hematopoietic deficiencies.

The treatment of hematopoietic deficiency may include the application of a pharmaceutical composition containing multifunctional hematopoietic receptor agonists to a patient. The multifunctional hematopoietic receptor agonists of the present invention can also be useful for the activation and amplification of hematopoietic precursor cells by treating these cells in vitro with the multifunctional he20 matopoietic receptor agonist proteins of the present invention before injecting the cells into a patient.

Various immunodeficiencies, for example in T and / or B lymphocytes, or immunodeficiency disorders. for example, rheumatoid arthritis, can also be beneficially affected by treatment with the multifunctional hemato25 receptor topical agonists of the present invention. Immunodificièncías can be the result of viral infections, for example HTLVI, HTLVI1, HTLVIU, severe radiation exposure, cancer therapy or the result of other medical treatment. The multifunctional hematopoietic agonist receptors of the present invention can also be used alone or in combination with other colony-stimulating factors, in the treatment of other blood cell deficiencies, including thrombocytopenia (platelet deficiency), or anemia. Other uses for these new polypeptides are in vivo and ex vivo treatment of patients recovering from bone marrow transplants, and in the development of monoclonal and polyclonal antibodies generated by standard methods for diagnosis or therapeutic use

Other aspects of the present invention are therapeutic methods and compositions for treating the conditions referred to above. Such compositions comprise a therapeutically more effective amount of one or more of the multifunctional hematopoietic receptor agonists in a mixture with a pharmaceutically acceptable carrier. This composition can be administered either parenterally, intravenously or subcutaneously. When administered, the therapeutic composition for use in this invention is preferably in the form of a parenterally acceptable aqueous pyrogen-free solution. The preparation of a parenterally acceptable protein solution, with due attention to pH, isotonic acid15, stability and the like, is within the practice and skill of the art.

The dosage regimen involved in a method for treating the conditions described above will be determined by the attending clinician considering the various factors that modify the action of drugs, for example, the condition, body weight, sex and diet of the patient, the severity of any infection, application time and other clinical factors. Generally, a daily regimen can be in the range of 0.2 -150 pg / kg of multifunctional hematopoietic receptor agonist protein per kilogram of body weight. Dosages would be adjusted for the activity of a given multifunctional hematopoietic receptor protein and it would be unreasonable to note that the dosage regimen may include doses as low as 0.1 micrograms and as high as 1 milligram per kilogram of body weight per day. In addition, there may be specific circumstances where dosages of multifunctional hematopoietic receptor agonist would be adjusted upwards 30 or below the range of 0.2 - 150 microgranules per kilogram of body weight. These include co-application with other colony-stimulating factors or IL-3 variants or growth factors; the co-application of chemotherapeutic drugs and / or radiation: the use of glycosylated multifunctional hematopoietic receptor agonist protein: and several notifications regarding patients mentioned earlier in this section. As indicated above, the therapeutic method and compositions may also include co-application with other human factors. A non-exclusive list of other appropriate colony-stimulating factors (CSFs), cytokines, limfoquins, haematopoietic growth factors and Interleukins for simultaneous or serial co-application with the polypeptides of the present invention includes GM-CSF, G-CSF, c- mpl (also known as TPO or 10 MGDF), M-CSF, entropoietin (EPO), IL-1. IL-4, IL-2, IL-3, IL-5, IL-6,

IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13. IL-15, IL-16, LIF, flt3 / flk2 ligand ₍ B cell growth factor, B cell differentiation factor, and eosinophil differentiation factor, embryonic cell factor (SCF) also known as steel factor or kit binder 15, or combinations thereof. The dosage prescribed above would be adjusted to compensate for such additional components in the therapeutic composition. The progress of the treated patient could be monitored by periodic assessment of the hematological profile, for example differential cell count and the like,

23 Materials and Methods

Unless otherwise noted, all chemicals were obtained from Sigma Co. (St Louis, MO). Restriction endonucleases and T4 DNA ligase were obtained from New England Biolabs (Beverly, MA) or Boehringer Mannheim (Indianapolis, IN).

Transformation of E. coll strains

Strains And call such DH5a eating ^r (Life Technologies, Gaisthersburg, MO) and TG1 (Amersham Corp., Arlington Heights, IL) are used for transformation of ligation reactions and are the source of plasmid DNA for transfecting mammalian cells. E. coll strains such as 30 JM101 (Yanisch-Perron et al., Gene, 33: 103-119, 1985) and MON 105 (Obukowicz et al., Appt And Envir. Mier., 58: 1511-1523, 199.2) can be used to express the multifunctional hematopathic receptor agonists of the present invention in the cdoplasma or in the periplasmic space.

MON105 ATCC # 55204: F-. lambda-, IhlÇrrnD, rrE) 1, rpoDt-, rpoH358

DH5o ' ^$ : F-, phi80dlacZdeítaM15, delta (lacZ ¥ A-argF) U169, deoR, recA1, endA1, hsdR17 (rk-, mk-fo, phoA, supE44lambda-, ihi-1 ₍ gyr96, relA1

TG1: delta (lac-pro), supE, thi-1, hsdD5 / F '(traD36, proA + lac-b. LacZdeltaMT5)

JM101 ATCC & 33876: delta (prolac), supE, thi, F ^ aD36 ' ₍ by A-H3 * fecíq, ZacZdeltaMIõ)

DH5a '^l> subdoning efficiency cells are acquired as competent cells and are ready for transformation using the manufacturer's protocol, while both strains E, colí TG1 and MON1Q5 15 are made competent to take DNA using a CaCI ₂ method.

Typically, .20 to 50 ml of cells are growing in the LB medium (1% bacto-tripeptone, 0.5% bacto-yeast extract, 150 mM NaCI) at a density of approximately 1.0 optical density unit at 600 nanometers (OD600) as measured by a Spectronic 20 spectrophotometer from Bausch & Lomb (Rochester, N York). The cells are collected by centrifugation and resuspended in a culture volume of one-fifth of CaCb solution (50 mM CaCh. 10 mM tris-CI, pH 7.4) and maintained at 4 ° C for 30 minutes. The cells are collected again by centrifugation and resuspended in a culture volume of one-tenth solution of 25 CaCú bound DNA is added to 0.2 ml of these cells, and the samples are kept at 4 ° C for 30-60 minutes. The samples are taken to 42 * C for two minutes and 1.0 ml of LB is added before stirring the samples at 37 ^S C for one hour. Cells from these samples are spread on plates (L8 medium plus 1.5% bacto-agar) containing either ampicillin (100 micro30 grams / ml, µg / ml) when selecting ampicillin resistant transformants, or spectinomycin (75 µg / ml) when selecting re55 • 20 transformers resistant to spectinomycin. The plates are incubated overnight at 37 C.

Colonies are selected and inoculated with the appropriate antibiotic LB plus (100 µg / ml ampicillin or 75 µg / ml spectinomycin) and bloom at 37 ° C while agitated.

Methods for creating genes with the N-terminus / C-terminus nevus

Method t Creation of genes with N / C termination that contain a binding region (L?).

Genes with new N / C terminus that contain a link region ( ₁₂ ) separating the original C-terminus and N-terminus can be made essentially by following the method described in LS Mullins, and others J. Am. Chem Soc 116, 5529-5533, 1994). Multiple steps of chain reaction amplification (PCR) polymerase are employed to rearrange the DNA sequence encoding the protein's amino acid sequence. The steps are illustrated in figure 2.

In the first step, the first primer set ("new start" and "start link) is used to ennose and amplify, from the original gene sequence, the DNA fragment (start fragment") that contains the sequence encoding the new N-terminus portion of the new protein followed by the ligand (l ₂ ) that connects the C-terminus and N-terminus of the original protein. In the second step, the second primer set (“new end and“ stop link ”) is used to create and amplify, from the original gene sequence, the DNA fragment (“ Stop the fragment ”) that encodes the same ligand that used above, followed by the C terminus portion of the new protein. The "new start" and "new end" primers are designed to include the appropriate restriction sites that allow cloning of the new gene into expression plasmids. Typical PCR conditions are a melting cycle at 95 ^to C for two minutes; 25 cycles of denaturation at 94C for one minute, nesting for one minute and extension to 72 * 0 for one minute; another extension cycle at 72 ° C for seven minutes. A Core Perkin Elmer GeneAmp PCR reagent kit is employed. A 100 µl reaction contains 100 pmoles of each primer and one µg of DNA matrix; to 1 x PCR buffer, 200 µM dGTP, 200 µM dATP, 200 µM dTTP, 200 µM dCTP, 2.5 units of AmpliTag DNA polymerase and 2 mM MgC12. The PCR reactions are performed on a model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT).

'Start of fragment and end of fragment that have complementary sequence in the binding region and the coding sequence for the two amino acids on both sides of the linker, are joined in a third PCR step to make the full-length gene encode the new protein. The DNA fragments start fragment and stop fragment are resolved on TAE 134 gel, stained with ethidium bromide and isolated using a Qiaex gel extraction kit (Qiagen). These fragments are combined in equal amounts, heated to 70 ”C for ten minutes and slowly cooled to allow progress through their sequence divided at the beginning of the linker and end of the linker. In the third PCR step, new beginning and new end primers are added to the annotated fragments to create and amplify the total length of the new N terminus and C terminus gene. Typical conditions are a melting cycle at 95 ”C for two minutes; 2.5 cycles of denaturation at 94 C for one minute, 60 ^ft C annealing for one minute and 72 ° C extension for one minute; plus a cycle of 72oC for seven minutes. A Core Perkin Elmer GeneArnp PCR reagent kit is used. A 100 µl reaction contains 100 pmoles of each primer and approximately 0.5 µg of DNA; and 1 x PCR buffer, 200 µM dGTP, 200 µM dATP, 200 µM dTTP, 200 µM dCTP, 2.5 units of AmpliTaq DNA polymerase and 2 mM MgCi2. PCR reactions are purified using a Wizard PCR preparation kit (Promega),

Ü method. Creation of genes with new N / C terminus without a binding region.

New N-termination / C-termination genes without a linker joining the original N-termination and the C-termination can be made using two stages of PCR amplification and an inactivated end ligation. The steps are illustrated in figure 3. In the first step, the primer set (“new start” and start of Pb?) Is used to create and amplify, from the original gene sequence, the DNA fragment (start of fragmentation ¹ ' ) which contains the sequence encoding the new N-terminus portion of the new protein. In the second step, the pnmer (new start "and end of P-bl) 5 set is used to create and amplify, from the genetic sequence, the fragment of

DNA (Stop fragment) containing the sequence encoding the new C-terminated portion of the new protein. The "new start" and "new end" primers are designed to include appropriate restriction sites that allow the new gene to be cloned into the expression vectors. Typical PCR conditions 10 are a fusion cycle at 95 ° C for 2 minutes; 25 cycles of denaturation a

94 ^Ô C for one minute, annealing at 50 C for 45 seconds and extension at 72 ° C for 45 seconds. Deep Vent Polymerase (New England Siolabs) is used to reduce the occurrence of protrusions under the conditions recommended by the manufacturer. The primers "P-bl start and P-bl stop" 15 each are phosphorylated at the 5 ^one another to aid in subsequent binding end inactivated fragment of starting and stopping fragment. A 100 µl reaction contained 150 µg of each primer and one µg of DNA matrix; and 1 x Vent buffer (New England Biolabs), 300 µM dGTP, 300 µM dATP, 300 µMDTTP, 300 µM dCTP, and a 20 Deep Vent polymerase unit. PCR reactions are performed on a 480 modeio DNA thermal scraper (Perkin Elmer Corporation, Norwalk, CT).

PCR reaction products are purified using a PCR Wizard preparation kit (Promega),

Primers are designed to include appropriate restriction sites that allow cloning of the new gene into expression vectors.

Typically ’’ start of the fragment is designed to create Ncol restriction sites, and stop of the fragment is designed to create a Hindlll restriction site. Restriction digestion reactions are purified using a magic DNA cleaning system kit (Promega). Start and stop fragments are dissolved in a 1% TAE gel, stained with ethidium bromide and isolated using a Qiaex gel extraction kit (Qiagen). These fragments are combined with the ends and longed for a fragment of vetoing 3800 basic Ncol / Hindlll pairs of p MON 3934 by heating at 50 ° C for ten minutes and allowing to cool slowly. The three fragments are livers employing T4 DNA ligase (Boehringer Mannheim). The result is a plasmid containing the full length gene with new N-terminus and C-terminus. A portion of the ligation reaction is used to transform DH5a cells (Life Technologies, Gaithersburg. MD) from E. coli sepas. Plasmid DNA is purified and the sequence is confirmed as below.

Method III. Creation of new genes with N / C termination by tandem duplication method.

New genes with termination N / termination C can be prepared based on the desonto method in R. A. Horlick and others Protein Eng. 5.427431, 1992). The amplification of the polymerase chain reaction (PCR) of the new genes with N / C terminus is performed using a DNA matrix duplicated two by two. The steps are illustrated in figure 3.

The duplicated tandem DNA matrix is created by cloning and contains two copies of the gene separated by DNA sequence encoding a primer connecting the original C-terminus and N-terminus of the two copies of the gene. Specific primer sets are used to create and amplify a gene with N / C terminus in the duplicated tandem DNA matrix. These primers are designed to include appropriate restriction rings that allow cloning of the new gene into expression vectors. Typical PCR conditions are melting at 95 ° C in one cycle for two minutes; 25 cycles of denaturation at 94 ^Q C for one minute, annealing at 50 ° C for one minute and 72% extension for one minute; a further 72 * 0 cycle at 72 ° C for seven minutes. A Core Perkin Elmer GenAnp PCR reagent kit (Perkin Elmer Corporation, Norwalk, CT) is used. A 100 µl reaction contains 100 pmoles of each primer and one µg of DNA matrix; and a 1x PCR buffer, 200 µM dGTP, 200 µM dATTP, 200 µM dTTP, 200 µM dCTP, 2.5 µm AmpliTaq DNA polymerase and 2 µM MgCL PCR reactions are performed in a model DNA thermal citizen

480 (Perkin Elmer Corporation, Norwalk, CT). PCR reactions are purified using a Wizard PCR preparation kit (Promega).

Cloning of new genes with N / C terminus in multifunctional receptor agonist expression vectors

The new gene ending N / ending Ç is grouped with restriction endonucleases to create ends that are compatible with insertion into an expression vector containing another gene with colony stimulating factor. This expression vector is also grouped with restriction endonucleases to form compatible ends. After purification, the gene and vector DNAs are combined and linked using

DNA-T4 ligase. A portion of the ligation reaction is used to transform plasmid E. coli UNA is purified and sequenced to confirm correct insertion. The reel clones are grown for protein expression.

DNA isolation and characterization

Plasmid DNO can be isolated by a number of different methods and using commercially available kits known to those skilled in the art. Some such methods are shown here, plasmid DNA is isolated using the Promega Wizard 20 mini-preparation kit (Madison, Wl), Qiagen QJAwell Plasmid isolation kits (Chatsworth, CA) in a Qiagen plasmid kit. These kits follow the same general procedure for isolating plasmid DNO. Briefly, cells are pelletized by centrifugation (5000 xg), plasmid DNA is detached with sequential treatment of NaOH / acid, and the cell fragment is removed by centrifugation (10,000 xg). The supernatant (containing the plasmid DNA) is loaded in a column containing a glossy DNA resin, the column is washed, and plasmid DNA diluted with TE. After monitoring the colonies with the plasmid of interest, E. falling cells are inoculated in 50-100 ml of appropriate antibiotic LB 30 plus for overnight growth at 37 ° C in an agitated air incubator. The purified plasmid DNA is used for DNA sequencing, in addition to restriction enzyme digestion, additionally subclone of DNA fragments. and transfection in mammalian cells, E co / f and other cells.

Sequence confirmation

Purified piasmid DNA is resuspended in dH ₃ O and quantified by measuring the absorbance at 260/280 nm in a Spectromc 601 UV spectrometer from Bausch and Lomb. ONA samples are sequenced using ABI PRISM * 'DyeDeoxy * chemical sequencing terminator kits (Applied Biosystems Division of Perkin Elmer Corporation, Lincoln City, CA) (Part number 401388 or 402078) according to protocol 10 suggested by commonly modified manufacturers. by adding 5% DMSO to the sequencing mix. Sequencing reactions are performed on a model 480 DNA thermal cycler (Perkin Elmer Corporation, Norwalk, CT) following the recommended amplification conditions. Samples are purified to remove excess dye 15 terminators with Centri-Sep * 'spin columns (Princeton Separations, Adeíphia. NJ) and lyophilized. Sequencing reactions labeled with fluorescent dye are resuspended in deionized formamides, and sequenced in denatured 8M 4.75% polyreacrylamide urea gels using an ABI model 373A automated DNA sequencer. Overlapping DNA sequence fragments are analyzed and grouped into master DNA contigs using DNA Sequenoher v2.1 analysis software (Genes Codes Corporation, Ann Arbor, Mt).

Expression of multifunctional receptor agonists in mammalian cells

Mammalian cell transfection / production of conditioned media

The BHK-21 cell line can be obtained from ATCFC (Rockville, MD). The cells are cultured in Dubelcco's modified Eagle medium (DMEM / high glucose), supplemented with 2 mM (mM) of L-gutamine 30 and 10% fetal bovine serum (FBS). This formula is called BHK growth medium. Selective media are BHK growth medium supplemented with 453 units / ml of hygramycin B (Calbiochem, San Diego, CA). The BHK-21 cell line was previously transfected stably with the HSV VP16 transactivation protein. which transacted the IE110 promoter observed in plasmid p MON3359 (see Híppenmeyer et al., Bia / Technology, pp. 1037-1041, 1993). The VP16 protein causes the expression of genes inserted behind the IE110 promoter. BHK-21 cells expressing the VP16 transacting protein are designated BHK-VP16. Plasmid p M0N1118 (See Highkin et al., Poufáy Sei, 70: 970-981, 1991) expresses the hygromyin resistance gene of the SV40 promoter. A similar plasmid is available from ATCC, pSV2-hph.

BHK-VP16 cells are seeded in a 60 millimeter (mm) culture tissue dish into 3 x 10 ^s cells per dish 24 hours before transfection. Cells are transferred for 16 hours in 3 ml of ΌΡΤΙΜΕΜ '* (Gibco-BRL, Gaithersburg, MD) containing 10 µg of plasmid DMA containing the genes of interest, 3 µg of hygromycin resistant plasmid, p M0N1118, and 80 µg of Gibco-BRL TIPOFECTAMINE '' * per dish. The medium is subsequently aspirated and replaced with 3 ml of growth medium. 48 hours after transfection, medium is collected from each dish and tested for activity (conditioned transient medium). The cells are removed from the dish by EDTA tryppsin, diluted 1:10 and transferred to 100 µl tissue culture dishes containing 10 ml of selective medium. Resistant cells grow to form colonies many millimeters in diameter, after approximately 7 days in selective medium. The colonies are removed from the filter dish (cut to approximately the same size as the colonies and soaked in trypsin / EDTA) and transferred to individual wells of 24 well plates containing 1 ml of selective medium. After the clones grow until confluence, the conditioned medium is retested, and positive clones are expanded into a growth medium.

Expression of multifunctional receptor agonists in E. co //

Strains Strain E. MON105 or JMiO1 harboring the plasmid interest are grown at 37 C in M9 medium plus casamino acid with stirring on an air incubator Model G25 from New Brunswick Scientific (Edison, New Jersey) .. The growth is monitored OD600 until it reaches a value of 1 _: 0. time in which nautical acid (10 milligrams / ml) in 0.1 N NaOH is added to a final concentration of 50 pg / ml. The cultures are then shaken at 37 ⁵ C for an additional three or four hours, a high.

degree of aeration is maintained throughout the culture period to achieve maximum production of the desired gene product. The cells are examined under a light microscope for the presence of inclusion bodies (IB). An aliquot in ml of the culture is removed for analysis of the protein content by boiling pelletized cells, treating them with reduced buffer 10 and electrophoresis. via SDS-PaGE (see Maniatis et al., Mo / ecu / ar C / on / ng, A laboratory Manual, 1982). The culture is centrifuged (5000 x g) to pellet the cells

Preparation of çofpcsdejnci ^^^^ lysis, DEAE chromatography, and jjps characterization. multifunctional he15 agonists receptors that accumulate as inclusion bodies in E aoii

Isolation of inclusion bodies.

The cell pellet of a 330 ml E. coli culture is resuspended in 15 ml of a buffered solution with sonic hydrochloride (tris20 HCI) of (W mM 2-amino-2- (hydroxymethyl) -1,3-propanediol , pH 8.0 + 1 mM ethylenediaminetetraacetic acid (EDTA) These resuspended cells are exposed to sonic irradiations using the sonic irradiating Cell Separator microtype sample (model W - 375, Heat Systems-Ultrasonis, Inc., Farmingdale, New York.) Three stages of sonic irradiation in 25 sonic buffer followed by centrifugation are used to separate the cells and wash the inclusion bodies (IB) .The first sonic irradiation step is a 3 minute break followed by 1 minute of disruption, and the final two stages of sonic irradiation are 1 minute each.

Extraction and refolding of proteins from inclusion body pellets

X03

Following the final centrifugation step, the IB pellet is resuspended in 10 ml of 50 mM tris-HCI, pH 9.5, 8 M urea and 5 mM dithiothreitol (DTT) and stir at room temperature for approximately 45 minutes to allow denaturation of the expressed protein,

The extraction solution is transferred to a beaker containing 70 ml of 5 mM Tris-HCI, pH 9.5 and 2.3 M urea and is gently agitated while exposed to air at 4 ° C for 18 to 48 hours. allow proteins to fold, folding is monitored by analysis on a high pressure liquid (RP-HPLC) chromatographic column (RP-HPLC) with 10 C18 Vysdac reverse phase (Hesperl, Ca). A linear gradient from 40% to 65% acetonitrile, containing 0.1% trifluoroacetic acid (TFA). is used to monitor the fold. This gradient is developed for 30 minutes at a flow rate of 1.5 ml per minute. Denatured proteins generally dilute later in the gradient than folded proteins.

Purification.·

Following folding, contaminated E.coli proteins are removed by acid precipitation. The pH of the folded solution is titrated between pH 5.0 and pH 5.2 using 15% (v / v) acetic acid (HOAc). This solution is stirred at 4 ^rt C for 2 hours and then centrifuged for 20 minutes at 12,000 xg 20 to pellet any insoluble protein.

The supernatant from the acid precipitation step is dialed using a Spectra / Por 3 membrane with a molecular weight (MWCO) of 3,500 daltons. Dialysis is against two 4-liter changes (a 50-fold excess) of 10 mM Tris-HCI, pH 8.0 for a total of 18 hours.

Dialysis decreases the conductivity of the sample and removes urea before OEAE chromatography. The sample is then centrifuged (20 minutes at 12,000 x g) in pellets of any insoluble protein following dialysis.

A bio-rad Bio-scala OEAE2 column (7 x 52 mm) is used for ion exchange chromatography. The column is equilibrated in a 30 buffer solution containing 10 mM Tris-HCI., PH 8.0, and a 0 to 500 mM sodium chloride gradient (NaCI), in equilibrium buffer, and above 45 column volumes are used to dilute the protein

A flow rate of 1.0 ml per minute is employed through the process. Column fractions (2.0 ml per fraction) are collected through a gradient and analyzed by RP HPLC in a Vydec ooluna (hesperia, Ca.) Cl 8 ( 0.46 x 25 cm). A linear gradient of 40% to 65 '% of acetonitrile is used, containing 0.1% of trifluoroacetic acid (TFA). This gradient is developed for 30 minutes at a flow rate of 1.5 ml per minute. Accumulated fractions are then dialyzed with 2 changes of 4 liters (excess 50 to 500 times) of 10 mM ammonium acetate (NH4Ac), pH 4.0 for a total of 18 ivy. Dialysis is performed using a Spectra / Por 3 membrane with a molecular weight (MWCO) of 3500 daltons. Finally, the sample is sterile filtered using a 0.22 µm syringe filter (pSíar LB syringe filter, Costar, Cambridge, Ma.), And stored at 4 ° C.

In some cases, multiplied proteins can be purified by affinity using affinity reagents such as mAbs or receptor subunits linked to an appropriate matrix. Alternatively, (or in addition) the purification can be performed using any of a variety of chromatography methods such as: ion exchange. gel filtration or hydrophobic chromatography or reverse phase HPLC.

These and other protein purification methods are described in detail in Methods in Enzymology, Volume 182, Guide to Protein Purification edited by Murray Deutscher, Academic Press., San Diego, CA (1990).

Protein Characterization:

The purified protein is analyzed by RP-HPLC, mass spectroscopy per electroborrifo, and SDS-PAGE. Protein quantification is done by amino acid composition, RP-HPLC, and determine from Bradford protein. In some cases, tryptic peptide mapping is performed together with electrobornfo mass spectroscopy to confirm the identity of the protein.

AML Proliferation Assay for Human Interleukin-3 hjoatxm The factor-dependent AML 193 cell line was obtained from the American Type Culture Collection (ATCC. Rockville, MD). This established cell line from a patient with acute myelogenous leukemia, is a growth factor-dependent cell line 5 that showed high growth in the medium added with GM-CSF (Lange, B _.: et al., 8 / ood 70: 192, 1987; Valtíeri, M., et al., J Zmmuno (138: 4042, 1987). The ability of AML 193 cells to proliferate in the presence of human IL-3 has also been documented. (Santob, D., et al., J. / mmunof. 139: 348, 1987) A cell line variant 10 was used, AML 193 1.3 later by supplementary tissue culture medium (see below) with human IL-3 .

AML 193 1.3 cells are washed 6 times in Hanks cold balanced saline (HBSS. Gibco, Grand Island, New York) by centrifuging cell suspensions at 250 xg for 10 minutes followed by 15 decanting of the supernatant. Pellet cells are resuspended in HBSS and the procedure is repeated until six wash cycles are completed. Cells washed six times by this procedure are resuspended in tissue culture medium at a density ranging from 2 x 10 ⁵ to 5 x 10 ^δ viable cells / ml. This medium is prepared by supplementing 20 Dulbecco medium modified by Iscove (IMDM, Hazelton, Lenexa, KS) with albumins, transferrin, lipids, and 2-mercaptoethanol. Bovine albumins (BoehringerMannheim, Indianapolis. IN) is added in 500 pgfmí; human transferin (Boehringer-Mannheim, Indianapolis, IN) is added at 100 µg / ml, soybean hpidio (Boehnnger-Mannheim, Indianapolis, IN) is added at 50 µg / ml; 25 and 2-mercaptoet.anol (Sigma, S. Louis, MO) is added at 5 x 10 ' ⁵ M.

Serial dilutions of human inierleukin-3 or multifunctional hematopoietic receptor agonist proteins are made in triplicate sequences in supplemented tissue culture medium as mentioned above on 95 tissue culture plates in 3596 Costar cavity, Each 30 containing 50 µg of medium containing inferleukin-3 eu multifunctional hematopoietic receptor agonist proteins since the serial dilutions are complete. Control wells only contained tissue culture medium (negative control) AML 193 1.3 cell suspensions prepared as above are added to each well by pipetting 50 pg (2.5 x 10 ⁴ cells) into each well. Tissue culture plates are incubated at 37 ° C with 5% CO ₂ in humidified air for 3 days.

On day 3, 0.5 pCi of Ή-thymidine (2 Ci / mM, New England Nuclear, Boston, MA) was added in 50 μ! of tissue culture medium. Cultures are incubated at 37 ° C with 5% CO ₂ in humidified air for 18-24 hours. Cellular DNA is collected on glass filter pads (Pharmacia LKB, Gaithersburg, MD) using a TOMTEC cell collecting machine (TOMTE.C, Orange, CT) that used a water wash cycle followed by a water wash cycle. 70% ethanol. Filter pads are allowed to dry in dry air and then are placed in sample bags to which scintillation fluid is added (Scintiverse II, Fisher Scientific. St. Louis. MO or BetaPlate Scintillation Fluid, Pharmacia LKB, Gaithersburg, MD ). Beta emissions from samples of individual tissue culture wells are counted in a LKB BetaPlate scintillation counter model 1205 (Pharmacia LKB, Gaitherburg, MD) and data are expressed as counts per minute of Ή-thiamidine incorporated into cells in each well for tissue culture. Activity of each human interleukin 3 preparation or multifunctional hematopoietic receptor agonist protein preparation is quantified by measuring cell proliferation (Ή-thiamidine incorporation) induced by graduated concentrations of interleukin-3 or multifunctional hematopoietic receptor agonist. Typically, concentration ranges ranging from 0.05 pM - 10 ⁵ pM are quantified in these assays. Activity is determined by measuring the dose of interleukin 3 or multifunctional hematopoietic receptor agonist protein that provides 50% of maximum proliferation (ECkj ™ 0.5 x (maximum mean count per minute of Ή thymidine incorporated per well between triplicate cultures of all concentrations) of interleukin 3 tested base proliferation measured by incorporation of 'H thymidine observed in triplicate cultures without interleukin 3).

This EC _S o value is also equivalent to 1 bioactivity unit.

Each assay is run with interleukin-3 as a reference standard so that levels of relative activity could be assigned.

Typically, multifunctional hematopoietic receptor agonist proteins were tested in a concentration range of 2000 pM to 0.06 pM titrated in serial folded dilutions.

Activity for each sample was determined by the concentration that produced 50% of the maximum response by adjusting a four-parameter logistic model for the data. It was observed that the upper plateau (maximum response) for the sample and the standard with which it was compared did not differ. Therefore, the calculation of the relative power for each sample was determined from EC5G estimates for the sample and the standard as indicated above. AML 193.1.3 cells proliferated in response to hlL3, hGM-CSF and bG-CSF. Therefore, the following additional assays were performed for some samples to demonstrate that the G-CSF receptor agonist portion of the multifunctional hematopoietic receptor agonist proteins was active. The proliferation assay was performed with the multifunctional hematopoietic receptor agonists neutralizing more and less monoclonal antibodies to the hlL-3 receptor agonists portion. In addition, a fusion molecule with the factor Xa dividing site was cleaved then purified and the halves of the molecule were tested for proliferative activity. These experiments showed that both components of the multifunctional hematopoietic receptor agonist proteins were active.

TF1 c-mpl ligand-dependent proliferation assay

The proliferative activity of c-mpl ligand can be tested using a subclone of the pluripotential human cell line TF1 (Kitamura et al., J, Cell Physio! 140.323-334. (1989)). TF1 cells are maintained in an h-IL3 (100 U / ml). To establish a subclone sensitive to the c-mpl ligand, cells are maintained in passage medium containing 10% supernatant from BHK cells transfected with the gane expressing the 1-153 form of Hgante c-mpl (p M0N26448). Most cells die, but a subset of the cells survive. After dilution of the cloning, a clone sensitive to c ~ mpi ligand is selected, and these cells are disrupted in passing medium to a density of 0.3 x 10 cells / ml the day before the assay was organized. Means of passage for these cells is as follows'. RPM! 1640 (Gibco), 10% PBS (Harlan, Lot # 91206), 10% BHK transfected cell c-mpl supernatant. 1 mM sodium pyruvate (Gibco), 2. mM glutamine (Gibco), and 100 µg / ml penicuine-streptomycin (Gibco). The following day, cells are harvested and washed twice in RPMI or IMMDM medium with a final wash in ATL medium or assay medium. ATL medium consists of the following: IMDM (Gibco), 500 µg / ml bovine serum, 100 ug / ml of human transferrins, 50 ug / ml of soybean peptides, 4 x 10-8M beta-mercaptoeanol and 2 ml of A9909 (Sigma, antibiotic solution) per 1000 ml of ATL. Cells are diluted in assay medium to a final density of 0.25 x 10 “cells / ml in a 96 well low evaporation dish (Costar) at a final volume of 50 ul, Transient supernatants (conditioned media) of clones transfected samples are added to a volume of 50 µl as duplicate samples at a final concentration of 50% and diluted three times to a final dilution of 1.8%. Triplicate samples of a curved dose of p1313288 variant IL-3 starting at 1 ng / ml and diluted using triple dilutions to 0.0014ng / ml are included as a positive control. Plates are incubated at 5% and 37% CO _S. On the sixth day of culture, the plate is pulsed with 0.5 Ci of 3H / well (NEN) in a volume of 20 µl / well and allowed to incubate at 5% CO ₂ and 37 ° C for four hours. The plate is harvested and counted in a Betaplate changer.

Other cell-based proliferation assays in vitro

Other in vitro cell-based assays, known to those skilled in the art, may also be useful in determining the activity of multifunctional hematopoietic receptor agonists depending on the factors that comprise the molecule in a similar manner as described in the AML 193.1.3 proliferation assay. cell phone. The following are examples of other useful tests.

TF1 proliferation assay: TF1 is a pluripotential human cell line (Kitamura et al., J Cell Physiol 140: 323-334. ([1989]) that 5 responds to hLL-3;

32D Proliferation Assay: 32D is a murine IL-3 dependent cell line that does not respond to human IL-3 but responds to human G-CSF that is not restricted to species.

Baf / 3 proliferation assay: Baf / 3 is a murine IL-3 tooth dependent cell line that does not respond to human IL-3 or human c-mpl but responds to human G-CSF that is not restricted to species.

T1165 proliferation assay: T1165 cells are an IL-6 dependent murine cell line. (Nordan et al., 1986) which responds to IL-6 and IL-11.

Coagulated plasma human meg-CSF assay: Used to test megakaryocyte colony forming activity (Mazur et al., 1981)

Transfected cell lines;

Cell lines such as the murine 8af / 3 cell line can be transfected with a colony stimulating factor receptor, such as the human G-CSF receptor or the human plasmid receptor, which the cell line does not have. These transfected cell lines can be used to determine the activity of the ligand for which the recipient has been transfected into the cell line

Such a transfected Baf / 3 cell line was made by cDNA cloning encoding c-mpl from a library made of a sensitive cell line and cloned at the multiple cloning site of the pcDNA3 plasmid (Invitrogen, San Díego, Ca.}. Baf / cells 3 were transfected with the plasmid via electroporation The cells were created under G418 selection in the presence of IL-3 rat in mere conditioned Wehi Clones were established by limited dilution.

In a similar way, the human g-CSF receptor can be transfected into a Baf / 3 cell line and used to determine the bioactivity of multifunctional hemapoietic receptor agonists.

Analysis of proliferattva hgante c-mpl activity

Methods

1. Bone marrow proliferation test

The. Purification of CD34 + cell:

Bone marrow aspirates (15-20 ml) were obtained from normal allogeneic bone marrow donors after informed consent. Cells were diluted 1: 3 in phosphate buffered saline (PBS, Gibco-BRL.), 30 ml layered on 15 ml Hístopaque-1077 (Sigma) and centrifuged for 30 minutes at 300 RCF. The mononuclear interface layer was collected and washed in PBS. CD34 + cells were enriched from the preparation of mononuclear cells using an affinity column given according to the manufacturer's instructions (CelIPro, Inc. Brothel! WA). After enrichment, the purity of CD34 + cells was 70% on average as determined using flow cytometric analysis using monoclonal antibody antiCD34 conjugated to fluorescine and antiCD38 conjugated to phyentin (Becton Dickinson, San Jose CA).

Cells were resuspended in 40,000 cells / ml in 10 ex-vivo media (8io-Whittaker, Walkersville. MD) and 1 ml was applied to 12 wells with tissue culture plates (Costar), Growth factor rhlL-3 was added to 100 ng / ml, (p MON5873) was added to some wells. HlL3 variants were used at 10 ng / ml up to 100 ng / ml. Conducted media from BHK cells transfected with plasmid encoding Hgante c-mpl or multifunctional hematopoietic receptor agonists were tested by adding 100 μΙ of supernatant added to 1 ml of cultures (approximately a 10% dilution). Cells were incubated at 37 ° C for 8-14 days in 5% CO ₂ in a 37X humidified incubator.

B. Cell harvest and analysis:

At the end of the culture period, a total cell count was obtained for each condition. For fluorescent analysis and to determine ploidy.

cells were washed in megakaryocyte buffer (MK buffer solution, 13.6 mM sodium citrate, 1 mM theophylline, 2.2 pm PGE1, 11 mM glucose, 3% in pesofvol, BSA in PBS, pH 7.4) (Tomer and others, Blood 70. 17351742, 1987) resuspended in 500 μΙ of buffer buffer MK containing anti5 anti-CD41a anti-FITC body (1: 200, AMAC, Westbrook, ME) and washed in buffer MK. For DNA analysis cells were permeabilized in MK buffer solution containing 0.5% Tween 20 (Fisher, Fair Lawn NJ) for 20 minutes on ice followed by fixation in 0.5% Tween-20 and 1% paraformaldehyde (Fisher Chemical) for 30 minutes followed by incubation in 10 propidium iodide (Calbiochem. La Jolía Ca) (50 pg / ml) with RNA-ase (400 U / ml) in 55% v / v MK buffer solution (200 mOsm) for 1 -2 hours on ice. Cells were analyzed on an F AC Scan or Vantage flow cytometer (Becton Dickinson, San Jose, CA). Green fluorescence (CD41a-FITC) was collected along with linear and log signals for red fluorescence (PI) to determine ploidy DNA. All cells were collected to determine the percentage of cells that were CD41 +, Data analysis was performed using LYSIS software (Becton Dickinson, San Jose, CA). The percentage of cells expressing the CD41 antigen was obtained from flow cytometry analysis (Percentage). The absolute number 20 (Abs) of cells / CD41 + ml was calculated by (Abs) - (Cell count) * (percentage) / 100.

2. Megakaryocyte fibrin coagulation test

Population enriched in CD34 * fos isolated as described above. Cells were suspended in 25,000 cells / ml with or without cytocl · 25 na (s) in a medium consisting of Iscoves IMDM base medium supplemented with 0.3% BSA, 0.4 mg / ml apo-transferrin. 6 _? 67 μΜ FeCla, 25 pg / ml CaCh, 25pg / ml L-asparagine, 500 pg / ml εamino-n-capranoic acid and penicillin / streptomycin. Prior to application on 35 mm plates, thrombin was added (0.25 unit / ml) to initiate clotting formation. Cells were incubated at 37 C ^and for 13 days at 5% CO ^ in a humidified mcubador at 37 C.

At the end of the culture period, plates were fixed with methanol: acetone (1: 3). air dried, and stored at -200 ° C until stained. A peroxidase staining procedure by immunocyclochemistry (Zymed, Histostaín-SP. San Francisco. CA) was used using a cocktail of primary monoclonal antibodies consisting of antiCÜ41a, CD42 and CD61. Colonies were counted after spotting and classified as negative, CFU-MK (small colonies, with 1-2 foci and smaller than approx. 25 cells), BFU-MK (large colonies, multi-foci with> 25 cells) or colonies mixed (mixture of both positive and negative cells).

Ensaio..de.Metiloeiulpse

This assay reflects the ability of colony-stimulating factors to stimulate normal bone marrow cells to produce different types of hematopoietic colonies in vitro (Bradley et al., Aust Exp. Biol Scí 44: 287-300, 1966), Pluznik et al. J. Cell Comp. Physio 66: 319-324,1965).

Methods

Approximately 30 ml of healthy, fresh, normal bone marrow aspirates are obtained from individuals after their informed consent. Under sterile conditions samples are diluted 1: 5 with 1X PBS solution (# 14040.059 Life Technologies, Gaithersburg, MD) in a 50 ml conical tube (# 25339-50 Corning, Cornig MD). Ficoll (Hístopaque 1077 Sigma H-8889) is layered under the diluted sample and centrifuged, 300 x g for 30 minutes. The mononuclear cell strip is removed and washed twice in 1 x PBS and once with 1% BSA PBS (CelíPro Co., Bothel, WA). Mononucleat cells are counted and CD34 · * · cells are selected using the Ceprate LC column kit (CD 34) (CellPro Co., Bothel, WA). This fractionation is performed since all the embryonic and progenitor cells inside the bone marrow show the GD34 surface antigen.

Cultures are established three to three with a final volume of 1.0 ml in a 35 x 10 mm petri dish (Nunc # 174926). Culture medium is purchased from Terry Fox Labs, (HCC-4230 medium) (Terry Fox Labs, Vancouver.

B. C., Canada) and erythropoietin (Amgen, Thousand Oaks, CA.) is added to the culture medium, 3,000-10,000 CD34 + cells are added per dish.

Racambinating IL-3 purified from mammalian cells or E. co / i, and multifunctional hematopoietic receptor agonist proteins, in conditioned medium of transfected mammalian cells or purified from conditioned medium of transfected mammalian cells or E. cati, are added to produce final concentrations ranging from 0.001 nM to 10 nM. HIL-3 reoombinant ligand, GM-CSF, c ~ mpl and multifunctional hematopoietic receptor agonist are provided in the home. G-CSF (Neupogen) is from Amgen 10 (Thousand Oaks Calf.). Cultures are resuspended using a 3 cc syringe and 1.0 ml is distributed per dish. Control cultures (basic reference response) did not receive any colony stimulating factors. Positive control cultures received conditioned media (human cells stimulated by PHA): Terry fox Labs. H24Q0). Culture output of incuba15 at 37 ° C, 5% CO in humidified air _S. Hematopoietic colonies that are defined as being greater than 50 cells are counted on the day of the peak response (days 10-11) using a Nikon inverted phase microscope with a 40x objective combination. Groups of cells containing less than 50 cells are referred to here as clusters (clusters). 20 Alternatively colonies can be identified by spreading the colonies on a slide and stained or they can be separated, resuspended and pulled back on cytospine slides to stain.

Hemopoietic Factor Assays of Human Umbilical Cord Blood,

Bone marrow cells are traditionally used for in vitro hemaiopotetic colony stimulating factor (CSF) assays. However, bone marrow is not always available, and there is considerable variety among donors. Umbilical cord is comparable to bone marrow as a source of hematopoietic embryonic cells and progeny ·· 30 ras (Broxmeyer et al., PA / AS USA 89: 4 109-113, 1992; Mayani et al., B / ood 81> 3252- 3258, 1993). In contrast to bone marrow, cord blood is more readily available on a regular basis. There are therefore

a potential to reduce the variability of the assay by cells from freshly obtained wells from various donors, or to create a bank of cells preserved for this purpose. By modifying the culture conditions, and / or analyzing specific strain markers, it is possible to test 5 specifically granulocyte / macrophage colonies (CFU-GMj, for megakaryocytic activity, or for supper activity (HPP-CFC) forming a colony with a potential proliferating potential. Methods • 10 16 Mononuclear cells (MNC) are isolated from umbilical cord within 24 hours of collection, employing a standard density gradient (1,077 g / ml Histopaque). Umbilical cord MNCs were further enriched by embryonic and progenitor cells by several procedures, including immunomagnetic selection for CD14, CD34 + cells; fraction batch S8A-, GD34 + using coated flasks from Applied immuno Science (Santa Clara, CA); and CD34 + selection using a CellPro avidin column (Boihell · WA) Fractions enriched with CD34 + cell enriched either recently isolated or cryopreserved, are used for the assay. Duplicate cultures for each serial sample dilution (1 pM to 1204 pM concentration range) are prepared with 1x1204 cells φ ²⁰ in 1 ml of 0.9% methylcellulose containing medium without additional growth factors (Methocuít H4230 from Stem Cell Technologies, Vancouver. BC.) In some experiments, Methocuít H4330 containing erythropoietin (EPO) was used instead of Methocuít H4230, or embryonic cell factor (SCF), 50 ng (Biosource International · Camarillo, CA) was added. 25 culture for 7-9 days, colonies containing> 30 cells are counted. To exclude subjective biases in the assessments, the trials are blindly assessed. Additional details about recombinant DMA methods, which can be used to create the variants, express them in bacteria. 30 mammalian cells, or insect cells, purification and refolding of the desired proteins and assays for detecting protein bioactivity can be found in co-archived applications WO 95/00646, WO

94/12639, WO 94/12638, WO 95/20976, WO 95/21197, WO 95/2097? .. WO 95/21254 and US 08/383 035 which are incorporated herein entirely by reference.

Other details known to those skilled in the art can be found in T. Maníatis. and others, Molecular Cloning., A Laboratory Manual. Cold Spring Harbor Laboratory. 1982) and references cited herein, incorporated herein as reference: and in J. Sambrook et al., Molecular Cloning. The Laboratory Manual, second edition, Cold Spring Harbor Laboratory, 1989) and references cited therein, incorporated herein by reference.

Table 1

Oliqonuc leofc ids, WWIWW »MiWlWWWW * WM *! ¹¹ ί? I ¹ »<wwAwwwwwwwrt * AA ^ wft * · * ·» c-ft ^ lNcaZ

ÃCGTC I ATGG 0? TXCN0CNGG? 4CCN’C0TGCTTGTGC AC ^ CGA <SEC XD NO: 13?

zA. > \ j ILO Ί

atgcacgaattzcctgacgcagagggtgga tSEO XD NO: 14)

ο -Πφΐ HcndXX X TGACAAGCZTACOTGACGCAGAGGGTGGACCC (SEC ID NO: 15;

SL-3 '

81 ~ q ’

SL-3 '

- 5 '

5 - ^c '

3 ’

39-3 '

43-3 '

43-3 '

45-5 '

45-3 ^r

9-5 'f - 3 ’

AATTOGGCAA ÍSEQ ZD NO: 16)

CAOGTTGCCG (SEQ ZD NO; 17)

AATTCGGCGGCÀA (EEQ ZO NO: 18)

CATGTTGCCGCCG (SEQ XO NO; 19)

AATTCGGCGGCAACGGCGGCAA (SEQ XD NO; 2Q) CATGTTGCCGCCGTTGCCGCCG ISEQ XD NO: 21) CGATCCATGGAGGTTCACCCTTTGCOT (SEQ I3> NO: 22 ^ GATCAÃGCTTATGGGCACTGGCTCAGTCT IS ^ n Tx CGATACATGTTGCCTACACCTGTCCTG (SEQ XD NO-24) GATOAÀGOTAAGGGTGAACCTCTGGGCA (EEQ XO NO: 25, CGATCCATGGTCCTGCTGCCTGCTGTG (5E0 ID NO : 25) GA * u, ^ AGCTTAAGGTGTAGGCAAAGGGTG (SEQ NO »7) CGATCCATGGCTGTGGACTTTAGCTTGGGA (SEQ ID NO: 28)

GA- ^ AAGCTTAAoGCAGCAGGACAGGTGT (SEQ ID NO '29) u ^ AT ^^ ATGGACTTIAGCTrGGGAGAA (SEQ XD NO: 3 0) gat -> ^ agcztacacagcaggcagcaggac (SEQ ZD NO * 3 ^) CwATCA ATG GATCAÀGOTACAAGCIAAAOTCCACAGC (SEQ ID NO; 33)

GATCAAGCTTACTTGTGAGCTGTGGTCCT (EEQ

CGATCCATGGCCATCTTCOTGAGCTTCCAA (SEQ ID NO: 44}

ΟΑΤΟΑΑΟΟΤΤΑΆΤΤΟΟΟΑΤΟΟ ^ '^ Ο'Τ'ΓϊΆΟ ^^;' '^ ·

ISEQ XD ND; 45)

L3syn, tor

13gyn.rev

AATTCCGTCG TAAACTGACC GAACGCGCAG GCTCAACAGT TOC iSEQ ZD NO: 46}

COGGGGAGCC TCCACCGCCC CGCGTTCTCG AAGGTTTT ^ a CGG (SEQ ZD NO ^ 47}

GTTACCCTTG AGCAAGCGCA

CTÀACTGCTC XATAATGAT

CGATCATTAT AGAGCAGTTA

CTGCGOTTGC TCAAGG (SE (

GOTACCCTTG ÀGCAAGCGCA CTGGCGGTGG OAGCQGCGGC GAT {SEQ t _D kojSQ)

CGATCATTAT AGAGCAGTTA

GCCAGAGCCA CCAOCCTG ⁴ ^

ÍSEQ XD NO: 51) ttctatctga AAADCTTGGA

TCTACGTACT GTTGAGCCXG

GATAGAAGGT CAGTTTACGA

GGAACAACAG GGTGGTGGCT (SEQ ZD NO: 48)

GAGCCACCAO OCTGTTG'T ' ^{, T} ' ^Z ~? ZD NO: 4 $)

GGAÃCAACAG GGTGGTGGCT GGTTCTAACT GCTCTATAAT

GAACCGCCGC CGCTGCCACr

GTTCCTGCGC TTGCTCAAGG

: í * «

Table2

Genes of Seqdências gciaactgctctataatgaccgatgaaattatacatcacttaaagagac ^ a-A'-c-ttgctggacccgaacaacctcaatgacgaagàcgcctctatcctgatggaccga CGACTTCCAAACCTGGAGAGGTTCGTAAGGGCTGTCAAGAACTTAGAAÀA ^ ^ L ^ ^ A ^ Ar ^^ ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCAC '**' ^ ^ Aj Cua. C ^ AATCAí CA * CAAGulAGGTGAC TGGCÀAGAATTCCGGGAÀAAACTGA ^rr G ^mw, r TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACÀGTACGTAGAGGGCGGTGGAGGC ^ C ~ CCGGGTGAACCATGATTG '

PMOK26458

Xx2SÍ2 ^? S ^AC S ^TGCW ^ ^{GACCTCCGACTCCTCagtaãac} ^ ^sct ^ CGTGACTCCCAT

- a '~ ^'', ALiCAGACTGAGCCÀGTGCCCAGAGGTTCACC ^r, mT''i ^, GP (2 ^, T ^> A ^íW ' Aí ^ C ' ^T ''' * T '' * ' ^, r ** r'i''^ S ^ 2 ^ “ ^SG3 ^« = ^ = ™ TGGM _S AG ^ a ^ XX ^^^ ^A '''èH ^CTG ^ ^GAGU ^ ^{GTGACCCTTCTGCTS} ^ ^A ^ ^G « ^A GTGATGGCAGCACGGGGACAA J ^ í2í ^^ ^A S ^ ^G ^? R ^CATCCCTCOTí ^ ^ ⁱ ^ ^CTT ^ CTGGACAGGTCCGTCTCCTC - - ^ '^ --'- TGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGAC ACAGtor; 25u £ Y (i-IT2I i ^{ATCTTC ::} - ^ ATGCTTGTAGGAGGGTeCACCCTCTGCOTCAGGGAATTC ^sagcttccaac acctgctccgaggaaaggtgcS TTCCT (SEQ NO 1 · 79 ^{^!}

PMOK28548; CCCCAGCTCCACCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGAC CT ^ Cr ^ ^ ^ ^ TTCAQAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTT gcm ^ A ^ A ^ ^^ r ^ rr * S: SS2 ^ ^A ^ ^^^ ^AGOTG AAAACCCAGAÍGGÍGGÍÈ2êAÂ55rí ™ "^ ™ X2 ^{GCCTCT TCCCTC} ^^ ^» ^ 5CTTTCTS3ACAGGT'-TCGC CeC ^: 'CTTGGGGCCCTGCAGAGCCTCOTSGAACCCAGCTTCCTCCA ^ AGcíriAíírAl - »^

CÍ ~~ Sí ^{x TGTAGGAGGGTCCACCCTCt} ^ G ^, ^ C3GGAATTCGGCGGCAACATGG ^ * ^: 'g? ^ ASg' ™ Í— ^; ^. ^^ ^A ^ X ^? ^^ ^A ^^^ ^{CCCAGAGaTTCACCCTTTGCC} ^ ^A CÃCCTGTCCTGTCCTG

A ^ 4. ^ S ^C ^^ ^A ^ ^C ^ ' ^aG ^ ^{AGAATGGAAàACCCAGA, r} ^ ^s ^ ^A GGAGACCAAGG ^ A ^ ^ - i ^ S? S ^ ÉS ^{TCCC? CCTG} ^ ^CMC ' ^: í ^, ^ t ^ GACAGGTCCGTCTCCTC ^^ 3 ^ x ^ x ^ ^{x T} IX ^'Aí3Aw "^" ^I "* ^r ^ ^{GGAAÍ C' i ASÍ3} 3CAGGACCACAGCrCACÀAGGAT ^r ^ ^^ AATGCCATCTTCCTGAGC SCAN""c rww # 'r'" _mx * ^vs - ^AA '“ ^A '” '“* ^í » CTCv.GAü _f GAAAGGTGCGTTTCCTGATG ⁱ * ^ r ü * A «« À ^ GTC> -ACCCTCTGCGTCAGG 15EQ m NO-80'

PMON28500 ^ iS ^!: = SS5SJ ^{COTSOT0TSACCT} SASrcCTCAGTAAACTGC _{RTC-CTG-ACT-TAA} C ^ ^ CCAGAGGTTCACCCTTTGCCr'A ^^^^^^^^^^^^^ IXX 'GTrrTr The ^^^ ⁱ ^ "' - ^^ CTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA pM 'TGTGí

8ι

ΓΛ ''

NO: 8 agtaaaV 'uu AçxAtTGG AGG AG AQ'PA An 1 J.GTGACCC ”'TCTGC'TGGX> n ^ r'a ₁ ^m ' ^f ' ^ * λλ ^^ · ~ λ ^ ΑΤΧ, ΧΧΧΧΧ A GAT ^ GCAGGACGGGGas.

. _λα ^ k-x v.GTGGGGCAGCTTTCTGGACAGGTCCGTr uu "T'r '^ X ^ X ^ CCTTGGAACCCAGCTrCCTCCACAGGGCAGSÍGaA; ^^ .ATuTTCCTGAGCTTCGAACACCTGCTCCGAGGAAAGG · ^"^' * SGGTCCACCTOTGGGTCAGGGAATTCGGCGGCAA-the-- ^tgtgacct stcctcagtaaactgctcgt ^^ ^ i- ^ XX ^ i; ^AGAOTGAGC ^ ^G ^ ^S; “^ ^CAGAS ^ TCACCCrTTGCr * a'ACA ^ '* r ^' ^: '' ^:: ' ⁱ T' - CTGTGGA ^ TJ'TACr ^ r '^ ra ^^ XXX —a G * uuTu ^ggaaaaccca ^ tggaggagaccaaggga ^: pATp4P? rP ™ í ™ I ± ^íí “ ^G5CASCACGSGG ACA ?. aa uUííkACCCAGCTTCC ^ CnA ^ AC ^^^ a λ «**>s>-»> X.XT „Z '^ - ^ - ~ A ^ A ^^ Aw« ACCACAQeT>

r ^^ Q ^^. ^ - ^ iZXXX ^ XZ ^ Z ^ Xx ^^ - ^ CTCCGAGGAAAGGTGCG ^ * vA. _y .i iGaa «^^^ TuCACCCTOTGCGTCAGG íSEQ τη -hrn, g;

X ~ rx: XX: ^ ^CCTCC ^^ - ^ AGTAAACTGOTTCGTGAC ^ r ^ .- a ^ -> ^ I ™ X ^ 2I2J2 ^{CAGAGGTTCACCCTTTG} XCTACACCTG ^ o ^:: tg «« «AuTTI AuuTTGl» GAGAATGGAAAACCCAGGGGGGGGGG ^ Trmí ^^ zS '^^' ^ ^ TTGOrTr'i'r'a'nr · '-''^*' * '' ^^^ *. ^, ^ U.isGGGACAA: TTGGGGCCCTGCAGAGCC ^ e * FTGr a ^ XLZZ ^ ZZZXXT ^ _u 'OCGTCTCCTG ^ _n? Hu _A TC <.CAATGCCATCTTCCTGAGC ^ r A * ~ a ^G <- »AC ^ Au Av ^ T'tcctgatgcttgtaggaggg-t'ccacc ^^ m ^ - T ^^ S ^ ^AGGAAAGGTG iACA ^ GCGTm ^^^ m ^^^^ - r-mX ^ XZXZ ^u ' ^vw7 ' “ ^Awwwt AATTCGGCGGCAACGGr'GG ^« \ as_xs A '-''-'- «OuViUuGCCTGCTTGTGSre ^ rrr' Irmn ^ mn X Λ. ~ • 'W s 4. <~ L \? Ãka «CC ^ CAG ^ AAAC ^'T'rJ ^ 'T * ^^» ** »^» ^{, Ai} - a uu ^ aI ^ TwCTTCACAGCAGACTGAGrrar ^ rr' ^ ' - '», __- iaa

LAG *. GCv ^ ALxAtxyG ^, T ^w PCÃC * CC ' ^í T ^> ^ ^w T ^> P ^ ⁱ ** ^< ^' 7 r * * .CCAAGGCACAGGACA ^ T ^ r 'AX C

XXXC * ^L ~ ^ SAGCAGTGAuCCTT ^ TG ^ Tor XAXX uuuuACAAC'TGGaACCCACTTGCCTCT ^ AT '' ^ ^? 'T ^^ Tr' - ~ 'rríííS ^ ^T ^ ^AT ^''' ^, ^ ^AGCÂ GTCTGCTrr '** T »r: nn ^ r'r' ^ r. ₁ - ------ ΣΧΧΧ. „^ ^Ν * ™ ^ '' ^ΛΚϊ ^ ^ι - ^Αί3 9 ^ ΤΤΟΤθθΑ · ΟΑ3ηΤΓ

AOCACAGCTCACAAGGATCCCAATGCCATCT '^ ^GT3CamcCT SATGCTTGTAGGAGGGT _i isEQ ED NO: 83)

TGCGTCAGG

CATGGCTAAC TGGTCTATAA GACCA.22TCC ACCTTTGCTG

TCTATZGTGA TGGACGGAAA AAGGGCTGTC AAGAACTTAG GTAATCTCGA ACCATGTCTG * ^{Λ Λ} ~ "* aaggcagg GTGCTATCTG GTTACCCTTG GTAACTGCTC CATAATGATC CCTGCACZTT TGCTGGACCC CCTGATGGAC CGAAACCTTC ZTGTCAAGAA CTTAGAAAAT TCCAAGCAT GTCTGCCCTC CATCATCAAG GCAGGTGACT A7CTGSTTAC CCTTGAGCAA ID: Ο _^: · ϊ: 84 f

-U ^ -ZGATGA ATACAI GACCZGAACA ACCTCAATG. ~ CDTTCGAGTT CGAAAICTGI ÀAAATGGATC AGGTATTGAG CCCTGTGCCA GGGCGGCAZ2 TGAGTGGCAA GAATTCCGGGG

AGCAAGGGCA GATGAAATTA GAACAACCTC GACTTCCAAA GGATCAGGTA TGCCACGGCC G'G C AAG AATC GCGCAGGAAC aA GAA G AG TAGATZACGT AATGACGAAG CCTGGAGAGI TTGAGGCAAT GCACCZTCTC GGA

aggtztzzag

GACATCCAAT

CTGAGGTTGT

SynzarJ .iii

201

3G1

£ 401 c n

501 ill

651 lii

C A.T GG GT AAG

GAGCAGGTGC

TZTATCCTGA AAGGGCTGTC GTAATGTCCA CCAATCATCÀ GTTCTATCTG gtggcggtgg ATTATACAGG OCTZAATGAC

GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT

TGGACCGAAA aagaacttag ACCATGTCTG TCAAGGCAGG

GTTACCCTTG

CAGCGGCGGC ACTTAAAGAG gaagacgtct gaggttcgta CAATTCTTCG tctcgagatc AÀAACTGACG AC (SEQ ID

TGATCGATGA GACCCGAACA CCTTCGACTT AÀAATGCATC CCCTCTGCCA TGACTGGCAA AGCAAGCGCA GGTTCTAACT accacctgga CTATCCTGAT AGGGCTGTCA TAATCTCCAÀ ciaatcatcat TTCTATCTGG NQ; 85;

AATTATACAT CACTTAAAG * ACCTCAATGA CGAAGACGTG CGAAACCTGG AGAGCTTCGT AGGTATTGA.G GCAATTCTTC '-GGCGGCAOC ctctcgacat GAATTCCGGG AAAAACTGAC GGAACAACAG GGTGGGGGCT gctctataat gatcgatgaa CCTTTGCTGG AGCCGAACAA ggaccgaaac cgtcgacttc agaacttaga aaatgcatca CCATGTCTGC CCTCTGCCAC CAAGGCAGGT GAGTGGCAAG L-N- lXTTGA gcaagggcag

PBOA-3U.03

101

151

201

251

3GI

411

451

ATGGCTCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA ATAÀTGATCG GTACGTAGAG CTACTATCAÀ ATGGCTACCC

ACCC GAACAA CTTCGACTTC aaatgcatca gctctgccac gactggcaag gcaagcgcag atgaaattat GGCGGTGGAG CCCGTCTCCT AGGGTGCCAT

CCTCAATGAC

CAAAC CTGG A

GGTATTGAGG GGCCGCACCC AATTCCGGGX GAACAACAGG

ACATCACTTA GOTCCCCGGG

CCGTCTAAAG

GCCGGCCTTC

GAAGA0GTG7 GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG GTGGTGGCTC AAGAGACQAC TGAACCGTCT AATCTCATAA GCCTCTGC '' ^T ''' ^Y '

CTATCCTGAT agggctgtca TAATCTCCAA CAATCATCAT TTGTATCTGG TAACTGCTCT CTGCACCTTT ggtccaatct ATCTCCAAAC TCCAGCGCCG

GT Site ^: - ^: ^ .TGGTT · ^ CTAaGClATCT GC AGAGC * '''”' CTGG ^ GG ^ Cm

5SI CGTACCGCG7 TCTACGCCAC CTTGCGCAGO 'CCTOTGGCGG CTCTGGCGGC - l - · * ·' ~~ ~ λ «γΑ«? ~ Τ TwCTLvTwftíi G a uGTTAGAG CAAGTGAGAA AGATCCA3GG

551 CGATGGCGCA GCGCTOCAGG AGAAGCTGCG TGGCaAGGTA '' 'AAG ^ L' ^ L ' "701 ACCCCGAGGA GCTGGTGCTG CTCGGACACT CTCTGGGCAT CGCGTG ^' '* 751' CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CAGGTGGCAG C <TG ™ GAG 802 CCAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG methyl-I J ^ As. sGá.sA, TAT1→GAGTTG GGTCCCAGCT TGGACAOACT GCA3CTGGA ~ 901 GTCGCCGACT TTGCCACCAC GATCTGGOAG CAGATGGAÀG AACTGGGAAC 951 GGCCCCTGCC CTGCAGCCCT AATAA -ISSOG ○?

ATGGCTAATG CATCAGGTAT

TCTGOCCTCT GCCACGGCCG

1.01 CAGGTGACTG GCAAGAATTC

151 CTTGAGCAAG CGCAGGAACA

0'1 GATCGATGAA ATTATACATC

251 AC C CGAAC AA C CTCAATGAC

301 CTTCGACTTC CAAACCTGGA

152 ATACGTAGAG G3CGGTGGAG

401 CTACTATCAA CCCGTCTCCT

451 aATGGCTACCC AGGGTGCCAT

501 GGCAGGAGGG GTCCTGGTTG

551 CGTACCGCGT TCTACGCCAC

601 TCTCAGAGCT TCCTGCTCAA € 51 CGATGGCGCA GCGCTCCAGG

702 ACCCCGAGGA GCTGGTGCTG

751 SAMSTGAGCT CCTGCCCCAG

SC1 CCAACTCCAT AGCGGCCTTT

852 AAGGGATATC ACPCGAGTTG

901 GTCGCCGACT TTGCCACCAC

951 GGCCCCTGCC CTGCAGCCCT

TGAGGCAATT CTTCGTAATC TCCAACCATG CACCCTCTCG ACATCCAATC ATCATCAAGG CGGGAAAÀAC tgacgttcta. tctggttacc ACAGGGTGGT GGCTCTAACT GCCCCATaAAC ACTTAAAGAG ACCACCTGCA CCTTTGCTG ^ GAAGACGTCT CTATCCTGAT GGACCGAAAC GAGCTTCGTA AGGGCTGTCA AGAACTTAGA GCTCCCCGGG TGAACCGTCT GGTCCAATC ^ CCGTGTAAAG AATOTCATAA ATCTCCAAAC GCCGGCCTTC GCCTCTGCTT TCCAGCGCCG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT CTTGCGCAGC CCTCTGGCGG CTCTGGCGGC GTCTTTAGAG CAAGTGAGAA AGATCCAGGG AGAAGCTGTG TGCCACCTAC AAGCTGTGCC CTCGGACACT CTCTGGGCAT CCCCTGGGCT CCAGGCCCTG CAGCTGGCAG GCTGCTTGAG TCCTCTACGA GGGGCTCCTG CAGGCCCTGG GGTCCCACCT TGGACACACT GCAGCTGGAC CATCTGGCAG CAGATGGAAG AACTGGGAAT AATAA ISHO CD NO: 87;

PMON311

101

152

201

251

331

251

02

452

501

551

6C1

651

ATGGCTGCAC AGAATTCCGG AGGAACAACA ATACATCACT CAATGACGAA ACCTGGAGAG ATTGAGGCAA CTACGTAGAG CTACTATCAA ATGGCTAGCC wajcUAGGAGGG CGTACOGCGT TCTCAGAGCT CGATGGCGCA

CCTCTCGACA GàAAAACTGA GGGTGGTGGC TAAAGAGACC GaACGTCTCTA CTTCGTAAGG TTCTTCGTAA GGCGGTGGAG CCCGTCTCCT AGGGTGCCAT GTCCTGGTTG TCTACGCCAC TCCTGCTCAA GCGCTAGG

TCCAATCATC CGTTCTATCT TCTAACTGCT ACCTGCACCT TCCTGATGGA GCTGTCAAGA TCTCCAACCA GCTCCCCGGG CCGTCTAAAG GCCGGCCTTC CTAGCCATCT CTTGCGCAGC GTCTTTAGAG AGAAGCTGTG

ATCAAGGCAG GGTTACCCTT CTATAATGAT TTGCTGGACC CCGAAACCTT ACTTAGAAAA TGTCTGCCCT TGÀACCGTCT AATCTCATAA gcctctgctt GCAGAGCTTC CCTCTGGCGG CAAGTGAGAA TGCCACCTAC

GTGACTGGCA GAGCAAGCGC CGATGAAATT CGAACAACCT CGACTTCCAA TGCATCAGGT CTGCCACGGC GGTCCAATCT ATCTCCAAAC TCCAGCGCCG CTGGAGGTGT CTCTGGCGGC AGATCCAGGG AAGCTGTGCC

'wA. u to AAGTGGGAAT

AATAA (SEQ ID DO: 89)

Ί Ί AC w V 0

ATGGCTCTGG ACCCGAACAA

GGACCGÀAAC CTTCGACTTC 101 AGAÀCTTAGA AAATGGATCA 151 CCATGTCTGC CCTGTGCOAC

- uAAGGCAGGT GACTGGCAAG

251 TTACCCTTGA GCAAGCGCAG 301 AGGGGCGGCG GTTCTAAGTG 351 CTTAAAGAGA CCACCTGCAC 401 CGGGTGAACC GTCTGGTCCA 451 AAAGAATCTC ATAAATCTCC .551 ATCTGCAGAG CTTCCTGGCA 6T CAGCCGGCA 6Cl CAGCC

701 TGTGTGCCAC CTACAAGCTG

CCTCAATGAC GAAGACGTCT CTATC2TGAT CAAACCTGGA GAGCTTCGTA AGGGCTGTCA GGTATTGAGG CAATTCTTCG TAATCTCCAA GGCCGCACCC TCTCGACATC CAATCATCAT AATTCCGGGA AAAACTGACG TTCTATCTGG GAACAACAGG GTGGTGGCTC TGGCGGTGGC CTGTATAATG ATCGATGAAA TTATACATCA CTTTGTACGT AGAGGGCGGT GGAGGCTCCC ATGTCTACTA TCAACCCGTC TCCTCCG ^ T AAACATGGCT ACCCAGGGTG CCATGCCGGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC GTGTCGTACC GCGTTCTACG CCACCTTGCG CGGCTCTCAG AGCTTCCTGC TCAAGTCTT ^ AGGGCGATGG CGCAGCGCTC CAGGAGAAGC TGCCACCCOG AGGAGCTGGT GCTG ^ T ^ GGA GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC TGAGCCAACT CCATAGCGGC CTTTTCCTCT CTGGAAGGGA TATCCCCCGA GTTGGGTCCC 'CGA

GGGTGAACi

ATCTGCAGAG CAGCCCTCTG AGAGCAAGTG

ACCCAGGGT

AGGGGTCCT

AQCTTCCTG ·

K3 »5

CACTGCAGCT GAAGAACTGG »0121110

AAAGAATCTC

ATCTGCAGAG

GTCTQGTCCA

CTTCCTGGAG

GCGGCTCTGG

AGAAAGATCC ft

ACCTTGGACA

AGC AG ATG (SEQ ID ND:

CCTGCAGGCC

CACTGCAGCT

GAAGAACTGG

AGGGCGATGG TGCCACCCCG

TGAGCCAACT CTGGAAGGGA GGACGTCGCC <** X X <* «· <*» | Ι ** / * », *« ♦ X «\

ACCTCAA.TGA CCAAACCTGG AGGTATTGAG / ** / **. ***? * ·· »: <** 7 * C> * f · * A'i.u i

AAACATGGCT

AGGGCGATGG TGCCACCCCG GGCTCCCCTG TGAGCCAACT CTGGAAGGGA GGACGTCGCC GAATGGCCCC

TuAAGT

CCATAGCGGC

GACTTTGC

TGCCCTÇn

GCAGCGGCGG CACTTAAAGA

CGAAGACGTC

AGAGCTTCGT GCAATTCTTC

TCAACCCGTC ACCCAGGGTG AGGGGTCCTG GCGTTCTACG AGCTTCCTGC CGCAGCGCTC AGGAGCTGGT AGCTCCTGCC CCATAGCGGC v «Vj *** £ · * '• x

CTGÀ

GTAATCTCCA f **

CCATGCCGGC GTTGCTAGCC CCACCTTGCG TCAAGTCTTT CAGGAGAAGD GCTGCTCGGA CCAGCCAGGC CTTTTCCTCT GTTGGGTCCC CCACCATCTG CCCTAATAA sc .TC> HQN

GAG wwí «.j, AACI

GCTCTATAAT

L w \ * V <& W «

AGGGCGATG G

CTGGAAGGGA

GGACGTCGCC

CTTCGACTTC

AGAACTTAGA

CCTCTGCCAC GACTGGCAÀG G C -rtAG C G C AG La X Vf λ a La à va <3 GAGCTGGTGC

CCTCAATGAC CAAACCTGGA GGTATTGAGG aacatggct: r ^ rnr ^ rnr ^ W ¹

Vic * V à. V? V? \ 3 \ và

G GAAGGGATA ά VlXffVS X

CÀTCTGC.

ATGGCCCCTG

TGCTTTCCAG

GCTTCCTGGÀ

Vm Va X3 \ J \ S

GGTGTCGTAC

GCGGCTCTCA

ZAGATGGA v * C ACSíjr

CGCGTTCTAC GAGCTTCCTG

GAGAAG 'CGATGAA ATTATACATt

ACTTAAAGAG

TIT

ΌΛΛΛν

CCTCAATGAC

CAAACCTGGA *

.......; 1211 '........

s'TSl .....

402. ·

451

502

Ξ51

602

652

Λ1 / <~ _: 5ts

South

552 • 9C1

2

A! <.. ·: G 2? TGT 7 A

CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC CTGTGCCACC CTGGGCTCCC GCTTGAGCCA GCCCTGGAAG GCTGGACGTC TGGGAATGGC GCCTCTGCTT GC AGAGCTTC CZTGTGGCGA T3 AGAGTGAGA T3

'AGA .GAACTT CCATGTCTGC - ΛΛώ GGA GG 7 TTACCCTTGA TGCCCGGGTG gtctaaagaa CCGAGGAGCT OTGAGCTCCT ACTCCATAGC GGATATCCCC GCCGAGTTTG CCGTGCCCTG TCCAGCGCCG gtggaggtgt CTCTGGCGGC I AGATCCAGGG TAA SEQ CO aaatgcatca cctctgccac "A>" You GU AAGCGC GGC AA AG AACCGTGTGG TCTGATAAAT GGTGCTGCTC gccccagcca GGCCTTTTCC CGAGTTGGGT CCACCACCA7 CAGCCCACCC GGCAGGAGGG ACCGGGT TCTCAGAGOT CGATGGCGCA ^: NO: 95;

ULi „** xT7'GAUv_- ^f ss \ 3 x, u GC AC C i. Λ-'νΤ'Τ GuA GAA'CAACAGT 7CCAATCTCT CTCCÀAACAT ggacactcto GGCCCTGCAG TCTACCAGGG CCCACCTTGG CTGGCAGOAG agggtgccat GTCOTGGTTG TCTACGCCAC TCCTGCTCAA gcgcc

AC AC ACTG CA AT G GAAGAA ~ GCCGGCCTTC CTAGCOATCT x-TTGCGCAG 2 GTCTTTAGAG A <j AAG CT GTG pMGKlAlSá

122

dl

352

401

452 ^: 'β! / 551

601

O51: 101 /

15 '

802

S3 2

901

ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CCGAGTTGGG GCCACCACCA GCÀGCCCACC GGGCAGGAGG TCGTACCGCGGGCGGGGC

GCTCTATAAT

Ggaccgaaac CCTTTGCTGG AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG TCCCACCTTG TCTGGCAGCA X ^ Au sksTGCCA GGTCCTGGTT TTCTACGCCA TTCCTGCTCA AGCGCTCCAG AGCTGGTGCT TCCTGCCCCA TAGCGGCCTT CCTAATAA ^ -is ATCGATGAA ACCCGAACAA CTTCGACTTC ÀAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG GACACACTGC GATGGAAGAA TGCCGGCCTT GCTAGCCATC CCTTGCGCAG AGTCTTTAGA GAGAAGC7GT gctcggacac GCCÀGGCCCT TTCCTCTACC SQ ID NO: 96

ATTATACATC CCTCAATGAC CAAACCTGGA ggtattgagg GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC AGCTGGACGT CTGGGAATGG CGGCTCTGCT TGCAGAGCTT CCCTCTGGCG gcaagtgga TCtgg

ACTTAAAGAG GAAGACGTGT gagcttggta CAATTCTTCG TCTCGACATC AAAACTGACG ÀCGTAGAGGG aacatggctg CGCCGACTTT HotFTGCCCT TTCCAGCGCC CCTGGAGGTG

ÀAGATCCAGG CAAGCTGTGC TC-CCCTGGGC

GGCTGCTTGA GCAGGCCCTG

PMOH13185 r; 101

0 ί.

552.

302

Ί Γ ATGGCTAACT ACCACCTGCA CTATCCTGAT

TAATCTCCAA CAATCATCAT TTCTATCTGG

CGGTGGAGGC

GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG

GA.TCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG gcaagcgcag AACCGTCTGG

ATTATACATC

CCTCAATGAC CAAACCTGGA GGTATTGAGG ggccgcaccc aattccggga gaagaacagt TCCAATCTCT acttaaagag

GAAGACGTCT GAGOTTOGTA

TCTCGACATC aaaactgacg ACGTAGAGGG

ACTA.TCAACC

451

501 gSs ·

TGG

Α € 51

Wi * <j! AvoAAAGA ^:

GTGCTG

GGGCA '

Ml: $ 7 i

CTCCTGGA ·

PMGNX3188

101

2Ò:

251

IQ

4C1, s K · -!

501 δ 01

551

701 * 7 ~ -:

801

851

Atggctaagt ggtctataat 801 * The AC 2ACCTG C2TTTGCTGG ctatcotgat ggaccgaaac AGGGCTGTCA AGAAGTTAGA vAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATGTGG TTACC2TTGA cggtggaggc tccccgggtg TGGCCCGTGC CCTGCAGCCC GCTTTCCAGC GCCGGGCAGG Cp'CCTGGAG GTGTGGTACC GCGGCTCTGG CGGCTCTCAG AGAAAGATCC AGGGCGATGG CTACAAGCTG TGCCACCCCG GCATCCCCTG GGOTC'CCCTG TGAGCOAACT CCTGCAGGCC CTGGAAGGGA CAGTGCAGCT GGAGGTCGCC GAAGAACTGG GATAATAA {$ gatcgatgaa attatacatc ACCGGAACAA CCTCAATGAC CTTCGACTTC CAÀACCTGGA AAATGCATCA GGTATTGAGG COTCTGCCAC GGCCGCACCC ^ S ^ p'SS AAG AATTCCGGGA gcaagcgcag gaacaacagt GTGGTTCTGG CGGCGGCTCC ACCCAGGGTG CCATGCCGGC AGGGGTCCTG GTTGCTAGCC GCGTTCTACG CCACCTTGCG AGCTCQTGC TCAAGTCTTT CGCAGCGCTC CAGGAGAAGC AGGAGCTGGT GCTGCTCGGA agctcctgcc ccagccaggc CCATAGOGGC CTTTTCCTCT TATCCCCCGA GTTGGGTCCC GACTTTGCCA CCACOATOTG £ Q XD ND: 98)

GAAGACGTC7 GAGCTGCGTA CAATTCTTCG TCTCGACATC AAAACTGACG acgtagaggg aacatggcta CTTCGCCTCT ATCTGCAGAG CAGCCGTCTG agagcaagtg TGTGTGCCAC CACTCTCTGG CCTGCAGCTG ACGGGGCT

PM0NIM87

101

305

251

302

35.1 Ί 01

451

502

551 AGGGCTGTCA sQl atggctaact ACCACCTGCA CTATGCTGAT TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC GCTGCCCTGC CCAGCGCCGG * '^^ AGGx'GTC T2TGGCGGCT gctctataat CCTTTGCTGG ggaccgaaac AGAACTTAGA CCATGTGTGC CAAGGCAGGT TTACCCTTGA GCCCCGGGTG GTCTAAAGAA AGCCCA.CCCA GCAGGAGGGG gtaccgcgtt CTCAGAGCTT

GATCGATGAA

ACC2GAACAA

CTTCGACTTC aaatggatca CCTCTGCCAC gactggcaag GCAAGCGCAG AACCGTCTGG TCTCATAAAT GGGTGCCATG TCCTGGTTGC ctacgccacc CCTGCTCAAG attatacatc CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT CCGGCCTTCG TAGCCATCTG TTGCGCAGCC TCTTTAGAGC

ACTT AAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TDTCGACATC AAAACTGACG ACGTAGAGGG actatcaacc ggctatggcc CCTCTGCTTT cagagcgtcc CTCTGGCGGC aagtgagaaa ο

ε ~ „. The GATOCAGGG-GATGGCGCAG CG2THAGGA GAAGCTGTG * '^^^^ GGTA CA 7C <AGGTGTGCGA OOCCGAGGAG CTGGTGCTGO TCGGACAGTG TOTGgÕÕaTO 75.1 CCCTGGGCTC CCCTGAGCTC 801 CTGOOCOAGO CAGGCCOTGO AG2TGGGAGG GTGOTTGAGC CAACT2CATÀ GCGGCGTTTG AGGCCCTGGA AGGGATATCC CGTGTACCAG GGGGTGGTGC 851 CCCGAGTTGG GTCCGACCTT GGACAGAGTG, & 0 "' CAGGTGGACG TCGCCGACTT TGCCACCACC AGCTGGOAGO: AGATGGAAGA £ 5.1 A0TGGGA7AA TAA ÍSEC ID NO: 99) pNONlllSS

ATGGOTAAC? GC7CTATAAT

ÀOOAOCTGCA CCTTTGCTGG CaATuuTGAT GGAGCGAAAC

151 AGGGCTGTCA AGAACTTAGA

221 TAATGTOOAA CCATGTCTGG

251 CAATCATCAT CAAGGCAGGT 3Cl TTCTATCTGG TTACCCTTGA

352 CGGTGGAGGO TGCCCGGGTG

122 CCCAGGGTG1 CATGCCGGCC

452 GGGGTCOTGG TTGCTAGCCA

301 CGTTCTACGC CACCTTGCGO

3 2 GCTTCCTGCT CÀAGTCTTTA

602 GCAGCGCTCC AGGAGAAGCT

551 GGAGCTGGTG CTGCTCGGAC

701 GCTOGTGCGC CAGCCAGGCC 31 OATAGCGGCC TTTTCCTCTA »02 ATIXCCCGAG TTGGGTC02A

851 ACTTTGCCAO CACCATOTGG

901 GCOCTGCAGC CCTAATAA (5

GATCGATGAA ATTATACATC AOTTAAAGAG ACCCGAAGAA OCTCAATGAC GAÀGACGTOT CTTCGACTTC CAAACOTGGA GAGCTTGGTA AAATGCATCA GGTATTGAGG CAATTCTTCG CCTCTGCCAC GGCGGCACCO TCTCGACATC GACTGGCAAG AATTCCGGGA AAAACTGACG GCAAGCGCAG GAACAACAGT AGGTAGAGGG GTGGTTCTGG CGGCGGCTGC AACATGGCTA TTOGCCTCTG CTTTCCAGCG CCGGGCAGGA TCTGOAGAGC TTCCTGGAGG TGTCGTACCG AGCCCTCTGG CGGCTCTGGC GGCTCTCAGA GAGCAAGTGA GAAAGATCCA GGGCGATGGO GTGTGCCACC TACAAGCTGT GCCACCCCGA ACTCTCTGGG GATCCCCTGG GCTCCCCTGA CTGCAGCTGG CAGGCTGCTT GAGCCãACTC CCAGGGGCTC CTGCAGGCCG TGGAAGGGA.T CGTTGGACAC ACTGGAGCTG GACGTCGCCG CAGCAG.ATGG AAGAÀCTGGG AATGGGCCCT SQ ID NO: 100}

PMON13Í89

ATGGCTAACT GCTCTATAAT

ACCACCTGCA CCTTTGCTGG 101 AGGGCTGTCA AGAACTTAGA OTATCCTGAT GGACCGAAAG 151 201 25.1 TAATCTGOAA CCATGTCTGC CAATCATCAT CAAGGCAGGT 301 TTCTATCTGG TTACCOTTGA TCGCCGGGTG 352 CGGTGGAGGC 401 CGTCTCCTCC GTCTAAAGAA 452 GGTGCCATGC CGGCCTTCGC 502 CCTGGTTGCT AGCCATCTGC 551 CTGCTCAAGT CTTTAGAGCA TACGCCAOCT TGCGCAGCCC 601 651 701 TGGTGCTGCT CGGACACTCT GCTCOAGGAG AAGCTGTGTG 751 CGGCCTTTTC CTCTACCAGG 801 TGCCCCAGCO AGGCCCTGCA 852 CCGAGTTGGG TCCCACCTTG

GATCGATGAÀ ATTATACATC ACTTAAAGAG ACCCGAACAA CCTOAATGAO GAAGACGTCT CTTCGAOTTC CAAACCTGGA GAGCTTCGTA AAATGCATCA GGTATTGAGG CAATTCTTCG CCTCTGCCAC GGCCGCACCO TCTGGACA.TC GACTGGCAÀG AATTCCGGGA AAAACTGACG GCAAGCGCAG GAACAACAGT AGGTAGAGGG AACCGTCTGG TCCAATCTCT ACTATCAACC TCTCATAAAT CTCCAAACAT GGCTACCCAG CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT AGAGOTTCCT GGAGGTGTCG TACCGCGTTC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC agtgagaaag atccagggcg atggcgcagc ccacctacaa gctgtgccac cccgaggagc CTGGGCATCC CCTGGGCTCC CCTGAGCTCC GCTGGCAGGC TGCTTGAGCC AACTCCATAG GGCTCCTGCA GGCCCTGGAA GGGATATCCC GACACACTGC AGCTGGACGT CGCCGACTTT

wa V 4.

· 5ί

151

801 '9 Cl

C «η

GGTCTATAAT GATCGATGAA CCTTTGCTGG ACCCGAACAA ggaccgaaac cttcgactto agaacttaga aaatgcatca ccatgtctgc cctctgccac caaggcaggt QACTGGCAAG ttaccgttga gcaagcggagag

ATTATACATC CGTCAATGAC CAAACCTGGA GGTATTGAGG aattccggga GAACAACAGT TCCAATC ’^ n'r CTCCAAACAT

TCGTACCGCG TTCTACGCCA

CTCTCAGAGC TTCCTGCTCA

GGGTCCCACC '“’ PJ, I · *? <«Τι>.

ACGf * A. “« Τ, ίγ, i _{? 1} I gaagacgtct 17? Wjm .-. V

S ^ tX ^: S · ’. ♦. Λ Xm <\ 3 χΓ *. CAATTCTTCG TCTCGACATO ^ A / w> v * T ^ ss / ^ Cu, ACGTAGÀGGG ACTATCAACC ***

TGGAGAGCTT CCCTCTGGCG GCAAGTGAGA GTGCCACCTA ΪΤ <»** Ύί ^ J * tWi

There

GCAGCTGGCA AGGGGCTCCT TTGGACACAC <3x * AGAtTGGAA CCATGCCGGC

PMGN13192

pMONXSlíl

GAAGCTGTGT

GGTCTATAAT GATCGATGAA ATTATACATC COTTTGCTGG ACCGGAACAA CCTCAATGAC GGACCGAAAC CTTCGACTT2 CAAACCTGGA AGAACTTAGA AAATGCATCA GGTATTGAGG CCATGTCTGC CCTCTGCCAC GGCCGCACCC CAAGGCAGGT GACTGGCAAG AATTCCGGGA TTACCCTTGA GCAAGCGCAG GAACAÀCAGT TCGCCGGGTG AACCGTCTGG TCCAATCTCT GTCTAAAGAA TCTCATAAAT CTCCAAAGAT CCGAGGAGCT GGTGCTGCTC GGACACTC ° C CTGAGCTCCT GCCCCAGCCÀ GGCCCTGCAG ACTCCATAGC GGCGTTTTCC TCTACCAGGG GGATATCCCQ CGAGTTGGGT CCCACC ^ GG GCCGACTTTG CCACCACCAT CTGGCAGCAG CCCTGCCCTG CAGCCCACCC AGGGTGCGA ^ TCCAGCGGCG GGCAGGAGGG GTCCTGGTTG CTGGAGGTGT CGTACCGCGT TC ^ A ^ G ^ AC GGGCCCTGGC AGCTCCCTGC CCCAGAGC ^ T AAGTGAGAAA GATCCAGGGC GATGGCGC £ GCCACA (

^ .GXX AAAG AG

GAAGACGTOT

ATGGAAGÀAC / X, * »*> * S J * s> 5 \« A x ^. · Af,

CTAGCCATCT

CTTGOGCAGO

CGCTCCAGGA pMON2

ATGGCTAACT GCTCTATAAT

ACCACCTGGA CCTTTGCTGG

AGGGCTGTGA AGAACTTAGA

GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGÀCTTC CAAACCTGGA AAATGCATCA GGTATTGAGG • * 4 * S * · <κ ·: w ΖΛ ^ Γ ^ χ '^. ΧίϊΛ.ΧΧΐ

GAAGACGTCT GAGCTTCGTA CAATTCTTCG

_a : ^: A7 _: s lit:!: :: 133- :: 551: The . . „,. ....... uuTOTGCCAC GGCCGCACCC TCTCGA-CA'i '*' ^ λλΙ ^ Α ^ -Α, Τ CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGATΪΞΞΞ-ΪγΤΪϊ H ^ ?: r ^T ~ ^GA gcaagcgcag gaacaacagt wgtaggg TCCCCGGGTG GTGGTTCTGG CGGCGGCTC 'ΑΆ'Ά' ^ ^{Τ τ Ξ ο ΞίΞ ττ :: '3} gacagactgc agctggacgt CGCCGACTTT GCCAi'CACCA TCTGGCAGOA GATGGAAGAA CTGGGAATGG G2AGCCCACC CAGGGTGCCA TGCCGGCCTT CGCCTCTGCT TTCCAGCGC' GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAG.AGCTT iCl 1   8 22 £ 22 : 9: 82 ::: TCGTACCGCG TTCTACGCGA CCTTGCGCÀG CCCACACCAT TGGG ^^^ L '""ϊίΐϊ'ΙΐίΞ JTCCAGAG- TCCTGCTCAA GTCTTTAGAG CAÃgTGAGaÃ' λλγ4 """j<.u: ATGGCGCA GTGCTCCAGG AGAAG 'TGTO ^ - ί ± ΞΞ" Ξ i' S i ^AGS E22 = 'SSTSCK. cTcsàlcÃc? 98533? -Tccce ^ G c; asscc ™ c- casctssc ^ - '''Λ— ~ “A- AGCSSCCT-T TCGTCTACCA 0533-- ¹ - AASGSATATG CTAATAA ÍSEQ IE KOsXOi;

222

382

Γ. ;

Βϊ

451

SC 2

111 $ 22 til: dSsr ·

802

5Ϊ1 Ml $ 22

ATGGCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG - '-TwiT GGAOCGAAAC AGGGCTGTCA AGAACTTAGA TAATCTCOAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACCCTTGA CGGTGGAGGC TCCCCGGGTG CGTCTCOTCC GTCTAAAGAA TTGGCTCCCA CGTTGGACAC CACCATCTGG CAGCAGATGG CCACCCAGGG TGCCATGCCG GGAGGGGTCC TGGTTGCTAG CCGCGTTCTA C GCCACCTTG CCGTGCCCCA GAGCTTCCTG CAGGGCGATG GCGCAGCGCT GTGC1ACCCC GAGGAGCTGG GGGCTCCCCT GAGCTCCTGC TTGAGCGAAC TCCATAGCGG COTGGAAGGG ATATCCTAÀT

GATCGATGAA ATTATACA.TC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA AAATGCA.TCA GGTATTGAGG CCTCTGCCAC GGCCGCACCC GACTGGCAAG AATTCCGGGA GCAAGCGGAG GAACAACAG "AACCGTCTGG TCCAATCTCT TCTCATAAAT CTCCAAACAT ACTGCAGCTG GACGTCGCCG AAGAACTGGG AATGGCCCCT GCCTTCGCCT CTGCTTTCCA CCATGTGGAG AGOTTCCTGG CGCAGCCCAC ACCATTGGG CTCAAGTCTT TAGAGCAAGT CCAGGAGAAG CTGTGTGCCA TGCTGCTCGG ACACTCTCTG CCCAGCCAGG CCCTGCAG CCTTTTCCTC TACCAGGGGC AA ^ GD iSSQ NO: 107 )

AGTTAAAGAG GAAGACGTGT GAGGTGCGTA CAATT OTTCjC TGTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GGOTCCCGAG ACGTTGCCAC GCCCTGCAGC GCGCCGGGCA AGGTGTCGTA GOTGCCCTAGGG

PHON13194

152

2D1

251: 382 ::

351

402

ATGGCTAACT ACCACCTGGA CTATCGTGAT AGGGCTGTCÀ TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC TGGCCCCTGC ggtctataat

GGACCGAAAG

CCATGTCTGC

CAAGGCAGGT

TTAGCC? TGA

TCCCCGG-GTG CCTGCAGCCC

GATCGATGAA ACCCGAACAA CTTCGACTTO aaatgcatqa CCTCTGCCAC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG ACGCAGGGTG

ATTATACATC

CGTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC CGATGCCGGC acttaaagag gaagacgtct GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG A ^ i ^ TTC AGGGG

^, TTTú.CAG_ GCCGGGCAGG AGGGGTCCTG GTTGOTAGll. ATCCGCàGAG 5 02 OTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTT3CG OAGCCCAC.AC

CA.TTGGGCCC TGCCAGCTOO CTGCCCCAGA GCTTCCTGCT CAAGT? ^, '' ~ * oOà gagcaagtga GAAAGATCCA GGGCGATGG2 GOA.GCGCTCC AGGAG- ^ G ^ to 2. GTGTGCCACC TACAAGCTGT GCCACCCCGA GGAGCTGGTG C ^ -T .. ™ ¹ 702 - · ACTCTCTGGGCTCCCCT

CTGCAGCTGG CAGGCTGOTT GAGCCAACTC 802 CATAGCGGCC TTTTC2T0TA OOAGGGGCTC CTGCAGGCCC TGGAAGGGAT ATCGCCCGAG 'GGN ^ R ^ p-CA ACTGCAGCTG GACGTCGCCG ACTTTGCCAC S50 CZTTGGACA2 ÔÃggGEtGG 981 CAGOAGÀTGG AAGAAOTGGG ATAATAA (SEQ XD NO.:108' pNGNXOl 95

..... moon)

061

302 • j ~ 403

451

601

651 Bi> 51

£ 801 5 '

901

951

ÀTGGCTAACT AOCAOCTGCA CTATCCTGAT AG GGOTGTCA TAATCTCCAA CAATCATCAT CTCTATCTGG 1GGTGGAGGC CGTCTCCTCC 2CTGCCCTGC CCAGCGCCGG TGGAGGTGTC GGCCCTGCGGGGGCGA

GCTCTATAAT C2TTTGCTGG GGACCGAAAC AGAA2TTAGA 2CATGTCTGC CAAGGOAGGT TTACCCTTGA T2CCCGGGTG GTCTAAAGAA AGCC2ACCCA GCÀGGAGGGG GTACCGGGTGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGG

GATCGATGAÀ A ^, * _ U UaAl AA CTTCGACTT2 AAATGCATCA CCTCTGCOÀC GACTGGCAAG GCÀAGCGCAG AACCGTCTGG TCTCATAÀAT GGGTGCCATG TGOTGGTTGC CTAOGCCACC CCAGAGCTTO ATGGGGCTGCGCGCAGCAGCAGCAGGCTGCGCGCAGGCTGCGCGCGCAGGCTGCC

ATTATA2AT2 CCTCAATGAC CAAÀCCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT CCGGCCTTCG TAGCCATCTG TTGCGCAG20 CTGCTCAAGT GCTCCAGGGTT

AOTTAAAGAG

GAAGACGTXT GAGOTTOGTA CAATTOTTCG TCTCGA2ÀT0 AAAACTGACG A \ ~ x ^ _ AvAQGsl ACTATCAAC2 ggctatggcc cagagottcc CACA.CCATTG CTTTÀGAGCA AAGCTGTGTG CGGAOACTCGGTCAGTCA

PMOK13196

101

251

202

252

302

351

402

451

501

551

602

651

ATGGCTAAOT '«.A'w.' ^ TGCA ctatcctgat AGGGCTGTCA TAÀTCT2CAA CAATCATCAT TTOTATCTGG CGGTGGÀGGC CCCAGGGTGC GGGGTCCTGG CGTTCTACGC TGCCCCAGGGGGGG

GCTCTATAAT COTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTOTGC CAAGGCAGGT TTACOCTTGA TOCCCGGGTG CATGCCGGCC TTGCTAGCCA CACCTTGCGC OTTCCTGCTC CAGCGCTCOA GAGCTGGTGC

GATCGATGAA ACCCGAACAA CTTOGACTTC AAÀTGCATCA C0T2TGCCAC GACTGGCAAG GCAAGCGCAG GTGGTTCTGG ’’ ’’ T’ G C TC u TCTGCAGAGC AGCCCAOACC AAGTCTTTAG GGAGAGCTG TGCTCGGA

ATTATACATC OCTCAATGAC CAAACCTGQA GGTATTGAGG GGCCGCACCC ΛΛ 4. * s- s- ks '^ sXJA GAACAACAGT CGGCGGCTCC CTTTCCAGCG TTCCTGGAGG ATTGGGCCCT agcaagtgag TGTGCCACCT CTCTCTGGGC acttaaagag GAAGACGTCT GAGCTTCGTA CÂATTCTTCG TCTCGACATC aaaactgacg AuwTAGAGGG AACATGGCTA CCGGGCAGGA TGTCGTACCG GCCAGCTCCC AAAGATCCAG ÀCAAGCTGTG ATCCCCTGGG •' d dddTGAG COCCTGCOCO agccaggocg tccacctgqc aggotgottg 51 AGOOAAOTOO AXAGOGGdT TXTCGTCTAO OAGGGGOTCC ÔgÒÃggÕÔÔo a - üjArtwwi-r. 7C2CC2GrtGT TGGSTOwCí.v O ^ TGGmQACA CTuCAGC ^ vv, „„ A. „· -: j, - λ .-. G-T-j -., Àí3 - *, AGA” GGA ·· AGAA0TGG3A

y. _. .. * ί. - x3xj - - - ο -.3. A o'— u 0 YYYY.—,: MON - 'No: 210 · pMONdisr d 215 ^ 1 ⁷ ^ ⁷ £ 0 — TATAAT GATCGATGAA ATTATACATC AOdAAAGAG

- - AdAdTGC.A 0CTTT3CTGG ACOOGAACAA GCTOAATGAO GAAG ug '' '^' CTATOCTGAT Id GGACCGAAAC 152 CTTOGACTTC CAAACOTGGA GAddTCdA AGGGdGTuA AGAÂCTTAGA AAATGOATCA GGTATTGAGG CAA'd '·' ^ ™ 'dl TAATddAA OOATGTCTSO CCTCTGCCAC GGCCGOAOCC TCTCGACATC ^ jiAi'ddAT CAAGGCAGGX GACTGGCAAG AAdCoGGGA AAAAdGAd 3d dCXATOTGG TTACCCTTGA GCAAGCGCAG GAÀCAACAGT AGGTAGAGGG

--- OGGTGGAGGO TdOCGGGTG AACCGTdGG TCCAATCTd ACod ~ ò '~

4C.1 CGTCTGOTd GTCTAAAGAA TCTCATAAAT CTCCAAAGd G ^ -Ã ^ A ^

451 GGTGdATGC CGG0C7TCGC CTCTGCTTTC CAGOGCCGGG CAGGAGGGG ^

CCTGGTTGCT ÀGCCATCTGC AGAGCTTCCT GGÀGGTGTCG TACCGCGTTC

TAdCCACd TGOGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCO od CAGAGOTTCC TGdCAAGTO TTTAGAGCAA GGGAGAAAGA TdAGGGCGA td. GGGCGCAGCG CTCCAGGAGA AGCTGTGTGC CACGTACAAG dGTGCCACC

701 CCGAGGAGd GGTGCTGCTC GGACACTCTC TGGGCAXCCC CTGGGCTCd / 33 CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA

8d AGTCCaTAGC GGCCddCC TCTAOCAGGG GCTCCTGCAG GCGCTGGAAG

GGATATCCd CGAGTTGGGT CCCACCTTGG ACACAGTGCÀ GGTGGACGTC

2d GCCGACTTTG CCACCACCAG CTGGCAGCAG ATGGAAGAAO TGGGAA ^ G'd

-3 * CCCTGCCCTG CAGCGCTAAT ÀA (SEQ d NO: 111) pMONdlvs

101

151

202.

251

3C2

401

451

5d

£ 552 01 • 551

701

751

801

101-i

ATGGCTAACT ACGACCTGCA CTATCCTGAG AGGGdGTCA TAATCTCCAA CAATCATCA7 TTCTATCTGG CGGTGGAGGC CTGCTTTCCA AGCTTCCTGG ACCATTGGGC TAGAGCAAGT CTGTGTGCCA ACAOTdCTG CCGGGCGGGCGG

GdCTATAAT CCTTTGOTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TGCCCGGGTG GCGCCGGGCA AGGTGTCGTA COTGCCAGCT GAGAAAGATC CCTACAAGCT GGOATCCGAGGGCGGCGCGGCGCAGCG

GATCGATGAA ATTATACATC ACTTAAAGAG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTTCGACTTC C.AAACOTGGA GAGdTCGTA AAATGCATCA GGTATTGAGG CÀATTCTTCG CCTCTGCCAC GGOCGCACCC GACTGGCAAG AATTCCGGGA AAAACTGACG TCTCGACATC GCAAGCGCAG GÀACAACAGT GTGGTTCTGG CGGCGGCTCC AACATGGCTT ACGTAGAGGG GGAGGGGTCC TGGTTGCTAG CCATCTGCAG CCGCGTTCTA CGCCACCTTG CGCAGCCCAC CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT CAGGGCGATG GCGCAGCGCT CCAGGAGAAG GTGCCÀCCCO GAGGAGCTGG TGdGd ^ GG GGGCdXCCT GAGCTCCTGC CCCAGCCAGG TTGAGOCAAC TCCATAGCGG CCTTTTCCTC CCTGGAAGGG ATAGCCCCCG AGTTGGGTCC TGGACGTCGC CGACTTTGCC ACCACCATCT GGAATGGCCC CTGCCCTGCA GCCCACCCAG CTAATAA (SEC · XD NO: 112) pNOK.

<· Ν \

Χι «Τ»

Λ fc

Urtj x:>. <

9G x x £

pMOE

- \ 3 \ Ϊ> Χ.2

ΛΛλ \ tepxvmq

V? ^ λΗλ;

AAGI

GCTGCTTGAG ν ^ Λ; V? \ Ax_kas_xH. A'— x- «v-'jtfwswm‡PCTGAGCT or * & & πτρρ &» r

DGAGTTl ^ L3 \ a · 4V? L> A · ^ \ -χ rts u «*. VSLi'VJ / V'i.u

G G AC AAT AAí>> A * * St

Wow. * ΛΛΑϋ. “ΙΛ m?“ * X? **> ** y *. VS V ·? SÍ Vv-’jf '+ XJS \ m * \ w w.

OTTAGAGCA

AAGCTGTGTG

LíLSV-LaLaC- 4

AA (SEC TD

GATGAA

GAATGCATCA

CGCTAGCCAC

TCTCATAAAT? T> rprp

AGAGCTTCCT

AGTGAGAAAG

CCACCTACAA

GATGGAAGAA ¹ ND; 114} ksv *

GAGA

GGAGGTGTCG

CTGGCGGCTC

TGCTTGAÍ

AGCTGGACGT x ~ 4 VS V31 V53ÍWV1 vsv?

GCTCTAACAT GATCGATGAA CCGUGCTGG ACTTGAACAA GGAAAATAAC CUCGTCGTC AGTCTCTGCA GAATGCATCA CCATGICTGC CCCTGGCCAC CGGTGACGGT GACTGGAATG AA OCT «Μ. si X »<·

AGCCAT2TGC AGAGCTTCCT TGCGCAGCCC TCTGGCGGCT ft / * <·>, <x and *> x * A «n m m. ^ * * * vA / ‘iCi J> Azyj & K ^ -f ^ rAi / ^ xy

AAGCTGTGTG CCACCTACAA CGGACACTCI CTGGGCATCc AGGCCCTGCA GCTGGCAGGC CTCTACCAGG GGCTCCTGCA TCCCACCTTG GACACACTGC TCTGGCAGCA GATGGAAGAA TAA {£ EQ ID NG: 116)

GGAGGTGTCG CTGGCGGCTC A .. -CAGGGGG

W'w X XJt i \ v \ vkssi ^ \,

CCTGGGCTCC * \ 3 «, the i gggcctggaa AGGTGGACGT CTGGGAATGG

Λ. ¹ - ». 1GAAGCA

GAAGACCAAG ggcattcaac GCATTCTTAA ACGCGACATC taaagtgacc acgtagaggg AGTATCAACC ggctacccag CAGGAGGGGT TACGGCG '^' ^ 'C TCAGAGCTTC ATGGCGCAGC <- s_. G GAG GAG C CCTGAGCTCC aactccatag GGGATATCCG CGCCGACTTT /?>

'-x * —i s3s „\„ U. ».

P.MON3U15

ATGGCTAACT gctitaacat GÇCACCGCTG CCGCTGCTGG ATATCCTAAT GGACAATAAC CGTGCTGTCA AGTOTCTGCA AAATCTCITG CCATGTr ”TQr CAATCCATAI CAAGGACGGT TTCTATCTGA AAACCTTGGA

GATCGATGAA ACTTCAACAA CTTCGTCGTC GAATGCATCA CGCTAGCCAC GACTGGAATG GAACGCGCAG

ATCATCACCC CCTCAATGGT CAAACCTCGA GCAATTGAGA GGCCGCACCC X. y_S ’T'M’fh'—» / »X

GGTGAACAGT

ACCTGAAGCA GAAGACCAAG GGCATTCAAC GCATTCTTAA “J * ·· *’ X *.

Τ ’X. χ. Τχ, · *** ^ **>

AG AG GG

PMCN2350S / * ♦ ** *. fl

1 UvJAx. , ** · *. ywy yw <λ y ^ -y ^ Wrsy 'λ-, 1 ~ ^' ^ AA ^ CO ^ .ClAGDTTCCTCCACAGGGCAGGACCACAGCTÜACAAGGATG TGAGCTTCCAACACCTGCTCCGAGGAAÀGGTGCGTT TGAVOn ^ ^^ r ^ uACCCTCTGGGTCAGGGAATTCGGCGGCAACATGGGGT crcG ^'7' ^

PMGN2850Ô

Λ ^ 'Ηΐν IL? V »X L-ΤΆ1 AATGA ^^^ AT · ^ ** 2 * & Ά ^w X / *** m, · *** _xx * ~ _Λ -?: X: λ * Λ * Ακ , Λ.Τ ν_Λ · · ^ ^ CT ΤΤ AAAGAGACCACCTGCACCT AATGACGAAGACQTCT CTATC CTGATGGA ^r ~ G AAA ^ ^^^ ^CCAACCAT TGCCCTCT gccacggccgcaccctct 'X ^ I ^^' ^^^ J ^{AGGCAGCTGAC C 'r} ^^ ⁱ ^ ** ^AGC CAAGAATTCCGGGAAÀAACTGACGTTC J ^AGCGCAS 6AACAACAGTACGTAGAGGGCGGTGGAGGC'PCC ^{^^^^^^^^^^^^^^^^^^^} CGTCTAAAGAATCT ^ vTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTFG? ^AG J ^ ^{GGCACAG <3ACAI} TTCTGGGAGCAGTGACC ACGGGGACAAC TGGGAC GGACTTGCC ^<T 'C ^T ' ^r A TGC

- .’CCGTCTCCTCCTTGGGGCC ^ G ^ AGAG ^^^

Χ; »^ Ξ22 ^{ο" οσΑ: δ} = ^Α ° ^ΑΙΚΑε = »^ εΑδετεΑεΛΑβ3Ατακ ΪΜίΑ7 Lys?"; Yl ^CAAI - ^{ACCT0CK: CSAGSAAA SSTSCS,} TTCCTGATs ~ '^ r: _i TAGGj QgQl ~ í ^ yl!': ^ X ^ ^GA 22 ^G ^ ^{TTCGGCGGCAACATGSeGTGTG} -CGCTCCGCCTGCTTGTGA ^ X ^ ™ ^^ ÍS ^ ^{ctgotcgtgactcccatgtcctt} ^ cagcagactgag ^ ag - ^ GlAGAGGTTCACCCT ISEQ TD κοπίδι

ATAAATÍ

TGGAGGGAGTGATG;

PMOH285C

GC7AA.CTGCTCTATAAT3ATCGATGAAATTATACATCACTTAAAGAGACCACCTGCÀTTT

TTGCTGGàCOCGAACAAGCTTAATGACGAAGACGTOTCTATCCTGATGGAGTGAàà ^ C '' ”

CGACTTCOAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGGATCAG ^ · ATTGAGGCàATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTÕÕÕ

CGACATCCAATCATCATOAAGGOAGGTGACTGGOAAGAATTCCGGGAAAAACTGACGTTO

T ACC GTT CTG TAA CTTGAG CAAGC GC G CAA AAC AG AG AG GT CA AGGGCGGTGGAGG T ^'1 ^' CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGaÃtO CATAAAT CTCCAAACATGGTCOTGCTGCCTGCTGTGG ACTTTÀGCTTGGGAG AATGG the AAA acccagatggaggàgaccaagggacaggacattctgggagcagtgacccttctgctggag GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGG ~ ^ • * ¹ CTTTCTGGACAGGTCCGTGTCCTCOTTGGGGCCCTGCAGAGCCTCGTTGGAACCCAGC ^ CCTCCACAGGGCAGGACCÀCAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCCA

CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTC

AG GGAATT CGGCGGC AAC AT GGCGT CTC CCG CT C CG C CT GCTT GTGAC C TC CGAG ^τ C O '”AGTAÀACTGOTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTG ^^ - AGÃgJ ^ t CACCCTTTGCCTACCT ÇSE

PMON28508

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACOTTGCTGGAOCCGAACAACCTCAATGACGAAGACGTeTCTATCCTGATGGACCGAAACC CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGG ** ^ 'ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT C G C C ACAT AATCATCATCAAGGCAGGTGACTGGCAAGAATTCC GGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAAC CGTCTGGTCCAATC TCTACTATCAAC CCGTCTCCTCCGTCTAAAGAAT cataaatctccaaacatggctgtggactttagcttgggagaatggaaaacccaga ^ ^ ^ ggag gagacoaaggoacaggacattctgggagcagtgacccttctgctggagggagtgatgg the gcacggggacaactgggacccacttgcctctcatccctcctggggcagctttctggacÃg GTCCGTCTCCTCCTTGG3GCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGG' AGGACCACAGCTCACAàGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTGCACCCTCTGCGTCAGGGAATTnGnc 'SGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGC' ^^ n ^ ^^^ CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCÀGAGGTTCACrr ACACCTGTCCTGCTGCOT (SEQ CN CD: 121?

PMON28509

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGA.TGGACCGAAACCTT "-" ALAC TG ^ ^^ ^ x ^ aCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCA CAGGT Ai + Ai mjcgacatccaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgacgttc GAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACC ^ ^ .1 ^{'KüTTAi.CCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGr'TC:} The ccgggtg.aaccgtctggtccaatctctactatcaacccgtctcctccgtctaaÂgaÃtc ^ cataaatctccaaacatggactttagcttgggagaatggaaaacccagatggaggagacc% <jis ^ ^ ATGG .alAuisAC ATTCTG GGAGCAGTGACCCTTCTGCTGGAGGGAGTG AGC “C gg GGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGG ^ qT ctgctccttggggccctgcagagcctccttggaacccagcttcctccacagggcaggÃcc

AC AG CT GACAAGGATCCCAATGCCATCTTC OTGAGCTTCCAAG ÀCCTGCT 1 CG A GAA A ν'Ί vix.xsT - T „OTGA.TGCTTGTAGGAGGGTCCACCGTPTGGGTCAGGGAATTCGG ^ GC '' ^ x · agtaaagtgctcc ^. '. r --- TTCA.CAaGCàGATDGAGGCAGTGCCCàGAGGTT '”ACC ^í ” * ^rw G't, -'- x

GTCCTGCTGCCTGCTGTG <SECTION TD NO; 222:

pMDNzâãlv

CT $ 4 * 5A ^;

ACT AAAC

ΡΝΟΝ28Ξ11

PMON28512 ^ uTAACTGCTCTA-TAATGA-TCGATGÀAATTATArATCAr ttgctggacccgaacâacctc a atvs% £ λ _Λ 'AAAGAGÀCCACCTGCACCT

CAGTG ·

100

TO AGGGOAGGACOAOAGCTO A '

PHONOS5

PMOK2S514 (SEC ZD NO; 125j

DTQ

TCAGGT.;. ^ X ^^^^ XX ^^^^^^^ TGACTGGCAAGAATTCCGGGAAAAA-- ' ^J U ^ T ^ AACOGTCTGGTCCAATCTaTAC ^ ATr _AA -rE - ^^ AE ^^ ^CG ^ ^T

------- ^^^^ í ^^^ A ^ llllTCTCCTCCGTCTAAAGAA ^ ^? 2 £ ^ ^totct - ^a - ^ ccaacac '^^ TAl ^ AGGGTCCACCCTCTGCGTCAGG AA C ^ G r • wpf'fwf »&« pr? > / -.> 0 · Λ <· 0 Λ ^Λ vuTTGTG AC CT CCG AGTC CTCAGT ^{1 (} ^ ^T ^ ^ACTCCCATG TCGTTCAOA * GCAGACTGAQr ^ Arr «r— ^A ^ ^T

-TTTGCCTACACCTGTCCTGCTGCr-Gr ^ _í ; ± ^^ ^AG X ^A ? IY ^C '- ^ ^A ^ GTTCAC AGATGGAGGAGAeCA ^ GGGACAGGÃcA ^^ TÍjÍjÒ *? ^; J ^^ ^{ÍAAATGGAAAACC} tgatggcagacacgg. _S GACAGOTCC _GT c _T c.CTCCTTSSSSCcAaASAríÍ? R ~ PE »; S ° ^G3CASC ” GACASGGÇASSACCACÁ! ^ R> -, „ULS? ^ —TC ^ TTuííAACí-CAGCTTCCT

TGCTCCGAGGAAAGGTGCG

101

GCTAACTGGTCT? .TAA.TGATCGATGAA ^ -TTA.TACATCACTTAAAGAGACCA.CCTGOA.CCT TT G CIG GA 0 0 CG AA G AAC CT O AAT G AO G AA \ »AOG T 0 T GT A« T COT G AT GG AC ~ G ΑλΑ STUMP CGACTT 0 0 0 T AAAC GG AG C GT AGCTT AAGGGCTGTC AAGAACTTA GAAAATGC AT -AGGT ATTGAGGCAATTOTTCGT AATCTC CAACCATGTCTGCCCTCTGCCACGGCC GOAT Z CT CTGT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGÀAAAAOTGACGTTC TATCTGGTTACCCTTGAGCAAG CGCAGGAACAAOAGTACGTAGAGGGOGGTGGAGG G 0 COGGGTGÀACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAÀAGAATCT CATAÀATCTCCAÀAOArGGATCCCAATGCCATCTTOCTGAGCTTCCAACAOCTGCTCCG.A GGAAAGGTGGGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGG GGGAAOATGGCGTCTOCCGCTCCGCCTGCTTGTG.ACOTOCGAGTCCTCAGT.AAAGTGOTG .OGTGACTCCCATGTCCTTCAOAGCAGAOTGAGCCAGTGCCCAGAGGTTOACCCTTTGGTT AGAOCTGTCCTGCTGCOTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG gagaccaaggoacaggacattctgggagcagtgacccttctgctggagggagtgatggca GCACGGGGAGAAGTGGGACCCACTTGCCTOTCATCCCTCaTGGGGCAGOTTTGTGGACAG AGG GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGOTTCGTGCACAGGGO ACCAOAGOTCAOAAG (SEO CD NO: 128)

PMGN18S16

GCTAACTGCTCTATAATGATGGATGAAATTATACÀTCACTTAAAGAGACCACCTGCACCT ttgctggacccgaacaacctoaatgacgaagacgtototatcctgatggacogaaacctt CGAOTT 00 AAAO CTGGAGAGCTTC AAGGGCTGTCAAGAACTTAGAAÀATG GT CAT C-AGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAÀGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACOCTTGAGCAAGCGCAGGAAC AACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCr * CATaAAATCTCCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGÀAAGGTG cgtttcctgatgcttgtaggagggtccaccctctgcgtcagggaattcgqcggcaacatg gcgtctcccgctccgcctgcttgtgacctccgàgtcctcagtaaactgcttcgtgactcc CATQTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTC CTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAG GCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA CAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTmr OTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCÀGGACCA ^ GCTCACAAGGATCCCAAT FSSO "D NO: 129 I

PMON28519 ggtaactgctctataatgatcgatgaaattatacatcacttaaagagaccacctgcàcct TTGCTGGACCCGÀACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACC ^ 'cgacttccaaacctggagagcttcgtaagggctgtcaagaacttagaaaatgcatcaggt attgaggcaattcttcgtaatctccaaccatgtctgccctctgccacggccgcaccctct C s ^{AuATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGAr'GTT: |} 'TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC COGGGTG AACCGTCTGGTCCAATCTCTACT ATC AACC CGTCTCCTCC GTC'? ' AAAG

CATAAATCTCCAAACA TGGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTG GAOTTTAGCTTGGGAGÀATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATT ^ TG-ggagcagtgacccttctgctggagggagtgatggcagcacggggacaactgggacccà ^ t ^ TGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTCC GGGGCrCTG CAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAGGAmCGC AATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCmT GTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCT '

~

Ag> «a '. << V. rf * ¹ · X · '

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACC7 TTGCTGGACCCGAACAACCrrCAATGACGAÃGACGTCTCTATCCTGATGGACCGAAACCT ^ C'GACTTCCAAACCTGGAGAGCTTCGTAAGGGGTGTCAAGAACTTAGAAAATGCATCAGGT attgaggcaattcttcgtaatctccaacgatgtctgccctctgccacggccgcàccctct cgacatccaatcatcatcaaggcaggtgactggcaagaattccgggaaaaagtgacgttc tatctggttacccttgagcaagcgcaggaacaacagtacgtagagggcggtggaggctcc CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTOCAAACATGGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAG GGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGOAG CTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCGTGCAGAGCCTCCTTGGAACCCAGGT ^ CGTGCACÀGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTrcCAA CACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGeTrGTAGGAGGGTCCACCCTCTGCGTC AGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGT · AÀACTGCTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC \ 'w ·. · · X XX Ί? χλ »· * X à. feufc '· - --- / - / · · AS ·' ¹ ·; -.- / λ 'ι · ύ <-ι ·; <τ ^' ·? <ΐί: j · ·

PMON28S22 gctaactgctctataatgatcgatgaaattatacatcacttaaagagaccacctgcacc ^ TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGG ^'1 attgaggcaattcttcgtaatctccaaccatgtctgccctctgccacggccgcaccctct CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAÀCTGACGTTC TATCTGGTxACCCTTGA.GLAAGOGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTcr' ccgggtgaaccgtctggtccaatctctactatcaacccgtctcctccgt aaagaà ^ ^^ ^ CATAAATCTCCAAACATGGCTGTGGACTTrAGOTGGGAGAATGGAAAACCCAGATGGAG sagaccaaggcacaggacattctgggagcagtgacccttctgctggagggagtga GGCA

103% ** x y ^ rwrx / ** ^ · *** \ jAv5 at 4 Vm

w.

rCGATGAAATTATACATCACTTAAAGAGAi rCAATGACGAAGACGTCTCTATCCTGATG

AGGT

ATTGAGGCAATTCTTCGTAATCT

CCTCTGCCACGGGCGCACCCTCT ggtgactggcaagaattccgggaaaaactgacgttc y'rr ^ T '^^' Tvy. ^ Vjrj.M ^. ^ Jj ^^^. ^^ r ^ rs ^ ACAACAGTACGTAGAGGGCGGTGGAGGOTCO. ccgggtgÂÂccgtctggtccaatctctactatcaacccgtctcctcggtctaaagaatct AAATCTCCAAACATGGGAGAATGGÃAAÃCCCAGATGGAGGAGACCAAGGCACAGGAC Ar ^ A ^ ^ tctgggagcagtgacccttctgctggagggagtgatggcagcacggggacaactggga CCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTGCTCCTTGGG Grr rGrAnAG ATG ^ ^ CTCCTTGGAACCCAGCTTCCTCCACAGGGCAGGACCACAGCTCACAAG gÃtcccÃatgccÃtcttcctgagcttccaacacctgctccgaggaaaggtgcgtttcctg ttGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCT C7Gr- Gc _T ^ L _ST ecTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCATGTCCTTCAC AGcÃGACTGAGCCAGTGCCCAGAGGTrCACCCTTTGCCTACACCTGTCCTGCTGCCTGCT GTGGACTTTAGCTTG ISEQ ID NO: 135?

ΡΜΟΝ28525

-C ^ AAC ^ GCTCTATAATGATCGATGAAATTATACA.'TCACTI'AAAGAGACCACCTGCACCT

TTGCTGGACCCGAACÀCCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT cgacttccaaacctggagagottcgtaagggctgtcaagaacttagaaaatgcatcaggt attgaggcaattcttcgtaatctccaacogggctctctct

pMON28526 aTAATG.ATCGATGAAATTATACATCACTTAAAGAGAC oacot CACGTG - ^^ RR 2 g GGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGAOCGAAACCTT AG AGCTTCGT AAGGGCTGTC AAGAACTTAG AAAATGC AT AGGT 0 ^ G ^ I-AA ^ o ^ ^ CGTAATCTCCAACCATGTCTGCCCTCTGCOACGGCCGCACCOTCT CGAOATCOÀATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC tgagcaagcgcàggaacaac.agtacgta.gagggcggtggaggctcc gÍÃccgtÔtgg ggg ^ ^ ^ aatctcgaaacatgggaagccagctcctccacaggggaggaccacagctgagaag ^ -it qcaatctctactatcaacccgtctcctccgtctaaagàatgt m _C rv, * GC ^r 'ATCTTCCTGAGGTTCCAACACCTGOTCCGAGGAAAGGTGCGTTTCCTG _? ÇA _c ^ _g ^ 5 * _G ggJg gtcCACCCTCTGCGTCAGGGAATTCGGC ACATGGCGTCTCCCGCT AG .- '^ G ^ C ^ C ^ TG'rGA CCGAGTCCTaAGTAAACTGCTTCGTGACTCCCATGTCCTTCAG AGGAGACTGAGeCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGGT GTGGAGTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATí · C ^ GGGAGCAGTGACGCTTCTGCTGGAGGGAGTGxATGGCAGCACGGGGACAACTGGGACCC ACTTGeCTCTCATCCGTeCTGGGGCAGCTTTCTGGACAGGTCCGTCTGCTCCTTGGGGCC CTGCAGAGCCTCCTT (SEG ΣΕ NO: 137)?

PMON28527

GOTAACTGTTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGGTGGACCGGAACAACCOC ^ TGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCàAGAACTTAGAAAATGCATCAGGT aotgaggcaattcttcgtaatctccaaccatgtctgccctctgccacggccgcaccctct rGACATCCAATCATCATGAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC tatctggttacccttgagcaàgcgcaggaacãacagtacgtagagggcggtggaggctcc CnGGGTG GCC ^ ^ ^ CTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAAACATGGGCAGGACCACAGCTCACAAGGATCeCAATGCCATCTTOTG AGC TCCAACACCTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACC CTCTGCGTCAGGGAATTCGGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTCCGA gtcctcagtaaactgcttcgtgactcccatgtccttcacagcagactgagccagtgccca gaggttcaccctttgcctacacctgtcctgctgcctgctgtggactttagcttgggagaa tggaÂxacccagatggaggagaccaaggcacaggacattctgggagcagtgacccttctg rTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTG gggcagctttctggacaggtccgtctcctccttggggccctgcagagcctcottggaacc CAGCTTCCTCCACAG (SEQ IE NO: 138;

ρΜ0Κ2 S528

pN0K2852

G2TAACTG CT-27 C ATAATGATCGATGΑΑΑΤΤΆΤ ACATCACTT AAAGAGAC AC CTG C-ACCT TTGCTGGACCCGAACTiACCTCAATGAC GAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT attgaggcaattcttcgtaatctccaaccatgtctgccctctgccacggccgcaccctct CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC tatctggttacccttgagcaagcgcaggaacaacagtacgtagagggcggtggaggctcc C CGGGTG AACCGTCTGGTCC AATCTCTaCT ATCAACC CGTCTCCTC 2GT CT AAAGAÀTCT catAxAatctccaaacatggatcccaatgccatcttcctgagcttccaacacctgctccga ggaaaggtgcgtttcctgatgcttgtaggagggtccaccctctgcgtcagggaattcggc AACATGGCGTC'TCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGT gactcccatgcccttcacagcagactgagccagtgcccagàggttcaccctttgcctaca gtcctgctgcctgctgtggactttagcttgggagaatggaaaacccagatggaggag

AAGGC A2AGGACATTCTGGGAGL · .AGTkiA'x » ^t ~ CT '~. CT ^ sx, «ouAG ^ vsAGTuATwsGCAGCA v * 4- * v> Λ 4 L? *» * · * * ItAa λ ww X λ aa 1 J.

CGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCCAGCTTCCTCCACAG-GGCAGG

ACCACAG2T2ACAAG ÍSEQ TD NO: 140}

PMQN2.g.53O.

GCTAACTGCTCTATÀATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCeAAAGCTGGAGAGCTTCGTAÀGGGCTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCGGTCTAAAGAATCT CATAAATCT-GCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTOGGCAACATGGCG TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT GTC2TTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCCTG CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA 7 ** X rft-rxy / · '*' * j. r * f -x,: -,

106

r? M0N2 δ 5 ί 5

ρ ^ ΟΝ28534

! L ^ * ^ CG ^ AAC TATAATGATCGATGAAATTATACAJTCACTTAAAGAGACCACCTGCACCX --GGTGGA00CGAACAACCTCAATGÀCGAAGACGTC7CTATCCTGATGGACCGAAA0GTT CGA ^^ CGAAACCTGGAGAGCTTCGTAAGGGGTGTCAAGAACTTAGAAAATGCATCAGGT The '' 'rGAGGGAA77C7TCG7AATC7CCAACCATGTCTGCCCTCTGCCACGGCCGCACC0TCT ogacatcgaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgacgtgc ^^ C ^ tctggttacccgtgagcaagcgcaggaacaacagtacgtagagggcggtggaggctcc GnTGÂÃcCGTCTGGTCCAATCTCTACTATCAACOCGTCTCCTCCGTCTAAAGAATCG cataÃa7C7CCaaacatgttgcc7ACacctgtcctgctgcctggtgtggactttagcttg GGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGuAksTGAs-íGTTC7GCTGGAGGGAGTGA7GGCAGCACGGGGACAACTGGGACCCAG77GCCTCTCATCC RTO ^ TGGGGCAG0T7TCTGGACAGGTCCG7CTCCTaC7TGGGGCCCTGCAGAGCGTCOTT GGAACCCAGCTTCCTCCAGAGGGCAGGACCACAGCTCACAAGGATCCCAATGCCATCTTC CTGAGCTTCCAACACCTGCTCCGAGGÀAAGGTGCGTTTCCTGATGCTrGTAGGAGGGTCC àccctctgcgtcagggaattcggcggcaacggcggcaacatggcgtccccagcgccgcgt gcÍJgggacctccgagtcctcagtaaactgcttcgtgactcccatgtccttcacagcaga CGGAGCCAGTGCCCAGAGGTTCACCCT (SEQ XD NO: 143} pMON2B525

GCTAACTGCTOTATAATGA.TCGAZrGAAATTATACATCACTTÃÀAGAGACCACCTGCACCT 'rrGCTGGACCCGAAGAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGAOTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCAOGGCCGCACCCTCT CGAOATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCrGGTCCAATCTCTAGTATCAACCCGTCTCCTCCGTCTAAAGÀATCT caxaaatctcgaaacatggtcctgctgcctgctgtggactttagcttgggagaatggaaa

107

AICCAG ATGGAGGAGÀCC AAGGCACAGGAC ATTOTGGGAGCAGTGAGC CTTCTGCTG GAG GGAGTGATGGCAGCACGGGGAGAACTGGGAGCCACTTGCGTOTCATCGGCC wIGGGwIAv ctttctgg AOAGGTCCGTCT CCTCCTTGGGGOCCTGC AGAGC CTCOTTGGAAC CCAG ICTCv CTT AC -> Aw> wrAw \ - ν -i-A ™ Λ. J. v * »- -« Λ \! ~ - - s - ^. * 7- * ·; OACCTGCT CCGAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCAGC ~ -i TGTGCGTO AGGGAítT CGGuGGCAACGGCGG The AACATGGCGTCCCC AGCGGCGCCTG OTTGTGAC C CGAGTC CT CT CC CAGTàAACTGCTTCGTGACT CATGTCCTTCACAG The C AG GAG A.CTG AGTG OOAGAGGTTCACCCTTTGCCTACACCT 2D iSec NO: 144;

: ρϊθα · 8: 53 ^:

GCTAACTGCTCTATAATGATCGATGAAATTATACATCAOTTAAAGAGACCAGCTGCACCC ΤΤΟΟΤΟΟΑΌΟΟηΑΑΟΑΑ'ΟΟΤΊΑΑΤ ΑΟΟΆΑΟΑΟΟΤΟΤΟΤΑΤΟΟΤδΑ'ΤΟΌΑ ^ ^, ΟυϊΑΑΑΟΟΤΟ CGACTTOCAAAC CT GT GGAGÀG CTTC AAGGGCTGTCAAG AACTTAGAAAAT GCATCÀGGT attgaggcaattcttcgtaatctccaaccatgtctgccctctgccacggccgcacoctot CGACATCCAATCATC, 4TC'AAGGCAGGTGACTGGGAAGAATTCOGGGAAAAACTGAO'GTTO TàTCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC aCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAAAGATGGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGGAGCTTTCTGGA.OAG GTCCGTCTCCTCCTTGGGGCCOTGCAGAGCCTCCTTGGxAACCCAGCTTCCTCCACAGGGC aggacgagagctcacaaggatcccaatgccatcttcctgagcttgcaacacctgctccga GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTOGGC GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT AAACTG CTTCGT GACT 0 C CAT GTC AGG AG OTTCAC ASCAG AGTGAGCCAGTGCCC TTC AC CCTTTGCCTACACCTGTCCTGGTGCCT ISEQ CD £ 0: 145} pMGN'2853 "gotaactggtgtataatgàtcgatgaaattatacatcacttaaagagaccacctgcacct TTGCTGGACCCGAACAACCTCAÀTGACGÀAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGGTTCGTAAGGGCTGTCAAGAACTTAGAAÂATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCGAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAÀTCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGGAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAATCTCCAAACATG'XAOTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACC aaggcacaggacattctgggagcàgtgacccttctgctggagggagtgatggcagcacgg ggacaactgggacccacttgcctctcatccctoctggggcagctttctggacaggtccgt ctcctccttggggccctgcagagcctccttggaacccagcttcctccacagggcaggacc ACAGCTCACAAGGATCCCAATGCCATCTTCCTGAGCTTCOAACACCTGCTCCGAGGAAAG GTGCGTTTCCTGATGCTTGTAGGAGGGTGCACCCTCTGCGTCAGGGAATTCGGCGGCAAC GGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGAOOTCCGAGTCCTCAGTAAAOTG CTTCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAOCCTTTG CCTACACC TGTCCTGCTGCCTGGTGTG (SSQ TD £ 0: 146}

PMON28S38

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TTGCTGGACCGGAACAAOCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT ^ oA'_ Tj. C-_ λλλ \ _> „.l ^ üta <sA \ suTT '*. A» to AAwmsG ^ TG í uAAGAACTTAGAAAATGCATCAGGT

108 λ * iwhuu ^ / vi 1 --- - νίήΛ .__ a -vftft> - »AiWi-Xu'-vki„; v) _s , _v AwW'J »'» «vh„ _ww . -. · - * “« - - ·. ». ». jt '/ - j. <* t / * j. ? '* f *> ⁱ *' f * ϊ λ «· λ» * ?. a; Τ χ & ί * »·”. · -, · * »j. aa ”**» * »-. ΛΛ-. 1 \ - -? I. -Λ .. ν, ΛΑ ^ _νν Ζ »ΙΛ '-? -« Λ-άχΛ> Λ-ΛΛ «ΛΛ * --- ^ Ά» «» ΖΐΛΛ «Λ—- ν'Λ ^. - - - '- -. .— <- »- .— - —- <-κ --- * Λ · * ** ·? <X« Λ »» ». _λη ^ _Λ ΛΛ / Μ »'Λ» 1 \ - - - - _Λ Λ1 - Λ' -J \; - - »* l · - S. - - - - ΛΛ-J-Ara - -Γ ^ - X Ms„ \ S - Λ. «ΤΛ. \ Λ \ β-AS» xaxSiVAf AS - - - ~

? ATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGASTGATGGCAGCACGGGGA.CAAC TGG'GA CCCACTTGCZTCTCATOeCTCCTGGGGCÀGCTTTCTaGACAGGTCuGTCTOCTXOTOGGG gccctgcagagcctccttggaacccagcttcctccacagggcaggaccacagcocacaacGATCCCAATGOCATCTTGZTGAGGTrCCAACACGTGCTCCGAGGAAAGGTGGGTTTOCGG atgcttgtaggagggtccaccctctgcgtcagggaattcggcggcaacggggggaacagg GCGTOCOCAG-GCCGZOTGCrrGTGACCTOGGAGTCOTOAGTAAACTGCTTGGTGACTGO CÀTGTOCTTCACAGCAGACTGAGCCAGTGGCGAGAGGTTCACCCTTTGGCTACÀCETGTÍ 'OTGCTGOCTGC TGTGSACTTTAGGTTG EQ i £ IE NO: 147) £ pM0N2853

GCTAACTGCOOTATAATGATCGATGAAATTATACATCACTTAAÀGAGACCAOCTGuACOT TTGCTGGACOCGAACAACCTGAATGACGAAGACGTCTCTATCGTGATGGACCGAAACCTT CGACTTCCAAAeCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT .TTGAGGOAATTCTrCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACGCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGOAAGAATTCCGGGAAAAACTGAOGTTC TATeTGGTrACrCTTGAGCAAGCGCAGGAACAAGAGTACGTAGAGGGCGGTGGAGGCTCC OCGGGTGAACCGTCTGGTCGAATCTCTACTATCAACCCGTCTCCTCCGTGTXAAGAATCT OATAAATOTCCAAAaATGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGCTTTCTGGA CAGGTCCGTCTCCTCOTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGeTtCCTCCACAG GGCAGGACCACAGCTGACAAGGATCCCAATGeeATCTTCCTGAGCTTCCAACACCTGCTG CGAGGAAAGGTGCGTTTCOTGATGCTTGTAGGAGGGTCCACeCTCTGCGTGAGGGAATTC GGCGGCAACGGGGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACOTCCGAGTCCTC AGTAAACTGCTTCGTGACTCeCATGTCOTCACAGCAGACTGAGCCAGTGCCCAGAGGTT CACCGI ^ TGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAA ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGOTGGAG GGAGTGATGGCAGCACGGGGACAAOTG (SEQ XD NG: 1.4 8)?

PMON28548

GCTAACTGCTOTATAATGATCGATGAAATTATACATCACTTAAAGAGACCAOTGCACCT TrGCTGGACCCGAACAACCTCAATGAeGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTrCCAfcACOTGGAGAGCTTCGTAAGGGGTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCrGCCCTeTGCCACGGCnGn nrrxr ^ '^ CGACATCCAAT'OATCATOAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATOTGGTTACCCTrGAGCAAQCGCAGGAACAACAG'XACGTAGAGGGCGGTGGAGGrTC ccgggtgaaccgtctggtccaatctctactatcaacccgtctcctccgtctaaagaÍ ^ ^ ^ cataaatctccaaacatgggaacccagcttcctcgacagggcaggaccacagctcacaag GATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCff TCC G ^ ATGOTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGCGGCAACATG GCGTCCCCAGCGCCGCCTGOTGTGACCTGCGAGTCCTCAGTAAACTGCTTCGTGACTCC catgtccttcacagcagactgagccagtgcccagàggttcaccctttgcctacacctgtc ctgctgcctgctgtggactttagcttgggagàatggàaaacccagatggaggagaccàag SCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGA OAACTGGGACCCACTTGeCTCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTG CTCCTTGGGGCCCTGCAGAGCCTCCrr ISEQ ID 180: 144>

109

pMON'38542

GCTAACTGCTGTA.TAATGATCGATGAAATTA.TACATCACTTAAAGAGACCACCTGCACC7 _{TTGCTGGACCCSÃÃCAACCTCAATGA} CGAAGACGTCTCTATCCTGATGGACCGAAACCTT CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCA7CAGGT ATTGAGGCAATTCTTCGTAATaTCCAACGATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACGTTC TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGGTCGAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT cataaatctccaaacatggctcacaagga.tcccaatgccatcttcctgagcttccaacac CTGCTCCGAGGAAAGGTGCGTTTCCTGATGCTrGTAGGAGGGTCCACCCTCTGCGTCAGG λ »» j. <»<» << «* J, f · * f * ςιΛΛΧ ii —wL λ« ís AwALí »w - υΑ

GTCCTCAGTAAACTGCTTCGTGACTCCCATGTCGTTCACAGCAGACTGAGCCAGTGCCCA «nw; ii, hvVví * 4W *. 'V« ΑνΛνΐ- - ~' · ~ - λ Λ ι ^ '-, Λχί i <s \ s-s .'- · * ΐ. i

TGG AAAAC CC AG ATGGAGGAGACC AAGGCAC AGGACATTCTGGGAGC AGTG ACC CTTCTG CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTOTCATCCCTCCTG λν <* · 7 * * * * * * * * * * '*. χ * τ * .λ ^ λζμ »« (** · ** · λ * · *.

~ »X x- ώ Li. I.v.X'w.u.a a sjax ^ j ^^ / Uçav *. ^ Λ V v

CAGCTTCCTOCACAGGGCAGGACCaCA (£ E0 XD NO: 151)

PHON28543

GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACG7 TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT

CGACTTCCAAACCTGGAGAGCTTCGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT

ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGOCCTCTGCCACGGCCGCACCCT0T cgacatccaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgacgttc TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACACTACGTAGAGGGCGGTGGAGGCTCC CCGGGTGAACCGTCTGG7CCAATCTCTACTATCAACCCGTCTCCTCCGTCTAAAGAATCT CATAAÀTCTCCAAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA GGAAAGG7GCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGT AAACTGCTrCGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCAC CCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTrAGCTTGGGAGAATGGAAAACC

110 "1 AGATGGAGGA.GA1 AA30 T ^ .dAGGAixATO DGuisAG" * £ AGTGACCCTTdGCTGGAGGG The GTGATGGOAGCACGGGGACAACTGGGACCCA TTGGCTCTCATCCCTCGTGGGGCAGGTT TCTGG ACAGGTCCGTCT2 CTCCTTGGGG DC CTGCAGAGCCTC CTTGGAACCCAGCTTCGT 2CACAGGGCAGGA0CACAGCTCA0AAG (SEC ID: 152) £ 544 pK0D2

GCTAACTGCTCTATAnTGATCGATGAAA.TTATACATCACTTAAAGAGA-D CCACDDGCACCT TTGCTG GAG AAC CT GAAC C CAATGACGAAGACGTCT CTATC CTGATGGAC C GAAAC OCT CGACTTCCSGVvCCTGGAGAGCTTOGTAAGGGCTGTCAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT cgacatccaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgacgttc tatctggttacccttgagcaagcgcaggaacaacagtacgtagagggcggtggaggct-cc-ccgggtgaaccgtctggtccaatctctactatcaacccgtctcctcggtctaaagaatct CATAAATCTGCAAACATGGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTG CGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGCGGCAACGGC ggcaaoatgg cgtccccagcgccggctgcttgtgacctccgagtcctcagtaaactgctt CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGQTTCACCCTTTGCCT AC ACCTGTCCTGCTG cctgct gtggactttag cttggg agaatggaaaacc c AG atggag gagaccaaggcacaggacattctgggagcagtgacccttctgctggagggagtgatggca GCACGGGGAGAACTGGGACCCACTTGCGTCTCATCCCTCCTGGGGCAGCTTTCTGGACAG gtccgtctcctccttggggccctgcagagcctccttggaacccagcttcctccacagggc AGGACCACAGCTCACAAGGATCCCAAT (SEC ID NO: 153;

PMQN28545

TTGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACCTT GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACC ^ C C C GACTT AAACCTGGAG AGCTTC GTAAGGGCTGTC AAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAAXCATGTCTGCCCTCTGCCACGGCCGCACCCTer cgacatccaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgacgttc datctggttacccttgagcaagcgcaggaacaacagtacgtagagggcggtggaggctcc ccgggtgaaccgtgtggtccaatctctactatcaacgcgtctcctccgtctaaagaatct cataaatctccaaacatggatcccaatgccatcttcctgagcttccaacacctgctccga GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACATGGCGTCTCCCGCTCCGCCTGCTTGTGACCTGCGAGTCCTCAGTAAACTGCTT CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCeTTTGC ^ T ACACCTGTCCTGGTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG GAGACCÀAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA gcacggggacaactgggacccacttgcctctcatccctcctggggcagctttctggacag gtccgtctcctccttggggccctgcagagcctccttggaacgcagggcaggaccacagct CACAAG (SEC DD DC 154)

PMON15981

ATG3CTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA CCTTTGCTGG ACCCGÀACAA CCTCAATGAC GAAGACGT ^ T 101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA yl AGAACTTAGA AAATGCATCA GGTATTGAGG AxGGGCTGTCA CAATT ^ 201 TAATCTCCAA CCATGTCTGC TTCG CCTCTGCCAC GGCCGCACCC TCTCGACATC 211 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACC ui λΰΟ TTCTATCTGG TTACdTTGA GCAAGCGCAG GAACAACAGO ACGTAGAGGG

250 CGGTGGAGGO TOCGCGGGTG ÂACCGTCTGG TCCAATCTCT ACTATOAAOC OGTOTOOTCO GTCTAAAGAA 401 TCTCATAAA7 OTCCAAACAT GTCOTAOAAG 451 CTGTGuCACC CCGAGGAGC7 GGTGCTGCTO GGAGACTCTO TGGGOATCCO 501 CTGGGCTCCC CTGAGCTCCT GCCCCAGCOA GGCCGTGCAG 551 GCTTGAGCCA ACTCCATAGC GGCCTTTTCC 2CGG1AGGOT TCTAGOAGGG GCTGCTGCAG 651 GGATATCCCC CGAGTTGGGT CCCACCTTGG GCOCTGGAAG AOACACTGCA 6 51 GCTGGACGTC GCCGAdTTG CGACCACCAT CTGGCAGCAG ATGGAAGAAO

701 CCCTGCCCTG TGGGAATGGO CAGCCCACCO AGGGTGCCAT GCCGGCOTTO 5.1 GOOTDDGGTO GGCAGGAGGG GTCCTGGTTG CTAGCCATCT TGCAGCGCCG §01 GOAGAGCTTC CTGGAGGTGT CGTACCGCGT TOTACGCCAC CTTGCGCASC 551 OGGGCGGCGG CTCTGACATG GCTACACCAZ TAGGCCCTGC CAGCTCCCTG 511 CCCCAGAGCT TCCTGOTCAA GTCTTTAGAG CAAGTGAGGA AGATC 951 CGATGGCGCA GCGCTCCAGG AGAAGCTGTG uAGGG TGCCACCTAA TAAR

ISEQ I »NO: 155) pNONlSSSl

ATGGGTAAGT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA CCTTTGCTGG AGCCGAACAA CCTCAATGAC GAAGACGTCT 101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAACCTGGA GAGCTDCGTA .151 AGGGCTGTCA AGAACTTAGA AAATGCATOA GGTATTGAGG CATATTGGGACATATG

251 CAATCATCAT CAAGGCAGGT GACTGGOAAG AATTCCGGGA AAAACTGACG 301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG CGGTGGAGGC TCCCCGGGTG AACCGTCTGG 3SI TCOAATCTCT ACTATCAACC 401 GTCTAAAGAA TCTCATAAAT CTCCAAACAT CGTCT1XTCC GTCTCCCGAG 451 TTGGGTCCCA CCTIGGACAC AGTGCAGGTG GACGTCGCCG A2TTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT 501 GCCCTGCAGC 551 TGCCATGCCG GCCTTCGCCT CTGCTTTCCA CCACGCAGGG GCGCCGGGCA 601 GGAGGGGTCC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA 551 CCGCGTTCTA CGCCACGTTG CGCAGCCOGG CGGCGGCTGT GACATGGCTA

CCCTGCCAGC 702 TCCCTGCCCC AGAGCTTCCT GCTCAAGTCT CAOCATTAGG 751 TTAGAGCAAG TGAGGAAGAT CCAGGGCGAT GGCGCAGCGC TCCAGGAGAA 801 GCTGTGTGCC ACCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG 851 GACACTCTCT GGGCATCCCC TGGGCTCCCC TGAGCTCCTG CCCCAGCCAG 901 TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT GCCCTGCAGG 951 CTACCAGGGG CCCTGGAAGG GATATCCTAA TAA CTOCTGCAGG:

IS "Q ID NO: 156)

PMON15965

ATGGCTAAGT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG

ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT 101 CTATOCTGAT GGATCGAAAC CTTCGACTTC CÀAACCTGGA GAGCTTCGTA 151 AGGGCTQTCA AGAACTTAGA AAATGCATCA GGTATTGAGG CÀATTCTTCG 201 TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACA ^ 251 CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG 301 TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG 351 CGGTGGAGGC TCCCCGGGTG ÀACCGTCTGG TCCAATCTCT ACTATCAACC 401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTTCTGCT 45 * TTCCAGCGOG GGGCAGGAGG GGTCCTGGTT GCTAGCCATC TGCAQAGOTT

112

Q £? ç

* rrrr * * rn xf * *, Γ \ A ίΊΧ.Λ. «3 (τΧμ®Γ%. Ir Xw» · CCTOAATGAC UAAACCTGGA γ> ϊ ** ΓΡ λ ry »rr> _s *** *

M3kl a à * * kJtJ & L ^ Lz / *> λ **> x * \ - ^ xRr> “v-¾ · y ** / * # / ** k # U? LL O wK ks. \s. AATTCCGGGA GAAC AAC AG T / * J ₄ ft .®V Xv · X * A JkÍLik ^ h. wL>. Xyv '? W / L Γ ^ ΓΓ' ^ & ΑΓ '^ Τ' X ^. aw JT * · JLccggccttcg TAGCCATCTG TTGCGCAGCC AGCTCCCTGC GATCCAGGGC AGCTGTGCGA CCCTGGGCTC CTGCTTGAGC AG xi x. l, l, TGG A CAGCTGGACG ACTGGGATAA

DM01115 967

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG 51 ACCACCTGCA CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT 101 CTATCCTGAT GGATCGAAAC CTTCGACTTC CAAAOCTGGA GAGCTTCGTA 151 AGGGCTGTCA AGAAOTAGA AAATGCATCA GGTATTGAGG CAATTCTTCG 201 TAATCTCCAA COATGTCTGC CCTCTGCCAC GGCCGCACCC TCTCGACATC 251 CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG OAATCATCAT

UsAACAaCAGT 251 CGGTGGAGGC TCCCCGGGTG acgtagaggg AACCGTCTGG TCCAATCTCT ACTATCAACC 401 CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GTCTACCCAG GGTGCCATGC CGGCCTTCGC CTCTGCTTTC 451 CAGCGCCGGG CAGGAGGGG'r CCTGGTTGCT AGCCATCTGC AGAGCTTCCT GGAGGTGTCG 501 TACCGCGTTC 551 TACGOCACCT TGCGCAGCCC GGCGGCGGCT CTGACATGGC TACACCATTA 5C1 GGCCCTGCCA GCTCCCTGCC CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA t-5x ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG AGTGAGGAAG AÀGCTGTGTG

113

702 dACCTACAA GCTGTGCXAC CdGAGGAGO TGSTGCTGCD

752 CTGGGCATd CCTGGGCTCC CCTGAGCTCC TGOCCCAGCC AGGCCdGC *

802 GCTGGCAGGG IGCTTGAGd AACTOGATAG 2GG22TTTTC CTCTAdAGG sc • -i GGCTCCTGOA GGCICTGGAA GGGATATCCC CCGA.GTTGGG GCdACCTTfe 9G2 GACACA7TG7 AGITGGACGT CGGCGACTT7 GCCACCACGA TdGGCAGCA 952 GATGGAAGAA CTGGGAATGG CCCCTGCCd GCAGCCGTAA TAA (SEQ IS NO: 25 pMON15960 & I

2. ATGGCTAOAC GATTGGGdC TGdAGdd CTGCGCGAGA GCTTCCTGd - 'XAAGTCTTTA GAGCAAGTGA GGAAGATCCA GGGCGATGGC GGAGCGCTG'. 1 * aggagaagct GTGGGCCAd tagaagctgt gecacgccga ggagctggtg 252 GCTCCCCTGA CTGdCGGAl ACTCTGTGGG CATCGCCTGG GCTCdGCd 2C2 CAGCCAGGd CTGCAGCTGG CAGGGTGCTT GAGCCAACTG CATAGCGGC7> ci TTTTCCT0TA CCAGGGGCTG CTGCAGGCCC TGGAAGGGAT 301 TTGGGTCCCA ATCdCCGAG ACTGCAGCTG GACGTCGCCG ACTTTGCCAC C2TTGGACAC? CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT GCCGTGCAGC 401 CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA 452 GGAGGGGTCC tggttgctag ccatctgcag aggttcctgg aggtgtcgta 501 CCGCGdCTA CGCCACCTGG CGCAGCCCGG CGGCGGETCE GAGATGGCTA 551 CACCATTGGG CCCTGCCAGC TCCCTGCCCC AGAGGTTCCG GGTCAAGTC7 6C2 TTAGAGCAAG TGAGGAAGAG CCAGGGCGAT GGCGGAGCGC TCCAGGAGAA 551 GCTGTGTGCC ACOTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG 7 01 GACACTCTCT GGGCATCCCC TGGGCTCOCC TGAGCTCCTG CCCCAGCCAG 751 GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA CTCCATAGCG GCCTTTTCCT CTACCAGGGG 8Q1 dCCTGCAGG CCGTGGAAGG 851 GAGTTGGGTC CCACCTTGGA CACACTGCAG GATA.TGCCCC CTGGACGTCG CCGACTTTGC 901 TGGCAGCAGA TGGAAGAACT GGGAATGGCC CAGCACCATC CCTGCCCTGC AGCCCACCCA 1001 XCGTGGTTGC CAGAGCTTCC TGGAGGTGTC GTACCGCGTT 1052 TAGCGATCTG CTACGCOACC TTGCGGAGCC CTGAEAA (SEC ID NO: 160)

PMON32132

TCTCCCGCTCCGCCTGCTIGTGA-CdCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAC GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTCGTG CTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAGGAGACCAAGGCA CAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCAGCACGGGGACAA CTGGGACCGACTTGCdCTCATCCCTCCTGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGOTCCTCCACAGGGexAGGACCACAGCT CACAAGGATCCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAAAGGTGCGT TTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCdCAGG (SEQ ID NO: 249}

PMON32133

TCTCCCGCTCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAACTGCTTCGTGACTCCCAT GTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCTACACCTGTGCTG CTGCCTGdGTGGACTTTAGCTTGGGAGAATGQAAAACGCAGATGGAGGAGACCAAGGCA CAGGAC ATTCTGGGAGCAGTGACC CTTC7G CTGG AGGGAGTGATGG CAG 2 ACGGGGACAA CTGGGACCCACTTGCCTCTCATCCCTCCrGGGGCAGCTTTCTGGACAGGTCCGTCTCCTC dTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCACAGCTCACAAGGATCCC

114

OOATGGCTAA CTGOTCTATA ATGATCGATG AAATTATACA TCACTTAAAG AGACCACCTG CACCTTTGQT GGACCCGAAC AACCTCAATG ACGAAGACGT CTGTATCQTG ATGGA.TCGAA ACCTTCGACT TCCAAATCTGGGTAGATT

GGTÀATCTCC AACCATGTCT GCCCTCTGGC ACGGCCGCAC CCTCTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATST GGTTACCCTT GAGCAAGCGC AGGAACAACA GTACGTAgag ggcggtggag gccaCCCGGG TGAÀCCGTCT GGTCCAATGT CTACTATCAA CCCGTCTCCT CCGTCTAAAG AATCTCATAA ATCTCCAAAC ATGTAAGGTA

CGCATGCAA GCTT (SEQ ID NO: 257)

Pmar.13130.Seg

OCATGGCTAA CTGCTCTATÀ ATGATCGATG AAATTATACA TCACTTÀÀAG

AGACCACCTG CACQTTTGCG GGACCCGAAC AACCTCAATG ACGAAGACGT

101 CTCTATCCTG ATGGATCGAA ACCTTCGACT TCCAÀAOCTG GAGAGCTTCG

151 TAAGGGCTGT CAAGAACTTA GAAAATGCAT CAGGTATTGA GGCAATTCTT

X. · \ * 7 A Χα · «1 Sm ΛΛ.λΜν-.Λ A \ 3 X Xm a \ 3Xm1om * w X χ ^ χμ Ίμ \ m '^ í

251 TCCAATCATC atcaaggcag GTGACTGGCA AGAATTCCGG GAAAAACTGA

102 Γ · (3Τ'Τ ^, αΤΑ'Τ ' ^Γ * 1 GG'TrACC''''''*' G ^ GCAAG ^ 'G' AGGAACAADA GTAGG ^ fcfra-. ·. <X. xv.'m'X «V.« Μ. X. X λμ. A>. Vwí «m à vJ.Sm.àwVaw · χ SX jCàk \ 7 vú5 íJXjiXa ίΤΟψ'ΛΧ ^ .ψϊ. Χ3ϊ 4 * X? · Χ» vA '- .THE

151 ggoggtggag gatececGGG tggtggttct ggcggcggct ccaacatgtã 401 AGGTÃCCGCA TGCAAGCTT (SEQ ID NO; 25S)

115)

Table 3

Protein Sequences p? Oü26458pep

If P ^ oA ^ a ^ ¹ ^ eProAíaCy SASP euArgValLeuSerLysLeuLeuArgAspS erHi s VaÍLÍuHx5SerArqLeuS "erGlnCysProGluVaIHisProLeuProThrProValLev '.gx proAlaValAspPheSer ^ ^ ^ euGlyGiuTrpLysThrG nMetGluGxuThrLysAia L INASP XI eLeuG lyAlaWl Tnr LeuLeuLeuG lug lyValMe c AlaAxaAr gu iy -> ^LeuG: cThrCysLeuSerSa v ^ ~ X! euLeuGlyGxriLeuSarGlyGXnVarAx "gIjeuX <LeuGlvÃlaLeuGlnSerLeuLeüGlyThrGlnieuProProGlnGlyArgThrThr.Ala i '^, g, YsA5PProAsxiAlaXlôPhel» £ eu.SerPHeGlnHxs jeux; euArgu> Ayl <ysV â ~ A »g PheLeuPletõeuValGlyGlySerThrLeuCysValArgGluPhe (XO SEQ NO: 161) pMON28548pap

3er? S roAlaProProAlacysAspLeuArgVall.euS erkysteulauArgAspSerHi ValLeuHxsSerArgLeuSerG Incy s ProG luValHi s ProLeuPrcThr OVA Pr * ll I LeuProAlaValAspPheSfirLeuGlyGluTTpLysThTGlnMetGluGluThrLysAla GlnAspXleLeuGlyAlaValThrI 'exxLeuLeuGluGlyValMetAlaAlaArgGlyGlu LeuGlvProThrCysLeuSerSerbexibeuGiyGiriLeuGerGlyGlnvalArgLeuCeu LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla HislysAspProAsnAlallePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg PheLeuHetbeuValGlyGlySerThrL.euCysValArgGluPheGlyGlyA2nHetAla serProAlaProProAlaCysAspbetiArgVallíeuSerLysLeuLeuArgAspSerHis vãlGeuEisSerArgLeuSerGlnCysProGluValHisPro ^ euProThrProvalLeu leuPr OAL avalAspPhe S * r l EUG LYG luTrpLysThrG InMe tG lug luThr Lys Al GlnAspXlôLeuGlyAlaValThrLeWGeuLeuGluGlyValMetAlaAlaArgGlyGln the LeuG lyProThr CysLeuS ether LeuLeuG be lyGlnLeuSerG iy glnV wing aleuLev LeuGlvAlaLeuGlnSerLeuLeuGlyThrGlnGlyArgThrThxAlaHisLysAspPro AsnAlaXlePheLeuSerPheGlnHisbeuLeuArgGlyLysValArgPheLetiMetLeu valGlyGlySerThrieuÇysValArg (SEQ XD NO: 162)

PMON28500

S er Pr Al APR the ProAlaCy s AspLeuArgValLeuS erly sbeuLeuAr g ASPs erHi s ValLeuHisSerArgLeuSerG Incy sProGluValHisProLeuProThr Support Ile LeuProAlaValAspPheSerLauGlyGluTrpLysTbxGlPMetGluGluThrLysAla L InAspX 1 eLeuG XyAlaValThrLeuLeubauG lug lyValMe t AlaAlaArgG lyGlxi LeuG ly ProThrOysLeuS er S er LeuLeuG ly GlnLeuS ERG LYG Inv al ArgLeuLeu LeuG ly AlaLeuG ins ether LeuLeuGlyThr L InLeuPra Pr oG XnGlyAr gThrThr Ala HisLysAspPTeAsnAlallePheLeuSerPheGinHisLeuXieuArgGlyLysVaiArg PheLeuHetLeuValG lyGly SerThrleuOy sValArgG luPheGlyAsnMet AlaSer PraAlaProProAlaCysAspLeuArgVaXLepSerLysGeuLeuArgAspSerHisVal beuHisSerArgLeuSerGlnCy sProGluValHi ^f £ ^ ProLeuProThrProValLeu.Lev PrQMaValAspPheSerLeuGlyGluTrpLysThrGlnMecGluGl'uThrLysAlaGln AsplleLeuGlyAlaValThrLeuLeubepGluGlyValMetAlaAlaArgGlyGlnheu GlyProThrCysLeuSarSerLeuLeuGlyGlr euSerGlyGlnValArgLeuLeuLeu GlyAlaLeuGlnSerLeuLeuGiyThrGlnLeuProProGlnGlyArgThrThrAlaHis

116

- v ^ ASOProAenAial lePAeLeuSerPheGxnHiSueuLeuArgulyLysν '& j, ^ ~ .rgΟΉe LeÜHeLLêuValGlyGlySerTnrLeu ^ sValArç; SE2 π / νο ~: Γο3 ^: pMÔKzSTOl

Being ProA laPrc ProAlaOysAspLeuàr gValLeuS erly sLeuLeuAr g AspSer His ValLéüEiáSerArgLeuSerGlnCysProGiuValHisProLeuProThrProValLeu LeuProAlaValAspPheSerLeuGlyGluTrpLysT & rGlnMezGluGluThrLysAla Goa ^ spXiaLeuGlyAlav & lThrLeuLeuLeuGluGlyValMetAlaAiaArgGlyGln LeuGlyProTurC> 'sLeuSerSerLeuLeuGlyGlnLeuSerGlyGXnValArcLeuLeu LeuGlyAlaheuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlyArgThrThrAla HxsLysA ^ pPrcAsnAlaxlePheLeuSerPheGlnHisLeuLeuArgGlyLysValArg PheLeuMeuLeuValG LYG ly SerThrLeuO / sVal ArgGl uPheGly L lyAsnM ether Al S er Pr OAL aProProAlaCy sAspLeuAr gValLeuSerLy sLeuLeuArgAspSer Hi s valLeuHrsSerArgLeuSerGlr.CysProGluValHisProLeuPraThrProValLeu LeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlmeuGluGluThrLysAla G G XnAspG leLeuGIyAlaValThrLeuLeuleuGluGly ValMeoAlaAlaArgGly in LeuGly ProT.hr Gy sLeuSerSerLeuLeuGlyGlxlLeuSerGlyGlnValArgLeuLeu G ly Leu Al EUG InSerLeuLeuG al ly GlnLeuProPr Thr Ala oG InGlyAr gThrThr HmLvsAsDProAsnAlaXlePheLeuSerPheGlnHisLeuLeuArgGlyLvsValAra PheLeUMetLeuValGivGlySerThrLe uCysValArg (SEQ XL ND: 164>

PHON185C2

SerProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHis vs 11 euHisS er Arg! EUS ERG .1 nDysProGl u s ValRi ProLeuProThrProValLeu LeuPrcAlaValAspPheSerLeuGlyGluTrpLysThrGlnMeuGluGluThrLysAia GmAspr ieueuGlyfAlaVaiThrÍjeuLeuLeuuluGlyValMe uAiaAlaArgG lyGln LeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu LeuG Lyal aLsuGlnSer LeuLeuGlyThrGlnLeuProProGlnG XyArgThrThr Ala HisLysAspProAsnAlallePheLeuSerPheGlnHisLauLeuArgGlyLysValArg PheLeuMexLeuValGlyGlySerThrLeuCysValArgGluPheGlyGlyAsnGlyGly AshMet AiaSer.pTQAlaPrGProAlaOysAspLeuArgVaXLeuSerLysLeuLeuArg AspSerHxsValLeuHisSerArgLeuSerGlnCysProGluValHisPrcLeuProT.hr ProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGluGlu GhrLysAlaGlnAspIleleuGlyAlaValThrLeuLeuLeuGluGlyValMetAlaAla ArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnVal Air gLeuLeuLeuG lyAlaLeuGlnS erLeuLeuG lyThrG InLeuProProGlnGly Arg TnrThrAl xsLy H s 1 and AspPr oAsnAl al Ph eleuS er Ph eG InHi sLeuLeuArgGly Ly sVal ArgPheLeuMetLeuV al GiyGly SerThrLeuCy sValAra iSEQ ZD NG: 165)

13162, Pep

Asn Cys

Pro Pro

Will be

Ser Phe ίΧ · aL. ki. yes

X * AS * A,

Ch? ÍaL Ch

Gin GIu uscLn tíà

Ser He Hex lie Asp Glu He Ala Pro Leu Leu Asp Pro Asn lie Leu Meo Asp Arg Asn Leu Vai Arg Ala Vai Lys Asm Leu lie Leu Arg Asm Leu Gin Pre · Pro Ser Arg His Pro Xie Xie Phe Arg Glu Lys Leu Tor Phe Glr. Giu Gm Gin Tyr Vai Gm lie His His Leu Lys Arg Asn Leu Asp Asp Glu Asp Arg Leu Pro Asn Leu Glu Glu Asm Ala Ser Gly Xie Cys Leu Pro Ser A.la Thr Xie Lys Ala Gly Asp Trp Tyr Leu Vai Thr Leu Glu Gly Gly Gly Gly Ser Pro

117

Thr Gin Gly Ala Met. λ.la Gly Giy Vat Leu Val Ser Tyr Arg Will Be Gly Gly Ser Gin Art Lye lie Gin Gly Ala Thr (SSQ XD NO:

Goy Goy Ser Asn

Ser cys Pro Ser Gin Lou His Ser Gly 'Leu Glu Gly Xis Ser ProLeu ASp Va * AlS Asp Glu Leu Gly Met Ale Pro Ala Ph & Ala Ser Vai Ala Ser Hrs Leu Leu Arg His Leu Ala Ser Phe Leu Leu Lys Asp Giy Ala Ala Read 16 6 i

Tie Asp Glu Tie Xie Leu Asp Pro Asn Asn asp Arg Asn Leu Arg Val Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pre Tie He Xie Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Gly Pro Xie Ser Thr lie Lys Ser Pro Asn Met Will Read Read Gly His Ser Cys Pre Ser Gin LiSu h. ^ * S ...... If * .Giy. Heu Glu Gly Xie Ser Pro Leu Asp Vai Ala Asp Gxu ueu. Gly Meo Ala Pro Ala Phe Ala Ser Vai Ala Ser Bis Leu Leu Arg Hrs Leu Ala Ser Phe Leu Leu Lys Asp Gly Ala Leu Wing 167)

His His Leu Lys Arc Leu Asn Asp Giu Asp Leu Pro Asr. Leu Giu asp Ala Ser Gly Xie Leu Pro- Ser Ax a Thr Lys Ala Gly Asp Trp .mêu Vai Thr i ^ eu Glu Gly Gly Gly Ser Pro t ^ XO

Wing Tyr Lys Leu Cys Ser Leu Gly Xie Pro Wing Leu Gin Leu Wing Phe Leu Tyr Gin Gly Giu Leu Gly Pro Thr Phe Wing Thr Thr Xie Pro Wing Leu Gin Pro Am Phe u ~ n Arg Arg Gun Ser Phe Leu Glu Gin Pro Ser Gly Gly Ser Leu Glu Gin Vai Gin Glu Lys Leu Cys

13184.Pept

Asn Cys Ser Xie Met Pro Pro Ala Pro Leu val Ser Xie Leu Met Sex 'Phe val Arg Ala Glu Ala Xue Leu Arg Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu Gm Ala Gm Giu Gin Gj.y Giy Gly Ser Giy

Xie Asp Glu Xie Xie Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Giu Asn Leu Gin Pro Cys His Pro Xie Xie Xie Lys Leu Thr Phe Tyr Gm Tyr vai Glu Gly Gly Gly Ser Asn Met

His His Lev Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly Xie Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Val Thr Leu Glu Gly Gly Gly Gly Ser Pro Aia Pro Giu Leu Gly

118

PiilOyfLil; jAFFlBhr ^

Gin Pre Tnr Gin. Gly Arg., Arg .... Al to · .Sly. .'Gly LiilBiL: lvll: The 'SW' Gly Guy Ser Gly Gly Gin val Arg Lys lie | euiOBliAlai; |||: | ^: Xy: r ^: Leu Gly His Ser Leu

Pre Ser Gin Are Leu

Ser Gly Leu Phe Leu Tyr l.a s «L: SH'l rp NO: 16%

Leu Gin Leu Asp Met Glu Gin Leu Au a Mei Pre A.la val Leu Vai Ale Ger Arc Val Leu Arg His Ser Gin Ser Phe Leu Gir, Gly Asp Gly Ala Lys Leu Sys His Pro Gly Xie Pro Grp- Ale Gin Leu Ala Gly Cys

Gin Gly Leu Leu

Go Wing Asp Wing Till Gly Met Wing Wing Pre Wing Read Phe Wing Be Wing Wing Gin

His Leu Gin Ser Phe Leu Ala Gin Pro Ger u> eu .Uys Ser w £ ^! j G „u Ala Leu Gin. Glu l..ys Glu Glu Leu Vai Leu Pre Leu Ser Ser Cys Leu Ser Gin. Leu His Gun A ^ a ^ I g ~ u Gj.v

12181.Pept

Asr. Oys Ser lie Met Xie Asp Giu Pro Pro Ala Pro Leu Leu Asp Pro Vai Ser lie Leu Met Asp Arg Asn Ser Phe Val Arg Ala V®1 Lys Asn Glu Ala lie Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg Hrs Pro 11® Gi.r. Glu Phe Arg Glu Lye Leu Thr Gin Ala Gin Glu Gin Gin Tyr Vai Gly Glu Pro Ser Gly Pro lie Ser Ser Lys Glu Ser His Lye Ser Pro Pro Thr Leu Asp Thr Leu Gin Leu Tnr lie Trp Gin Gin Met Giu Glu Gin Pre Thr Gin Gly Ala Met Pro Arg Arg Ala Gly Gly Vai Leu Vai Leu Glu Vai Tyr Arg Vai Leu Gly Gly Ser Gly Gly Ser Gin Ser Gin. Go Arg Lys lie Gin Gly Asp Leu Cys Ala Thr Tyr Lys Leu Cys Leu Gly His Ser Leu Gly Xie Pro Pro Ser Gin Ala Leu Gin Leu Ala Ser Gly Leu Phe Leu Tyr Gin Gly lie Ser ISSE XL NO: 159;

Xie lie Hxs Hrs Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ale Ser Gly Xie Pro Cys Leu Pro Ser Ala Thr Xie lie Lys Ala Gly Asp Trp Phe Tyr Leu Vai Tnr Leu Glu Glu Gly Gly Gly Gly Ser Pro Thr Xie Asn Pro Ser Pro Pro Asn Met Ala Pro Glu Leu Gly Asp Vai Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu Ala Phe Ala Ser Ala Phe Gin Ala Ser His Leu Gin Ser Phe Arg His Leu Ala Gin Pro Ser Phe Leu Leu Lys Ser Leu Glu Gly Ala Ala Leu Gin Glu Lys Hrs Pro Glu Glu Leu Vai Leu Trp Ala Pro Leu Ser Gin Cys Gly Cys Leu Ser Gin Leu His Leu Le Ala Leu Glu Gly

13186 * Pept Asn Cys To be lie Men Xie Asp Glu XI® Xie His His Read Lys Arg Pro Pro Allah Pro Read Read Asp Pro Asn Asn Read Asn Asts Glu Asp Go er Xie Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe val Arg Allah Val Lys Asn Read Glu Asn Allah To be Gly Xie Glu Allah Xie Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro To be Arg Hrs Pre· Xie Xie Xie Lys Allah Gly Asp j ΤΤΊ Gin Glu Phe Arg Glu Lys Read Thr Phe Tvr Read Val Thr Read Glu Gin Allah Gin Glu Gin Gin Τντ Val Glu Gly Gly Gly Gly To be Pro Gly Gly Gly To be Gly Gly Gly To be Asn Met Allah Met Allah Pro Allah Read Gin Pro Tnr Gin Gly Allah Met Pro Allah Phe Allah To be Allah Ph®

Lite. pepo

Asn. Cys Ser lie Mor lie Asp Pro Pre Ala Pro read Leu Asp val Ser lie- Leu Mer. Asp Axg Ser Phe Vai Arc Ala Vai Lys Glu Ala Xie Lev Arg Asn Leu Ala Ala Pro Ser Arg Hrs Pro Gin Glu Phe Arg Giu Lys Leu u xn Aza <^ m Giu Gin Gan Tyr Giy Glu Pro Ser Gly Pro lie Ser Lye Glu Ser His Lys Ser ίίδΌ Gm Pro Tor Gin Gay Aza Gin .Arg Arg Aia Gly Gly Va_ Poe Leu Glu Vai Tyr Arg Ser Giy Gly Ser Gly Gly Ser Glu Gin Vai Arg Lys Xie Gin lye Leo Cys Ala Thr Tyr Lys i »eu _ · 'Βν Gly Hrs Ser j ^ eu Gly Cys Pro Ser Gin Ala Leu Gin His Ser Gly Lev Phe Leu Tyr uiy He Ser Pro' Gou Leu Gly .Asp Vai Am Asp Phe Ai.a. Thr Leu Gly ISXQ ID NGi171;

Glu Xie Xie Hrs His Leu Lys Arg Pro Asn Asn Leu Asn Asp; Glu Asp Asn lieu Arg Leu Pro Asn Leu Gau Asn Leu Glu Asn Ala Ser Gly Xie Gin Pro Oys Leu Pro Ser Ala Thr Xie Xie Xie Lys Ala Giv Asn Trp Thr Phe Tyr Leu vai Thr Leu Glu Vai ulu oly Gly uiy Giy Ser Pro Ser Thr lie Asn Pro Ser Pro Pm Pro Asn Men Ala Met. Pro Wing Wing Met Wing Wing Phe Wing Wing Wing Phe Leu. Vai Aia Sex Has Leu Gin Ser Vai Leu Arg His Leu Ala Gm Pro Gin Ser Phe Leu Leu Lye Ser Leu Gly Asp Gly Ala Ala Leu Gin Glu Leu Cys His Pro Glu Glu Leu Vai He Pro Tip Ala Pro Leu Ser Ser Leu Ala Gly Cys Leu Ser Gin Leu Gin Giy Leu Leu Gin Ala Leu Glu Pro Thr Leu Asp Thr Leu Gin Leu Thr Xie Trp Gin Gin Met Glu Glu

13188, Pent

Asn Cys Ser He Met Xie Asp Pre · Pro Ala Pro Leu Leu Asp Vai Ser Xie Leu Men Asp Arg Ser Phe Vai Arg Ala Vai Lys Glu Ala ale Leu Arg Asn Leu Ala Ala Pro Ser Arg His Pro Gin Glu Phe Arg Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr Gly Gly Gly Ser Gly Gly Gly Men Pm Ale Phe Aia Ser Ala Leu Vai .Ala Ser Has Leu Gin

Glu Xie Xie His His Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu ^% sn ueu Glu Asn Axa Ser Giv Xie Gin Pm Cys Leu Pro Ser Ala Thr Xie Xie Xie Lys Ala Gly Asp Trp Thr Phe Tyr Leu Vai Thr Leu Glu Vai Glu Gly Giy Giy Gly Ser Pro Ser Asn Met Ala Thr Gin Gly Ala Phe Gin Arg Arg Ala Gly Giy Vai Ser Phe Leu Glu Vai Ser Tyr Ara

120

Vãl Leu Arc HrS A-.a G- * Gln 0 © r le le Le Lys Ser Glv asp Giy Al® Al® Leu Gin Leu Cys Hüs Pre Glu Glu Leu 1.1 and Pre TTP Ale Pre- Leu Ser Leu Ala Giy Cys Leu Ser Gin Gin Gly Leu Leu Gin Ala Leu Pro Ter Leu Asp Tr.r Leu Gin Thr lie Trp Gin Gin My Glu Gin Pm íSHl ZD NCu u7u. ·

Pro Ser Gly Gly Ser Gly Guy Ser Leu Glu Gin val Arg Lys Gin Glu Lys Leu Cys Ala T.nr Tyr Lys Val Leu Lea Gly His. Ser Leu Gly Ser Cys Pre Ser Gin Ala Leu Gin Leu Hus Ser Gly Leu Phe Leu Tyr Giu Gly Lie Ser Pro Glu Leu Gly Leu Asp Val Ala Asp Pne Aln Tnr Glu Leu Gly Met. A.ua Pro Wing ^ eu

2.Σ.189. PeptAen Cys Ser lie Met Xie ASp Pro Pre Alè Pro Leu Leu Asp v®2 Ser Xie Leu Neu Asp Arg Ser Phe Vai Arg Ala Vai Lys Glu Ale ZD- Leu Arg Asn Leu Ala Wing Pro Ser Arg His Pro Gin Glu Pine Arg Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr Gly Glu Pro Ser Gly Pro Xie Ser Lys Glu Ser Hrs Lys Ser Met Pro Ala Phe Ale Ser Alu Leu Vai Ala Ser His Leu Gin Vai Leu Arg His Leu Ala Gin Gin Ser Phe Leu Leu Lys Ser Gly Asp Guy aj, ® ala Leu Gun Leu Cys His Pro Glu Glu Leu Lie Pre Trp Ala Pro Leu Ser Leu Ala Gly Cys Leu Ser Gin Gin Gly Leu Leu Gin Ala Leu Pro Thr Leu Asp Thr Leu Gin Thr Xie Trp Gin Gin Met Glu Gin Pro (SSQ ZD NO: 173)

Glu Xie Xie His Hus Leu Lys Arc Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Asn Ala a ex uly ~ ue Gin Pro Cys Leu Pro Ser Ala Thr Xie He Xie Lys Ala Gly Asp Trp Thr Phe Tyr Leu Val Thr Leu Glu Val Glu Gly Gly Gly Gly Gly Ser Pro Ser Thr Xie Asn Pro Ser Pro Pro Pro Asn Met Ala Thr Gin Gly Ala Phe Gin Arg Arg Ala Gly Gly Val Ser Phe Leu Giu Val Ser Tyr Arg Pro Ser Gly Gly Ser Gly Gly Ser Leu Giu Gin Val Arg Lys lie Gin Glu Lys Leu Cys Ala Thr Tyr Dys Val Leu Leu Gly His Ser Leu Gly Sei Cys Pro Ser Gin Ala Leu Gin Leu His Ser Gly Leu Phe Leu Tyr Glu Gly Xie Ser Pro Glu Leu Gly Leu Asp Val Ala Asp Phe Ala Thr Glu Leu Gly Met Ala Pro Ala Leu

13190 ₄ Peps

Asn Cys Ser Xie Met Xie Asp Glu Pro- Pro Ala Pro Leu Leu Asp Pro Val Ser Xie Leu Met Asp Arg Asn Sei- Phe Val Arg Ala Val Lys Asn Glu Ala lie Leu Arg Asn Leu Gin Ala Pro Ser Arg His Pro Xie Gin Glu Phe Arg Glu Lys Leu Thr Gin Ala Gin Glu Gin Gin Tyr Val Gly Gly Gly Ser Gly Gly Gly Ser Arg Arg Ala Gly Gly val Leu val Leu Glu Val Ser Tyr Arg Val Leu Gly Gly Ser Gly Ser Gin Ser

Zle lie His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ala Ser Gly Xie Pro Cys Leu Pro Ser Ala Thr Xie Xie Lys Ala Gly Asp Trp Phe Tyr Leu Vai Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Asn Met Ala Ser Al Pha Gin Ala Ser His Leu Gin Ser Phe Arg His Leu Ala Gin Pro Ser Phe Leu Leu Lys Ser Leu Glu

121

Asn Cys Ser cis Met Tie Asp Pro Pro Ala Pro Leu Leu Asp Vsl Ser lie Leu Met Asp Arg Ser Phe Vai Arg Ala Vai Lys Oil / ii-β * ueu .ur.o asp iueu Ala Wing Pre Ser Arg His Pro Gin Glu Phe Arg Glu Lye Leu Sir Ala Gin Glu Gin Gin Tyr Gly Glu Pro Ser Gly Pro lie Ser Lys Glu Ser His Lys Ser Arg Ar $ Ara Gly Giy Vai Leu Leu Glu Vai Be Tyr Arg Vai Gly Gly Ser Gly Gly Ser Gin Gin Vai Arg Lys lie Gin Gly Leu Cys Ala Thr Tyr Lye Leu Leu Gly His Ser Leu Gly lie Pro Ser Gin Ala Leu Gin Leu Ser Gly Leu Phe Leu Tyr Gin Xie Ser Pro Glu Leu Gly Pro vai Ala Asp Phe Ala Thr Tnr Guy Met Aza Pro Wing Leu Gm Phe Wing ISSQ ”0 NO: 175)

Glu Xie Xie His His Leu Lye .Arg Pre Asn Asn Leu Asn. Asp Glu Asp Asn played Arg played for Asn rev Suu Asn ueu. Giu Asn Aj.a Ser Gly Xie Gin Pro Cys Leu Pre Ser Ala Thr Xie Xie Xie Lys Ala Gly Asp Trp Thr Phe Tyr Leu Vai Thr Leu Glu Vai Glu Gly Gly Gly Gly Gly Ser Pro Ser Thr Xie Asn Pro Ser Pro- Pro Pro Asn Met Ala Ser Ala Phe Gin Vai Ala Ser His Leu Gm Ser Phe Leu Arg His Leu Ala Gin Pro Ser Ser Phe Leu Leu Lys Ser Leu Glu Asp Gly Ala Ala Leu Gin Glu Lys Cys His Pro Glu Glu Leu Vai Leu Pro Trp Ala Pro Leu Ser Ser Cys Ala Gly Cys Leu Ser Gin Leu His Gly Leu ^ eu Gin Aaa Leu Glu Gly Thr Leu Asp Thr Leu Gin Leu Asp lie Trp Gin. Gin Met Glu Glu. Leu Pro Thr Gin Gly Ala Met Pro Ala

13192.Pept

Asn Cys Ser He Het Xie Asp Pro Pro Ala Pro Leu Leu Asp val Ser Xie Leu Met Asp Arg Ser Phe Vai Arg Ala Vai Lys Glu Ala lie Leu Arg Asn Leu Ala Ala Pro Ser Arg His Pro Gin Glu Phe Arg Glu Lys Leu Gin Wing Gin Glu Gin Gin Tyr Gly Gly Gly Ser Gly Gly Gly His Pro Glu Glu Leu. Go Leu Trp Ala Pro Leu Ser Ser Cys Gly Cys Leu Ser Gin Leu His i ^ eu Leu oln Ala ueu Glu Glu

Glu Xie Xie His His Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu. Pre Asn Leu Glu Asn Leu Glu Asn Wing Ser Gly Xie Gin Pro Cys Leu Pre Ser Wing Thr Xie Xie Xie Lys Wing Gly Asp Trp Thr Phe Tyr Leu. Vai Thr Leu Glu Vai Glu Gly Gly Gly Gly Ser Pro Ser Asn Met Ala Tyr Lys Leu Cys Leu Gly His Ser Leu Gly Xie Pro Pro Ser Gin Ala Leu Gin Leu Ala Ser Gly Leu Phe Leu Thur Gin Gly Xie Ser Pro Glu Leu Gly Pro Thr

122

13192. Peer

Asr. Cys Ser lie Mee Xie Asp Glu Xie Xie His His read lys Arc Pro Pro Ala Pro read read Asp Pre Asa Asn Leu Asn Asp Glu Asp Vai Ser leu Met Asp Arg Asa Leu Arc Leu Pro Asn Leu Glu Ser Phe Vai Arg Ala Vai Lys Asn Leu Glu Asn Ale Ser Gly He Xlu Ala Ils Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pre He He lie Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr val Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Xie Ser Thr He Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Tyr Lys Leu Cys His Pro Glu Glu Leu Vai Leu Leu Gly His Ser Leu Gly He Pro Crp -Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Sly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Le Al Gin Lea Leu Glu Gly Xie Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Vai Ala Asp Phe Ala Thr Thr He Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Alô Ser Phe G Wing in Arg Arg Ala Gly Gly Vai Leu Vai Ala Ser His Leu Gin Ser Phe Leu Glu Vai Ser Tyr Arg Vai Leu Arg His Leu Ala Gin Pro Thr Pro Leu Gly pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lá Ser Leu Gáu Gin ford. Arg Lys He Gm uty Asp Giy Ala Ala x ^ eu Gin Glu Lys Leu Cys Ala Thr ISSEQ X.D NO; 177;

rtSTQfl Pj & Ty **

Asn Cys Ser He Met Xie Asp Glu Xie Xie His His Leu Lys Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Vai Be He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly He Glu Ala He Leu Arg Asn Leu Gin Pro cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Xie Xie He Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Vai Glu Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Vai Ala Asp phe Ala Thr Thr He Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gm Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gin Arg ^- Arc Ala Giy Gly Vai Leu Vax Ara Ser Hrs Leu Gun Ser Phe Leu Glu Vai Ser Tyr Arg Vai Leu Arg His Leu Ala Gin Pro Thr

read Pro Gin Ser Phe Leu LevLys

Xie Git Ή asu Gey Ara rus ^ eu ^ ^y r LA ^ Sx lu ^ li Ov ^ p'X * CGlV

Leu Gly He Pro Trp Ala ProLeu

Leu Gin Lev Ara G-iy Cys LeuSer

Leu Tyr Gm Giy Leu Leu G-.r.Au®

Y.J. · ’· >>.

Asn Cys Ser lie Met lie Asp p-o Pre Ala Pro Leu Leu Asp Vai Ie Leu Met Asp Arg jy \ n ^ V & ~. riXQ j & jlcí v -Wj -id Glu .Ala Xie Leu Arg Asn Leu ·> · '- ’Ί.« Pf-'. Cssr- jsT-rt Hie Pro Glr Glu Phe Ara Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr Gly Glu Pro Ser Gly Pre He Ser Lys Glu Ser Hus Lys Ser Pre · Thr Lee Asp Thr Leu Gin Thr Xie Try Gin Gin Men Glu Gin Pro Thi Gin Gly Ala Met Are Arg ..->. 0® uoy Hy va * i ^ eu Leu Glu val ser Tyr Arg val Pro Leu Gly Pro Ala Ser Ser Ser Leu Glu Gin Vai Arg Lys Gin Glu Lys Leu Cye Ala Thr Leu Vai Leu Leu Gly Hrs Ser Ser Ser cys Pro Ser Gun Al® Gin Leu His Ser Gly Leu Phe Leu Glu Glv Xie Ser (SEQ XL

Glu Xie He Kos Has Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Asn. Ala Ser Gly He Gin Pro Cys Leu Pro Ser Al® Thr He Xie Xie Lys Ala Gly Asp Trp Thr Phe Tyr Leu Vai Thr Leu Glu Vai Glu Gly Gly Gly Gly Guy Ser Pro Ser Thr Xie Asn Pro Ser Pro Pro Asn Meo Ala Pro Glu Leu Gly Leu Asp Vai Ala Asp Phe Ala Thr Glu Lev Gly Met Ala Pro Al a Leu Pro Ala Phe Ala Ser Ala Phe Gin Vai Ala Ser His Leu Gin Ser Phe Leu Arg His Leu Ala Gm Pro Thr Leu Pro Gin Ser Phe Leu Leu Lys: 1s Gin Gly Asp Gly Ala Ala Leu Tyr Lys Leu Cys His Pro Glu Glu Leu Gly He Pro Trp Ala Pro Leu Leu Gin Leu Aaa Guy cys Leu Ser Leu Tvr Gin Gly Leu ueu Gin Aus NO: 17S)

13194. Papt

Asn Cys Ser He Met He Asp

Pro Pro Wing Pro Leu Leu Asp

It Will Be He Leu Meo Asp Arg

Ser Phe Vai Arg Ala VaiLys

Gm Aia Xie Leu Arg AsnLeu

Al® Al® Pro Ser Arg HisPro

Gin Glu Phe Arg Glu LysLeu y * -x * 1 -s i> * * 5 *>. r * Ί »'γ» * Γ? Ί r * T **

ΛΧώ X3-1> U \ 21.d \ aXli *

Gly Gly Gly Ser Gly GlyGly

Read Gin Pro Thr Gin GlyAla

Gin Arg Arg Ala Gly Gly

Phe Leu Glu Will Be Tyr Arg

Thr Pro Leu Gly Pro Ala Ser

Lys Ser ¹ Leu Glu Gin Vai Arg

Leu Gin Glu Lys Leu Cys Wing

Glu Xie He Kos Hrs Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Asn Al® Ser Gly Xie Gin Pro Cys Leu Pro Ser Ala Thr He Xie He Lys Ala Gly Asp Trp Thr Phe Tyr Leu Vai Thr Leu Glu Vai Glu Guy Gly Gly Gly Ser Pro Ser Asn Met Ala Met Ala Pro Ala Met Pro Ala Phe Ala Ser Ala Phe Leu val Ala Ser His Leu Gin Ser Vai Leu Arg His Leu Ala Gin Pro Ser Leu Pro Gin Ser Phe Leu Leu Lys He Gin Gly Asp Gly Ala Al a Thr Tyr Lys Leu Cys His Pro Glu

Her Glu Glu Leu Gly

Gly Hxs ser Leu Giy Ser Gin Ala Leu Gin Gly Leu Phe Leu Tyr Ser Pre Glu Leu Gi.y Ata. Asp? Fi & Au® Tur </ - 'ζΛ, -'. - * * “·. M. * x \ 1 □ f 1 ’*** · *“ ’Xv w <.MfeWV. ·

· * - ’y τ x C? & O ~

Gly Glu Pre ser Gly Pro Xie .Ser Lys Glu Ger His Lys Ser Leu Gin Pre Thr Gin Gly Ala Gin Arg Arg Ala Gly Gly Tel Phe Leu Glu Vai Tyr Arg Thr Pro Leu Gly Pro Ala Ser Lvs Ser Leu Glu Gm vax. Arg Leu Gin Glu Lys Leu cys Ala Glu Leu Val Leu Leu Gly His Leu Ser Ser Cys Pro Ser Gin Ser Gin Leu His Ser Gly Leu Ala Leu Glu Gly lie Ser Pro Leu Gin Leu Asp Vai Ala Asp Met Glu Giu Leu Giy iSuQ ~ .T

Glu He He His Has Leu Lye Arg Pro Asn Asn i »eu Asn Asp Gtu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu uiu Asn asa aez v * y ~» ΐ “Gin Pro Cys Leu Pro Ser Ala Thr He He He Lys Ala Gly Asp Trp Thr Phe Tyr Leu Val Thr Leu Glu Val Glu Gly Gly Gly Gly Gly Ser Pro Ser Thr Xie. Asn Pro Ser Pro Pro Pro Asn Met Ala Meo Ala Pro Ala Met Pro .Ala Phe Ata aer Ata Pne Leu Val Ala Ser Tils Leu Gin Ser Val Leu Arg Hrs Leu Ala Gin Preset Leu Pro Gin. Ser Phe Leu Leu Lys He Gin Gly Asp Gly Ala Ala Thr Tyr Lys Leu Cys His Pro Glu Ser Leu Gly He Pro Trp Ala Pro Ala Leu Gm Leu Ala Gly Cys Leu Phe Leu Tyr Gin Gly Leu Le Glu Leu Gly Pro Thr Leu Asp Thr Phe Ala Thr Thr He Trp Gin Gin NO: 181)

12156. Part

Asn Cys Ser He Met Xie Asp Glu Pre Pro Ala Pro Leu Leu Asp Pro A *. Ser «reads Leu Met Asp Arg Asn Ger Phe Vai Arg Ala val Lys Asn Glu Ala He Leu Arg Asn Leu Gin Ala Al Pro Ser Arg His Pro He Gin Glu Phe Arg Glu Lys Leu Thr Gin Ala Gin Glu Gin Gin Tyr val Gly Gly Gly Ser Gly Gly Gly Ser Met Pro Wing. Phe Ala Ser Ala Phe m v & u Ara Ser Hts ueu Gm Ser Val Leu Arg His Leu Ala Gin Pro Ser Leu Pro Gin ser · Phe Leu Leu Lys xj_e Gan Guy Asp Guy Aaa Ala Thr Tyr Lys Leu Cys His Pro Glu Ser Leu Gly He Pro Trp Ala Pro

He He His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu .uau Gxu Asn? Js ser Gly lie Pro Cys Leu Pro Ser Ala Thr lie He Lys Al® Gly Asp Trp Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Asn Met Ala Thr Gm Gly Ala Gin Arg Arg Ala Gly Gly val Phe Leu Glu Val Ser Tyr Arg Thr Pro Leu Gly Pro Ala Ser Lys Ser Leu Glu Gin Val Arg Leu Gin Glu Lys Leu cys Wing Glu nsu Val Leu Leu Gly His Leu Ser Ser Cys Pro Ser Gin

Giv Cvs Leu Ser Gin Leu neu Gm Ala Leu Leu Asp Thr Leu Gin 'v * * ** t / X' 1. *>. * ”Th * · ** · - \ ~ ·· * ~ ·» · *: * ·· * '- ** -S · * «· (SSQ XL NO: 181'

Leu His Ser Gly Leu Glu Giy lie Ser Pro Leu Asp Vaz A .-. A. Asr

Glu Leu Gzy Mac Wing

1319 “. Pent

Asn -Cys Ser —ie Met Pro Pre Ala Pre Leu will be Xie Leu Met Ser Phe vax Arg Ala Glu Ala lie Leu Arg Ala Ale Pro Ser Arg Gin Giu Phe Arg Glu uln Aza Gin Giu Gin Gly Glu Pro Ser Giy Ser Lys Glu Ser Hrs Met Pre Ala Phe Ala Leu Vai Ala Ser His Vai Leu Arg His Leu Ser Leu Pro Gin Ser Lys He Gin Gly Asp Thr Tyr Lys Leu Cys Ser Leu Gly Tie Pro Ala ljSu u-zn ueu Ala Phe Leu Tyr Gin Gly Glu Leu Gly Pro Thr Phe Ala Thr Thr He Pro Ala Leu Gin Pro

He Asp Glu He He Leu Asp Pro Asn asx Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pro Cys Hie Pro Xie Xie Xie Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Giy Pro Xie Ser Thr Xie Lys Ser Pro Asn Met Ser Al Pha Gin Arg Leu Gin Ser Phe Leu Ala Gin Pro Thr Pro Phe Leu Leu Lys Ser Gzy Ala Al Leu Gm His Pro Glu Glu Leu Trp Ala Pro Leu Ser Gly Cys Leu Ser Gin Leu Leu Gin Aza Leu Lep Asp Thr Leu Gin Trp Gin Gin Met Glu (SEC XL NO: 1S3)

His His Leu Ινε Arc Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Ann Aia Ser Giy Xue üôu Pro Ser Ala Tnr Lys Ala Gly Asn Trp i-fSu Vaz Thr Leu Gzu Gly Gly Gzy Ser Pro Asn Pro Ser ProAla Thr Gin Gly Aia Arg Aia Gly Gly Vai Glu Vai Tyr Arg Leu Gly Pro Aza Ser Leu Glu Gin Vai Arg Glu Lys Leu Cys Ala vai Leu Leu Giy His Ser Cys. Pro Ser Gin Leu His Ser Gzy Leu Gzu Gly He Ser Pro Leu Asp Vai Ala Asp Gzu Leu Gly Met Aza

131 $ δ. Pep ”.

Asn Cyra Ser Xie Met Pro Pro Ala Pro Leu Vai Ser Xie Leu Met Ser Phe Vai Arg Ala G ^ u ai3 ile Leu Arg Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu uln Aza Gin Glu Gin Giy Giy Gly Ser Gly Arg Arg Ala Gly Giy Leu Glu Vai Tyr Pro Leu Gly Pro Ala Ser Leu Glu Gin Vai Gin Glu Lys Leu Cys íj®u vaz ueu Leu Gly Ser Ser Cys Pro Ser

He Asp Glu He Xie Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pro He He Xie Lys Leu Thr Phe Tyra Gin Tyr Vai. Glu Gly Gly Gly Ser Asn Met Vai ueu Vai Aza Ser Arg Vai Leu Arg His Ser Ser Leu Pro Gin Arg Lys Xie Gin Gly Ala Thr Tyr Lys Leu His Ser Leu Gly He Gin Ala Leu Gin Leu Leu Phe Leu Tyr Gin

His His Leu Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Gzu Asn Ala Sex * Gly He Leu Pro Ser Aia Thr Lys Ala Gly Asp Trp Leu Vai Thr Leu Glu Gly Gly Gly Gly Ser Pro Ala Ser Ala Phe Gin His Leu Gin Ser Phe Leu Ala Gin Pro Thr Ser Phe Leu Leu Lys Asp Gly Ala Ala Leu Cys His Pro Glu Glu Pro Trp Aia Pro Leu Ala Gly Cys Leu Ser

G.zy. x & i i ^ i uzn A.x ^

126

Giu Giy Xxs SeT Pro Giu Gii

Giu Giu read Gly Met Wing Pro Mei Pro Wing Phe. Ala? SEC ID

Lsu Gly Pro Thr Leu Asp Thr Leu Wing Thr Thr Tie Trp Gin Glr. Mee Ax to x ^ au Gin Pro. Tnr Çar δ — v Ax.a NO: 184 '

Ast Cys Ser Xie Mee Ils Asp Pro Pro Ax a Pro Leu Leu Asp Val Ser Xie Leu Met Asp Arc Ser Pne Vai Arg Ala Vai Lys Giu Ala Tie Leu Arg Asn Leu Ala Ala Pro Ser Arc rile Pre Gin Giu Pne Arg Giu Lys Leu Gia Ala Gia Giu Gia Gin Tyr Gly Giu Pro Ser Gly Pro lie Ser Lys Giu Ser Hrs Lys Ser Arg Arg Ala Gly Gly 'Vai Leu leu Giu Vai Ser Tyr Arg Vai Pro Leu Gly Pro Ala Ser Ser Leu Giu Gin val Arg Lys Gin Giu Lys Leu Cys Ala Thr Leu Val Leu Leu Gly His Ser Ser Ser Cys Pre Ser Gin. Wing Gin Leu Hrs Ser Gly Leu Phe Leu Giu Gly Xie Ser Pro Giu Gin Leu Asp Val Wing Asp Phe Giu Giu Leu Gly Met Wing Pro Met Pro Wing Phe Wing iSEQ XD

Giu lie Xie Has Has Leu Lye Arg .Pre & sn Asn Leu Ast Ast. · Giu Asp Asr. Leu Arg Leu Pro As? Leu Giu Asn Leu Giu Asm Ala Ser Gly lie Gin Pro Cys Leu Pro Ser Ala Thr Xie Ils lie Lys Ale Gly Asp Trp Tar Pile Tyr Leu Vai Thr Leu Giu Lac xsuu Gxy Guy Guy 'Gay Ger Pre Ser Thr lie Asn Pro Ser Pro Pro Pro Asn Met Ala Ser Ala Phe Gin Vai Ala Ser His Leu Git Ser Phe Leu Arg Hrs Leu Ala Gin Pro Thr Leu Pro Gin Ser Phe Leu Leu Lys Xie Gau Gly Asp Gly Ala Ala Leu Tyr Lys Leu Cys His Pro Giu Giu Leu Gly Xie Pro Trp Ala Pro Leu Leu Gin Leu Ala Gly Cys Leu Ser Leu Tyr Gin Gly Leu Leu Gin Ala Leu Gly Pro Thr Leu Asp Thr Leu Ala Thr Thr Xie Trp Gin Gin Met Ala Leu Gin Pro Thr Gin Gly Ala NO: 185 ) '31104, Pap

Leu Asp Pro Asn Asn Leu Asn Asp Asp Arg Asn Leu Arg Leu Pro Asn Vai Lys Asn Leu Giu Asn Ala Ser Aar. Read Pro Gin Cys Read Pro Ser His Pro Xie lie Xie. Lys Ala Glv Lys Leu Thr Phe Tyr Leu Vai Thr Gin Gly Gly Gly Ser Asn Cys Ser His His Leu Lys Arg Pro pro Ala Gly Gly Ser Pro Gly Giu Pro Ser Pro Ser Pro Pro Ser Lys Giu Ser Thr Gin Gly Ala Met Pro Ala Phe Ala Gly Gly Vai Leu Vai Ala Ser Vai Tyr Arg val Leu Ara Has Ser Gly Gly Ser Gin Ser Phe Leu Arg Lys Xie Gin Gly Asp Gly Ala Ara Thr Tyr Lys Leu Cys Hrs Pro Hrs Ser Leu Gly Xie Pro Trp; Allah

Giu Asp Val Ser lie Leu Met Leu Giu Ser Phe Val Arg Ala Gly Xie Giu Ala Xie Leu Arg Ala Tor Ala Tor Ala pro Ser Arg Asp Trp Gin Giu Phe Arg Giu Leu Giu Gin Ala Gin Giu Gin Xie Met Xie Asp Giu Tie lie Pro Leu Tyr Val Giu Gly Gly Gly Pro lie Ser Thr Xie Asm Hrs Lys Ser Pro Asn Met Ala Ala Ser Ala Phe Gin Arg Arg His Leu Gin Ser Phe Leu Giu Leu Ala Gin Pro Ser Gly Gly Leu Lye Ser Leu Giu Gin Val Ala Leu Gin Giu Lys Leu Cys Giu Giu Leu Val Leu Leu Gly Pro Leu Ser Ser Cys Pro Ser

t.

Let; , Λ:

At

- ia

AX & $ 5 ^ Λ # Χ ν ' ; :; n ΡΧΌ Ssr hXC * AxhJ uslV Asp Trp Val Xi’Sx Glu cys S ^ r lie Met Ax © Leo Çí » X I Met Phe go* Arg Al a Gly Giy To be Pro Pro To be py Gly A-a Met. <* '* χ,, Gly Vs. J. To be ΑχΌ Val

x and uys

Val (? Lv

Asp

i.-.lU x> **

ASH xy lie Asn Leu Leu

Pro

Asn

His

LivV S

Read ie he

If:

Read

Tyr

His

Asn Asp

Let ueu lie

Met * '

AxS:

At a Arg Phe

Phe

If

Phe

Read

If

If.

Lys

Read □

wow

Glu

Read

Read

Allah

Read

Allah

Ser Asp

Allah Tyr Lys Read Cys His Pre Glu Glu Read Go Read Read H1S To be Read Gly Xle Pro Trp Ax a Pro Read To be To be Cys Pro Allah Read Gin Read Allah Gly TVs Read Xi <h> Gin Read His, To be Phe Read Tyr Gin Gly Read Read Gin Allah Read Giu Gly Xie ? ^ Γ0 Gl.'x wow Gly Pre Thr Read ASp Thr Read n *) n · \ 3XXjfe < Read Asp Val Asp Phe Allah Thr Thr xle Gin Gin Met Glu Glu wow Gly -jCiXíSx Pro - *% X © Read Gin Pro (SEQ XI : AT THE : 187}

Gly

Set ”

Al a

Met

Arg

311Q6. Pep

Ala Pre Ser Arg Hxs Pro Xie Glu Phe Arg Glu Lys Leu Thr .Ala Gin Glu Gin Gin Gly Gly Asp Glu ile Xie His His Leu Asp Pro Asn Asn Leu Asn Asp Arg Asn Leu Arg Leu Pro Asn Lys Asn Leu Glu Asn Ala Ser Leu Gin Pro Cys Leu Pro Ser Gly Gly Ser Pro Gly Glu pro Pro Ser · Pro Pro Ser Lys Glu Thr Gin Gly Ala Met Pro Ala Ata Gly Giy Vai read Val Aia Val Ser Tyr Arg Val Leu Arg Ser Giy Gly Ser Gin Ser Phe Arg Lys Xie Gin Gly Asp Gly Ala Thr Tyr Lys Leu cys His His Ser Leu Glv Xie Pro Tro

Xie Xie Lys Ala Gly Asp Trp Gin Phe Tyr Leu Val Thr Leu Glu Gin Gly Ser Asn Cys Ser Xie Met. Xie Lys Arg Pro Pro Ala Pro Leu Leu Glu Asp Val Ser Xie Leu Met Asp Leu Glu Ser Phe Val Arg Ala val Giy lie Glu Ala Xie Leu Arg Asn Ala Thr Ala Tyr Val Glu Gly Gly Ser Gly Pro Xie Ser Thr Tie Asn Ser His Lys Ser Pro Asn Met Ala Phe Ala Ser Ala Phe Gin Arg Arg Ser Hxs Leu Gin Ser Phe Leu Glu His Leu Ala Gin Pro Ser Gly Gly Leu Leu Lys Ser Leu Glu Gin Val Ala Ala Leu Gin Glu Lys Leu Cys Pro Glu Glu Leu Val Leu Leu Gly Ala Pro Leu Ser Ser Cys Pro Ser

128

Gin Ala Leu Gin Leu

Leu Phe Leu Tyr Gin

^,. 1 Λ ** l) £ d · _u v wv w> .Am · * ·, v. * ·> ·. '

lie Tm Gin Gin .Mac Pre »SEQ XL NO: .188

Sin Leu Asp Vai Ala ’» j „u us ~ .u i ^ eu wasiv Met.

Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Tat u * eu Gau uan Ara Gm oat llr. Gm Gly Gly uly Ser Asn Cys Ser Xie Bee lie Asp Glu Xie Xie His His Leu Lys Arg Pre Pre Ala Pre Leu Lep Asp Pre Asn Asn Leu Asn Asp Glu Asp It will be lie Leu Met Asp Arg Asn. Leu Arg Leu Pro Asn Leu Glu Ser Phe Vai Arg A.iS · Vai. Lye Asn Leu Gru Asn Axa Ser Gay Xia Glu A.2 Xie Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro lie Xie Xie Lye Tyr Vai Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro lie Ser Thr Xie asp Pro ser Pre Pro Ser Lys Glu Ser Hrs Lys Ser Pro Asn Met. Ale Tnr Gm Gay Aa »Hex Pro Ale Phe Ala Ser Are Phis Gin Arg Arg A ~ s Gay Gay Vaz. Leu Vai Ala be His Leu Gin Ser Phe Leu Glu Vai Be Tyr Arg Vai Leu Arg Has Leu Ala Gin Pro Ser Gly Giv Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Vai Arg Lys Xia Gin Gly Asp Gly Ala Ala Leu Gan Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Vai Leu Leu Gly Has Ser 'Lev. Gly Xie Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser

Read Gin Read Aaa Gly Cys Saw· Gin ΆμΓΛαχ Vi His To be Gly Lev Phe Read / 111 / Gly Read Read Gin Allah Read Glu Gly Xle To be fx ‘Ή -Í  4 * '4 *' V * *. Μιλ Srf · Read Gvy Pro Read Asp Thr LfiU Gin Read Asp V to v Allah Asp Phe Allah Φητ X Xle Trp Gin Gin Met Glu G ' Read Gly Met

Aza Pro Ala Leu Gin Pro (ISQ XD NO: 189)

31109. Pep

Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Vai Ser lie Leu Met Asp Arg Asn Leu Arg Leu Pro Ann Leu Glu Ser Phe Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly xle Glu Ala He Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arc Has Pro Xie lie Xie Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Tim Phe Tyr Leu Vai Thr Leu Glu Gin Ala Gin Glu Gin Gin Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Ser Asn Cys Ser xle Met. He Asp Glu Xie ale Has His Leu Lys Arg Pro Pro Ala Pro Leu Tyr Vai Glu Gly Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly pro Hs Ser Thr Xle Asn Pro Ser Pro pro Ser Lys Glu Ser His Lys Ser Pro Asn Met. Ala Thr Gin Gly Ala Met pro Ala Pne Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Vai Leu Vai Ala Ser His Leu Gin Ser Phe Leu Glu Vai Be Tyr Arg Vai Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Ser Gin Ser Phê Leu Leu Lys Ser Leu Glu Gin Vai Arg Lys Xie Gin Gly Asp Gly Aaa Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Gau G ~ ui ~ -eu Vaa ueu Leu Gly Has Ser Leu Gly Xle Pro Trp

129

C 'X Ο +. ΜΐΒΤν '7 ** CjíU' * ·· Γ?} V Τ 'í? lsl Pro Ser Wing Thr Lys Wing Gly Asp Trp Leu Vai Thr Lev Glu Gly Gly Gly Ser Gly «·· ~” A “* A sic« is Ο -X »« X -A. wv X ·· - .W-Xv ΛΧΛΜΛν ** Α · Κ · '

Pre Asr Asn Leu Asn Asm Leu Arg Leu Pre Asn Leu ü ~ Tyr V »- Ser Gly Pre- Xle Ser Ser Hoe Lye Ser Pro Phe Ale Ser Ala Phe Ser Hzs ueu Gif. Ser Hue Leu Wing Pro Gin Leu Leu Lye Ser Leu Wing Wing Leu Gin Glu Pro Glu Giu Leu v’Sj. p.1 a Pro Leu Ser Ser Cys Leu Ser Gin Leu Leu Gin Aza x ^ eu u Asp Ter Leu Gin. x ^ I Gin Gin Met Glu Glu

ISSEQ XL NO: 191)

31110. Pep

Ala Pro Ser Arg His Glu Phe Arg Glu Lys Ala Gin Glu Gin Gin Gly Ser Asn Cys Ser Lye Arg Pro Pro Ala Glu Asp Vai Ser lie Leu Glu Ser Phe Vai Gzy Xie Glu Ala. zze Ala Thr Ala Tyr Vai Ser Gly Pro lie Ser Ser His Lys Ser Pro Phe Ala Ser Al Phe Ser His Leu Gin Ser His Leu Pls Gin Pro Leu Leu Lys Ser Leu Ala Ala Leu Gin Glu Pro Glu Glu Leu Vai '' .χ .- 'J r- _; Χίΐ

x .. X ώϊ. + ,. -A- x ··> * - * * ** · ** 'Sx: <0 <? £ *** · - (JXV LíC £ V J’Tl’S

S&T PgTO G-LAl

31ax- £ & aLj1> s? . + * Su. C> Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu Gin Ala Gin Glu Gin Glv Gly Ser Asn Cys Leu Lys Arg Pro Pro Asn Glu Asp Gonna Be Asn Leu Glu Ser Phe Gau Gly Gly Gly Gzy Gzy Thr Xie Asn Pro Ser Asn Met Ala Thr Gin Gin Arg Arg Ala Gly Poe Leu Glu Va— Ser Ser Gly Gly ser Gly .ox ·. x $ z * - v x-x x ^ y s Lys Leu Cys Ala Thr Leu Leu Gly His Ser Cys Pro Ser Gin Ala His Ser Gly Leu Phe Gly Xie Ser Pro Glu Asp Vai Ala Asp Phe Leu Gly Met Ala Pro

Pro Xie lie Xie Lys Leu Thr Phe Tyr Leu Gly Gly Gly Ser Gly lie Met Xie Asp Glu Pro Leu Leu Asp Pro Leu Met Asp Arg Asn Arg Ala Vai Lys Asn. Read Arg Asn Read Gin Gzu. Gzy Goy Gly Gly Thr Tie Asn Pro Ser Asn Met Ala Thr Gin Gin Arg Arg Ala Gly Phe Leu Glu Will Be Ser Gly Gly Ser Gly

Leu Leu Gly His Ser

Ser Xie Met lie Asp Ala Pre Leu Le Asp Xie Leu Met Asp Arg Vai Arg Ala Vai Lys Ser Pro Gly Glu Pro Pro Pro Ser Lys Glu Gly Aza Met Pro Ala Guy Vai Leu Vai Aza Tyr Arg Vai Leu Arg Gly Ser Gin Ser Phe Xie Gin Gly Asp Gly Tyr Lys Leu Gys His Leu Gly xle Pro Trp Leu Gzn z> eu Aza Gzy Leu Tyr Gin Gly Leu Leu Gly pro Thr Leu Aza Thr Thr ale Trp Ala Leu Gin Pro

Ala Gly Asp Trp Gin Vai Thr Leu Glu Gin Gly Gly Ser Gly Gly Xle lie His His Leu Asn Asn Leu Asn Asp Leu Arg Leu Pro Asn Leu ulu Asn Ala Ser Pro Cys Leu Pro Ser Ser Pro Gly Glu Pro Pro Ser Ser Lys Glu Gly Ala Met Pro Ala Gly Vai Leu Vai Ala Tyr Arg Vai Leu Arg Gly Ser Gin Ser Phe Xle Gin Gly Asp Gly Tyr Lys Leu Cys H is Leu Gly Xle Pro Trp

130

Asp Thr · Let 31Γ. Read

Gin Gin Met Glu Glu, OIL'h; -x-1- ·· LNV- ·. «x · ^ ** Í

Read Gly Met Ale. Pro oeu w—- neu m it;

Read Tyr Gin Gly ~ I

Read Gxy Poo Tnr _ ^ eu

Pre- Glu Glu Leu Va «.

Pre Leu Ser Sa ^- * 'Cys Leu Ser Gin Leu j ^ Sw tsun Auc ueu Gun Asp Thr Leu Gin Leu Gin Gin Men Glu Glu (SEC TP' NG: 19 3>

Glu Phe Arg Glu Lye / uui * Isxu \ ^ iu ks-A. *:

Gly Ser .Asn Cys Ser

Lvs Arg Pre Pro- Axa

Glu Asp Will Be Lie

Leu Glu Ser Phe Vai

1 'V' ..... A. ΐ ^. .XÀK αΑϊ'.ΑΑ '. Box W.3.U

Thr Wing Al Wing Wing L, y Μ. > · Χ · V · X> \. <· * »^ · '·' \ Slw> 2. <£> * 'k« 2 · ^ «λ · ^ ·

Thr Xie Asn Pre Ser

Asn Met Ala Thr Gin

Gin Arg Arg Ala Gly

Phe Leu Glu Gonna Be

Being Gly Gly Being Gly

Glu Gin Vai Arg Lys

Lys Leu Cys Ala Thr

Leu Leu Gly His Ser

Cys Pro Ser Gin Ala

His Sex 'Gly Leu Phe

Gly Xie Ser Pre- Glu

Asp Vai Ala Asp Phe

Leu Gly Met Ala Pro

Leu Thr Phe Tyr read Gly Gly Gly Ser Gly Xie Met lie Asp Glu Pro Leu Leu Asp Pro Leu Met Asp Arg Asn Arg Ala Vai Lys Asn Leu .Arg Asn Leu Glr. Ser Arg His Pro lie Ser Pro Gly Glu Pro Pro Pro Ser Lys Glu Gly Ala Met Pro Ala Gly Va_ Leu Vai Ax. a Tyr Arg Vai Read Arg Gly Ser Gin Ser Phe x x «...... u. <α> .λ λ G · xy χχ ly Tyr Lys Leu Cys His Leu Gly lie Pro Trp Leu Gin Leu Ala Gly ueu Tyr «m oi.y xe.i Leu Gly Pro Thr Leu λ1« * .η Thr «* δ Trp Axa ueu Gin Pro

PMGN.X5981

Met Ala AsnCy sSer X Xeme t X leAspGlu X lelleHi sHisLeuLy s.ArgPr oPr oAla ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerXleLeuMetAspArgAsn LeuArgLeuProAsnLeuGluSerPheV & lArgAlaValLysAsnLeuGluAsnAlaSer 21νΖ1θ31νΑ1ΑΧ1ΑΰβνΑταΑ3ηΑαηαΐηΡζοαρ ^ 1οηΡ ^ ο5βΓΑ1ΗΤηηΑ1άΑ1 & Ροο S er ArgHi spr the XleXl and X Lely sAlaG.lv AspTrpG InGluPheArgG Luly sLeuThr PheTyrLeuValThrLeuGluGlnAlaGlnGluGlnGluTvvValGlÕGlyGlyGlyGly SerProGlyGluProSerGlyProXleSerThrXleAsnProSerProProSerLysGlu SerHisLysSerProAsnnetAlaT-yrLysLeuCysHxsProGluGluLeuValLeuLeu GlyZ-isSerLeuGlyXleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGln LeuAlaGlyCysLeuSerGlrXeuHrsSerGlyLeuPheLeuTyrGlnGlyLauLeuGln λ aii and ux w. uG ly x.i. and S iy air xuueuu Pr Pr o oT hr xj euAspT L i nr G1 Nleu PV G 1 AlaAspPheAlaThrThrlleTrpGlnGlnMetGluGluLeuGlyMecAlaProAlaLeu InProThrG InGlyAlaMetPr oAlaPhe lyGly Val AlaSer AlaPheG InArgArgAlaG LeuValAlaSerHi sLeuGlnSer PheLeuQluV al.S erTyr Air gva lLsuArqH.is .LeuAlaGlnProGlyGlyGlySerAspMehAlaThrProLsuGlyProAl & SerSerLeu ProGXnSerPheLeuLeuLysGerLeuGluGlnValArgLyslleGlnGlyAspG lyAla A.laLauGlnGluLysLeuCysAlaThr ISEQ XL NO: 194)

131 pMON15,982

Xl & NetAàaAsnCvsSsr NeoXleAspGluXleXleHx.sHxsieuXjysArgPraProA .-. ProLfeu to the UAS and t> Pr cAsnAsiiGeu As.rsAspG uAspVa 1 j-1 Seri eLeuMe T g Asn Asp Air LeuArcLeuPx cAenLeuGluSer PmeValArgAlaVaiOysAsTi-Gly usuGciiAsTLA leases XleG 1 g uAlaX leleuAr A. '* r LeuGlnPr Ocy sLeuProS er Al aTnr A2 aAl aPr c SexArgHisProXlellelleLysAlaGlyAspTrpG InGluPheArgGl'alysLeuTcr Ph a Tv r 1 eu Va 1 Thr 1 eu G1 uG ~ & A 1 aG 1 nG 1 u. 1 nG nTyr V G1 1G su y _ L L Syu IYU ~ \ 'SsrProGlyGlaPrQSerGlyPrQXleSerTnrXleAanPrpSerProProSerLysGlu Ser His AVS SerProAsnMec.Ala? R G1 uLeuG ly ProThrLeuAspThrLeuG XnLeu AspValAlaAspPheAlaTbrThrXleTrpGlnGluMetGluGluCeuGlyMecAlaFrc Alal »© G 2 euGXnPrcThrGlnGlyAlaMetPrGAlaPheAlaSerAlaPheGlnArgArgAl vGly VaXLeuV alAxaS erHxdeuG 2 Nonly PhebeuGxuValS erTyr Air gV axueu Le gIry Air GHxs a GlnProG lyG 1 y G ly Ser AspMe r Al aThr Pre L euG ly Pr o A1 aS er Series Pr oGlcSer PheLeuLeuLy sSerLeuGluG InVai Argly s 11 eG InG ly Asp G ly Ala Al aL-euGlnGlLLSLeuLLeLeGlLeLeLeGlLeLeLeLeLeLLG sSex LeuGly 2 leProTrpAlaProbeuSerSerCy sPrc-SerGln AlaLeuGlnLeuAJ-aGlyCysLeuSerGlnLeuHisSerGlyLeuPhebeuTyrGlnGly XeuLeuGlrjAlaLeuGluGlyXleSer 9l

MerAlaAsr22ysSerXXeMetXleAspGlullelleHi HxsLeuLysArgProPrG £ ^ & ProleuleuA Xa spPteoAsnAsnLeuAsnAspGluAspValSerXleLeuMet.AspArgAsn LeuArglieuProAsnLsuGluSerPheVaXArgAlaValLysAsnLeuGluAsnAlaSer GlylleGluAlaXl & LeuArgAsnLeuGlnPrGCysLeuProSerAlaThrAlaAlaPro SerArgHisProXleXleXleLysAlaGlyAspTrpGlr.GluPheArgGluLysLeuThr PheTyrGeuValThrLeuGluGlnAlaGlftGluGlnGln.TyrValGXuGlyGXyGlyGly SerPraGlyGluProSerGlyProXleSerThrXleAsnPrQSerProPrQSerLysGlu SerHisLysSerProAsnMetAlaSerAlaPheGlnArgArgAXaGlyGlyValLeuVal Hi er al As sL EUG insertion Pnel> I G1 UVA 1S erTyr ArgVa XLeuAr GHI sLeuA XAG In ProGlyGlyGlySerAspMepAlaThrPraLeuGlyPraAXaSerSerLeuProGlnSer PheI> EUL> euLysSerLeuGluGlnValArgLy £ lleGlnGlyAspGlyAlaAlaLeuGin GliiLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeut / alLeulieuGlyHis SsrLeuGlyxlePrcTrpAlaPrüLeuSerSerCysProSerGlriAlaLeuGlnLeuAla GlyCysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlKGlyLsuLeuGlnAlaLeu GluGlyXleSerPrcGluL> euGlyProThrl »exxAspThrlieuGlnLeuAspValAlaAsp PheAlaThrluGleMletGlMGet laProAlaLeuGlnPro TnrGlnGlyAlaMetProAlaPhaAla 'SEQ XO NO: 196) pMON15966

MetAlaAsrJ2ysSerXleMetXleAspGluIleIleHlsHisLeuX, yiSArgPrcProAla? R er als QLeuLepAspProAsnAsnLeuAsnAspGluAspv X1 ebeuMet AspArgAsn LeuArgLeuProAsaLeuGluSerPheValArgAlaValLiysAsnljeuGluAsnAlaser G ly 21 eG luAlalleLeuArgAsnLeuGlnPr oCysLeuProSerAlaThrAlaAlaPra δΓΑ $ £ ^ Η1 ΡτοΧ1βΧ1 € Χ1 © ^ 901 ^ ^ γ5Α1Β01γΑ8ρΤτρβ1ηΘ1νΡΠ © γδΐ, ®'αΤηΓ PheTyrLeuV alThrLeuGluGlnAlaG XnGluGlnG InTyrValGluG lyGlyG LYG ly SerProGlyGluProSerGlyProXleSerThrXleAsnProSerProProSerLysGlu SerHisLysSerProAsnMetAlaMetAlaProAlaLfeuGlnProThrGlnGlyAlaMet ProAlaPheAlaSer AlaPheGlnArgArgAlaG LYG lyValLeuVaXAl a erHisbeu

132

GlnSsrPh & LeuGluValSerT \ ^? rArgValLeuArgHisLeuAlaGlnProG lyGlyGüy SerAsnMet-AlaTnr PrcleuGlyProAlaSerSerLeuProGinSerPheLeuLeulys serLeuGluGlr ^ alArgLysXleGlnGiyAgpGiyAlaAlaLLGGAAAHLLGG sprog lug 1 uLeuValL euLeuG úyHlsS ether LeuGly XI and Pr oTmAlaPr olsuSer S er Cy s Preser L InAlaLeuGlnLeuAl aG 1 and OysLeuS ether GlnLeu HR S S er G1 y LeuPnaLeuTyr GlnGly LeuLeuGlnAlaLe uG luGly lleSer ΡΓθ01αΰ £ υ £ 1νΡηοΤΕτ1 'υΑδρΤ & ζ ^ βη31η1θΗΑ £ ρν31Α1. & Α5ρ? Η®Α1ετητΤητ XleTrpGXnGlnMetGluGluLeuGly (SECTION X: 197 pMON1396 ”

Me Ala AsnOysSerl t 1 t eMe IleAspGluXl elleHisH- sleuly s ArgProPro Al pr olauLeu AspProAsnAsnleuAsrjAspGluAspValSer X leLeuMetAspArgAsn LeuArgLeuProAsnLeuGluSerFheValArgAlaVallysAsnleuGluAsnAlaSsr Gly leGluAlall I eleuArgAsnLeuGlnPrGCy sLeuPraS air ATHR Al AlaAlaPrc SerArgKxsProZlellsXl & LysAlaGlyAspTrpGlnGluPn & ArgGlülysLeuThr PneTyrLauValThrLeuGiuGlnAlaGlnGiuGlnGlnTyrValGluGlyGiyGlyGly SerProGlyGluProSerGlyPralleSerThrlleAsnProSerProProSerlysGlv SerHxslysSarProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe GlnArgArgAlaGlyGlyValLeuValA laSerHisLeuGlnSerPheLeuGluValSer-T: /rArgValLeuA.rgH.isLeuAlaGlnPrcGlyGlyGlySerAspMepAlaTnrPrnLeu Gly Pro Al aSerSerLeuProG INSER PheLsuLeulysSerLeuGluGlnValArgLys X1 eG LnGlyAspGlyAlaAlaLeuGlnGluLysLeuCy sklaThrTyrLysLeuOysHxs ProGiuGluLeuValLeuLeuGlyHisSerL.euGlylleProTrpAlaProl.euSerSer · oysPrcSerGlnAlaLeuGlrileuAlaGlyCysLeuSerGlnLeuHisSerGlyLauPha LeuTyrGlnGlyLeuLeuGlnAlaLeuGluGlyXleSerProGluLeuGlyProThrLeu AspThrLeuGlnLeuAspValAlaAspPheAlaThrThrl leTrpGlnGlnMetGluGin LeuGlyMetAlaProÀlaLeuGlnPrc íSEQ ID NO: 198) pMON31112.pep

MetAlaAsnCysSerAsT ^ stlleAspGluIlelleThrHisLeuLysGlnProproLeu ProLeuLeuAspPheAsnAsnLeuAsnGiyGiuAspGlnAspXleLeuMetAspAsnAsr; Air gH LeuArgArgProMnLeuGluAlaPheAsnArgAlaValLysSerleuGlnAsnAlaSer AlaXleGluSerlleLeuLysAsnLeuleuProCysLieuPrQLeuAlaThrAlaAlaPro Thr Pr ο X1 is X1 EHI s ely sAspG XyAspTrpAsnG 1 uPhe Air GAR Gly sheuThr PheTyrLe'ulyEThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluGlyGlyGlyGly SarProGlyGluPrDSerGlyProXleSerThrlleAsnProSerProProSsrLysGlu SerHisLysSerProAsnMetAlaThrGlnGlyAlaMebPrQAlaPheAlaSerAÍaPhe GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluValSer TyrArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGlnSerPhe LeuLeuU'sSerLeuGluGlnValArgLysXleGlnGlyAspGlyAlaAlaLeuGlnGlu LysLeuOysAlaThrTyrLysLeuCizsHisProGluGluLeuVaiLeuLeuGlyHísSer LeuG ly X1 eProTrpAlaProLeuSerSer Cy sProS erGlnAlaLeuG InLeuAlaGly CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLexiLeuGlnAlaLeuGlu Gly XleSer ProGl uheuGly ProThrLeuAsoThrLeuGlnLeuAspValAlaAsp h ^ • AlaThrThrXleTrpGlnGlnMetGluGluLeuGlyMetAlaProAlaLevGlnPro SEQ Z.0 NO: 199)

133

OM0N31113. cap

Me d-_l aAsrdy s S er AsnMepIle AapGlcI lei leThrHe sDeuly sG In Pre Pr c-Le u Pr olnuoSuAsp 'PheAsn.AsnijCu.ASii-srf.y'viX'uAspG mAspI j. eLeuJMerGiuAsnAsr. 1> βυΑταΑταΡΓθΑ £; πΙ _! βν31χιΑ1 £ ΡηβΑ5ηΛΤ9Λ23ν & 1ΕγεΕ © ^ βυ01ηΑ3ΏΑ1 £ 5εΓ AlalleGluSer IleLeuLysAsnleuLeuProGysLeuProLeuAlaTãrAlãAlaPrc Thr Air GHIS Pr the Ilallell eArgAspGlyAspTrpAsnG luPhe Ar g Air Gly sL edhr Ph ely r LeiiLy s Thr 1 EUG luAsnAl aG Laal ag ing Inty RVA 1G 2UG LYG 1 and G ly G ly Ser Pr oG lyGluPreS er Gly ProlleS erThr IleAsnProS er Pro ProSerly sGl e SeiHxsLysSerPr0AsnMebAlaThrGlnGlyÀlaMec? roAlaPheAlaSerAlaPn.e GlnArgArgAlaGlyGlyValleuValAlHerGlHerGlHer euGly PROAL aS erSerLeuPrc GlnSerPhel-S s euLeuLysSerLeuGluGlnValArglyslleGlnGlyAspGlyAlaAla LeuGlnGluLysLeuCysAlaThrTyrLysleuCysEisProGluGluLeuValLeuleu GlyHi erLeuG iyllePrcTrpAlaProleuSerSerCys ProSerG inal aDeuGln LeuAl & GlyCy LeuSerGlnleuHi £ 11 £ SerGiyLeuPheLeuTyrGlnGlyLeul.euGln AlaleuGl ugly Eser ProGluleuGly ProThrLeuAspThrleuGlnle'aAspval AlaAspPheAl aThrThr I leTrpGlnG InMe Lyme t Al t GluGluLeuG Apr oAlaleu GlnPro ISEQ ID NO: 20 CH pMON31114..pep

MecAlaAsn sSerAsnMetlleAspGluIlelleT.hrHisL-^ o ^ euLeuAspPh eulysGlnProProLeu Pr & AsnAsnLseuAsnGlyGluAspG IxiAsp I leLeuMe PGluAsnAsn LeuArgArgProAsnl> 11 l euGluAlaPheAsnArgAlaValLysSerL.euGlrxAsnAlaSer AlalleGiuSerlleLeuLysAsuLeuLeuProCysLeuProLeuAlaThrAlaAlaPro ThrArgHrsPi elieX1 eArgAspGlyAspTrpAsnGluPheArgArgly ^ © LeuThr PhelyrLeulysThrLeuGluAsnAlaGlr XaGlnGlnTyrValGluGlyGlyGlyGly SerProGlyGluProSerGlyProlleSerThrlleAsnProSerPrQProSerbysGlu SerHislysSerProAsnMetAlaThrGlrJSlyAla & etProAlaPheAlaSerAlaPhe <aj.nArgArgAd.aG LYG xy V ^ x ^ r lAlaSerHislieuGinE the EUV P # * IEL 1 eVG uValSer ly Ser Tyr ArgValLeuArgHisLeuAlaGlaProSerGiyG GlyGlyS ERG InSerPh LeuLeulysSerLeuGluGlnValArgLyslleGlnGlyAspGlyAlaAlaleuGlnGlu and Ly sLeuC ysAlaThrTyrLy sLeuCysHis ProGluG luleuValleuDeuGlvEi sS ether LeuGlylleProTrpAlaProleuSerSerCysProSerGlnAlaLeuGlnLeuAlaGly CysLeuSerGlnLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGlnAlaLeuGiu 01νΙ1 © 36ΓΡ ο11ηΝ ^ 'η01νΡΓθΤ0τ1βυΑ3ρΤητΕΑπδ1η1' ιιΑκρ · '^ 1Α1ΒΑ2θ Ρπβ AlaThrTtir I leTrpG InGlmecG luGiuLeuGlvMetAl aPr PAlaLeuG InPr ^

Í.SEÇ ID NG: 2QI)

PMGN31115.pep

MetAlaAsnOysSerAsnMetlleAspGluIlelleThrHãsLeuLysGlnProProLeu

Pr 1 oLeule'aAspPheAsnAsnLeuAenGlyGluAspGlnAspI © LeuMet AspAsnAsn LeuArgArgProAsnijeuGxuAlaPheAsnArgAlaV alLysS erleuG InAsnAlaSer AlalleGluSerlleLeuLysAsnLeuLeuPraCysLeuProLetiAlaThrAlaAlaPro ThrArgHi Pre eHisI 11 leLysAspGlyAspTrpAsnGluPheAr q ArgLy sbeuThr PheTyrLeuLysThrLeuGluAsnAlaGlaAlaGlnGlnTyrValGluGlyGlyGlyGiy SerProGlyGluProSerGlyProlleSerTnrlleAsnProSerPrQProSerLysGlu - ^{ϊ ®} * £ ~ ^ and D.-. CAsnMe walaTi * r «i, nv5.1yAxat'íeOProA.d.aPb & AlaSerAlaPh.e

134

GlnArgArgAlaGlvGly '». "> EuValAlaSerHi; 'LeuGinSerPneleuGiuVaiSer TyrArqVaÍLeuArgHxsLeuAlaGlnPrcTnrProLeuGlyProÀiaS erSerLeuPre L" NSSR eieuLeuLysSerLeuG Ph 1 X i s uGxnV aXArgLy eG * xnGlyAspG Aya ®Ara yãuGlnGluLy sLeuOys Al aTnrTyr LysLeuOysHxsProG lug luLeuVa iLeule GlvHisSerLenGlyXieProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGir u, XeuAI aGlyCys-lei erGlnLeuHi sSerG LeuPheLeuTyrG ly ing ly LeuLeuGlr. AlaLeuGiuGiy xleSerProGluLevGlyProThrLeuAspThrLeuGlhLeuAspval. Al aAspPhaAlaThrThr X1 eTrpGlnGlnMet GluGl uLeuG lyMe cAl aPr oAlaLeu GInPr0 í SEI XD NO1202:

pMDN28S2õ

SS AlaAsnOy ether X1 eMe clleAspG iulleZl the eHisHisLeuLysArg Pr? R APR the OAL Leu Asp Pro AsnAsnLeuAsnAspG luAspValS erXleLeuMe nAspArgAsnLeu / XrgLsu ProAsnLeuG Luser Phe Val. G AlaValLys Air AsuLeuGluAsnAl aS ERG ly lleGluAla2ieLeuArgAsrh2euGlnProOysLeuPrQSerA.laThrAlaAlaPros®r s GHI Air Pro X1 and X1 and X1 Eby's aG Al ly ing AspTrpG luPheAr g g and Luly sLeuThr Ph XytrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerGlyProXleSerTrxrxlaAsnProSerProProSerLysGluSer HxsLysSerProAsnMer.GluValHisProLeuProThrProVal.LeuL.euProAlaVal AspPhe series Gly Thr GluTrpLy s GlnMe tGluG luThr Lys Alag INASP X1 EBEU GlyAlaValTnrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGlnLeuGlyPrcThr CysLeuSerSerLeuLeuGlyGlríleuSerGlyGlnvalArgLfôuLieuLeuGlyAlaLeu L ins er Le uleuG lyThr GlnLeuPr Pr oG English rHisValLeuHxsSer ArgLeuSerGinCysPro iSEQ ID NG: 203)

PMON28506

Al s Ser & AsnOy Hemet 11 eAspGluI Lell ERA shi sLeuLysArgProPr oAlaPro LeuLeuPiSp? RoAsnAsriLeuAsnAspGluAspValserIleL> euMetAspArgAsnLeu ArgleuProAsnLeuGluâerPheValArgAlaValLysA * £ X leg nLeuGluAsnAla.S erGly 1 u Al 2 leLeuAr aAsnLeuGinPr the AAL-Apr Oy sLeuProSer AlaTrwAl Being ArgHxsProIleXlelleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe TyrLeuVslThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlyser ProG lyGluProSerGlyProI leSerThrlleAsnProSerProProSerLysGluSer HisLysserProAsnMetLeuProThrProValLeuLeuPraAlaValAspPheSerLeu GlyGluTrpLysThrGlnMePGluGluThrLysAlaGlnAsplleLeuGlyAlaValThr Le- Denser xLeuLeuGluGlyValMePAlaAlaArgGlyGlnLeuGlyProThrCysLeuserSer LeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeu GlyThrGlnLeuProPrQGlnGlyArgThrlhrAlaHisLysAspProAsnAlallePhe PheGinHisLeuLeuArgGlyLysValArgPheLeüMetLeuValGlyGlyser Thr LeuOy sval ArgGi uPheGly GlyAsnNe t er al as aprotic A1 Pro Pr OAL ACY SASP LeuArgvalLeuSerLysLeuLeuArgAspserfíisValLeuEisSerArgLeuSerGln oysPraGluValHisPrc (SEQ ID NO : 204)

PMQN28S07

AiaAsnCysSerXleMetxxeAspGluXlelleHisHisLeuLysArgProProAlaPro

135

Argx; eu.Pr gAíb nxiSUxa xus er PheValAr gxA aVaxx ^ y s AsnLeuG xuAsnAx.as εγ G 2 v ~ leSiu Al aZ 1 eLeuArg AsnLauGlnPr oCysLeuProSerAlaThr AlaAl a ProGer Ar gHi s Presses. Ile XleLysAlaG ly AspTrpG England u phear aGluLvsL euThr Pne TyrLeuV & lTnrLeuGluG inal the GlnGluGlnG ÃnTyr vaig luGiyG ly G ly G1 ys ether ProGlyG 1 u ProSerG ly Pr hi XeSerThrXleAsnProSe r Pro ProserLysG Luser HisLysSerProAsnMetValLeuLeuProAlaValAspPheSerLeuGlyGluTmLvs Tnr GlnJía tGluGluThrLysAla L INASP ZleLeuG iyAl aValTnrLeuLeuLeuGlu GlyVaiMepAlaA.laArgGlyGlnLeuGiyproThrCysLeuSerSerLeuLeuGiyGln LauSerGiyGlnValArgLeuLeuLeuGiyAiaLeuGlnSerLeuLeuGiyThrGlnLeu PruProGlnGiyArçThrThrAlaHisLysÀspProAsnAlalisPheLeuSerPheGln HisLeuLeuÀrgGlyLysValArgPhelíeuMetLeuValGiyGlySerThrLeuGvsVal ArgGluPheGJyGiyAsnMecAlaEerProAlaProProAiaCysAspbauArcrValLeu S erLy sLeuLauAr gAspSerHx s .ValLeuHisSerArgLeuS erG Incy s ProGlu vál SIxsSrcLauProThrP.ro {SEÇ

PMON2S508 saAsnC λ \ '* sx> er * leMet.xxeAspGxuxx eXieHlsHisLeuLysAmProProAZaPm Leu AspPr oAsnAsnLeuAsnAspGluAspVaiS ether X1 X1 eLsuMe ÕAsuÃrcAsnLeü ArgLeuProAsnLeuGluSarPheValArgAlaValLysAsnLeuGlxxAsnAlãserGÍv eGluAlaXleLeuArgAsnLeuGlnPr oCysheu ProSar AlaThrAiaAxaProSer Argers Pr and X 1 oX iexiehy sAlaGlyAspTrpGinGluPheArgGl uLvsLeuThr Phe Tyr LeuValTnr LeuG luGlnAlaG IhGluG InGlnTyrValG luGiyGlyGiyG lys ProGiyGluPinSerGlyProlleSerThrlleAsnProSerProProSerLvsGlu ^ er is' Sly x H s s er ProAsnMet AlaValAspPheS srLeuGly GluTrpLy sThrGlnMetG 1 u GluThr Lys AiaGlnAspIleLeuGlyAlaValThrLeuLauLeuGluG IvVa iMe shut AlaArgGlyGir enGlyProThrCysLeuSerSerLexiLeuGlyGlnLeuserGIyGln v ^ Ar gLeuLeuLeuG al ly er al aLeuGlnS LeuLeuG 1 yThr G and G InLeu Pro Pr iv ing ArgThrThrAiaHisLysAspProAsnAlaXlePheLeuSerPheGlnHisLeuLeuArg '-'tyLysVaiArgP.ne.LeuMecLauVaiGlyGlySarThrLauOysVal .AroGluPhsGlv GlyAsnMetAiaSerProAlaProProAlaeysAspLeuArgVaiLeuSerLysLeuLeu ArgAspSerEisvalLôuHisSerAroLeuSerGlnCvsProGiuValF ⁴ Thr ProVaiLauLeuPrc (SEQ Xd ”nd: 206)

PMON235D?

rtia sn ^ y ^ xx sSer EMAT XleAspGluX I and II eHisH x sLeuLysArg ProProAl aprotic íjSu. etLfiSpPr oAsnAsnLauAsnAspGxuAspVals ether ™ EL-X1-euMecAspAr gAsnLau AysLeuProAsnLe iGluSerPhevalArgAlãvalLysAsnLauGluAsnAlaSarGlv XieGluA * ^ xaXleLeuArgAsnLeuGinProCysLeuPr0SerAlaThrAlaAlaProsêr gHxsProXxeXleXleLysAlaGlyAspTrpGlnGiuPheArgGluLysLeuThrPhe LeuGluGlnAl aGinGiuGlnGlnTyrValGluG lyGlyG 1 Vgl vSer PraGlyGluProSerGlyPrQXleSerThrlleAsnPraSerProPrcSarLvsGlusar HxsxíysSeryroAsnMet.AspPn.eSerLeuGlyGluTrpLysThrGlnMec.GluGluThr * A j. a íjí InAs pxx eL eu G xy Al a V a 1T hr L euL sul euG lu G ly V alMe t Al a A1 aAr g 2 ^? - -luxnijeuGiyyroTnrCysLeuSerSerLeuL ^i> eu.GlyGlnLeuSerGlyGl.riValArg -'SuLau ly-Leu · "Al EUG al XNS ether LeuLeuG lyTnrG INL EuPR PROG ^ ing IvArg hr <irAÍaHí Sly SASpProAsnAl aX 1 ePheLeuSer PheGlAHisLeuLeuArgG VLV ¹ ^ V ^ & xArgPneLeikMetLeuValGlyGlySerThrLauCysVaiAroGiu heGlvG'vAs? Mer.ÀxaSerPrc-AlaProProAla ^ sA.spLeuArgValLeuSerLysLeuLeixAÍaAsp bsrxis v a. x-euRi s Ser Ar g L i S erG x nCy s Pr oGluVa iHÍ s Pr cLeuPruThr Pr e

135

Va—, 2> euDsuProAla • ‘• G NO; zu /.

pMON28510

AlaAsnOy sSer ólemë tlleAspGluIlelleHi sH & isLeuLysArgPraProAl ro-DeuleuAspProAsnAsnLeuAsnAspGluAspValSer IleLeuMerAspArgAsnleu Argle'uProAsnl. euGluSei'Prie'val ArgAlaValLysAsm _{Í í} * euG2'úA 3nAlaSerGly IleGluAlalleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPrQSer ArgHxsPrrllellelleLysAlaGlyAspTrpGlnGluPheArgGluLyaleuThrPhe TyrLeuValTnrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerGiyProlleSerThrllaAsnProSerProProSerLysGluSer HxsLysSerProAsnMstGlyGluTrplysThrGlnMetGluGluThrLysAlaGlnAsp ^ le ^ & euGzyAlaValTnrDeul uLeuGAuGzyVaXMePAlaAlaArgGlyGlnlfeuGly ProThrC-ysLeuSerSerLeuLeuGlyGlnDeuSerGlyGlnValArgLeuLeuLeuGly AlaLeuGlnSerLeuLeuGxyThrGlnl ^ £ uProPrDGlnGlyArgThrThrAlaHxslys ..M pProAsnAxallePneLeuSerPheGlnHlslsuDeuArgGlyLy? svalA.rqPnaL> i: M £ Al cLeuValGlyGlySerThu7LeuCy5ValArgGluPheGiyG.iyAsnMepAlaSerPro Apr oPr oAlaCysAspLeuArgVa iDeuS erly sLeuLeuAr gasps erHi sValLau HzsSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeuLeupro AlaValAspPheSerLeu (SEC XD NO: 208)

PMON2Ê511

Al aAsnCy sS aryl eMe methyl eAspG 1 ul 1 el 1 HLB s sl H> euLys Ar g Pro ProAlaPra 1 EUL uS spPr the AsriAsnL euAsnAspGluAspValS ether 11 eLeuMe tAspAr gAsiiêu ArglsuProAsrOueuGluSerPheValArgAlaValLysAsnLeuGluAsnAl aSerGly lleGluAlslleLeuArgAsnLeuGlnProCysLeuProSerAlaThrA ^ laAlaProSer ArgHisPrcIlelleileLysAlaGlyAspTrpGlnGluPheArgGlxiLysLeuThrphe TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlvGlvGlvSer ProGly L luPrcSerGlyProl leSerThr IleAsnProSerProProSerLy sG Luser HislysSerProAsuMetGlyProThrCysbeuSerSerLeuLeuGlyGlnLeuSerGlv GloValZ gLeuLeuLeuGlyAlaLeuGlrxSerOeuLeiiGlyThrGlriLeuProPx ^ G-OGlr Lyar gThrlhr Alahi sLysAspProAsnAlal 1 ePhaLeus ether PheGlnHi sbeuheu Air gG ly Ly SVA lArgPheDeuMet beuVal GlyGlyS erThrheuCy sValArgG luPhe G4yGlyA £ * nNecAlaSerPreA laPraPrcAJ.aCysAspLeuArgValLeuSerLysLeu LeuArgAspSerHisValLeuHisSerArgLeuSerGlnCysProGluValHisProbeu ProThr Pr oValleuLeu PrcAlaValAspPheSerLeuG LYG luTrpLy sThrGlnMe tw ly will uGiul nr sAlaGlnAspIleleuGly AlaValThrLeuLe'uLeuG luGlvValMet AxaAiaArgGlyGlnLeu ISSEQ ID NO: 209)

PMON28512

Al aAsnCy s S er 11 eMe t II eAspG lul 1 el leHi sH IsLeuLy sArgPr oPr a A1 aPr o Áj s uL eu ^ spPr o asias nLe «AsnAspG xuAst? V a 1 Ser 21 el sum et Asr> & rga stiL eu ArgLeuPr oAsnLeuGluSer PheValArgAlaValLy s AsnLeuG luAsnAlas erGly X ^ GlüAlalleDeuArgAsnbeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgHisPr ollelxelleLy sAlaGlyAsplrpG InGluPheArgGlulysLeuTtxrPhe Tyu ueuVal * ^ Hz ^ weuGxuGlnAlaGznGluGAnGlnlyrValGluGlvGlvGlvGlv and '** ^ ys ProGIyGluProSerGlyProIleSerThrlleAanPreSerProProSerLysGluSer IIIs SerProAssMet Glyi NR G InLeuProFroGlnGlyArgThrThrAl a.Hi sLvs AspPrGAsnAlallePheDeuSerPheGlxiHisLeuDeuArgGlyLvsValArgPheljêu Me tLeuValG ly GlyS erThrLeuCy sValArgGluPheG LYG t lyÁsnMe Ala. Be Pro

AlaProProAlaCysAspLeuArgValLeuSerLysLeuLeoArgAspSerHisValLeu HisSerArgLeuSerGlnCys ProGluval Hi s Al ProLeuProThrPr OVA LleuLeuPr Ava 1 AspPheSexLeuGly GluTrpLy sTHR GlnMetG lug Uthr 1 Gy s AL aG INASP X1 eLeuGlyAl Ava IThrLeuLeuLeuGluGly V alMeuAlaAlaArgGlyGlnLeuGly ProTnrGysLeuSerSerLeuLeuGlyG IhLeuS G ly er al LNV Air gL L euLeuL EUG .AiaLeuG x 3 y ^ nger " ieuuSu (ώ> χ> Ό ΚνίιώχΟ $ dHDNG8513

Al aAsnCy sSer 1 leMeh 11 eAspG 1ul1e11 eHi sHisLeuLysArgProProA ™ for LsuLeu..AspProAsn> AsnLeuAsnAspGluP »spVal S er 11 eLeuMet. 12. aspartic g AshLeu ArgLeuProAsnLeuGiuSerPheValArgAlaValLysAsnLeuGluAsnAiaSerGiy eg 1 ^ uA alleLeuArgAsnLeuG InProCysLeuProS ether AlaThr AlaAl Apr ER Air GHR s XlelieLysAl Pro He Phe Tyr Agly AspTrpGlnGluPheArgGluLy sLeuThr ueuV the rThmeuGluG InAlaG ing ing jliíTv rVaiG luGiyGryG j.yG i vSer ProGlyGluProSerGlyProIleSerThrlleAsnProSerProProSerLysGluSer Hi s Lys er S Pr oAsnMe t G1 yArgThrThrAl aH.i Sly s AspPr the All® Asnal Phel s I er PHEG InHxsLeuLeuArgG lyLysValArgPheLeuMe tLeuValG LYG lySerThr LeuCysValArgGluPheGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeu ArgValLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlncys Pr oG are pre Lu v alHi oLeuPr Uthr Support LLeuLeuPr OAL ave al AspPheS erLeuGiy L luTrpLy sTHR GlnMe tGluG s luThrLy AlaG InAspIleLeuG ly Al aval Thr Leu LeuLeuGluG lyvalMe oAl aAlaArgG lyG InLeuG ly ProThrCy sLeuS er S erLeu LeuGlvGlnLeuSerGlyGlnvalArqLeuLeuLeuGlvAlaLeuGlnLEGlNlElLGlNG (5)

PMON28514

Al & AsnCysSerXieMetlleAspGluTlelleHisHisLeuLysArgProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerTleLeuMetAspArgAsnLeu ArgLeuProAsnLeuGluSerPheVaÍArgAlaValLysAsnLeuGluAsnAlaSerGly 1 leGluAl aXleLeuArgAsnLeuGlnPr oCysLeu Pr ES ether AlaThrAl aAlaProS ether air GHIS Pro X1 to 11 and X Lely sAlaGlyAspTrpGlnG luPheArgGluLy sLeuThr Phe Tyr L I V alThr LeuG 1 uG inal ag ing lug ing InTyrVa 1G IUG ly G ly G1 y G Lys ether ProGlyGluProSerGlyProXleSerThrlle.AsnProSerProProSerLysGluSer HisLysSerProAsnMePAlaHisLysAspProAsnAlaXlePheLeuSerPheGlnHis LeuLeuArgGlyLysValArgPheLeuMeuLeuValGlyGlySerThrLeuCysValArg GluPheGlyGlyAsnMetAlaserProAlaProProAlaCysAspLeuArgvllLeuSer LysLeuLeuArgAspSerHisvalLeuHisSerArgLeuSerGlnCysProGluValHis ProLeuPrcThrProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpLysThr L IhHetGluG luThr Lys Alag InAspIl eLeuGlyAlaValThrLeuLeuLeuG luGly ValMecAlaAlaArgGlyGlxiLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeu SerGlyGlnvalArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuPro ProGlnGlyArgThrT.hr (SEQ ID NO : 212: PMON28515

AlaAsnCysSerneMet leAspGlu * -r ± ielj.eHisHosLeuLy gProProAlaPro LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlleLeuMehAspArgAsnLeu Ax'gLeuProAsnLeuGluSerPhaValArgAlaValLysAsnLeuGluAsnAlaSerGly HeGluAlaTLeDeuArgAsnLeuGlnProCh ^f sLeuProSerAlaThrAlaA.laProSer ArgHnsyroIiellelleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe

138

Tv'rLeuValThr LeuGluGlnAl a GlnGzuG InG InTyrV alG zuGlyG lyGiyGzyS er? R qG 1 vG 1 a? S erThrLeuCy s V a 1 Ar g G1 u Ph e G; x G IvAsnMenAlaSar proAxaProProAzaCy sAsp ^ euArgv alLeti ^ erLy sra etiuen Ar crAsrS er Hi5 · Va- LeuH za S er Air gLeuSer GznCy s ProG mVsxr.- s Pr ozeiiPr t Thr ProV & lLeuLeuLUrLuLuLuLuLuLuLuUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUUU from 30th From from the age of 5 sL eu G zy Az a V a 1Thr L e uL e uL suG z uGiy V a zn e A «a AlaArgGzvGlnLeuGlyPrnTnrCy sLeuSerSerLeuLeuG lyGxnL euSer GzyGzr. yalArgLeuLeuLeuGlyAzaLeuGlnSerLeuLeuGlyThrGlnLeuPrQProGlnGly ArcTnrThrAla.HisLvs (SEC IL NO: 2: 13:

pM0N28 5 z 6

AzaAsnOysSerlleMetXleAspGluIlelzeHisHisLeuLysArgProProAlaPro LeuLeuAspProAsnAsnDeuAsnAspGluAspValSerlleLeuMetAspArgAsnLeu Ar gL I Pr o As ra e u G z «. S er Ph avaz Ar g Az a Va x Ly a AsnL e uG z uA nA za S er G zy XleGluAlaXleLeuArgAsnLeuGlnProCysLeu ProSer AlaThrAl aAxaProSer Ar g Hi. sLeuThr Phe tyrLeuValThxLeuGluGlnAlaGznGluGznGznXyrValGluGlyGlyGlyGlySer ProGzyGzuPrcSerGIyProXieSerThrXleAsnProSerProProSerLysGluSer HisLysSerPruAsnMetAl & XzePheLeuSerPheGznHisLeuLeuArgGzyLysvai Air gPheLeuMe tLeuV alGlyGly serThr LeuCysV wing gG luPheG ly GzyAsnMe t ZLaSerPmAlaProProAlaCysAspLeuArgValLeuSerLYsLeuLeuArgAspPez HisVelLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProval Leu PROAL aV alAspPheSerLeuGlyGluTrpLy sThrGznHetG XuGluThrLy s Al aGlnAspX laLeuGly AlaValThrLeuLeuLeuG lug lyValMet Al aAlaArgGly L InLeuG ly P_ oThrCysLeuSer s erLeubeuGlyGlnLeuSerGlyG znVal ArgLeu LeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlriLeuProProGlnGiyAraThrThr AlaHisLysAspProAsn (SEQ XD NO: 214;

PMON28519

ÀlaAsnCysSerXleMetXleAspGluãzezleHisHisLeuLysArgPrc-ProAlaPro LeuLeuAspPr the AsnAsnLeuAsnAspG luAspval S er XzeLeuMatAspAr gAsnLeu ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAzaSerGly IleGluAlaXleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgExsProXlezleXleLysAlaGlyAspTrpGlnGlnPheArgGluLysLeuThrPhe TyrLeuVelThr LeuGl uG InAlaGlnGlu GlnGlnTyrValG zuGiyGlyGly L lyser ProGlyGluProSerGlyProXleSerThrXleAsnProSerProFroSerLysGiuSer HisLysSerProAsnMetGluValHisProLeuProThrProValLeuLeuPrcAlaVax AspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAspXleLeu Gly Al ave alThr LeuLeuLeuG luGlyValMe t Al AAL AAR gG LYG INL EUG ly Pr othr GysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnvalArgLeuLeuLeuGlyAlaLeu G1 ns ether LeuLeuG lyThr L InLeuPr oPr oG ing ly ArgThr Thr Al aHi Sly sAspPr the Asnal ax 1 ePheLeuSer PheGlnHisLeuLeuArgGlyLy sValArgPheLeuMe tLeu ValGzyGlySerThxLeuCysValArgGluPheGlyAsnMetAzaSerProAlaProPro AzaCysAspLeuArgvalLeuSerLysLeuLeuArgAspSerHxsValLeuHisSerAra LeuSerGlnCysPro ISEQ ID NO: 215) nM0N2 8 S 2 0

139

ÀlaAsnXysSerTl Omer r - A = £ pG ~ le 1 lux eHxsHisLeuLysArg PreProAlaPrc LeuL6uAspProAsnA.snLeuAsnAspGluAspValSer XleLeuMe tAsnArgAsnLeu ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerG-r c · 11 XleGluAAaXleLeuArgAsnLeuGlnProCysLeuPrcSerAlaThrAlaAlaPruSer ArgHisPr all ε s XleLy AlaGlyAspTrpG InGluPheArgGl uly sLeuThr Leu Val Tyr Pne ThrleuGluG InAlaGl nGluGlnGlr.TyrValG luGl yGlyG LYG lyser ProGlyG lu Pr cSerG ly? r olleSerThr X1 eAsnPrcS erProPraS erLysGluSer HrsLysSerPrc-AsnMet LeuProTUr ProV alLeuLeuProAl aValAspPheSerLeu GlyG luTrpLysTnrG InMe tGluGluThr Ly sAlaGlnAspIl eleuG Al ly Ava iThr LeuLeuLeuG luGlyvalM.ee Al aAlaArgG lyGlnleuGlyProThrCy sLeuS ether Ser Leu Gly G G ly GlnLeuSer iNVA lArgLeuLeuLeuGlyAl aLsuG InSexL euLeu G lyThr GlnLeuPr oProGlnG ly Ar gThrThr AlaHi sLy sAspProAsnAlal 1 ePhe L euS er PheG InHx sLeuLeuArg G lyLy s V a 1 ArgPh eLeuMe t Leu va 1G ly G lv sValLeuHisSerAraLeuSerG 'ü ^; ”V ^ ProGluValHisPro (SEO XD NCÜ216) ~ —-cPMON2SS21

AlaAsnCysSerXleMetxleAspGluXlaXleHlsEisLeuLysArgPraProAlaPrG LeuLeuAspProAs.nAsnLeuA.mAspGlu.AspValSerXlaLeuMet.A.spxAro'AsnLau ArgLeuProAsnLeuGluSerPheValArgA.laValLysAsnLeuGluAsnAlas'erGlv Xx & G1 UAL ^{aXleLeu.ArgAsnLeuGlriPro!} XysLeuProSerAlaThrAlaAlaPraS ^c> R ArgHisPraXleX ± eXi.eLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe TyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrvalGluGlyGlyGlyGlvSer ProG ly G1 Pr uProSerGly the TleSerT.hr X1 eAsnProSerProPr THE erly sGlu S s S diethyl ether HisLy Pr AsnMet the ValLeuLeuPr Ala ValAsuPheS erLeuG 1 vG Iut ^ CLVS TnrGlnMer GluGl Uthr LysAlaGlnAspI leLeuG Lyal avalThrLeuLeuLeuGlu · Pr slyVaaMetAxaAlaArgGxyGlnLeuGlyPrnThrCysLeuSerSerLeuLeuGlyGlr LeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGinSerLeuEeuGlyThrGlnLeu PProGlnGlyArgThr Thr AlaHisLy sAspPr oAsnAl aX 1 ePheLeuSer PheGln-d ^ is ^ euueuArg iyLysVaaArgPheLeuMetLeuValG.iyGiySerThrLeuCViSVa.l ArgGluPheGlyAstMetAlaSerPraA.laProProAlaCysAspLeuArgValLeuSer LysLeuueuArgAspSerHisValLeuHisSerArqLeuSerGlnCvsProGluValH's ProLeuPrcThrPro (Tp SEQ No: 217)

PMON28522

AxaAsnOysSexXleMetlleAspGluIleXieHisHisLeuLysArgProProAlaPro LeubeuAspPr be oAsnAsnLeuAsnAspGluAspVal X1 eLeuMet AspArgksnLeu Ax-gaeuProAsnLeuGluSerPhevalArgAlaValLysA.snLeuGluAsnAlaGerGlv X 1 leGluAlaX eteuAr gAsnLeuGlnPr oCysLeuPrcSer AlaThrAlaAlaProS ether ArgtixsPr Oc.c ex xeXceLysAlaGlyAspTrpGlnG luPheAruGluLysLeuThrPhe uValThrLeuGluGlnAlaGlnGluGlnGlriTyrValGluGlyGlyGlyGlySer Ty ^ y Pr og er G ly GiuPr the X1 Pr ο S er er Thr X leAsnProS Pr oPr er Lys G lu Ser HxsLysSerPruAsnM.euAlaValAspPheSerLeuGlyGluTrpLysThrGlnMetGlu xuThr Ly s ^ 1 aG InAs pXleLauG ly Al a Va iThr Leu I., py} ,. G i ρ YV lug 1 'μ® / «gG AlaAr GlnLeuGlypr oThrCysLeuS ly ~ erg erSerLeuLeuGlyG InLeuS LYG In VacArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGlnGlv Air gTnrTnrAl aHa Sly s AspPr the Asnal X1 and Phel Euser PHEG InHi sLeuL euAru CcyLysValArgPheLeuMehLeuValGlyGlySerThrLeuCysValArgGluPheGlv AsnMetAl the ether ProAlaPr upro AlaCysAspLeuAr gValLeuSerL' / sLeuLeuArΰ

140

AspSer Η1 s va XLeuEi sS er Ar gLeuS er GlnCys ProGluValHigpr c LeuPr proV & XLeuLeuPre iSEQ ID ND: 218;

AlaAsnly sSer I rudder t IleAspGluIl and I Lehi sHisLeuLysArgPr oPrcAlaPr c LeuLeuAspPr 0A £ nAsnLeuAsr * AspGlu AspVaiS ether Xi eLeuMetAspAr g AsnLeu ArgLeu Pr oAsnLeuG LU SerPheValArgAl aValby sAsnLeuG luAsrAlaS ERG iy 11 eGiuAI al 1 eLeuAr g AsnLeuG InProCy sLeuPrcS er al ATHR AlaAlaProSer Air GHI and Pro! leilei 1 Sly sAlaGly AspTrpGlnG luPheArgG Luly sLeuThr Phe Tyr Leu v arTurLeuG luGmAx aGlnGzu GLNG InTyrV 1G luGzyG iy g zy g zy be PruGlyGluPruSerGlyPreXleSerThr XleAsnProSerProProSerLysGluSer Hi sLys S er Pr c · AsnMe t AspPheS erLeuGlyG1 uTrpLy sTHR g INM et G1 uG 1 UTR .r y LysAlaGXnAspXleLeuGlyAiaValThrLeuLeuLeuGluGlyValMecAlaAlaArg G1 G1 nL EUG ly Pr othr cy sLeuS S er er 1 LeuLeuG LYG LYG nLeuSe rG xnv 1 g LeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlhLeuProProGlnGlyArgTnr Air GhrAlaHisLysAspPruAsnAlaHePheLeuSerPheGlnHisLeuLeuArgGlyLys ValArgPheLeuMetLeuValGlyGlySerThrLeuCysValArgGlu.PheGlyAsnMet HisValLeuHisserArgLeuSerGlnCi ^ Pro AlaSer ProAlaProProAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSer GluValHiePrcLeuProThrProVal LéULeuPróAlaVaX f SSQ ID ND ϊ 219) pMON2 8524

AlaAsnCysSerXleMetXleAspGluXlelleHisHisLeuLysArgProProAlaPro LeuLeuAspProAsrAsnLeuAsnAspGluAspValSerlleLeuMetAspArgAsnLeu ArgLeu Pr oAsnLeuGluSer PheValArg AlaValhy sAsnLeuGluAsnAl aSerGly 21 eGluAlall aLeuArg AsnLeuG INPR oey sLeuProSer AiaThrAlaAlaProS ether ArgHisPrpXielleXleLysAlaGiyAspTrpGlnGluPheArgGluLysLeuThrPhe TyrLeuValThrLeuGluGlnAlaGlnGluGInGlxiTyrValGluGlyGlyGlyGlySer ProGlyGluProserGlyProlleSerThrXleAsnPrcSerProProSerLysGluSer HxsLysSerPrGAanMetGlyGluTrpLysThrGlnMetGluGluThrLysAiaGlnASip HeLeuGlyAlaValThrLeuLeuLeuGluGlyvalMeuAlaAlaArgGlyGlnLeuGly Pr Cy cThr sL I S S er er i L Leu L InLeuSer LYG LYG Nva 1 1 Air gLeuLeuLeuG AlaLeuGlnSerLeuLeuG15 ^z iy ThrGinLeu.PraProGinGlyArgThrThrAlaHxsLy I £ AspProAsnAlallePheLeuSerPheGlnHisLeuLeuArgGlyLysValArgPheLeu tLeuVaXGlyGlySerThrLeuCysValArgGluPheGlyAsnMetAlaSer ProAla ProPrcAlaCysAspLeuArgValLeuSerLysLeuLeuArgAspSerHisValLeuHis s er Air Ts gL L er s Incy Pr G1 will υ s Hi Pr Pr aLeuPr cThr OVA ILeuLeu Pro Ala ValAspPheSerLeu ( SEQ ID NO: 220;

PMON28525

AlaAsnCysSer XleMetXleAspGlullelleHisHisLeuLysArgProProAlaPro xjeuLeuAspyr oAsnAstiZfeuAsnAspGiuAspvalS ether HeLsuMetAspArgAsixLeu ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaserGlv zleGIuAlalieLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgHisProIlelleXleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe Xi ^ rLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGiuProSerGlyProXleSerThrXleAsnProSerProProSerLvsGluSer Hz sLys SerProAsnMetGly Pr cThr CysLeuSer SerLeuLeuQlyG InLeuSerG ly ArgueuneuLeuGlyAlaLeuGlnSerLeuLeuGlyTrirGlnLeuPraProGlr;

141

GlyArgThrTxnr-Ala «i £ LyeAspProA.snAlaIlePheDeu.SerPheGl: h-: isLeuDeu ArgGlybysVaiP.rgPheLeuMeobeuValGiyGlySerThrbeuCysValArgGluPhe G lyAsn Me alA sR PrA lA sR PrA lA rA sR Pr sA pr - i sValbeuHr s S ar Ar gbe u S erG InCysProGluValH 1 s Pr ob ®u Pr:

AlaAsnCy sSer 11 emet I1 eAspGluIleXleHisH xsLeuLysAr g PraProAlaPr LauLeuAspPro AsnAsnbeuAsnAspG c 1 u g XlebeuMeoAspAr Ser AspVal Asnbeu Air gLeuPr oAsnbeuGluSer PheValAr g AlaValby the AsnbeuG luAsnAl aSerGly IieGluAlaIleLeuAjrgAsnLeuGlnProCysLeuProSerA.laThrAlaA.laProSer AxgHo s Hell Pro elleby SA-lag lyAspTrpGlnG luPhe Argg luby sbeuThr Phe lyrbeuValThrbeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGlyGlySer ProGlyGluPrcSerGlyProIieSerThrlleAsnProSerProProSerbysGluSer HxsbysSer ProAsnMet Ala GlyThr GlhbeuPr oProGlnGiy ArgThrThr ?: Sly i s AspPr oAsnAla 11 aPheLeuSer PheGlnHisbeuLeuArgGlyLysValAroPneLeu MehLeuVaiGlyGlyserThrLeuCysvalArgGluPheGlyAsnMeoAlaSerPraAla Pro Pr OAL ACY s AspbeuAr by GVA IbeuS ether sbeub euAr g Asps ether Hi s sValbeuHi serArgbeuSerGlnCysProGluValHisPrQLeuProThrProValLeuLeuProAl® ValAspPheSerbeuGlyGluTrpLysThrGlnMerGluGluThrLysAlaGlnAspXle L I g ly ava Al NR 1Q L are uL euL and uG ru G uy V a oM a p. A ύ a Al aAr g G ly G mb eu G ly Pr o ThrCysLeuSerSerLeuLeuGlyGlhLeuserGlyGlnValArgLeuLeuLsuGlyAia beuGlnSerbauLeu (SEQ ID £ 0: 222) pMON2S520

AlaAsnCysSerlleMetXleAspGluXleXleHisHisLeuLysArgProProAlaPro beubeuAspProAsnAsnbeuAsnAspGluAspValS ether X1 b euMer AspArgAsnbeu ArgLeuProAsr & euGluSerPheValArgAlaValbysAsnbeuGluAsnAlaSerGly XleGluAiaXleLeuArgAsriLeuGlnProCysbeuProSerAlaThrAlaAlaProSer Air GHI's Pro 11 X1 ell eby Palag lyAspTrpGinG luPheAr gGluLy sbeuThr Phe TyrbeuvalThrbeuGluGlnAlaGlnGluGlnGljriTyrValGluGlyGlyGlyGlySer Pr oGlyGiuPro S erGly Pr oil eSerThr 11 eAsnProSerPr oProSerLysGluSer Hr SBY s S er ProAsnMe T L lyArgThrThr Alahi sLys AspPr oAsnAlax 1 ePhebeu SerPheGlnHisLeuLeuArgGlyL-ysvalArgPhebeuMeoLeuValGlyGlySerThr LeuCysValArgGluPheGlyAsmetAlaSerProAlaProProAlaCy & AspLeuArg ValbeuSerLysbeuLeuArgAspSerHisValLeuHisserArgLeuSerGlnCvsPro GluValHisProbeuPraThrProValbeubeuProAlaValAspPheSerLeuGlyGlo TrpLysThrGlnMetGluGluThrLysAlaGlnAspXleLeuGlyAlaValThrLeubeu LeuGluGlyValMetAlaAlaArgGlyGlribeuGlyPraThrGysLeuSerSerLeuLeu L 1 lyGlrxLeuSer GlyGlnValArgbeubeubeuGlyA aLeuGlnSerLeuLeuG IvThr GlnbeuProProGir. sequence ID NO: 223;

PMOK2852S

AuaAsnCysSerXleMet. XbeAspGluXlelleHisHisLeuLysArgproProAlaPro LeubeuAspPro AsnAsnbeuAsnAspGluAspVal S er 11 ebeuMe t AspArgAsnbeu ArgbeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGeuAlGsAerLeGeuAlGeAerLeGeAlGeLeGeAlGeLeGeAlGeLeGeAeGeLeGeAeGeLeGeAeGeLeGeAeGeLeGeAeGeLeGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGWG

142

ArgHxsProI 1 eõ 1 ell eLys Al aGlyAspTrpGlnG luPheArgGluLy sLeuThr Phe ^ rLeuValThrLeuGluGinAlaGlnGluGlnGlr.TyOValG XuG lyG lyGlyG lySer PraGlyGluProSerGG ProProSerG ly ProGer ProGER XSER PRGER

GluPneG lyAsnMe T-Pr M. EIAs the AiaProProAiaCy s AspLéuAr gV al Ts ^ s erly LeuLeuArgAspSerHtsValLeuHxsSerArgLeuEerGinCysProGmV & lHmPrc LeuPr c-Thr ProvalLeuLeuProAlaValAspPhaSerLeuG LYG luTrpLy STNR G in MetGluGluTnrLysAlaGlnAspXIeLeuGlyAlaValThrLeuLeuLeuGluGlyVal MetAlaAiaPjrgGlyGlnLeuGiyProThrCysLeuSerSerLeuLeuGiyGinLeuSer G.1 In vG V alArgLeuLeuLeuGlvAlaLeuG InSerLeuLeuGiy Thr GlnL I ProPrc GlnGlyArgThrThr ISEQ ID NC: 224)

PMGN28529

AAsnCysSer x Al 1 '11 Met eAspGlullel leEisHisLeuLy Sar gProPraAlaPr c LeuLeuAepProAshAsnLeuAsnAspGluAgpValserlleLeuMenAspArgAshLeu ArgLeuProAsnLeuGiuSerPheValArgAlaValLysAsnLeuGluAsnAiaS erGly XleGluAlaXleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgHis oils Pr I law Lely sAlaGlyAspTrpGlnG luPheArgGluLysDeuThr Phe TyrLeuVaiThrLeuGluGlnAlaGlnGluGlnGlnTyrValGltiGlyGlyGIyGlySer ProGlyGluProSerGlyProXleSerThrXleAsnProSerProPrQSerLysGluSsr HisLysSerPrnAsnMstAspProAsnAlallePheLeuSerPheGlnHisLeuLeuArg GiyLysValArgPhebeuMetLeuValGlyGlySerThrLeuCysValArgGluPheGly AsnMetAlaSerProAlaPraProAlaCysAspLeuArgValLeuSerLysIieuLeuArg AspSeiv-XsvalLauHlsSerArgLeuSerGXrmysProGluvalHisPrcLeuProThr ProValLeuLeuProAlaValAspPheSerLeuGlyGluTrpXjysThrGlnMetGluGlu ThrLysAlaGlnAspIleLeuGIyAlaValThrLeuLeuLeuGluGlyValMet; A.laAla ArgQlyGlnLeuGlyPrcTnrDo ^ ins sLeuSerSerLeuLeuGlyGlnLnuSerGlyGlnVal ArgLeuLeuLeuGlyAlaLeuG erleuleuGlyThrG InLeuProProG InGlvArg ThrThrAlaFasLys (SEQ ID NO: 225}

PMGN28530

1 AiaAsnCysSerXleMetXleAspGluXleXleHisHisLeuLysArgProProAlaPro suLeuAspProAsnAsnLeuAsnAspGluAspVals ether ArgLeuProAenlieuGIuSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly x 11 eLeuMet AspArgAsnLeu leGluAlal leLeuArgAsnLeuGlnPr Ooy sLeuProS ether Al aThrAl aAlaProser Air Pre gHxs I is 11 el. Lely s AlaGlyAspTrpGlnG luPheAr gGluLysLeuThr Phe TomLeuValThrLeuGluGlnAlaGlnGluGlriGlnTyrValGluGlyGlyGlyGlySer ProGlyGluProSerGlyprolleSerThrlleAsnProSerProProSerLvsGluSer HisLy ss ether ProAshMetAlal 1 ePheLeuSerPheGlnHisLeuLeuArgGlvLvsVal ArgPheLeuMeoLeuValGlyGlySerThrLeuCysvalArgGluPheGlyAsnMepAla SerProAlaProProAiaCysAspLeuArgValLeuSerLveLetiLeuArgAsnS ^ rr> yalLetHiisserArgLeuSerGlnOysPrÕGluValHisProLeuProThrProvãlLeu LeuPr the Al ly GluTrpLy alAspPheSerLeuG aV L sThrGlnMet lug room luThrly k? * xX Asp v x ~ xy eLeuu / v IXa axThrLeuLeuLeuG lug IVV AlMe t AiaAlaArgGly Goa psuGlyPrpThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGlnValArgLeuLeu LeuGlyAlaLeuGlnSerLeuLeuGlvThrGlnLeuProPra'GlnGlvArcThr HRA ^ '> the HisLysAspProAsn (SEQ ID NO: 225) ~

PMON28533

AxaAsn ly s S er Xzeiieo - 1 eAspGlu ^. 1 e ~ x e.Ha. sH u sxieixLy Sar cs proProAx APR c LeuLeuAspProAsnAsnLeuA nAspGluA £ £ £ pValSerXleLeuMeo.AspArgAsriIi uArgbeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGly XleGluAlaZleLeuArgAsnLeuGinProCysLeuProSerAiaThrAlaAlaProSer ArgHis Pr ozx and Σ1 and X are Alag Lely ly AspTrpGlnG u 1 gG phear Luly sLeuThr Phe TyrLeu va IThrLeuGluGlnAlaGlnGl uGlnGxnZyrValG lug LYG lyGlyG ly be pre oG ly G1 o If UPR R G ly Ile Pre erThr XleAsnProSerProProS S er G ly sGluSer HisLysSerProAsnMetGluValHisProLeuProThrProValLeuLeuProAlaVax AspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAiaGlnAEplleLeu lyAla Va Va IThrLeuLeuLeuG luGly IMetAlaAlaAr gGlyG 1 nLeuG ly Pr oTnr CysLeuSerSsrLeuLeuGlyGlrJjeuSerGxyGlnValArgLeuLeuLeuGxyAlaleu GlnSerLeuLeuGlyThrGlnLeuProProGxnGlyArgThrThrAlaHisLysAspPrc AsnAlaXxePheLeuSerPheGlnHisLeuLeuArgGxyLygvalArgPhsLeuMetLeu VaxGlyGlySerThrLeucysvaxAjrgGluPheGxyGlyAsnGlyGlyAsnMetAlaSer rGAlaProPruAlaCysAspLexArgValLeuSerLy LeuLeuArgAspGerH.xsVal £ ^ © euHxsSerArgxieuSerGxnCysPr (SEQ XL NO: 32 j

PHON28Õ34

AAsnCy Al X1 are S er XIeMet eAspG lull 11 eH..rsHi sLeuLysArg Pro Pro Ala Pro Le ^ euÀSpProAsnAsnLeuAsnAspGluAspValSerZleLeuMeÕAspArgAsnleu ArgLeuProAsnLeuGluSerPheValArgAlaValLysAsnLeuGxwAsnAlaSexGlv XleGluAlaZlaLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAiaProSer ArgHisProZlelleXleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe MyrLeuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGlyGxyGlySer ProGlyGIuProSerGxyProileSerThrXleAsnProSerProProSerlysGluSer HislysSerProAsnMetLeuProThrProValLeuLeuProAlaValAspPheSerLeu L lyGluTrpLy sTlirGlnMecG lug xuThrLysAiaGlnAspl leLeuG Lyal aValThr I to eul EUG G ly V ju Hie Al a Al aAr gG 1 y G1 η! EUG ly Leu Pr othr Oy s s r S r L LeuLeuGlyGlrALeuSerGlyGlnValArgLeuLeuLeuGlyAlaLeuGlnSerLsuLeu iyThr Glnleu ProProGlnG lyArgThrThr Alahi Sly sAspPr oAsnAlal lePhe L-selves ether PHEG InHisLeuLeuArgGiy Lysva home gPheLeuMe t LeuVal G ly Gly s ThrueuCysVaiArgGxuPneGlyGlyAsnGlyGlyAsnMeo.A ether, xaSerProAiaProPro AlacysAspLeuArgValLeuSerLysLeuleuArgAspSerHisValLeuHisSerAra LeuS.erGlnCysProGluvalHisPro (SEC ID NO: 228}

PMDN28535

AlaAsnGy sSer XleMeoX 1 1 eAspGlul ell eHisHisLeuLy s.Ar gPraProAl aprotic ^ xl edeuAxspPr DAsriAsnlfeuAsnAspG luAspVals ether eLeuMerAspArcAsTílieu ArgLeuProAsnLeuGluSer the PHEV Arg Alava iLy sAsALeuGluAsnAlaS * erGly lieGxuAlalleLeuArgAsnLeuGlnProcysLeuProSerAxlaThrAlaAlaProSer .ArgHisPrQXleXleXleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe: / * I LeuV. j. hr '' ^ r ^ vGmGlnAlaGj.ndu.GlnGmxyrValGluGlvGlvGlyG Ivs PruGlyGluPrQSerGxyPrcZleSerThrXleAsnProSerProProSerLysGluSer HxsLysSerProAsnMetValLeuLeuProAlaValAspPheserLeuGlyGluTrpLye * y * w 1 lyMehwilu Uthr Lys Al INASP aG x G leLeuG Lyal aV alThr euLeuLeuG 2 'SlyValMetAlaAlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlvGln heuSerGzyGmValArgDeuLeuLeuGlyAlaLeuGlnSerLeuLeuGIyThrGlrlLeu Pr oPr G1 nGlyAr gThrThr Al aHi sly s al 1 AspProAsnAl ePheL euSer PheGln Hi sleuLeuAr gGly Ly sVal Arg PheLeuMe tLeuV a 1G lyG ly S erThr LeuCv SVal

144

ArgGluPheGlyGlyAsnGlyGlyAsnMetAlaSerProAlaProPrpAlaCysAspLeu AròvalLeuSer Ly sLeuLeuArg AspSer Hxs ValLeuHi s Ser Ar gL euS erG _r, Cy s ProGluValHrsProLeuPrcThrPro (SEQ -L} NO9;

AlaAsnCvsSer XleMetXleAspGluTleXleHisHisLeuLysArgProPruA ^ :: Apr LeuLeuAspProAsnAsnLeuAsnAspGluAspValSerXleLeuMetAspãrgAsnLeu AroLeuProAsnLeuGluSerPheValAr Galava iLy sAsnLeuG uAsnAi i aS erGly 11 ASL & UAI XleLeuArg AsnLeu InProCysLeuPraS L er al AlaThr aAlaProSer Air Η q - Pr ε ο 2 and 11 and all Lys Ai. G ly zu Asp Trpg in G P R A tie GGX uuy su I and T sn τ nr \ 'xLsuValThrLeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGiyGlyGlySer ProGlyGiuPrGSerGlyProIleSsrThrlleAsnProSerProPrQSerLysGluSer HisLysSerProAsnMetAlaValAspPheSerLeuGlyGluTrpLysThrGlriMetGlu GluThr Lys AlaGlnAspl 1 eLeuG lyAlaValThrLeuLeuLeuGluGiy V AlMe t.Ala AlaArgGlyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGiyGln ualArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLsu.ProProGln.Gly ArgThrThrAlaHisLysAspProAsnAlaXlePheLeuSerPheGlnHxsLeuLeuArg L lyLysV reaming PheLeuMetLeuValGly GlySerThrLeuCy sValAr gGluPheG ly GlyAsuGlyGlyAanMetAXaSerPrcA laProPraAlaCysAspLeuArgValLeuSer LvsLeuLeuAx'g.AspSerIHisValLeuHisSerArgLeuSerGlr * '2j ^z s? roGlu'Val.2;

£ r vÚ *?

AlaAsr.CysSarllêMetXleAspGlullaXleHisHisLeuLysArgProProAlaPro LeuLeuArpProAsnAsnLeuAsnAspGluAspValSerXleLeuMatAspArgAsnLau g Air Self ProAsnLeuGiuSer PneValArgAiaVaxLysAsnLeuGluAsnAi.aS Erg-iy X1 eG luAlalieLeuAr gAsnLeuGlnPr Ocy sLeuPr cS er AlaThr Al Aala Pr oS er ArgHisPraXleTlelleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe Ty rLeuVal Thr LeuG Lug Inal AGL nG lug ing InTyrV alGluG LYG G ly ly ly G Being ProGlyGluProSerGlyPralleSerThrXleAsnPrcSerProPruSerLysGluSer HisLy air ProAsnMe s s t AspPheSerLeuGlyGluTrpLysThrG InMe tGluGl Uthr LysAlaGlnAsplleLeuGlyA.laValThrLetiLeuLeuGluGlyValMetAlaAlaArg GlyGlnLeuGlyProThrCysLeuSerSerLeuLôuGlyGlnLeuSerGlyGlnValArg LeuLeuLeuGlyAlaLeuGlnS ether LeuLeuGlyThrGlnLeu Pr oProG ing lyArgrhr ThrAlaHisLysAspProAsnAlallePheLeuSerPheGlnHísLeuLeuArgGlyLys VALAR gPheLeuMetLeuValGlyGly SerThrLeuCy sVal Argg luPheG LYG lyAsn GlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuSerLysLeu LeuArgAspSerHisvalLeuHãsSerArgLeuSerGlnCysProGluValHisProLeu ProThrProValLeuL euProAlaVal (SEQ xo NCt231)

PMON2853S

AlaAsnCysSerXleMatXleAspGluIlelleHisHisLeuLysArgProProAlaPro LeuLeuAspProAsnAsr; LeuAsrxAspGluAspyalSerXleLeuMetAspArgAsnLeu ArgLeuProAsiiLeuGluSerPheValArgAlaValLysAsnLeuGluAsriAlaSerGly XleGluA.iaXleLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer ArgHlsProll & XleXleLysAlaGlyAspTrpGlnGluPhaArgGluLysLeuThrPhe TyrLeuValThrLeuGluGlnAl ag ing luGlnGlnTyrValG luGlyG LYG LYG lyser ProGlyGluProSerGlyPraXleSarThrlleAsnProSerProPrOSerLysGluSer HisLysSerProAsnMetGlyGluTrpLysThrGlnMetGluGluThrLysAlaGlnAsp eLeuG 1 v AlaVal Thr LeuLeuLeuGluGàyV aàMecAlaAl aArgG L x y t> v ^^^ nT / ^ ^ LevSerSerLeuLexiGxyG Anleu eruiy glnV Argxie'aLeu- aa; & «.% * - x AlaLeiSlnSerLeubeuG lyThrGlnLeu Pro ProG InGly Ar gThrTnr Al aHa sLy £ j. _s -, ^ _T -, _The ef.jLi £ _i 22sphaL>suSaa'PheGanHisLeuLeuArgGlyLysva - ArgP ~ aLeu MetLeuVaiGlyGlySerThrLeuTysVelArgGluPheGlyGlyAsnGlyGlyAsnMez 'Ί ^& -eria ProLaSLSL ProL

Hi ^ valLiuHisSerArgLeuSerGlnCysProGluValHisProLeuPrcThrProVal Leu-XL euProAlaValAspPheSerLeu íSBG KO: 232 pMON28529 _A i} Asne ₀ \ '£ SerXleMet21eAspGluIleXleHisHxsLeuLysArgProProAlaPrc LeuLeuAscPr the AsnAsnLeuAsnAspGl uAspValS ether XaeLeuMe Asp-Air gAsruieu AroLeuPrÔAsnLeuGluSerPheValArgAlaVa.lLysAsnLeuG.IuÀsnÀiaSerG .y - 1 x eG iuAl leLeuArg AsnLeuGlnPr oCysLeuProS AlaThxAl ether. aAlaProSer ÃrgHxsPr gX 1 and 11 elleLysAlaG lyAspTrpGlnGluPheArgG luLysLeuThrPhe TvrLeuValThrLeuG luGinAlaG ing luGlnG InTyrValG luGlyG LYG LYG ProGlyGluProSerGlyPrQXleSerThrXaeAsnProSerProPrPSerLysGiuSer Lys Hi er er sLvsS ProAsnMe rGlyProThrCy brs euSerS erLeuLeuGlyQ InLeuS ether y L

L Ivar Qthr Thr AlaHasLy sAspProAsnAl AAL EPH & Lei ether PHEG InHisLeuLeu ArgGlvLvsvalArgPheLeuMeoLeuValGlyGâySerThrLeuCysValArçGl.uPhe GlyGlyAsnGlyGlyAsrJtfecAlaSerProAlaProProMaCysAapLeuArgValheu SerLysheuLeuArgAspSerHisValLeuEisSerArgLeuSerGlnCysProGluVaa HisProheuProThrProVaàLeuLeuProAiaValAspPheSerLeuGlyGluTrpLys ThrGlrütetGluGluTrmLysAlaGlnAspXleLeuGlyAlaValThrLeuLeuLeuGlu GàyValMetAlaAâaArgGlyGlnLeu ISHQ ID NO: 23 3?

pMON2.8-540

SsaM AãaAsnCy XieMev X i ieAspGluIlea lenisH sheuhy sArgProProAlaPro LeuLeuAgpProAjsnAsnLeuAsnAspGluAspvalseraleLeuMetAspArgAsnLeu Air will oLeiiPr oAshLeuGàtiSer Phe Arg Azavalx / y-sAsnx. euuluAs.nAl ERG aS ^ ly XleGluAlaxleLeuArgAsr euGlnProCysLeuPraSerAlaThrAlaAlaProSer gH Air is Proll eXleXaeLy sAlaGlyAspTrpGlnG LU PheArgGluLysLeuThr Phe Leu Ty r ValThr LeuG luGlnAl ag ing 1 uG InGlnTyrValG 1 uG iy L LYG ly G ly s er ProGlyGluProSerGlyProlieSerThrlaeAsnProSerProProSerLysGluSer Hi shy are being PraAsnMe * G lyThrGlnLeuPr cPr oGlnG XyArgThrThr Al aHi sLys AspPr the AsnAlal lePheheuSer PheGInHisLeuLeuAr gG LYLY sValAr gPheheu MetLeuvalGlyGlySerThrL-euCysValArgGluPheGlyGlyAsnGlyGlyAsnMet AlaSerProAlaProProAlaCysAspUeuArgValLeuSerLysLeuLeuArgAspSer HisValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProVal Leu Pro Al Ava lAspPheSer LeuG LYG 1 uTrpLy sTHR G InMe t G luGluThr Lye AlaGlnAspXleLeuGlyA.1 aValThrLeuLeuLeuG luG lyValMecAlaAlaArgG ly GlnLeuGlyProThrCysLeuSerSerLerLeuGlyGlnLeuSerGlyGl nValArgLeu LeuLeuGlyAlaLeuGlnSerLeuLeu (SEO XL 140: 234)

PMON28541

AlaAsnCysSerXleMetXleAspGlu.XleXleHisHisLeuLysArgProProAlaPro LeuL euAspPr oAsnAsnLeuAsnAspGluAspVa 1 £ er X1 eL euMe t AspArg AsnLeu ArgLeuProAsnLeuGluS erPheValArU

Σ1 eGluAlaΣ lereeArg.- .. G InProCysXeuProSarAlaThrAlaAlaPraSer

Ar gHis Pre: le Ilex 1 a l <y sAl aGly AspTrpG InG luPheArgG luX.y sLeuTnrPne XyrXeuValThr GwGluGlnAiaGlnGluGlnGlnTyrValGluG lyG lyG lyG iYSer ProGlyGluProser. les 'R' ~ is r 1 eAjsnPreSer ProPras erLyaGlus ether ether HisbysS prcAsimet GlyArgThrTnr AlaHxsLysAspProAsnAl axlePhebeu SerPneGlrlHxaLeuLeuArgGlylysValAX'gPheLeuMegLeuValGlyGiySerThr LeuCy val Argg uPneGly 1 L lyAsnGlyGly AsnMetAlaS air Pr Gai appropr oAla GysAspleuArgvalieu s arly sleuleuArgAspSer HxsVa Ibeu Haeser Air-gl-I erGlniy S s? r oGluvalH xsProLe'aProchrPrpValLa'aLauPr oAlaVa lAsoPhe SerXeuGlyGluTrpLysTnrGlnMecGluGluThrLysAlaGinAspIleLeuGlyAla ValTnrLaüLeuLeuGuGlyeuLaGlAlLaGlAGlA a uG euG 1 y A .1 aCe uG 1 nS a r LeuLauGlyl’hrGlnLeuProProGln iS & Q Σ0 NO: 235)

PNON28542

A * Σ aAsnOys be Lemac XxeAspG suXseXl eH.x sHxsLeuLys ArgPr oProAl APRC LeuLeuAspPraAsnAsnLauAsnAspGluAspValSerXleLeuMeiAsDArgAsnLeu ArgLeuPrcAsriLeuGluSarPheValArgAlaValLysAanLeuGluAsnAlaSerGly XI eg 1 uAlaX 1 eLeuArgAsxxLeuGlnProCysLeuProSer AlaThr AlaAlaP- the E ^ * · ArgHis? * X-rcXleXleXleLysAlaGlyAspl pGlnGluPheArgGluLysLeuThrPhe lyrLauValThrXeuGluGlnAlaGlnGluGlnGlnTyrValGluGlyGiyGlyGlvSar ProGlyGluProSerGlyPrcXleSerThrZleAsriPraSsrProProSerLvsGluSer HxaGysSarProAstMePAlaHxsOysAspProAsnAlaXlePheLeuSerPheGl.nKis LeuLeuArgGlyLysValArgPheLeuMetLauValGlyGlySerTtirLeuCysValArg G1 uPheG ly AsnG LYG LYG ly AsnMet AlaSer Pr oAlaProProAl ACY sAspL euAr g · V © L & lLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSarGln.CvsPr xuva 2 AeuProThr Pro Hi SPRR ValLeuLeuPr OAL aValAspPheS erLeuGlvGlo TrpLysThrGlnMetGluGluThrLysAlaGl.nAsplleOeuGlyAlaValThrLeuLeu Xe ^ Glo.GlyValMetA.laAiaArgGlyGlnL ^{_{(euGlyPrhThrC>)} r} _sLeuSerSerX! eiiGe'j GiyGrr ^ & uSerGlyGlnValArgLeuLenLeuGlyAlaLeuGlnSerLeuLeuGlvThr GlnbeuProProGlnGlyArgThrThr iSEQ XD NO: 236) pMON28543

Eser AlaAsnCy XleMet X1 eAspGluIl eXi EHI sHisLeuLysArgProProAlaPro ^ '& LeuAspPrpAsnAsnLeuAsnAspGluAspvalSerXl LauMetAspArgAsnLeu êl ^F t oAsnLeuGxuS air PbeValArg AlavalLy SAsnLeuG luAsnAlaSerGlv 21eGluAiaxleLieuArgAsnl.euGlnProCysLeuPr0SerAlaThrAlaAlaProSer ArgHi eProXx & XleXxeLysAlaGlyAepTrTGlrJGluPheArgGluXysLetrrhrPhc TyrLeuValThr euGluGlnAlaGlnGluGlnGlnxynrValGlÜGlvGlyGlvGlyS ^ ^ r ^ ProGlyGl roSerGlyPrpxieSarThrXieAsnPrQSerProProSarLysGluSer HisLysSerProAsnMetAspProAsnAlaXlePheLeuSerPheGlnHisLeuLsuArã GxyLyaValArgPheLeuHecLeuValGlyGXySerTnrLeuCysvalAraGluPheGly GxyAsnGlyGlyAsnMet wings ether ProAlaProPrpAl aCysAspLeuArgValLeuSer OysLeuLeuArgAspSerHisValLeuHxsSerArgLewSerGlncysProGluValHds ircLe'dProThrProValXeuLeuPrQAlaValAspPheSerLauGlyGluTrpLvsX'hr G' .nn et ka xuG 1 uTty ly s A aa <»IrAs px 1 ePeuG xy Ax a V a IT hr Ge uX euLsu G1 uG Iv ^ 'Í ^^^^^^^^^^^^^ P ^ oThr ^ sLeuSerSerLeu ^ euGlyGlnLeê SerGlyGlnValArgLeuLeuLeuGlyAlaLsuGlnSerLeuLeuGlvThrGlnLeuPrc ProGxnGlyArgThrThrAlaEisLys {SEQ IE NO: 237)

147

s.2 & -4snCy SerXleMeclleAspGl'aXleHeHisKisLeuLysArcI £ ^'> & r PrcAlaPre LeuLeuAsoProAsnAsi * ** LeuAs AspGx.uAspv axSe r ^ x-euMet .spArg Astl-Sar gLeuPr oAsrLeuG ~ u Ser PHEV Axar gAxaV allys ASNL euGltxAsnAxaS ether Gjy lleGluAiaXleLeuArgAsnLeuSlnPrGCysLeuProSerAlaThrAlaAlaProSer Air CHx s Fro XI and Al X1 Eli elys aGlyAspTrpG InGluPheAr gGluLy sLeuTr.r Phe TyrLeuValThrLeuGiuGlnAlaGlnGluGlnGlnTyrValGluGlyGiyGlyGiySer PToGlyGluProSerGlyPrôXleSerThrxleAsnPrQSerProProSerLysGluSer Hx Slye SerProAsnMe Alai t 1 ePheLeuS erPneGInHi sLeuLeuAr 1 gGiyLysVa Arg-heLeuMetLe grape, iQ i.yGuySerTarLeuLysValArgG.iuPheG xyGryAsnG GlyAsnMetAlaSerProAlaProPraAlaCysAspLeuArgValLeuSerLysLeuLeu jy s air AspSerHx g ValLeuHis SerArgLeuS ERG Incy s ProGluVa iHis Pr oLeuPro TerProVãlLeuLeuProAi backing AspPheSer LeuGly GluTrpLy sThrG mM L et Glu luThrLy AlaGlnAsp £ 11 eLeuGly LEV alThrLeuLeuLauG luGlyVa IMET Ala P.laÀrgGiyGlnLeuGlyProThrCysLeuSerSerLeuLeuGlyGlnLeuSerGlyGla V x Ar g-i, · ly -® uxj EUG Air XNS I er g euLeuG hr RYT EuPR G x Pr x oG ry ArgThrThrAlaHisbysAspProAsn nG (SEQ XD NO; 238 'xOuViwAÍ' t · Λ i>'XK·' ··% to .ElaAsnCysSerXleMecXleAspGluXlelIeHisHisLeuLysArgProProAlaPrc LeuLeuAspProAsnAsnLeuAsiiAspGluAspVa.lSerXleLeuMetAspArgAsriLeu ArgLeuProAsiiLenGluSerPheValArgAlaValLysAsnLeuGluAsnAlaSerGiy X1 al eGluAl 1 eLeuArg AsnLeuG InPraCysteuProSer AlaThr AXaAlaProSer ArgHisPrcI lelleXleLysAlaGlyAspTrpGlnGluPheArgGluLysLeuThrPhe TyrbeuValThtLeuGluGliiAlaGlnGluGlnGlnTyzValGluGlyGlyGlyGlySer ProGlyGiu.PrQSerGlyPrGXleSerThrXleAsnProSerPro.PrQSerLysGluSer HxsLysSerPrGAsnMetAspProÃsnAlaZiePheLeuSerPheGlxsMísbeuLeuArg GlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysvalArgGluPheGly GlyAsnMetA.laSerProAlaProProAlaCy-His'sAspLeuArgValLeuSer'LysLeuLeu ArgAspSer V alheuHi sSer Air gLauSerGlnCy ProG luValH s i u G1-sProLauPro ThrProValLeuLeuPrcAlavalAspPheSerLeuGlyGluTrpLysThrGl.nMet.Gl Uthr LysAlaGInAsp11 U eL euGlyAlaValThr euLeuLeuG 1 uG ly VA falls iMe aiaArgGtyGlnLeuGlyProThrCysLeuSerSe rLeuLeuGlyGlnLeuSerGlyGlii ValArgLeuLeuLeuG ly AlaLeuG InSer LeuLeuG i vThrG InGl vAroThrThr Ai a HisLys ÍSEO XO NO: 239;

pMQKl2132

S er Pr Pr OAL aprotic oAlaCy sAspLeuArgValLauS erly sLeuLeuArgAspS erHis ValLeuHisSerArgLeuSerGlnCysProGluValHisProLeuProThrProValLeu LeuPraAlavalAspPheSerLeuGlyGluTrpLysThrGlnMetGluGluThrLysAla GlrAsplieLeuGlyAlâValThrLeuLeuLeuGluGlyValMetAlaAlaArgGlyGln LeuGiyProThrCysLeuSerSerLeuLeuGlyGXnLeuSerGlyGlnValArgLeuLeu LeuGlyAlaLeuGlnSerLeuLeuGlyThrGlnLeuProProGinGlyArgThrThrAla dx s ^ {ysAspProAsnAlaXlePheLeuSer PheGlnHisLeuLeuArgGlyLysValArg PheLexsMetLeuValGlyGlySerThrLeuCysValArg SEQ 00 ^ 0 ^ 252)

PMÍ

148

The following examples will illustrate the invention in greater detail although it will be understood that the invention is not limited to those specific examples.

Example 1

Parenteral BHK Expression Vector Construction

A. Removal of Afllil site from mammalian expression plasmid.

A new mammalian expression vector has been constructed to accept fragments of Ncol-Hinlll or AflHI-HindIII gene framed and 3 'to the hll-3 receptor agonist gene pMONl3146 (WO 94/12638) and a mouse igG2b linker fragment. First, the single Afllil site was removed from pMON3934, which is a derivative of pMON3359, PMON3359 is a vector based on pUC18 containing a mammalian expression cassette. The cassette includes a herpes simplex viral promoter IE110 (-800 to +120) followed by a modified human IL-3 signal peptide sequence, and a late poly-fadanylation (poly-A) signal SV-40 was sub-cloned into the polylinker pUC18 ( See Hippenmeyer et al., Bio / Technoiogy, 1993, pages 10371041). The modified human IL-3 signal sequence, which facilitates the secretion of genetic products outside the cell, is flanked by a BamHl site at the 5 'end and a single NcoI touch at the 3' end. A unique HinH site is 3 'from the Ncol site and 5' from the poly-A sequence. The DNA sequence encoding the signal peptide is shown below (restriction enzyme sites are indicated above). The ATG codon (methionine) with the Ncol site is in-frame with the ATG primer of the signal peptide (underlined):

BamHl Ncol

5OGAAATCCACCATGAGCCGCCTGCCCGTCCCTGCTCCTGF CTCCAACTCCTGGTTCCGCCCCGCCATGG (SEQ ID NO: 255)

The Afllil single site was removed from pMON3934 by digestion with Afllil followed by filling in the ridges by adding DNA polymerase and nucleotides. The digested DNA fragment was purified via the Magic PCR cleaning kit (Promega) and ligated with T4 DNA ligase. The ligation reaction was transformed into DH5a ™ and the cells were applied in

149 ampicillin LB-agar plus. Individual colonies were monitored for loss of the Alftll site through restriction analysis with Afllll and Hidlll which results in a single fragment if the Afllll site was removed. The resulting plasmid was designated p MON30275.

8. Transfer of cassette p MON134l6 / lgG2b receptor agonists hít-3 in p MON3Ô275.

The Ncol-Hindlll fragment (about 425 bp) of p MON30245 was ligated to the Ncol-Hindlli fragment (about 3800 bp) of p MON30245, p MON30245 (WO 94/12638) contains the gene encoding the hiL-3 receptor 10 agonists ρ M0N13416 attached to a mouse IgG2b joint fragment, immediately 3 'to the IgG2b joint and 5' to the Hindlli site is an Afllll site. Genes can be cloned at the Afllll Hindlli sites as NcoIHindlli or AflIlí-HindíB fragments in the mold with the hlL-3 p MONl34l6 / igG2b joint variant to create new chimeras. The Ncol site and the Afllll site have compatible projections 15 and will connect, but both reconnaissance sites are lost. The plasmid, ρ MON30304 containing the DNA sequence of (SEQ ID NO: 78) _; encoding the hlL-3 ρ MON13416 variant, it bound to a lgG2b mouse joint region _{: it} was a result of this cloning.

Example 2

Construction of an intermediate plasmid containing a copy of the c-mpl (1-153) ligand gene from the dimer matrix.

To generate a plasmid DNA with the c-mpl (1-15'3) ligand coding sequence followed by a unique EcoRI restriction site, the gene is isolated via reverse transcriptase / polymerase chain reaction 25 (RT / PCR ). Human fetal RNA A ⁺ (batch # 38130) and adult liver (batch # 46018) are obtained from Clontech (Paio Alto, CA) for a source of RNA messenger c-mpl ligand (mRNA). The first reactions of cDNA elements are performed using a cDNA Cycle * kit obtained from Invitrogen (San Diego, CA). In the RT reaction, random pnmers and oligo dT primers are used to generate cDNA from a human liver mRNA combination. and fetal liver, For amplification of c-mpl ligand gene fragment encoding amino acids 1-153, the RT product serves as the matrix for PCR with

150 a combination of primers, front primer: c-mopINcol (SEQ ID Ν ^Λ : 13) and reverse primer: Ecompl. The c-mpINcol pnmer links to the c-mpl linker gene (bases # 279-311 based on the c-mpl linker sequence from accession # 1.33410 from the genetic bank or Sauvage et al., Nature 369 533-538 (1934)) and encodes an Ncol restriction enzyme site immediately 5 'from the first codon (Ser + 1) of the c-mpl ligand. The Ncol restriction enzyme site encodes methionine and ayanine codons before Ser + 1 a includes codon degeneration for codon Ala and the first four codons (Ser, Pro, Ala, & Pro) of the c-mpl ligand. Prima Ecompl rings with bases # 720-737 of c-mpl ligand and encodes a local EcoRI m-frame (GAATTC) immediately following Arg-153. The EcoRI sites create Glu and Phe codons followed by Arg153. The PCR product. about 480 bp was purified, digested with NcoI and EcoRI and linked to the fragment of the Ncol-EcoRI vector of p MON3993 (about 4550 bp). p MON was a derivative of p MQN3353 (described in example 1). The 15 peptide sequence means! human IL-3, which has been subcloned as a BamHI and poly-A fragment, contains an Ncol site at its 3 'end and is followed by a single locus! EcoRI. The plasmid, p MON26458 containing a DNA sequence of (SEQ ID NO * 73), encoding 1-153 amino acid c-mpl ligands (SEQ ID 161). I was the result of this cloning.

Example 3

Construction of parenteral plasm ideas containing the second gene of the dimer matrices.

For amplification of the c-mpl ligand gene fragments starting with amino acid 1 (Ser) with a stop codon followed by amino acid 153 (Arg), the RT reaction from Example 2 serves as the matrix for PCR with a combination of the following primers, c-mpíNcoil (SEQ IS No: 13) (front primer) and c-mplHindlll (SEQ ID: 15) (reverse primer). The primer (SEQ ID: 13) is described in example 2. The primer c-mpí Hindlll (SEQ ID N °; 15) _: which rings to bases # 716-737 of linker c-mpl, adds a codon 30 of terminus and a HindiII restriction enzyme site immediately following the final codon, Arg ^1: 2

151

Two types of PCR products are generated from RT cDNA samples, one with a suppression of codons for amino acids 112-115 and one without a suppression of those codons. The c-mpl linker PCR products (about 480 bp) are digested with Ncol and restriction enzymes Ncol and 5 HlndlH to transfer a mammalian vector expression, p MON3934. P MON 3934 is digested with Ncol and Hindlll (about 3800 bp) and will accept PCR products.

Plasmid, ρ MON32132 (SEQ ID N *: 249), encoding for amino acid c-type ligands 1-153 (SEQ 10 N * 252) was a result of this cloning. Plasmid, ρ MON32134 (SEQ IO N ^ô : 251), encoding amino acid c-mpl ligand 1-153 with a codon suppression (Δ112-115) was also a result of this cloning.

Example 4

Generation of 5L matrix of PCR genus with a deletion of 15 (Δ112-115) in the second ligand gene c-mpl

A PCR matrix for generation of new forms of c-mpl ligand is constructed by ligating the 3.7 Kbp BstXI / EcoRI fragment from ρ MON26458 to the Kbp Ncol / BstXI fragment from ρ MON32133 (containing a 112-115 amino acid deletion) along with the 5l EcoRI / AflHI synthetic oligonucleotide © 20, 51-5 '(SEQ ID hf: 18) and 51-3' (SEQ ID NO: 19).

The EcoRI end of the linker will connect to the EcoRl end of ρ MON26458. The AlflH end of the ligand will attach to the NgoI site of p MON32133, and neither the restriction site will be maintained with the link. The SstXI locations of ρ MON26458 and ρ MON 32133 will also connect. Plasmid, 25 ρ MON28548, is a result of cloning and contains the DNA sequence of (SEQ ID NO: 80) encoding the amino acid c-mpl 1-153 ligands fused via a GluPheGlyGlyAsnMetAla ligand (SEQ ID NO: 222 ) the amino acid c-mpl linker 1-153 which contains an amino acid suppression 112-115 (SEQ ID NO: 162).

152

Example 5

Generation of 41 PCR dimer matrix

A PCR matrix to generate new forms of c-mpl ligand is constructed by linking the 3.7 Kbp BstXl / EcoRl fragment of ρ MON26458 to the 1 Kbp Ncol / BstXI fragment of ρ MON32132 together with the synthetic oligonucleotide ligand 4RI EcoRI / AfHII 4L- 5 '(SEQ ID NO: 16) and 4L-3' (SEQ ID NO: ^ô: 17)

The Econ end of the linker will connect to the EcoRí end of ρ MON2658. The Afllll end of the ligand will attach to the Ncol site of p MON32132, and neither the restriction site will be maintained with the ligation. The BsfXI locations of ρ MON26458 and ρ MON 32132 will also connect. The plasmid, ρ MON28500. it is a result of cloning and contains the DNA sequence of (SEQ ID 82 ^σ ; 82) which encodes amino acids 1-153 lycant c-mpl fused via a (41) ligand (SEQ ID NO: 223) GluPheGlyAsnMetAla the c -mpl of amino acids 1-153 (SEQ ID NO: 163).

Example 6

Generation of 51 PCR dimer matrix

A PCR matrix for generation of new forms of c-mpl ligand is constructed by ligating 3.7 Kbp BstXl / EcoRl fragments from p MON26458 to the 1 Kbp Ncol / BstXI fragment from ρ MON32132 together with the synthetic oligonucleotide EcoRI / AfilH 5L, ligand 5L.-5 '(SEQ ID NO ^at 18) and 5L.-3' (SEQ ID NO : 19).

The EcoRI end of the linker will connect to the EcoRI end of ρ MON26458. The Afllll end of the ligand will bind to the Ncol site of p MON32132, and no restriction sites will be maintained with the binding, Plasmid, ρ MON28501 is a result of cloning and contains the DNA sequence (SEQ ID NO: 82 ) encoding c-mpl linker from 1-153 amino acids fused via a GiuPheGlyGlyAsnMetAia (5L) linker (SEQ ID NO: 22.2) to amino acid 1-153 c-mpl linker (SEQ ID NO: 164).

153

Example 7

Generation of 8L matrices of PCR dimer

A PCR matrix to generate new forms of c-mpl ligand is constructed by linking the 37 Kbp BstXI / EcoRI fragment of p MON2658 to the 5 1 Kbp Ncol / BstXI fragment of p MON32134 together with the Synthetic oligonucleotide ligand EcoRI / AflIH 81, 81-5 '(SEQ ID Ν °: 20) and 81-3' (SEQ ID No. ^ft : 21).

The EooRI end of the linker will attach to the EcoRI end of p MON 26458. The Afllll end of the linker will attach to the NcoI site of p 10 MON32134, and no restriction site will be maintained with the link. The Bs26XI locations of p MON26458 and MON32134 will also connect. Piasmide p MON28502 is a result of cloning containing the DNA sequence of (SEQ ID NO: 83) and encodes o-mpl (8L) ligands of amino acids 1-153 fused via a GluPheGlyGlyAsnGlyGlyAsnMetAla (SEQ ID NO: 224) a li15 the Ghent-MPL amino acids 1-153 (SEQ ID NO : ^c: 165).

Examples 8-44

Generation of new c-mpl ligand genes with new ending N and ending C

A. Generation of PCR genes encoding new receptor agonists c-mpl ligands.

Genes encoding new c-mpl binding receptor agonists were generated using method III (Horlick et al., Pro, Eng. 5: 427-433, 1992). The PCR reactions were performed using dimer matrices, p MONs 28500, 28501. 28502, or 28548 and one of the slantetic primer settings shown below (The first number refers to the position of the first amino acid in the original sequence. For example, 31 -5 'and 31-3' refers to primers 5 'and 3' oligo, receptively, for the start of the sequence at the codon corresponding to residue 31 of the original sequence.).

31-5 '(SEQ ID Ν' ⁵ : 22) and 31-3 '(SEQ ID Ν ^β : 23), 35-5' (SEQ ID N:

24) and 35-3 '(SEQ ID 25). 39-5 '(SEQ ID NO: 26) and 39-3' (SEQ ID Ν ': 27),

43-5 '(SEQ ID NO: 28) and 43-3' (SEQ ID Ν ' ⁵ : 29), 45-5' (SEQ ID Ν ' ⁵ : 30) and 45-3' (SEQ ID Ν ' : 31), 49-5 '(SEQ ID Ν': 32) and 49-3 '(SEQ ID NO: 33), 82-5' (SEQ iw

N ^s: 34) and 82-3 '(SEQ ID NO: 35) 109-5' (SEQ ID 36} & hT 109-3 '(SEQ ID bf: 37) 115-5' (SEQ ID NO: NO: 38) and 115-3 '(SEQ ID Ν': 39) 120-5 '(* SEQ ID NO: 40) and 120-3 (SEQ ID NO ^tO. 41) * 123-5 (SEQ ID N *: 42) and 123-3 '(SEQ ID N143), 126-5' (SEQ ID Ν ': 44) and 126-3' (SEQ ID N ^c : 45).

b The matrixes and oligonucleotide sets used in the reactions

PCR are shown in Table 4. The products that were generated were about 480 bp and were purified via Magic PCR kits. Clean up (Promega).

8. Subcloning of new products of c-mpl receptor agonist genes in a mammalian expression vector for the generation of chimeras.

The PCR products of c-mpl receptor agonist genes were digested with restriction enzymes Ncol and HindllI or Afilll and Hindlll (about 470bp) to transfer to a mammalian expression vector. The expression vector, p MON30304, has been digested with Ncol and Hindlll (about 4200 bp) and accepts the PCR products as Ncol-Hindlll or Afllll-Hndndt fragments The restriction digest of the PCR product and the resulting peptides are shown in Table 4 ,

Table 4 Exesrspo # Mate PCR PsM ^ PCR corçuf & ide primer l ^ esástefe resteãoife pKxWPCR Pasn> dareatoe RxTtyle to Sganfeompl • ExempbS PMON28501 31 Ncol / Hindllí 51 ... 28505 3031 Example 9 pMQN28501 35 AHIII / Hindi 51, 28506 34-35 Example 10 pMON28501 39 Nco ^ HindlU SL 28507 3839 ExampleU PMON28501 43 Nocl / Hindlll 51 28508 42-43 Example 12 PMON28501 45 Ncol / Hnálll 5L 28509 4445 Exempb13 PMON28501 49 Nooí / Hhdlll 5L 28510 4849 Exerrplo14 pMON285Ü1 82 NoolHndlH 5L 28511 8132 Bsmplo15 PMQN28501 109 NcoVHindlll 5L 28512 108-109 Example 16 pMON28501 116 NcoVHindlll 5L .28513 115416

155

Tabda 4 (oor ^ rwcâo)

EwrW # Ma & tePCR PCR product Oigeslãocte LkjíTíte Amazing Port of corp-fete rest; ã> te the rest reptorene pnmer PCR product also ligantoíxnpf Example 17 pMON285D1 120 NcoVHndIH 5L 38514 119-W Example 18 pMQN28501 123 NaoDHindlll 5L 28515 122-123 Example 19 PMON28501 126 Nool / Hhdlll 51 28516 125-126 Example 20 P & O12850Q 31 NooVHindl! L 41 28519 30-31 Example 21 pMON2850Cí 85 AW-Ml 4L 28520 34-35 Example 22 pWN28500 39 NooLWlII 41 28521 38-39 PMON28SOO 43 Nosl / Hindlll 41 28S22 42-43 Exenpto24 PMON28500 45 Nrxl / EMI 4L 28523 44-45 Example 25 pMON285DO 49 Noc ^ -Ml 4L 28524 4849 Exempk> 26 p MON28500 82 htoVHndlll 41 28525 81-82 Example 27 p MON285ÜO 109 btol / Hindlll 41. 28526 108-109 Example 28 pMON285QO 116 NoolHndill 4L 28527 118116 Example 29 PMON28500 120 Ncoí / HM 41 28528 119-W Example 30 PMQN28500 123 Hod / TMI 4L 28529 122-123 Example 31 pMON285ÜO 126 NcüífrfrMI 41 28530 125-126 Example 32 p MON285Q2 31 NcolHhdlll 81 28533 3031 Example 33 pMON28502 35 The 28534 3485 Example 34 PMON28502 39 Nool / Hindlll 8! .. Z8535 38-39 Example 35 PNOM28502 43 NooVHndlll 8L 28536 42-43 Example 36 PMON28502 45 NcoVHÍndiH 8L 28537 44-45 Eempto37 PMON285Q2 49 Ncd / Hiodlll 8L 28538 4849 Example 38 PMON2 & 502 32 rtoVHbdlll 8L 28539 81-82

156

Table.4 (continued)

Example # MafnzPCR Ro & tePCR Digestion <fe LJgarfe Pasmd Potode ax ^ ocufe stressed iUptiXBΠΟ fwi Tart Sganteíxnpl Example 39 pMQH285O2 109 NcoVHndlll 8L 28540 108-109 Example 40 P & OI28Õ02 116 Nool / HndlH 81 28541 115-116 ExmpE41 PMON28502 120 Ncd / Hindlll 8L 28S42 119-120 Example 42 PMON28502 123 Ncolâ-ltólll 8L 28643 122-123 Eorplo43 pbO42S5G2 126 NooVHindlll 8L 28544 125-126 Example 44 pM0N28548 NooVHhdlll 5L 28545 122-123

Example.45

Construction of the MON15960 p

Construction of p MON 15960, an intermediate plasmid used to construct plasmids containing DNA sequences encoding G-CSF Ser ¹⁷ with a new N and C termination. The plasmid DNA pACY177 (Chang Α.0Ύ. And Cohen, S, N. v. phytene /. 134: 1141-1156, 1978) was digested with Hindlli and BamHI restriction enzymes resulting in a base pair of 3092 Hindll, BamHI fragment. Plasmid DNA, p MON13037 (WO / 21254), was digested with Bglll and Fspl, resulting in a 616 Bglll base pair, Fspl fragment. A second sample of plasmid DNA ,. p MON13037, was digested with Ncol and Hindlll, resulting in a base pair 556 Ncol fragment, Hindlll. The synthetic DNA oligonucleotides iGGGSfor (SEQ ID NO: ^and: 76) and IGGGSrev (SEQ ID NO:. 77} were annealed to each other, and then digested with AfHII and FspI , resulting in a base pair 21 AfHII fragment FspI Fragments restriction strains were ligated, and the reaction mixture was used to transform E. colí K-12 strain JM101. Transformant bacteria were selected on plates containing ampicillin.Plasmid DNA was isolated and analyzed by restriction analysis to confirm correct insertion .

157

Example 46

Construction of the MO N15981

The construction of ρ MON15981, a plasmid containing DNA sequences encoding a multifunctional hematopoietic receptor agonist. Plasmid, ρ MON15960 was digested with restriction enzyme Smal and used as a matrix in a PCR reaction using synthetic oligonicleotide DNA terminator 38 (SEQ ID NO: 65) and primer 39 (SEQ ID NO:

64) as primers, resulting in the enlargement of a DNA fragment from

576 base pairs. The magnified fragment was digested with Hindlli and Ncol restriction enzymes, resulting in a 558 base pair Hindlli, Ncol fragment. Plasmid DNA, ρ MON13181, was digested with Hindlli and Afllll. resulting in a 4068 base pair fragment. The restriction fragments were ligated, and the ligation reaction mixture was used to transform E cqH L-12 strain JM101. Transforming bacteria were selected from plates containing ampicillin. Plasmid DNA was isolated, analyzed by restriction analysis and sequenced to confirm carriage insertion. The plasmid, ρ MON15981, contains the DNA sequence (SEQ ID NO: 155) which encodes the following amino acid sequence:

MetAiaAsnCysSeríleMetlleAspGlullelleHisHisLeul.ysArgProProAla

ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlieLeuMetAspArgAsn

LeuArgLeuProAsnLeuGluSefPheValArgAlaValLysAsnLeuGluAsnAlaSer

GlylleGluAlalieLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro SerArgHisProliellelleLysAlaGlyAspTrpGInGIuPheArgGluLysleuThr PheTyrLeuValThrLeuGluGInAlaGInGluGalGIGGGGGGGGGGG

SerProGlyGluProSerGIyProlleSerThrIleAsnProSerProProSerLysGlu

SerHisLysSerProAsaMetAiaTyrLysLeuCysHisProGluGluLeuValLeuLeu

GlyHisSerleuGlylleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGIn leuAlaGiyCysLeuSerGInLeuHisSerGlyLeuPheleuTyrGinGlyLeuLeuGIn AlaLeuGluGlylleSerProGluLeuAl

AlaAspPheAlaThrThdleTfpGlnGInMetGluGluLeuGlyMeiAlaProAíaleu

GlnProThrGInGlyAlaMetProAlaPheAlaSerAlaPheGInArggArgAlaGlyGly

ValLeuValAlaSerHisleuGInSerPheLeuGluValSerTyrArgValLeuArgHis

158

LeuAlaGInProGlyGlyGlySerAspMetAlaTbrProLeuGlyProAlaSerSerLeu ProGInSerPheLeuLeuLysSerLeuGluGínVaíArgLysIleGínGlyAspGiyAia AlaLeuGInGlutysLeuCysAlaThr (SEQ: NO): ID: 195

Example 47

Construction of ρ M0N15982

Construction of ρ MON15982, a plasmid containing DNA sequence encoding a multifunctional hematopoietic receptor agonisla. Plasmid, ρ ΜΟΝΊ5960, DNA was digested with restriction enzyme Smal and used as a matrix in a PCR reaction. using synthetic oligonucleotide DNA 96 stop (SEQ ID NO: 67) and start 97 (SEQ ID NO: 68) as primers, resulting in the amplification of a 576 base pair DNA fragment. The amplified fragment was digested with Hindlll and Ncol restriction enzymes, resulting in a Hind III, 558 base pair Ncol fragment. Plasmid DNA, ρ MON13181, was digested with Hindlll and Afllll, re15 sultartoo in a Hindlll, AflIH fragment of 4068 basic parts. The restriction fragments were ligated, and the ligation reaction mixture was used to transform E. cofí K-12 strain JM101. Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm correct insertion. Plasmid ρ MON15982 contains the DNA sequence (SEQ ID rf: 157) which encodes the following amino acid sequence: M@tAlaAsnCysSerlleMeilleAspGlullelleHísHisL.euLysArgProProAía ProLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlIeLeuMetAspArgAsn LeuArgLeuProAsnLeuGluSerPheValArgAlaVaiLysAsnLeuGluAsnAlaSer

2.5 GlylleGíuAlalleLeuArgAsnLeuGInProCysLeuProSerAlaThrAlaAlaPro

SerArgHisProllellelleLysAlaGlyAspTrpGInGluPheArgGluLysLeuThr PheTyrLeuValThrLeuGluGInAlaGlnGluGInGInTyrValGIuGlyGlyGlyGly SefProGlyGluProSerGIyProlleSerThrGLPro

AspValAlaAspPheAlaThrThrlIeTrpGInGInMetGluGluteuGlyMetAlaPro AlaleuGInProThrGInGlyAlaMetProAlaPheAlaSerAlaPheGInArgArgAla GlyGlyValleuValAiaSerHisLeuGySalHerLeuGlNer

159

ArgHísLeuAlaGInProGlyGlyGlySerAspMetAlaThrProLeuGlyProAlaSer

SerLeuProGlnSerPheLeuLeuLysSerLeuGluGInValArgLyslleGlnGlyAsp

GlyAlaAlaAlaLeuGInGluLysLeuCysAlaThrTyrLysLeuCysHisProGiuGiuLeu

ValLeuleuGlyHisSerLeuGlyHeProTrpAlaProLeuSerSerCysProSerGIn

AlaLeuGInLeuAlaGlyCysLeuSerGInLeuHisSerGlyLeuPheLeuTyrGInGly

LeuleuGInAlaleuGluGlylieSer (SEQ ZD NO; 196)

Example 48

MON15965 p construction

Construction of ρ MON15965. a plasmid containing DNA sequences encoding a multifunctional hematopoietic receptor agonist. DNA plasmid p MON15960 was digendo with restriction enzyme Smal and used as template in a PCR reaction using DNA synthetic oligonucleotides terminator 142 (SEQ ID NO: ^ô: 73) and primer 141 (SEQ ID NO: 72) as primers, resulting in the enlargement of a DNA fragment 15 of 576 base pairs. The extended fragment was digested with restriction enzymes Hndlll and Ncol, resulting in a Hndlll, Ncol fragment of 558 base pairs. Plasmid DNA, ρ MON13181., Was digested with Hindlll and Afllll, resulting in a 4058 base pair Hindi !!, Afllll fragment. The restriction fragments were ligated, and the reaction mixture was used to transform £ coti K-12 strain JM101. Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated, analyzed by restriction analysis and sequenced to confirm correct insertion. The plasmid, ρ MON15965, contains the DNA sequence of (SEQ IO N “·. 157) which encodes the following amino acid sequence:

MetAlaAsnCysSerlIeMetlleAspGlulleileHisHisLeuLysArgProProAla

ProteuLeuAspProAsnAsnLeuAsnAspGluAspValSerlIeLeuMetAspArgAsn

LeuArgLeuProAsnLeuGluSerPheValArg.AlaValLysAsnLeuGluAsnAlaSer

GlylíeGluAlaZIeLeuArgAsnLeuGInProCysLeuProSerAlaThrAlaAlaPra

SerArgHisProZIellelleLysAlaGlyAspTrpGinGiuPheArgGluLysLeuThr

PheTyrLeuVal FhrLeuGluGInAlaGInGluGInGInTyrValGIuGlyGlyGlyGly

SerProGiyGluProSerGIyProlleSerThrlIeAsnProSerProProSerLysGlu

SerHisLysSerProAsnMetAlaSerAlaPheGInArgArgAlaGlyGlyValLeuVal

160

AlaSerHísLeuGlnSerPheLeuGfoValSerTyrArgValLeuArgHisLeuAlaGln ProGlyGlyGlySerAspMetAlaThrProLeuGiyProAlaSerSerleuProGInSer PheLeuLeulysSerLeuGluGInValArgLysileGInGlyAspGlyAlaAlaLeuGIn GluLysleuCysAlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHis 5 SerleuGlylieProTrpAlaProLeuSerSerCysProSerGInAlaLeuGInLeuAla

GlyCysleuSerGlnLeuHisSerGlyLeuPheLeuTyrGInGlyLauLeuGlnAlaleu GluGlylleSerProGluleuGlyProThrLeuAspThrLeuGInteuAspValAlaAsp PheAiaThrThrlleTrpGInGlnAetGluGlnMetGlu

Example 49

MON 15966 p construction

The construction of ρ MON15966, a plasmid containing DNA sequences oodifying a multifunctional hematopoietic receptor agonists. Plasmid DNA, ρ MON15960, was digested with a Smal restriction enzyme and used as a matrix in a PCR reaction using synthetic stop oligonucleotide DNA 126 (SEQ ID N: 68) and 125 start (SEQ ID N * '69) as primers, resulting in the amplification of a 576 base pair DNA fragment. The amplified fragment was digested with Hindlll and Ncol restriction enzymes, resulting in a 558 base pair Hindlll, Ncol 20 fragment. Plasmid DNA, ρ MON13181, was digested with Hindlll and Afllll, resulting in a Hindlll fragment. Afllll of 4068 base pairs. The restriction fragments stick together, and the ligation reaction mixture was used to transform E. ca / i K-12 strain JM101.

Transforming bacteria were selected, analyzed by restriction analysis and sequenced to confirm correct insertion. The plasmid, p MON159S6, contains the DNA sequence of (SEQ ID N °: 158) that encodes the following amino acid sequence: MefAiaAsnCysSerlIeMetlleAspGlullelieHisHisLeuLysArgProProAla ProLeuLeuAspProAsnAsnleuAsnAspMlA

LeuArgLsuProAsnLeuGluSerPheValArgAlaVaiLysAsnLeuGluAsnAlaSer GlylleGluAialleLeuArgAsnLeuGInProCysleuProSerAlaThrAlaAlaPro SerArgHisProUellelletysAlaGlyAspTrheGlA

ΊΟ i

PheTyrleuValThrleuGluGInAlaGInGluGInGInTyrValGluGlyGiyGlyGly SerProGlyGluProSerGíyProlleSerThdíeAsnProSerProProSerLysGlu SerHisLysSerProAsnMetAlaMetAlaProAlaLeuGInProThrGInGlyAlaMet ProAlaPheAlaSerAlaPheGInArgArgAlaGlyGlyValleuValAlaSerHisLeu GlnSerPheleuGluValSerTyrArgValleuArgHísLeuAlaGInProGlyGlyGly

SerAspMetAlaThrProLeuGíyProAlaSerSerLeuProGInSefPheLeuLeuLys SerLeuGluGInValArgLysIleGInGiyAspGlyAiaAlaLeuGInGluLysLeuCys AlaThrTyrLysLeuCysHisProGluGluLeuValLeuLeuGlyHisSerLeuGlylle ProTrpAlaProLeuSerSerCysProSerGInAlaLeuGInLeuAlaGíyCysLeuSer GlnLeuHisSerGlyleuPheLeuTyrGInGlyLeuLeuGlnAlaLeuGíuGlyileSer ProGluLeuGíyProThrleuAspThrLeuGínLeuAspValAlaAspPheAlaThrThr IleTrpGInGInMetGluGluleuGly (SEQ ZD NO: 198)

Example 50

Construction of MON15967 p

The construction of p MON15967, a plasmid containing ONA sequences encoding a multifunctional hematopoietic receptor agonists. Plasmid DNA, p MON15960 was digested with Smal restriction enzyme and used as a template in a PCR reaction using synthetic oligonucleotide DNA terminator 132 (SEQ ID NO: 71) and primer 133 (SE.Q 1D NO 70 ) as primers, resulting in the amplification of a 576 base pair DNA fragment. The extended fragment was digested with Hindi II and Ncol restriction enzymes, resulting in a 558 base pair Hid III, Ncol fragment. Plasmid DNA, p M0N13181, was digested with Hindlll and Afllll, resulting in a 4068 base pair Hindlll, Afllll fragment. The restriction fragments were ligated, and the ligation reaction mixture was used to transform E. co / i k-12 strain JM101. Transforming bacteria were selected on plates containing ampicillin Plasmid DNA was isolated, analyzed by restriction analysis, and sequenced to confirm correct insertion. The piasmid, p MQN15976, contains the DNA sequence (SEQ ID N °; 159) which comprises the following amino acid sequences:

MetAlaAsnCysSerlIeMetlleAspGlullelleHisHisLeuLysArgProProAla ProLeuLeuAspProAsnAsnLeuAsnAspGluAspVaiSerllel.euMetAspArgAsn

162

LeuAfgLeuProAsnLeuGluSerPheValArgAlaVallysAsnLeuGluAsnAlaSer

GlylleGluAlaíleleuArgAsnleuGlnProCysLeuProSerAlaThrAlaAlaPro

SerArgHísProllelielleLysAlaGlyAspTrpGInGluPheArgGiuLysLeuThr PheTyrleuValThrLeuGluGinAlaGInGluGinGInTyrValGluGlyGlyGlyGly

SerProGlyGluProSerGIyProlleSerThrlteAsnProSerProProSerLysGlu

SerHisLysSerProAsnMetAlaThrGInGlyAlaMetProAlaPheAlaSerAlaPhe

GlnArgArgAlaGlyGh / ValLeuValAlaSerHisleuGInSerPheLeuGluValSer

TyrArgValLeuArgHisLeuAlaGinProGlyGlyGlySerAspMetAlaThrProLeu GlyProAlaSerSerLeuProGInSerPheLeuLeuLysSerleuGluGInVaíArgLys

IleGInGlyAspGlyAlaAlaLeuGInGluLysLeuCysAlaThrTyrLysteuCysHis

ProGluGluLeuValleuLeuGlyHisSerleuGlylleProTrpAlaProLeuSerSer

CysProSerGInAlaLeuGInLeuAlaGlyCysLeuSerGInLeuHisSerGIyLeuPhe

LeuTyrGInGlyLeuLeuGInAlaLeuGluGlylleSerProGluLeuGlyProThrleu

AspThrLeuGInleuAspValAlaAspPheAiaThrThrlIeTrpGinGInMetGiuGlu

LeuGlyMetAlaProAlaieuGtn

Example 51

Construction of p MON 13180, an Intermediate plasmid used for the construction of plasmids containing DNA sequences encoding multifunctional hematopoietic receptor agonists.

Plasmid DNA, p MON 13046 (WO 95/21254), was digested with Xmal and SnaBI restriction endonucleases, resulting in a 4018 base pair vector fragment. The 4018 base pair fragment was purified using a Magic ONA Clean-up System kit (Promega, Madison, WI) in which the inserted 25 base pair XmabSnaBI fragment is not maintained. The complementary pair of synthetic oligonucleotides, glyxal (SEQ ID N ^G : 74) and glyxa2 (SEQ ID Ν ': 75) was designed to remove the coding sequence from a factor Xa dividing site. When properly combined, these oligonucleotides also result in Xmal and SnaBI ends. The primers, Glyxat and glyxa2, were annealed in an annealing buffer solution (20 mM tris-HCI at pH7.5, 10 mM MgCfo 50 mM NaCI) by heating at 70 ^G C for ten minutes and allowed to resin slowly. The 4018 base pair Xmal -SnaBI fragment of MON13046 powder

163 was ligated with the assembled pligonucleotides using T4 DNA ligase (Boehringer Mannheim, Indianapolis .. IN). A portion of the ligation reaction was used to transform E co / i DH5a embryonic cells (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated from the transformants and analyzed using a PCR-based test. The plasmid DNA of selected transformants was sequenced to confirm correct insertion of the oligonucleotides. The resulting plasmid was designated p MO NI 3180 and contains the DNA sequence of (SEQ ID No. **).

Example 52

Construction of p MON13181, an intermediate plasmid used to construct plasmids containing DNA sequences encoding multifunctional hematopoietic receptor agonists

Plasmid DNA, p MON13047 (WO 95/21254), was digested with Xmal and SnaBL restriction endonucleases resulting in a 4063 base pair vector fragment. The 4063 base pair Xmal-SnaSI fragment was purified using a Magic DNA Clean-up System kit (Promega. Madison, Wl) in which the fragment inserted in the 25 base pairs XmaLSnabl is not maintained. The pair of complementary synthetic oligonucleotides, 20 glyxal (SEQ ID NO: 74) and glyxa2 (SEQ ID NO : ^c: 75), were designed to remove sequence encoding the divagem site of factor Xa. When properly combined, these oligonucleotides also result in Xmal and SnaBL ends Glyxal and glyxa2 were annealed in a ring buffer solution by heating at 70 ° C for 10 minutes and allowed to cool slowly. The Xmal-SnaBI fragment of the 4063 base pairs of M0N13047 p was ligated with the oligonucleotides pooled using T4 DNA Igase (Boehringer Mannheim. Indianapolis, IN). A portion of the ligation reaction was used to transform E cells / t strain DH5a (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated from the transformants and analyzed using a PCR-based test. Plasmid DNA from selected transformants was sequenced to confirm color insertion

Straight oligonucleotide IM. The resulting plasmid was designated p MON13181 and contains the DNA sequence of (SEQ ID NO: **).

Example 53

MON 13182 p construction

The new C-terminus-N / C-terminus gene in ρ MON 13182 was created using Process I as described in Materials and Methods. Primer Fragment was created and amplified from sequence G-CSF Ser ¹ 'in p MON13037 using primer set, 39 primer (SEQ ID NO.64) and L-11 primer (SEQ ID NO. 60). Terminator fragment was created and amplified from 10 sequence G-CSF Ser powder MON 13037 using the primer set, 36 terminator (SEQ ID NO: 65) and L-11 terminator (SEQ ID NO: 61). The new G-CSF Ser17 end-N / end-C gene was created and amplified from the beginning and end of ringed fragments using primers 39 primer and 38 terminator :.

The resulting DNA fragment containing the new gene was digested with Ncol and Hindlll restriction endonucleases and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The intermediate plasmid, p MON 13180, was digested with restriction endonucleases Hindlll and Afllll, resulting in a vector fragment of 4023 pairs of ba20 ses, and purified using a Magic DNA Clean-up System kit (Promega,

Madison. Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform cells of E. coli strain DH5o (life Technologies, Gaithersburg, MD). 25 transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated ρ MON13182.

E. coli strain 101 was transformed with ρ MON13182 for protein expression and protein isolation from inclusion bodies,

The plasmid.p MON13182. contains the DNA sequence of (SEQ ID NO: 94) which encodes the following amino acid sequence:

165

Asu Cys Ser Xie Met Zle Asp Glu Hs Xl® tils His Leu Lys Axg

Pre »Pro AX to Pro Leu Leu Asp Pro Asn Asn Leu asm Asp Glu Asp

Will Be Lie Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

Ser Phe Vai Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly Zle

Glu Ala Xie Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr

Wing Ax * pro Set Arg Hrs Pre Xie xx Xie Lys Aza Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu

Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Gly Ser Pro

Gly Gly Gly s®r Gly Gly Gly Ser Asn Met Ala Tyr Lys Leu Cys

His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly lie Pro

Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala

Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly

Leu Leu. Gin Ala Leu Glu Gly Xie Ser Pro Glu Leu Gly Pro Thr

Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr xle

Trp Gin Gin Met Glu Glu Leu Gly Met Wing Pro Wing Wing Gin Pro

Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Ax a Phe Gin Arg Arg

A * a wiy Gxy Val Leu Val Ala Ser ills Leu Gin Ser Phe Leu Glu

Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly

Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin val

Aruys 1.1® Gin wly Asp Gly Ala Ax Leu Gxn Glu Lys Leu Cys

Thr wing (SEQ ID NO: 166.)

ΕοπιρΙρ., Μ

Construction p MON 13183 new N-termination / C-termination gene in ρ MON13183 was created using α Method I as described in Materials and Methods, Initial Fragment was created and amplified from G-CSF Ser sequence ¹ '' in p MON13037 using primer set, 39 primer (SEQ ID NO: 64) and L11 primer (SEQ ID NO: 60) Fragment Terminator was created and amplified from G-CSF Ser sequence ¹ 'in ρ MON13037 using primer set, 38 terminator SEQ ID NO65) and 1.-11 terminator (SEQ ID NO: 61). The new G-CSF Ser ^ÍZ terminus-N / termination-C gene of entire length was created and amplified from the beginning and end of ringed fragments using 39 imitator and 38 terminator

The resulting DNA fragment containing the new gene was digested with restriction endonucleases Ncol and Hindlll and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The intermediate plasmid, ρ MON13181, was digested with Hindlll and Aflül restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN).

166

A portion of the ligation reaction was used to transform E cells, coli strain DH5a (Life Technologies, Gaithersburg, MD), Transforming bacteria were selected on ampulla contention plates, DNA and plasmid were isolated and sequenced to confirm correct insertion of the 5 plasmid resultant was designated as MON 13183,

And, coli strain JM1D1 was transformed with ρ MON13183 for protein expression and protein isolation from inclusion bodies,

Q plasmid., P MON 13183, contains the DNA sequence of (SEQ ID NO: 95) which encodes the following amino acid sequence:

Asr. Cys To be lie Her lie Asp Glu lie lie His His Read Lys Arg Pro Al® Pro Read Read ASp Pro Asn Asn Read Asn Asp Glu Asp val To be 11® Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe Val Arg Allah Val Lys Asn Read Glu Asn Allah To be Gly lie Glu Ouch lie Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro To be Arg His Pro lie Tie Tie Lys Allah Gly Asp Trp Gin Glu Phe. Arg Glu Lys Read Thr Phe Read Val Thr Read Glu G Allah Gin Glu Gin Gin Tyr val Glu Giy Gly Gly Gly To be Pro Gly Glu Pro To be Gly Pre lie To be Thr Xie Asn Pro To be Pro Pro Lys Glu To be His Lys To be Pro Asn Met Allah Tyr Lys Read cys Hxs Pro G Jax Glu Read Go Read Read Gly His To be Read Giy Tie Pro Trr; Allah Pro Read To be To be cys Pro To be Gin Allah Read Gin Read Allah Giy cys Read To be Gin Read HiS To be Gly Read Phe Read Gin Giy Read Read Gin Allah Read Glu Gly lie To be Pro Glu Read Giy Pro Thr Asp Thr Read : Lev Asp val Allah Asp Phe Ai a Thr Thr Xie Trp Gfo Gin Met Glu Glu Read Gly Met Allah PmTQ Allah Read Gin · * £ * • H · ’· * · Glr Gly A_>. The Met ? TO Allah Pne Allah To be Allah Phe Gin Arg Arg Giy Gly Val Read val Allah To be His Read Gin To be Phe Read Glu Go To be Tvi Arg Val Read Arg His Read Allah Gin Pro To be Gly Gly To be \ & ly Gly To be Gin To be Phe Read Read Lys To be Read Glu Gin Val Ax'S Lys Xis Gin Gly Asp Giy Allah Allah Read Gin Glu Lys Read cys

Thr Wing (STQ XO NO: 157)

Example 55

MON 13184 p construction

The new N-term / C-term gene in ρ MON13184 was created using Method I as described in Materials and Methods. Initiator fragment was created and amplified from the O-CSF Ser ¹ sequence ^? in ρ MON13037 15 using the primer set, 97 primer (SEQ ID NO: 66) and L-11 primer (SEQ ID NO, 60). Terminator Fragment was created and amplified from G-CSF Ser ^v in p. MON 13037 sequence using the primer set, 96 terminator (SEQ ID NO; 67) to L-11 terminator (SEQ ID NO: 61). The new G-CSF Ser ^v terminus-N / terminus-C gene of entire length was created and amplified from the beginning and end of ringed fragments using 97 initiator and terminator.

The resulting DNA fragment containing the new gene was digested with Ncol HlndiH restriction endonucleases and purified using a Magic DNA Clean-up System kit (Promega. Madison, Wl). The intermediary piasmidic, ρ MON13180, was digested with Hindlll and Afllll restriction endonucleases. resulting in a 4Q23 base pair vector fragment, and purified using a Magic Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN).

A portion of the ligation reaction was used to transform E cells, coli strain DH5a (Life Technologies, Gaithersburg, MD). Transformed bacteria were selected on plates containing ampieiline. Plasmid DNA was isolated and sequenced to confirm correct insertion The resulting plasmid was designated ρ MON13184.

E. coli strain JM101 was transformed with ρ MON13184 for protein expression and protein isolation from inclusion bodies,

Q piasnfidio, ρ MON13184, contains the DNA sequence of (SEQ ID NO: 96) which encodes the following amino acid sequence:

Asn cys Ser He Met Xie Asp Pro Pro Ma Pro Leu Leu Asp Par Ser Lie Leu Met Asp Arg Ser Phe vai Arg Ala vai Lys Giu Aia 11 «Leu Arg Asn Leu Aia Ala Pro Ser Arg His Pro Cia Glu Phe Arg Glu Lys Leu Gin Ala Gin Glu Gin Glr, Tyr Gly Gly Gly Ser Giy Gly Gly Pro Thr Luu Asp Thr Leu Gin Tfo · He Trp Glr. Glr: Mera Glu Gin Pro Thr Gin Gly Ala Met Arg Arg Ala Gly Gly Vai Leu Leu Giu will Be Tyr Arg will Giy Gly Ser Gly Gly Ser Gin Gin Vai Arg Lys Xie Gin Giy Leu -Cys Ale Thr Tyr Lys Leu Leu Gly Mis Ser Leu Gly Xie Pro Ser Gin Ala Leu Gin Leu Ser Gly Leu Phe Leu Tyr Gin He Ser ISEQ IP NO: 1681

Glu He lie His His Leu Lys Αχ-g Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Ass Leu Glu Asn Aia Sex Gly Xie Gin Pre Cys Leu Pro Ser Aia Thr lie Ils Xie Lys Ala Gly Asp Trp Thr Phe Tyr Leu Vai Thr Leu Glu Vai Glu Gly Gly Gly Gly Ser Pro Ser Asn Met Ala Pro Glu Leu Gly Leu Asp Vai Aia Asp Phe Ala Thr Glu Leu Gly Met Ala Pro Ala Leu Pro Ala Phe Ala Ser Ala Phe Gin Vai Ala Ala Ser Mis Leu Gin Ser Phe Leu Arg His Leu Ala Gin Pro Ser Ser phe Leu Leu Lys Ser Leu Glu Asp Gly Ala Ala Leu Giri Glu Lys Cys His Pre Glu Glu Leu vai Leu Pro Trp Ala Pro Leu Ser Ser Cys Ala Gly Cys Leu Being Gin Leu His Gly Leu Leu Gin Ala Leu Glu Giy

Example 56

Construction of p M0N13185

The new gene N-terminus / C-terminus in p MON13185 was created using Method I as described in Materials and Methods. Inhibitory fragment was created and amplified from G-CSF Ser ¹ 'sequence in p13 MON37D37 using the primer set. 97 primer (SEQ ID NO: 66) and L-11 primer (SEQ ID NO: 60). Terrininating Fraction was created and amplified from G-CSF Ser ¹ 'sequence in MON13037 using primer, 96 terminator (SEQ ID NO: 67) and L-11 terrininator (SEQ ID NO: 61). The new GCSF gene Ser ^,? full-length N-terminus / C-terminus was created and amplified from the beginning and end of ringed fragments using 97 start and 96 end.

The resulting DNA fragment containing the new gene was digested with Ncol and Hindi restriction endonucleases !! and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The intermediate plasmid 15, p MON13181, was digested with restriction endonucleases Hndlll and AM III, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl) . The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN).

A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicu. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated as MON13185.

E. coli strain JM101 was transformed with p MON13185 for protein expression and protein isolation from inclusion bodies.

□ plasmid, ρ MON13185, contains the DNA sequence of (SEQ ID NO: 67) which encodes the following amino acid sequence

169

He Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Gin His Pro He Lys Leu Thr Gin Tyr Val Pro He Ser Lys Sex * Pro Leu Gin Leu

Ase Cys Ser Xie Met Pre Pro Al Pro Leu Val Ser Xie Leu Met. Ser Phe val Arg Ala Glu Ale 11 «Leu Arg Ale Ala Pro Sex * Arg Gin Glu Phe Arg Glu Gin Ala Gin Glu Gin Gly Glu Pro Ser Gly Ser Lys Glu Ser His Pro Thr Leu Asp Thr

Thr Xie Trp Gin Gin Meo Glu Glu Gin Pro Thr Gin Gly Ala Met Pro Arg Arg Ala Gly Gly Val Leu Val Leu Glu Val Ser Tyr Arg Val Leu Gly sly Ser Gly Gly Ser Gin Ser Gin Val Arg Lys lie Gin Gly Asp Leu Cys Ala Thr Tyr Lys Leu Cys Leu Gly His Ser Leu Gly He Pro Pro Ser Gin Ala Leu Gin.Leu Ala Ser Gly Leu Phe Leu Tyr Gin Gly He Ser iSEQ XL HO; 1691

Xie Xie His His Leu Lys Arg Asn Asn Leu Αδη Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ala Ser Gly He Pro Cys Leu Pro Ser Ala Thr lie Xie Lys Ala Gly Asp Trp phe Tyr Leu Glu Glu Glu Gly Gly Gly Gly Ser Pro Thr He Ann Pro Ser Pro Pro Asn Met Ala Pro Glu Leu Gly Asp val Ala Asp Fhe Ala Th.r

Leu Gly Met Ala Pro Ala Leu Ala Phe Ala Ser Ala Phe Gin Ala Ser His Leu Gin Ser Phe Arg His Leu Ala Gin Pro Ser Phe Leu Leu Lys Sex 'Leu Glu Gly Ala Ala Leu Gin Glu Lys His Pro Glu Glu Leu Val Leu Trp Ala Fro Leu Ser Ser Cys Gly Cys Leu Ser Gin Leu His Leu Leu Gin Ala. Leu Glu Gly

Example 57

MON 13186 p construction

The new MON13186 p-terminus-N / C-terminus gene was created using Method I as described in Materials and Methods. Starting fragment was created and amplified from the sequence G-CSF Ser ^: 'in p MON 13037 using the primer set, 126 primer (SEQ ID NO: 68) and L-11 primer (SEO ID NO: 60). Terminator fragment was created with amplification of G-CSF Ser ⁷ sequence in p MON13037 using α primar set, 125 terminator (SEQ ID NO: 69) and L-11 terminator (SEQ ID NO: 61), The new G10 CSF gene Ser ”terminus-N / terminus-C was created and amplified from the beginning and end of walking fragments using 126 initiator and 125 terminator

The resulting DNA fragment containing the new gene was digested with Ncol and Hindlll restriction endonucleases and purified using a Magic DNA Clean-up System kit (FTomega, Madison, Wl). The intermediate plasmid · 15 dio, p MON13180, was digested with Hindlll and AH III restriction endonucleases, resulting in a 4023 base pair vector fragment, and purified using a Magic Ciean-up System kit (Promega, Madison, Wl ), The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN).

170

A portion of the ligation reaction was used to transform E. coli cells into DH5a DNA (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampullin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting 5 plasmid was designated as MON13186.

E. coli hnhagem JM101 was transformed with p MON13186 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13186, contains the DNA sequence of

SEQ ID NO.98 which encodes the following amino acid sequence:

Asn Cys Ser Ixs Met- Xue Asp Glu Xle Xle Mis His Leu Lys Arg

Pro Pro Wing Pre Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

Val Ser lie Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

Ser Pne Var Arg Ala val Lys Asn Leu Glu Asn Ala Ser Gly He

Glu Ala tie Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ttur Wing

Als Ala Pro Ser Arg His Pro lie He He Lys Ala Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu

Gin Ale Glu Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly be Pro

Gly Gly Gly Ser Gly Gly Gly Ser Asn Mat Ala Met Ala Pro Ala

Leu Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Al® Ser Ale Phe

Gin Arg Arg Ala Giy Gly Val Leu Val Ala Ser His Leu GlrS »r

Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala GinPro

To be Gly Gly to be Giy Gly To be Gin To be Phe Leu Leu LysSer

Giu Gin val. Arg Lys He Gin Gly Asp Gly Ala a.U Lehi g £ Íu uys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Giu LeuVal «eu Leu Gly Hrs Ser Leu Gly He Pro Trp Ala Pro Leu SerSe

Cys Pro Ser Gin Ma Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu

His ^ er Gly ^ I Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu

Gly He Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu

Asp Vai Ala Asp Phe Ala Thr Thr lie Trp Gin Gin Met Glu Glu

Leu Gly (S £ Q XL NO: 170)

Example 58

Construction of p MON 13187 new N-termination / C-termination gene in p MON13187 was spliced using Method I as described in Materials and Methods, Primer Fragment was created and amplified from G-CSF Ser ^{! I} sequence in p 15 MON 13037 using the primer set, 126 primer (SEQ ID NO: 68) and L11 primer (SEQ ID NO: 60), Terminator Fragment was created and amplified from the G-CSF Ser ^! MON13037 using primer set, 125 terminator (SEQ ID NO.69) and L-11 terminator (SEQ ID NO: 61). The new G-QSF Ser ' ^? end-N / end-C was created and amplified from

171

Beginning and end of ringed fragments using 126 initiator and 125 terminator.

The resulting DNA fragment containing the new gene was digested with Nco! Restriction endonucleases. and Hindlll and purified using the Magic DNA Clean-up System kit (Promega, Madison, Wl). The intermediate plasmid, p MON13181, was digested with Hindlll and Afllll restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. ooli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated as MON13187.

E. coli strain JM101 was transformed with MON13187 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13187, contains the DNA sequence of (SEQ ID NO: 99) which encodes the following amino acid sequence:

Asn cys To be T'i λ riw Mk · iL Mee lie Asp Glu He He His His Read Lys Arg Pim Pro Allah Pro Read Read ASp Pro Asn Asn Read Asn Asp Glu Asp Go To be lie Read Met Asp Arg Asn Read Arg Read Pro Asn La .Ji Gru Sbt Phe Go Arg Allah Go Lys Asn Read Glu Asn Allah To be Gly Tie Glu Allah lie Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Ara Allah Pro To be Arg His Pro Xie He He Lys Allah Gly ASP Trp Gin Glu Phe Arp Glu Lys Read Thr Phe Tyr Read Go Thr Read Glu Gin Allah Gin Glu Gin Gin Tyr Go Gxu Gly Gly Gly Gly To be Pro Cxy Glu Pro To be Gly Pro lie To be Thr He Asn Pro To be Pro Pro To be Lys To be Hie Lys To be Pro Asn Met Allah Men Allah Pro Read Gin Pro Thr Gin Gly Allah Met. Pro Ara Phe Allah To be Allah Phe Gin Arg Arg Allah Gly Gly val Read Go Allah To be His jL & U Gin To be Phe Read Glu Go To be Tyr Arg Go Read Arg His Read Allah Gin Pro To be Gly Gly To be Gly Gly To be Qin To be Phe Read Read Lys To be Read Glu Glr Go Arg Lys lie Gin Gly Asp Gly Allah Ara Read Gin Glu Lys Read Cys Allah Thr Tyr Lys Read Cys HXS Pro Glu Gru Read Go Read Read Gly His To be Read Gly He Pro Trp Allah Pro Read To be To be Cys Pre To be Gin Allah Read •Gin Read Allah Gly Cys Read To be Gin Read Hi 5 To be Gly Read Phe Read Tyr Gin Gly Read Read Gin. Allah Read Glu Gly Xle. To be Pro Glu Read Gly Pro Thr Read ASp Thr Read Gin Read Asp go Ara ASp Phe Allah Thr Thr lie Trp Gin Gin Met Glu Glu Read Gly (sec x 0 NO _v 1 )

Example 59

MON13188 contraction

The new N-terminus / C-terminus gene in p MON13188 was created using Method I as described in Materials and Methods. Fragment 5 Initiator was created and amplified from G-CSF Ser ¹ sequence ^? MON 13037 powder using primer set, 133 primer (SEQ ID NO: 70) and L11 primer (SEQ ID NO: 60). Terminator fragment was created and amplified from G-CSF Ser ^v in p sequence MON13037 using the primer set, 132 terminator (SEQ ID NO71) and L-11 terminator (SEQ ID NO: 61). The 10 new gene G - CSF Ser ¹ 'N-terminus / C terminus in full length was created and amplified from the beginning and end of ringed fragments using 133 initiator and 132 terminator,

The resulting DNA fragment containing the new gene was digested with Ncol and Hindlll restriction endonucleases and purified using a Magic Clean-up System kit (Protnega, Madison, Wl). The intermediate plasmid, p MON13180 _V was digested with Hindlll and Af1 III restriction endonucleases. resulting in a 4023 base pair vector fragment, and purified using a Magic Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform cells of E. coh strain DH5a (Life Technologies, Gaithersburg, MD). Transferring bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated p MON13188.

And, the JM101 strain was transformed with p MON 13188 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13188, contains the DNA sequence of (SEQ ID NO. 100) which encodes the following amino acid sequence:

Asn Cys Ser xi _and Het He Asp Glu

Pre Pro Wing Pre Leu Leu Asp Pro

Val Ser Tie Leu Met Asp Arg Asn

Ser Phe Val Arg Ale val Lys Asn

Glu Asa He Leu Arg Asn Leu Gin

Ala Ala Pro Ser Arg His Pro-He

Gin Glu Phe Arg Glu Lys Leu Thr

Gin Wing Gin Glu Gin Gin val

Gly Gly Gly Ser Gly Gly Gly Ser

Met Pro Al Pha Ala Ser Al Phe Ala

Leu val Ala Ser His Leu Gin Ser

Val Leu Arg .His Leu Ala Gin Pro

Gin Ser Phe Leu Leu Lys Ser Leu

Gly Asp Gly Wing Wing Wing Gin Glu

Leu Cys His Pro Glu Glu Leu Val lie Pro Trp Ala Pro Leu Ser Ser

Leu Ala Gly Cys Leu Ser Gin Leu

Gin Gly Leu Leu Gin Wing Leu Glu

Pro TAr 1,612 Asp Thr Leu Gin Leu

Thr lie Trp Gin Gin Met Glu Glu

Gin Pro ÍSHQ IP NQ: 172)

Example 60

Construction of ρ MON13189

The new terminus-N / ten genes

^ .í $ His Hrs Leu Lys Arc, Asn Asn Leu Asp Asp Glu Asp x ^ eu Arg Leu Pro Asn Leu Glu o ^ eu Glu Asn Ala Ser Glv He Pro Cyâ Leu Pro Ser Ala Thr He He Lys Ala Gly Asp ^T rp . Phe Tyr Leu Val Thr Leu Glu ulu Gly Gly Gly Glv Ser Pro Asn Met Ala Thr Gin Gly Ala Gin Arg Arg Ala Gly Gly val Phe osu Gru Val Ser Tyr Arc Ser Gly Gly Ser Gly _G ^ _{y Se} Ç Glu Gin Val Arg Lys He Gin Lys Leu Cys Ala Thr TVr Lvs Leu Leu Gly His Ser Leu Gly Cys Pro Ser Cm Ala Leu Gin

H.Á.S Ser Gly ueu Pne Leu Tyr Gly He Ser Pro Glu Leu Glv Asp Val Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu lino-C in ρ MON13189 was called using Method I as described in Materials and Law Suit. Fragment

Initiator was created and amplified from G-CSF Ser ^{! I} sequence in p

MON13037 using the primer set, 133 initiator (SEQ ID NO: 70) and L11 Initiator (SEQ ID NG: 60). Terminator fragment I was created and amplified of G-CSF Ser ' ⁷ sequence in ρ MON13037 using the primer set, 132 terminator (SEQ ID N0.71) and L-11 terminator (SEQ ID N0: 61), 0 new G gene -CSF Ser ' ⁷ termination-N / termination-C of entire fol length created and amplified from the beginning and end of ringed fragments using 133 initiator and 132 terminator.

The resulting DNA fragment containing the new gene was digested with restriction endonucleases Ncol and Hindlll and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The intermediate plasmsdie, p MON 13181, was digested with Hindlll and AfUIL restriction endonucleases resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Cleaning-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Ιπ

174 dianapolis, IN) .. A portion of the fol binding reaction used to transform E cells, coli strain DH6a (Life Technologies. Gaithersburg. MD). Transforming bacteria were selected on ampicillin plates,

Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated as MON13189.

E. coli strain JM101 was transformed with MON13189 p for protein expression and protein isolation from diseased bodies.

The plasmid, p MON13189, contains the DNA sequence of (SEQ ID NO: 101) which encodes the following amino acid sequence;

Asn Cys Ser lie Met Pre Pro Ale Pro Leu Vai Ser lie Leu Met Ser Phe Vai Arg Ala Glu Ala He Leu Arg Ala Ala pro Ser .Arg Gin Glu Phe Arg Glu Gin Ala Gin Glu Gin Gly Glu Pro Ser Gly

Ser Lys Glu Ser His Met Pre Ala phe Ala Leu Vat Ala Ser His Vai Leu Arg His Leu Gin Ser Phe Leu Leu Gly Asp Gly Ala Ala Leu Cys His Pro Glu He Pro Trp Ala Pro Leu Ala Gly Cys Leu Gin Gly Leu Leu Gin Pro Thr Leu Asp Thr Thr He Trp Gin Gin Gin Pro (SPQ H> HO:

lie Asp Glu He He Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pro Tie He He Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Gly Pro Xie Ser Thr He

-ys Ser pro Asn Met Ser Ala Phe Gin Arg Leu Gin Ser? he Leu Ala Gin Pro Ser Gly Lys Ser Leu Glu Gin Leu Gin Glu Lys Leu Glu Leu Vai Leu Leu Leu Ser Ser Cys Pro Ser Gin Leu His Ser Alu Leu Glu Gly He Leu Gin Leu Asp Vai Met Glu Glu Leu Gly

His His Leu Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly He Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Vai Thr Leu Glu Gly Gly Gly Gly Ser Pro Asn Pro Ser Pro Pro

Ala Thr Gin Gly Ala Arg Ala Gly Gly Vai Glu Vax Ser Tyr Arg Gly Ser Gly Gly Ser Vai Arg Lys He Gin Cys Ala Thr Tyr Lys Gly His Ser Leu Gly Ser Gin Ala Leu Gin Gly Leu Phe Leu Tyr Ser Pro Glu Leu Gly Asp Phe Wing Thr Met Wing Pro Wing Wing Leu Wing

Example 61

MON 13190 p construction

The new N-terminus / C-terminus gene in p MON13190 was called using Method I as described in Materials and Methods. Initiator Fragment was created and amplified from G-CSF Ser ^v in sequence 15 MON13037 using the primer set. 142 primer (SEQ ID NO: 72) and L ~ primer (SEQ IO NOion). Terminator fragment was created and amplified from sequence G-CSF Ser ^iz in p MON 13037 using the primer set.

141 terminator (SEQ ID NO: 73) and L-11 terminator (SEQ ID NO: 61). The new G-CSF Ser ¹⁷ full-length N-terminus / C-terminus gene created and

175 • 10 amplified Start and end of ringed fragments using 142 initiator and 141 terminator

The resulting DNA fragment containing the new gene was digested with Ncol and Hindlll restriction endonucleases and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl) The intermediate piasmid, p MON 13180, was digested with endonucleases from Hindlll and Af1 III restriction, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli DH5a cells (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated ρ MON13190.

E. coli strain JMW1 was transformed with ρ MON13190 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON13190, contains the DNA sequence of (SEQ ID NO: 102) which encodes the following amino acid sequence:

Asn cys Ser He Hex He Asp Pre Pro Ala Pro Leu Leu Asp Val Ser Ire Leu Met. Asp Arg Ser Phe Val Arg Ala Vai Lys C.iu Ala lie Leu Arg Asn Leu Ala Ala Pro ser Arg His Pro Gin Giu Phe Arg Giu Lys Leu Gin Ala Gin Giu Gin Gin Tyr Gly Gly Gly Ser Gly Giy Glv Arg Arg Ala Gly Giy Val Leu Lsu Giu Val Ser Tyr Arg Val Sly Gly Ser Gly Gly s _er sin Gin val Arg Lys He Gin Gly Leu cys Ala Thr Tyr Lys Leu Leu Gly His Ser Leu Giy He Pro Ser Gm Ala Leu Gin Lev Ser Gly Leu Phe Leu Tyr Gin He Ser Pro Giu Leu Gly Pro val Ala Asp phe Ala Thr · Thr Gly Met Ala Pro Ala Leu Gin Phs Ala (SEQ ID NO: 174) olu He He His His Leu Lvs Arg Pro Asn Asn Leu Asn Asp Giu Asp Asn Leu Arg Leu pro Asn Leu Giu Asn Leu Giu Asn Ala Ser Gly He Gin Pro Cys Leu Pro Ser Ala Thr jkle He Tie Lys Ala Gly Asp T ^ n Thr Phe Tyr Leu val Thr Leu Giu Val Giu wily Gly Gly Gly Ser Pre ser Asn Met Ala ser Al Phe Gin Val Ala Ser His Leu Gin Ser Phe * j> eu Arg His Leu Ala Gin Pro Ser Ser Phe Leu Leu Lys Ser Leu Giu Asp Gly Ala Ala Leu Qin Giu Lvs Cys His Pro Giu G.lu Leu Val Leu Pro Trp Ala Pro Leu Ser Ser Cys Gly Cys Ward Leu Ser Gin Leu Hi «Gly Leu Leu Gin Ala Leu Giu SÍ Thr Leu Asp Thr Leu Gin Leu Asp Ire Trp Gin Gin Met Giu Giu Leu Pm Thr Gin Gly Wing Met Pro Wing

176

Example 62

MON13191 p construction

The new termination-N / termination-C gene in p MON 13191 was created using Method I as described in Materials and Methods. Primer Fragment was created and amplified from G-CSF Sei ⁷ in powder MON13037 sequence using primer set, 142 primer (SEQ IO NO: 720 and L-11 primer (SEQ ID NO: 60). Terminator Fragment was created and amplified in sequence G-CSF Ser ' ⁷ in powder MON 13037 using primer set, 141 terminator (SEQ ID NO: 73) and L-11 terminator (SEQ ID NO: 61). Q new GCSF gene Sei ⁷ N-terminus / C-terminus of full length was created and amplified from the beginning and end of ringed fragments using 142 initiator and 141 terminator,

The resulting DNA fragment containing the new gene was digested with Ncol and Hindill restriction endonucleases and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The intermediate plasmid, p MON13181, was digested with Hindill and Afllll restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, WI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coll cells to DH5a lineage (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampoilin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated as MON13191.

E. ooli strain JM101 was transformed with p MON13191 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13191, contains the DNA sequence of (SEQ ID NO: 103) which encodes the following amino acid sequence:

177

Asn Cys Ser xle Nez He Asp Glu He lie His His read Lys Arg

Pro Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

It Will Be He Leu Meo Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

Ser Phe Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly He

Glu Ala He Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr

Ala Ala Pro Ser Arg His Pro He Xle He Lys Ala Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu

Gin Ala Gin Glu Gin Gin Tyr Vai Glu Gly Gly Gly Gly Ser Pro

Gly Glu Pro Ser Gly pro xle Ser Thr He Asn Pro Ser Pro pro

Ser Lys Glu Ser Hus Lys Ser Pro Asn Met Ala be PheSir Ward.

Arg Arg Ala Gly Gly Vai Leu Vai Ala Set * His Leu Gin SerPhe

Leu Glu Gonna Be Tyr Arg Vai Leu Arg His Leu Ala Gin ProSer

Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser LeuGlu

Gin Vai Arg Lys He Gin Gly Asp Gly Ala Ala Leu Gin GluLys

Leu Cys Ala Thr Tyr Lys Leu cys His Pro Glu Glu Leu VaiLeu

Leu Gly His Ser Leu Gly He Pro Trp Ala Pro Leu Ser SerCvs

To Be Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin LeuHis

Ser Sly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly

He Ser Pro Glu Leu Gly Pro Thr Lev Asp Thr Leu Gin Leu Asp

Go Wing Asp Phe Wing Thr Thr Xle Trp Gin Gin Met Glu Glu Leu

Gly Het Ala Pro Ala Leu Gin Pro Thr Gin Gly Ala Met Pro Ala phe Ala (SEQ w NO: 175)

Example 63

Construction of p MON 13192 new N-termination / C-termination gene in p MON 13192 was created using Method II as described in Materials and Methods. Ini5 ciator fragment was created and amplified from G-CSF sequence in p MON 13037 using primer set, 39 primer (SEQ ID NO: 64) and P ~ bl primer (SEQ ID

NO.S2). Terminator fragment was created and amplified from GCSF Ser ^{1, T} in powder MON13037 using primer set, 38 terminator (SEQ

ID NO: 65) and P-bl terminator (SEQ ID NO: 63). Primer Fragment was digested with restriction endonuclease Ncol, and Terminator Fragment was digested with restriction endonuclease Hindllt After purification, the beginning and end of digested fragments were combined and ligated to the Ncol-Hindllt vector fragment of approximately 3800 base pairs of p M0N3934 .

The intermediate piasmide described above contained the new gene

G-CSF Ser ^ÍZ end-N / end-C of full length and digested with restriction endonucleases Ncol and Hindllt The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide, and the new GCSF Ser gene ¹ 'N-terminus / C-terminus of entire length was isolated using

Geneclean (Bio101, Vista, CA). The intermediate plasmid, p MON13180, was

178 digested with Hindlll s Ag1 III restriction endonucleases, resulting in a vector fragment of 4023 pairs of Oases, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase 5 (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg. MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the. correct insertion of the new gene, The resulting plasmid was designated ρ MON13192.

E. coii strain JM101 was transformed with ρ MON13192 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON13192, contains the DNA sequence of (SEQ ID NO '. 104) which encodes the following amino acid sequence:

13192, Pepc

Asn Cys To be 11 and Met lie ASp Glu He He His His Read Lys Arg Pro Pro Allah Pro Read Read Asp Pro Asn Asn Read Asn Asp Glu val He Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe val Arg Allah Val Lys Asn Read Glu Asn Allah To be Gly Tie Glu Allah He Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro To be Arg Bis Pro He He He Lys Allah Gly Asp * · * · Gin Glu Phe Arg Glu Lys Read Thr Phe Tyr Read val Thr Read Glu Gin Allah Gin Glu Gin Gin Tyr val Glu Gly Gly Gly Gly To be Pro Gly Gly Gly To be Gly Gly Gly To be Asn Met Allah Tyr Lys Read Cys Hxs Pro Glu Glu Read Val Read Read Gly Hih To be Read Gly He Trp Allah Pro Read To be to be Cys Pro To be Gin Allah Read Gin Read Allah Gly Cys Read it. To be Gin Read Hxs To be Gly Read Phe Read Tyr Gin Gly Read Read Gin Allah Read Glu Gly Tie To be Pro Glu Read Gly Pro Thr Read Asp Thr Read Gin Read Asp Val Allah Asp Phe Allah Thr Thr He Trp Gin Gln Met Glu Glu Read Gly Met Allah Pro Allah Read Gin Pro Thr Gin Gly Allah Met Pro Allah Phe Allah To be Allah Phe Gin Arg Arg Allah Gly Gly Val Read Val Allah To be HIS Read Gin To be Phe Read Glu Val To be Tyr Arg Val Read Arg His Read Allah Gin Pro Thr Pro Read Gly Pro Allah To be To be Read Pro Gin To be Phe Read Read Lys To be Read Glu Gin Val Arg Lys Xle Gin Gly Asp Gly Allah Allah Read Gin Glu Lys Read Cys Allah Thr (SEl 2 IT> MO; 17F)

Example 64

Construction of ρ M0N13193

The new N-terminus / C-terminus gene in ρ MON13193 was created using Method II as described in Materials and Methods. Initiator fragment was created and amplified from G-CSF Ser sequence ^{15 * 17} in p

179

MON 13037 using the primer set, 39 primer (SEQ ID NO: 64) to Pb1 primer (SEQ ID NO: 62).

Terrininador fragment was created and amplified from G-CSF Ser ^1? in ρ MON13037 using the primer set. 38 terrininator (SEQ ID NO: 65) S and P-bl terrininator (SEQ ID NO: 63). Primer Fragment was digested with Ncol restriction endonuclease, and Terrinin Fragment was digested with Hindlll restriction endonuclease. After purification, the start and end of digested fragments were combined with and linked to the approximately 3800 base pair NcolHindlll fragment of ρ MON3934 .

IP The intermediate plasmid described above contained the new gene

G-CSF Ser ' ⁷ terminus-N / terminus-C of full length and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the new G-CSF Ser ' ⁷ terminus-N / terminus-C gene was isolated using Geneclean (Bio101, Vista, 15 CA). The intermediate plasmid, ρ MON13181, was digested with Hindi restriction endonucleases !! and Af1 III, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim. In20 dianapolis, IN). A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated ρ MON13193.

E. coh strain JM101 was transformed with ρ MON13193 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON13193, contains the DNA sequence of (SEQ ID NO: 105) which encodes the following amino acid sequence.

180

Asr. Cys Sex He Met lie Asp Glu Pre Pro Ala Pro Leu Leu Asp Pro Will be Xie Leo Met Asp Arg Asm. Ser Fhe val Arg Ala Vai Lys Asm Glu Ala Ils Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg His Pro lie Gin Gin Phe Arg Glu Lys Leu Thr Gin Ala Gin Glu Gin Gin Tyr Vai Gly Glu Pro Ser Gly Pro Xie Ser Ser Lys Glu Ser His Lys Ser Pro His Pro Glu Glu Leu Val Leu Le Le Trp Ala Pro Leu Ser Ser Cys Pro Gly Cys Leu Ser Gin Leu His Ser Leu Leu Gin Ala Leu Glu Gly Xie Leu Asp Thr Leu Gin Leu Asp Vai Trp Gin Gin Met Glu Glu Leu Gly Thr Gin Gly Ala Met. Pro Ala Phe Ala Gly Gly val Leu val Ala Ser Val ser Tyr Arg Val Leu Arg His Gly Pro Ala Ser Ser Leu Pro Gin Glu Gin Val Arg Lys Xie Gin Gly Lys Leu Gys Ala Thr ISSEQ XL HO: 1 lie He His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu pro ash Leu Glu Leu Glu Asn Ala Ser Gly Xie Pro Cys Leu Pro Ser Ala Thr Xie He Lys Ala Gly Asp Trp Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Gly Ser Pro Thr He Asn Pro Ser pro Fro Asn Met Ala Tyr Lys Leu Cys Gly His Ser Leu Gly He Pro Ser Gin Ala Leu Gin Leu Ala Gly Leu Phe Leu Tyr Gin Gly Ser Pro Glu Leu Gly Pro Thr Ala Asp Phe Ala Thr Thr He Met Ala Pro Ala Leu Gin Pro Ala Ser Ala Phe Gin Arg Arg His Leu Gin Ser Phe Leu Glu Leu Ala Gin Pro Thr Pro Leu .Ser Phe Leu Leu Lys Ser Leu Asp Gly Ala Ala Leu Gin Glu 77}

Example 65

MON.25190 p construction

The new MON25190 p-terminus-N / C-terminus gene created using Method II as described in Materials and Methods. Starting fragment was created and amplified from G-CSF 'sequence in p MON13037 using primer set, 97 primer (SEQ ID NO: 66) and P-b1 primer (SEQ ID NO; 62), Terminator fragment was created and amplified from GCSF sequence ^Ser7 in p MON 13037 using primer set, 96 terminator (SEQ ID NO: 67) and P-b1 terminator (SEQ ID NO: 63). Primer Fragment was digested with Ncol restriction endonuclease, and Terminator Fragment was digested with Hindlll restriction endonuclease. After purification, the beginning and end of digested fragments were combined with and linked to the approximately 3800 base pair Ncol-Hindlll vector fragment of p

MON3S34.

The intermediate plasmid described above contained the entire length of a new G-CSF Ser ^!,? terminus-N / termination-C and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the new full length GCSF Ser ' ⁷ termm-N / terminus-C gene was isolated using 20 Geneclean (Bío10l Vista, CA). The intermediate plasmid, p MON13180, was digested with Hindi H and Aft Hi restriction endonucleases resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Cfoan-up System kit (Promega. Madison, Wl) . The purified restriction fragments were combined and ligated using T4 DNA hgase 5 (Boehringer Mannheim, Indianapolis, IN). A portion of the fci binding reaction used to transform cells of E. coii strain DH5a (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was called p MON25190.

E. strain JM101 was transformed with p MON25190 for protein expression and protein isolation from inclusion bodies,

The plasmid, p MON25190, contains the DNA sequence of (SEQ ID NO: 106) which encodes the following amino acid sequence:

ASO ero Cys Ser érc Ala Xie Men xie ASp Asp Glu He Xie Asn. Hrs Read His WING Leu Lys Arg Asp Pro L ^ U Read Pro Asn Asp Glu % to 1 To be lie read Met Asp Arg As η Read Arg Read Pro Ass Read To be Fhe go Asg Allah go Lys Asn Read Glu Asn Allah To be Gly lie Glu Allah Tie Read Axg Asn Read Gin Pro Cys Read Pro To be Allah Tbr Al « Allah Pro To be Arg His Pro lie lie Xie Lys Allah Gly Asp T3Tp : || 11 ) 11: Phe Ara Glu Lys Read Thr The Tyr Read Go Thr Read Giu Gin Allah Gin Glu Gin Gin Tyr val Glu Gly Gly Gly Qiy Ssr Pro Ciy Gly Gly To be Gly Gly Gly & er Ass Met Allah Pro Glu Read Gly erc Thr Read ASp Thr Read Gin Read Asp Go Allah Asp Phe Allah Thr Λ Thr lie Txrp Gin Gin Met Glu Glu Read Gly Met Allah Pro Allah Read Gin Pro Thr Gin GiY Allah Met Pro Allah Phe Allah To be Aia Phe Gin Are Αχ «J Allah Gly Ciy Go Read Go Allah To be His Read Gin To be Phe He gave Glu Saw To be Tyr Arg Go Read Arg His Read Al. A Gin Pro Thr Pro Read hi Pre Allah To be To be Read Pro Gin To be The Read Read Lys To be Read Glu Gin Go Arg Lys Xie Gin Gly Asp Giy Allah Allah Read Gin Glu Lys Read Cys Allah Thr Ty ~ Lys Read Cys His Pro Glu Glu Sen Va 1 Read Read Gly HiS To be Read Gly Xie Pro- Grp Allah Pro Read Sen To be Qys Pro To be Gin Allah Read Gin Read Allah Gly Cys Read To be Gin Read His To be Gly Read The Read Tyr Gin Glu Read Read Glu Allah LAU Glu Gly To be {££ $ XO NO : 178)

Exempjo56

MON25191 p construction

The new gene N-terminus / terminus-C in p MON25191 was created using Method II as described in Materials and Methods. Primer Fragment was created and amplified from G-CSF Ser '' sequence in p MON 13037 20 using primer set, 97 primer (SEQ ID NO: 66) and P-b primer

182 (SEQ ID NO: 62). Terminator fragment was created and amplified from G-CSF Ser ^1? in ρ MON13037 using the primer set 96 terminator (SEQ ID NO: 98) and P-b1 terminator (SEQ ID NO: 63). Primer Fragment was digested with Neo I restriction endonuclease, and Terminator Fragment was digested with Hindlll restriction endonuclease · After purification, the Start to digested fragments were combined with and linked to the approximately 3800 base pair Ncol-HindllI vector fragment. p MON3934.

The intermediate plasmid described above contained the new G-CSF Ser ^! end-N / end-C of entire length and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide, and the new full length GCSF Ser ⁵⁷ terminus-N / terminus-C gene was isolated using Geneclean (Bío'101, Vista, CA ) The intermediate plasmid, ρ MON13181, was digested with Hindlll and Afllll restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehnnger Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion of the new gene. The resulting plasmid was designated ρ MON25131.

E. coli strain JM101 was transformed with ρ MON25191 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON25191, contains the DNA sequence of (SEQ ID NO. 107) which encodes the following amino acid sequence:

183

Asn cys To be .Xle Met Pro Pro Allah Pro Read Go To be Xle Read Met To be Phe Go Ar g Allah Glu Allah Xle Read Arg Allah Allah Pro To be Arg Gin Glu Phe Arg Glu Gin AÍã · Glu Gin Gly Glu Pro To be Gly To be Lys Glu To be His -fo Thr Read Asp Thr ’T + isf X le * / -ib * Gin Gin Gin Pro Gin Gly Arg Arg Allah Gly Gly Read Glu go To be Tyr Pro LSU Gly Pro Allah To be Read Glu Gin go Glr. Gr u Lys Read Cys Read Go Read Read Gly To be To be Cys Pro To be VA3 VA UI 44 Read EiS To be Gly ulu Gly Xle To be

lie Asp Glu lie Xie Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pre Cys His Pro lie Xie Xie Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Gly Pro Xie Ser Thr Xie Lys Ser Pro Asn Met Leu Gin Leu Asp Vai Met Glu Glu Leu Gly Ala Met Pro Ala Phe Vai Leu Vai Ala Ser Arg val Leu Arg His Ser Ser Leu Pro Gin Ara Lvs Xie Gin Gly

Wing Thr Tyr Lys Leu His Ser Leu Gly Xie Gin Wing Leu Gin Leu Leu Phe Leu Tyr Gin {SHQ XL NO: 179)

His His Leu Lys Arg Lev Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly He Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Vai Thr Leu Glu Gly Gly Gly Gly Ser Pro Asn Pro Ser Pro Pro Ala Pro Glu Leu Gly Wing Asp Phe Wing Thr Met Wing Pro Wing Wing Leu Wing Wing Phe Gin His Wing Wing Gin Ser Phe Wing Wing Wing Pro Ser Ser Phe Leu Lys Wing Wing

Cys His Pro Glu Glu Pro Trp Ala Pro Leu Ala Gly Cys Leu Ser Gly Leu Leu Gin Ala

Example 67

MON 13194 p construction

The new gene N-terminus / C-terminus am ρ MON13194 was created using Method U as described in Materials and Methods. Initiating fragment was created and amplified of sequence G-CSF Ser ¹ 'in p MON 13037 using the primer set, 126 primer (SEQ ID NO: 68) and P-b1 primer (SEQ ID NO: 62). Terrininador fragment was created & amplified of sequence G-CSF Ser ¹⁷ in ρ MON13037 using the primer, 125 terrininator (SEQ ID NO.67) and P-b1 terrininador (SEQ ID NQ: 63). Primer Fragment was digested with restriction endonuclease Ncol, and Fragment Terrininator was digested with restriction endonuclease Hindlll. After purification, the start and end of digested fragments were combined with and linked to the approximately 3600 base pair N39-MON3934 vector fragment Ncol-Hindlll.

The intermediate plasmid described above contained the new gene

G-CSF Ser ¹⁷ termination-N / termination-C and was digested with Ncol and Hindlll restriction endonucleases, the digested DNA was resolved on a 1% TAE gel, stained with ethidium bromide and the new G-CSF Ser ”gene terminus N / terminus-C of full length was isolated using Geneclean (ΒΐαίΟΙ. Vista, CA), The intermediate plasmid, p MON1318Q, was digested with restriction endonucleases Híndllí and Afilll, resulting in a vector fragment of 4023 base pairs, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments 5 were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coii cells to the DH5 line. (Life Technologies, Gaithersburg, MD), Transforming bacteria were selected on plates containing ampicillin. Plasmid AQN was isolated and sequenced to confirm the correct insertion of the nevus gene. The resulting plasmid was designated p M0N13194.

E. coli strain JM101 was transformed with p ΜΟΝ13Ί94 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13194, contains the DNA sequence of (SEQ. ID NO: 108) which encodes the following amino acid sequence:

ASO Cys Ser He Met Xle Asp Glu Ile Xle Ris rí _s Leu Lys Ara

Pro Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Wing Asp Glu Asp

1 “'Be lue Leu Met. Asp Arg Asn Leu Arg Leu Pre · Asn Leu Glu

Ser Phe yal Arg Al® Val Lys Asn Leu Glu Asn Ala Ser Gly He

Giu Ala XI® Leu Arg Asn Leu Gin Pro cys Leu Fro Ser Al® s * hr

Ace Wing Pro Set Arg His pro Xle Xle 11® Lys Al® Gly Asp Trp

Gin Glu. Ph® Arg Glu. Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu

G_n Ale Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Gly Ser Pro

C-y Gly Gly Ser Gly Gly Gly Ser Asn Met. Met All Pro Ale Wing

Leu Gin Pro Thr Gin Gly Ale Met Pro Ale Phe Al® Ser Al® Phe

G.ih Arg Arg Ale Gly Gly Val Leu Val Ala Ser Hi® Leu Gin Ser

Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro

Thr Pro Leu Gly Pre Ala Ser Ser Leu Pro Gin Ser Ph® Leu Leu

Lys Ser Leu Glu Gin Val Arg Lys Xle Gin Gly Asp Gly Ale Ala

Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His torn Gd ’

Glu Leu v®l Leu Leu Gly His Ser Leu Gly II® Fro Trn Al® Pro

Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cvs Leu * er ueu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin A * a «®u Glu Gly rue Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr ueu Gun Leu Asp Val Ala Asp Phe Ala Thr Thr Xle Tro Gin GlMet Glu Glu Leu Gly ISE0 HO ID: 180)

Example 68

Construction of p M0N13195

The new iérmino gano-N / C-terminus powder MQN13195 was created using Method II as described in Materials and Methods fragment Ini2.0 ciadorfoi created and amplified from G-CSF Ser sequence ^5'powder MON13937

185 using the primer set, 126 primer (SEQ ID NO: 58) and P-bl primer (SEQ ID NO: 62). Terminator fragment was created and amplified from G-CSF Ser ¹⁷ sequence in p MON13037 using the pnmer set, 125 terminator (SEQ ID NO: 69) and P-b1 terminator (SEQ ID NO: 63). Primer Fragment was digested with Ncol restriction nedonuclease, and Terminator Fragment was digested with Hindlll restriction endonuclease. After purification, the start and end of digested fragments were combined cam and ligated to the approximately 3800 base pair MQN3934 p fragment Ncol-Hindlll.

The intermediate plasmid described above contained the new 10 G-CSF Ser ' ⁷ end-N / terminus-C gene of full length and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide and a new GCSF Ser · ⁷ terminus-N / terminus-C gene of full length was isolated using Geneclean (BíolOI, Vista, CA), O intermediate plasmid, p ΜΌΝ13181, was digested with Hindlll and Afllll restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl), Os purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction 20 was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on ampicillin-containing plates. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated as MON13195.

E. coli hnhagem JM101 was transformed with p MON13195 for protein expression and protein isolation from inclusion bodies

The plasmid. p MON13195, contains the DNA sequence of (SEQ ID NO :. 109) which encodes the following amino acid sequence:

136

Asn Cys Ser He Met Xie Asp Glu Xie Tie His His Leu Lys Arg

Pro Pre Ale Pro L «u Leu Asp Pre Asa Asn Leu Asn Asp Glu Asp

Val Ser 11 «Lsu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

Ser Phe val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly He

Glu Ala He Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr

Ala Ala Pre Ser Arg His Pro He Xie He Lys Ally Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu

Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Gly Ser Pro

Gly Glu Pro Ser Gly Pro He Ser Thr Xie Asn Pro Ser Pro Pro

Be Lys Glu. Ser His Lys Ser Pro Asn Met Ala Met Ala Pro.

Leu Qin Pro Thr Gin Gly Ala Met Pro Ala phe Ala Ser Al Phe Ala

Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin Ser

Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro

Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu

Lys Ser Leu Glu Gin Val Arg Lys He Gin Gly Asp Gly Ala Ala

Leu Gin Glu Lys Leu Cys Wing Thr Tyr Lys Leu Cys His Pro Glu

Glu Leu Val Leu Leu Gly His Ser Leu Gly He Pro Trp Ala Pro

Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu

Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin

Wing Leu Glu Gly Xie Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr

Leu Gin Leu Asn Val Ala Asp Phe Ala Thr Thr He Trp Gin Gin

Met Glu Glu Leu Gly I SEQ IO NOx181)

Example 60

Construction of p MON 13196 new gene N-terminus / C-terminus am p MON 13196 was created using Method li as described in Materials and Methods. Initiator Fragment was created and amplified of G-CSF sequence in p MON13037 using the primer set. 133 initiator (SEQ ID NO: 7Q) and P-bl initiator (SEO. ID NO: 62). Terminator fragment was ennado and amplified from the GCSF Ser ' ^? in MON13037 p using the primer set, 132 terminator (SEQ ID NO: 71) and P-b1 terminator (SEQ ID NO: 63). Primer fragment was digested with Ncol restriction endonuclease, and Terminator fragment was digested with Hindlll restriction endonuclease. After purification, the start and end of digested fragments were combined with and ligated to the approximately 3800 base pair N39-MON434 vector fragment Ncol-Hindlil.

The intermediate plasmid described above contained the new G-CSF Ser ¹⁷ term-N / terminus-C gene of entire length and was digested with restriction endonucíeases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide and the new GCSF Ser ^v end-N / end-C gene of full length was isolated using Genedean (Bio101, Vista, CA). The intermediate plasmid, p MON13180, was digested with Hindlll and Af1 III restriction endonucíeases, resulting in a 4023 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Prornega Madison, Wl). The purified restriction fragments were combined and ligated using T4 DMA ligase (Boehnngar Mannheim, Indianapolis, IN) .. A portion of the 5 fos ligation reaction used to transform DH5a E. coll cells (Life Technologies, Gaithersburg, MD) . Transfiguring bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated p MON13196.

Coil lineage JM101 was transformed with MON13196 p for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13195, contains the DNA sequence of (SEQ ID NO: 110) which encodes the following amino acid sequence ·.

Asn Cys Ser Xle Met. Âle Asp Glu Xl »Xle His His Leu Lys Are

Pro Pre Ale Pre Leu Leu Asp Pre Asn Asn Leu Ask Asp Glu Asp

Gonna Be xle Leu Mee Asp Arg Asn Leu Arg Leu Pro Asm Leu Glu

Ser Phe Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly Xle

Glu Ala. Xle Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr

Ala Ala Pro Ser Arg Hxs Pro He He He Lys Ala Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu V & l Thr Leu Glu

Gin Ala Gin Glu Gin Gin Tyr Vai Glu Gly Gly Gly Gly Ser Pro

Gly Glu Pro Ser Gly Pres He Ser Thr Xle Asn Pro Ser Pro Pro

Ser Lys Glu Ser His Lys Ser Pro Asn Mec Ala Met> Ala Pre Ale

Leu Gin Pro Thr Gin Gly Ala Met Pre Ala Phe Ala Ser Al Phe Ala

Glu Arg Arg Wing Gly Gly Vai Leu Vai Wing Be His Leu Gin be

Phe Leu Glu Gonna Be Tyr Arg Vai Leu Arg His Leu Ala Gin Pro

Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin. Ser Phe Leu Leu

Lys Ser Leu Glu Gin Vai Arg Lys He Gin Gly Asp Gly Ala Ala

Leu Gin Glu Lys Leu Cys Wing Thr Tyr Lys Leu Cys Hrs Pro Glu

Glu Leu Vai Leu Leu Gly His Her Leu Gly He Pro Trp Ala Pro

Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu

Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin

Wing Leu Glu Gly He Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr

Read Gin Read. At". Go Wing Asp Phe Wing Thr Thr Xle Trp Gin Gin

Het Glu Glu Leu Gly (SSQ ZD ML 181J

Exbmolq 70

C onstruction depMON13197

The new N-terminal / C-terminal gons in p MON13197 was created using Method II as described in Materials and Methods. Primer fragment was created and amphficated from G-CSF Ser ^:: p sequence MON13Q37 using primer set, 133 primer (SEQ 10 NO: 70) and P-b1 primer 20 (SEQ ID NO: 62). Terminator fragment was created and amplified sequentially

188 cia G-CSF Ser ^? in ρ MON13037 using the primer set. 132 terminator (SEQ ID NO: 71) and P-b1 terminator (SEQ IO NO 63 63). Initiator Fragment was digested with Ncol restriction endonulceases and Terminator Fragment was digested with Hindlll restriction endinuclease. After purification, the Initial and 5 end of digested fragments were combined with and linked to the approximately 3800 base pair Ncol-Hindlll vector fragment.

MON3934.

The intermediate plasmid described above contained the new G-CSF Ser ¹⁷ terminus-N / terminus C gene of full length and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide and the new GCSF Ser ' ⁷ terminus-N / terminus-C gene was isolated using Geneclean (Bio101, Vista. CA). The intermediate plasmid, ρ MON13181, was digested with Hindlll and AfUII restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (Promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli cells into the DHfxx strain (Life Technolo gies, Gaithersburg, MD). Transformed bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion of the new gene. The resulting plasmid was designated as MON 13197.

E. coli strain JM101 was transformed with ρ MON13197 for protein expression and protein isolation from inclusion bodies.

The plasmid. ρ M0N13197, contains the DNA sequence of (SEQ ID NO: 111) which encodes the following amino acid sequence:

189

Asn Cys Ser lie Met He Asp Pro Pro Ala Pro Leu Leu Asp Val Ser lie Leu Met Asp Arg Ser Phe Val Arg Ala Val Lys Glu Ala He Leu Arg Asn Leu Ala Ala Pro Ser Arg His Pro Gin Glu Phe Arg Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr Gly Gly Gly Ser Gly Gly Gly His Pro Glu Glu Leu Val Leu Trp Ala Pro Leu Ser Ser Cys Gly Cys Leu Ser Gin Leu His Leu Leu Gin Ala Lev Glu Gly Leu Asp Thr Leu Gin Leu Asp Trp Gin Gin Met Glu Glu Leu Thr Gin Gly Ala Met Pro Ala Ala Gly Gly Val Leu Val Ala Val Ser Tyr Arg Val Leu Arg Gly Pro Ala Ser Ser Leu Pro Glu Gin Val Arg Lys lie Gin Lys Leu Cys Ala Thr (SEQ ID

Glu He He His His Leu Lys Arg

Pro Asn Asn Leu Asn Asp Glu Asp

Asn Leu Arg Leu Pro Asn Leu Glu

Asn Leu Giu Asn Ala Ser Gly He

Gin Pro Cys Leu Pro Ser Ala Thr

He He Xie Lys Ala Gly Asp Trp

Thr Phe Tyr Leu Val Thr Leu Giu

Val Glu Gly Gly Gly Gly Ser Pro

Ser Asn Met Ala Tyr Lys LeuCys

Leu Gly His Ser Leu Gly HePro

Pro Ser Gin Ala Leu Gin Leua

Being Gly Leu Phe Leu Tyr GinGly

Xie Ser Pro Glu Leu Gly proThr

Val Ala Asp Phe Ala Thr ThrXie

Gly Met Wing Pro Wing Leu Gin Pro

Phe Ala Ser Ala Phe Gin Arg Arg

Ser His Leu Gin Ser Phe Leu Giu

His Leu Aia Gin Pro Thr Pro Leu

Gin Ser Phe Leu Leu Lys Ser Leu

Gly Asp Gly Wing Wing Wing Gin Glu

NO: 1H3)

Example 71

MON 13198 p construction

The new N-terminus / C-terminus gene in ρ MON13198 was created using Method II as described in Materials and Methods, Primer Fragment was created and amplified from the G-CSF sequence in p MON 13037 using the primer set. 142 primer (SEQ ID NO: 72) and P ~ b1 primer (SEQ 10 NO: 62). Terminator fragment was created and amplified from the G-CSF SeP ⁷ sequence in ρ MON13037 using the primer set, 141 terminator (SEQ ID NO: 73) and P-b1 terminator (SEQ ID NO.63). Primer fragment was digested with Ncol restriction endonuclease, and Terminator fragment was digested with Hindll restriction endonuclease. After purification, the start and end of digested fragments were combined with and linked to the approximately 3800 base pair MQN3934 powder fragment Ncol-Hindlll.

The intermediate plasmid described above contained the new G-CSF Ser ⁵⁷ terminus-N / terminus-C gene of entire length and was digested with restriction endonucleases Ncol and Hindlll. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide and the new GCSF Ser ¹⁷ terminus-N / terminus-C gene in full length was isolated using Geneclean (δίο101, Vista, CA), O intermediate plasmid, ρ MON13180, was digested with Hindill and Af1 III restriction endonuoteases, resulting in a 4023 base pair vector fragment, and purified using a Magic ONA Clean-up System kit (Promega. Madison. VVI). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). A portion of the ligation reaction was used to transform E. coli cells to the DH5 strain. (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated p MON 13198.

And, coli strain JM101 was transformed with MON13198 p for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON13198, contains the DNA sequence of (SE.Q ID NO: 112) which encodes the following amino acid sequence:

Asn Cys Ser lie Met lie Asp Glu He He Hls Bis Leu Lvs Arg

Pro Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

It Will Be He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Giti

Ser Pne Va. ·. Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly He

Glu Ala Xie Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr

Ala Ala Pro Ser Arg His Pro He He lie Lys Ala Gly Asp Trp

Gin Glu Ph * Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu

Gift ΑΛ & Gin. Glu Gin Gin Tyr Va.1 Glu Gly Gly Gly Gly S & r? Ro

Gly Gly Gly Ser Gly Gly Gly Ser Asn Met Ala Ser Phe Gin Ward

Arg Arg Axa Gly Gly val Leu Vai Ala Ser His Leu Gin Ser Phe

Leu Glu Will Be Tyr Arg Vai Leu Arg His Leu Ala Gin .Pro Thr

Pro Leu Gj.y Pro Ala Ser Ser Leu Pro Gin Sex ’Phe Leu Leo Lys

Be Leu Glu Gin Vai Arg Lys Xie Gin Gly Asp Gly Ala Ala Leu

Gin Hu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu

Leu Vai Leu Leu Gly Hrs Ser Leu Gly He for Trp Ala Pro Leu

Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser

Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala

Leu Glu Gly lie Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu

Gin Leu Asp Vai Wing Asp Phe Wing Thr Thr He Trp Gin Gin Met

Gm Glu Leu Gly Met Wing Pro Wing Wing Le Gin Pro Thr Gin Gly Wing

Met Pro Wing Phe Wing iSEQ XL NO: 184)

Example 72

Construction of the MON 13199 p

The new gone-terminus-N / termination-C in p MON 13199 was created using Method It as described in Materials and Methods. Primer Fragment was created and amplified from G-CSF Ser ⁵⁷ sequence in p MON 13037 using the primer set, 14.2 primer (SEQ ID NO.72) and P-bl primer

191 (SEQ ID NO.62). Terminator fragment was created and amplified from G-CSF Ser ^v sequence in ρ MON13037 using the primer set, 141 terminator (SEQ ID NO: 73) and P-b1 terminator (SEQ ID NO: 63). Initial fragment was digested with one Ncol restriction endonuclease. and Fragments Termina5 dor was digested with Hindlil restriction endonuclease After purification, the

Start and end of digested fragments were combined with and ligated into the approximately 3800 base pair N394-base fragment of MON3934 powder.

The intermediate plasmid described above contained the new 10 G-CSF Ser ^v terminus-N / terminus-C gene of entire length and was digested with Ncol and Hindlil restriction endonucleases. The digested DNA was resolved on a 1% TAE A gel, stained with ethidium bromide and the new full length GCSF Ser ¹⁷ terminus-N / terminus-C gene was isolated using Geneclean (Bla101, Vista, CA). The intermediate plasmid, ρ M0N13181, was digested with Hindlil and Afllll restriction endonucleases, resulting in a 4068 base pair vector fragment, and purified using a Magic DNA Clean-up System kit (promega, Madison, Wl). The purified restriction fragments were combined and ligated using T4 DNA ligase (Boehringer Mannheim .. Indianapolis, IN). A portion of the 20 fol binding reaction used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the correct insertion of the new gene. The resulting plasmid was designated ρ MON13199

E. coli hnhaagem JM101 was transformed with ρ MON13199 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON13199, contains the DNA sequence of (SEQ ID NO: 113) which encodes the following amino acid sequence:

192

Asn Cys Ser lie Met He Asp Glu He He His His Leu Lys Arg? Ro Pro Ale Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

It Will Be He Leu Met Asp Arg Asn Leu Arg Leu for Asn Leu Glu

Ser Phe Vai Arg Ale Vai Lys Asn Leu Glu Asn Ala Ser Gly He

Glu Ala He Leu Arg Asn Leu Gin pro Cys Leu Pro Ser Ala Thr

Ala Ala Pro Ser Arg His Pro He lie He Lys Ala Gly Asp Trp

Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu

Gin Ala Gin Glu Gin Gin Tyr Vai Glu Gly Gly Gly Gly Ser Pro

Gly Glu Pro Ser Gly Pro He Ser Thr He Asn Pro Ser Pro Pre

Ser Lys Glu Ser His Lys Ser Pro Asn Met Aia Ser Ala phe Gin

Arg Arg Aia Gly Gly Vai Leu Vai Ala Ser His Leu Gin Ser Phe

Leu Glu Gonna Be Tyr Arg Vai Leu Arg His Leu Ala Gin Pro Thr

Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys

Be Leu Gxu Gia Vaz Arg Lys me Gin Gly Asp Gly Ala Ala Leu

Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu

Leu Vai Leu Leu Gly His Ser Leu Gly He Pro Trp Ala Pro Leu

Ser Ser- Cys Pro Ser Gin Ala Leu Gin Leu Ala Glv Cvs Leu Se ^

Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Giy Leu Leu Gin Ala

Leu Glu Gly He Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu

Gm Leu Agf Vai Wing Asp Phe Wing Thr Thr He Trp Gin Gin Met

Gm Glu Leu Gly Het Wing Pro Wing Wing Leu Gin Pro Thr Gin Glv Wing

Met Pro Ala Phe Ala (SEQ ID HQ: 185)

Example 73

Construction of duplicate tandem plasmid mold, Syntanl

To create the ρ MON13416 tandem duplicated hlL-3 receptor agonist template, Syntanl, three DNAs were ligated by means of ligation using T4 DNA ligase (Boehringer Mannheim). The three DNAs are: 1) ρ MON13046, containing ρ MON13416 hlt-3 receptor agonist, digested with BstEII and SnaBI; 2) the complemented pair of synthetic oligonucleotides, Llsyn.for (SEQ ID NO: 48) and Llsyn.rev (SEQ ID NO: 49), which contains a sequence encoding the linker that connects the termini10 no-C and terminus-N the original protein and a small amount of ρ MON13416 surrounding sequence and that when properly assembled result in BstEII and Ciai ends; and 3) a portion of p13131616 ρ MON13046 digested hlL-3 receptor agonists with Clia (DNA was developed in dam cells, DM1 (Life Technologies)) and SnaBI. The dn managed DNAs were resolved on a 0.9% TAE gel, stained with ethidium bromide and isolated using Geneclean (Bid01).

A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Miniprep DNA was isolated from the transformants, and the transformants were selected using a PCR-based assay. Plasmid DNA

193 of selected transformants were sequenced to obtain the mail template. The resulting plasmid was designated syntanl and contains the DNA sequence of (SEQ ID NO: 84).

Example 74

Duplicate tandem mold construction, syntan3

To create the MON13416 tandem duplicated hlL-3 receptor agonist template, suntan30, three DNAs were ligated using T4 DNA ligase (Boehringer Mannheim). The three DNAs are: 1) p MON13046, containing p MON 13416 hlL-3 receptor agonist. digested 10 with BstEil and SnaBI: 2) the complemented pair of synthetic oiigonucleotides .. L3syn.for (SEQ ID N0.50) and L3syn.rev (SEQ ID NO: 51), which contain a sequence encoding the link that connects the ends termiπο-C and end-N of the original protein and a small amount of surrounding MON 13416 p sequence and which when properly assembled 15 result in BstEil and SnaBI ends; and 3) a portion of p1 MON13416 agonist of h1 ~ 3 receptor digested from p1 MON13046 with Clal (DNA was developed from dam cells, DM1 (Life Technologies)) and SnaBI. The digested DNAs were resolved on a 0.9% TAE gel, stained with ethidium bromide and isolated using Genclean (Bio101).

A portion of the ligation reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg, MD). Miniprep DNA was isolated from the transformants, and the transformants were sieved using a PCR-based assay. Plasmid DNA from selected transformants was sequenced to obtain the correct template. The resulting plasmid was called syntan3 and contains the DNA sequence of (SEQ ID NO: 85).

194

Example 75

Construction of ρ M0N31104

The new N-terminus / C-terminus gene ρ MON31104 was created using Method 111 as described in Materials and Methods. The new full-length 5-terminus-N / termination-C gene MON 13416 hlL-3 receptor agonists was created and amplified from the intermediate plasmid, Syntanl, using the primer set 35 (SEQ ID NO: 52) and 34 rev (SEQ ID NO: 53) resulting DNA fragment containing the new gene was managed with restriction endonucleases Ncol and SnaBI. The digested DNA fragment was resolved on a 1% TAE A gel, stained with ethidium bromide and isolated using Geneclean (Boi01, Vista, CA). The purified digested DNA fragment was ligated into the expression vector, ρ MON13189, using T4 DNA ligase (Poehringer Mannheim, Indianapolis, IN). Ρ MON13189 DNA was previously digested with Ncol and SnaBI to remove ρ MON13416 hlL3 receptor agonist encoding sequence and the 4254 base pair vector fragment was isolated using Geneclean (8io101, Vista, CA) after resolution on a gel 0.8% TAE and staining with ethidium bromide. A portion of the ligation reaction was used to transform cells, from E. coli strain DH5a (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampullin. Plamid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated p MQN31104.

E. coli strain JM101 was transformed with ρ MON31104 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON31104, contains the DNA sequence of (SEQ ID NO: 86) which encodes the following amino acid sequence:

195

Read Asp Pro Asn Asn Read Asn Asp Giu Asp V *! g _er H _and Leu Met

Asp Arg Asn Leu Arg Leu Pre Asn Lev Giu ner The Veil Ãrg Ala

Val Lys Asn Leu Giu Asn Ale Ser Gly lie Giu Ale He Leu Arg

Asn Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing Pre Ser Arg Wing

His Pro He He He Lys Ala Gly Asp Trp Qin Giu Phe Arg Giu

Lys Leu Thr Phe Tyr Leu Val Thr Leu Giu Glr Ala Gin Glü Gin

Gin Gly Gly Gly Ser Asn Cys Ser lie Her He Asp Giu He He

His His Leu Lys Arg Pro Pro Ale Pro Leu Tyr val Giu Glv Giy

Gly Gly ser pro Gly Giu Pro Ser Gly Pro He Ser Thr He Asn

Pro Ser Pro Pro ser Lys Giu Ser His Lys Ser Pro Asn Met Ala

Thr Gxn Gly Ala Met Pro Ala Phe Ala Ser Al Phe Gin Arg Arg

Ara Guy uly Val Leu Val Ala Ser Hrs Leu Gin Ser Phe Leu Giu

Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser GlyGlv

Ser Gly Gly Ser Gin Ser phe Leu Leu Lys Ser Leu Giu GinVal

Arg Lys He Gin Gly Asp Gly Ala Ala Leu Gin Giu Lys Leuevs

Thr Thr Tyr Lys Leu Cys His Pro Giu Giu Leu Val Leu LeuGly

Hrs Ser Leu Gly He Pro Trp Ala Pro Leu Ser Ser Cys ProSer

Gin. Wing Leu Gin Leu Wing Gly Cys Leu Ser Gin Leu His SerGlv

Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Giu Glv H _e s _e jPro Giu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala

Asp Phe Ala Thr Thr He Trp Gin Gin Met Giu Giu Leu Glv Met

A4.a pro Ala Leu Gin Pro (SEQ ns «0: 186}

Example 76

Construction of ρ M0N31105 new N-terminus / ~ C terminus gene in ρ MON31105 was created using Method III as described in Moten a is and Methods. The new full-length N-terminus / C-gene 5 of ρ MON13416 hlL-3 receptor agonist was created and amplified from the intermediate plasmid, Syntanl. using primer set 70 initiator (SEQ ID NO: 54) and 69 rev (SEQ ID NOW

The resulting DNA fragment containing the new gene was managed with Ncol and SnaBI restriction endonucleases. The digested DNA fragment was resolved on a 1% TAE A gel, stained with ethidium bromide and isolated using Geneclean (Bio101, Vista, CA). The fragment of

Purified digested DNA was ligated into the expression vector ρ MON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The ρ MON13189 DNA was previously digested with Neal and SnaBI to remove ρ MON13416 agonists from hll.3 receptor encoding sequence and the 4254 base pair vector fragment isolated using Geneclean (Bio101, Vista, CA) after resolution on am 0.8% gelTAE and staining with ethidium bromide. A portion of the ligation reaction was used to transform DH5a E. coli cells (Life Technologies ,. Gaithersburg.

MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated ρ MON31105.

E. ooli strain JM101 was transformed with ρ MON31105 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON31105, contains the DNA sequence of (SEQ ID NO: 87) which encodes proteins with the following sequence of armnoacids:

Asn Ala Ser Gly Xie Glu Ala lie Lea Arg Asn Leu Gin Pro Cys

Leu Pro Ser Ala Thr Ala Ala Pre Ser Arg His Pro Tie TI © Tie

Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr

Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Giy Gly Gly Ser

Asn Cys Ser lie Met Tie Asp Glu lie Xie His His Leu Lys Arg

Pro Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp

Val Ser Tie Leu Meo Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu

Ser Phe Val Arg Ala Val Lys Asn Leu Glu Tyr Val Glu Giy Gly

Gly Gly Ser Pro Gly Glu Pre- Ser Gly Pro Tie Ser Thr Tie Asn

Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser pro Asn Met Ala

Thr Gin Gly Met Met Wing Phe Wing Ser Wing Phe Wing Arg Arg

Ally Gly Gly Val Lev Val Ala Ser His Leu Gin Ser Phe Leu Glu

Val Ser Tyr Arg val Leu Arg His Leu Ala Gin Pro Ser 'Gly Gly

Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val

Arg Lys lie Gin Gly Asp Gly Aia Ala Leu Gin Glu Lys Leu Cys

Thr Thr Tyr Lys Leu cys His Pro Glu Glu Leu Val Leu Leu Gly

His Ser Leu Gly 11 © Pro Trp Ala Pro Leu Ser Ser Cvs Pro Ser uln Al Lev Lev Leu Ala Gly Cys Leu Ser Gin Leu His Ser Glv

Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Glv Tie Ser

Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Va 'Alã

Asp Phe Ala Thr Thr Tie Trp Gin Gin Met Glu Glu Leu Glv Men

Pro Wing Wing Leu Gin Wing l SEQ ID NO: 187}

Example 77

Construction of ρ M0N31106 new N-terminus / C-terminus gene in ρ MON31106 was created using Method III as described in Materials and Methods The new N-terminus / C-terminus gene of the entire length of ρ MON13416 agonists of

IS hll-3 receptor is created and amplified from the intermediate plasmid, Syntanl, using primer set 91 initiator (SEQ ID NO.56) and 90 rev (SEQ ID

NO'.57).

The resulting DNA fragment containing the new gene was digested with Ncot and SnaBI restriction endonucleases. The digested DNA fragment was resolved on a 1% TAE A gel, stained with

197 ethidium and isolated using Geneelean (Bid 01, Vista, CA). The purified digested DNA fragment was ligated into the expression vector p MON13189, using T4 DNA ligase (Boehringer Mannheim ,. Indianapolis, IN). The YEAR p MON13189 was previously digested with Ncole SnaBI to remove the p

MON13416 hlL3 receptor agonists encoding sequence and the 4254 base pair vector fragment was isolated using Geneclean (Bio! 01,

Vista .. CA) after resolution on a 0.8% TAE gel, and staining with ethidium bromide. A portion of the ligation reaction was used to transform E coli cell line 0Η5α (Life Technologies, Gaithersburg, 10 MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated p MON31106.

E. coli strain JM101 was transformed with ρ MON31106 for protein expression and protein isolation from inclusion bodies.

The plasmid, p MON31106, contains the DNA sequence of (SEQ ID NO: 80) which encodes the protein with the following amino acid sequence:

Ala Pro Sex Arg His Fro lie He lie Lys Ala Gly Asp Try Gio

Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin

Ala Gin Glu Gin Gin Gly Gly Gly Ser Asn Cys Ser He Met. He

Asp Glu He He His His Leu Lys Arg Pro Pro Ala Pro Leu Leu

Asp Pro As π Asn Leu Asn Asp Glu Asp Val Ser He Leu Met. Asp

Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Wing val

Lys Asn Leu Glu Asn Ala Ser Gly He Glu Ala lie Leu Arg Asn

Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing Tyr Val Glu Gly Gly Wing

Gly Gly Sex * Piro Gly Glu Pro Ser Gly Pro He Ser Thr He Asn

Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Ann Met Ala

Thr Gin Gly Met Met Wing Phe Wing Ser Wing Phe Wing Arg Arg

Ally Gly Gly Val Leu val Ala Ser His Leu Gin ser Phe Leu Glu

Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly

Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val

Arg Lys' He Gin Gly Asp Gly Wing Wing Leo Gin Glu Lys Leu Cys

Thr Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly

His Ser Leu Gly Xie Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser

Gin Ale Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly

Read Phe Read Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly lie To be Pro Glu Read Gly Pro Thr Leu Asp Thr Leu Gin Asp Val Allah Asp Phe Allah Thr Thr He Trp Gin Gin Met Glu Glu Read Gly Met Allah Pro Allah Read Gin Pro (SEQ IQ NO: 188)

Example 78

Construction of ρ M0N31107

The new N-terminus / C-terminus gene in ρ MON31107 was created using Method III as described in Materials and Methods. The new full-length N-terminus / C-terminus gene of ρ MON13416 agonist of hlL-3 receptor was created and amplified from the intermediate plasmid, Syntanl, using the primer 101 primer (SEQ ID NO: 58) and 100 rev (SEQ ID NO: 59).

The resulting DNA fragment containing the new gene was digested with Ncol and SnaBL restriction endonucleases. The digested DNA fragment was resolved on an A1E TAE gel, stained with ethidium bromide and isolated using Geneclean (Bio101, Vista, CA ). The purified digested DNA fragment was ligated into the expression vector p MON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The MON 13189 p DNA was previously digested with Ncol and SnaBI to remove p MON13416 hlL3 receptor agonists encoding sequence and the 4254 base pair vector fragment was isolated using Geneclean (BioW1, Vista, CA) after resolution on a TAE gel At 0.8% and ethyde bromide stain. A portion of the ligation reaction was used to transform E cells with DH5a lineage (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm the comet insertion. The resulting plasmid was designated ρ M0N31107.

E. coli strain 3M101 was transformed with ρ MON31107 for protein expression and protein isolation from inclusion bodies

The plasmid, ρ MQN3H07, contains the DNA sequence of (SEQ ID NG: 89) which encodes the following amino acid sequence:

Wing Gly Asp Trp Gin Glu Phe Val Thr Lsu Glu Gin Al® Gin cys Ger He Mat lie Asp Glu Fro Wing Pro Leu Leu Asp Pro Ser He Leu Met. Asp Arg Asn Phe Val Arg Ala Val Lys Asn Ala Xie Leu Arg Asn Leu Gin Ala Pre- Ser Arg His Pro Xie Gly Gly Ser Pro Gly Glu Pro Pre Ser Pro Pro Ser Lys Glu Thr Gin Gly Ala Met Pro Ala Gly Gly Val Wing Leu Val Ala Val Ser Tyr Arg Val Leu Arg Ser Gly Gly Ser Gin Ser Phe Arg Lys Xie Gin Gly Asp Gly Ala Thr Tyr Lys Leu Cys His His Ser Leu Gly He Pro T.rp Gin Ala Leu Gin Leu Ala Gly Lac Phe Leu Tyr Gin Gly Leu Pro Glu Leu Gly Pro Thr Leu Asp Fhe Wing Thr Th, r Xie Trp Wing Pro Wing Wing Gin Pro (SE <

Arg Gru Lys Leu Thr Phe Tyr Leu

Glu Gin Gin Gly Gly Gly Ser Ash

He He His His Leu Lys Arg Pro

Asn Asn Leu Asn Asp Glu Asp Val

Leu Arg Leu Pro Asn Leu Glu Ser

Leu Glu Asn Ala Ser Gly n _s Glu Fro Lys Leu Pro Ser Ala Thr Ala Ils He Lys Tyr Val Glu Gly Gly Ser Gly Pro lie Ser Thr He Asn Ser His Lys Ser Pro Asn Met Ala Fhe Ala Ser Ala Phe Gin Arg Arg Ser His Leu Gin Ser Phe Leu Glu His Leu Ala Gin pro Ser Gly Gly Leu Leu Lys Ser Leu Glu Gin Val Ala Ala. Leu Gin Glu Lys Leu Cys Pro Glu Glu Leu Val Leu Leu Gly Ala Pro Leu Ser Ser Cys Pro Ser Cys Leu Ser Gin Leu His Ser Gly Leu Lin Ala Leu Glu Gly Hg Ser Asp Thx 13eu Gin Leu Asn Vs. ¹ Ala Sin Gin Met Glu Glu Lei G1J mI ID MO: 189}

Example 79

Construction of p MON31108 new N-termination / C-termination gene in p MON31108 was created using Method li as described in Materials and Methods, The new gene

S-termination-N / C-termination of entire p-length MON13416 erlector agonist hlL ~ 3 fol created and amplified from the intermediate plasmid, Syntan3, using primer set 35 primer (SEQ ID NO: 52) and 34 rev (SEQ ID NO : 53).

The resulting DNA fragment containing the new gene was d? 10 managed with Ncol and SnaBI restriction endonucleases. The digested DNA fragment was resolved on a 1% TAE A gel, stained with ethidium bromide and isolated using Geneclean ( Bid 01, Vista, CA), The purified digested DNA fragment was ligated into the expression vector p MON 13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). MON13189 15 p DNA was previously digested with Ncol and SnaBI to remove the p

MON13416 hlL3 receptor agonist encoding sequence and the 4254 base pair vector fragment was isolated using Genedean (Biol 01, Vista, CA) after resolution on a 0.8% TAE gel and ethidium bromide stain. A portion of the ügation reaction was used to transform cells of E. coli strain DH5a (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated p M0N31108.

And, coli strain JM101 was transformed with MON31108 p for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ M0N31108, contains the DNA sequence of (SEQ IO NO 90) which encodes the following amino acid sequence:

Read Asp Pro Asn Asn Read flB Asp Arg Asn Read Arg Read W Vai Lys Asn Read Asn Asn Read Glh ' Pro cys Xt & V Hrs Pre He lie He Lys Lys Read Thr Phe Tyr Read Gin Gly Gly Gly To be Gly To be He Met He Asp OXti Allah Pro Read Tyr Go Glu To be Gly ϊ * το He To be Thr To be ΗΛ2 Lys To be Pr © Asn Phe Allah to be Allah Phe Gin To be His Read Gin To be Phe H1S There I Allah Gin Pro To be Read Read Lys To be Judge Glu Allah Allah Read it. Gly Glu Lys Pre Glu Glu Read val Read Axa Pro Read To be To be Cys cya Read To be Gin Read Mrs Read: GÀn Allah Glu Gly A.Sp Thr Read Gin Read Asp Gin Gin Met Glu Glu Read

Asn Asp Glu Asp Will Be Lie Leu Met

Pr © Asn Leu Glu Ser Phe Vai Arg Ala

Ala be Gly He Glu Ala He Leu Arg

Pro Ser Ala Thr Ala Ala Pro Ser Ala

Wing Gly Asp Trp Gin Glu Phe Arg Glu

Go Thr Leu Glu Gin Ala Gin Glu Gin

Gly Gly Ser Gly Gly Gly çy _S

He He Hrs His Leu Lys Arg Pro Pro

Gly Gly Gly Gly Be Pro Gly Glu Pro

Le Asn Pro Ser Pr © Pro Ser Lys Glu

Met Wing Thr Gin Gly Wing Met Pro Wing

Arg Arg Ala Gly Gly Vai Leu Vai Ala

Leu Glu Will Be Tyr Arg Va.l Leu Arg

Gly Gly Ser Gly Gly Ser Gin Ser Phe

Gin Vai Arg Lys He Gin Gly Asp Gly

Leu Cys Ala Thr Tyr Lys Leu Cys Hrs ueu Gly Hrs Ser Leu Gly Xie Pro Trp

To be Gin Ala Leu Gin Leu. Wing Gly

Be Gly Leu phe Leu Tyr Gin Gly Leu

He Ser Pro Glu Leu Gly Pro Thr Leu

Go Ala Asp phe Ala Thr · Thr He Trp

Gly Met Wing Pro Wing Leu Gin Pro (SEQ

Example 80

Construction of ρ M0N31109

The new N-terminus / C-terminus gene in ρ MON31109 was created using Method III as described in Materials and Methods. The new full-length N-terminus / C-terminus gene of ρ MON13416 hLL-3 receptor agonists was created and amplified from the intermediate plasmid, Syntan3 _; using primer set 70 initiator (SEQ ID NO: 54) and 69 rev (SEQ ID

NOiSS).

The resulting DNA fragment containing the new gene was digested with restriction endonucleases Ncol and SnaBI. The digested DNA fragment was resolved on a 1% TAE A gel, stained with eOdio bromide and isolated using Geneclean (Biol 01, Vista, CA). The purified digested DNA fragment was ligated into the expression vector ρ MON13189, using T4 DMA iigase (Boehringer Mannheim .. Indianapolis, IN). The MON 13189 fol DNA was previously digested with Ncol and SnaBl to remove the MON13416 hh..3 receptor agonist encoding sequence and the 4254 base pair vector fragment was isolated using Genedean (Bio101, Vista, CA) after resolution on a 0.8% TAE gel and aphid bromide stain A portion of the reaction was used to transform E. coli cells to the DH5a strain (Life Technologies, Gaithersburg. MD). Transforming bacteria were selected on plates containing ampicillin. Plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated ρ MDN31109,

E. coli hnhagem JM101 was transformed with p MON31W9 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON31109, contains the DNA sequence of (SEQ ID NO: 91) which encodes the following

Asn Ala Ser Gly Xle Glu Ala 11 «Leu Fro Ser Ala Thr Al® Ala Pro Lys Ale Gly Asp Trp Gin Glu Phe Leu Vai Thr Leu Glu Gin Ala Gin Gly Gly Gly ser Gly Gly Gly Ser Glu lie He His His Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Tyr Vai Glu Gly Gly Sex Gly Pro lie Ser Thr Xle Asn Ser His Lys Ser Pro Asn Man Ala Phe Ala Ser Ala Phe Gin Arg Arg Ser Ris Leu Gin Ser Phe Leu Glu His Leu Ala Gin Pro Ser Gly Gly Leu Leu Lys Ser Leu Glu Gin Vai Ala Ala Leu Gin Glu Lys Leu Cys Pre Glu Glu Leu Vai Leu Leu Gly Ale Pro Leu Ser Ser Cys Pro Ser Cys Leu ser Gin Leu His Ser Gly Leu Gin Alu Leu Glu Gly Xle Ser Asp Thr Leu Gin Leu Asp Vai Ala Gin Gin Met Glu Glu Leu Glv My Xb NQ: lâl |

Example 81

Construction of ρ M0N3110 amino acid sequence;

Leu Arg Asn Leu Gin Pre Cys Ser Arg His Pro He Lie Xle Arg Glu Lys Leu Thr Phe Tyr Glu Gin Gin Gly Gly Gly Asn Cys Ser Xle Met XÍe Asp Pro Pre Ara Pro Leu Lep Asp Vai Ser He Leu Met Asp Arg Ser Phe Vai Arg Ala vai Lys Gly Gly be Pro Gly Glu Pro Pro Ser Pro Pro Ser Lys Glu Thr Gin Gly Ala Men pro Ala Ala Gly Gly Vai Leu Vai Ale Vai Be Tyr Arg Vai Le Arg Ser Gly Gly par Gin Ser Phe Arg Lys Xie Gin Gly Asp Gly Ala Thr Tyr Lys Leu Cys His His Ser Leu Gly xle pro Tro Gin A ^ a Leu uln Leu Ala Gly Leu Phe Leu Tyr Gin Gly Leu for Glu Leu Gly Pro Thr Leu Asp Phe Ala Thr Thr He Trp Ala Pro Wing Leu Gin Pro 1S £ Q

202

The new N-terminus / C-terminus gene in ρ MON31110 was created using Method III as described in Materials and Methods. The new end-N / end-C gene of ρ MON13416 agonists of hLL-3 receptor was created and amplified from the intermediate plasmid. Syntan3, 5 using the primer set 91 initiator (SEQ ID NO: 56) and 90 rev (SEQ ID NO: 57).

The resulting DNA fragment containing the new gene was digested with Ncol and SnaBL restriction endonucleases. The digested DNA fragment was resolved on a 1% TAE A gel. stained with 10 ethidium bromide and isolated using Geneclean (Bío101, Vista, CA). The purified digested DNA fragment was ligated into the expression vector ρ MON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). The ρ MON13189 DNA was previously digested with Ncol and SnaBI to remove ο p MON 13416 hlL3 receptor agonists encoding sequence and the 4254 base pair vector fragment 15 was isolated using Geneclean (Bio10i _;

Vista, CA) after resolving on a 0.8% TAE gel and ethidium bromide stain, a portion of the reaction was used to transform E. coli cells to the DH5a strain (Life Technologies. Gaithersburg, MD). Transforming bacteria were selected on plates containing ampici20 line. Piasmicho DNA was isolated and sequenced to confirm correct insertion. The resulting piasmicho was designated ρ MON31110.

E, coli strain JM101 was transformed with p MQN31110 for protein expression and protein isolation from inclusion bodies

The plasmid, ρ MON31110, contains the DNA sequence of 25 (SEQ ID NO; 92) which encodes the following amino acid sequence '

203

Ala Pro Ser Glu Phe Arg Ala Gio Glu Gly Ser Asn Lys Arg Pro Glu Asp Vai Leu Glu Ser Gly He Glu Ala Thr Ala Ser Gly Pro Ser His Lys Phe Ala Ser Ser His Leu His Leu Ala Leu Leu La Ala Leu Ala Le Gla Glu Ala Pro Leu Cys Leu Ser Leu Gin Ala Asp Thr Leu Gin Gin Met Xh N0.-1S2}

Arg His Pro Glu Lys Leu Gin Gin Gly Cys Ser He Pro Ala Pro Ser He Leu Phe Vai Arg Ala lie Leu Tyr Vai Glu He Ser Thr Ser Pro Asn Ala Phe Gin Gin Ser Phe Gin Pro Ser Ser Leu Glu Gin Glu Lys Leu val Leu Ser Ser Cys Gin Leu His Leu Glu Gly Gin Leu Asp Glu Glu Leu

Tyr Ser

Asp

Asp

Arg

Lys

Read

Gly Gly

He lie Tie Thr Phe Gly Gly Met He Leu. Read

Met Asp Ala Val

Arg Asn Gly Gly

He Asn Pro Met Ala Thr Arg Arg Ala Leu Glu Val Gly Gly Ser Gin Val Arg Leu Cys Ala Leu Gly His Pro Ser Gin Ser Gly Leu He Ser Pro Val Ala Asp Gly Het Ala

Lys Ala Gzy Leu Val Thr Gly Gly Gly Glu He He Pro Asn Asn Asn Leu Arg Asn Leu Glu Gin Pro Cys

Be Pro

Ser Pro Pro Gin Gly Ala Gly Gly Val Ser Tyr Arg Gly Gly Ser Lys Tie Gin Thr Tyr Lys Ser Leu Gly Ala Leu Gin Phe Leu Tyr Glu Leu Gly Phe Ala Thr Pro Ala Leu

Asp Trp Gan Leu. Glu Gin Ser Gly Gly His His Leu Leu Asn Asp Leu Pro Asn Asn Ala Ser Leu Pro Ser Gly Glu Pro Ser Lys Glu Met Pro Ala Leu Val Ala Val Leu Arg Gin Ser Phe Gly Asp Gly Leu Cys His He Pro Trp Leu Al® Gly Gin Gly Leu Pro Thr Leu Thr He Trp Gin Pro (SEQ

Example 62

Construction of p MON31111 new N-terminus / termination-C gene in ρ MON31111 was created using the UI Method as described in Materials and Methods. The new S-terminated-N / terminated-C gene MON13416 hlL ~ 3 receptor agonist was created and amplified from the intermediate plasmid, Syntan3, using the primer set 101 primer (SEQ ID NO.58) and 100 rev ( SEQ ID NOW resulting DNA fragment containing the new gene was managed with restriction endonucleases Ncol and SnaBI The digested DNA fragment was resolved on a 1% TAE A gel, stained with ethidium bromide and isolated using Geneclean (8io101, Vista, CA).

Purified digested DNA was ligated into the expression vector p MON13189, using T4 DNA ligase (Boehringer Mannheim, Indianapolis, IN). MON 13189 15 p DNA was previously digested with Ncol and SnaBI to remove p

MON13416 hIL3 receptor agonists encoding sequence and the 4254 base pair phot fragment vector fragment using Genedean (81010 _t Vista, CA) after resolution on a 0.8% TAE A gel and ethidium bromide stain. A portion of the bonding reaction was used to transform cel

204 squid of E. coii strain DH5a. (Life Technologies, Gaithersburg, MD). Transforming bacteria were selected on plates containing ampicillin, plasmid DNA was isolated and sequenced to confirm correct insertion. The resulting plasmid was designated ρ MON31111.

E coli strain JM101 was transformed with ρ MON31111 for protein expression and protein isolation from inclusion bodies.

The plasmid, ρ MON31111, contains the DNA sequence of (SEQ ID NO: 93) which encodes the following amino acid sequence:

Ale Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu

Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Gly Gly Gly Ser Gly

Gly Gly Ser Gly Gly Gly Ser Asn Cys Ser He Mei He Asp Glu

He He Hrs His Leu Lys Arg Pro Pr © Ala Pro Leu Leu Asp Pro

Asn Asn Leu Asn Asp Glu Asp Will Be He Leu Met Asp Arg Asn

Leu Arg Leu Pro Asn Leu Glu Ser Phe Vai Arg Ala Vai Lys Asn

Leu Glu Asn Ala Ser Gly He Glu Ala He Leu Arg Asn Leu Gin

Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro He lie He Lys Tyr Vai Glu Gly Gly Gly Gly Ser Pro Gly Glu pro

Ser Gly Pro He Ser Thr He Asn Pro Ser Pre? Pro Ser Lys Glu

Ser His Lys Ser Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala

Phe Ala Ser Ala Phe Gin Arg Arg Ala Gly Gly Vai Leu Vai Ala

Ser His Leu Gin Ser Phe Leu Glu Gonna Be Tyr Arg Vai Leu Arg

Hrs Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe

Leu Leu Lys Ser Leu Glu Gin Vai Arg. Lys lie Gin Gly Asp Gly

Wing Wing Leu Gin Glu Lys Leu Cys Wing Thr Tyr Lys Leu Cys His

Pro Glu Glu Leu Vai Leu Leu Gly His Ser Leu Gly He Pro Trp

Wing Pro Leu Ser Ser cys Pro Ser Gin Wing Leu Gin Leu Wing Gly

Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu

Leu Gin Ala Leu Glu Gly He Ser Pro Glu Leu Gly Pro Thr Leu

Asp Thr Leu Gin Leu Asp Vai Wing Asp Phe Wing Thr Thr He Trp

Qin Gin Met Glu Glu Leu Gly Met Wing Pro Wing Wing Le Pro Gin (SEO

ZD NO: 193J

Example 83

Construction of ρ MON 31112

Construction of ρ MON31112, a plasmid containing DNA sequence encoding a multifunctional hematopoietic receptor agonists that activates the hLL-3 receptor and G-CSF receptor. Plasmid,

MON13189 ρ DNA was digested with restriction enzymes Ncol and Xmal resulting in an Ncol vector fragment. Xmal which was isolated and purified from a 0.8% agarose gel. The DNA of a second plasmid, p

MON13222 (WQ94 / 12639), US Serial # 08/411 796) was digested with Ncol and EcoRl resulting in a 281 base pair Ncol, EcoRI fragment. This fragment was isolated and purified from an agarose gel

205

1.0%. Two oiigonucteotides SYNNQXA1.REQ (SEQ ED N0; 240) and SYNNOXA2.REQ (SEQ IO NO: 241) were annealed and ligated with the 281 base pair DNA fragment of ρ MON13222 to the DNA vector fragment of ρ M0N13189. A portion of the ligation mixture 5 was then transformed into E. coli K-12 strain JM101. Transforming bacteria were selected on plates containing ampicillin.

Plasmid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to co rrfect with co r re tions.

The plasmid; ρ MON31112, contains the DNA sequence of (SEQ ID ΝΟΊ14) which encodes the following amino acid sequence:

Probe MetAlaAsnCysEerAsnMetXleAspGlxàllelleThrHisbeuLysGlnProProLeu ubeuAspPheAsxiAsnLeuAsnGlyGluAspGlnAsplleLeuMetAspAsnAsn LeuArgArgProAsnLeuGluAlaPheAsnArgAlaVaXLysSerLeuGlnAsnAlaSer AlaXleGluSerlleLeubysAsnLeuLeuProCysLeuFroLeuAlaThrÀlaAlaPro TrmAx'gKj.sP cIleHisIleLysAspGlyAspTrpAsnGluPhaArgArgLysLeuTb ^ '^ Phely rLeuL.ysThrLeuGluAsnAlaGlnAlaGlnGlnTyrValGluG lyGlyGlyG SerProGlyGluProSerGXyProXleSerThrlleAsnProSerProProSerLvsGlu Ç * · · SerHxsLysSerProAsnMevAlaThrGlnGlyAlaMetProAlaPheAlaSerAiaPhe GlnArgArgAlaGlyGlyValLeuVaXAlaSerHisLeuGlnSerPheLeuGiuValSe TyrArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGlySerGXnSerPhi LeuDeuLysSerLeuGluGlnValArgLysXleGlnGlyAspGlyAlaAlaLeuGlnGlu lysLeu ^ ^ sAlaThrlyrLyaLeuCysHisProGluGluLeuValLeuLeuGlyHisSe LeuGlyXleProTrpAlaProLeuSerSerCysProSerGlnAlaLeuGlnLeuAlaGlv CysLeuSetGLnLeuHisSerGlyLeuPheLeuiyrGlnGlyLeuLeuGlnAlaLeuGlü GlylleSerProGluLeuGlyProThrLeuAspThrLeuGlnLauAspValAlaAspPhe AlaThrThrlleTrpGlnGlnMetGluGl-uLeuGlylSetAlaProAlaLeuGlnPrD (SEQ ID NO: 199)

Construction of ρ MON3113

Construction of ρ M0N31113, a plasmid containing DNA sequence encoding a multifunctional hematopoietic receptor agonist 15 that activates the hlL-3 receptor and G-CSF receptor. Plasmid, DNA ρ MON13197 was digested with restriction enzymes Ncol and Xmal resulting in a vector fragment Ncol, Xmal which was isolated and purified from a 0.8% gal agarose. The DNA of a second plasmid, ρ MON13239 (WO94 / 12639), US Serial # 08/411 796) was digested with Ncol and EcoRI resulting in a 281 base pair Ncol EcoRI fragment. This fragment was isolated and purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXA1.REQ (SEQ ED NO: 240) and SYNNOXA2 REQ (SEQ ID NO.241) were annealed and

206 linked with the 281 base pair MON13239 DNA fragment to the MON13197 DNA vector fragment. A portion of the ligation mixture was then transformed into E. coli K-12 strain JM101. Transforming bacteria were selected on ampicillin-containing plates. Ptasmid DNA 5 was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm correct insertions.

plasmid, p MON31113, contains the DNA sequence of (SEQ ID NO: 115) which encodes the following amino acid sequence:

MetAlaAsnCysSerAsnMstXXeAspGluXlelXeThrHisLeuIíysGlnProproLeu ProLeulieuAspPheAsnAsnLeuAsnGlyGluAs-pGlnA ^ pXleLeuMetGIuAsnAsr. LeuArgArgProAsaLeuGluAXaPheAsnArgAlaValLysSerl 'euGXnAsnAlaSer AlalleGluSerlleLeuLysAsnLeuLeuProCysLeuProLeuAlaThrAlaAlaPro ThrArgHisProIlelielleArgAspGXyAspTrpAsnGluPheArgArgLysLeuThr PheTyrLeuLy sThrLeuGXuAsnAXaGlnAlaGlnGlnTyrValGXuGly L LYD XYG ly SerPraGlyGluProSerGlyProIleSerThrXleAsnproSerPraFroSerLysGlu SerHi s Ly sSer PrcAsnMet AlaThrGlndlyAlaMexProAlaPheAl Asher AlaPhe L XnArgArgAlaGlyGlyVaXLeuV alAlaSerHisLeuGlnS ether PheLeuGluVa X are ether TyrArgvalLeuArgHisLeuAXaGlnProThTProLsuGlyProAlaSerSerDeuPro GlíiSerPheLeuLeuLysSerLeuGXuGXnVaXArgLysIXeGinGlyAspGlyAl & wing LeuGlnGXuLyaLeuCysAlaThrTyrLysLeuCysHxsProGluGluLeuValLeuLeu L lyHx sSerLeuG Xy X-X and Pr oxrp AXaProLeuSerS Ercy sProSerG InAlai' EUG In LeuAlaGlycysLeuSerGXuLeuHisSerGlyLeuPheLeuTyrGlnGlyLeuLeuGXn Al aLeuG XuG ly Σ1 eSerProGluLeuGXy ProThrL euAspThrLeuG InLeuA spVa 1 AlaAspPheAlaThrThrlleTrpGlnGlnMetGluGXuLeuGXyMetAlaPrQAlaLeu Glnpro (SEQ ID 0: 200)

Example 85

Construction of p M0N31114

Construction of p MON31114, a plasmid containing DNA sequence encoding a multifunctional hematopoietic receptor agonist that activates the hlL-3 receptor and Plasmid G-CSE receptor, DNA p MON13189 was digested with Ncol and Xmal restriction enzymes resulting in an Ncol vector fragment , Xmal which was isolated and purified from a 0.8% agarose gel. The DNA of a second plasmid, p MON13239 (WO94 / 12639), US Serial # 08/411 '796) was digested with Ncol and EcoRI resulting in a Ncol fragment, 281 base pair EcoRI, This fragment was isolated and pu25 rified of a 1.0% agarose gel. Two SYNNOXA1.REQ (SEQ ED NO.-240) and SYNNOXA2.REQ (SEQ ID NO.241) oligonucleotides were annealed and

207 hg with the DNA fragment of 281 base pairs of MON 13239 a and DNA vector fragment of ρ MON13189. A portion of the ligation mixture was then transformed into E. coli K-12 strain JM101. Transformative bacteria were selected on plates containing ampicillin. Plasmid DNA 5 was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm correct insertions.

The plasmid, ρ MON31114, contains the DNA sequence of (SEQ ID NO: 116) which encodes the following amino acid sequence:

MecAlaAsnCy sSerAsnMet I leAspGluIlelleThrHisLeuLy sG InProProLeu ProLeuLeuAspPheAsoAsnLeuAsnGlyGluAspG InAspI leLeuMetGluAsnAsn LeuArgArgProAsnLeuGluAlaPheAsxiArgAXavallysSerLeuGlnAsnAlaser Alai leGluSer 11 eLeuhys AsnLeuLeuProCy sLeuPr oLeuAlaThrAl aAlaPro ThrArgHísProIlellelleArgAspGlyAspTrpAsnGluPheArgArgLysLeuThr PheTyrLeuLy sThrLeuGluAsnAlaGlnAlaGlnG InTyrValGluGlyGlyG lyGly SerProGlyGluProSerGlyProllôSerThrlleAsnProSerProProSerLysGlu SerHisLysSerProAsnMetAlaThrGlnGlyAlaMetProAlaPheAlaSerAlaPhe GlnArgArgAlaGlyGlyValLeuValÀlaSerHisLeuGlnSerPhfôLeuGluValSer 'Tyr ArgValLeuArgHisLeuAlaGlnProSerGlyGlySerGlyGly S ERG InSerPhe LeuLeuLysSerLeuGluGlnValAi ^ LysIleGlnGlyAspGlyAlaAlabeuGlnGlu Ly sLeuCy salt aThrTyrly sLeuCysHx s Pr oG lug iuLeuV alLeuLeuGly Hi s If r LeuGly I lePr oTrpAla ProLeuSerS erCys Pros erGlnAlaLeuG InLeuAl aG ly CysLeuSerGlnLeuHisSerGlyLeuPheLauTyrGlnGlyLeuLeuGlnAlaLeuGlu GlylleSerProGluLeuGlyProThrGLLAspAG G 1 uLeuGlyMe t Al a Pr oAl abexiG InPro {SEQ ID NG: 201).

Construction of ρ M0N31115

Construction of ρ MON311145, a plasmid containing DNA sequence encoding a multifunctional hematopoietic receptor agonist that activates the hlL ~ 3 receptor and G-CSF receptor. Plasmid, 15 DNA ρ MON13197 was digested with restriction enzymes Ncol and Xmal resulting in a vector fragment Ncol, Xmal which was isolated and purified from a 0.8% agarose gel. DNA from a second plasmid. p MON13222, was digested with Ncol and EcoRI resulting in a 281 base pair Ncol, EcoRI fragment. This fragment was isolated 20 s purified from a 1.0% agarose gel. Two oligonucleotides SYNNOXA1.REQ (SEQ ED NCY240) and SYNNOXA2.REQ (SEQ ID NO: 241) were

208 ringed and ligated with the 281 base pair MON 13222 DNA fragment to the MON 13197 DNA vector fragment. A portion of the ligation mixture was then transformed into E. coli K-12 strain JM101. Transforming bacteria were selected on plates containing ampicillin.

Plasmid DNA was isolated, analyzed by restriction analysis to show the presence of an EcoRV fragment, and sequenced to confirm correct insertions.

The plasmid, ρ MON31115, contains the DNA sequence of (SEQ ID NO: 117) which encodes the following amino acid sequence:

Met AlaAsnCysSerAsnMeClleAspGluXlôXlaThxHisLeuXíysGXnProProLeu ProLeuLeuAspPheAsnAstiLeuAsnGlyGluAspGlnAspXleLeuMetAspAsnAsn LeuAr ArgPr g * sS aValLy the AscLeuGluAl aPheAsnAcgAl ecLeuG xoAsnAl ^ ase Alax leGluSer HeLôuLysAsnLeuLeuProCysLeuProLeuAl aThtAlaAlaPro Thx ArgHis ProX Lehi s XeLysAspGly X MpTrpAsnGluPheArgArgLysLeuThr PheTyrLeuLysThrL EUG luAsnAl ag ing InAlaG InTyrV 1G xuG XYG XYG LYG ly SerProGlyGluProSerGlyProTleSerThrXleAsnProSerProProSexLysGlu SerHisLysSerProAshMecAlaTixcGlhGlyAlaMet.ProAlaPheAlaSerAiaPhe GlnArgArgAlaGlyGlyValLeuValAlaSerHisLeuGlnSerPheLeuGluvalser Ty Air GVA ÍLsuArgHisLeuAl aG InProThr Pro Pr LeuGly ProAlaSerS erLeu the GlnSer PheLeuLeuLy sSerLeuGluGlnValArgLys X leg Ing lyAspGlyAlaAla LeuGlnGluLvsLeuCysAlaThrTyxLysLeuCy shi sprog XuGluLeuVaXLeuLeu GlyHxsSerLe.uGlyIleProTrpAlaProLeu £ erSereysProSerGlnAlaLeuGln LeuAlaGlyCysLeuSerGlnLeuHisSerGlyLeuPheLeUTyrGlnGlyLeuLeuGln AlaLeuGluGlyXleSerProGluLeuGlyProThrLeuAspThrLeuGlnLeuAspVal AlaAspPheAlaThrThr 11 eT rpGlnGlnMe cG luGluLeuGlyMe cAlaProAlaLeu Glnpro (SEQ IP NO: 2 02)

Example 87

Determination of in-vifro activity of multifunctional hematopoietic receptor agonist proteins

The protein concentration of the multifunctional hematopoietic receptor agonist protein can be determined using a sandwich ELISA based on a purified polyclonal antibody affinity. Alternatively, the protein concentration can be determined by analyzing the amino acid composition. The bioactivity of the multifunctional hematopoietic receptor agonist can be determined in a number of in vitro assays. For example, a multifunctional hematopoietic receptor agonist that binds to hLL-3 receptor and G-CSF receptor can be assayed in cell proliferation assays using cell lines expressing the re

209 hlL ~ 3 and / or G-CSF captors. One such assay is the AML-193 cell proliferation assay, AML-193 cells respond to IL-3 and G-CSF which allows the combined bioactivity of the multifunctional hematopoietic receptor agonist IL-3 / G-CSF to be determined, One another such assay is the TF 1 cell proliferation assay.

In addition, another cell line dependent factor, such as M-NFS-60 (ATCC. CRL 1838) or 32D which is a murine IL-3 dependent cell line, can be used. IL-3 activity is species-specific while G-CSF is not, so the bioactivity of the G10 CSF component of the multifunctional hematopoietic receptor agonist lt-3 / G-CSF can be determined independently. Cell lines, such as BHK or murine Baf / 3, that do not express the receptor for a given ligand can be transfected with a plasmid containing a gene encoding the desired receptor. An example of such a cell line is BaF3 transfected with the hG-CSF receptor (BaF3 / hG-CSF). The activity of the multifunctional hematopoietic receptor agonist in these cell lines can be compared with hll-3 or G-CSF alone. or together. The bioactivity of examples of multifunctional hematopoietic receptor agonists of the present invention tested in the TF1 cell proliferation and 20 cell proliferation assays. BaF3 / hG-CSF is shown in Table 5 and Table 6. The bioactivity of the multifunctional hematopoietic receptor agonist is expressed as relative activity compared to a standard protein ρ MON13056 (WO95 / 212.54). The bioactivity of examples of multifunctional hematopoietic receptor agonists of the present invention tested in the BaF3 / c-mpl cell proliferation and TF1 cell proliferation assays is shown in Table 7 and Table 8.

210

Table 5.

Table 5 (continued)

IL-3ZG-CSF Double Receptor Agonist Cell Prolifetary Activity

nd ~ undetermined 'The biativities of multifunctional hematopoietic receptor agonists are expressed as relative activity compared to a standard protein p

MON13056. N - 3 or greater

Table 6

212

Iabela.6 (continued)

Prolifectatile Activity of Doal IL-3 / G-CSF Receptor Agonist Cell

pMON BaF3foGCSF receptor cell proliferation assay relative activity * Cell proliferation ensab TF 1 relative activity 31113 + THE' 31114 The- 31115 ........GRANDFATHER 31116 na rid 31117 na na

nd - not determined * The bioactivity (n ~ 1 or 2) of the multifunctional hematopoietic receptor agonist is expressed as activity compared to a standard protein p M0N13056.

’V‘ indicates that the molecule was comparable to ρ MON13056.

lLâ.bOfe, Z.

Cell Proliferation Activity

213

Table. 7 (continued)

Cell Proliferation Activity ρΜΟΝ ΐ Real cell preconfiguration assay Cept cell effect assay

285Í2: 1- +

214

Table ./...(continued)

Cell Proliferation Activity

'Activity measured in the Baf3 cell line transfected with the c5 mpl receptor, relative to the c-mpl ligand (1-153).

+ activity measured in relation to MON 13056.

In a similar manner, other cell line dependent factors known to those skilled in the art can be used to measure the bioactivity of the desired multifunctional hematopoietic receptor agonists. The methyl cellulose assay can be used to determine the effect of multifunctional hematopoietic receptor agonists on the expansion of hematopoietic progenitor cells and the pattern of different types of hematopoietic colonies in vitro. The methyl cellulose assay can provide an estimate of precursor frequency as long as someone measures the frequency of parents per 100,000 input cells. Stromal-dependent cultures were used to outline primitive hematopoietic progenitors and hsste cells. This assay can be used to determine whether the multifunctional hematopoietic receptor agonists stimulates the expansion of very primitive parents and / or stem cells. In addition, limitation of 20 dilution cultures can be performed which will indicate the frequency of primitive parents stimulated by the multifunctional hematopoietic receptor agonist ·

215

Table 8

28514 i * i +

216

Example 88

G-CSF variants that contain single or multiple amino acid substitutions have been manufactured using mutagenesis techniques of

PCR as described in WO94 / 12639 and WO94 / 12638. These and other variants (that is, amino acid substitutions, insertions or deletions and N-terminus or C-terminal terminations) can also be performed, by someone skilled in the art, using a variety of other processes 10 including synthetic gene assembly or targeted mutagenesis - site (see Taylor et al., Nucí. Acid.Res. 13: 7864-8785 [1985]; Kunkel et al., Proc.

Natl. Acad. Sci., USA, 82: 488-492 (1985); Sambrook et al., Molecular Cioning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory 'Press, Cold Spring Harbor, NY, [1989], (WO94 / 12639) and (WO94 / 12638)). These 15 substitutions can be made by someone at a time or in combination with other substitutions, and / or deletions, and / or insertions and / or extensions of amino acids. After verification following the changes, the DNA

217 plasmid can be transfected into an appropriate mammalian cell, insect cell or bacterial strain such as E. coli for production. Known variants of G-CSF, which are active, include substitutions at positions 1 (Thr to Ser, Arg or or Gly, 2 (Pro to Leu), 3 (Leu to Arg or 5 Ser) and 17 (Cys to Ser) and amino acid deletions 1-11 (Kuga et al ..

Biochemical and Biophysical Research Comm. 159: 103-111 (1989)), These G-CSF amino acid substitution variants can be used as the template for creating G-CSF receptor agonists where a new N-terminus and new C-termini are created. Examples of 10-amino acid substitution variants G-CSF are shown in Table 9.

Example 89

Determination of Bioactivity of GCSF Amino Acid Substitution Variants

G-CSF amino acid substitution variants can be assayed for cell proliferation activity using Baf / 3 cell line transfected with the human G-CSF receptor. The bioactivity of G-CSF amino acid substitution variant samples is shown in Table 9 in relation to native human G-CSF. One indicates activity comparable to native activity and one indicates significantly reduced activity or 20 none measurable.

Table 9

Cell Proliferation Activity of G-CSF Variants in Cell Line

BAF3 Transfected with the Receiver Human G-CSF aa Position Nafevaaa Mutant & a Aimdade 13 Phe To be ....... * 13 Phe His 13 Phe Thr li ·· 13 Phe Pm ..... i: 16 Lys Pro • f 16 Lys To be 4-

218

Table 9 (continued)

Cell Proliferation Activity of G-CSF Variants in Cell Line

BAF3 Transfected with Human G-CSF Receiver aa Native Position aa MUarteaa Activity *

16 Lys Thr 16 Lys His +: 18 Read Pro * 4 18 Read Thr + 18 Read His 4- 18 Read Cys 4 18 Read lie -4 19 Glu Aia 19 Glu Thr 19 Ghu Arg 19 Glu Pro 19 Glu Read - 19 Glu To be 22 Arg Tyr 22 Arg To be • 4 OOid · Allah 4- 22 Atq Thr 4 24 tie Pm 4- 24 lie Read 4 24 Ife Tyr 4 27 Asp GV 4

219

Table 9 (continued)

Cell Proliferation Activity of G-CSF Variants in Cell Line

BAF3 Transfected with Human G-CSF Receptor

aaFdÇâc Native aa Aa mutant Activity ....., ................ ~~~~ ......................—-------------------- .................................................. ..... 30 Allah tie + 30 Allah Read 34 Lys To be + 43 His Gly 43 Hg Thr • f 43 His Val •1· 43 His Lys 43 His Trp • l · 43 His Allah -i- 43 His Ary «+ · His Cys + 43 His Li ^ j + 44 Pro Ay 4 ^a 44 Pm Asp -¼ 44 Pm Val 4 ⁷ 44 Pro Allah 4 · 44 Pro His + 44 Pro Gin 44 Pm Trp + 44 Pro Gly 44 Pro W +

220

Table 9 (continued)

Cell Proliferation Activity of G-CSF Variants in Cell Line

8AF3 Transfected with Human G-CSF Receptor

f ^ OísstíÇíSíO ' Nabva aa Aa mutant Activity 46 Glu Ay 4 ~ 46 Glu Ml 4 47 Read Πτ 4 49 L, OJ · Phe 4 49 Read Arg 4- 49 Read To be + S0 Read His 4τ 54 Read Hís 4 67 Gh Lys 4 * 67 Gh Read -¼ 67 Gin Cys 4 70 Gin Pro 70 Gin Read * 70 Gin Arp 70 Gn To be 104 Asp Gly 104 Asp Go + 108 Read Allah + 108 read Go 108 Read Arg 4 · 108 Read Gly 4 ~

221

Table 9 (continued)

Cell Proliferation Activity of G-CSF Variants in Cell Nail

BAF3 Transfected with Human G-CSF Receiver aa Native Position aa Mutant aa Activity *

108 Read 108 Read 115 Thr · 115 Ibr 115 Thr 144 Phe 144 Phe 144 Phe 144 Phe 144 Phe 146 Arg 147 • : 156 His | 156 His I 156 His I 159 To be I 159 To be 159 To be 159 To be I 159 To be [162 i______________ GU

Trp Gh His + Read Allah 4 · His Ag 4- Pro Read + Glu ..... 4 · Gh 4- ^: L Gin 4 · Asp Asp Gly .4: ........ ! <<: <<<< I Arg 4 · ........ Thr 4 Tyr 4- ........... Go 4 Giy + ..... Gly-

222

Table 9 (continued)

Cell Pro! Iteration Activity of G-CSF Variants in Cell Line

8AF3 Transfected with Human G-CSF Receptor

activity related to native na hG-CSF - not determined

Still without elaboration, it is. It is believed that someone skilled in the art, using the previous description, uses the present invention to its full extent. The following preferred embodiments are, therefore, to be constructed as merely illustrative, and not limited to the rest of the exhibition in any way.

More details regarding molecular biology, protein purification and bioassay techniques can be found in WO94 / 12639, WO94 / 12638, W095 / 20976, WO95 / 21197, WO95 / 20977, WO95 / 21254, incorporated herein by reference in their entirety .

All references, patents or patent applications cited herein are hereby incorporated by reference in their entirety as if written here.

Several other examples will be visible to the person skilled in the art after reading the present description without departing from the spirit and scope of the invention. All such other examples are intended to be included within the scope of the claims

223

Translation of terms, listed in the following sequence listings

Name = Name

General information ™ General information

Applicants ~ Applicant

Street - Street

City ~ city

State ~ State

Country - Country

Postal Coda ~ Postal code

Telephone ~ Telephone

Title of invention ~ Title of invention

Number of sequences ~ Number of sequences

Computer Readabel form ~ computer readable form medium type / floppy disc ~ type of flexible floppy disc

Operating system - operating system

Current Application data ~ Data from the present order prior aplicatlon date ~ data from the previous order filling date - deposit date length ~ length

Type ~ type

Strandedness filament topology ~ topology

Molecule type ~ type of molecule

Feature ~ characteristics amino acids - amino acids unknown - unknown protein == protein name / kay: Modified-site ~ name / key: modified site location ~ location other information: note other information ', note position, is, or - position, é , or

224 bstage of sequences (1) General Information (í) Applicant (A) NAME: G. D. Searle & Co.

(B) Street: P; O. box 5110 (C) City: City (D) State. Illinois (E) Country .: United States of America (F) Postal code (ZIP): 60680 (G) Telephone: (708)470-6501 (H) Fax: (708)470-6501 (ή) Title of the invention: Hematopoietic REcepting Agonists

Multifunctional (iii) Sequence number 258 (iv) Computer readable form (A) Media type: Floppy disk (8) Computer: IBM compatible PC (C) Operating system: PC-DOS / MS-DOS (D) Software: Patentin Release # 1.0 Vers (v) Data of this application:

Order number: US 2910 (A) Order number: US 60 / 004,834 (8) Deposit date: 10/05/1995 (2) Information for SEQ ID NO.1 (i) Characteristics of the sequence (a) length: 174 amino acids (b) Type: amino acid (c) Filament: unknown (d) Topology: unknown (h) type of molecule: Protein (ix) Characteristic:

225 (A? NAME / KEY ·. Modi £ ied-site (B> LOCATION :!

ID; OTHER INFORMATION; / note * 'Kaa at position 1 is Thr. Ser, Arp. Tyr or Gly: *> / y,; _; (1X5 FEATURE:

(A? NAME? KEY; Modified-site (B? LOCATIONS

CD) OTHER INFORMATION ', / note- * Kaa at position 2 is Pro o Leu;

i IX · FEATURE:

{Al NAME / KEY: Modified-site (B? LOCATION-.3

CD) OTHER INFORMATION: / nope® * Xaa at position 3 is Leu. ...... Arg, Tyr-or Ser; ‘

ÜX) FEATURE:

(A) NAME / KEY; Modified-site (Si LOCATION: 13

Φ5 OTHER INFORMATION ·. / Note® Xaa Ser, His, Th ~ or Pro; ’ at position 13 is Phe Ux) FEATURE: {THE; NAME / KEY: Modified-site (St LOCATION: 1δ ID} OTHER INFORMATION: / note * * Xaa at position IS is Lys Pro, Ser, thr or Hxs; * (1x5 FEATURE: (THE) NAME / KEYr Modified-site (35 LOCATIONcl? (05 OTHER INFORMATION: / note® ’Xaa at position 17 is Cys Ser, Gly. Ala, Ils, Tyr or Arg; * (ix) FEATURE; (THE) NAME / KEY: Modified-site (B) LOCATION: 18 (THE OTHER INFORMATION ·. / Note® ^K Xna at position IS is Leu

Thr, Pio, His, Xie or Cys; * iix) FEATURE:

(A) NAME / KEY: Modified-site

ÍB) LOCATION: 22 (O) OTHER INFORMATION: / note® * Xaa at position .22 is Arg, Tyr, Sat, Thr or Ala, - * (ix) FEATURE:

(A) NAME / KEY; Modified-site (E) LOCATION124 (D) OTHER INFORMATION: / note * “Kaa at position 24 is lie, Pro, Tyr or Leu;

iix) FEATURE:

22t (A) MAME / KEY: Modstied-site (SI LOCATION-. 2 “(Di OTHER INFORMATION; / note» 'Xaa at position 2 ^ xs Asp, (ixi FEATURE' (A) NAME / KEY: Modified-site ( B) LOCATION: 30 (D) OTHER INFORMATION: / note- 'Xaa at position 30 is Ala, He, Leu or Gly; ”fix) FEATURE;

(Ai NAME / KEY: Modified-site (Bl LOCATION: 34 (D5 OTHER INFORMATION: / note® 'Xaa at position 34 is Lys ........ c: Ber. · ^A ..... .. ..................

(ix) FEATURE :.

(A? NAKE / KEY: Modifred-site (31 LOCATION: 36 fD) OTHER INFORMATION; / note- ’Xaa at position 3 δ is Cys or Ser;’ (ix) FEATURE:

(Al NAME / KEY: Modxfxed-sxte (B) LOCATION: 42 (EC OTHER INFORMATION: / note® “Xaa at position 42 is Cys or Ser;’ fix) FEATURE:

(A) NAME / KEY: Modified-site (B) LOCATION: 43 (B) OTHER INFORMATION: / note® 'Xaa at position 43 is His, Thru Gly.- Val, Lys, Trp, Ala, Arg, Cys, or Leu; 'fix) FEATURE:

(A) NAME / REY: Mcdified-site (Bl LOCATION: 44 (El OTHEF; INFORMATION; / note® 'Xaa at position 44 is Pre, Gly, Arg, Asp, Val, Ala, His, Trp, Gin, or Thr ; 'fix) FEATURE;

(A) NAME / KEYr Hadified-site (S '; LOCATION: 46 (0) OTHER INFORMATION; / note® “Xaa at position 46 is Glu ,. Arg, Rhe, Arg, He ox Ala;’ fix) FEATURE:

(A) NAME / KEY: Modified-site (B) LOCATION: 47 (DI OTHER INFORMATION: / note® 'Xaa at position 47 is Leu ...... or Thr;' ......... ..... ......

FEATURE;

(A 'ΝΑΜΕ / ΧΕΪ; Mcd „: ied-site

Á. «. • Lt AT / 10L- '4 ~ (OTHER · OTHER INFORMATION; / note®‘ Xaa at position 4 $ is Leu.

Phe. Arg or Ser, · ”

U.x; FEATURE:

ÍAÍ ΝΑΜΕ / ΚΞΥ; Modifleõ ^ site fpj LOCATION: eg

ID; OTHER INFORMATION: / note® Xaa ar, position SO is Leu.

HIS <PXO OX * TVS; *

Hx) :. FEATURE;

(A; NAME / KEY: Modified-site; ’S. LOCATIQN;: S4 .........................

{D; OTHER INFORMATION: / note® ‘Xaa at position S4 is Leu or Has; '· (lx · EEATUREi

LA) NAMEZEEY; Modifiedsite («} LOCATION; ¢ 4

Oj OTHER INFORMATION: / note® 'Xaa at position 64 is Cys or Ser; “(Ixl FEATURE:

(A) NAME / KEY: Mcsdif ied-site (Si LOCATION; e7 (Hi OTHER INFORMATION: / note® Xaa at position £ 7 is Qin. ................. Lys Lsa or Cys; '........ ...... ......

ux; FEATURE:

ÍA) NAME / KEY: Ktadified ~ slte {Bi LOCATION; 7C (D; OTHER INFORMATION: / note® “Xaa at position 70 is Gin, Pro, Leu, Arg or Ser; ^K iix; FEATURE:

ÍAi NAMS / KEY: Modifieo-site (B) LOCATIONs74

ID? OTHER INFORMATION: / note® 'Xaa at positron 74 is Cys or Ser; ” (lx) FEATURE:

LA) NAME / KEY: Modi f ied · ’sit e

IB; LOCATION: 104 (DJ OTHER INFORMATION; / note® “Xaa at position 104 is Asp, Gly or Wlrfix) FEATURE:

tA- ΝΑΜΕ / ΕΕΎ: Modif ·; r »(B; LOCATION: 1.56 (D? QTHEP, INFORMATION: / note® 'Xaa at · position IOS is Let, Ala, Vai. Arg, Trp, Gin or Gly, iix) FEATURE;

225 µA; NAME / 'KEY t Hoci i i - s i £ &

/ κ * ^w t? *> v ^x 1 “\ Art / Λννι <>« ΑΛ Vi <><X> »*

> D> OTHER INFORMATION: / not® = His, I »» u or Ala, '* Kaa at; posttton US xs Thr, i ix> FEATURE; (λ! NAME, 'KEY: Modifxeh-sita CB} LOCATION.! 20 (Hi OTHER INFORMATION: / note® Gly. Arg, Lys or Hi « ^K ’Xaa The: position 120 xs Gin, <X J FEATURE: (A; NAME / KEY: Modified-Sit.® (B- LOCATION; 123 ÍXH OTHER INFORMATION; / note® Arg, Ph® or Thr ‘Xaa at position 123 xs Glu, (ix) FEATURE; (AS NAME / KEY; Modified-site (B? LOCATION: 144 (LU OTHER INFORMATION: / not®® Xaa His, Arg, Pro, Lev ,. Gin or at pcsiricn Glu; ” 144 xs Phe, {ix) FEATURE; (A) NAME / KEY: Modi * i®d-sit® {B} LOCATION; Ϊ46 (5} OTHER IJÍFORMÜiTION: / note « or Gin; * Xaa air position.146 xs 1 trg (ix} FEATURE; W NAME / KEY: Modifled-sit® (B> LOCATION: 147 io: OTHER INFORMATIONx / net® » or Gin; ‘Xaa at position 147 is Arp Í ixl FEATURE: (A) NAME / KEY: Modified-siv® (3! LOCATION; 156 (D) OTHER INFORMATION: / not® » Gly or Ser; ’ Xas at position 156 is His, (XX) FEATURE: (A! NAME / KEY: Modifiec-site (3- LOCATION: 155 iOS OTHER INFORMATION; / note® Arg., Thr, Tyr, Vai cr * Xaa Gly; * at position 15.9 is To be, iix} FEATURE: (A) NAME / KEY: Modified-site (B) LOCATION; 1§2 {D; OTHER INFORMATIONi / note® Xaa at position 162 is Glu.,

Leu, Gly or Trp; ’(1%) FEATURE:

229

ÍA · NAME / KEy. Bcâiíieà-siLe («; LOCATION; 183 {D · CTREE ItfFORMATIO ??; / note® Xaa position 163 is'? Al <®ly, Arg ox: Aza;

2.X; FEATURE: <

ξΑί NAME / KEY: Modif ied-Site

CB> LOCATION: 169 (R? OTHER INFORMATION; / note * "Xaa ax. Position 16? Is Arg. Ser, Leu, · Arg or Cys.- iix: FEATURE;

The; NAME / KEY '. Modified-site> ^f E · LOCATION; 17C (D; OTHER INFORMATION: / nats? - 'Xaa at position 170 is His, Arg az Ser;

{xi; SEQUENCE DESCRIPTION: SEQ ID NO.- 1, -

Xaa Xaa Xaa \> _Λ V Pro 5 Allah To be To be LrHHl Pro 10 Gin To be Xaa Read Read 1 Xaa Xaa Xaa Glu Gin Val Xaa Lys Xaa Gin Gly Xaa Gly Allah Xaa Read Gin 2 0 25 30 Glu Xaa m'GIX Xaa Allah Thr Tyr Lys Read Xaa Xaa .Xaa Glu Xaa Xaa Val .4 ·: $ 40 45 Xaa Xaa 'ί ^Λ ' · '·' ϊ »v wiy Hrs To be Xaa Gly lie Pro Trp Allah Pro Read To be To be Xaa 50 55 60 Pro Se- Xaa Allah Read Xaa Read Allah u I v Xaa To be VíIaÍ ** su His Eer 65 7 0 75 80 Gly Read Phe wow Tyr Gin Gly Read Read Gin Allah Read Glu Gly lie To be §5 90 95 Fra Glu Read Gly Pro Thr Read Xaa Thr Read Gin Xaa Asp Val Allah Asp 100 105 110 Ros Allah Xaa Thr lie Tsrp Gin. Gin Met Glu Xaa Xaa Gly Met Als Pro 115 120 125 Allah Read Gin Pro Thr Gin Gly Allah Met Pro Allah Phe Allah To be Al® Xaa 130 135 140 Gin Xaa Xaa Allah Gly Gly Val Val Allah To be Xaa Read Gin Xaa Phe 145 Á 0 1H5 160 Read Xaa Xaa To be Tyr Arg Val Read Xaa Xa ^ Read Allah Gin Pro 165 170

INFORMATION FOR SEQ ID NG: 2:

30

SEQUENCE CHARACTERISTICS: u: · LENGTH; L33 asuna acids ί>ήξ> ç · p * ¹ * ^ ζΧ ^, Ο í C; · STRAiroLD'iESS; S ipgi fe (Dj TOPOLOGY: 1 infear

MOLECULE TYPE; pretext iix; FEATURE:

f-A- »NAME / KEY; Mcdified-Site (B? LOCATION-.17 {»? OTHER INFORMATION:? ROC« «Xaa at position 17 is Ser.

Lys .. Gly. Asp. Met, Sir *, or Arg; ·

u.X; FEATURE.s

LA) NAME / KEY? Modified-site iB> LOCATION; 18

O; OTHER INFORMATION: ‘Xaa at position 18 is Asn,

His. Read it, Xis. Phe, Arg, or Tin; *! ix. > FEATUREj

ÍA} NAME / KEY: Modified-site (B; LOCATION <0; OTHER INFORMATION: / nciie = ‘Xaa at position 19 tS Met,

Phe, Xie, Arg, Gly. Ala, csr Cys; ’Iix! FEATURE;

(A) NAME / KEYx Modifted-Site {Bi LOCATION; 20

IO; OTHER INFORMATION: / notes * Xaa at position 20 is lie,

Cys, Gin, Glu, Arc, Pro, or Ala; ^,: XX; FEATURE:

IA) ΚΑΜΕ / ΚΕΪ: Modified ifed-SXtfe (B) LOCATION: 21 (E) OTHER INFORMATION: / note- 'Xm at position 21. is Asp, Phe, Lys, Arg, Ala, Gly, Gl «, Gin, Asn , Thr, Ser or iixi FEATURE;

ÍA} KAME / KEY: Modified-site

IBj LOCATION: 22 (D) OTHER INFORMATION; / note- * Xaa at position 22 is Glu, Trp, Pro, Ser. Ala, His. Asp. Asn, Gin, Leu, Val or iix; FEATURE;

(A) NAME / KEY '. Modifxed-site (B) LOCATION: 23 (0) OTHER INFORMATIONx / note® Xas at position 23 is Xia. Val, Ala, Trp, Lys, Phe, lieu, Ser, cr Arg: ‘

23.1 fix FEATURE:

(A? FAMS'.CV. 'Moditieò-Slte (g: LOCATION; 24 {pj OTHER INFORMATION; / note * Xaa an position 24 .ix Il->, Gly, Visi. Arg, Ser, Rhe, Leu;' fix ? FEATURE;

(A · KAME / KEY: Modi * ied-site (Si LOCATION125 (D: OTHER INFORMATION: / note® 'Xaa at positron 25 is Thr, His .. G »y.- Gxr *. Ax, Fuc · .ex Axá .;

! ίχ: FEATURE:

{A} NAME / KEY ·. Modi £ i eõ-site

B? LOCATION: 25

O) OTHER INFORMATION; / note® ^K Xa «« t position 2 € is Mrs .. Thr, Pae _f Gly, Arg, Ala, Try;

Ux> FEATURE;

(A; NAME / KEY- Modified-site • B: LOCATION: 27 ru; OTHER INFORMATION: / note * “Xaa at position 2” xs Leu, Gly, Arg. Thr, Ser, or Ala; ’iix; FEATURE:

(A; NAME / KEY: Modified-site (B: LOCATION: 28

IO; OTHER INFORMATION; / note * 'Maa at position 28 is Lys. Arg .. Leu, Gin, Gly, Tro, Vai or Trp; * iix.i FEATURE;

(A; NAME / KEY; Modified-Site (St LOCATION: 28

ÍD) OTHER INFORMATION: / note * “Maa at position 25 is Gin, Asn, Leu, Fro, Arg, or Vai;’ iix) FEATURE:

(A> NAME / KEY: Modified-site (B> LOCATION: 3C <D) OTHER INFORMATION; / note * ”Xaa at position 3B is Bro, His, Thr, Gly, Asp, Gin, Ser, Leu, or L, .. “iix J FEATURE.:.

(A) NAME / KEY: Modi * ied-site>: E; LOCATION;:?!

(OJ OTHER INFORMATION: / note * “Maa at position 31 xs Pro, Asp, Gly, Ala, Arg, Leu, or Gin;’ (ix> FEATURE;

(A; ΝΑΜΕ / ΚΕΎ: Modified-site (Bi LOCATION; 32 (0} OTHER INFORMATION: / note® ’Xaa at position 32 is Leu.

Go, Arg, Gin, Ast, Gly? Ala, cr Gh :; “

232

IX: FEATURE:

(A; NAME / KEY: Hodi :: ied-site

S: 7 _; OCATION:? 3

-0 · OTHFR .INFORMATION; / nocg = ^k Xsa at position 33 is Pro.

Leu, Gin, Ala, Thr, ox Siu; *: txi FEATURE ·: ··· ...... ......

(A · NAME / KEY: Nodlfieã ~ «xce? Ε · LQCATIC> N; 34 (Di OTHER INFORMATION: / note®« Xaa at position 34 is Leu,

Val, Gly, Fri. Lys, Glu, Gin, Tax, Arg .. Ala. Pbe, He iist} FEATURE ·.

(A- NAME / KEY: Modified-site

ÍS) ...... LOCATION s 3 5 {£} OTHER INFORMATION: / note- «Xaa at position 35 is Leu, ....... Ala., ... dy ·:,. .Asn, Pre, Gin, crVal;

(χ, χ; FEATURE;

i. A) NAME / KEY .- Modi f i ed ~ s i to {Si LOCATION-.36 iO) OTHER INFORMATION: / note® Xaa at position 3 £ xs Asp.

Read, or Val: «iix: FEATURE:

(A) N / iME / KEi '. Moâirieâ-sxte (Bl LOCATION: 37 (H OTHER INFORMATION: / note »« Xaa at position 37 is Rhe, Ser, Pro, Trp, or Ils; * iix) FEATURE:

{Aj NAME / KEY: Modified'-sit® (B) LEGATION: 38 to) OTHER INFORMATION; / note- «Xaa ar position 38 is Asm, or Ala;

(ix: FEATURE:

(A- NAME / KEY: Modified-site

ÍB; LOCATION: 40 (Di OTHER INFORMATION; / note »« Xaa at position 40 is Leu, Trp, or Arg; iix} FEATURE:

ÍA) NAME / KEY: Modified-site {R) LOCATION: 41 (D.) OTHER INFORMATION: / note® Xaa at position 41 is Asn Cys, Arg, Leu, His, Mat, or pro; · {XX) FEATURE:

IA; NAME / KEY: Modified-site (B) LOCATION; 42 ip} OTHER INFORMATION: / note »’ Xaa at position 42 is Gly,

233

Asr:. to be. ..ys. Asn, Cys, Thr, Leu. Go., Giu. Fhe, Tyr. Cie, Met

....... ..... cr Ala, r: FEATURE:

<A; ΠΑΚΕ / ΚΕΥ: Modified-site

ÍHJ LOCATION: 42 íDi OTHER IRFGRHATIUN: / nste = ‘Xaa ar position 43 is Glu, Asn. Tyr. Read it, Phe. Asp. Ala, Uys. Gin, Arg, Thr. Gly, or Ser V 'irx; FEATURE:

LAí NAMEZKSY: Modified-sire

TB) U5CATX © Mi44 ·: D; OTHER INFORMATION: ./nona » ^x Xaa ar. position 44 is Asp.

Ser, Leu, Arg, Lys, Thr, Het, Try, Glu. Asn, Gin, Ala er Pro;

ίίκ; FEATURE ·· íA? NAMEXKEX ·. Modified-site

JB; LOCATION: 4§

P; OTHER INFORMATION: / note »’ Xaa ar position 4S is Gin, Pre ·, Phe, Vai, Her. Leu, Thr, Lys, Trp, Asp, Asn. Arg, Sas, Ala,

Xie, Glu or Hisr “

Ux) FEATURE:

(A) NAME / KEY: Modified-site (B? LOCATION: 4S (0} OTHER INFORMATION: / note · »* Xaa st position 46 is Asp.

Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys, His. Ala, Tyr, iAA;; ísVhU: i or Gly; ^Λ (rxj FEATURE :.

ÍÀ} KAME / KEY: Hodified-site {Bl LDCATT0H: 4S

ID) OTHER 1NF0RMATXCR: / note ”Xaa at position 4? is XIsj,

Gly, Val, Ser, Arg, Fro, or His; 'ilxl FEAOjRR ·.

{Al NAME / REYt ModifXsd-site i'B) L0CATX0H: 4S (TH QTKEP, TEFC'RMATXOH -. / Note ^ Maa at position 46 is Lau,

Ser, Cys, Arg, Xie, His, Rhe. Glu, Lys, Thr, Ala. Met Vai or

As n:

tix} FEATURE:

| A) Ϊ4ΆΜΕ / ΚΕΪ ·. Modified-site (Bi LOCATION: 45

S'U; OTHER INFORMATION: / note »Xaa. at position 4S is Met.

Arg, Ala, Gly, Fro, Asn, His, or Asp;

•, ι X FEATCHE ίλ. ’CAÍEE -xCEi; ModlfÍed ~ £ itS; s. · LECA ’- 'XON: 5Π (ΐ>; OTHÃR I / íFORMATION; / note» “Xaa at pomiGX SC i * Glu,

Leu, Thi, Asp, Tyr, Ly *. Asr ;, Ser. Ala, IàS. Come on, Hxs, Phe. Met cr G, l.n; ~ il.xj FEATURE:

(A.J NAME / KEY: Modifisd-site i'B) LOCATIONí51 (D; OTHER INFORMATION; Znôte »* Xa & at position 51 is Asn.

Arg. Met. Pro. · Set, Thr., Cr his;

iix> ~ ΕΛΤΟΡ “'(A? NAME / KEY; Modòfied-sire (BJ LOCATION-.52 (Xh OTHER INFORMATION; / note» * Xaa at. position 51 is Asn,

Hiâ <Arg. Read .. Gly, Ser, or Thr; · (xvt 'ff'ti' ft urtttrjtí '»$ * v <V>' a- VÍ \ w» v (A? NAME / KEY; Modified-site {B # LOCATION; S3 (hi OTHER INFORMATION; / note® 'Xaa at position 53 5 $ Leu,

Thr, Ala, Gly, Giu, Pro, Lys, Ser, or 'N ... ”i; x; FEATURE:

(A) NAME / KEY: Mndified-site

ÍR} LOCATION; 54 {£ ·} OTHER INFORMATION: / note »Xaa at position 54 is Arg, Asp, Ila, Ser, Val, Thr, Gin, Asn, Lys, His, Ala or Leu; * '

41 *} FEATURE; ..........................

(A) NAMEZ KEY; Modi f ied-site (Bl LOCATION: 55 (Ο) OTHER INFORMATION; / nene »’ Xaa at position 55 is Arg,

Thr, Val, Ser, Leu, or Gly; “iixl FEATURE;

{THE? NAME./KEY; Modi * ieo-site

ÍS) LOCATION: 56! D) OTHER INFORMATION-./note »'Xaa at position 56 is Pro, Gly, Cys, Ser, Qin, Giu, Arg, His, Thr, Ala, Tyr, Phe, Leu, ... ..Val ............ ...... ....................

or Lys- ϋκ} FEATURE;

(AS NAME / KEY: Modified-site (B) LOCATION: 57 {0! OTHER. INFORMATION; / note · ’Xas at position 57 is Asn

........: ervGiy.r “· ..............

iixJ FEATURE;

235

i '~>; OTHER INFORMATION / πο £ β «'Xaa 8i pcs it. * On 52 is Leu. Ser. Asp, Arg, die, Va_, or uy.í; _:

Usage FEATURE ·:

{A} NAME / KEY; Modiiied ~ site <S * LOCATION: 5 P

CD; OTHER INFORMATION; / note »Xaa at posit! ar» 5§ xs Glu. Tyr. Hrs .. Leu, Pre ·, er Arg; * u :: FEATURE:

ί’Α; ΝΑΜΕ / ΚΞΎ: Modified-sxte (: B: ·; LOCATION: 6 £ · 'D <OTHER INFORMATIONi / note® ”Xaa ar position SO is Ala, Ser, Pro. Tyr, Asn, or Thr;’

FEATURE;

iA; NAME / KEY: Modified-site (BJ LOCATION: 61 (□) OTHER INFORMATION: / note® ’Xaa at position 51 is Phe,

Asn, Glu, Pro, Lys, Arg, or Ser; * {XX · FEATURE:

(A · NAME / KEY: Modified-sxte {B; LOCATION; 52 (D) OTHER INFORMATION: / note® 'Xaa at positron 52 is Asn, His, Vai, Arg, Pro, Thr, Asp, or He; * r XX i FEATURE: · (A) NAME / KEY; Modifled-site (E> LOCATION: 63

CD? OTHER INFORMATION: / note® ’Xaa at position 53 is Arg, Tyr, Trp, Lys, Ser ,. His, Pro, or Vai; * iXX; FEATURE:

{A} NAME / KEY; Modifiad-site

CBS LOCATION: 64 (Dj OTHER INFORMATION; / note »· *‘. Xa & at position E4 is Ala, Asn, Pro, Ser, or Lys; *: ix; FEATURE:

(A? ΝΑΜΕ / ΕΕΎ: Modified-site

LOCATION: 65

ID) OTHER INFORMATION: / note- ’Xaa at position 65 is Vai, Thr, Pro, His, Leu, Phe, or Ser;’

Cix? FEATURE:

fA) NAME / KEY: Modxf ied-site

Yeah? LOCATION: 56 (D) OTHER INFORMATION: / note® Xaa at position 65 is Lys, Tie, Arg, Vai, Asn, Glu, or Ser;

XX! FEATURE:

23δ (Α; NAME / KEY; Modifxed-site í 31 LOC AT CON:. · 67 (0} OTHER INFORMATION: / uote® Xaa at postion 6? Is Ser.

Ala, Pna, Val, Gly. Asn. XXe, Pro, cr His;

írx; FEATURE;

(There NAME / REY: Moõlfied-site (Si LOCATION: 68 was OTHER INFORMATION: / note * Maa ac position 68: s Read,

Val. Trp, Ser, Ile, Phe, Thr, cr His; * ílx} FEATURE ·. · (A) NAME / KEY: Modiiieü-Site (B; LOCATION: 69 {O- OTHER INFORMATION: / note® 'Xaa ar position 6 $ is Gin, Ala, Pro, Thr, Glu, Arg, Trp. Gly, or L. » ¹ ·

Í.1MÍ FEATURE * (A; NAME / KEY: Modxfied-sita (Bi LOCATION; 70 (0; OTHER INFORMATION: / note * ’Maa at position 70 is Asn,

Leu, Val, Trp, pro, or Aia; “iix} FEATURE:

(A) NAME / KEY: Modiflad-site (B) LOCATION:?!

(D} OTHER INFORMATION: / note * Xaa at position. 71 is Ala. Mat, Leu, Pro, Arg, Glu, Thr, Gin, Ττρ, or Asn; ^H (ix) FEATURE:

(AS NAME / KEY: Modiflad-site (B} LOCATION: 71

Sb} OTHER. INFORMATION: / note * ^B Xaa at position 72 is Ser, Glu, Met, Ala, His, Asn. Arg, or Asp; * (XX? FEATURE: (THE) NAME / KEY: Modified-site {AND} LOCATION: 73 (D) OTHER INFORMATION: / note® ‘Maa at position 73 is Ala,

Glu, Asp, Leu, Ser, Gly, Thr, or Arg;

(XXJ FEATURE:

! A} NAME / KEY: Modilied-site (B) LOCATION:? ^ (O) OTHER INFORMATION: / note- '& »at position 74 is Tie, Mat, Thr, Pro, Arg, Gly, Ala;' (ix ? FEATURE:

(A} NAME / KEY; Modifiec-site

ÍB) LOCATION: 75 (0} OTHER INFORMATION: / note * 'Maa at position 75 is Glu, Lys, Gly, Asp, Pro, Trp, Arg, Ser, Gin. Or Leu;

(XX) FEATURE:

237

Αί NAME / LET: Hadi fifâà-Slta {THE OTHER INFQEMAIION - / note® Xsa at peal: io> £ · is Yer,

Go, Ala, Asr ,, Trp, Glu, Pio. GJ? - '. or A., ': {ix; FEATURE i íA.j NAME / KEY; Modi fled-site {«} LOCATION: 77 to OTHER INFORMATION; / note- ‘Xaa at positicr. ~~ is He. .......To be. Arg. Thr, or .Leu ,; ’t'ixl FEATURE;

here; nami / KEY-. Modified-site (E) location.-7 &

(to OTHER INFORMATION: / note® 'Xaa at position 78 is Leu,

Ala, Ear, Glu, Phe. Gly, or Arg? ’

X; FEATURE:

(A; KAME / KEY '-. Modii.ied-site iE; LOCATION.-75 (to OTHER INFORMATION: / note * * Xa & at. Position ~ 5 us Lys, Thr, Asn, Met, Arg, He, Gly, or Asp; iix) FEATURE;

(A: NAME / KEY: Modifred-site (E) LOCATION; 80 (to OTHER INFORMATION-. / Note * ‘Xaa position at 80 is Asn,

Trp, Val, Gly, Thr. Read it, Glu. or Arg; "Iix) FEATURE;

(A) NAME / KEY; Modifled-site (E) LOCATION: 81

CO) OTHER INFORMATION-./note®· ‘Xaa at. position 31 xs Leu, Gin, Gly, Ala, Trp. Arg, Val, or Lys; * (ix) FEATURE:

(A) HAME / KEY; Moditred-stte (B'i LOCATION; 82 (0) OTHER INFORMATION: / note * * Xaa at position 82 is Leu, Gin, Lys, Trp, Arg, Asp., Glu, Asn, His, Thr, Ser, Ala, Phe, ......

Ila, Met or val;

• ix) FEATURE:

{A) KAME / KEY; Modiiied-site (B) LOCATION; 83

50) OTHER INFORMATION: / note® * Xaa at position 83 is Pro, Ala. Thr, Trp, Arg, or Met;

(ix) FEATURE;

(A) NAME / KEY; Modified-site

ÍB} LOCATION: 84 (L; OTHar. UNrORMATXON: / note * * Xa & at position 84 is Cys. Glu. Gly, Arg, Met, or Val; *

238 {AisAI-Ol 'KRY ·, Mcdixred-sxte

ÍS: .'X.CATTMLSB (D) OTHER INFORMATION: / note »« Xaa at position 85 is Let

Asn .. val .. or Gin; “(Ix:> FEATURE:

iA.j NAME / KEY: Modified-sits

IB? LOCATION; 88 (O. · OTHER INFORMATION: / note * 'Xas at positron 88 is PreCys ,. Arg ,. Ala <or Lys. · * \ .Y' ç * · »*» x * {Λ} NAME / KEYx Modiried ~ sxte

ÍB? LOCATION: 87 (D? OTHER INFORMATION-./note »* Xaa at position 87 is Leu. Ser, Trp, or Gly;

iix; FEATURE;

ai NAME / KEY; Modi £ i fed-s it®

IS) LOCATION: $ 8

:Ί: OTHER INFORMATION: / note® 'Xaa as. position SB is Ala. Lys ,, Arg, Val, or Trp; *: (XX) FEATURE t (A- NAME / KEY: Modified ~ site (El LOCATION: B§ (Di OTHER INFORMATION .- / note »“ Xaa at position SS j, _s Asp, Cys, Leu. Val, Glu, His, Asn, or (ix j FEATURE:

íà) NAME / KEY; Modified-site (B) LOCATION; $ G

(ID) OTHER INFORMATION: / note »Xaa at positron 90 is Ala. Rro, Ser, Thr. Gly, Asp, lie, or, Met;

Crx) FEATURE;

(A? NAME / KEY; Modified-sits

ÍS) LOCATION: 91 {D; OTHER INFORMATION: / not®ss Xae at position 91 is Ala, Pro. $ Er <Thr, Phe, Leu, Asp, or His; ·

IIX) FEATURE:

ia) NAME / KEY: Modi; * ied-sxte (8} LOCATION; 91 (OJ OTHER INFORMATION; / note® Asa at position 92 is Pro, Rhe, Arg, Sex, Lys, Hrs. Ala, Gly, lie or Leu ;

(ix) FEAIWE:

(A · NAMEZKEY: Modified-site (8; LOCATION; 9 3 (O) OTHER INFORMATIONX / note® * 2 £ aa at position 93 is Thr, Asp, Se ~, Asn, Fro, Ala, Leu, or Arg; ' '

FEATURE ::

(A; NAME .- 'KEY: Modifled-site

ÍSÍ LOCATIOK: 94 (D · OTHER INFORMATION: / note * Xaa at position 84 is Arg, lie, Ser. Gm. Ijeu, Vai, Um, Lys, His, Aia. Or Pro;

lx.) FEATURE:

(A; NAME / KEY: Modified-sitfi <E} LOCATION: 85 (0: OTHER INFORMATION; / note »* Xaa at position 85 is His,

Gin. Pre, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser.

Ph.e. .... ........ ......

Xie, or Tyr; '·

Xx.; FEATURE:

ia) NAMEZKEY: Modiiied-site {B? LOCATION: 86

D) OTHER INFORMATION: / note »* χ <_& at position 96 is Pro, Lys, Tyr, Sly, He, or Thr; * (mi FEATURE:

(THE). NAME / KEY: Modified-site (B; LOCATION: 87 (!> .; OTHER INFORMATION: / note * “X & a at position 97 is lie.

Val, Lys, Ala, or Asn; ':' Ix; FEATURE:

{A- KAME / KEY: Modified-sits

ÍB) LOCATION: 9δ

S'Oi OTHER INFORMATION: / note * Xaa at position 9E _iS Hi _s , Xie, Asn, Leu, Asp, Ala, - Thr, Glu. Sxa, Ser, Pho, Met, Lys,

Arg, Tyr ,: or Pro;

f 1 v y \ / 1 JL Milii w (A) NÂMEZKEY: Modified-site (25 LOCATION: 88

(OO) OTHER INFORMATION: / note * 'Xaa at position 88 is n _e .

w * &. Arg, Asp> Vai> Pro, Gin., Gly, Ser, Ph®, or His:

(ix: · FEATURE:

{Aj NAME / KEY: Modified-site

ÍB) LOCATION; IDO (D; OTHER INFORMATION: / note »Kaa at position 100 is Lys.

Tyr, Leu, His, Arg .. Ils, Ser, Gin, or.,.

<ix; FEATURE:

(A; NAME / REY; Modified-site (B; LOCATION: 101 {P; OTHER INFORMATION; / note® Maa at position Is Asp, Pro, Met, Lys, His, Thr, Vai. Tyr, Gl _u , Asn, Ear, Ala, Gly.

Leu, or Gm; “

240 (Α; NAííE / KEY: - «odxfied-site

Í.8: LOCATION: 102 (ΣΗ OTHER INFORMATION: / note® ’Xaa at position 1CC zs Gly,

Read, Gin, Lys. Ser, Tyr, nr? Ro; ‘

Í, 1.x i .FEATURE:

(A λ NAME / KEY: Modified-site {£; LOCATION: 103 m OTHER INFORMATION; / note »'Xaa at. Position 103 xs Asp, ............. or Ser; ·· .

FEATURE:

4A; NAME / KEY: Modified ~ S3.ce (S; LOCATION: 104 (D) OTHER INFORMATION; / note® «Xaa at position 104 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Les, Gin. Lys. Ala, Phe, ly>

iXX; FEATURE:

ÍA · NAME / KEY; Modifled-sxt® (B) LOCATION: 10S (D) OTHER INFORMATION: / note® 'Xaa at position 105 is Asn, Pro, Ala, Phe, Ser, Trp, Gin, Tyr, Leu, Lys, He, Asp, fix ) FEATURE:

fA; NAME / KEY; Moditied-site (B) LOCATION: 106 (E? OTHER. INFORMATION; / note® ’Xaa at position IOS is Glu.

Ser, Ala. Lys, Thr, He, · Gly, or Pro; ’fix? FEATURE;

ÍA) NAME / KEY; Modified-site (B) LOCATION: 108 iOi OTHER INFORMATION: / note * * Xaa at position 108 is Arg, Lys, Asp, Leu, Thr, He, Gin, His, Ser, Ala or Pro; ” ixx; FEATURE:

(A; NAME / KEY; Modified-site (3 5 LOCATION; 102 (D) OTHER; INFORMATION: / note® 'Xaa at position 100 is Arg, Thr, Pro. Glu, Tyr. Leu, Ser., Or Gly;

fix? FEATURE;

(A} NAME / KEY; Modified-site (B; LOCATION; 110 (D) OTHER INFORMATION; / note® · ^K Xaa at positisn 11C is Lys, Ala, Asn, Thr, Lap, Arg, Gin, His, Glu, Ser, or Trp; '' fix) FEATURE:

(A) MAME / KEF; Modified-sits

IB} LOCATION; 111

241 (1-- OTHER irJFORMATIGN; / note »Aaa st position 111 ts Leu, lie, Arg. Asp. Or Met:; · ./ix} FEATURE.! Α · NAME / KEY; Modifled-site {B> LOCATION ' .112

OTHER INFORMATION: / nota® 'Xaa at position 112 is Th-, Val, Qin, Tyr, Glu, His ,. Ser ,, or Phe: '

1.x j FEATURE t (A; NAME / KEY; Modified-site

LOCATION CBs; 113

50i OTHER INFORMATION: / note- * Xaa at position 113 is Phe, Ser, Cys ;. His. Gly, Trp. Tyr, Asp, Lys. Leu, lie Va ΟΪ As ».- i, lx! FEATURE;

i A · NAME / KEY -. Modi f tec - si te i 'E): LOCATION ill 4 (Di OTHER INFORMATION; / note »Xaa _at position 114 is Tyr, Cys, His, Ser, Trp, Arg. Or Leu, * (lx; FEATURE;

(A? NAME / KEY: Modifieô-sits

IS; LOCATION; 115 mi OTHER INFORMATION: / dote® * x _aa at position 115 is Leu, Asn, Val. Pro, Arg, Ala, His, Thr, Trp, or Met;

íi-χϊ FEATURE:

A'i NAME / KEY: Modi £ ied-site (B) LOCATION: 115

E5 OTHER INFORMATION: / note® ^x Xaa at position 118 is Lys. Leu, Pro, Thr, Met, Asp, Val, Git, Art, Trp, Set-As His. Allah,

Tyr, Phe, Gin, or Ils: 'itxj FEATURE;

{AJ NAME / KEY: Modified-srte

ÍB) · LOCATION-.117 vD} OTHER INFORMATION: / note it® at position 117 is Thr, Ser, Asn, He, Trp, Lys, or Pro; * {ÍM :: FEATURE:

ΪΑ) NAME / KEY; Modi died — site (Bl LOCATION: .118

ID) - OTHER INFORMATION: / note® 'Xaa at positron 118 i $ Leu. Ser, PmAla, Glu, Cys, Asp, csr Tyr; ’Iixl FEATURE:

(A) NAME / KEY: Modifred-site (B) LOCATION: 119 (E; OTHER INFORMATION: / note »" Xaa at position 119 rs Ql _u , Fri, Lys, Pro, leu. Thr, Tyr., Or Arq; "

242 tux: FEATURE, η • A. mHE / KEY. Mt di :: xed-sx r® {£: L0CAT2ON; 12 <

(D; OTHER INFORMATION; / note * ‘Xae ar. Pcsxtxon 120 is Ast, Ala, Pre, Leu, His, Vai, or Gin; *: xx: FEATURE :;

UV NAME / KEY ·. Modified-site

Yeah.? LOCATION: 121! D: OTHER INFORMATION; / note® Xaa at position 121 is Ala. Ser, lie. Asm. Pro, Lys, Asp, or Gly; “{XX · FEATURE ·.

(A) NAME / KEY; Modified-site

ÍH; LOCATION-122 (0; OTHER INFORMATION: / note® ‘Xas at positron 122 Gin, Ser, Met, Trp, Arg, Phe, Pro, Hrs. Ils. Tyr, or Cys;

(dm FEATURE;

(As NAME / KEY: Modified-sita (E; LOCATION; 123 (*> j OTHER INFORMATION; / note® Xaa at position 123 is Ala, Met, Glu, Hrs, Ser, Fro, Tyr, or Leu:

ixi} SEQUENCE DESCRIPTION; SEQ IP NO; 2:

Allah ...... Pro Met Thr Gin 5 Thr: Tnr To be Read Lys 10 Thr To be Trp Go Asn Cys Xaa Xaa Xaa Xaa .22 Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xsa 30 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asn Xaa 40 : laa Xaa Xaa Xaa Xaa 4 5 Xaa Xaa Xaa Xaa Xaa 50 Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa so Xaa Xaa Xa® Xaa Xaa S3 Xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa 75 Xaa Xaa Xaa Xaa Xaa 60 Xs a Xaa Xaa Xaa Xaa 65 Xaa Xaa Xaa Xaa Xaa 90 Xaa Xaa Xaa Xaa Xaa 95 Xaa Xaa Xaa Xaa Xaa 100 Xaa Xaa Xaa Xaa Xaa 105 Xaa Ph® Xaa Xaa Xaa 110 Xaa Xaa Xaa Xaa Xaa 115 Xaa Xaa Xaa Xaa X&H Xaa Xaa Xaa Glu Cln 0: 5 Thr Thr Lt & u

Ser Leu Ala lie Phe

130

243 {1: SEQUENCE CHARACTERISTICS;

(A? LENGTH; 332 asinc acids (B; TYPE: ajrd.no acid (C; GTRANGEDNESI: unkfiOWn

Γδ! TOPOLOGY; unknown ill) MOLECULE TYPE; protein {XX; FEATUREr (A) NAME / KEY; Modirlad-site (B> LOCATION: 1X2

ID) OTHER INFORMATION; / note- “position 122 is deleted or Leu, Ala, Vai, lie. Pro, Phe, Trp, cr M ... * iix; · FEATURE;

i'Ai NAME / KEY: Modi fled-site fS) LOCATION: 113

ID; OTHER INFORMATION; / note * “position 113 1.5 deleted or Pro.F‘Oe, Ala, Leu. He, Trp, or Met “six) FEATURE:

(A) NAME / KEY: Modifiedsite <) E) LOCATION; 114 (D; OTHER INFORMATION: / note® “position 114 is deleted or Fro, Phe, Ala, Vai, Leu, He, Trp or Met” (ix) FEATURE :

(A) NAME / KEY; Modified-site (B? LOCATION: 115

ÍU · OTHER INFORMATION; / note® 'position 115 is delated or Gin, Gly, Sex, Thr, Tyr or Asn ixii SEQUENCE DESCRIPTION · SEQ IL NO: 3:

To be Fro Allah Pro Pro 5 .Allah Cys Asp Read Arg 10 Go Read To be Lys "I 15 Read Arg Asp To be His Go Le ^ His To be Arg Read To be Gin Cys Pro Glu Go 20 2S ’ y 0 His Pro Read Pro Thr Pro Go Read Read Pro Allah Go Asp Phe To be Read 3S 40 45 Gly Glu Lys Thr Gin Met Glu du Thr Lys Allah Gin Asp lie Read ONLY 60 Gly Allah Go Thr Read Lox Read Glu Gly Go Met Allah Allah Arg Sly Qin 65 ”0 75 80 Read Gly Pro Thr Oyx Read To be To be Read Read Gly G_n Read To be Gly Gin

Shah?

Xaa

Xaa

To be

Read

To be

Arg

To be

Read ex

Read

Read

244

Xaa

Alva.

Mis ueu pha

Her

Arg

Thr

Lek.

Pne

18C

To be

Allah

IPG

Thr ueu

Tire

G ^ .n

To be

Le

215

Asp

For $ ^ me

At

Read

Gl>

235 «me

Pne

Gly

Arg

245

Asp

To be

Gly

To be

Asp

Gly

Read

As.n

Pro

To be

Pro

His

Pro

28C

255

Glr

Read

Phe

If uu

Pro

290

Read

Pro

Pro

-2S5

Go

His

Pro

Lex

Pro

Pro

To be

Pro

Thr

310

Th:

Pro

Read

Read

Asn

To be

Thr Hie

Asn

Read

To be

ORMATIOK FOR SEQ ID JJO: 4:

{THE)

SEQUENCE CHARACTERISTICS;

LENGTH: 1 amino acids TYPE: amino acid STRANDESNESS: single TOPOLOGY: linear ih)

MOLECULE TYPE; pictftir.

ί à.x FEATURE. ·.

ÍÀ '· NAME / KEY; Protein.

{Si LOCATION :!

ID) OTHER. INFORMATION: / note »“ where x «(giyglyglyser; n and where · n. Is as mt.eger * ixx; SEQUENCE DESCRIPTION ·. SEQ 10 NO: 4-.

Xaa

1) INFORMATION FOB SEC · ID NO: 5-.

SEQUENCE CHARACTERISTICS t i x s & uro adda (SO TYPE: ajaino acid (Cj 5TRANDESNESS; single (D? TOPOLOGY .- linear

MOLECULE TYPE: protein iixj FEATURE:

(A; NAME / KEY: Peptise {«· LOCATION: 1 (D; OTHER INFORMATION: / note®“ where (glyglyglyglyser jn and where n is an integer '· ixi- SEQUENCE DESCRIPTION · ·; SEQ ID ND: 5:

• Xea {2} INFORMATION FOR SEQ ID NO: 6:

(ii SEQUENCE CHARACTERISTICS:

{A} LAW ^ CTH: 1 SMino acids {&;TYPE; aru.no acid iCi- STRANDEDNESS: single {D> TOPOLOGY: linear iii) MOLECULE TYPE: protein (ixj FEATURE:

(A) NAME / KEY; Protein; B) LOCATION: 3.

<01 OTHER INFORMATION: / note® “where k * igiyglygiyglyg_yser) n aná where n js an integer xi j Si:! T‘3; CS DESCRIPTION; SEQ ID NG:

Xaa ...... ......

(2) INFORMATION FOR EEQ ID NO: 7:

i; SEQUENCE CHARACTERISTICS:

THE; LENGTH: i ajsino acids

ÍB? TYPE: amino acid (C) STRANDEDNESS; single (D; TOPOLOGY; linear: ii> MOLECULE TYPE: protein [ix.i FEATURE;

(A? NAME / KEY; Protein (B) LOCATION: 1 (Dj OTHER INFORMATION: / note® ’'where x ~ (gly n serin end where n is an integer * ixi) SEQUENCE DESCRIPTION: EEQ ID NO: 7:

Xaa

INFORMATION PGR EEQ ID NO: 8:

ii) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 1 amino acids (B) TYPE- amino acid (C) STRANDEDNEES: single (D; TOPOLOGY: linear (ii) MOLECULE TYPE: protein ix; FEATURE:

DA) NAME / KEY; Protein (B) LOCATION ;!

{D.Í OTHER INFORMATION: / note «“ where x® (alaglyser} n and where n is an integer (% i) SEQUENCE DESCRIPTION: SEQ ID NO; 6;

Xaa

247

INFORMATION FOR SEQ · II · ND- 9 ·.

rl SEQUENCE CHARACTERISTICS · (A> LENGTH; 3 5 amino acids (B · TYPE: amino acid {C · STRAKDEDNESS: single (Di topology. · linear i 11! MOLECULE TYPE: protein (XI; SEQUENCE DESCRIPTION: SEQ ID NO: 9 ;

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Glu Gly Glv Ser

I ^: s 10 15 *

Glu Gly Gly Gly Ser Giu Gly Gly Gly Ser Glu Gly Gly Gly Gly Bar Giy

25 3 0

Gly Gly Bar ill INFORMATION FOR SEQ ID NO: 10:

: i) SEQUENCE CHARACTERISTICS:

(A; LENGTH ;. 24 extent acids (Bi TYPE; aainc acid? E> STRANDEDNESS: single {D? TOPOLOGY: lineaxr ill! MOLECULE TYPE; protein (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10;

lie Ser Glu Pre Ser Gly Pre lie Ser Thr lie Asn Pre Ser Pro Thr .. * - 10 15

Ser Lys Glu Ser Hrs Lys Ser Pre (2) INFORMATION FOR SEQ ID NO: 11;

(1; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 28 amino acids (B) TYPE; amino acid (C) STRANDEZSSESS: single

ID; TOPOLOGY, · linear

ÍÜ; MOLECULE TYPE; protein

Xi · SEQUEKCE DE5CF; * PTXDK-. SEO ID tlG: 11;

lie Glu Gly Ara lie Ser Glu Pro Ser Gly Pre- lie Ser Thr He Asr

Pre- Ser I ^ ro Pro Ser Lys Glu Ser Els Lys Ser Pro 7C os

INFORMATION FOR SEQ ID NO: 12:

ú; SEQUENCE CHARACTERISTICS;

IA; LENGTH; 4 «mino acids

IS; TYPE; asaino acid (C; STRANDEDNESS .; sxngle (0! TOPOLOGY; linear

MOLECULE TEPE: protein izl; SEQUENCE DESCRIPTION: SEQ IE NO: 12;

Giy G.iy Gly Ser

INFORMATION FUR SEQ ID NO: 13:

iij SEQUENCE CHARACTERISTICS:

(A) LENGTH: 45 base pairs (B; TYPE: nucleic acid

IC; STRANDEmESS: single.

iDj TOPOLOGY: linear (it} MOLECULE TEPE; other nucleic acid (A) DESCRIPTION; / desc = * DNA {synthetic) ^K (xi j SEQUENCE DESCRIPTION: SEQ ID NO: 13 -,

GTCCATGG CNTCNCCNGC NCCNCCTGCT TGTGCACTCC GAGTC (2; INFORMATION FOR SEQ ID NO: 14;

ii; SEQUENCE CHARACTERISTICS;

(Ai LENGTH: 30 base pairs

58) TYPE: nucleic acid

249 i C Ç ETRATJDEDNES E. si ng 1 a; D: TC-PCLOGY · linear 'ii; MOLECULE TYPE; other nucleic acid (A) DESCRIPTION-. / desc = DMA (synchetxc! ’

SEQUENCE DESCRIPTION; SEQ ID NG: 14;

ATGCAOGAAT TCCCTGACGC AGAGGGTGGA

0 (3) INFORMATION FOR .SEQ ID NO: 15;

(:) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 33 .base pairs j3; TYPE: nucleic acid •: o STRANDEDNESS ', single (D Í TOPOLOGY; 1ineax <ii · MOLECULE TYPE; other nucleic acid (Al DESCRIPTION; / ôésc «' DNA (synthetic) * (Ml} SEQUENCE DESCRIPTION: SEQ rp NG: 15 :

TGACAAGCTT ACCTGACGCA GASGGTGGAC CCT <2- INFORMATION FOR SEQ ID NO: 1 £:

(is SEQUENCE CHARACTERISTICS;

(A) LENGTH ·; 10 base pairs (Bi TYPE: nucleic acid! C) STRANDEDNESS: single (D) TOPOLOGY '; linear (ii) MOLECULE TYPE; ocher nucleic acid (A? DESCRIPTION: / desc ® 'DNA (synthetic)' (xi> SEQUENCE DESCRIPTION: SEQ ID NQ; IS:

AATTCGGCAA

I Q.....................

(I) INFORMATION FOR SEQ ID NO; 1";

250 ii? SEQUENCE CHARACTERISTICS;

(A. <LENGTH: 10 ossa parrs; E? TYPE- nuclerc acid i ·. Ijrw. C ϊ> ν * χ * · ₍ λ χ · «» Λ * v> „_ __ _ ·> ·.

-. X-. ? Λ: ΧΛ ^ ΐ:> Λ «ΒΜώ: hif» Ç * e (D; TOPOLOGY: linear (11? MOLECULE TYPE: other nuclexc acid.

(A? DESCRIPTION: / desc »ΈΝΑ (synthetic)” (xr J SEQUENCE DESCRIPTION.- SEQ ID NO:

V ;: a (2) INFORMATION FOE SEQ ID NO: IS:

SEQUENCE CHARACTERISTICS:

{A · LENGTH: 13 base pairs (B; TYPE: nutlate acid (CJ STRAKDEDNESS; single (Di TOPOLOGY: linear (11; MOLECULE TYPE; other nucleic acid (A) DESCRIPTION; / desc = ΈΝΑ. (Synthetic) ”

5x1} SEQUENCE DESCRIPTION: SEQ IE NO; IS;

AATTCGGCGG CAA

13 ................... ............ ..........

(2) INFOBMATION FOR SEQ IO NO: IS;

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 13 base parrs {B) TYPE: nucleic acid (C) STEANDEWESS: single

ÍD) TOPOLOGY; linear

Uil MOLECULE TYPE: other nucleic acid (Ai DESCRIPTION: Zdesc »’ DNA (synthetic) * txi? SEQUENCE DESCRIPTION; SEQ ID NO: IS:

ΛλίΏ * A \ »t, a. ^ M.x? Va '> w «‘ - XCÍ

2H1

INFORMATION FOR SEQ ID NO: 21:

it) SEQUENCE CHARACTERISTICS;

(A .; LENGTH; 22 base pairs iB> TYPE: nucleic acid fCi STRANDEDNESS; single iC? TOPOLOGY. · Linear liii MOLECULE TYPE; other nucleic acid

Li; DESCRIPTION; / desc »“ DNA (synthetic) * (xij SEQUENCE DESCRIPTION; SEQ IO NO; 21;

ATGTTGCCG CCGTTGCCGC CG

INFORMATION FOR SEQ IO NO: 22r (1) SEQUENCE CHARACTERISTICS;

(A; LENGTH: 27 baste pairs {B; TYPE? Nucleic acre (C) STRANDEENESS; single

CD) TOPOLOGY; linear iil) MOLECULE TYPE; other nncieic acid {λ? DrSuRIPTlC'K; / aesc = ‘SNA (synthetic) * ixc; SEQUENCE DESCRIPTION: SEQ ID NO: 22;

252

SEQUENCE CHARACTERISTICS, (A; LENGTH; 29 base pairs

IE 'TYPE: nucleic acid

IC · STRANDEDNESS; single ίθ · TOPOLOGY; linear

MOLECULE TYPE; s ^ e: nucleic acid% a,. ·> ^ '<-> χ + ** · Λ.νκ *. *. -i. Kv * V '. . ' CX & S ^ £ DwA> £ VXltCXllSs' *

(I.? INFORMATION FOR SEO ID MO: 14;

(i; SEQUENCE CHARACTERISTICS '.

(As LENGTH; 27 base pairs

ÍB1 TYPE: n-ttclfixc acxd (C) SIRANDEBNESS: single

IT; TOPOLOGY ': linear (li) MOLEOÜLE TYPE; ocher nucleic acid (A; DESCRIPTION; {synthetic); xi> SEQUENCE DESCRIPTION: EEQ ID NO: 24:

CGATACATGT TGCCTACAQC TGTCCTG (2! INFORMATION FOR SEQ ID NO. 25:

(i) SEQUENCE CHARACTERISTICS; (AI LENGTH: 29 Dasa pairs (Bl TYPE: nucleic acid ÍC) STRANDEDNESS; single {D? TOPOLOGY: linear ill} MOLECULE TYPE: other nucleic acid

DESCRIPTION. * / Dare «DNA isynthetic}

253

1X1: SEQUEKCI DESCRIPTION-. SEQ ID NO; 3 = ·.

xsATuAAuCTT AAGGGTGAAU CTCTGGGCA

INFORMATION FOR SEO ID NO-. 26;

i11 SEQUENCE CHARACTERISTICS ·> A; LENGTH ·. 2? base pairs

ÍB; TYPE: nucleic acid> C; STRANSEDNESS ·. single (E: TOPOLOGY. linear, * .. ,,; ί-ι, otner nucxexc acro <λ; DESCRIPTION: / desc »DNA (svTíthetie: ^; xi; SEQUENCE DESCRIPTION; SEQ IÉ NO: 36:

CGATCCATGG TCCTGCTGCC TGCTGTG (21 INFORMATION FOR SEQ τη NO; 27 _; ii; SEQUENCE CHARACTERISTICS:

(Aj LENGTH- 2S base pairs sxs? ViPx .: nucleic acid

Icon STRANDEDNESSt single

CD) TOPOLOGY: linear ί'ιι, ί MOLECULE TYPE: other nucleic acid (A). DESCRIPTION; / desc # * DNA (syntheticr ixi .; SEQUENCE DESCRIPTION; SEQ ID NO; 27;

GATCAAGCTT AAGGTGTAGG CAAAGGGTG

Í2; INrORMATION FOR SEQ ID 80: 28;

ill SEQUENCE CHARACTERISTICS;

(A? LENGTH: 30 base pairs fS? TYPE: nucleic acid (C3 ETRANDEONESS: single {D | TOPOLOGY - linear

Ui! MOLECULE TYPE: other nucleic acid

254

Isthmatic DNA:

AT THE;

CGATCCATGG CTGTGGACTT · TAGCTTGGGA

W í - ........ · ........ oá << ............ AliiLla ........

;: a information for seq id no: 2 ?.

ii; SEQUENCE CHARACTERISTICS;

IA; length: 2 «aes« paxrs •: si TYPE; nucleic acid

IC; STRANDEDNESS; single; C; TDPDLOGS. ' Imear í; i> KÔLÊTJLE TYPE. · Ether nucleic acid

DESCRIPTION: / desc «DNA <synthetic ixi) SEQUENCE DESCRIPTION: SEQ ID NO: 29;

GATCAAGCTT AAGGCAGCAG GACAGGTGT (2} INFORMATION FOR SEQ ID NO: 90:

<i) SEQUENCE CHARACTERISTICS;

(A) LENGTH: 27 base parrs {£ · TYPE; nucleic acid (0) STWmWNESS: single (D) TOPOLOGY: linear

MDuECQLE TYPE: ether nudscc acid (A: DESCRIPTION: / dear = “ONA (synthetic) (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:

CGATCCATGO ACTTTAGCTT GGGAGAA (2) INFORMATION FOP SEQ ID NQ _; 31;

iii SEQUENCE CHARACTERISTICS:

iA} LENGTH; 29 baee pairs (B) TYPE: nucleic, acid

IC5 STRANDEDNESS; single ο εκ ·; -Γ ν. ' ; C 'TOPOLOGY; kMar

MOLECULE TYPE: Giner nuclsuc acid

IA; DESCRIPTION: Zdesc »DNA (synthetic} '· (xi} SEQUENCE DESCRIPTION: SEQ ID NO; 31;

GATCAAGCTT ACACAGCAGG CAGCAGGAC

INFORMATION FOR SEQ ID NO; 32:

ÍÜ SEQUENCE CHARACTERISTICS ·.

iAs LENGTH; 2? base pairs (E? TYPE; nucleic acid (C5 STRAIÍDEDNESS: single

TOPOLOGY ID: linear

Ui; MOLECULE TYPE, other nucleic acid kA; 5 * ô '»ÍU PT * ON; / dasc ~ DMA (synthetic) * txij SEQUENCE DESCRIPTION: SEQ ID NO; 32;

CGATCCATGG gagaatggaa AACCCAG

Í2; INFORMATION FOR SEQ ID NO; 33:

Íi i SEQUENCE CHARACTERISTICS:

(A>LENGTH; 29 base pairs ÍBJ TYPE; nucleic acid (Ci STRANDEDNESS; single (D) TOPOLOGY; linear in} MOLECULE TYPE: other nucleic acid: a ₍ DaSCF.iPT ^ ON; / d & SC ® ΌΝΑ {Sl ^ nnhetic l · ”<Xi5 SEQUENCE DESCRIPTION; SEQ ID NO: 33:

GATCAÀGCTT ACAAGCTAAA CTCCACAGC (2) INFORMATION FOR SEQ ID '0: 34;

<1; SEQUENCE CHARACTERISTICS;

56

Ϊ'Α LENGTH; I 'base pairs; B ^: TYPE: m: claic acic? C) STRANDEDNESS. single ^? 3; TOPOLOGY; linear (ii; MOLECULE TYPE: other nucleic acid <A) LLS0RI PT I ON:, · 'date ® Σ3ΝΆ (s yn the cic; ”(xi? SEQUENCE DESCRIPTION: SEQ ID NO: 34;

CGATCCATGG GACCCAOTTG CCTCTCA

INFORMATION FOR SEQ ID NO: 35:

ii) SEQUENCE CHARACTERISTICS:

ia? LENGTH: IS nase pairs

IE? TYPE: nucleic acid

IT? STRANDEDNESS; Single iD? TOPOLOGY; linear lie; MOLECULE TYPE; other nucleic acid

ÍA) DESCRIPTION: / desc ® “DMA (synthetic)” txi; SEQUENCE DESCRIPTION; SEQ ID ND; IS-.

GATCAAGCTT ACAGTTGTCC CCGTGCTGC

QS ......................

<2) INFORMATION FOR SEQ ID NO: 36 (1Ϊ SEQUENCE CHARACTERISTICS:

{AJ LENGTH: 17 base cairs i'Bs TYPE: nucleic acid (C) STRANDEDNESS: single

ÍD) TOPOLOGY: linear ill) MOLECULE TYPE; ether nucleic acid {λ; description. · / dee © «“ DMA (synthetic) *

1.X SEQUENCE DESCRIPTION: SEQ ID NO: 36;

CAGTCCA.TGG GAACCCAGCT TCCTCCÀ <A; LENGTH; 3 $ base for B: TYPE ·. nucleic acid! C> STRANDEDNESS; single -: D · TOPOLOGY ·, linear '11' MOLECULE TYPE, other nuclei

IA; DESCRIPTION. · / Desc a tie ’DNA {synthet;

{Xi · SEQUENCE DESCRIPTION: SEQ- ID

GATCAAGCTT AAAGGAGGCT CTGCAGGG

INFORMATION FOE SEQ ID NO; 38;

(i _f > SEQUENCE CHARACTERISTICS:

iAi LENGTH; 2 base par ¢ 3) TYPE; nucleic acid {C) STRANDEDNESS; single (D? TOPOLOGY- linear ill; MOLECULE TYPE; ether nucleic (A; DESCRIPTION: / desc »acid

DNA (synnhebi ixi) SEQUENCE DESCRIPTION; SEQ ID

CGATCCATGG GCAGGACCAC ÂGCTCAC

NO- 38.

{! INFORMATION FOR SEQ ID NO: 38:

iiJ SEQUENCE CHARACTERISTICS:

IA; LENGTH: 30 base pairs (S) TYPE: nucleic acid {C; 5TFANDEDNESS; single (D) TOPOLOGY: linear ire; MOLECULE TYPE; ocher nucleic {A} DESCRIPTION; / deSC ® acid

DNA (syntheci (XI? SEQUENCE DESCRIPTION; SEQ ID

ND: 39:

INFORMAHQN FOF SEQ ID NG; 40:

i i? SEQUENCE CHARACTERISTICS:

A) LENGTH: 3C base parts (S3 TYPE; nuclei, c acid <C} STRÂNDEDNESS: sxng1a v -, a Qr'uwCLs £, .. λ mear ii.i) MOLECULE TYPE · ocher nucleic acid iA) DESCRIPTION: / desc «“ UNA; synthetic;

; xi} SEQUENCE DESCRIPTION; SEQ Ip NO; 4G:

INFORMATION FOP. SEQ ID NG; 41;

! D SEQUENCE CHARACTERISTICS .;

(A) LENGTH; 29 base parrs (RS TYPE: nucleic a-cid (C) STRANDEDNESS: sragle fO; TOPOLOGY; linear iii; MOLECULE TYPE; ocher nucleic acxd ^ 4rSCr. ^. Pi ^ Mix:;., / Dasc • '•' OKA ( synthetic} '(Xi- SEQUENCE DESCRIPTION; SEQ ID NO; 41;

GATCAAGCTT ATGTGGTCCT CCGCTGTGG (3} INFORMATION FOR SEQ ID NO; 42r (ii SEQUENCE CHARACTERISTICS;

• A) LENGTH; 30 base pairs (B) TYPE: nuclsrc acid (C) STRANDEDNESS; single (DJ TOPOLOGY: linear in) .MOLECULE TYPE: other nucleic acid vfti DEi5U £ »uFTION: / dear ® ^ DNA (synthetic)’ «; 9; kl SEQUENCE ΕΈΕΙΡ.ΙΡΤΙΟΧ. SECTION H NI. 42.

ÜGAT: CãT53 atcccaxtgc catcttcctg (1; INFORMATION FOR SEQ IE NQ _; 43:

{:.; SEQUENCE CHARACTERISTICS · <Ά ·· LENGTH; 29 isase parrs (Bi TYPE. · Nucleic acid id STRAKDEDNESS; single m; topology. · Linear (XL · MOLECULE TYPE; Otter Hiiclei acid (A; DESCRIPTION. / D «SC ~ UNA (synthetic:

IXL? SEQUENCE DESCRIPTION: SEQ ID NO; 43.

GATCAAGOTT ACTTGTGAGC TGTGGTCOT

2?

Í3! INFORMATION FOR SEQ ID ND; 44;

i i? SEQUENCE CHARACTERISTICS;

(A · LENGTH: 3P base pairs (B; TYPE; nucleic scid (GJ STRANDEDNESS; single (Di TOPOLOGY · linear; ll! MOLECULE TYPE: ocher nucleic acid

IT? DESCRIPTION; / ciesc “DKA {synthetic}

ILX; SEQUENCE DESCRIPTION; SEQ ID NO-. 44:

CGATCCÂTGG CQATCTTCCT GAGCTTCCAA on ..........

ill INFORMATION FOR SEQ ID NO: 4S:

ii; SEQUENCE CHARACTERISTICS:

(A '; LENGTH; 32 base pairs (H; TYPE: nucleic acid (C) STRANOEDNEES: s ing1a {D · TOPOLOGY ;, linear> ii} MOLECULE TYPE; other nucleic acid (A; DESCRIPTION: / desc * * UNA ( synthe ή 0

(I: INFORMATION FOR SEQ ID NO: 4έ:

7.xy ' ^í ** ^Wff ' S * í2 '''^:?>' Y. »* · £.

V; · '..... λ Μ λ: è aS Χλ && {$: S>

(. «) TYPE; nucleic acid i’Ci STRAKDEDNES5: sxngle: D5 TOPOLOGY: 1xnear <„c; MO ** K, CViiE TYPE: other nucleic acid (A) DESCRIPTION; / desc »* DNA (syntheti.

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

ÀATTCCGTCG TAAACTGACC TTCTATCTGA ÀAAICTTGGA GAACGCGCAG GCTGAATAOT

AOGTAGAGGG CGGTGGAGGC TCI • S3 ............................................. .

L3) INFORMATION FOR SEQ ID NO: 47:

ii; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 83 has® pairs

5B) TYPE: nucleic acid (C? STRANTHDNRSS; single (D) TOPOLOGY: linear iiii MOLECULE TYPE ·, other nucleic acid (A; DESCRIPTION; Xdesc ® 'DNA (synthetic)' (Xi) SEQUENCE DESCRIPTION; SEQ ID NO: 47 :

coggggagcc tccaccgccc tctacgtact sttgagcctg cgcottctcc aagotttca gatagaaggt cagtttacga ugg ***} INFORMATION FOR SEQ ID KG: 48;

<C .; STRANDEDNESS; single i'm TOPOLOGY: linear {ii? MOLECULE TYPE; other nucleic attd i A) DESCRIPTION:. ' des; c ® DNA (syn th® t1 (Xi? SEQUENCE DESCRIPTION: SEQ ID NO; 4S ·.

r'frtffiA V λννν, Λ, Λίί / VW ** V M4 V Mb A

- UxacAA ^ AXCAG CTAACTGCTC T- ^ TKA (2? INFORMATION FOP SEQ ID NO: 49.-.

<1; SEQUENCE CHARACTERISTICS;

> A, LENGTH. ·, 5 £ has® patr® (S? TYPE ·, nucleic acid

IC · STRANDEDNESS ·. single (D; TOPOLOGY ·, linear iit; MOLECULE TYPE: other nuclexc acid

ÍA) DESCRIPTION; / dear «’ DNA (synchet.

: xt; SEQUENCE DESCRIPTION; EEQ ID RO: 49;

ATCA7TAT AGAÍSCAGTTA GAGCCACQAC CCTGTTGTTC CTGCGQTTCC TCAAG

Í1: INFORMATION FOR SEQ ID _N O; ONLY;

i ~ J SEQUENCE CHARACTERISTICS;

(A) uENGTH; SC has® pairs (δ; TYPE: nucleic acid (0; STRANDEDNESS; Single (DJ TOPOLOGY: linear {er .; MOLECULE TYPE ·, other nucleic acid (A; DESCRIPTION: Zdesc «ΈΝΑ ísynthetic)) (Xi; SEQUENCE DESCRIPTION; SEQ ID NO; 50:

, ** · 'v + w + wz + w * :: + ς + ζ · ¹ * • e + x ·' ·: «+> +: tV» · λ «si>. 1 A> ik. si Z 4. FU-iill INFORMATION FOR SEQ CD NO: El:

U) SEQUENCE CHARACTERISTICS;

(A? LENGTH; SO base pairs (Si TYPE; nucleic acid (C: STRANDEDNESS: sing1a

O? TOPOLOGY: linear • in? MOLECULE TYPE; other nucleic acid iA; DESCRIPTION; zdssc «DNA (synthetic? ^v txij SEQUENCE DESCRIPTION: SEQ ID NO; Si:

CGATCATTAT AGAGCAGTTA GAACCGCCGC

CGCTGCCACC GCCAGAGCCA CCACCCTGTT ’

TTGCTCAAGG • 2> INFORMATION FQ.K SEQ · ID NO: SI:

iii SEQUENCE CHARACTERISTICS:

{THE; LENGTH? 3Q base pairs fB) TYPE ·, nucleic acid <C) STRANDEDNESS; single (Dj TOPOLOGY; linear i ~ xi MCuECGLE TYPE; other nucleic acid (A) DESCRIPTION: / base ® ‘DNA (syncheti i’xi? SEQUENCE DESCRIPTION: SEQ ID NO; 52;

GATCQACCAT GGCTCTGGAC ÕCGAACAACC (2) INFORMATION FOE SEQ ID ND; S3;

(SEQUENCE CHARACTERISTICS:

ÍÀ) LENGTH: 2S base pairs (S) TYPE; nucleic acid <C: STRANDEDNESS: single (D) TOPOLOGY: linear “: ciiàPxAí

EKGTE; 32 base pair • £ F £; nuclei: - acis FRAKDEDNESS: single GEOLOGY; linear

nucleic acid / desc = ’’ DNà (synthet

Ui SEQUENCE CHARACTERISTICS;

ÍA) LENGTH: 28 base pairs (Bi TYPE: nucleic acid (C) STRANDEDNESS; single (»; TOPOLOGY · .- linear ill) MOLECULE TYPE: other nucleic acid; Ai DESCRIPTION: / dale« DMA (synthe ixi) SEQUENCE DESCRIPTION: SEQ ID NO: 5.¾ -.

CTCQATTACG TATTCTAAGT TCTTGACA il · INFORMATION FOR SEQ ID NO: 5c:

{1} SEQUENCE CHARACTERISTICS:

> A) LENGTH; 32 base pairs ie

254

POWDER.

OLE TYPE: cth-s:

DESCRIPTION:

/ aesc

UEQUENCE CHARACTERISTICS: i'A; LENGTH: 26 base pairs if? TYPE; nucleic acic • Xi STRANDEDNESS; single ÍD) TOPOLOGY: linear

1; MuLECULE TYPE: other nucleic add

IA; DESCRIPTION: / desc »’ DMA {synthetic fxi? SEQUENCE DESCRIPTION: SEQ ID NO:

JAGAQGGí

SEQUENCE CHARACTERISTICS:

LENGTH: 32 base pairs

TYPE: nuêleic. acid

STRANDEDNESSτ single

TOPOLOGY; 1inesr nucleic acid / desc ss ΈΝΑ {synnheti fxi} SEQUENCE DESCRIPTION: SEQ ID NO: S§.

INFORMATION FD:

8 (A; LENGTH ·. 2 8 base pairs (E; TYPE ·, nucleic acid (C) · STRANDEDNESE: single (D: TOPOLOGY; linear •; ii; MOLECULE TYPE: other nucleic acid {A? DESCRIPTION; / ciesc »» DNA (synthetic) (Xi 'SEQUENCE DESCRIPTION: EEQ IO NO: SB;

CTCGATTACG TACTTGATGA TGATTGGA *> £ ΪΪΪ / / 92 ........

(2) INFORMATION FOR SEQ IO NO: EG;

I i .; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 54 base paars

ÍB; TYPE; nucleic acid (C) STRANDEDNESS: single

TOPOLOGY CDi ·. linear (iij MOLECULE TYPE; other nucleic acid (As DESCRIPTION: / desc * “UNA (eynthetici“ iXi: SEQUENCE DESCRIPTION; SEQ; ID NO: 60-. GCTCTGAGAG CCGCGAGAGC CGCCAGAGGG CTGCGCAAGG TGGUGTAGAA CGCG

Si .. .... ................................ ........... ....................

(2) INFORMATION FOR SEQ IO NO: $ 1;

; i; SEQUENCE CHARACTERISTICS;

(A · LENGTH: 54 base pairs (Bi TYPE: nucleic acid (Ci STRANLEUNESS: single (Di TOPOLOGY; linear (ill MOLECULE TYPE: other nucleic acid íA} DESCRIPTION: / desc * “UNA (synthetic} '(Xi; SEQUENCE DESCRIPTION : SEQ ID NO; 61 ·.

6

(Xi) SEQUENCE DESCRIPTION ·. SEQ ID NO: 62:

»2 INFORMATION FOR SEQ IO NO. · 63:

ii; SEQUENCE CHARACTERISTICS:

(A · LENGTH ·. If base pairs (S; TYPE: nucleic acid iC; STRANDEDNESS: single (D) TOPOLOGY ·. 1 inear iii) MOLECULE TYPE: other nucleic arid

Dx-UxR ^ PTIOis: Zciesc ® * DNA (synthetic! * (Xi) SEQUENCE DESCRIPTION: SEQ ID NO; 63:

ACACCATTGG GCCCTGCCAG C (I: INFORMATION FOR SEQ ID NO ·. 64.U) SEQUENCE CHARACTERISTICS. (A: LENGTH: is base pairs

ÍB) TYPE: nucleic acid (O) ETRANDEDNERS: single (D) TOPOLOGY: linear

'. ~ i> MOLECULE TYPE; other nucleic acid (A) DESCRIPTION: / dear * DNA (synthetic) ·

267 ^v '· RD: <54:

: GACCAT GGCTTACAAG CTGTGCCACC u ~

INFORMATION FOR SEQ ID NO: 65r í 1 · SEQUENCE CHARACTERISTICS:

ia? LENGTH: 36 base pairs • ÍEi ΤΥΡΙ ’· nucleic acid

50 'STRAKDEDNESS: single ίΤ; TOPOLOGY. ' linear iiii MOLECULE TYPE: ether nucleic aciê (A; DESCRIPTION: Zdesc - “DNA {svntheti ixi: SEQUENCE DESCRIPTION; SEQ ID * $ G: 55.-.

CQATOGAAQC TTATTAGGTG GCACACAGCT ICT CO '

6 {I? INFORMATION FOR SEQ ID NO; 6S:

(i) SEQUENCE CHARACTERISTICS:

(A; LENGTH: 32 base pairs (B) TYPE: nucleic acid (Ci STRANOEDNESE: single i'D: topology; linear (ii) MOLECULE TYPE; other nucleic acid (A- DESCRIPTION; / desc ® DNA (synthetic) * ( XI; SEQUENCE DESCRIPTION: SEQ IR NO; 66:

GATCGACCAT GGCTCCCGAG TTGGGTCCCA CC i 2) INFORMATION FOR SEQ EQ NO; 57 _; (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 36 base pairs (B) TYPE; nucleic acic (Tj STRANDEDNESS: single (D) TOPOLOGY; linear (ii) MOLECULE TYPE; ocher nucleic acid (A) DESCRIPTION: / deac = DNA (synthetic) '

X5 SEQUENCE DESCRIPTION: SEQ ID NO: £ 7.CGATCGAAGC TTATTAGGAT ÀTCCCTTCCA GGGCCT

{2} INFORMATION FOR SEQ ID NGt £ 8;

(I; SEQUENCE CHARACTERISTICS;

íA · LE3ÍK5TH: 31 base parrs; b; TYPE; nucleic acid ÍCSTRANDEDNESS; single {D; TOPOLOGY: linear ~ (ex) 'MOLECULE TYPE; ocher nucleic acid {AS DESCRIPTION: / desc »“ DNA {sjmchenc (xi) SEQUENCE DESCRIPTION: SEQ ID NG; £ 6;

GATCGACCAT GGCTATGGCC OCTGCCCTGC AG <1? INFORMATION FOE SEQ ID NO: S9:

(i> SEQUENCE CHARACTERISTICS:

1a) LENGTH; 36 base pairs (Si TYPE; nucleic acid iC) STRANDEDNESS; single (Di TOPOLOGY; linear (iii MOLECULE TYPE; other nucleic acid (A) DESCRIPTION: / base ® 'DNA {synthetic}' ’(xi) SEQUENCE DESCRIPTION: SEQ ID NO; S9;

CGATCGAAOC TTATTATCCC ASTTCTTCCA TCTGC ^ '

......................... '*

(2) INFORMATION FOR SEQ ID NO: 7Q _; (i) SEQUENCE CHARACTERISTICS:

(A. <LENGTH; 32 base pairs {R} TYPE; nucleic acid (Ci STRANDEDNESS: single (Di TOPOLOGY; linear

Μ ner nut / des rhe

EQUENC:

PTION. ' SEQ TO THE SYSTEM '

EQUEKCE CHARACTERISTICS: (A; LENGTH; 36 base pairs ίE> TYPE: mcleic acid (T; STRANDEDNESS; single »D) TOPOLOGY: linear. Ether nuc

ION; / des

Dka. <synth © i xi; SEQUENCE DESCRIPTION: SEQ ID NO: 71;

ATCGAAQC TTATTAQGGC TGCACGGCAG GGGQCA

P; INFORMATION FOR SEQ ID NO; 72:

ii SEQUENCE CHARACTERISTICS;

go? LENGTH; 36 base pairs. a z 7) .nmiem asm (Ci STRANDEDNESS; single

IO; TOPOLOGY; Imear in; MOLECULE TYPE: ether nucleic acxã; λ; uES \ .n ~ PTIUN; / desc ~ DNA ίsynthetic '* ^ίχ 1) SEQUENCE DESCRIPTION; SEQ ID NO: 72;

cuATc ^ AAOC TTATTAOGSC TGCAGGGCAG GGGCCA • 2; INFORMATION FOR SEQ ID NO; 73;

(i) SEQUENCE CHARACTERISTICS .;

(A) LENGTH: 3 6 base pairs

-. '. rt .. · nucjeir acid

λ .. _w ; · ..

TOPOLOGY; 11 near <: .. 3> íÍOlEGJLE TYPE ·. nuclear etheric acic (A; DESCRIPTION; / desc = * DNA> synthetx?

2; INFORMATION FOR SEQ ID ND: 74 ·.

SEQUENCE CHARACTERISTICS ·.

ί.Α: LENGTH, · 21 .base pairs (E> TIRE: nucleic acic (0? STRANDEDNESS.- single ÍD> TOPOLOGY. · linear id; MOLECULE TYPE; other nucleic acid, λ <DESua ^ PT-ON; / desc ® * 'ΠΝΑ (synthetic (xi) SEQUENCE DESCRIPTION; SEQ ID ND; 74;

QTAGAGGGCG GTGGAGGCTC 0

Í2; INFORMATION FOR SEQ ID NO: 75;

SEQUENCE CHARACTERISTICS;

vA 'LENGTH; 25 base pairs {B; TYPE: nucleic acid <C; STRAMDEDNESS-. single {D) TOPOLOGY; linear iii; MOLECULE TYPE; other nucleic acid (A? DESCRIPTION; / desc ® ΌΝΑ (synthetic) id (SEQUENCE DESCRIPTION: SEQ ID NO; 75;

CCGGGQAGOC TCCACCGCCC TOTAC: 2} INFORMATION FOR EEQ ID NO; 75:

íK * · »* ÍL £’ <. · A · <í * * »> X * C · '· · í«; LENGTH; 53 base parrs iillllÇt ................: ........ ..............

ili STRANDEDNESS: single i, n.> TOPOLOGY: iinsâ *

MCÍICUüS TYPE: other nutletc acic (A: DESCRIPTION: / dest ~ DNA i synthetic · '

SEQUENCE DESCRIPTION; SEQ ID NO: 76:

- a * .. K. ^ xauvWvu ^. ^ iímílAa <χίΊ s ^ TACACCA TTG

INFORMATION FOR SEQ ID NO; 77;

SEQUENCE CHARACTERISTICS;

(A! LENGTH; S3 base pairs (B; TYPE. ·, Nucierc acrd! C · STRMÍDEDNESS; single CD) TOPOLOGY; linear> * ii MOLECULE TYPE.- other nucleic acid (A) DESCRIPTION .; / dest »“ DNA synthetic 1 {Xi; SEQUENCE DESCRIPTION; SEQ ID NO; 77;

CAnTuGTQTA GACJxTGTCAG AGCCGCCQQC GGGOTGCQCA AGGTGGCGTA GAA (2; INFORMATION FOR SEQ ID NO: 76:

li; SEQUENCE CHARACTERISTICS:

{ A; LENGTH; 43.9 base pairs ίΡ · TYPE: nucleic acid (C · STRAÍ03EDNESS: Single (Di TOPOLOGY ·, linear {li} MOLECULE TYPE: ether nucleic acid (A) DESCRIPTION: / desc »ΈΝΑ {syntheti r

xij SEQUENCE DESCRIPTION: SEQ ID NO:? fe:

> χ «τ» λ ·>. <* χ χ · ν> χν ·; Ow Λ N3CL k-

«» · Ϊ *. ».4 / * Λ„ \ 3ΧΧ ~ a Λ

360

CECuGTGAAO

Ililllfi

CATAAÀTCTI

HAT

CGAACÀACEI

ACOTOGAGAE

\ * xa> 4 k- x <4> \ £

OAAACATGT • μ. ζ $ λ 1 uaC G Az ·.

TGG GAAGAXT

GAAEAGTACG

ATCAAOCCGT χΤ; à * χ-Λ

TAGAGGGCGG

•2; XMFORMATION FOR SEQ W NO: 7 $ i ii} SEQUENCE CHARACTERISTICS?

U \; LENGTH: 4SS base pairs iS; TYPE; nucleic acid (CJ STRANDEDKESS; single

TOPOLOGY ID5; linear

Hi) MOLECULE TYPE; ether nucleic acid (A? DESCRIPTION: / dear »’ DNA (syntheti? XL} SEQUENCE OESCEXPTICN: SEQ γη,

ÃUutuAGCTC CACCTGCTTG TGACCTOCGA GTCCTCAGTA AACTGCTTCG

GTCOTTCACA GCAGACTGAO

CCAGTGCCCA GAGGTTOACC

IT? y »> <νχ · Μη« rx * Αν λ *.

• «Χνλ ~.« VJíí ^ ã:

T C OGGGAAAa

TQGAGGTTCC '

TAAAG & ATCT

TOA'OTCOQAT

CTTTGCCTAC ACCTGTCCTG crcccraciG lands ctksggmm. tcgwaccc mwtowcs * «* A C CAAGQQ A cAGwACRTTO TGGGAGQAGT GACC ^ T ^ CTG

s

CTGGAGGGAG TGATGGCAG acggggacaa

ITGGGACCCA CTTGCCT’C '’’ ^' 'J ** * *** · *** Ai »u, L <* L-λ * i \ s

J GO gggcagcttt ctggacaggt ccgtctccto

SEQUENCE CHARACTERISTICS;

;THE.; LENGTH; S3? base pairs; B: TYPE: nucleic acid <C;STRANDEDNESS; tingle (D; TOPOLOGY: Linear iii) MOLECULE TYPE; ether nucleic acid ^! , Λ: DEcsCal FTION; / desc ® DNA (synthetic ^ 'ixis SEQUENCE DESCRIPTION; SEQ ID NO: 80;

TCCCCAGCTC CACCTGCTTG

TGACCTCCGA OTCCTCAQTA AACTGCTTCG

TGACTTCCAT

TCCTTCACA GCAQAOTGAG CCAGTGCCCA GAGGTTCACC CTTTGCCTAC ACCTGTCCTG

TGCCTGCTG TGGÀCTTTAG CTTGGGAGAA TGGAAAACCC AGATGGAGGA GAOCAAGGCA

CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC ACGGGGACAA

CTGGGACCCA CTTGCCTCTC ATCCCTCCTG GGGCAGCTTT CTGGACAGGT rCGT ^ ’'^ · ^'» · 3

CTTGGGGCCC TGCÀGÃGCCT CCTTGGAACC CAGCTTCCTC CACAGGGCÃG GACCACAGCT

352

CàOÀAGGATC CCAATGCCAT CTTCTOAGC TTCCAACACC TGCTCCGÀGG AAAGGTGCGT

................. ...... ...... ..................... .....................

TTCCTGATGC TTGTAGGAGG GTCCACCCTC TGCGTCAGGG AATTCQGCGQ OAACATGGCG * C CwCuTGCTTG tgaoctccga gtcctcagta aactgcttco toactcccat

274

GIAGACTGAO CCACTGCCCA GAGGTTCACC. '^ • r' wx ν? Μγ \ * »^ η * · χ v \ * <5 -λ * λ ... i» õ G / page>.5K: <* <>»'- i <· VS · ». Í «* SS * <^ _v L.

l ^ v '....................

CTGGGACCCA

OTTOGGG C 0 C

840

ÀATGCCATCT> 0 ........

GTAGGAGGGT

V *> ** <* «·. **. <* <? * X Ζ-> · Λ S

GAC CCTTCTG

GCTTGGAACC

OCAACACCTG

CGTCAGG «'ft,' ** · * -. X -X X ·> .ΛΓ »·. To L. <

GGGCAGCTTT fs »<τχ **» ΛΧ * »»; ««

CTCCGAGGAA

y. · ** y. J’YV ’” '> »» x

4- v ^^^ xJtkS _A - \

Ai-X »* i ·« x? 4 ..

iww *. ^ Λ: * x »\ ** l ^ -Aii-ííktóiC ^ TCA

AGGTGCGTTT

AUGGGGACAA

C C

INFOSUÜVIXOK FDR SEQ ID NO: 81:

i i; SEQUENCE CHARACTERISTICS:

(A! LENGTH: 936 base pairs (2) TYPE: nucleic acid (Ci STRAKDEDNESS: single (D) TOPOLOGY: linear (iii MOLECULE TIRE; other nucleic acid (A) DESCRIPTION; / desc «DNA (synthetic)

Sxt) SEQUENCE DESCRIPTION: SEQ ID NQ _; 81TCCCCAGQTO CACCTGCTTS 6C

GTCCTTCACA GCAGACTGAU

120

CTGCCTGCTG TGGACTTTAG

IS δ

CAGGACATTC TGGGAGCAGT ctgggaccca cttgcctctc

300

ΛΜ · ΡΗ »» Χ * yx _ λ ix, _w TGCAGAOCCT

ONLY

TQACCTCCGA GTCCTCAGTA

CCAGTGCCCA GAGGTTCACC

CTTGGGAGAA TGGAAAACCC

GACC-CTTCTG CTGGAGGGAG

ATCCCTCCTG GGSCAGCTTT

CCTTGGAACC CAGQTTCCTC

AACTGCTTCG TGACTCCCAT

CTTTGCCTAC ACCTGTCCTG

AGATGGAGGA GACQAAGGCA tgatggcagc acggggacaa

CTGGACAGGT CCGTCTCCTC

CACAGGGCAG GACCACAGCT

CTT2ACAGCA GACTGAGCCA. GTGCCCAGAG GTTCACCCTT TGCCTACACC TGTCCTG ^ Tn

THE... ;.; _Λ ·. _Λχ _i .. AAAACCCAGA TGGAGGAGAC CAAGGCACAG

aaggatccca atgccatctt cctgagcttc caacacctgc TCCGAGGAAA GGTGCGTTT *

925

CIGATQCTTG taggagggtc caccctutgc GTCAGG

93S il: INFORMATION FOE SEQ ID ND; 82;

(i? SEQUENCE CHARACTERISTICS '.

(A; LENGTH '. 939 Ja & se pairs (A; TYPE; fiucleic acid (C) STRAND EDNESE; single ÍD} TC’PCLCGY; linear

MD, u £ »», u. »: £. Tth; other nucleic acid

ÍA) DESCRIPTION: / âesc ® «DNA {synthetic) (Xi) SEQUENCE DESCRIPTION: ..SEQ ID NG; 82;

TCCCCAGCTC CACCTGCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCQ TGACTCCCAT uTCcTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTCACC CTTTGCCTAC ACCTGTCCTG

27b

540

GTCCTTCACA GCAGACTGag OCAGTGCCCA

500 ........

CTGGCTGCTG TGGACTTTAG CTTGGGAGAA

660 :: .... ..........

OAGGACATTC TGGGAGCAGT GACICTTOTG 72C

CTGGGACOGA CTTGCCTCTC ATCCCTCmTG

CTTGGGGCC2 TGCAGAGOCT CGTTGGAACO 840 \ ~ ACAAGGATC CCAATGCCAT CTYCCTGAG '·'

900

TTCGTGATGC TTGTAGGAGG GTCCACCCTC

Φ Ct

TGGAAAACCG AGATGGAGGA GACCAAGGCA

CTGGAGGGAG TGATGGOAGI ACQGGGACAA

GGGCAGCTTT CTGGACAGST CCGTCTCCTC CAGCTTCCTC CACAGGGCAG GAC2A0AG27

- tgctccgagg aaaggtgogt

TGCGTCAGGG AATTCGGCQG CAACATSGCG GTCCTCAGTA AACTGCTTCG TGACTCCCAT GAGGTTCACC CTTTGCCTAC AOCTGTCCTG TGGAÀAACCC AGATGGAGGA GAOCAAGGCA CTGGAGGgcggggggcgggggggggg

CACAGGGCAG GACCACAGO '' ¹ TTCQAACACC TGCTCCGAGQ AAAGGTGCGT TGCGTCAGG ί2ί INFORMATION FOR SEQ ID NO ·. S3;

(i) GSQDSNCS CHARACTERISTICS; {A) LENGTH; 948 base pairs JB} TYPE: nucleic acid <C) STRANDEONEES. ' single (D) TOPOLOGY: linear

MOLECULE TYPE; other nucleic acid (A) DESCRIPTION ~ DMA (synthetic)

CAGGACATTC GGGGAGGAGT GAOCCTTCTG

240

CTGGGACOQA CTTGCUTCTC ATCCCTCCTS

0

OTTGGGGCDC TGCAGAGCST CCTTSGAACC

36C

CAOAAGGATC CCAATGCCAT CTTCCTGAGC, 4li ^:

TTCCTGATGC TTGTAGGAGG GTCCACCCTC

Ç

AACATGGCGT‡ ACAGCGCC QCCTGCTTGT

540

GACTCCCATG TCCTTCACAG CAGACTGAGC

CÇTGTCCTGC TGCCTGCTGT GGAGTTTAGC §60

ACCAAGGCAC AGG ^ CATTOT GGGAGGAGTG

CGTCTCCTCC TTGGGGCCCT GCAGAGCCTC

840

ACCACASCTC ACAAGGATCO CAATGGCATG

SCO

AAGGTGCGTT TCCTGATGCT TGTAGGAGGG

s

(2) TATGR24ATION FOR SEQ ID NO: 8

Ξ'χ · ΣΣ) NO; £ 3 *

GTCCTCAGTA AACTGCTTCG TGAC7CCCA1 GAGGTTCACC CTTTGCDTAC ACCTGTOCTG - KsGAAAfsu-C AuATGGAGGA GAQUAAGGOA _Λ GG ^ x Lik> ^ QT ^ ATSGUAGl acggggacaa GGGCAGim CTGGACAGGT CCGTCTCCTC • CAGCTTCCTC CAGAGGGCAG GACCACÀGCT TTOCAACACC TGCTCCGAGG AAAGGTGCGT TGCGTCAGGG AATWGGCGG CAACGGCGGC GACCTOCGAG TCCTCAGTAA ACTGCTTGGT CAGTGCCCAG AGSTTCACCC TTTGCCTACA TTGGGAGAAT GGAAAACCCA GATGGAGUAG ACCCTTCIGC TGGAGGGAGT GATGGCAGCA TCCCTUCTGG GGCAGCTTTC TQGACAGGTC CTTGQAACCC AGCTTCCTCC ACAGGGCAGG TTCCTGAGCT TCCAACACCT GCTCCGAGGA TCQACCCTCT QCGTCAGG in? ·. '

ATTER1

8 8 by acid

DNA

auAGCTT

TGACTGGCAA

AAAAACTGAC

AGCAAGCG

GGAACARCAG

GGTGGTGGCT

482

AAAGAGA

TGATGGAC

G 'CAAGAA

CTTAGAAAAT

AGGTA

TTGAGGCAAT

CATCATCAAG

G

GCAGG7GACT

ICAAGAATT

ATCTGGTTAC

CCTTGAGCAA

688

SB;

2 ^Τ 3 iKi) SEQUENCE DESCRIPTION; SEC ID NO; 85:

CATGGCTAAC TGCTCTATAA TGATCGATGÀ acccttgctg gacccgaaca acctcaatga

CDTTCGACTD CCÀAACCTGG AGAGCTTCGT

S......

300

GTTUTATCTQ GTTACCCTTG AGCAAGCGCA

CAGOGGCQGD GGTTCTAACT GCTCTATAAT

ACCACCTGCA CCTTTGCTGG ACCCGAACAA

80

GGACOGAAAC CTTCGACTTC CAAACCTGGA

S4C

AAATGCATCA GQTATTGAGG CAATTCTTCG

800

GGCCGCACCC TGTCGACATC CAATCATCAT

680

AAAACTGACG TTCTATCTGG TTACCCTTGA

AATTATACAT CACTTAAAGA GACCACCTGC

CGAAGACGTC TCTATCGTGA TGGACGGAAA

AAGGGCTGTC AAGAACTTAG AAAATGCATC

ACGATGTCTG CCCTCTGCCA CGGCCGCAOT

TGACTGGCAA GAÀTTCCGGG AAAAACTGAC

GGAACAACAG GGTGGTGGCT CTGGGGGTGG

GATCQATGAA ATTATACATC AOTTAAAGAG

CCTCAATGAD GAAGAGGTOT DTATCOTGAT

GAGCTTC2TA AGGGCTGTCA AGAACTTAGA

TAATCTCCAA CCATGTCTGC CCTGT3CCAC

OAAGGCAGGT GACTGGCAAw AATTCCGGCa gCLí * usuGCAG GAAGAACAwT AC (2; FORMATION FOB SEQ ID NO; 86. ·

U; SEQUENCE CHARACTERISTICS;

(A) LENGTH; 975 base pairs (Bj TYPE; nucleic acid (C) STRAKPEDNESS ·. Single

28Γ i, * zj TuPQ-mCSI ·. linear

ÍOLECULE TYPE. other nucleic asud iA: DESCRIPTION- / «« «-« * DNA (synthetic) jxd! SEQUENCE DESCRIPTION: SEQ · ID NO: 66:

ATGGCTOTGG ACOCGAACAA CCTCAATGAC GAAGACGTCT CTÀTCCTGAT GGACCGARAC CTTCGACTTC CAAACCTGGA GAGOTTCGTA AGGGCTGTCA AGÂACTTAGA AAATGCATCA j. 2 C?

GGTATTGAGG CAA7T0TT0G TAATCTCCAA CCATGTCTGC COTCTGQCAC GGf’CG ^ AC ^ ''

Igo

T „. x uwAi./ki x. X.AATCATCAT CAAGGCAGGT GACTGGOAAG AATTCCGGGA. AAAACTQACG v

TTCTATCTGG TTACCCTTGA GCAAGCGCAQ GAACAACAGG GTGGTGGCTC 3QC ’'“

ATAATGATCG ATGAAATTAT ACATCAQTTA AAQAGACCAC CTGCACCm GTAQPTAGAG

360 i * Gx, 'jix * TGu.AG GCTCCCCQGG TQAACCGTCT GGTCCAATCT CTACTATQAA CCCGTCTCCT 430 * · -. «Λ

CCGTCTAAAG AATCTCATAA ATCTOCAAAO ATGGCTACCC AGGGTGCCAT GCCGGCCTTC

U «-X- * xu.vAGx.vfk.Cw ^ uAG '^ AGGG CTCCTQGTTG CTAGCCATCT GGAGAGTT ^< '

40- * s.

CTÕGASGTGT CGTACCGCGT TCTACGCCAC CTTGCGCAGC CCTCTGGCGG CTCTGGCQGC

600

TCTCAGAGCT TCOTCCTCAA GTCTTTAGAG CAAGTQAGAA AGATCCAGGG CGATGGCGCA 660 ..........

^ ICCAseG agaagctgtg tgccacctac aaqctgtgcc accccgagga qctggtgctg CTCGGACAOT CTCTQGGCAT CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG COCCTGGGCT CAGCTGGCAG GCTGCTTGAG C-CAACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTG CAGGCCCTGG AAGGGATATO COCCGAGTTG GGTCCCACCT TQGACACACT GCAGCTGGAC

Ci

281

ί 1 SEQUENCE CHARACTERISTICS:

(A) · LENGTH ·. 97 base pairs

ÍB; TYPE; nucleic acid (Ci ETRAI-OHDNESS; single (0! TOPOLOGY; linear in; MOLECULE TYPE; other nucleic acid

A) DESCRIPTION; / desc * ‘DNA (synthetic) · (xi j SEQUENCE DESCRIPTION: SEQ ID NO: 87?

ATGGCTCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGÀÀAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTQTCA AGAACTTAGA AAATGQATCA QGTATTGAGG CAATTCTTCG TÀATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCSCACCC vs * ^ '^ YJ As.Ad ivnTuAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTQACG ~ ij.TA.uTGv> TTAUCCTTGA GCAAGCGCAG GAACAACAGG GTGGTSGCTC TAACTGCTCT ATAATGATCG ATGAÀATTAT ACATCAUTTA AAGAGACCAG CTGCACCTTT GTACGTAGAG GGCGGTGGAG GCTCCCCGGG TGAACCGTUT GGTCCAATCT CTACTATCAA CCCGTCTCCT *! fr ί '^ V ^TCTCATAA ÃTCTCCÃAAC ATGGCTACCC AGGGTGCCAT GCCGGCCTTG SCUTCTGCTT TCCAGCGCCG GGCAQGAGGG GTCCTGGTTG CTAGCCATCT GCAGAGC ^^, * 4 3 ¹ .¼ · V · GTGGAGGTGT CGTACCGCGT' · OT'ar'Grr'ir _Soc. orTucwuAGC CCTCTGGCGG CTCTGGCGGC

282 • NÍX *** »* '» *. ** X »*** · ** ♦>: V». X Ζ- \, - * Χν-χ χ ί, Ζ- »X ν» .ν ^ Λ V * · *% Μ - A Ww,. v * / Vi Dit Λ _ν * Akwv ^ ι.Α (χυ.: v £ »* UaèU> V ^ C ^ AT ^ C ^ VsiJjkj CxsATx ^ & SQ

CCIOTCCACG AGAAGOTGTG TGCCACOTAC AAGCTGTGCT ACCCCGAGGA GCTGQTGCT

CTCGGACACT CTCTGGGCAT SAMSTGGGCT COCCTGAGCT CCTGCCCCAG CCAGGCCCT ·

7SS

CAGCTGGCAO GCTGCTTGAv CCÂACTCCAT AGCGGCCTTT TCCTCTACCA GGGGCTCCTi

840

CAGGCCCTGG AAGGGATATC SAMSGAGTTG GGTCCCACCT TGGACACACT GCAGCTGGAi

S δ: · 0 · ir csaUcwAcT TTOCCACCAC CATCTGGCAG CAGATGGAAG AACTGGGAAT GGOCCCTGCÍ 95C

CTGCAGCCCT AATAX

S7.S • 2; XNFORMATXOK FOP, SEQ ID NO: 88;

ii) SEQUENCE CHARACTERISTICS;

(A> LENGTH; $ 75 base pairs (8; TYPE; nucleic acid {C) · STRANDEDNESS: s ingle (D) TOPOLOGY; linear; ~ i> MOuECULa, TYPE: other nucleic acid $ A) DESCRIPTION: / <âesc ® DNA (synthetic) (XX) SEQUENCE DESCRIPTION: SEQ ID NO: 88;

ATGGCTGCAC CCTOTCGACA TCCAATCATC ATCAAGGCAG GTGACTGGCA AGAATTCCQG £ 0:

GAAAA.ACTGA CGTTCTATCT GCTTACCCTT GAGCAAGCGC AGGAACAACA> GGGTGGTGGC TCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTOCACCT - a'Jv.TGcAcC CuAACAACCT caatgacgaa gacgtctcta tcctgatgga ccgaaacctt CGACTTCCAA ACCTGGAGAO CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT aitgaggcaa ttcttcgtaa tctccaacca tgtctgccct ctgccacggc ctacgtagag

283

GCT3283GS0 TGAACCGTCT GGTQUAATCT CTACTATCAA

422 -. ~ CCGTCTAAAG ÀATCTCATAA ATCTCCAAAC ATGGCTACCC AGGGTGCUAT GCCGGCOT ^

4 & 0

GC'_ i ι_Τι »· _Τ; TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG CTAGCCATCT GCAGAG '* ^w * t' 540: ·· ................... * ..... ”......“ '. ......

OTGGAGGTGT CGTACCGCG7 TITACGCCAI CTTGCGCAGC CCTCTGGCGG DTCTGGCGGC 6G0 ~

TCTCAGAQCD TCCTGCTUAA GTCTTTAGAG OAAGTGAGAA AGATCCAGGG CGATGGCGCA

GCGCTCCAQG AGAAGCTGTG TGCQACCTAC AAGCTGTGCC ACCCCGAGGA GCTGSTGCTG CTCGGACACT CTUTGGGCAT CCCCTGGGCT OXCTGAGCT CCTSCCCCAG CCAGGCCCTG CAGOTGGCAG GOTGCTTQAG CUAAOTUCAT AGCGGGCTTT TCCTCTACCA GGGGCTCUTG CAGGCUCTGG AAGGGATATC CCGCGAOTTG GGTGCCACCT TGGACACAe? GCAGCTGGAC GTCGCCGACT TTGCGACCAC CATCTGGGAG CAGATGGÀAG AAOTGGGAAT GGCCCCTGCC CTGCAGCCOT AATAA.

S75

Í2? INFORMATION FOR REQ ID NO; §5;

ii) SEQUENCE CHARACTERISTICSiA) xmENGTH: 975 fes.se pairs (3) TYPE; nucleic acid (Cl STRANDEDNESS: single iD! TOPOLOGY: linear i-i; MDuECuDE TYPE; other nucleic acid (A; DESCRIPTION. · / desc ~ * DNA {synthetic.! '' (d; SEQUENCE DESCRIPTION: SEQ ID NO: 89;

ATGGCTGCÀG GTGACTGGCA AGAATTCCGG GAÀAAACTGA CGTTCTATOT GGTTAQCCTT? 84 · Χ> \ ^ Λ% ', · * A -. «Á-SJw. A · »A Mw * \ v ^ Λ Xa <. _m . -M x * -Λ ^ ΤχχΑΎ \ .U> AA \ X & jA \ Zx'T ^ ATACATCaÍ T Ί AAAGAGACC AC2TGCAC2I TTGCTGGACT CGAACAÀCCT CAATGACGAA

ISO

GACGTCTCTA TCCTGATGGA CCGAAACCTT OGACTTCCAA ACCTGGAGAG CTTCGTAAGG

L 4 0

GCTGTCAàSâ ACTTAGAAAA TGCATCAGCT

3GÜ ^ <** ϊ ^ <χ * <γ5 '·>ζ' ί ^>> *> · τ * 'τϊί, ίΎη ρ'ίΓ'νΛΧ ^'/><< κ χ / "τ .. **. ^, «* ^ 7 ^ / ** ^. , Λ · .W. *: W ^ «^ Sv'w x · 'aa. * S ^^'wA./rV'^tKky.k. χ.Λ ^ χ.Λ ** · \ a · <mi U i

A <* ·

Λ ».MV.

ggcgstggag gctucccggg TGAACCGTCT

420

CCGTCTAAAG AATCTCATÀA ATCTCOAAAC

4SC. W. \ »W» * * «Í UUk.AijfsJ'ik'jfkavf

S40 ..............

CTGGAGSTGT CGTACCGCGT TCTACGCCAC

600

TCTCAGAGCT tcctgctcaa GTCTTTAGAG £ 65 .............

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA «« ΑνATv. 2Αλ TCATCATCAA GTACGTAGAG

GGT2GAATCT OTACTATCAA CCCGTCTCCT ÀTGGCTACCC AGGGTGCCAT GCCGGCCTTÇ GTCCTGGTTG CTAGCCATCT GCAGAGCTTC CTTGCGCAGC CCTCTGGCGG CTCTGGCGQC CAAGTGAGAÀ AGATCGGCA

GCGCTCGAGG AGAAGCTGTG

TGCCACCTAC AAGCTGTGCC

ACCCCGAGGA GCTGGTGUTG

CTCGGACACT CTCTGGGOAT CGCCTGGGCT

782

CAQCTQGCAG GQTGCTTQAG CCAACTCCKT

8.40

CAGGCCCTGG AAGGGATATC SAMSGAGTTG

POO

GTCGCCGAOT TTGCCACCAC CATCTGGCAG

98Õ

SAMSTGAGCT CCTGGCCCAG CCAGGCCCTG

AGCGGCCTO TCCTCTACCA GGGGCTCCTG

GGTCCCACCT TGGACACAGT GCAGCTGGAC

CAGATGQAAG AAQTGGGAAT GGCQCCTGCC

CTGCAGCCCT AATAA

975

Í2- INFORMATXDN FOR ESQ ID NO; §0 _x (i) SEOUEÜKÍE CHARACTERISTICS:

(A) LENGTH; 99.8 base pairs (8} TYPE-, nucleic acid ÍC) STRANDEDNESS: single ¹ w. \ H-Wavw. ' .. ÍXm. Q-xlltx ... ί * <Λ x .. Λ ..> μ Λ * · »

DESCRIPTION. / desc «SNA fr / ntnerii.} 'ίχί) SEQUENCE DESCRIPTION: SEQ ID NO: SQ:

ÀTGGCTCTGG AUCOGAACAÀ OCTUAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC. «FlVVXAjrMtV ^ A ys V -A 7 X Λ λ Α,. 'Χ ^,' ΤΧΛΧν / ν. > X v _H x>. _v ΛΜ, ΑΧΧ

.... ,, .. awxsxs'-iu, u. AvAauTTAuA AAATGDACCA

GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCAC ·

TCTCGACATC CAATCAICAC CAAGGCAGGT SACTGQCAAG AATTCGGGGA AAAACTGACG

340

TTCTATCTC-G TTACCCTTGA GCAAGCGCAG GÃACAÀCAGG GTGGTGGCTC TGGCGGTGG ^

30C .............................................

AGCCGCGGCO GTTCTAACTQ CTCTATÀATG ATCGATGAAA TTATACATQA CTTAAAGAGA

360> _x.jxuí_Tts- ™ A '„. CTTTGTACd AGAGGQCGGT GGAGGCTCCC CGGGTGAACD

420

A7CTCTACTA TCAACCCGTC TCCTCCGTCT AÀAGAATCTC ATAAATCTCC AAAGATQGCT

ACCCAGGGTG CCATGCCGGC CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG

540

GT7GCTAGCC ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CACCTTGCG »00

CAGCCCTCTG GCGGCTCTGG CGGCTCTCAG AGCTTCCTGQ TCAAGTCTTT AGAGCAAGT3

AGAAÀGATCC AGGGCGATGG CGCAGCGCTC

G

TGCCACCCCG AGGAGCTGGT GCTGCTCGGA

780

CAGGAGAAGC TGTSTGCCAC CTACAAGCTG

CACTCTCTGG GCATCCCCTG GGCTCCCCTG

AGCTCCTGCC CCAGCCASGC

SAD

CCTGCAGCTG GCAGGCTGCT TGAGQCAACT

CCATAGCGGC

CTTTTCCTCT ACCAGGGGCT CCTGCAGGCC

90C

CTGGAAGGGA TATCCCCCGA GTTGGGTCCC ύ

> '*, Ν ν. I · ΪΙ> '' ·> *? .Λ: · y>. * W-> Χ fX MV »f '* ·: λ. <« * · Χ «». *. ·. «{2? INFORMATION FOE SEQ ED NO; ?1:

(i: · SEQUENCE CHARACTERISTICS:

(A .; LENGTH: 898 base pairs

ÍE) TYPE: nucleic acid

STRANDEDNESS ICONS ·. single (D? TOPOLOGY: linear iii 'MOLECULE TYPE: other nucleic acid {A) DESCRIPTION: Zdesc «’ DNA {synthetic! ’ixi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:

ATGGCTAATG CATCAGGTAT TGAGGCAATT CTTCGTAATC TCCAACCATG TCTQCCC ^ C ^

6G .....-- GCCACGGCCG CACCCTCTCG ACATCCAAT * ATCATCAAGG CAGGTGACTG GCAAGAA.m

Ix2C .....

CGGGAAAAAC TGACQTTCTA TCTGGTTACC CTTGAGCAAG CGQAGGAACA ACAGGGTGG®180

QGCTCTGGCG GTGQCAGCGG CGGCGGTTCT AACDGTTCTA TAATGATCGA TGAAATTATA 24C

CATCACTTÀA AGAGACCACÇ TGCACCTTTG CTSGACCCGA ACAACCTCAA TGACGAAGAC ΐΑΓ: '

GTCTCTATCC TGATGGACCG ÀAACCTTCGA CTTCCAAACC TGGAGAGCTT CGTAAGGG ^

ONLY

QTCAAGAAUT TAGAATACGT AGAGGGCGGT GGAGGCTCCC CGGGTGAACC GTCTGGTCCA 43C ~

ATCTCTACTA TCAACCCGTC TCCTCCGTCT AAAQAATCTC ATAAATCTCC AAACATGGCT

4S0 acccagggtg ccatgccggc cttcgcctct GCTTTCCAGC GCCGGGCAGG aggggtcctg

GTTGCTAGCC ATCTGCAGAG CTTCCTGGAG GTGTCQTACC GCGTTCTACG CCACCTTGCG

ij> SEQUENCE CHARACTERISTICS:

IA? LENGTH: 9S9 base pairs {Si TYPE: nucleia acid

IC; STRANDEDNESS; Singl®

ID? TOPOLOGY; linear iii? MOLECULE TYPE; other nucleic acid (A? DESCRIPTION; / desc ® OKA (synthetic) ixi) SEQUENCE DESCRIPTION; SEQ

ATGGCTGCAC CCTCTCGACA 6G

GAAAAACTGA CGTTCTATC7

Ç

ISC

CAdTAAAGA

^: · 30ΐ:

AAGAACTTAG

GCAGCGGCGG gaccacctgc

TGGAC x ~ <$ tAAA

AAAATGCATC

36Q

ID NO: 93;

TCCAATCATC ATCAAGGCAG

GGTTACCCTT GAGCAAGCGC

CGGTTCTAAC TCCTCTATAA

ÀCOTTTGCTG GACCCSAACA

CCTTCGACTT CCAAACCTGG

AGGTATTGAG GCAATTCTTC

QTGACTGGCA AGAATTCCGG

AGGAACAACA QGGTGGTGGC

TGATCQATGA AATTATACAT

ACCTCAATGA CGAAGACGTC

AGAGCTTCGT AAGGGCTGTC

GTAATCTCCA ACCATGTCTG

288

ACCCAGGSTG CCATGCCGGC CTTCGCUTCT & 40

AGCTCCTGCC CCAGCCA2GC CCTGCAGCTG

S ~ *> àxv \ »<sv 1 C t- Pkx ^ x ^ GCC ^ 00

ACCTTGGACA CACTGCAGCT QGACGTCGCC

SSCi

GAAGAACTOG gaatogcccc tgocctgcaq qOCt

CAGGAGAAGC tgtgtgccac ctacaagctg

CACTCTCTGG GCATCCCCTG GGCTCCCCTG

GCÂGGCTGCT TGAGCCAACT CCATAGCGGC

CTQGAAGGGA TATCCCCCQA GTTGQGTCCC

GACTTTGCCA CCACCATCTG GCAGCAGATG

CCCTAATAA »23 INFORMATION FOR SEQ IQ NO: 93;

(i · SEQUENCE CHARACTERISTICS;

íA) LENGTH: 959 base pairs (E? TYPE: nuclsie acid (C; STRANDEDNESS: Single (D) TOPOLOGY: linear iii! MOLECULE TYPE: other nucleic acid (A.) .DESCRIPTION: / desc »DNA í synthetic)” ( Xi) SEQUENCE DESCRIPTION · SEQ ID NO: S3;

ATGGCTGCAG GTQACTGGCA AGAATTCCGG GAAAAACTGA CGTTCTATCT GGTTACCCTT

289

CiAGIAAGCGI AGGAAGAACA GG KJTGGG TTPGGCGGTG GCASCGGCGG CGGTTCTAAC

TGCTCTATAA TGATCGATGA AATTATACAT CACTTAAAGA GACCACCTGG ACC ' ^, ' ^f ^ G''TS 182

GACCCGAACA AOCTCAATGÀ CGAAGACGTO TCTATCCTGA TGGACCGAAÀ CCTTCGACTT

240

CCAAACCTGQ AGAGCTTCGT AAGGGCTGTC AAGAACTTAG AAAATGCATC AGGTA ^ GAG

300 ......

GCAATTCTTC GTAATCTDCA ACCATGTCTG COCTCTGCCA CGGCCGCACC CTCTCGACAT

SO r * -AATCATiA TCAAGTACGT AGAGGGCGGT GGAGGCTCCC CGGGTGAACC GTCTGGTCGA 420 *

ATCTCTACTA TCAACCCGTC TCCTCCGTCT AAAGAATCTG ATAAATCTCC AAACATGGCT ·

480 ................................................. ..................................

ACCCÀGGGTG CCATGCCGGO OTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG 542 ...... ....................

GTTGCTAGCG ATCTGCAGAG CTTCCTGGAG GTGTCGTACU GCGTTCTACG CGACCTTGCG

CAGCGCTCTG GCGGCTCTGG CGGCTCTCÂG AOCTTCCTGC TCAAGTCTTT AGAGCAAGTG

..: 6. ft'D .... ...... ........ ............................. ...................................

A ^ «AAGATCG AGGGCGATGG CGCAGCGCTC CAGGAGAASC TGTGTGCCAC CTAUAAGCTG

Tuix.rtC-CCG AGGAGCTGGT GCTGCTCGGA CAUTCTCIGG GCATCQCeTG GGTQCCUTG ** *

AGCTCCTGCC CCAGCCAGGC CCTGCAGCTG GCAGGCTGCT TGAGCCAAÇT CCATAGCGGC

CTTTT ^ .CTCT ACCAGGGGCT CCTGQAGQCC CTGGÂÀGGGA TATGCCCCGA GTTGGGTCCC

ACDTTGGACA CACTGCAGCT GGACGTCGCO GACTTTGCCA CCACCATCTG GCAGCAGATG SOv

GAAGAACTGG GAATGGCCCQ TGCGGTGCAG ^ CCTAATAA

9SS

25 INFORMATION FDR SEQ ID NO: 94:

Ui SEQUENCE CHARACTERISTICS;

(A) LENGTH: 918 base pairs (B) TYPE: nuelerc acid (C> SmNDEDNESS: Single

{Xi; SEQUENCE DESCRIPTION: SEQ ID ND: 94;

ATGGOTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGO SO

CCTTTGCTGG ACCCGAACAA CCTGAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA ÀAATGCATCA CCATGTCTGe CCTCTGCCAT GGCCGCACCC GACTSGCAAG AATTCCGGGA AAAACTGACG GAACAÀCAGT ACGTAGAGGG CGGTGGAGGQ AACATSGCTT ACAAGCTGTG CCACCCCGAG ATCCCCTGGG CTCCCCTGAG GTCCTGCCCC AGCCAACTCC ATAGCGGCCT TTTCCTCTAC TCCCCCGAGT TGGGTCCCAC CTTG-Gacaca Au> _ATCTGGC Agca-GATGGA AGAACTGGGA GCGATGCCGG CCTTCGCCTC TGCTTTCCAG CATCTGCAGA GCTTCCTGGA GGTGTCGTAC GGCGGCTCTG GCGGCTCTQA GAGCTTCCTG CASGGCGATG GCGCAGCGCT CCAGGAGAAG

GGTATTGAG

CAATCATCAT

TAATCTCCAA

TTCTATCTGG

GAGCTGGTGC

CGCCGGGGAG

CGCGTTCTA ·

840 ‘AAGTC’ ^^

TGCTCGGACA

GGAAGGGATA

CCTGCAGÍ

GAGGGGTCCT

GCCACCTTGC

CACCGAGGCT

GGTTGCTAGC

GCAGCCCTCT

GAGAAAGAT

i'i! SEQUENCE CHARACTERISTICS:

IT? LENGTH; 9S3 base pairs ÍB · TYPE: nuclerc acid (Ci STRANDEDNESS; single fD? TOPOLOGY: linear iri ..> MOLECULE TYPE; ocher nucleic acid (A; DESCRIPTION. / Desc * 'DNA (synthetic} ίκϋ SEQUENCE DESCRIPTION: SEQ ID ND: 95:

ATGGCTAACT · GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCA ^^ SC

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAAOT.AQA AAATGCATCA 2.8Ό

GGTATTGAGG QAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCA ^ CC

0 *

TCTCSAÜATC CMTOVTCAT CMSCCAGST SACTOTCAAÍS ΑΛΤΚΧίΜΟΛ AAAACTSACC

TTCTATCT · ® TTACCCTTGA «AtóCGCM GAACAACAGT ACGTAGAWS COTTOGAGSC 4-QU.

TCCCCGGGTG AACCGTCTGG TCQAATCTCT ACTATCAACC CGTCTGCTCC GTCTAAAGAA 42 0

TCTCATAAAT CTCCAAACAT GGCTTACAAG CTGTGCCACC CCGAGGAGCT GGTGCTGCTC

GGÀCACTCTC TGGGCATCCC CTGGGUTCCC CTGAGCTCCT GCCCCAGCCA GGCCCTGCAG

CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTÀCCAGGG GCTCCTGCAG

CUV

GCCCTGGAAG GGATATCCCC CGAGTTGGST CCCACCTTGG ACACACTGCA GCTGGACGTC r, λΛχ. -si ά m? v wxS. <3 · ^ _A

GTCCTGGTTG QTAGCCATCT GCAGAGCTTC CTGGAQGTGT CGTACQGCG * ’T '^ Af

S40

TCAGAGCT

AG ·

INFORM *

DQ

96;

EQuENCE CHARACTERISTICS; OK; LENGTH. · .919 case pairs (Bi TYPE: nucleic acid (C! STRANDEENESS: single ID.! TOPQXiUGY; linear nuclei ·:

acid / d »sc ® 'DMA (synthetic) txi; SEQUENCE DESCRIPTION; SEQ IO NO; 94ATGGCTAACT GCTCTATAAT GATCGATSAA

Ç?

attatacatc acttaaagag accacctgca

CTTCGACTTC CÀÀACCTGGA

GGTATTGAGG CAATTCTTCG .240

TCTCGACATC CAATCATCAT

392

TTCTATCTGG TTÀCCCTTGA .360

CCTCAATGAC GAAGACGTCT

QAGCTTCGTA AGGGCTGTCA

TAATCTCCAA CCATGTCTGC

CAAGGCAGGT Q.ACTGGCAAG

GCAAGCGCAQ GAACAACAGT

CTATCCTGAT GGACCGAAAC

AGÀACTTAGA AAATGCatca

CCTCTGCCAC GGCCGCACCC aattccggga aaaactgacg ÀCGTAGAGGG CGGTGGAGGC

TCCCCGGGTG GTGGTTCTGG CGGCGGCTCC AACATGGCTC

CCGAGTTGGQ TCCCACCTTG

TGGGAATSG .'OCT GCAQCCCÀCC CAGGGTGCCA TGCCCGCCTT UGCQTCTGCT

TTcCAuCGCI GGGCAGGAGS GQTCCTGGTT GCTAGCCATC TGCAGAGCTT CCTGGAGOTG

65Í ........ ...... ’* · ν» ν .. ^^ TTuv- ^ nui uuLT-wTGGCG GCTCTGGCGG OTCTCAi is β 0

GG ^ íGCTTGA GCCAACTCCA TAGCGGCCTT TTCUTCTACC AGGGGCTCCT GCAGGCCCTi

GAAGGGATAT CQTAATAA

918 il; INFORMATION FOR SEQ ID NO: 97;

Í1) SEQUENCE CHARACTERISTICS. ·.

(Al LENGTH; 963 base pairs (Hi TFFE: nucleic acid (U j STRAHDEDNESS; single (D; TOPOLOGY; linear (ti) MOLECULE TYPE: other nucleic acid! «.> DjiSi-RzP i xON; / desc« * X3NA i Synthetic i ”

ÍKÜ SEQUENCE DESCRIPTION: SEQ ID NO; 97-.

AIGGCTAACT GQTCTATAAT GATCGATGAA ATTATACATQ ACTTAAAGAG ACCACQTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCQTGAT GGACCQAAAC

CTTCuaCTTC CAAACCTGGA GAGCTTCGTA AGGUCTGTCA AGAACTTAGA AAATGCATOA

294

GGTATTGÀGG CAATTCTTCO TAATGTCCAA CCATGT0TG2 CCTCTGCCAC GGOCGCACGC x r ·.

ZfcL

TCTCGACATC CAA7CATCÀT CÀAGGCAGU? GACTGGCAAG AATTCCQGGA AAAACTGACG

TTCTATCTGG TTACCCTTGA GCAAGOGCAQ GAACAACAGT ACGTAGAGGG CGGTGGAGGC 3È0

TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACO CGTCTCCTCC GTCTAAAGAA

-4 · 2 <·

TCTCATAAAT GTCCAAACAT GGCTCCCGAG TTGGGTCDCA CCTTGGAOAC ACTSCAGCTG

8 C '

GAUGTvGCDG ΑΟΤΤτκ.'ΌΑ * ', _

-'- w-w,. · ... «Λ ^> _ Λ.ι ~ * νιχ» AAGAACTGG’G AATGGCCCC ^

540

u.ívTGíí ·. u 'i \ ^ uCuAGGG TGCOATGCCG GCTTTCGCCT CTGCT MCA) 3 *** ^{Ό ί} ϊ *?' * ^';Λ' ** · GGAGGGGTCO CCATCTGCAG AGCTTCCTGG AGGTGTCGTA TGGCTGCTAG CCGCdTCTA CGCCACCTTG CGCAGCCCTC TGGCGGCTGT GSCGGCTCTC AGASC TCCT-TTAGAGCAAG TGAGAAAGAT CCAGGGCGAT GGCGCAGCGC GCTCAAGTUT TOCAGGAGÀA SCTSTGTGCC AGCTACAAGC TGTGCCACCC CGAGGAGCTG GTGCTGCTCG GACACTCTCT GGGCATOCCQ β ^w

TGGGCTCCCC TGAGCTCCTG IncorporaçõesAGCCAG GCC'CTGCAGC TGGGAGGQTG CTTGAQCCAA CKCATAGOG GCCTTTTCCT CTACCAMOT OTCTGCASS CCCTGSMÍK OATATCCTMl

TAA

963 (2) INFORMATION For s _E q _xr > _K0 . _{$ s;} SEIENCE CHARACTERISTICS:

(A) LENGTH: 928 base pairs {R} TYPE: nucleic acid

ÍC) STRAMDmiESS: single

ÍD) TOPOLOGY: linear (ii) MOLECULE TYPE; other nucleic acid (A) DESCRIPTION: / desc * DNA (synthetic) ’

CCTCAATGAí

GAAGACGTOT

ΤΑ '

AAACOTGGA

AGAACTTAGA

ΛΛ,

GTGGTTCTGG

TGGCCCCTGC

AC L '^ UAsíTt »

80

CATGCCGGí

CTTCGCCTCd '

C <* <> ** / ** z * «x * Λ AAk3 \« 9

AGGGGTCCTQ

GTTGGTAGCv

ATCTGCAGAG

CCTGGAG

GTGTOGTACC

GCGTTCTACG: GGCTCTCAG

AGAGCAAGTG

AGAAAGATCC όδδ

AGGGCGATGG

CAGGAGAAG ’

TGTGTG;

TACAAGCTG

GCATCCCCTG

xr> .bh

CCAGCCAG®: CAGC

TGAGCCAACT

CATAGCGGí

CTGCAGGC ·;

CTGGAAGGGA

ACCTTGGACA

900

CCACCA.TCTG

GCAGCAGATG

GAAGAACTGG c; ç.....

GÀTAATAA

2} INFORMATION FOR SEQ ID NO: 99:

€ 29 ii; SEQUENCE CHARACTERISTICS;

fA: LENGTH; 999 base parrs {»: TYPE: nucleic sole (c; PTBANDESNESS; single fDi TOPOLOGY; linear in) MOLECULE TYPE; other nucleic acid duCRIPTIQN; / desc * “SNA isynthetic!

sxi: SEQUENCE DESCRIPTION: SEQ ID NO; 9 $;

ATGGCTAACT gctctataat gatcgatgaa ATTATACATO ACTTAAAGAG accacctgca CCTTTgCTGu ACCCOAACAA CCTCAATGAC GAAGACSTCT CTATCCTGAT GGACCGAAAC v..v «A .. _; ·. CnAACvTwGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA AAATGCA ^ AI 'ftV * *

SGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC TUTCGACRTC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG TTCTATCTGG TTACCCTTGA gcaagcgcag GAACAACAGT ACGTAGAGGG cggtggaggq TCCCCGGGTG AACCGTCTGG TCCAATCTOT ACTATCAACC CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT GGCTATGGCC CCTGCCCTGC AGCCCACCCA GGGTGCCATG CCGGCCTTCG CCTCTGCTTT CCAGCGCCGG GCAGGAGGGG TCCTGGTTGC I'AGCCATCTG CAGAGCTTCC TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGCAGCC CTCTGGCGGC TCTGGCGGCT CTCAGAGCTT CCTGCTCAAG TOTTAGAGC AAGTGAGAAA GATCCAGGGC gatggcgcag cgctcgagga gaagctgtgt gccacctaca agctgtgcca ccccgaggag CTGGTGCTGC TCGGACACTC TCTGGGCATC CCCTGGGCTC CCCTGGGCTC CCCTGAGCTC CTGCCCCAGC

297 s · VVX · 'ZX Z + Z * / V <** + Λ ^ .Λ / VZX X Λ · Α A'MW ZV.ZJkZMZ ^ V »^ · * X ** X, W Λ ** νχ χ XAWlAy · Ά '· Χ w> χ. - ..> - -. —- - ___. _ ·. . · ... · ·. . ·. ,. ·. ·. · _ ~ -Ui V. IkíDvAuL »\. * Σ.'χ. . Ο. ^ Λ / ~ Τ ~ <* ΑΤΑ COTCTACCA3 δ 41GGGCTCCTGC AGGCCCTGGA AGGGATAICC CQCGAGTTGG GTCCCACCir OGADxOAUTO

S S

CAGCTGGACG TCGCCGACTT TGCCACCACC ATQTGG2AGC AGATGGAAGA ACTGGGATAA

960 i'2; INFORMATION FOR SEQ ID KO; IOC:

(1Í SEQUENCE CHARACTERISTICS (A) LENGTH; 916 base pairs tB? TYPE: nucleic acid

IC) STRANDEDNESS ;. single (D> TOPOLOGY; Imear ii.) MOLECULE TYPE. ·, other nucleic acid (A; DESCRIPTION: / desc »* DNA (syntnetic (Xii SEQUENCE DESCRIPTION; SEQ ID NO; ISO;

ATGGCTAACT GQTCTATAAT GATCGATGAA ATTATACÀTC ACTTAAAGAG ACCACCTGCA 60

CQTTTGGTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC lie

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA AÀATGCÀTCA

180

GGTÀTFSAGG CAAITCTTCQ TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCA ^ C ^

Ç

TQTOGAQATC caatcatcac caaggcaggt gactogcaag aattccggga aaaactgacg 3QC

TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG CSGTGGAGGG

360 ................................ ........ ......... ... ...... ........ ...............................

TCCCCGGGTG GTGGTTUTGG CSGC> SGCTCC AAGATGGCTA CCCAGGGTGC CATGCCGGCC • 420 .......... .......... .................... ...................................

TTCGCCTCTG CTTTCCAGCG CCGGGCAGGA GGGGTCCTGG TTGCTAGCCA TCTGCAGAGC 4 & δ

TTCCTGGAGG TGTCGTACCQ CGTTCTACGC CACCTTGCGC AGCCCTCTGG CGGCTCTGGC

C.A ·>?) · .....

298

,** S·. / · »/ *“ XV ZV.fX \ .X Jv Ά *; <. ΛΧ, ^ χ. _v c „Λ Α * A _ r wftuwrtnviw ·, υηπΛϋΛ; cc? - GGGCGATGG:

TACAAGOm GCUACOCUQi GGAGCTGGTC

CTGCAGCTGG CAGGCTGCTT GAGCCAACTC? Χ · M f \ ......... ................ ................ ..........................

:> »U

CTGCAGG ·

840

GACGTCGUCG ACTTTGOCAC CAOCATCTGG $ 80

TGGAAGGGAT atcccccgag ttgggtccca

CATAGQGGCC TTTTCCTCTA CCAGGGGCTC

COTGGACAC ACTGCAGCTG

CAGCAGATGG AAGAACTGGG AATGGCCOCT

GCUCTGCAGC CCTAATAA

818 (2; INFORMATION FOR SEQ ID NG: 101:

ii.) SEQUENCE CHARACTERISTICS; (A; LENGTH. · §63 base pairs {£} TYPE. · Nucleic acid (Os STRANDEDNESS; single {D · TOPOLOGY ;, linear

MOLECULE TYPE: other nucleic acid .A: OxiECRIFTlON; / desc ® 'DNA (synthetic) (xi) SEQUENCE DESCRIPTION; SEQ ID NO; 101.

GATCGATGAA ATTATACATC ACTTAAAGAG ATGGCTAACT GCTCTATAAI ACCACCTOCA CTTTG ^ ^ ^ TQ ACCCGAACAA CCTCAATGAC GAAGACGTOT CTATCCTGAT GGACCGAAAC ISC ^ '^{"{VrtAACCTG SA} AGGGCTGTCA AGAACTTAGA AAATGCATCA UAGCTTCGTA ggtattgagg caattcttcg taatgtccaa ccatotctgc cctctgcqac ggccgcaccc a- ^ A · ^ * ,. CAATCATCAT CAAGGGAGGT GACTGGCAAG AATTCCGGGP. AAAACTGACG

299

TCTCATAAAT CTCCAAACAT GGCTACCCAG

4SC .........

TACCGCGTTC TACGCCACCT TGCGCAGCCC

5SÇ .........

CTGCTCÀAGT CTTTAGAGCA AGTGAGAAAG

AAGCTGTGTG CCACCTACAA GCTGTGCCAC

CTGGGCATCC CCTGGGCTCO CCTGAGCTCC

780

TGCTTGAGCC AACTCCATAG CGGCCTTTTC

845

GGGATATCCC CCGAGTTGGG TCCCACCTTG

900

GCCACCACCA TCTGGCAGCA GATGGÂAGAÀ

960 ................. ................

TAP.

C>: C ~ <.....

·> V? w?

u; A'CdA ^ Jax-ZGG CGdGGAGGC AUTATCAAd CGTCTCT 'QC GTd.VJkGAA GSTGCCATGC CGGCCTTCÇC AGCCATCTGC AGAGCTTCCT GGAGGTGTCG CTCTGCTTTC TCTGGCGGCT CTGGCG-GCTC TCAGAGCTTD ATCCAGSGCG CCCGAGGAGC TGGTGCTGCT CGGACACTCT ATÇGCGCAGC GdOCAGGAG TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA GACACACTGC AGCTGGACGT CGCCGÂCTTG CTGGGAATGG CCCCTGCCCT GCAGCCCTAA

U? INFORMATION FOR SEQ IO NO; 132;

> 11 SEQUENCE CHARACTERISTICS:

(A) length. ' 918 base pairs TYPE: nucleic acxd

IC) STRANDEDNESS; single (D) TOPOLOGY: linear iii) MOLECULE TYPE; ether nucleic acid (A) DESCRIPTION; / dess »’ UNA (synthetic) * {Ki} SEQUENCE DESCRIPTION; SEQ ID NO: 102;

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGC

300

CCTCAATGAC GÀAGACGTCT CTATCCTGAT GGACCGAAAC

L'TVCGACGTC CAAACiFTGGA GAGCTTCGTA ISO

GGTATTGAGG CAATTCTTCQ TÀATCTCCAA

340

TCTOSÃOTQ CAATCATCAT CAAGGCAGG7

ÀGGGCTGTCA AGAACTTAGA AAATGCATCA

CCATGTCTGC CTTCTGCGAC GGCCGCACCC

UAtiUwuAAG AATTCCGGGA AAAACTGACG

GAACAACAGC ACGTAGAGGG CGGTGGAGGC

TCCCOGGGTG GTGGTTCTGG CGGCGGTTCC

420

AACATGGCTT GTGCTTTCCA GCGCCGGGCA

GGAGGGGTCC TGGTTGCTAG CCATCTGCAG

4S0

AGçttcctgg aggtgtcgta ccgcgttcta

CGCTAC'TTTG CGCAGCCCTC TGGCGGGTCT

540

GGCGGCTCTC AGAGCTTCCT GCTCAAGTCT

-: axaAGvAats TGAGAAAGAT CCAGGGCGAT »0C

ACCTACAAGT TGTQCCADCC CGAGGAGCTG $ 60

TGGG'GTGCCe 'TGAGCTCCTG CCCOAGCCAG

720

GGCGCAGCGC TCCAGGAGAÀ GCTGTGTGCC

GTGCTGQTCG GAQACTCTGT GGGCATCGÇÇ

GCCeTGCAGC TGGCAGGCTG OTGAGCCAA mCATAGTG GCcmrUCT ^ _A xx „T \» uA \ »w> C '- ^ TvG.AAGG GATATCCCCÇ

GAGTTGGGTC CCACGTTGGA CACACTGCAG CTGSACGTCG CCGACTOGC CAC'CACQATC • 34 „*

TGGCAQCAQA TGGAAGAACT GGGAATGGCC CCTGCCCTGC AGCQGACCG4 GGGTGCCATG

CCGGCCTTCG CCTAATAA

918 (2) INFORMATION FOR SEQ ID NO.-. 103 ·

ÍÍ) SEQUENCE CHARACTERISTICS: LENGTH: 5S3 base pairs TIRE: nuclexc acid.

STRANDEDNESS; single TOPOLOGY; linear

301 ic · MOLECULE TYPE. other nuciexc acid

IA; DESCRIPTION; / dese ~ * DNA (synthetic) ’ixii SEQUENCE DESCRIPTION: SEQ ID NO: 103:

ATGGCTAACT GCTCTATAAT GATCGATGAA

.... ........

CCTTTGCTGS ACCCGAACAA CCTCAATGAC

CTTCGAGTTO CAAACCTGGA GAGCTTCGTA

ISO

GGTATTGAGG CAATTCTTCO TAATCTCCAA

0 .....

TCTCGACATC CAATCATQAT CAAQGCAGGT

300

TTOTATCTGG TTACCCTTGA GCAAGCGCAG

360

TCCCCGGGTG AACCGTCTGG TCCAATCTCT

42C

TCTCATAAAT CTCCAAACAT GGCTTCTGCT

480

GCTAGCCATC TGCAGAGCTT CCTGGAGGTG

540

CCCTCTGGCG GCTCTGGCGG CTCTCAGAGC

600

AAGATCCAGG GCGATGGCGC AGCGCTCCAG

660

CACCCCGAGG AGCTGGTGCT GCTCGGACAC

720 ..........

TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA

780

TTCCTCTACC AGGGGCTCCT GCAGGCCCTG

Ü

ATTATACATC ACTTAAAGAG ÀCCACCTGCA

GAAGACGTCT CTATCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA AAATGCATCA CCATGTCTGC CCTCTGCCAC GGCCGCACCC QACTQGCAAG AATTCCGGGA AAAACTGACG GAACAACAUT ACGTAGAGGG CGGTGGAGGC ACTATCAACC CGTCTCCTCC GTCTAAÀGAA TTCCAGCGCC GGGCAGGAGG GGTCCTGGTT TCGTACCGCG TTCTACGCCA CCTTGCGCAÔ TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA GÀGAÃGCTGT GTGCCACCTA CAAGCTGTGC TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC GGCTGCTTGA GCCAACTCCA TAGCGGOCTT GAAGGGATAT CCCCCGAGTT GGGTCCCACC

TTGGACACAC TGCAGCTGGA CGTCGCCGAC TTTGCCACCA CCATCTGGCA GCAGA ™ GGAA

800

302

TGGCCCCTGC CCTGCAGCCC AOCCAGGGTG CCATGCCGGO CTTCGCCTAA

50

INFORMATION FOR SEQ ID NO: 104:

ii) SEQUENCE CHARACTERISTICS;

ÍAJ LENGTH: §2 base pairs (B) TYPE; nucleic acid; STRANDEDNESS: single (D; TOPOLOGY; linear [ii) MOLECULE TYPE: -ether nucleic acid iA, DESCRIPTION; / desc * 'DNA {.synthetic; ¹ '(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104:

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAQ ACCACCTGCA

EC

CCTTTGÇTGG ACCCGAACAA CCTCAATGAC GXAGACGTCT CTATCCTGAT GGACCGAAAC

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGX AAATGCATCA 180 '...... .... ..........................

GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC OCTCTGCCAC GGCCGCACCC 240

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCQGGA AAAACTGAOG

300

TTCTATCTGG TTACCCTTGA GCAAGCGCAQ GAACAACAGT ACGTAGAGGQ CGGTGGAGGC

3 $ 0 ................................

TCQCCGGGTG GTGGTTCTSG CGGCGGCTCC AACATGGCTT ACAAGCTGTG CCACCCCGAG

420

GAGCTGGTGC TGCTCGGACA CTCTCTGGGC ATCCCQTGGG CTCCCCTGAG CTCCTGCCCC 480

AGCCAGGCCC TGCAGCTOGC AGGCTGCTTG AGCCAACTCC ATAGCGGCCT TTTCCTCTAC

540

CAGGGGCTCC TGCAGGCCCT GGAAGGGATA TCCCCCGAGT TGGGTCCCAC CTTGGACACA Εδΰ

CTGCAGCTGG ACGTCGCCGA CTTTGCCACC ACCATCTGGC AGCAGATGGA AGAA ^ GGGA

660 ..........

303

ATGGCCCCTG CCOTGCAGCC CACCCAGGGT GCCATGCCGG CCTTCGCCTC

720

CG2CGGÜCAG GAGGGGTCCT GGTTGCTAGC CATCTGCAGA GCTTCCTGGA

780

CGCGTTCTAC GCCACCTTGC GCAGCCCACA CCATTGGGCC CTGCCAGCTC

840 agottcctgc tcaagtctti agagcaagtg AGAAAGATCC AGGGCGATGO

900

CAGGAGAAGL TGTGTGCCAC 'CTAATAA

927 (2 · INFORMATION FOE SEQ ID NO: 105:

(i) SEQUENCE CHARACTERISTICS;

(A; LENGTH: $ 72 ha.se pairs (B; TYPE: rsucleit acid (0; STRANDEUNESSt single (D> TOPOLOGY; linear

Ui) MOLECULE TYPE: other nucleic acid (A; DESCRIPTION: / desc «* DNA <synthetic) · (Xi? SEQUENCE DESCRIPTION: SEQ ID NO: IOS;

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG 60

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT ISO

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA ISO

GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC

240

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAÀG AATTCCGGGA SCO

TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG

360

TGCTTTCCAG Q3X5 A V »1 i-xa x Ax.

CCTGCCCCAG

CGCAGCGCTC

ACCACCTGCA

GGACCGAAAC

AAATGOATCA

GGCCGCACCC

AAAACTGACG

CGGTGGAGGC

TCCCCGGGTG AACCGTCTGG TCCAATCTCT ACTATCAACC CGTCTCCTCC GTCTAAAGAA

420

2G4

T0TCATAÀA7 CTCCAAACAT GGCCTACAAG CTGTGCCACC CCGAGGAGCT GGTGCTGCTD

480

GGAMAUTCTC TGGGOATCCG CTGGGCTCCG CTGAGCTCCT GCCUGAGCCA GGCCTTGCAG 540

CTGGCAGGCT GCTTGAGCCA ACTCCATAGC GÜCCTTTTCC TCTACCAGGG GCTCCTGCAG

630 gccctggaag ggatatccco ggagttgggt cccaccttgg acacactgca GCTGGACGTC

660 gccgactttg ccaccaccat ctggcagcag atqgaagaac tgggaatggc ccctgccctg

23

CAGCCCAGCC AGGGTGCCAT GCCGGCCTTC GCGTCTGCTT TCCAGCGCCG GGCAGGAGGG

S0

GTCCTS3TTG CTAGCCATCT GCAGAGCTTC CTGGAGGTGT CGTACCGCGT TCTACGCCAC

840

CTTGCGCAGC CCACACCATT GGGCCCTGCC AGCTCCCIGU CCCAGAGCTT CCTGUTUAAG

9CC

TCTTTAGAGC AAGTGAGAAA GATCGAGGGC GATGGCGCAG CGCTCCAGGA GAAGCTGTGT

863

GCCACCTAAT AA

572 ........................

{2) INFORMATION FOR SEQ XD NO: 206:

{<· SEQUENCE CHARACTERISTICS:

tAj LENGTH: 927 base pairs

ÍB5 TYPE: nucleic acid (C) STRANDEDNESS; single (D) TOPOLOGY; linear (iij MOLECULE TYPE: ocher nucleic acid (A) DESCRIPTION; / desc »* DNA (synthetic)“ {Xi) SEQUENCE DESCRIPTION: SEQ ID NO; 106:

ATGGCTÀACT GCTCTATAAT GATCGATGAA ATTATACAT0

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT

120

ACTTAAAGAG ACCACCTGCA

CTATCCTGAT GGACCGAAAC “TTL ^ A'w *; C uAAAuCTuGA gagcttcgta agg ^ sctgtca agaacttaga aaatgcatca

18C ........ ......................................... ... .................. ^: ·· * ..... ^: .....

305 iU * SL> V WWX <- _A a> aa «V?

^: w

TOTCGACATC CAATOATOAT

00

GACACACTOC AGCTSQACG7 ^: 4 80

CTGGGAATGG IncorporaçõesTGCCCT

546

T7CCAGCGOC GGGCAGGAGG 600

TCGTACCGCG TTCTACGCCA

68.6

CDCCAGAGCT TCCTGOTCAA

72C

GIGCTCCAGG AGAAGCTGTG

780

CTCGGACACT CTCTGGGCAT

CAGCTGGCAG GCTGCTTGAG 9C-0

CAGGCCCTGG AAGGQATATC

9Ϋ7

TAATCTCCAA CCATGTCTQC CAAGGCAGGT GACTGGCAAG GCAAGCSCAG GAACAACACT CGGCGGCTCC AACATGGCTC CAGGGTGCCA CGCCGACTTT GCCACCACCA GCAGCCCAOC ggtcctggtt GCTAGCCATC CCTTGCGCAG CCCACACCAT QTCTTTAGAG CAAGTGAGAA aks i A * μ, Ίμ CCCCTGGGCT CCCCTGA.GCT CCAACTCGAT AGCGGCUTTY CTAATAA

CCTQTGCCAO GGCCGCACCG .AÂ-. * Λ

ACGTAGAGGG CGGTGGAGGC CCGAGTT'GGG TCCUACOTTG TCTGGQAGCA GATQGAAGAA TGCUGGCCTT CGCCTCTGCT TGCAGAGCTT GCTGGAGGTG TGGGCCCTGC CAGCTCCCTG AGATCCAGGG CGATGGCGOA ACCCCGAGGA GCTGGTGCTG CCTGCCCCAG CCAGGCCCTG TCCTCTACCA GGGGCTCCTG I'2) INFORMATION FOR SEQ ID NO: 107;

U) SE0ÜS4CE CHARACTERISTICS;

SA; LENGTH; 72 base pairs! B? TYPE; nucleic acid

IC; STRANDEDNESS: single (D> TOPOLOGY; linear iicj MOLECULE TYPE; ether nucleic acid tAj DESCRIPTION; / àese «‘ DNA {synthetic)

306 ixi. ' SEQUENCE DESCRIPTION. SEQ ID NO; 107;

AYUGITAãCT ΟΓΤίΜΑΤΑΑΤ GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA 6v

CCTTTGCTGG KCCCGAADAA CCTCAATGAC GAAGACGTCT CTATCCTGAC GGACCGAAAC ISC ·

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA AAATÇQATCA 1W ....................... ..........

ggtattgagg caattcttcg TAATCTCCAA ccatgtctgc CCTCTGCCAC GGCCGCACCC 24 E

TCTCGACATS AATCATCAT CAAGGCAGGT GACTGGCAAG AATTCQGGGA AAAACTGACG ........ oof

TTCTATCTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAQAGGG CGGTGGAGGC 36C ...... .... ......

TCCCCGQGTG AACCGTCTGG TCQAATCTCT ACTATCAACC CGTCTCCTCC GTCTAAAGAA 42C

TCTCATAAAT CTCCAAACAT GGCTCCCGAG TTSGGTCCCA CCTTGGACAC ACTGCAGCTG

48C ................................. ................ .......... ..........

GACGTCGCCG ACTTTGCCAC CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT

S4C ................... .... .... ..............

GCCCTGCAGC CCACCCAGGG TGCCATGCCG GCCTTCGCTT CTGCTTTCCA GCGCCGGGCA

SCO

GGAGGGGTÜC TGGTTGCTAG CCATCTGCAG AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA »50

CGCCACCTTG CGCAGGCCAC ACCATTGGGC CCTGCCAGCT CCCTGCCCCA GAGCTTCCTG

720

CTCAACTCTT TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGOT CCAGGAGAAG

780

CTGTGTGCCA CCTACAAGCT GTGCCACCCC GAGGAGCTGG TGCTGCTCGG ACACTCTCTG

84C

GGCATCCCCT QGGCTCCCCT GAQCTCCTGC CCCAGCCAGG CCCTGCASCT GGCAGGCTGC

500

TTGAGCTAAC TCCATAGCGG CCTTTTCCTC TACCAGGGGC TCCTGCAGGC CCTGGAAGGG

950

ATATCCTAAT AÀ

Wi < ^s ................. s ........

<2) I.NFDRMATXCN FOE SEQ ID ND: XOg:

3Q7 ii; SEQUENCE CHARACTERISTICS:

{Ai LENGTH ·. $ 27 base parrs (B) TYPE-, nucleic acic. {C} STRANDEDNESS: SUSjle (Di TOPOLOGY; linear ii) MOLECULE TYPE: ether nucleic acid (A? DESCRIPTION :. / desc = “DNA (synthetic) txl) SEQUENCE DESCRIPTION; SEQ ID ND: £ 10:

atggctaact gctctataat GATCGATGAA attatacatc acttaaagag ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC 'GMK3ACGTCT CTATCCTGAT GGACCGAAAC 1: 2 0

CTTCGACTTC CAAACCTGGA GAGCTTCGTA ASGGCTGTCA AGAACTTAGA AAATGCATCA: 181

GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC

0

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCQGGA AAAACTGACG ice ..............

TTCTATCTGG TTACCCTTGA GCAASCGCAG GAACAACAGT ACGTAGAGGG CGGTGGAGGC

360

TCCCCGGGTG GTGGTTCTGG CGGCSGCTCC AACATGGGTA TGGCCCCTGC CCTGCAGCCC

420

ACCCAGGGTG CCATGCCGGC CTTCGCCTCT GCTTTCCAGC GCCGGGCAGG AGGGGTCCTG

480

GTTGCTAGCO ATCTGCAGAG CTTCCTGGAG GTGTCGTACC GCGTTCTACG CCACCTTGCG

540 .... ... ..

CAGCCCACAC CATTGGGCCC TGCCAGCTCC CTGCCCCAGA GCTTCCTGCT CAAGTCTTTA

600

GAGCAAGTGA GAAAGATCCA GGGCGATGGC GCAGCGCTCC AGGAGAAGCT GTGTGCCACC

660

TACAAGCTGT GCCACCCCGA GGAGCTGGTG CTGCTCGGAC ACTCTCTGGG CATCCCCTGG 720

GCTCCCCTGÂ GCTCCTGCCC CAGCCAGGCC CTGCAGCTGG CAGGCTGCTT GAGCCÀACTC? 3C

3Q8

CATAGCGGC2 TTTTCCTCTA CCAGGGGCTC CTGCAGGCCU TGGAAGGGAT ATCCCCCGAG

840

TTGGGTCCCS CGTTGG4CAC AOTGGAGCTG GACGTCGCCG ACTTTGCCAC CACCATCTSG

900 ........... ...............................

CAGCAGATGG AAGAACTGGG ATÀATAA

927 (2j INFORMATION FOR SEQ ID NO ·. 109;

(I; SEQUENCE CHARACTERISTICS;

(A; LENGTH: 972 base pairs {D-TYPE; nucleic ecid

IC; STRANDEDNEDS: single iD: TOPOLOGY: linear (ii) MOLECULE TYPE; ether nucleic acid (A? DESCRIPTION; / desc »« DNA {synthetic} * (Xi; SEQUENCE DESCRIPTION: SEQ ID NO: 109:

ATGGCTAACT GGTCTATÀAT GATCGATGAA ATTATACATU ACTTAAAGAG ACCACCTGCA SO

CCTTTGCTGG AGCCGAACAA CCTCAATGAC GAAGACGTCT UTATCGTGAT GGACCGAAAC 13 0

CTTCGACTTC CÀAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAACTTAGA AAATGCATCA

18BÍ ............ ............................ .... ..... . ......

GGTATTGAGG CAATTCTTCS TAATÜTÕCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC

240:

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTQGCAAG AATTCCGGGA AAAAQTGACG

300

TTCTATCTGG TTACCCTTGA GQAAGCGCAG GAACAACAGT ACGTAGAQGG CGGTGGAGGC

ONLY

TCCGCGGGTQ AACCGTCTGG TCCAATCTCT ACTATCAAQÇ CGTCTCCTCC GTCTAAAGAA

20

TCTCATAAAT CTCCAAACAT GSCTATGGCC CCTGCCCTGC AGCCCACCCA GGGTGCCATG

4BÕ ....... .......................................... ..................

CCGGCCTTCG CCTCTGCTTT CCAGCGCCGG GGAGGAGQGG TCCTGGTTGC TAG ^ CA ^ CTG

540

CAGAGCTTCC TGGAGGTGTC GTACCGCGTT CTACGCCACC TTGCGQAGCO CA ^ ACCATTG SOO

309

TG 77 'C ΑΑ & Τ CT'CTTAG AGTGA \ »AAA * ^

AÂGCTGTGTG CGACOTACAA G27GTGCCAC \ s · w XíÂtMXSjfXta X * sc «wmwivwíMíw * '

Vvr -wL iiyrss’wi-w U x ~ vi xszxoa

TGCTT3AGCC AAC7CCÀTAG CGGCCTTTTC

GGGATATCCC CCGAGTTGGG TCCQACGTT =

507

AGCTGGACGT

GCCACCACCA TCTGGCAGCA GATGGAAGAA

CTSOGATAA '> * (2) INFORMATION FOE SEQ ID KO; 11C;

(i} SEQUENCE CHARACTERISTICS;

(A) LENGTH: 927 base pairs (S <TYPE: nucleic aexd fC; STRANDEDNESS: single

CD) TOPOLOGY: linear (ii! MOLECULE TYPE: other nucleic acid {A; DESCRIPTION: / ãesc * * DNA {synthetic J “(Xi) SEQUENCE DESCRIPTION; SEQ ID NO; 110;

ATSGCTAACT GCTTTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGAUGTCT CTATCCTGAT GGACCGAAAC

7 .............................. ..............

CTTCGACTTC CAAACCTSGA GASCTTCGTA AGGGCTGTCA AGÀACTTAGA AAATGCATCA

ISO

GGTATTQAGG CAÃTTOTTCG TAATCTCCAA CCATGTCTGC CCTCTÔCCAC GGCCSCACCC

240

TCTCGACATC CAATCATCAT CAAGGCAGGT GAOTGGCAAG AATTCCGGGA AAAACTGACO

300

310

TTCTATOTGG TTACDCTTGA GCAAGCGCAG

3ÔC ..........

TCCCCGGGTG GTGGTTCTGG CGGUGGCTCC

420

TTCGCCTCTG CTTTCCAGCG OCGGGCAGGA

480 ........

TTCCTGGAGG TGTCGTACGG CGTTCTACGC

54.0 .............. ......

gcqagctccc tgccccagag cttcctgctc

600

GGCGATGGCG CAGCGCTCCA GGAQAAGCTG

660

QAGCTGGTGC TGCTCGGACA CTCTCTGGGC 720

AGCCAGGCCC TGCAGQTGGC AGGCTGCTTG

780

CAGGGGCTCC TGCASGCCCT GGAAGG-3ATA 840

Cii ^ vaCCxsA CTTTGCiw ^ ACC $ 00

ATGGCCCCTG CCCTGCAGCC CTAATAA $ 27

GAACAACAGT ACGTAGAGGG CGGTGGAGGI AACATGGCTA CCCAGGGTGC CATGCCGGCC QGGGTCCTGG TTGCTAGCCA TGTGCAGAG

CACCTTGCGC AGUCCACAC ”ATTGGGGC2T

AAGTUTTTAG AGCAAGTGÀG AAAGATUCAG

TGTGCCACOT ACAAGCTGTG CCACCCCGAG

ATCCCCTGGG CTCCCCTGAG CTCCTGCCCO AGCCAACTCC ATAGCGGCUT TTTUCTCTAC TCCCCCGAGT TGGGTCCCAC CTTGGACACA

ACCATCTGGC AGCAGATGGA AGAA.CTGGGA (2) INFORMATION FOR SEQ ID NO: Ill:

{if SEQUENCE CStóRACTERISTXCS:

IA; LENGTH: $ 72 base pairs? B) TYPE: nucleic acid (0) STRARDNDNESS; single (Dj TOPOLOGY; linear iii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION; / desc = ^: * DNA (synthetic} (Xi) SEQUENCE DESCRIPTION; SEQ ID NO: 111;

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCÀ «0

CCTTTGCTGG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTATCCTGAT GGACCGAAAC

311; , '._ Χ5Λ ftf:

GGí

480

FCCAGGAGA

840

GCCCTGGAAG

900

LzA.v £ \ 1v.v,

972

CTCCAAACAT

CCTGGTTGCT

AQAGCTTCCT

GCCCTGCCAG

TGCTCAAGT

AGCTGTGTG

GCTTGAGCCA

GGATATCCC

ACCÀCCAT

AP

TTTAGAGCAA

TGGGCTCCC

CGAGTTGGG ”atggaagaa:

TCCAGGGCGA

CCGAGGAGCT

GCCCCAGOCA

ACACACTGCA

GGTG gctggacgtc

CC ⁵ ***

INFORMATION FOR SãQ ID NO;

(THE?

ÍB)

Si) SEQUENCE CHARACTERISTICS;

LENGTH-. 927 ba.se pairs TYPE: nucleic acid singre .312

Ui; MOLECULE TYPE, other nucleic arid iAi DESCRIPTION ·. / deSC ~ DNA (synthetic) ”(XI) SEQUENCE DESCRIPTION; SEQ XU NO; 112:

atggctaact cctctataat gatcgatgaa attatacatc acttaaagag accacctgca sc

CCTTTGCTGC · ACCCGAACAA. CCTCAATGAC GAAGÀCGTCT CTATCCTGAT GGACCGAAAC ilof _{: K} ........ ........ ........ ........ ..... ·· .... ....

CTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGOTGTCÀ AGAACTTAGA AAATGCATCA :: 180 / _{::: <} .....

GGTATTGAGG CAATTCTTCG TAATCTCCAA CCATGTCTGO CCTCTGCCAC GGCCGCAGCG '240: ................

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGG.A AAAACTGACG

330

TTCTATCTGG TTACSXTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGC CGGTQGAGGC

340 .... ............ ............

TCCOCGGGTG GTGGTTCTGQ CGGCGGCTCC AACATGGCTT CTGCTTTCCA GCGCCGGGQA

420 ..........

GGAGGGgrCC TGGTTGCTAG CCATCTGCAG ÀGCTTCCTGG AGOTGTCGTA CCGCGTTCTA

480 '

CGCCACCTTG CGCAGCCCAC ACCAT7GGGC CCTGCCAGCT CCCTGCCCCA GAGCTTCCTG

542

CTCAAGT CTT TAGAGC.AAGT GAGAAAGATC CAGQGCGATG GCGCAGCGCT CCAGGAGAAG 8CC

CTGTGTGCCA CCTACAAGCT GTCCCAQCCC GAGGASCTGG T3CTGCTCGG ACAGTCTCTG

850

GGCATCCOCT GGGCTCCCCT GAGCTCCTSC CCCAGCGAGG CCCTGCAjSCT GGCAGGCTGC

720

TTGAGCCAAC TCCATAQCGG CCTTTTCCTC TACCAGGGGC TÇÇTGCAGGC CCTGGAAGGG

780

ATATCCCCCG AGTTGGGTCC CACCTTGGAC ACACTGCAGC TGGRCGTCGC CGACTTTGCC

84C

ACCACCATCT GGCAGCAGAT GGAAGAACTG GGAATGGCCC ctgccctgca GCCCACCCAG

900

313, d 1 y ^ -Ky U- ΑΛ; O INFORMATION FOR SEQ ID NO: 113:

i; SEQUENCE CHARACTERISTICS:

(A) LENGTH; 972 base pairs

ÍE} TYPE; nucleic acid tO STRANDEDNESS: axngle (D) TOPOLOGY: linear

Ui; MOLECULE TYPE; ether nucleic acid {A? DESCRIPTION: / date * DMA (synthetic) ’(XX) SEQUENCE DESCRIPTION: SEQ ID NO: 113:

ATGGCTAACT GCTCTATAAT 62

CCTTTGCTGG ACCCGAACAA .126

CTTCGACTTC CAAACCTGGA

IRQ

GGTATTGAGG CAATTCTTCG

240

TCTCGACATC CAATCATCAT

300

TTCTATCTGG TTACCCTTGA

360

TCCCCGGGTG AACCGTCTSG

420

TCTCATAAAT CTCCAAACAT

480

GCTAGCCATC TSCAGAGCTT

540

CCCACACCAT TGGGCCCTGC

00

CAAGTGAQAA AGATCCAGGG

660

AAGCTSTGCC ACCCCGAGGA

720

GATCGATGAÀ ATTATACATC CCTCAÀTGAC GAAGÂCGTCT GASCTTCSTA AGGGCTGTCA TAATCTCCAA CCATGTCTGC CAAGGCAGGT GACTGGCAAG GCAAGCGCAG GAACAÀCAGT TCCAATCTCT ACTATCAACC GGCTTCTGCT TTCCAGCGCC CCTGQAGQTG TCGTACCGCG CAGCTCCCTG COCCAGAGCT CGATGGCGCA GCGCTCCASG GCTGGTGCTG CTCGGACACT

ACTTAAAGAG ACCACCTGCA

CTATCCTGAT GGACCGAAAC

AGAACTTAGA AAATGCATCA

CCTCTGCCAC GGCCGCACCC

AATTCCGGGA AAAACTGACG

ACGTAGAGGG CGGTGGAGGC

CGTCTCCTCC GTCTAAAGAA

GGGCAQGAGG QGTCCTGGTT

TTCTACGCCA CCTTGCGCAG

TCCTGCTCAA GTCTTTAGAG

AGAAOCTGTG TGCCACCTAC

CTCTQGGCAT SAMSTGGGCT .314

SAMSTGAGCT DCTGCCCCAG CCAGGCCCTG CAGCTGGOAS GCTGCTTSAG CCAACTCCAT

780

AGCGGCCTTT TCOTCTACCA GGGGCTCCTG CAGGCCCTGG AAGGGATATC→GAGTTG

840 .............................................. ... ... ........

GGTCOCAOCT TGGACACACT GCAGGTGGAC GTCGCCGACT TTGCCACCAC CATOTGGCAG ajjg ...... ......

CAGATGQAAG AACTGGGAAT GGCCCCTGCC CTGCAGCCCA CCCAGGGTGC CATGCCGGCC

960 .............. .. ..

TTCGCCTAAT AA «72 (2? INFORMATION FOR SEQ ID NO: 114:

fi> SEQUENCE CHARACTERISTICS:

(A) LENGTH; 953 base pairs

CB) TYPE: nucleia acid (C) STRANDEDNESS: single (D> TOPOLOGY: linear • ill) MOLECULE TUBE: other nucleic acid (A) DESCRIPTION: / desc «* DNA {synthetic?

(XX) SEQUENCE DESCRIPTION: SEQ ID NO: 114;

ATGGCTAACT GCTCTAACAT GATCGATGAA ATCATCACCC ACCTGAAGOA GCCAUCGCTG SO

CCGCTGCTGG ACTTCAACAA CCTCAATGGT GAAGACCAAG ATATCCTAAT GGA-DAATAAC

120

CTTCGTCGTC CAAACCTCGA GGCATTCÂAC CGTGCTGTCA AGTCTCTGCA GAATGCATCA

180

GOAATTGAGA GCATTCTTAA AAATCTÜDTG CCATGTCTGC CGCTÀGCCAC GGCCGQACCr

240

ACGCGACATC CAATCCATAT CAAGGAGGGT GACTGGAATG AATTCCGTQG TAAACTGACO

Ç

TTCTATCTGA AAACCTTGGA GAACGCGQAG GCTCAACAGT ACGTAGAGQG CGGTGGAGGC

350

TCCCCGGGTG AACCGTOTGG TCCAATCTCT ACTATGAACC CGTCTCÕTC ”GTCTAAAGAA

420

315

TCTCATAÀAY CTECAAACAT GGCTACCCAG GGTGCCATGC CGGQCTTOGC CTCTGCTTTC

4FC

CAGCGCCGGG caggaggggt cctggttgct agccatctgc AGAGCTTCd 'ggaggtgtcg

540 ............... ........ ..............

TACCGCGTTC TACGCCACCT TGCGCAGCCC TCTvsG ^ uttóU.i t λ1 u,, ri

6QC .............. ...... ...........................

CTGCTCàAGT CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG ATGGOGCAGC GCTCCAGGAG 6δ 0

AAGCTGTGTG CCA.CCT / mV GCTGTGCCAC cccgaggagc tggtgctgct ^cggacactct: w ··

CTGGGCATCC CCTGGGCTCC CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC 7g0

TGCTTGAGCC AACTCCATAG CGGCCTTTTC CTCTACCAGG GGCTCCTGCA GGCCCTGGAA. S4C

GGGATATCCC CCGAGTTGSG TCCCACCTTG GACACÂCTGC AGCTGGACGT CGCCGACTTT

906

GCCACCACCA TCTGGCAGCA GATGGAAGAA CTGGGAATGG IncorporaçõesTGCCCT GCAGCCCTAA

9SC;

TAA

96.3 {Qi INFORMATION FOR SEQ IO NO; 115:

Í.1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 972 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single

TOPOLOGY ID: linear ill} MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: / desc ® ‘DMA (synthetic)’ '(Xi) SEQUENCE DESCRIPTION; SEQ ID NO: 115:

ATGGCTAACT GCTCTAACÀT GATCGATGAA ATCATCACCC ACCTGAAGCA GCCACCGCTG

ÍQs | 3 | ........... ..... s....... .....

CCGCTGCTGG acttcaaoaa cctcaatggt gaagaccaag atatcctgat ggaaaataac 120

CTTCGTCGTC CAAACCTCGA GGCATTCAAC CGTGCTGTCA AGTCTCTGCA GAATGCATCA

180

GCAATTGÂGA GCATTCTTÀA AAATCTCCTG CCATGTCTGC CCCTGGCCAC GGCCGCACCC

24u

ACQCGACATC CAATCATCAT CCGTGACGGT GACTGGAATG AATTCCGTCG TAAACTGACC

300

TTCTATCTGA AAACCTTGGA GAACGCGCAG GCTCAAGAGT ACGTAGAGGG CGGTGGAGGC

60

TCCCCGSGTG aaccgtctgg tcoâatctct ACTATCÀACC CGTCTCCTCC GTCTAAAGAA.

TCTCATAAAT CTCCAAACAT GGCTACCCAG GGTGCCATGC CSGCCTTCGC CTCTGCTTTC

480

CAGCGCCGGG CAGGAGGGGT CCTGGTTGCT AGCCATCTGC AGAGOTTCCD GGAQGTGTCG

540

TACCGCGTTC TACGCCACCT TGCGCAGCCC ACACCATTGG GCCCTGCCAG CTCCCTGCCC sco .............. ............................. .................................

CÀGAGOTTC2 TGCTCAAGTC TTTAGAGCAA GTGAGÀAAGA TCUAGGGCGA TGGCGCÀGCG SSO

CTCGAGGAGA AGCTGTGTGC CACCTACAAG CTGTGCUACC CCGAGGAGGT GGTGUTGCTC

GGACACTCTC TGGGCÀTCOC CTGGGGTCCC CTGAGCTCOT GCCCCAGCCA GGCCCTGCÀG

780 ............. .... ................................ ................

GTGGCAGGer GCTTGAGCCA ACTCCATAGC GGCCTTTTCC TCTACCAGGG GCTCCTGCÀO

B4ÍÍ

GCCGTGGAAG GGATATCCGC GGAGTTOGGT CCOACCTTGG ACACACTGCA GCTGGAGGTO

900

GCCGACTTTG CCACCACCAT CTGGCAGCkG ATGGAÀGAAC TGGGAATGGC CCCTGCCCTG

9 $ 0

CAGCCCTAAT AA

972 (2} INFORMATION FOR SEQ ID ND: 116:

(i) SEQUENCE CHARACTERISTICS;

(A) LENGTH; 963 base pairs

ÍB) TYPE: nucleic acid (C) STRANDEXJNESE Σ single (D) TOPOLOGY; linear iiii MOLECULE TYPE; cth® ”nucleic acid (A) DESCRIPTION: / deSC *’ DNA {synthetic) *

317 (κί · SEQUENCE DESCRIPTION; SEQ ID NO; .it;

ATGGCTAAOT GCTCTAACAT GATÜGATGAA

CCGCTGGTGG ACTTCAACAA CCTCAATGGT

CTTCGTCGTC CAAACCTCGA GGCATTCAAC

0

GQAATTGAGA GCATTCTTAA AAATCTCCTG

240 acgcgacato caatcatcat CCGTGACGGT

300

TTCTATCTGA AÂACCTTGGA GAACGCGOAG

60 ............

TCCCCGGGTG AACCGTCTGG TCCAATCTCT

4W .............

TCTCATAAAT CTCCAAAOAT GGCTACCCAG

480

Z *: * W *: ** »** -»:

viU * J \ j w £

S40

TACCGGGTTO TACGCCACCT TGCGCAGCCC

600

CTGCTCAAGT CTTTAGAGCA AGTGAGAAAG

660

AAGCTGTGTG CCACCTACAA GCTGTGCCAC

720

OTGGGCATDC CCTGGGCTCO CCTGAG'OTCC

780

TGCTTGAGCC AACTCCATAG CGGCCTTTTC

840

GGGATATCOC CCGAGTTGGG TCCCACCTTG

900

GCOACCACCA TCTGGCAGCA GATGGAAGAA

960

ATOATCACCC ACOTGAAGCA SCCACCGCTG GAAGACCAAG ATATGCTGAT GGAAAATAAO CGTGCTGTCA AGTCTCTGCA QAATGOATCA CCATQTCTGC CCCTGGCCAC GGCCGCACGC GAGTGGAATG AATTCCGTCG TAAACTGACO GCTCAACAGT ACGTAGAGGG CGGTGGAGGC ÀCTATCAACC CGTCTCCTDO GTCTAAAGAA GGTGCCATGC CGGCCTTCGC CTCTGOTTTC AGCCATOTGO AGAGCTTCCT GGAGGTGTCG TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC ATCGAGGGGG ATGGCGCAGC GCTCOAGGAG CCCGAGGACC TGGTGCTGCT CGGACACTCT TGCCCCAGCC AGGCCCTGCA GCTGGCAGGC CTOTACUAGG GGCTCCTGCA GGCCCTGGAA GAQACACTGC AGCTGGACGT CGCCGACTTT CTGGGAATGG CCCCTGCCCT GCAGCCCTAA

ύ) SEQUENCE CHARACTERISTICS. · (A; LENGTH; 972 base pairs (E; TYPE: nucleic acid (Ci STRANDEDNESS: single (D? TOPOLOGY ·· linear iii) MOLECULE TYPE; other nucleic acid {A) DESCRIPTION .; / best » “DNA isynthetic? * (XX? SEQUENCE DESCRIPTION; SEC CD ND; 117-.

ATGGCTAACT SCTCTAACAT GATCGATGAA

SC

CCGCTGCTGG ACTTCAACAA CCTCAATGGT

CTTCGTCGTC CAAACCTCGA GGCATTCAAC 180

GCAATTGAGA GCATTCTTAA AAÀTCTCCTG 240.

ACGCGACATC CAATCCATAT CAAGGACGGT

302

TTCTATCTGA ÀAACCTTGGA GAACGC3CAG

360 ....................

TCCCCGGGTG AACCGTCTGG TCCAATCTCT

420 tctcataaat ctccaaacat ggctacccag

480

CAGCGCCGGG CAGGAGGGGT CCTGGTTGCT

S40

TACCGCGTTC TACGCCACCT TGOGCAGCCC 6C0

CAGAGÇTTCC TGCTCAAGTC TTTAGAGCAA SOO

CTCCAGGAGA AGOTGTGTGC CAÇCTACAAG

ATCATCACCC ACCTGAAGCA GCCACCGCTG

GAAGACCAAG ATATCCTAAT GGACAATAAC

CGTGCTGTCA AGTCTCTGCA G.AATGC.ATCA

CCATGTCTGC CGCTAGCQAC GGCCGCACCC

GACTGGAATG AATTCGGTCG TAAACTGACC

SCTCAACAGT ACGTAGÀGGG CGGTGGAGGC

ACTATCAACC CGTCTCCTCC GTCTAAAGAA

GGTGCCATGC CGGCCTTCGC CTCTGCTTTC

AGCCATCTGC AGAGCTTCCT GGAGGTGTCG

ACACCATTGG GCCCTGCCAG CTCCCTGCCC

GTGAGAAAGÁ TCCAGGGCGA TGGCGCAGCG

CTGTGCCACC CCGAGGAGCT GGTGCTGCTC

319

TCTACCAGGG

GCCCTGGAAG

908

GGATATi

ATGGAAGAAC i'2j INFORMATION FOR SEQ TO NO; US;

¢ 1

SEQUENCE CHARACTERISTICS;

(THE;

(AND;

<C;

(Di

LENGTH: 818 base pairs TYPE: nucleic acid STRANDEDNESS; s ing1 © TOPOLOGY; linear

MOLECULE TYPE: other nucleic acid (A · DESCRIPTION: / desc «fsynthetic)

SEQUENCE DESCRIPTION: SEQ ID NO; 118:

GCTAACTGOT

CTATAATGAT

CGATGAAATT

ATACATCACT

TAAAQAGAC ·

CGAACAACCT

CAATGACGAA

TCCTGATGGA

CCGAAACCTT

CGACTTCCAA

180

ACCTGGAGAG

GCTGTCAAGA

ÀCTTAGAAAA

TGCATCAGGT

ATTGAGGCAÀ

240

TCTCCAACCA

TGTCTGCCCT

CTGCCACGGC

CGCACCCTCT

CGACATCCAA

300

TCATCATCAA

SGCAGGTGAC

TGGCAAGAAT

TCCGGGAAAA

ACTGACGCTC

TATOTGGTTA

CCCTTGAGCA

ACCGCAGGAA

CAACAGTACG

TAGAOGGCGG

TGGÀGGCTCC

CCGGGTGAAC

420

CGTCTGGTCC

AATCTCTACT

ATCAACCCGT

TAAAGAATCT

320

CATAAATCTC CPUACATGGA GGTTQACCCT TTGCCTACAC CTGTCCTGCT GCCTGCTGTG

480

SACmJC- '.' jOCSAGAATG gaaaacccag atggaggaga cgaagggaca ggacattcig

540 .....

GGAGCAGTGi dTTTCTGOT GGAGGGAGTG ATGGCAuCAC GGu ^ sACAAH: 6: 80 ::

TGCCTCTCA * C — CTCCTGGG GCAGCTTTCT GGACAGGTCC GTCTCCTCCT TGGGGCCGTG

660 ................

cagagdto; ttsgaaccca gcttcctcca cacggcagga ccacagctca caaggatccc

AATGGCATC7 T ^ TTGAGCTT CCAACATCTG CTCCGAGGAA ÀGGTGCGTTT CCTGATGCTT 780 ......................................... ...............

gtaggagggt cczaccctctg cgtcagggaa ttcggcggca acatggcgtc TCCCGCICOG

840

CXTGCTTGTC ACXTCCGACT CCTQAGTAAA CTGCTTCGTG ACTCCCATGT CCTTCAOAGC soo

AGACIGAGC? A3TGCCCÂ

S18 (2) INFGROSX & iS FDR SEQ XD ND: 119:

ii? SEyEJDJCE CHARACTERISTICS:

iRQ LENGTH: 918 base pairs tSQ TIRE: nucleic acid

X2 STRANDEDHESS; single; D3 TOPOLOGY ·, linear • ii) SOUSEULE TYPE: other nucleic acid {A.) DESCRIPTION: / desc * «DNA (synthetic) ·

(xi) SlSXJmCE DESCRIPTION: SEQ ID NO: 119:

GCTAACTGCr CTATAATGAT CGATGAAATT ATAQATCACT TAAAGAGACC ACCTGCACCT 66

TIGCTGGAOe CKSAACAAGCT caatgacgaa GACGTCTCTA tcctgatgga CCGAAACCTT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT 180

A.TTGAGGCRA TTCTTCGTAA TCTCCAACCA TSTCTGCCCT CTGCCACGGC CGCACCCTCT

0

321

CGACATCCAA TCATCATCAA GGCAGGTSAC TGGCAAGAAT TCCGGG.AAAA ACTQACGTTC

3C0

TATCTGGTTA CCCTTGAGCA AGCGCAQGàA CAACAGTACG TAGAGGGCGG TGGAGGCTCC llil ................

CCGGGTGAAC CGTCTGGTCC AATCTCTXCT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

0 ^:

CATAAATCTG CAAACATGTT GCCTACAGCT GTCCTGCTGC CTGCTGTGGA CTTTAGCTTG

480

GGAGAATGGA AAACCCAGAT GGAGGAG & OC àAGGCATAGG ACATTCTGGG AGCAGTGACC

540

CTTCTGCTGG AGGGAGTGAT GGCAGCAC4G GGACAACTGG GACCCACTIG CCTCTCATCC

600

CTCCTGGGGC AGCTTTGTGG ACAGGTCD1T 'CTCCTCOTTG GGGCCCTGGA GAGCCTCCTT 66C ..... ...... ........

GGÀACCOftGC TTCCTCCACA GGGCAGGAOC ACAGCTOACA AGGATCUQAA TGCOATCTTC

723

CTGAGCTTCC AACACCTGCT CCGAGGÃAAG · GTGCGTTTCC TGATGCTTGT AGGAGGGTCC? Δ · 3

ACCOTCTGCG TCAGGGAATT CGGCGGCAAT ATGGCGTCTC CCGUTUCGGC TGCTTGTGAC

840

CTUCGAGTCC TCAGTAAACT GCTTCOTGAC FCCCATGTCC TTCACAGCAG ACTGAGCCAG

900

TGCCCAGAGG TTCACCOT

918 (2) INFORMATION FDR SEQ ID NC; L20;

(i) SEQUENCE CHARACTERISTICS:

{A} LENGTH: 918 Jtaxrs (8) TYPE: nucleic acid

IC) STRANDEDNESS; sas & reads {D; TOPOLOGY; lines ™ (11} MOLECULE TYPE: ether fiutclelc acid (A) DESCRIPTION: ZcesC ® «DNA (synthetic} · (Xi J SEQUENCE DE ^ IPTIOJ ?: EEQ ID NO: 120:

322

GOTAACCGOY ΙΤΑΤΑΑΤίΑΤ

TTGTYQGACG CGAAOAAOCT

120

CGACTTCCAA ACCTGGA & AO

ISO

ATTGAGGCAA TTCTTCGTAA

240

CGAOATCCAA TCATCATC ^ A

00

TATSTGG7TA OOCTTSAGCA

360

CCGGGTGAAC CGTCTGCTCC

420

CATAAATCTC CAAACAIGOT

480

ACCCAGATGG ASGAGACGAA

540

GGAGTGsATGG CAGCAGG3C3G

60S

CTTTCTGGAC AGCTCCGTC1

60

CCTCCACAGG GCAGGA'XAC

720

CACCTGCTCC GAGGAAAG <3T

80

AGGGAATTCG QCGQCAACAT

840

AGTAAACTGC TTCGTSAC TO

900 ogatgaaatt atacatcact CAATQACGAA GACGTCTCTA 2TTCGTAAGG GCTGTEAAGA TCTCCAACCA TGTCTGCCCT GGCAGGTGAC tggcaagaat AGCGCAGQAA CAACAGTACG AATCTCTACT ATCAACCCGT CCTGCTGCCT GOTGTGGACT GGCACAGGAC ATTCTGGGAQ ACAACTG'GGA CCCACTTGCC CCTCCTTGGG GCCCTGCAGA AGCTCACAAG QATCCCAATG GeGTTTCeTG ATGOTTGTAG GGCGTCTCCC GCTCCGCCTG CCATGTCUTT CACAGCAGAC

TAAAGAGACG ACdOCACCO

TCCTGATGGA CCGAAACCTT

AÇTTAGAAAA TGCATCAGd

CTGCCACGGC CGCACCCTCT TCCGGGAAAA ACTGACGTTG TAGAGGGCGG TGGAGGCTCC CTOCTCCGTC TAAAGAATCT

TTAGCTTGGG ÀGAATGG.ÀAA

CAGTGACCUT TCTGCTGGAG

TCTCATCCCT CCTCGGGCAG

GCCTCCTTGG AACCCAGCTT

CCATCTTCCT GAGCTTCQAA

GAGGGTCCAC CCTCTGCGTC

CTTGTGACCT CCQAGTGCTC

TGAGCCAGTG CCCAGAGGTT

CACCCTTTGC CTACACXT

SI 8

(2) INFORMATION FOE, SEQ ID NO: 122;

i> SEQUENCE CMRACTERISTXCS:

(A) LES33TH; 918 base pairs {&} TYPE; nucleic acid

IC) S7RA2rOEDNES £: single i D: TOPOLOGY; - mear fll) MOLECULE TYPE ·. ether'ntóeic acid (A. · DESCRIPTION- / dasc »* D« A isynthat xc · '(Xi; SEQUENCE DESCRIPTION; SEQ ID NO; 121:

GCTAACTGCT CTATAATGAT CSATSAAATT ATACATCACT TAAAGAGAC ACCTGCACCT

TTGOTGGACO CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTI

CGACTTCCAA ÀTCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT 2.80

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCGTCT

240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGGAAGAAT TCCGGGAÀAA ACTGACGTTC

300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAÀCAGTACG TAGAGGGCGG TGGAGGCTCC

360

CCGGGTGAAC COTCTGGTCC AATCTCTACT ATCAACCCST CTCCTCCGTC TAAAGAATCT

420

CATAÀATCTC CAAACATGGC TGTGGACTTT AGCTTGGGAG AATGGAAAAC CCAGATGGAÇ

48-C ........ ............

GAGACCAAGG CACAGGACAT TCTGGGÂGCA GTGACCCTTC TGCTGGAGGG AGTGATGGCA S4C ......

GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC TGGGGCAGCT TTCTGGACAG

600

GTCCGTCTCC TCCTTGGGGC CCTGCAGAGC CTCCTTGGAA CCCAGCTTCC TCCACAGGQC

660

AGGACCACAG CTCACAAGGA TCCCAATGCC ATCTTCCTGA GCTCOVO CCTGCTCCGA

720

GGAAAGGTGC GTTTCCTQAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG GGAATTCGGC 780

GGCAACATGG CGTCTCCCGC TCCGGGTGCT TGTGACCTCC GAGTCCTCAG TAAACTQCTT

840

CGTGACTCCC ATGTCCTTCA CÀGCAGACTG AGCCAGTGCC CAGAGGTTCA CCCTTTGCOT '

900 ..................

324; i; INFORMATION FDR SEQ ID NO: 122:

(í? SEQUENCE CHARACTERISTICS:

(A) LENGTH: SIS base pairs (B? TYPE: nucleic, acid fC; ETRANDEDNESS: single

ID) TOPOLOGY: linear (ii '; MOLECULE TYPE: ocher nucleic acid (A) DESCRIPTION ·. / Õesc = ΈΝΑ {synthetic)

5Xi) SEQUENCE DESCRIPTION: REQ ID NO: 112;

CGATGAAATT ATACATCACT

UCTAACTGCT CTATAATOAT SC

TTGCTGGACC CGAACAACCT 12 C

CGAUTTCCAA ACCTGGAGAG ISO

ATTGAGGCAA TTÇTTÇGTAA 240

CGACATCCAA TCATCATCAA

300

TATCTGGTTA CCCTTGAGCA

ONLY

CCGGSTGAAC CGTCTGGTCC

420

CATAAATCTC CAAACATGGA

480

ÂAGCCÀCAGG ACATTCTGGG 540

GGACAACTGG GACCCACTTC áoc

CAATGACGAA GACGTCTCTA CTTCGTAAGG GCTGTCAAGA TCTCCAACCA TGTCTGCCCT GGCASGTGAC TGGCAAGAAT AGCGCAGGAA CAA.CAGTACG AATCTCTACT ATCAACCCGT CTTTAGCTTG GUAGAATGGA ASCAGTGGCT

TAAAGAGACC ACCTGCACCT TCCTGATGGA CCGAAACCTT ACTTAGAAAA TGCATCAGGT CTGCCACGGC CGCACCCTCT TCCGGGAAAA ACTGACGTTC TAGAGGGCGG TGQAGGCTCC CTCCTCCGTC TAAAGAATGGGGGGGGGGGGGGC

CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAÀCCCAGC TTCCTCCACA GGGCAGGA ^ C

660

325

ACAGCTOAOA AGGACCCCA? ·. TGCCATuTTC CTGAGCTTCC ÀACACCTGCT CCGAGGAAAG

720

GTGCGTTTCO TOATGCTTGT AGGAGGGTCC ACCC7CR5CG TCAGGGAACT CCGCG3CAAC 780

ATGGCGTCTC CCGCTCCGCC TGCTTGTGAC CTCCGAGTCC TCAGTAAACT GCTTCOTGAC

MO .......... ................ ..........

TCCCATGTCC TTCACAGCAG ACTGAGCCAG TGCCCAGAGG TTCACCCTTT GCCTACACCT §0i

CTCTTGCTGC CTGCTGTQ ili INFORMATION FOR SEQ ID NO: 123:

(1} SEQUENCE CHARACTERISTICS:

(A) LENGTH: 807 base pairs ip; TYPE: nucleic acid £ C} STRANDEDNESS; single (D) TOPOLOGY: linear iti} MOLECULE TYPE: other nucleic acid (A) DESCRIPTION :. / dear * “DMA (synthetic) · (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123:

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACQ ACCTGCACCT so

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

120

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

ISO ........ ........

ATTGAGGCAA TTCTTCGTAA. TCTCCAACCA TGTCTGCCCT CTGCCACGGC CUCACCCTCT .240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACQTTC

300

TATCGGTTAC UCTTGAGCAA GCGCAGGAAC AACAGTACGT AGAffiSGCGGT GGAGGCTCCC

3:50

CGGGGAACCG TCTGGTCCAA TCTCTACTAT CAACCCGTCT CCTCCGTCTA AAGAATCTCA 42®

TAAACTCCAA ACATGGQAGA ATGGAAAACC CAGATGGAGG AGACCAAGGC ÀCAGGACATT

480

326

CIGGAGCAGT gacccttctg ctggagggag tgatggcagc acggggacaa ctsggaccca> 40 ···· .......... ........

CTTGCTCTCA TCCCTCCTGG GGCAQCTTTC TGGACAGGTO CGTCTCCTCC TTGGGGCCCT $ oc

GCAGGCCTCC TTGGAACCCA GCTTCCTCCA CAGGGCAGGA CGACAGCTCA CAAGGATCCC

660 aatgcatctt CCTGAGCTTC CAACACCTGC tccgaggaaa gotgcgtttc ctgatgcttg

TAGGGGGTCC ACCCTCTGCG TCAGGGAATT CGGCGGCAAC ATGGCGTCTI CCGCTCCGCC

78C

TGCTGTGAOT TCCGAGTCCT CAGTAAACTG CTTCGTGACT CCCATGTCCT TCACAGCAGA

840

CTGACCAGTG CCCAGAGGTT CACCCTTTGC CTACACCTGT CCTGCTGCCT GCTGTGGACT

93C ............... ........ ...... ..........

’’ TW '* Fr ***** T * íTí:

X 4. * Ά Am?

907 {2 · INFORMATION FOE SEQ ID NO: 124:

Í1) SEQUENCE CHARACTERISTICS;

(A) LENGTH: §18 base pairs (Bl TEPE: nucleic acid (CJ STRANDEDNESS: single {D) TOPOLOGYr linear (ii) MOLECULE TYPE; other nucleic acid (As DESCRIPTION: .Meat ® DNA (synthetic) * (Xi) SEQUENCE DESCRIPTION: SEQ IE NO: 124;

G2TAACTGCT CTATAATGAT CGATGAAAdT ATACATCACT TAAAGAGACC ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT 120

CGACTTGCAA ACCTGGAGAG CTTCGTAAGG GCTCTCAAGA ACTTAGAAAA TGCATCAGGT 186

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

240 ........

327

CGACÀTCCAA TOATCATCAA GGCAGGTGAC TGGCAAGAAT TCOGGGAAAA ACTGACGTTC

7 '^: ........ ^ -7: 7: .........

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGCGCGS TGGAGGCTC2

360 .................. ........

CCGGGTSAAC CGTCTGGTCC ÂATCTCTACT ATCAACCCGT CTCCTGCGTC TAAAGAATGX

420

CATAAATOTC CAAACATGGG ACCCACTTGC CTCTCATCCC TCCTGGGGCA GCTTTCTGGA

460

CAGGTCCGTC TCCTCCTTGG GGCCCTGCAG AGCCTCCTTG GAACCCAGCT TCCTCCACAG

640

GGCAGGACCA CAGCTCACAA GGATCCCAAT GCCATCTTCC TGAGCTTCCA ACACCTGCTC

6C0

CGAGGAAAGG TGCGTTTCCT GATGCTTGTA GGAGGGTCCA CCCTCTGCGT CAGGGAATTC

660

GGCGGCAACA TQGCGTCTCC CGCTCCGCCT GOTGTGACC TCCGAGTCCT CAGTAAACTG

720

CTTCGTGACT CCCATGTCCT TCACAGCAGA CTGAGCCAGT GCCCAGAGGT TCACGCTTTG

SC

CCTACACGTC TCCTGCTGCC TGCTGTGGAC TTTAGCTTGG QAGAATGGAA AACQQAGATG

840

GAGGAGACCA AGGOACAGGA CATTCTGGGA GCAGT8ACCC TTCTGCTGGA GGGAGTGATG

900

GCAGCACGGG GAGAACTG

9X8 (2! XNFORMATION FDR SEQ ID NO: 125;

U) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 848 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ill MOLECULE TYPE: ether nucleic acid {A} DESCRIPTION: / desc * 'DNA (synthetic) (Xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 125:

GCTAACTGCT CTATAATGAT CGATQAAATT ATACATCACT TAAAQAGACC ACCTGCACC ^

328

TTGOTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGÀ CCGAAACCTT.:. «£ · .w

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT ISO

ATTGAGGCAA TTCTTCGTÀA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT 240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACGTTC ..... ....................................... ..... ..... ............. .....

tatctggtta cccttgagca AGCGCAGGAA caacagtacg TAGAGGGCGG TGGAGGCTCC 360 (XGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TÀAAGAATCT λ r? Γ *

Τί · 4> Si »·

CATAAATCTC CAAACATGGG AACCCAGCTT CCTCCACAGG GCAGGACCAC AGTTIAIAAG

80

GATCCCAATG CCATCTTCCT GAGCTTCCAA CACUTGCTCC GAGGAAAGGT GCGTTTCCTG 545

ATGCTTGTAG gagggtccac cctgtgcgtc agggaattcg ggggcaacat ggggtctccu S0 &

GCTCCQCCTG CTTGTGACGT ccgagtcctc agtaaactgc ttcgtgactc ccatgtcctt

660

CACAGCAGAC TGAGCUAGTG COGAGAGGTT CACCCTTTGe GTACACeiGT GCTGCTGCGT

7:20

GCTGTGGACT TTAGCT7GGG AGAATGGAAA ACCCAGATGG AGGAGACCAA GGCACAGGAC

ONLY

ATTCTGGGAG CAGTGACCCT TCTGCTGGAG GGAGTGATGG CAGCACGGGG ACAACTGGGA

840

CCCACTTG

848 .................

(2> INFORMATION FOR. SEQ ID NO: 126;

ÍÍ} SEQUENCE CHARACTERISTICS:

(A) LENGTH: SIS bats® pairs (B) TYPE: nucleic acid

ÍC) STRANDEDNESS: single (D) TOPOLOGY: linear fii) MOLECULE TEPE: ocher nucleic acid (A) DESCRIPTION: / desc ® * ISiA (synthetic) *

329 xj? SEQUENCE DESCRIPTION ·. SEQ EE KO; € 12;

GCTAAOTGÓ7 GTATAATGAT CGATGAAAT? ATACATCACT TAAAGAGACC ACCTGCACCT

TTCCTGGACC CGAACAACCT oaatgaggaa gacgtctcta tcctgatgga CCGAAACCTY

OGACTTCCXA ACOTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT 180

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

2 | 0 | Is 7 ·: »S 77

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

300 .... .... .... .. .. .. ......

TATCTSGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG TGGAGGCTCC

60

CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

CATAAATCTC CAAACATGGG QAGGACCACA GCTCACAAGG ATCCCAATGC CATCTTCCTG

UC ..... ...... ............ ..........

AGCTTCCAAC ACCTQCTCCC AGGAAÃGGTG UGTPTCCTQA TGCTTGTAGG AGGGTCCACC

540

CTCTGCGTCA GGGAATTCGG CGGOAACATG GCGTCTQCCG CTCCGCCTGC TTGTGACCTC

600

CGAGTCCTCA GTAAACTGCT TCGTGA.CTCC CATGTC-CTTC ACAGCAGACT GAGCCAGTGC

680

CCAGAGGTTC ACCCTTTGCC TACACCTGTC CTGCTGCCTG CTC3TGGACTT TAGCTTGGQA

720

QAATQGAAAA CCQAGATGGA GGAGACCAAS GCACAGGACA TTCTGGGAGC AGTGACCCTT

780

CTGCTGGAGG GAGTGATGGC AGCACGGGGA CAA.CTGGGAC CCACTTGGCT CTCATC ^ CTC

840

CTGGGGCAGC TTTCTGGACA GGTCCGTCTC CTCCTTGGGG CCCTGCAGAG CCTCCTTGGA

900

ACCCAGCTTC CTCCACAG

918 {2) INFORMATION FOR SEQ ID NO: 127:

330 ii; SEQUENCE CHARACTERISTICS;

ΐΛ; LENGTH ·. 918 base pairs its? TYPO; nucleic acic

MD STRAMDEDNESS: single

ÍD) TOPOLOGY ·· linear ill) MOLECULE TYPE; ocher nucleic acid (A) DESCRIPTION; / dear «” DNA (synthetic? ’; xi) SEQUENCE DESCRIPTION; SEQ ID NO; 127 ·.

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACC TAAAGAGACC

SC ............. .................................... ...

ACCTGCACCT

TTGd GGAO C

CGAACAACCT CAATGÀCGAA

GACGTCTCTA TCCTGATGGA

CCGAAAQOTT

CGACTTCCAA ACCTGGASAC CTTCGTAASG IL

GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

ATTGAGGCAA TTCTTCGTAA

TCTCCAACCA TGTCTGCCOT CTGCCACGGC

CGCACCOTOT

CGACATCCAA TuATCATCAA GGCAGGTGAC .0'3: 0 ·

TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

TATOTGGTTA CCCTTGAGCA AGCGCAGOAA CAACAGTACG TAGAGGGCGG TGGAGGCTCC

360

CCGGGTGAAO CGTCTGGTCC

420

CATAAATCTC CAAACATGGC

480

OTGCTCCGAG GAAAGGTGCG

GAATTCGGCG SCAACATGGC

SOD

AAACTGCTTC GTGACTCCCA

660

CCTTTGCCTA CACCTGTOCT

720

AATCTCTACT ATCAACCCGT TCACAAGGAT CCCAATGCCA TTTOCTGATG OTTGTAGGAG GTCTCCCGCT CCGCCTGQTT TGTOCTTCAC AGCAGACTGA

GCTGCCTGCT GTGGACTTTA

CTGCTCCGTC TAAAGAATGT

TCTTCCTGAG CTTOCAACAC

GGTQCACCCT CTOCGTCAGG

GTGAÇCTCCG AGTCCTCAGT

GCQAGTGCCC AGAGGTTCAC

GCTTGGGAGA ATGGAAAACG

CAGATGGAGG AGACCAAGGC ACAGGÀCATT CTGGGAGCAG TGACCCTTCT GCTGGAGGGA

7W ...... ................ .................... ....... ..........

331

GTGATGGIAG CACQGGGACA ACTG3GACCC AUTTGCCTCT CATCCCT'CCT GGGGCAGCTT & 4K ·

TCTGGACAGG TCCGTCTCTT CCTTGGGGCC CTSCAGAGCC TCCTJiiGft ^ / lASOTICTT

908 ....... ........................

CCAQAGGGCA GGACCACA

918? 2: INFORMATION FOR SEQ ID NO: 128:

(if SEQUENCE CHARACTERISTICS:

(A) LENGTH: $ 18 base pairs (B; TYPE: nucleic acid (Cl STRAJOEDNESS: single (Di TOPOLOGY: linear fiii MOLECULE TYPE; ether nucleic acid (A) DESCRIPTION; / desc «’ DNA (synthetic) *

Uli SEQUENCE DESCRIPTION: SEQ ID NO: 123;

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT 6C

TTGCTGCACC CGAACAACCT CAATGACQAA GACGTCTCTA TCCTGATGGA CCGAAACCTT 120

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTCTCAAGA ACTTAGAAAA TGCATCAGGT

ISC

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTQTGCCCT CTGCCACGSC CGCACCCTCT 240

CGACATCCÀA TCATCATCAA GGCAGGTGAC TGSCAAGAAT TQCGGGAAAA. ACTGA COTTI

380

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG TGGÂGGCTCC

380 ......... ...... .................................. .........

CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

430

CATAAATCTC CAAACATGQA TCCCAATGCC ATCTTCCTGA GCTTCCAACA QCTGCTCCGA

480

GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG GGAATTCGGC

540 ............................. ...... ..........

GGCAACATGG CGTCTCCCGC TCCGCCTGCT TGTGACCTOC GAGTCCTCAG TAAACTGCCT

800 .....................

CGTGACTCCO ATGTOCTTCA OAGCAGACT-O AGCCAGTGCC CAGAGGTTCA CCCTTTGCCT is Q

ACAGCTGTCO TGCTGCCTGC TGTGGACTTT AGCTTGGGAG AATGGAAAAC OCAGATGGAG

720

GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC TGCTGGAGGG AGTGATGGCA

780

GCACGGGGAC AACTGGGACC CACTTGCCTC TCATCCCTCC TGGGGCAGCT TTCTGGACAG

840:

4-x. 1 vu 1 wL - i uxxvS '^ y. i Síix- ^ sisJwav. V a icrciftA

90S

AGGA.GCAGAG CTCAGAAG o ^ i ⁵ · ..........

(2) XNFCaRMATXON FOR SEQ XD NO: 129:

id.? SEQUENCE CHARACTERISTICS. (A> LENGTH: 818 base pairs (8) TIRE: nucleic acid

IC; - STEANTEDNESS: sxngle (D? TOPOLOGY: 1inear <: ÜJ MOLECULE TYPE: ether nucleic acid (ΑΪ DESCRIPTION; / desc »’ DMA (synthetic) * (xi) SEQUENCE DESCRIPTION: SEQ ID NO ·. 129:

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TÀAAGAGACC ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGÀA GACGTCTCTA TCCTGATGGA CCGAAACCTT 12C ·

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

180

ATTGAGGCAA TTCTTCSTAA TCTCQAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

300

TATCTGGTTA CCCTTGAGCA AGCGCAGQAA CAACAGTACG TAGAGGGÇGG TGGAGSCTÇC

359 ...... .... .................... .......

333

CCSGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTOGTCCGTC TAAAGAATd

CATAAATCTC CAAACATGGC CATGTTCCTG AGCTTCCAAC ACCTGCT <'CG AGGAd-GGTG

480 ............................................. .... ....

CGTTTCCTGA TGCTTGTAGG AGGGTCCACC CTCTGCGTCA GGGAATTCGG CGGCAACATG

0 .......................... ....................... .............

GCGTCTCCCG CTCCGCCTGC TTGTGACCTC CGAGTCCTCA GTAAACTGCT TCGTGACTCO SCO

CATGTCCTTO ACAGCAGACT GAGCCAGTGC CCAGAGGTTC ACCCTTTGCC TACACUTGTD

S50 .............. .......................... ......... .......

CTGCT ^ CCTG CTGTGGACTT TAGCTTGGGA GAATGGAAAA CCCAGATGGA GGAGACCAAG

72.0 ........ ...... ......

GCACAGGACA TTCTGGQAGC AGTGACCCTT CTGCTGGAGG QAGTG.ATGGC AGCACGGGGA

ONLY

CAACTGGGAC CCACTTGCCT CTGATCCCTC CTSGGGCAGC TTTCTGGACA GGTCCGTCTC

840

CTCCTTGGGG CCCTGCAGAG CCTCCTTGGA ACCCAGCTTC CTCCACAGGG CAGGACCACA

90'0

GCTCACAAGG ATCCCAAT

918

2; INFORMATION FOR SEQ ID NO; 130;

ii; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 515 base pairs (B) TEPE: nucleic acid {0) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE; other nucleic acid (A) DESCRIPTION: / from »c ®’ Dna (synthetic) ’{Ki) SEQUENCE DESCRIPTION: SEQ ID NO: 1301

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT T.AAAGAGACC ACCTGCACC ^ 50

TTGCTGGACC CGÃACAACCT CAATGACGAA GACGTCTCTA TCUTGATGGA COGAAACCT ^

120 .............. ................ ..........

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGG * f ISO

334

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

CGACATCCAA TCATCATCAA GGCAGGTGAO TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

300

TATGTGSTTA CCCTTGAGCA AGCGCAGGAA CAACAGTAOG TAGAGGGCGG TGGAGGCTCC Γ ^{Κ | Ι} ζ ................... .......... id! .....

CCGGGTGÀAC CGTCTGGTCC AATCTCTACT ATCAACCCQT CTCCTCCGTC TAAAGAATCT

OR .......... ........

CATAAATCTC CAAACATGGA GGTTCACGCT TTGCCTACAC CTGTCCTGCT GCCTGCTGTG

480 ........... ...... ........

GACTTTAGCT TGQGAGAATG GAAAACCCAG ATGGAGGAGA CCAAGGCACA GGACATTCTG

540

GGAGUAGTGA CCCTTCTGCT GGAGGGAGTG ATGGCAGCAC GGGGACAACT GGGACCCAOT

600

TGCCTCTCAT eCCTCGTGGG GCAGCTTTCT GGACAGGTQC GTCTGCTCCT TGGGGCCCTS

6S0

GAGAGCCTCO TJGQÀACUCA GCT7CCTCGA CAGGGCAGGA. CCACAGGTCA CXAGGATCCC

AATGUCATCT TCCTGAGCTT CCAACACCTG CTCCGAGGAA AGGTGCGTTT CCTGATGCTT

780 .................. ** '

CTAGGAGGGT CCACCCTCTG CGTCAGGGAA TTCGGCAAQA TGGCGTCTCC CGGTCCGCC ^ 840

GCTTGTGACC TCCGAGTCCT CAGTAAACTG CTTCGTGACT CCCATGTCCT TCACAGCAGA

900

CTGAGCCAGT GCCCA

915 (2) INFORMATION FOR SEQ ID NO; 131:

íi} SEQVSNCE CHARACTERISTICS:

(A) LENGTHr 915 base pairs (B) TYPE; nucleic acid (C) STRANDDDNESS; single {D) TOPOLOGY: linear (laughs) NULECtFLE TYPE: other nucleic acid (A) DESCRIPTION: / desc ~ “DMA (synthetic)“

335

SEQUENCE DESCRIPTΙΟΙ ·. SEQ ID NO: iji;

GCIAACTSCT ctataatgat cgacgaaatt Atacatcact taaagagacc acctgcacci

........ ..... · <<<<<<< ........ ........ <............

TTGOTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

120

CGACTTCCAA ACOTGGAGAG CTTCGTAAGG GCTGTCAAGA ÂCTTAGAAAA TGCATCAGGT

ISO attgaggcaa ttcttcgtaa tctccaacca tgtctgccct ctgccacggc cgcaccctct • 240 ...... .................... ............ ... .........

CGACATCCAA TCATCATCAA ggcaggtgac tggcaagaat tccgggaaaa actgacgttc

3C-0

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG TGGAGGCTC

350 <

CCGGGTGAÂC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

420

CATAAATCT'C CAAACATGTT GCCTACACCT GTCCTGCTGC CTGCTGTGGA CTTTAGCTTG

480

GGAGAATGGA AAACCCAGAT GGAGGAGACC AAGGCACAGG ACATOCTGGG AGCAGTGACC

542:

CTTCTGCTGG AGGGAGTGÀT GGCAGCACGG GGACAACTGG GACCCACTTG CCTCTCATCC

6δδ

CTCCTGGGGC AGCTTTCTGG ACAGGTCCGT CTCCTCCTTC GGGCCCTGCA GAGCCTCCTT β

GGAACCCAGC TTCCTCCACA GGGCAGGACC ACAGCTCACA AGGATCCCAA TGCCATCTTC

720

CTGAGCTICC AACACCTGCT CCGAGGAAAG GTGCGTTTCC TGATGCTTGT AGGAGGGTCC

78C ......

ACCCTCTGCG TCAGGGAATT CGGCAÀCATG GCGTCTCCCG CTCCGCCTGC TTGTGACCTC

542

CGAGTCCTCA GTAAACTGCT TCGTGACTCC CATGTCCTTC ACAGCAGÁCT GAGCCAGTGC

90S ..... ............. ........ ........

CCAGAGGTTC ACCCT §15 ......

U; INFORMATION FOR SEQ ID NO: 132:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 915 base pairs

336

ÍH; TYPE; nucleic acid iC) STRANDEDNESS · Single {□ j TOCOLOGY: linear ill} MOLECULE TYPE: ether nucleic acid (A? DESCRIPTION; / dess = DNA (synthetic’s (κι j SEQUENCE DESCRIPTION.- SEQ ID NO; 132:

GCTAACTGCT CTATAATGAT CGATGÂAATT ATACATCACT TAAAGAGACC ACCTGCACCT

60 ..... .......... ............

TTGCTGGACC CGAACAACCT CAATGAOGAA GACGTCTCTÀ TCCTGATGGA CCGAAACCTT

CGAUTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

186

ATTSAGGCAA TTCTTCGTAA TCTCCÂACCÂ TGTCTGCCCT CTGCCACGGC CGCACCCTTT

240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAOAAT TCOGGGAAAI ^ ACTGACGTTC

302

TPiT'CTGGTTA CCCTTGAGCA AGCGCAGGAA CAÂCAGTACG TAGAGGGCGG TGGAGGCTCC

360

CCGGGTGAAC CGTCTGGTCO AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

420

CATAÀATCTC CAAACATGGT CCTGCTGCCT GCTGTGGACT TTAGCTTGGG AGAATGGAAA

460

ACCCAGATGG AGGAGACCAA GGCACAGGAC ATTCTGGGAG CAGTGACCCT TCTGCTGGAG

540

GGAGTGATGG CAGCACGGGG ACAACTGGGA CCCACTTGCC TCTCATCCCT CCTGGGGCAG

600 .....

CTTTCTGGAC AGGTCCGTCT CCTCCTTGGG GCCCTGCAQA GCCTCCTTGG AACCCAGÚTT

680

CCTCCACAGG GCAGGACCAC AGCTCACAAG GATCCCAATG CCATCTTCCT GAGCTTCCAA

0

CACCTGCTCC GAGGAAAGGT GCGTTTCCTG ATGCTTGTAG GAGGGTCCAC CCTCTGCG'K '

780 ...... .................. ......................... .....

AGGGAATTCG GCAACATGGC GTCTCCCGCT CCGCCTGCTT GTGACCTCCG AGTCCTCAGT

840

337 aaaotgctti gtgactccca tgtcottcac AGOAGACTGA gccagtgccc AGAGGTTCAC (2: INFORMATION FOR SEQ IT NO '. 133' · (ij SEQUENCE CHARACTERISTICS:

{THE; LENGTH: 815 base pairs (Si TYPE: nueisic acid iC · STRANDEDNESS: single (Di TOPOLOGY; linear (11; MOLECULE TYPE: ether nucleic acid (A! DESCRIPTION: / âesrc «“ ONA (Synthetici '(χχϊ SEQUENCE DESCRIPTION: SEQ IE NO; 133:

GCTAACTGCT CTATAATGAT CGATGAAATT

TTGCTGGACC CGAACAACCT CAATGACGAA

120

CGACSTCCAA ACCTGGAGAG CTTCGTAAGG

180 attgaggcaa ttcttcgtaa tctccaacca

240 cgacatccaa tcatcatcaa ggcaggtgac

300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

350

OCGGGTGAAÇ CGTCTGGTCC AATCTCTACT

420

CATAAATCTC CAAACATGGC TGTGGACTTT

4S6

GAGACCAAGG CACAGGACAT TCTGGGAGCA

540

GCACGGGGAC AACTGGGACC CACTTGCCTC

600

GTCCGTCTCC TCCTTGGGGO CCTGCAGASC

660

ATACATCACT TAAAGAGACC ACCTGCACCT GACGTCTCTA TCCTGATGGA CCGAAACCTT GCTGTCAAQA ACTTAGAAAA TGCATCAGGT TGTGTGCCCT CTGCCACGGC CGCACCCTCT TOGCAAGAAT TCCGGGAAAA ACTGACGTTC CAACAGTACG TAGAGGGCGG TGGAGGCTCC ATGAACCCG'T CTCCTCCGTC TAAAGAATCT AGCTTGGGAG AATGGAAAAC CCAGATGGAG GTGMICCTTC TGGTGGAGGG AGTGATGGCA TCATCCCTCC TGGGGCAGCT TTCTGGACAG CTCCTTGGAA CCCAGCTTCC TCCACAGGGC

338

AGGACCACAG CTCACAAGGA TCCCAATGCC ATCTTCCTGA SCTTCCAACA CCTGCTCCGA

726

GGAAAGGTGC GITTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG GGAA.TTCGGC

78C ....................................... ........

AACATGGCGT CTCCCGCTCC GCCTGCTTGT GACCTCCGAG TCCTCAGTAA ACTGCTTCGT. ·. · ................

GACTCCCATG TCCTTCACAG CAGACTGAGC CAGTGCCCAG AGGTTCACCC TTTGCCTACA .903

CCTGTCCTGC TGCCT

915

(2) INFORMATION FUR SEQ ID NO; 134;

iij SEQUENCE CHARACTERISTICS:

(A; LENGTH: SIS base pairs (E · TYPE; nucleic acid (C) STRANDEDNESS: single (0) TOPOLOGY; linear ill / MOLECULE TYPE ·: other nucleic acid (A) DESCRIPTION: / desc «« DNA (synthetic) *

IxiJ SEQUENCE DESCRIPTION; SEQ ID NO: 134;

gctaactgct ctataatgat cgatgaaatt

6δ ttgctggacc cgaacaacct caatgacgaa

126

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG

ISO

ATTGAGGCAA TT'CTTCGTAA TCTCCAACCA

246

CGACATCCAA TCATCATCAA GGCAGGTGAC 300

TATCT6GTTA CCCTTGAGCA AGCGCAGGAA

360

CCGGGTGAAC CGTCTGGTCC AATCTCTACT

420

ATACATCACT T.AAAGAGACC ACCTGCACCT

GÀCGTCTCTA TCCTQATGSA CCGAAACCTT

GOTGTCAAGA ACTTAGAAAA TGCATCAGGT

TGTCTGCCCT CTGCCACGGC CGCACCCTCT

TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

CÀACAÔTACG TAGAGGGCGG TGGAGGCTCC

ATCAACCCGT CTCCTCCGTC TAAAGAATCT

CATAAATCTQ CAAACATGGA CTTTAGCTTC- GGAGAATGGA AAACCCAGAT GGAGGAGACC

80

ArtO \ ídhvA \? V k \ * AVs # V ΑννΛν’Λ Lwa. ζ ^ ν

540 ggagaactgg gacccacttg CCTOTCATCD ctcctggggg agctttctgg ACAGGTCCGT

SCO

CTCCTCCTTG GGGCCCTGCA GAGCCTCCTT GGAACCCASC TTOCTCCACA GGGGAGGACC

665

ACAGCTCACA AGGATCCCAA TGCCATCTTO CTGAGCTTCQ AACAUCTGCT CTGAGGAAAG

GTGCOTTTCC TGATGGTTGT AGGAGGGTCC ACCCTCTGCG TCAGGGAATT CGGOAACATG 780

GCGTCTCCCG CTCCGCCTGQ TTGTGACCTC CGAGTCCTCA GTAAACTGCT TUGTGACTCQ S4Ô '

CATGTCCTTC AQAGCAGACT GAGCCAGTGC CUAGAGGTTC ACCCTTTGCC TACACCTGTC

900

CTGdGCCTG CTGTQ

INFORMATION FOR SEQ ID NO: 238:

(i) SEQUENCE CHARACTERISTICS:

(Al · LENGTH: 9X5 base pairs í> TYPE; nucleic acid (C> STRANDEDNEES: single (D; TOPOLOGYc linear (ii) MOLECULE TYPE; ocher nucleic acid (A, · DESCRIPTION.- / ãesc ® ’DNA (synthetic)‘

txx) SEQUENCE DESCRIPTION :. EEQ ID NO: 135:

GQTAACTGCT CTATAATGAT CGATGAÂATT ATACATCACT TAAAGAGACC ACCTGCACCT EC

TTGCTGGACC CGAACAACCT

120

CGACTTCCAA ACCTGGAGAG

280

ATTGAGGCAA TTOTTCGTAA

240

CAATGACGAA GACGTCTCTA

CTTCGTAAGG GCTGTCAAGA

TCTCCAACCA TGTCTGCCCT

TCCTGATGGA CCGAAACCTT

ACTTAGAAAA TGCATCA.GGT

CTGCCACGGC CGCACCCTCT

340

TCATCATCAA C'CjCA ^ GTGAx.

ft · * 'wvvii'T. ^ K ykyrw «^ · * * U'frss ^.> hz <' h5Z ^ 5 _Λ * xk. VXUSXX.iXfV ^ À .4 -À Xs

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

360 caaqagtacg tagagggcgg tggaggctcc

CCGGGTGAAC CGTCTGGTCC AATCTCTAOT ÂTCAACCCGT CTCCTCCGTC TAAAGAATCT

420 .......... ......

CATAAATCTC CAAACATGGG AGAATGGAAA ACCCAGATGG AGGAGACCAA GGCACAGGAC

OR

ATTCTGGGAG CAGTGACCCT TCTGCTGGAG GGAGTGATGG CAGCACGGGG ACAACTGGGA

540 .......... ...... ........ ................

CCCACTTGCC TCTCATCCCT CCTGGGGCAG CTTTCTGGAC AGGTCCGTCT CCTCCTTGGG soo ............... ............ ............ .... ....

GCCCTGCAGA GCCTCCTTGG AACCCAGCTT

560 ........ ........

GATCCCAATG CCATCTTCCT QAGCTTCCAA

720

A.TGCTTGTAG GAGGGTCCAC C2TCTGCGTC

80

CCQCCTGCTY GTGACCTCCG AGTCCTCAGT

840

CCTCCACAGG GQAGGACCAC AGCTCACAAG

CACCTGCTCC GAGQAAAGGT GCGTTTCCTG

AGGGAATTCG GCAACATGGC GTCTCCCGCT

AAACTGCTTC QTGACTCCCA TGTCCmAC

AGCAGACTGA GCCAGTGCCC AGAGGTTCAC CCTTTGGCTA CACCTGTCCT GCTGCCTGC ^ sou

GTGGACTTTA GCTTG

815 (21 INFORMATION FOR SEQ ID NO: 136:

SEQUENCE CHARACTERISTICS:

(A) LENGTH: 915 base pairs

ÍB} TIRE: nucleic acid

ÍC} ETRANDEDNESS: single

CD) TOPOLOGY; linear iii) MOLECULE TYPE; other nucleic acid.

ÍA) DESCRIPTION: / desc »ΈΝΑ. ! synthetic} ’(Xi) SEQUENCE DESCRIPTION: SEQ ID MO; 136-.

341

TATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGA7LGA CCGAAACCTI

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATGAGGT

380 ...... ......

ATTGAGGCAA TTCTTOGTAA TCTCCAACCA TGTCTGCCCT CTGCCAGGGC CGGACCCTCT

240 ........ ......

cgacatccaa tcatcatcaa ggcaggtgac tggcaagaat tccgggaaaa actgacgtto _k: ........ _......::: ........ ...........

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACASTACG TASAGGGCGG TGGAGGCTCO _ CCGSGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

CATAAATCTC CAAACATGGG ACCCACTTGC CTCTCATCCC TCCTGGGGCA GCTTTCTGGA

48G

CAGGTCCGTC TOTTCCTTGG GGCCCTCCAG AGCCTCCTTS GAACCCÀGCT TCCTCCACAG

S Β41ΝΓ2 ..... S (........ ........ ........ I ..... K li

GGCAGGACGA CAGCTCACAA GGATCCCAAT GCCATOTTCC TGAGCTTCCA AGACOTGGTC

630

CGAGGAAAGG TGCGTTTCCT GATGCTTGTA GGAGGGTCCA UCOTCTGCGT CAGGGAATTC

8:50

GGCAACATGG

CGTCTCCCGC TCCGCCTGCT TGTGACCTOT GAGTCCTCAG

TÀAATTGCTT

CGTGACTCee ATGICCTTCA CAGCAGAOTG AGOCAGTGCC GAQAGGTTOA CCCTTTGÍXT

7:80

ACACCTGTCC TGCTGOTTGC TGTGGACTTr AGOTTGGGAG AATGGAAAAC CCAGRTGGAG

840

GAGACCAAGG QACAGGAQAT TCTGGGAGCA GTGACCOTTC TGCTGGAGGG AGTGATGGCA $ 60 ............ ....... ........................

GCACGSGGAC AACTG

S '15 (2; INFORMATION FOR SEQ ID NO: 137;

ί1> SEQUENCE CHARACTERISTICS:

(Aj LENGTH: 9IS baae pairs

Yeah? TYPE: nucleic acid

ÍC) STRANDEDNESS: single

342 i D. TC · POLOGY; X irwa: r

MOLECULE TYPE: ether ntcieir acid (Λ) DESCRIPTION: / dear ~ * DNA ísyr.chestic;

ixi; SEQUENCE DESCRIPTION: SEQ ID NO; 137;

CCTAACTGGT CTATAATGAT CGATGAAATT

60 ........

TTGCTGGACC CGAACAACCT CAATGACGAA

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG ISO

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA

240

CGACATCCAA TCATCATÇAA GGCAGGTGAC

300

TATCTGGTTA CCCTTQAGCA AGCGCAGGAA

380

CCGGGTGAAÇ CGTCTGGTCC AATCTCTACT 420

CATAAATOTC CAAACATGGG AACCCAGCTT

480

GATCCCAATG CCATCTTCCT GAGCTTCCAA ........

ATGCTTGTAS GAGSGTCCAC CCTCTGCQTC

600

CCGCCTGCTT GTGACCTCCG AGTCCTCAGT

660

AGCAGACTGA GCCAGTGCCC AGAGGTTCAC

GTGGACTTTA GCTTGGGAQA ATGGAAAACU

780

CTGGGAGCAG TGACCCTTCT GCTGQAGGGA

84C ........ .... ..................

ACTTGCCTCT CATCCCTUCT GGGGCAGCTT

900

ATACATCACT TAAAGAGACC ACCTGCACUT

GACGTCTCTA TCCTGATGGA CCGAAACUTT

GCTÇTCAAGA ÀCTTAGAAAA TGCATCAGGT

TGTCTGCCCT CTGCCÀCGGC CQCATC2TCT

TGGUAAGAAT TCCGGGAAAA ATTGACGTTC

CAACAGTACG TAGAGGGCGG TGGAGGCTCC

ATCAACCCGT CTCCTCCGTC TAAAGAATCT

CCTCCACAGG GCAGGACCAC AGCTCACAAC

CACCTQCTCC GAGGAAAGGT GCGTTTCCTG

AGGGAATTCG GCAACATGGC GTCTCCCGCT

AAACTGCTTC GTGACTCCGA TGTCCTTCAC

CCTTTGCCTA CACCTGTCCT GCTGCCTGCT

CA.GATGGAGG AGACCAAGGC ACAGGACATT

GTGATGGCAG CACGGGGACA ACTGGGACCC

TCTGGACAGG TCCGTCTCCT CCTTGGGGCC

343

- *

Q ^ jv s · * «· ··’ (2) INFORMATION FOR SEQ ID ND: X3B:

ii? SEQUENCE CHARACTERISTICS:

, 'A.i LENGTH; 815 bass pairs (Bs TYPE; nucleic acid

ÍC) STRANDESNESS: single

ID? TOPOLOGY: linear> li) MOLECULE TYPE: other nucleic acid (A; DESCRIPTION; / desc »* DNA isynthetic)’

X1? SEQUENCE DESCRIPTION '. SEQ ID NO; 138;

gctaagtgct ctataatgat cgatgaaatt

TTGCTGGACC CGiAOAACCT CAATQACGAA ο ^:::::::::

CGACTTCCAA ACCTGGAGAG OTTCGTAAGG ISO

ATTGAGSCAA TTCTTCGTAA TCTCCAACCÀ

240 uwv> -nT £ X.AA TCJiTCATCAA GGCAGGTGAC

30v

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

368

CCGGGTGAAC CGTCTGGTCC AATOTCTACT

428

CATAAATCTC CAAACATGGG CAGGACCACA

80

AGCTTCCAAC ACCTGGTCCG AGGÂAAGGTG

54δ

CTCTGCGTeA GGGAATTCGG CAACATGGCG

680

GTCCTCAGTA AACTGCTTCG TGACTCCCAT

660

ATACATCACT TAAAGAGACC ACCTGCACCT

GACGTOTCTA TCCTGATGGA CCGAAACCTT

GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

TGTCTGCCCT CTGCCACGGC CGCACCCTCT

TGGCAÀGAÀT TCCGGGAAAA ACTGACGTTC

C »A '._ AGTAC £ S TAGAGGGCGG TGGAGGCTCC

ATCAACCOGT CTCCTCCGTC TAÀAGAATCT

GCTCACAAGG ATCCCAATGC CATCTTCCTG

CGTTTCCTGA TGCTTGTAGG AGGGTCCACC

TCTCCCQCTC CGCCTGCTTG TGACCTCCGA

GTCCTTCACA GCAGACTGAG CCAGTGCCCA

344

GAGSTTCACC CTTTGCCT'AC ACCTGTCCTG CTGCCTGCTG TGGÃCKTXG CTTGGGAGAA

720

TGGAAAACUC AGxTGiiAGGA GACCAAGGCA CAGiaAuATTL Tutr ^ As ^^ AGT t »% CCCT * vTG

760 ................ ......

CTGGAGGGAG TGATGGCAGC ACGGGGACÂA CTGGGACCCA CTTGCCTCTC ATUCCTCCTu $ 40 ...... .......... ......

'-'iC ^'GGA''AGG *** 'CQ' * ' ¹ ** χ- CT ^^ GGGG ^ H TGCAGAGC' *** ^ $ 00 .............. ................

9X5 .............. ..................

(2; INFORMATION FOE SEQ ID NO: 13 $:

(ii SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 $ base pairs (EG TYPE: nucleic acid

Mi STRANDEDNESS t single (D) TOPOLOGY .: linear (iii MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: / desc = ’DU A (synthetic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACO ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

Ç.......... ........

CGACTTCCAA ACCTGGAQAG CTTCGTAAGG GCTGTCAAGA ACTTAQAAAA TGCATCAGGT

ISO

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCAC-c ^ ’H '

240

CGACATUCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA AUTGACGTTC

300

TP.TCTGGTTA CCCTTGAGCA AGCGCAGGAA CAÀCAGTACQ TAGAGGGCGG TGGAGGCTCC 360

CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAAT ^ 42D

CATAAATCTC CAAACATGGC TCACAAGGAT CCCAATGCCA TCTTCCTGAG CTTCCAACAC 430

345

QTQSTCCGAC- GÂAAGGTGCG TTTOCTGATG CTTC-TAGGAQ GGTCCACCCT CTGCGTCAGG

SO ^: ......

GAATTCGGCA ACATGGCGTC TCCCGCTCCG CCTGCTTGTG ACOTCCGAGT CCTCAGTAAA

500

CTGCTTCGTG ACTCCCATGT CCTTCACAGC AGACTGAGCC AGTSCCCAGA GGTTCACCC7

860

TTGCCTACAC CTGTCCTGCT GCCTGCTGTG GACTTTAGCT TGGGAGAATG GAAAACCCAG

720

ATGGAGGAGA CCAAGGCACA GGACATTCTla GGAGCAGTGíí. CCCTTuTGCT GGAGGGAGTG

780

ATGGCAGCAC GGGGACAACT GGGACCCACT TGCCTCTCAT CCCTCCTGGG GCAGCTTTCT

840

GGACAGGTCC GTCTCCTCCT TGGGGCCCTG CAGAGCCTCC TTGGAACCCA GCTTCCTCCA

900

CAGGGCAGGA CCACA

915

(2) INFORMATION FOR SEQ 1D NOr 140;

(X) SEQUENCE CHARACTERISTICSo {A} LENGTH; 815 base pairs

CBj TYPE; nucleic acid (C) ETRANDEDÍÍESS: single (0} TOPOLOGY; linear

511} MOLECULE TYPE; other nucleic acid iA} DESCRIPTION: / desc = * DNA (synthetic) ‘{xi} SEQUENCE DESCRIPTION: SEQ ID NO: 140:

GCTAACTGCT CTATAATQAT CCATGAAATT ATACATCACT TAAAGÂGACC ACCTGCACCT 60

TTGCTGGACC CGAACAACCT CAATGACGAA GACSTCTCTA TCCTGATGGA CCGAAACCTT

120

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT ISC ·

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

240

346

CATAAA '

TCCTTCACAG cagactgag:

TGGCAAGART

GACCTCCGAG

CAGTGCCCAG

TTGGGAGAAT

-GGGAAAA

GGAATTCGG

TCCTCAGTAA

AGGTTCACCC

ACCAAGGCAC

730

AGÔACA '

GGGAGCAGTG

846

ACAGGGCAGG

ACCACAGCTC

915

ACAAG (2? INFORMATION FOR SEQ ID NO: 141:

(1) SEQUENCE CHARACTERISTICS:

(A · LENGTH: 915 base pairs {B} TYPE: nucleic acid (CJ STRANDEDNESS: single {D $ TOPOLOGY: linear {ii) MOLECTLE TYPE: ether nucleic acid {A) DESCRIPTION; / dear «’ DNA (Synthetic DNA) ’(xl) SEQUENCE DESCRIPTION: SEQ ID NO: 141:

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAQAGACC ACCTGCACCT

SC

347

TTGCTGGAOO CGAACAACOT CAATGACGAÀ GACGTCTCTA TCCTGATGGA CCGAAACCTT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGQATCAGGT

180

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CT'GCCACGGC CGCACCCTCT

240

CGACATCCAA TCATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

300

TATCTGGTTA CCCTTGAGCA AGCGCA3GAA CÀACAGTACG TAGAGGGCGG TGGAGGCTCC

350

CCGGGTGAAC CGTCT5GTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

420

CATAAATCTC CAAACATGGC CATCTTCCTG AGCTTCCAAC ACCTGCTCCG AGGÀAAGGTG

ONLY

CUTTTCCTGA TGCTTGTAGG AGGGTCCACC CTCTGCGTCA GGGAATTCGG CAACATGGCG

540

TCTCCCGCTC CGCCTSCTTG TGACCTCCGA GTCCTCAGTA AACTGCTTCG TGACTCCCAT

500

GCTGTTCACA GCAGACTGAG CCAGTGCCCA GAGGTTGACC CUIGCCTÀC ACCTGTCCTG

S50

CTGCCT3CTG TGGACTTTAG CTTGGGAGAA TGGAAAACCC AGATGGAGGA GACCAAGGCA

720

CAGGACATTC TGGGAGCAGT GACCCTTCTG CTGGAGGGAG TGATGGCAGC ACGGGGACAA

80

CTGGGACCCA CTTG2CTCTQ ATCCCTCCTG GGGCÀGCTTT CTGGACAGGT CCGTCTCCTC »40: ..

CTTGGGGCCC TGCAGAGCCT CCTTGGAACC CAGCTTCCTC CACAGGGÇAG GACCACAGCT

800

CACAAGGATC CCAAT

915 (25 INFORMATION FOR SEQ ID NO: 142:

(1) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 921 base pairs (δ) TYPE: nucleic acid (Ci STRANDEDNESS; single (D) TOPOLOGY: Linear

348 a nucleic & cíg (A; DESCRIPTION; / 'desc ~ ΌΝΑ (synthetic) * (xl) SEQUENCE DESCRIPTION: SEQ XS NO: 142;

GCTAACTGCC CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGQACCT ............. _s

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

GACTTCCAAA CCTGGAGAGC TTCGTAAGGG CTGTCAAGAA CTTAGAAAAT GCATCAGGTA isc ...... ............ ......................... ..........

TGAGGCAATT C7TCGTAATC TCCAACCATG TCTGCCCTCT GCCACGGCCG CACCCTCTCG 240

CATCCAATCA TCATCAAGGC AGGTGACTGG CAAGAATTCC GGGAAAAACT GACGTTCTAT

305

TGUTTACCCT TGAGCAAGCG CAGGAACAAC AGTACGTAGA GGSCGGTGGA GGCTCCCCGG

........ ..........................

TAACCSTCTG GTCCAATCTC TA ^ TATCAAC CCGTCTCCTC CQTCTAAAGA ATCTCATAAA 4j * 5 v ·

TCTCCAAACA TGGAGGTTCA CCCTTTGCCT ACACCTGTCC TGCTGCCTGC TGTGGACTTT 482

AQCTTGGGAC AATGGAAÀAQ CCAGATGGAG GAGACCAAGG CACAGGACAT TCTGGGAGCA

546

GTGACCCTTC TGCTGGAGGG AGTGÀTGGCA GCACGGGGAC AACTGGGACC CACTTGC ^ 60C>

TCATCCCTCC IGGGGCAGCT TTCTGGACAG GTCCGTCTCC TCCTTGGGGC CCTGCAGAG 6W

CTCCTTGGAA CCCAGCTTCC TCCACAGGGC AGGACCACAG CTCACAAGGA TCCCAATGCC

720

ATCTTCCTGA gcttccaaca CUTGCTCCGA GGAAAGGTGC CTTTCCTGAT GCTTGTAQGA

780 viG ^ iCuACCC TCTGCGTQAG GGAATTCGGC GGCAACGGCG GCAACATGGC GTCCCCAGQQ S40

CCGCCTGCTT GTGACCTCCG AG'TCCTCAGT AAACTGCTTC GTGACTCCCA TGTCCTTCAC

800

349

Í2? INFORMATION FOR SEQ ID NO: 143:

D? SEQUENCE CHARACTERISTICS:

(A; LENGTH: 927 base pairs

ÍB} TYPE: nucleic acid iC; STRANDEDNESS: single (0 .: TOPOLOGY: linear; ϋ) MOLECULE TYPE. · Other nucleic acid (A: description: / desc = ‘DMA (synthetic i

Ixl SEQUENCE DESCRIPTION: SEQ ID NO: 143;

gctaaotgct ctataatgat cgatgaaatt 6C

TTGOTGGACC CGAACAACCT CAATGACGAA

125

CGACTTCCAA ACCTQGAGAG CTTCGTAAGG

Sft

The QW

Z \ <i .4, W \ iWWY l Afeil

240

CGACATCCAA TCATCATCAA GGCAGGTGAC

0C

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA 360

CCGGGTGAAC CGTCTGGTCC AATCTCTACT 42 B;

CATAAATCTC CAAACATGTT OCCTACACCT 4 _8C

GGAGAATGGA AAACCCAGAT GGAGGAGACC 540

CTTCTGCTGG AGGGAGTGAT GGCAGCACGG

600

CTCCTGGGGC AGCTTTCTGG AUAGGTCCGT, _gw „

GSAACCCAGC TTCDTCCACA GGSCAGGACC

720

ATACATCACT TAAAGAGACC ACCTGCACCT GACG7UTCTA TCCTGATCKSA CCGAAACCTT GCTGTCAAGA ACTTAGAAAA TGCATCAGST TQTCTGCCCT CTGCCACGGC CGCACCCTCT TGGCAAGAAT TCCGGGAAAA ACTGACGTTC CAACAGTACG TAGAGGGCGG TGGAGOCTCC ATCAACCCGT CTCCTCCGTC TAAAGAATCT GTCCTGCTGC CTGCTGTGGA CTTTAG-CTTG AAGGCACAGG ACATTCTGGG AGCAGTGACC GGACAACTGG GACCCACTTG CCTCTCATGC CTCCTCCTTG GGGCCGTGCA GAGCCTCCTT ACAGCTCACA AGGATCCCAA TGCCATCTTC

350

0T3AGCTTCC AACACCTGGT CCGAGGAAAG GTGCGTCTCO TGÀTG2TTGT AGGAGGGTCC 7EL · ..........

ACCCTCTGCG TCAGGGAAT7 CGGCGGCAAC GGCGGCAACA TGGCGTCCCC AGCGCCGCCT

840

GCTTGTGACC TCCGAGTCCT CAGTAAACTG CTTOGTGACT CCCATGTCCT TCACAGCAGA

90S

CTGAUCCAGT GCCCAGAGGT TCACCCT

927 (2} ZNFDRMATIQN FOR SEQ ID NO: 144;

(1; SEQUENCE CHARACTERISTICS:

(A · LENGTH: 927 base pairs {g) TYPE: nucleic acid (Ci STRANDEDNESS: single {Di TOPOLOGY; linear {iij MOLECULE TYPE: other nucleic acid (A) DESCRIPTION; / that ® CHA {syntheticj (Xii SEQUENCE DESCRIPTION: SEQ ID NO; 144;

GCTAACTSCT CTATAATGAT CGATGAAATT

6C

TTGCTGGACC CGAACAACCT CAATGACGAA

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG

18Õ

ATTGAGGCAÀ TTCTTCGTAA TCTCCAACCA

240

CGACATCCAA TCATCATCAA GGCAGGTGAC

300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

380

CCGGGTGAAC CGTCTGGTCC AATCTCTACT

420

ATACATCACT TAAAGAGACC ACCTGCACCT

GACGTCTCTA TCCTGATGGA CCGAAACCTT

GCTGTCAAÔA ACTTAGAAAA TGCATCAGGT TGTCTGCCCT CTGCCACGGC CGCACCCTCT TGGCAAGAAT TCCGGGAAAÀ ACTGACGTTC ÇAACAGTACG TAGAGGGCGG TGGAGÔCTCC ATCAACCCGT CTCCTCCGTC TAAGA

CATAAATCTC CAAACATGGT CCTGCTGCCT GCTGTGGACT TTAGCTTGGG AGAATGGAAA

4SC

ixi} SEQUENCE DESCRIPTIONx SEQ IQ NO; 145;

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT

CÀATGACGAA GACGTCTCTA TCTTGATGGA TCCAA ^ C ^ '^

CGAOTTCCAA ACCTGQAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

ATTuAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGUCOT CTGCCACGGC CGCA · '' ^! ^^

U ^^ CAA TCATCÀTCAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACGTTC

352

CCGGGTGAAO CGTCTGGTCC

420

CATAAATTTC CÀAACATGGC

480 ü ΑκχΑλ ». uvivi k> C Au As ^ GA C AT 540

GCACGGGGAC AACTGGGACC

600

k »l Ajjxa ^ Xw λ ~ à j & k> GO ~ * MXXíxsA W

TCTGGGAGCA GTGACCCTTC <νΛ <Λ A ^ X. «Av, _Λ ^S ^ * Q.'vmL <MXv

CCTGCAGAGC CTCCTTGGAA

TCCCAATGCC ATCTTCCTGA

GGAAAGQTG GTTTCCTGAT

780

GCTTGTAGGA GGGTCCACCC

GGCAACGQCG GCAACATGG 84?

AAACTGCTT'C GTGACTCCCA 900

92?

TGTCCTTGAC AGGAGACTGA

CTC-CTCCSTC TAAÀGAÀTCT

AAIXAaAAAAC CCAGATGGAQ

TGGTGGAGGG AGTGATGGCA

TGGGGCAGCT TTCTGGACAG

CCCAGCTTCC TCCACAGGGC

GCTTCCAACA CCTGUTCCGÀ

TCTGCGTCAG GGAATTCGGC

GTGACCTCCG AQTCCTCAGT

GCCAGTGCCC ÀGAGGTTCAC

Í2! INFORMATION FOR SEQ 10 Node: 146;

yo? SEQUENCE CHARACTERISTICS c? À) LENGTH: 927 base pairs (Bí TYPE ·, nucleic acid (C · STRANDEDNESS; Single (IN TOPOLOGY; linear tri) MOLECULE TYPE; other nucleic acid $ A) DaSCRIFTION; / dear »DNA (synthetic1 (Xi ) SEQUENCE DESCRIPTION; SEQ ID NG; 145:

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GTTG7CÀAGA ACTTAGAAAA TGCATCAGGT lif'f ^s ........ l- ^: Z \ ........

ATTGAGGCAA TTCTTCGTAA TCTCCAACCH TGTCTGCCCT CTGCCACGGC CGCACCCTCT

CGACATCCAA TCATOATQAA GGCAGGTGAC TGGCAAGART TCC-GGGAAAA ACTGACGTTC> * \ X> * «** Ζ *. ***? Γ ^ RX *» ** ·>. »., ΛΛν ^« · ήΛ, · Λν ^ · χ V., -V * X / Τ, Λ JMrtA. «W _aa y <la a * <· -. ml λ / íc ^ l ^ lw; laAlaAl · 1 Αχ.ς »TAkíAGGGCGú TGGA.GGCTCC

£ 6

CCGGGTGAAC CQTQTGGTCC AATGTCTACT ATCAAOCCGT CTCCTCCGTC TAAAGAATCC

Ç......... ........................................ ......................

CATAÂÀTCTC CAAAOATGGA CTTTAGCTTG GGAGAATGGA AAACCCAGAT GGAGGAGAOC

AAGGCACAGG ACATTOTGGG AGCAGTGACC CTTCTGCTGG AGGGAGTSA ’’ ’GGCAGfW ^

540 ...... .................... ...................'... ..

GGACAACTGG GACCCACTTG CCTCTCATCC CTCCTGGGGC AGCTTTCTGG ACAGGTCCGT

5Ü0

CTCCTCCTTG QGGCCOGCA GAGCCTCCTT

GGAACCGAGC TTCCTCCACA

LsGGC Â.GG AC C

AQAGCTUACA AGGATCCCÃA TGGCATCTTC CTGAGCTTCC AACACCTGCT CGGAGGAAAG

TGAGGGAATT CGGCGGCAAC

GGCGGCAACA TGGGGTCCC

840

Ρ r * λ .x * A. · Ύ · Υ * Γ y ^. · * · 'WV'a · ά. . . 'w.'rtAiviXt’X «> X * K». * §0δ

AGCGGCGCCT GCTTGTGAGC

TCAOAGCAGA CTGAGCCAGT

TQCGAGTCCT CAGTAAACTG

GCCTAGAGGT TCACCCTTTG

COTACACTTG TÇCTGCTGCC TGCTGTG

S27 (2) INFORMATION FOR SEQ NU: 147;

{£; SEQUENCE CHARACTERISTICS;

(Ai LENGTH: S27 base pairs (S; TYPE: nucleic acid (Cj STRANDEDNESS: single (Di TOPOLOGY: linear ill; MOLECULE TYPE: other nucleic acid

354 / «esDESIRSPTIOS

CTATAATGÀ1

4 4.

ACTTAGAAAA

TGGCAAGAAT

TATCTGGTTA

36-C

CAACAGTACG

TAGAGGGCGG

TGGAGGCTí

AATCTCTACT

ATCAACCCGT

TAAAGAATCT uAAACATGGG

AGAATGGAAA

ACCCAGATGG

AGGAGACCAK

GGCACAGQAO

CA.GCACGGGÇ

SOO ‘CCGTCT

CCTCCTTGGQ

GCCCTGCAGA

S6C

AACCC.

CCTCCACAGG

AGCTCACAAG

CACCTGCTCC

GGCAACATG

GCGTCCeCAG

840

GTAAACTQCT

ACAGCAGACT

900 ’CAGTG:

CCAGAGGTTi

TACACCTGTÍ

CTGTSGACTT

355

INFORMATION FOP. SEQ ID NO: 14 8:

il? SEQUENCE CHARACTERISTICS:

i A · LENGTH 927 bas e hover i'E; TEPE; nucleic acid; C; ETRAIUJEDfJESE: tingle (D? TOPOLOGY; linear {ii: MOLECULE TYPE: ether nucleic acid (A · DESCRIPTION; Zdesc - DNA (synthetic;

(Xi; SEQUENCE DESCRIPTION; SEQ ID NO: 148;

GCTAACTGCT CTATAATGAT CGATGAAATT

TTGCTGGACC CGAACAACOT CAATGACGAA

CGACTTCCAA ÀCCTGGAGAG CTTCGTAAGG

180

ATTGAGGCAA TTCCTCGTAA TCTCCAACCA

340

CGACATCCAA TCATCATOAA GGCAGGTGAC

00

TATCTGGTTÀ CCCTTGAGCA AGCGCAGGAA

CCGGGTGAAC CGTCTGSTCC AATOTCTACT

420

CATAAATCTC CAAACATGGG ACCCACTTGC

480

CAOGTCCGTÇ TOCTCCTTGG · GGCOCTGCAG

540

GGCAGGACCA CAGCTCACAA GGATCCCAAT δ 00

CGAGGAAAGG TGCGTTTCCT GATGCTIGTA

6§Q

GGOGSCAACG GCGGCAACAT QGCGTCCCCA

720

ATACATCACT TAAAGAGACC AUCTGCACCT GACGTCTCTA TCCTGATGGA CCGAAACCTT GCTGTCAAGA ACTTAGAAAA TGCATCAGGT TGTCTGOCCT CTGCCACGQC CGCACCCTCT TGGCAAGAAT TCCGGGAAAA ACTGACGTTC CAÀCAGTACG TAGAGGGTGG TGGAGGCTCC ATCAACCCGT CTCCTCCGTC TAAAGAATCT CTCTCATCCC TCCTGGGGCA GCTTTCTGGA AGCCTCCTTG GAACCCAGCT TCCTCCACAG GCCATCTTCC TGAGCTTCCA ACACCTGCTC GGAGGGTCOA CCCTCTGCGT CAGGGAATTC GCGCCGCCTG CTTGTGAUCT CCGAGTCCTC

ACCCAGATGG AGGAGACCAA QGUACAGGAC ATTCTGGGAG CAGTGACCCT TCTGCTGGAG seeGGAGTGATGG CAGCAQGGGG ACAACTG 92

INFORMATION FOR SEQ ID NO: 14S.

SEQUENCE CHARACTERISTICS:

•THE? LENGTH: 92 has® parrs

ÍS) TYPE: nucleic acid (C · STRANDEDNESS: single

ID; TOPOLOGY: linear

MOLECULE TYPE; other nucleic acid (A) DESCRIPTION; / desc ® DMA (synthetic) ”

X1) SEQUENCE DESCRIPTION; EEQ ID NO; 149;

GCTAACTGCT UTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACGT

..6.0 ·

TTGCTGGACC CGAACAACCT GAATGACGAA GACGTCTCTA TCCTGATGQA CCGAAACCTT x to 0

CGACTTCCAA ACCTGGAGAG OTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT

ISO

ATTGAGGCAA TTCTICGTAA TCTCCAACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT 240 ..........

C-wauATCCAA tcatcatcaa ggcaggtgac tggcaagaat tccgggaaaa ACTGACGTTC

.. '^ CTGGTTA cqgttgagca agcgcaggaa caacagtacg tagagggcgg tggaggctco 366

CCGGGTGAAC CGTCTGGTCC AATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT

ÇXTAtóTCTC CMACATO® MCCCMCTT CCTCCACAGS SOWOiCCAC «CTCACAAS • s« s6

GATCCCAATG CCATCTTCCT GAGCTTCCAA CACCTGCTCC GAGGAAAGGT GCGTTTCCTQ r> 46

+. W <Ai · A *. A * X v. A »· Λ A> jw *. * · *. *. · Χ Alí '!' * A **** · A * NAA * + X / ** · *% ^Λ - Λν As A »Ai ♦ V ΑΧ + * + ΐζ ^ν ·; ν ;; Λ ^ '.. .... χ „*, j ... ..-: * .. /MVJnAl.·--S 'JX, A'. 'v

Γ \; GCGTCCeCAG

660 χ-ςΛΧ. x.sk> V \ -, 1 'ον f *. ** +,. + A ». | MSi: *: - fc *: there .4. x *. «Kv ^ J ^v l I * X /ΐ4*χΛ.·ν ..

OGT 6? THE

CATGTCCTTC ACAGCAGAC7 GAGCCAGTGO CCAGAGGTTC ACCCTTTGCC TACACCTGTC

CTGCTGCCTG CTGTGGACTT TAGCTTGGGA GAATGGAAAA CGCAGATOGA GGÀGÀCCAAG

780

GCACAGGACA TTCTGGGAGC AGTGACCSTT CTGÍTTGGAGG GAGTGATGGC

S 4 0 * R} *> *** / * <+>

ΛΙ »Χ ...« \, 'Χ> Χ ¥ ωί \ 3Λ

CAACTQGGAC CCACTTGCCT CTCATCOCT CTGGGGCAGC

900 ...... ........................ .........

7T7TGGACA

^ ^ ^ WftWAAAA Yo.OAXW ^ Ai-V + A>

£ $ <*?

i2) INFORMATION BY SEQ ID NG: 15C;

SEQUENCE CHARACTERISTICS r (A; LENGTH; 92? Base pairs

ÍB? TYPE ·, nucleic acid (Ci STRANDEONESS: single fD) TOPOLOGY; linear useful? MOLECULE TYPE; ether nucleic acid

ÍA · DESCRIPTION: / desc «’ DNA {synthetic} ’’ {Xi? SEQUENCE DESCRIPTION '. SEQ ID ND: 15G:

OCTAACTGCT

TTGCTGGACC

CTATAATGAT

CGAACAACCT

CGATGAAATT

CAATGACGAA

ATACATCACT

GACGTCTCTA

TAAAGAGACC

TCCTGATGGA

ACCTGCACCT

CCGÀAACCTT • GACTTCCAA ACCTGGAGAG

CTTCGTAAGG GCTGTCAAGA

ACTTAGAAAA TGCATCAGGT

ATTGAGGCAA

TTCTTCGTAA

TCTCCAACCA

CTGCCACGGC CGCACCCTCT

CGACATCCAA

3SC

TCATCATCAA GGCAGGTGAC TGGCAAGAA.T TCCGGGAAAA ACTGACGTTC x> 4 £ <£: AA.

AG G AAA <

Jib

AT *** 'v »K>

vk.A ^

CGTGACTCX

ACAGGACAT

A · \ »’ fcax3tf * <xy L / Tj.

Grandfather

AGTGATGGCA

GCACGGGGA '

ACTIONG C

TGCAGAGC i / λ-ιλΑ

INFORMATION FOR EEC

SEQUENCE CHARACTERISTICS;

U · LENGTH; §27 base pairs (S) TYFEr nucleic acid (C) STRANDEDNESS; single (D} TOPOLOGY; Linear nucleic cast ~ (Xi) SEQUENCE DESCRIPTION;

and;

GCTAAOTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC

6C

ACCTGCACCT ’GATGGA 'GAAACCTT

V ·. * Χ · k. SÀT, * «JíVshH. χ> ks ν ά Χϊ · α X · ^ 'WW ^ ZX ΛΧχ, λ .4 ίΧχΛ / ΙΛΛί'Χ <4S2TLa? v1 Xv ^ wx5 L

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA

24C

CGACATCCAA TCATCATCAA GGCAGGTGAC

300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA

50

CCQGGTGAAC CGTCTGGTCC AATCTCTACT

0 '

CATAAATCTC CAAACATGGC TCACAAGGAT

8C .......... ......

CTGCTCCGAG GAAAGGTGCG ITTCOTGATG δ

GAÀTTCGGCG GCAACGGCGG CAÀCA.TGGCG

SOS

GTCCTCAGTA AACTGCTTCG TGACTCCCAT

650

GAGGTTCACC CTTTGCCTAC ACCTGTCCTG

720

TGGAAAACCC AGATGGAGGA GACCAAGGCA

CTGGAGGGAG TGATGGCAGC ACGGGGACAA

840

TQGCAAGAAT TCCGGQAAAA. ACTGACGTTC

CAACAGTACG TAGAGGGCGG TGQAGQCTCC

ATCAACCCGT CTCCTCCGTC TAAAGÀATCT

CDCAATGCCA TCTTCCTGAG CTTCCAACAC

CTTGTAGGÂG GQTCCACCCT CTGCGTCAGG

TCCCCAGCGC CGCCTGCTT3 TGACCTCCGA

GTCCTTCACA GCAGACTGAG CCAGTGCCCA

CTGCCTGCT ^ TGGACTTTAG CTTGGGAGAÀ

CAGGACATTC TGGGAGCAGT GACCCTTCTG

CTGGGACCCA CTTGCCTCTC ATCCCTCCTG

GGGCAGCTTT CTGGACAGGT CCGTCTCCTC CTTGGGGCCC 90C ......

TGCAGAGCCT ccttggaacc

CAGCTTCCTC CACAGGGCAG GACCACA §27 {2i INFORMATION FOR SEQ ID NO: 152:

(i> SEQUENCE CHARACTERISTICSr {A? LENGTH: 927 base pairs (δ) ΤΥΡΕ: nucleic acid (Ο ETRA ^ EDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: ether nucleic acid {A} DESCRIPTION: / desc = ΈΝΑ (synthetic

360

-χ · .; FEOüTiCF DESCRIPTION: SRQ ID NO: 1E2 ·.

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT TAAAGAGACC ACCTGCACCT

TTGCTGGACC CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCASGT

180

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA TGTCTGCCCT CTCCCACGGC CGCACCCTCT 040 ........ ................

CGACA7CCAA TCATCATCAA GGCAGGTGAC TGGCAÀGAAT TCCGGGÀAAA ACTGACGTTC 300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACAGTACG TAGAGGGCGG TGGAGGCTCC

350 .................. ........ ....................... .....................

CCGGGTGAAC CGTCTGGTCO ÂATCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAATCT .0.0 ......... ........ ..............

CATAAATCTC CAAACÂTGGA TCCCAATGCC ATCTTCCTGA GCTTCCAACA CCTGCTCCGA

488

GGAAAGGTSC GTTTCCTGAT GCTTGTAGGA QGQTCCACCC TCTGCGTCAG GGAATTCGG * 540 u-GiAACGGCu QCAACATGGC GTCOCCAGCG CCGCCTGCTT GTGAC'CTCCG AGTCCTCAGT

AA ^ CTGCTTC GTGAOTCCCA TGTCCTTCAC AGCAGACTGA GCCAGTGCCC AGAGG ^ TFCAC

668

CCTTTGCCTA CACCTGTCCT GCTGCCTGCT GTGGACTTTÀ GCTTQGGAGA ATGGAAAACC? 2C

CAGATGGAGG AGACCAAGGC ACAGGACATT CTGGGAGCAG TGACCCTTCT GCTGGAGGGA

780

GTGATGGCAG CACGGGGACA ACTGGGACCC A'CTTCCGTCT CATCCCTCCT GGGGCAGCT’t

TCTGGACXGG TCCGTCTCCT CCTTGGGGCC CTGCAGAGCC TCCTTGGAAC CCAQCTTCCT

980

CCACAGGGCA GGACCACAGC TCACAAG

937 m INFORMATION FOR EEQ ID NG: 153:

SEQUENCE CHARACTERISTICS.

5A: LENGTH · 92 “ease pairs _{; £;} type. · nucleic arid. {Cj STRANDEDNESI: sing1e? D) TOPOLOGY: linear (ii; MOLECULE TYPE; other nucleic acid {A) DESCRIPTION; / desc = DMA (synthetic)! Xi: SEQUENCE DESCRIPTION: SEQ ID ND: 153;

GCTAACTGCT CTATAATGAT CGATGAAATT ATACATCACT

TAAAGAGACC ACCTGCACCT

TTGCTGGACT CGAACAACCT CAATGACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAAAA TGCATCAGGT is · ::

ATTGAGGCAA TTCTTCGTAA TCTCCAACCA 'TGTCTOCCCT CTGCCACGQC iiis ........................................... ...............s............ ......

CGCACCCTCT

CGACATCCAA TCATCA7CAA GGCAGGTGAC TGGCAAGAAT TCCGGGAAAA ACTGACQTTC

300

TATCTGGTTA CCCTTGAGCA AGCGCAGGAA CAACASTACG TAQAGGGCGG TGGAGGC ^ C ^

360

CCGGCTGAAC

420

CGTCTGGTCC

AATCTCTA

ATCAACCCGT

CTCCTCCGTC T.AAAGAATCT

CATAAATCTC CÀAACATGGC CATCTTCCTG AGCTTCCAÀC

480

ACCTGCTCCG AGGAAAGGTG

CGTTTCCTGA TGCTTGTAGI AGGGTCCACC CTCTGCGTCA GGGAATTCGG ε

CGGCAACGGC

GGCAACATGG CGTCCCCAGC GCCGCCTGCT TGTGACCTCC GAGTCCTCAG

600

TAAACTGCTT

CGTGACTCCC ATGTCCTTCA CAGCAGACTG AGCCAGTGCC

650

CAGAGGTTCA CCCTTTGCCT

ACÀCCTGTCC TGCTGCUTGC TGTGGACT7T AGCTTGGGAG AATGGAAAAC '720 ............

CCAGATGGAG

GAGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCCTTC TGCTGGAGGC AG ^ igjx760

362

.. -.4: 1,4.: 4.- Α - '^ νΛ \ 3ΐαΐ | άν k, · * «4-: .4 4.3ΛKXFWSy 4 1 v · 4 w ^ -AXvAxs ^ KSsm * z * x > * x xw „* x st - · χ: ^ * 'wmw ** w' *: * *» x “x ^ wmmx ^< * * w A ^ xxA '» k-. Ut / kw. ^ IM.vasjrA * ν..χ ^ Α * Ά ,.

INFORMATIQF FDR SEQ ID NO; 1H4:

ii; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 80c base pairs ÍB: TYPE ·, nuclexc acid; C) STRAMDESNESS; single! D? TOPOLOGY; linear

iii? TYPE molecule; other nucleic acid (A? DESCRIPTION; / desc * ΌΝΑ {synthetic?

(Xi? SEQUENCE DESCRIPTION; SEQ ID NO; 154;

GCTAACTGCT CTATAATGAT CQATGAAATT ATACATCAOT TAAAGAGACC ACCTGCÂCCT ec

TTGCTGGACC CGAACAACCT CAADOACGAA GACGTCTCTA TCCTGATGGA CCGAAACCTT

- * 'n vy

CGACTTCCAA ACCTGGAGAG CTTCGTAAGG GCTGTCAAGA ACTTAGAÀÀA TGCATQAGGT ss ^{_::: ::} .............

ATTGAGGCAA TTCTTCGTAA TCTCCÃACCA TGTCTGCCCT CTGCCACGGC CGCACCCTCT

CGACATCCAA TGATCATCAA GGCAGGTGAC TGGCAAGAAT TCCGGQÀAÀA ACTGACUTTC * v »*. »X ................................................ ...................................... ............ .................

TATCTGGTTA CCCTTGAQCA AGCQCAGQAA CAACASTACQ TAGAGGGCGG TSGAGG ’^ TCC 260

CCGG-GTGAAC CGTCTGGTUC AUiTCTCTACT ATCAACCCGT CTCCTCCGTC TAAAGAA ^ CT 4 20

CATAAATCTC CAAACATGGA TCCCAATGCC ATCTTCCTGA GCTTCCAACA CCTGCTCCGA 4SG

GGAAAGGTGC GTTTCCTGAT GCTTGTAGGA GGGTCCACCC TCTGCGTCAG GGAATTCGGC

540 ...... ......

GGCAACATGG CGTCTCCCGÜ TCCGCCTGCT TGTGACCTCC GAGTCCTCAG TAAACTG ^ T

60C

2

CGTGACTCCC ATSTCCTTDA CAGCAGÀCTC ÀGCCAGTGCC CAGAGGTTCA CCCTTTÇCCI ♦, ** X <* Ί Χ ^ ΓΧΧ <* · Τ · Χ! Ίχ * Ν Λ »« VXiCÍI Λ. <* \> X. * / - »X Ζ>> ί ^Λ . · ι · *> ν μ. <<* * AW Λ / · »» ή * * W * / * / * <* # » _Λ VS * iv'iwAw * u 1 Lr ,,> N * Ax> C *? Αν? Αλ x> vsA \ ?

GÂGACCAAGG CACAGGACAT TCTGGGAGCA GTGACCOTTC TGCTGGAGGG AGTGATGGCA gcacggggac aactgggacc CACTTGCCTC TCATCCCTCC TGQGGCAGCT ttctggacag

840

GTCCGTCTCC TCCTTGGGGO CCTGCAGAGI CTCCTTGGAÂ CCCAGGGCAG GACCACAGCT

CACAAG $ St

2. INFORMATION FOR SEQ ID ND: 155:

(i) SEQUENCE CHARACTERISTICS;

(AJ LENGTH; 993 base paars; B) TYPE: nucleic acid (C; STRANE'EDNESS :. single (D) TOPOLOGY: linear (ÜÍ MOLECULE TIER: other nucleic acid

ÍA) DESCRIPTION: / dasc '* DNA (synthetic)' (xij SEQUENCE DESCRIPTION: SEQ ID NO: 155;

ATGGCTAACT GCTCTATAAT GATCGATGAA ATTATACATC ACTTAAAGAG ACCACCTGCA

CCTTTGCTGG ACCCGAACAA CCTCÀATGAC

HB; ................................ ........ .......... .. ................................................ .....................

CTTCGACTTC CAAACCTGQR GAGCTTCQTA 180

QGTATTGAGG CAATTCTTCG TAATCTCCAA δ

GAAGACGTCT CTATCCTGAT GGATCGAAAC

AGSGCTGTCA AGAACTTAGA AAATGCATCA

CCATGTCTGC CCTCTGCCAC GGCCGCACCC

TCTCGACATC

306

CAATuATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA AAAACTGACG

TTCTATCTGG TTACCCTTGA GCAAGCGCAC GAACAACAGT ACGTAGAGGG CGGTGGAGQ ''

360

9} INFORMATION FDR SEQ ID NO: 156:

{i; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 993 base pairs (Bi TYPE.- nuelexc acid (C) STRANDEDNESS: single íD} TOPOLOGY: 1inear iii; MOLECULE TYPE: ether nucleic scid; A; Dr, S <_ni.PT ^ ON; Zde.sc ~ * DNA (synthetic) fxif SEQUENCE DESCRIPTION: SEQ XD NO: 158;

ATGGu TRACT GCTCTATAAT GATCGRTGAA ATTATACATC ACTTAAAGAG ACCACCTGCA $? M

PTOn-lGG ACCCGAACAA ÇCTCRATGAC GAAGACGTCT CTATCCTGAT GGATCGAAA

365

GGTATCGAGG

ACGTAGAGto i USksAksvs

GTCTAAAGAA

CTCCAAACA '

GTOTCCCGAi

ACTTTGCCA

CAGCAGATGG

AAGAACTGGG

CTGCITTCCA

VFWAhWVixJ Λ κ. > w

660

AGGTGTCGTA cggcgttcta at.

84C>

CGGCGGCTCT

CACCATTAGG

CCCTGCCAGi

TTAGAGCAAG

ACCTACAAGC

C GAGGAG CTC

TGAGCTCCK

GOCCTGCAG;

962

TGGCAGGCI

CTTGAGCCAA

ATAGGG

CTACQAGGQG

CCCTGGAA.GG

983

GATATC

TAÀ

INFORMATION FOR SEQ ID NO;

(is SEQUENCE CHARACTERISTICSi (A; LENGTH: 993 base pairs (B) TYPE: nucleic acid (C) STRANDWNESS: single> D) TOPOLOGY: linear

366 b Ύ * «* 'Λ, _Α Ji ίί. . Qk. ** <S. _w * ivl is .1 S Λ WO ^ AW i A i DE SC ΰχ Ρ Tx ON: / des c = * DNA · syti thetxc} (xi; SEQUENCE DESCEIFTXON: SEQ ID ND: 157:

ATGGCTAÀCT GCTCTATAAT GATCGATGAA

CCTTTGUTGG ACCCGAACAA CCTCAATGAC

GTTCGACTT2 CAAACCTGGA

X8Q

GGTATTGAG3 CAÀTTCTTCG TAATCTCCAA

240

TCTCGACATC CAATCATCAT CAAGGGAGGT

300

TTCTATCTGG TTACCCTGA GCAAGCGCAG

3S0

TCCCCGGGTG AACCGTCTGG TCOAXTCTCT

422

TCTCATAAAT CTCCAAACÀT GTCTTCTGCT

480 ..... ........ ........

GCTAGICATC TGCAGAGCTT CCTGGAGGTG

0 ....................

CCCGGCGGCG GCTCTGACAT GGCTACACCA $ 20 .....

GAGCTTCGTA AGGGCTGTCA

TTCGTGCTCA AGTCTTTAGA GCAAGTGAGG $ 80

GAGAAGCTGT GTGCCACCTA CAASCTGTGC

720

TCTCTGGGCA TCCCCTGGGC TCCCCTGAGC

780

GSCTGCTTGA GCCAACTCCA TAGCGGCCTT

846

GAAGGGATAT SAMSCGAGTT GSGTCCCACC

90Ç ...... ........

ATTATACATC ACTTAAAGAG ACCACCTGCA GAAGACGTCT CTATCCTGAT GGATCGAAAC AGAACTTAGA AAATGGATCA CCATGTCTG2 CCTCTGCCÀG GGCCGCACCC GACTGGCAAG AATTCCGGGA AAAACTGACG CGGTGGAGGA GTC

GCCCCAGAGC

AGUGCTCCAG GCTCGGACAC GCAGCTGGCA GCAGGCCCTG

GAACAÃCAGT ACGTAGAGGG

ACTATCAACC CGTCTCCTCC

TTCCAGCGCC GGGCAGGAGG

TCGTACCGCG TTCTACGCCA

TTAGGCCCTG CCAGCTCQQT

AAGATCCAGG GCGATGGCGC

CACCCCGAGG AGCTGGTGCT

TCCTGCCCCA GCCAGGCCCT

TTCCTCTACC AGGGGCTCCT

TTGGACACAC TGCAGCTGGA

367

x / Vkyvx ^. 7 ίγ 'Λτ, ^ ΛΊΧτ, Λ' Λ * Z * r * X> VtZ +:> * +:. · * + ZXW +. X ·. * «. ♦>.

A \ wv ~ T ~ Z \ W \? SU â V ’^ Xx-A + <i \ XWOv,

ÇC ·;

INFORMATION FOR SEQ ID NO: 158?

id) SEQUENCE CHARACTERISTICS;

(A; LENGTH: 993 bass pan's (Dj TYPE: nucleic acid (C; STRANDEDNEES; single! D: TOPOLOGY; linear ill: MOLECULE TYPE; other nucleic aciss (A? DESCRIPTION: / best ~ * DNA {synthetic) '· ixi ! SEQUENCE DESCRIPTION; SEQ ID NO: 158;

A 1 J. ZiZSV x.

GCTCTATAAT GATCGATGÃA. ATTATACATC

ACTTAAAGAG ACCACCTGGA

CCTTTGCTGG ACCCGAACÀA CCTCAATGAC

GAAGACGTCT

CTATCCTGAT GGATCGAAAC

CTTCGACTTC CAAACCTGGA GAGCTTÇGTA AGGGOTGTCA AGAACTTAGA AAATGCATCA

ISO

GGTATTGAGG

240

CAATTCTTCG TAATCTCCAA CCATGTCTGC f>. ** X. »* · ** y * -J-x z * -X

V <AA> 1 vw. i \ 3X. V. A \ - VavatUw · <ν w.

TCTCGACATC CAATCATCAT CAAGGCAGGT GACTGQCAAO

300

AATTCCGGGA. AAAACTQACG

TTCTATCTGG TTACCCTTCA GCAAGCGCAQ ISO

TCCCCGGGTG AACCSTCTGG TCCAATCTCT 420

TCTCÀTAÀAT CTCCAAACA'T GTCTATGGCC

480

GAACAACAGT ACGTAGAGGG CGGTGGAGGC

ACTATCAACC CGTCTCCTCC GTCTAAAGAA

CCTGCCCTGC AGCCCA.CCCÀ GGGTGCCATG

CCGQCQTTCG CCTCTGCTTT GCAGCGCCGG GCAGGASGGG TCCTGGTTGC TAGQcg ^ ç ^ g 54 C ''

CAGAGCTTCC TGGAGGTGTC GTACCGCOT -CTACGCQACC TTGCGCAGCC CGGCGGCGGC 600

TCTGACATGQ CTACACCATT AGGCCCTGCC AGCTCCCTQC

50

CCCAGAGCTT CCTGCTCAAG

68

TOTCTAuaU ',. AAGTGAGGAA GATCCAGGGC GATGGCGCAG CGCTCCAGGA GAAGCTGTG <*>; » x.y * · X, * ». ** **« * ·> ** - X T.. »» v

X »sxXx-Λχ * ΛΛΛ'χ. * -2 ÃsáXxXvA g Q x ** ’· 'Αλ <.λχ # \ λ \ ιλα ^ μχαχ kxV ^ X xsAsj ^ TC

84C *>: * * 6 »>: <** w * nm« · *

• .Arwx-.s «\. \ rtix * λ 1 x J.

9SG

CCCGAGTTGG GTCCCACCTT

988 atctggcagc agatqgaaga

SAMSGAGGAG CTGGTGOTGC

CTGCCGCAGC CAGGCCETGC <**. *** <7. '** GO ^ C ^

GGACACACTG CAGOTGGACG

ÀCTGGGATAA TAA

TO2GACACTC TCTGGGCAT:

AGCTGGCAGG CTGCTTGAG!

AGGCGCTGGA AGGGATATCÍ

TCGCCGAUTT TGCCACCACÍ

IfiFORMATCGK PDF. £ EQ. χρ κ _0; χ.5§ _; (Í; SEQUENCE CHARACTERXETXCS;

IA; LENGTH: 983 base pairs (B) · TYPE: nucleic acid> C) STRANDEDNES5; single (D; TOPOLOGY: linear iiij MOuECxíií, TYPE: other nucleic acid (A.) DESCRIPTION: / desc ® * WA laynthsticj *

i.xi> SEQUENCE DESCRIPTION: SEQ ID KO: 158:

Αχ ^ ιΤλΑΤΤ GCTCTATAAT GÀTCGATGAA ATTATACATC ACTTAAAGAG ACCACCTQCA CCTTTGCTGG ACCCGAACAA CCTCAATGAO GAAGACSTCT CTATCCTGAT GGATCGAAAC vTTCGACTTC CAAACCTGGA GAGCTTCGTA AGGGCTGTCA AGAÀCTTAGA AAATGCATCA ggtattgagg caattottcg taatctccaa gcatgtctgc cctctgccac ggccgcaccc v ^. ^ RtCATC CAATCATCAT CAAGGCAGGT GACTGGCAAO AATTCCGGGA AAAACTGACG TTCTATOTCG TTACCCTTGA GCAAGCGCAG GAACAACAGT ACGTAGAGGG CGGTGGAGGC

9

TCCCCGGGTG AÂCCGTCTGG TCCAATCTOT ACTATCAACD CGTCTCCTCC GTCTAAAGAA

42: 6: _:: / _:: ........ ........ _:: .................... ... .............

TCCQATAAAT CTCCAAACAT GTCTACCCAG * 8S

CAGCGCCGGQ CAGGAGGGGT CCTQGTTGGT s-ic

TACCGCGTTC TACGCCACCT TGCGCAGCCC sec

GGCCCTGCCA GCTDCOTGCC CCAGAGCTTC

662 ............

ATCCAGGGCG ATGGCGCAGC GCTCCAGGAG 72C

CCCGAGGAGC TGGTGCTGCT CGQACACTCT 80 .........

TSCCCCAGCC AGGCCCTGCA GCTGGCAGGC S40

CTdACCAGG GGCTUCTCCA GGCCCTGGAA

.....The-------------------------------------------- ---- ^{:: ::} “O0 ^: ........ 0: 000 <:; ^:

GACACACTGC AGCTGGACGT CGCCGÀCTIT

966

CTGGGAATGG IncorporaçõesTGCCCT GCAGCCCTAA »9.0

GGTGCCATCC CGGCCTICGI CTOTGOT: ??

AGCCATCTGC AGAGCTTCGT GGAGGTGTCG GGCGGCGGCT CTGACATGGQ TACACCATTA CTGCTCAAGT CTTTAGAGCÀ AGTGAGGAAG AAGCTGTGTC CCACCTACAA GCTGTGCGAC CTGGGCATCG CGTGGGCTCC: CCTGAGCTCG TGCTTGAGCC AAGTCCATAG CGGCCmTC GGGATATCCC dGAGTTGGG TOCGACCTTG ux-vACuACuA TUTGGCAGQA GATGGAAGAA TAA (2: INFORMATION FOR SSQ ID NO: 160;

(i) SEQUENCE CHARACTERISTICS ·.

(Ai LENGTH: 1027 base pairs (5) TYPE; nucleic acid (C.Í STRANDEDNESS .: single (D) · TOPOLOGY; linear

Lix) MOLECULE TIRE: ether nucleic acid (A; DESCRIPTION; Zdesc = ’DMA (synthe (Xi) SEQUENCE DESCRIPTIONr SEQ ID ND; 160.ATGGCTACAC CATTGGGCCC TGCCAGCTCC CTGCCUCAGA GCTTCCTGCT CAAGTCTTTA

GAGCAAGTGA GGAAGATCCA GGGCGATGGC GCAGCGCTCC AGGAGAAGCT GTGTGCCACC

70

TAúAAGCTvl GCCà / CCCGA GGAGCTGGTG

185

CTGCTCGGAC ACTCTCTGGG CATTCCCTGG

GCTCCCCTÜ2. GCTCCTCCCC CAGCCAGGCC CTGCA3CTGG

2.0

u.a.GQCTGCT7 GAGCCAACTC

CATAGCGGCC TTTTCCTCTA CCAGGGGCTC

300

TTGGGTCCCA CCTTGGACAC ACTGCAGCTG

36C

CÂGCAGATGG AASAACTGGG AATGGCCCCT í ............

GCCTTCGCCT CTGCTTTCCA GCGCCGGGCA 480

CTGCAGGCCG TGGAAGGGAT ATCCCCCGAG

GACGTCQCCG ACTTTGCGAC CACCATCTGG

GCCCTGCAGC CCACCCAGGG TGCCATGCCG

GGAGGGGTCC TGGTTGCTAG CCATCTGCAG

AGCCTCCTGG AGGTGTCGTA CCGCGTTCTA

540

GACATGGCTA CACCATTGGG CCCTGCCAGC ÓSÜ .......

TTAGAGCAAG TGAGGAAGAT CCAGGGCGAT 66G

ACCTAGÀAGC TGTGCCACCC CGAGGAGCTG

73C

TGGGCTCCCO TGAGCTCCTG IncorporaçõesAGCCAG

780 ............

ÇTCCATAGCG GCCTTTTCCT CTACCAGGGG

840

GAGTTGGGTC CCACCTTGGA CACACTGCAG

90C

QGCCACCTTG CGCAGCCCGG CGGCGGCTCT

TCCCTGCCCC AGAGCTTCCT GCTCAAGTCT

GGCGCAGGGC TCCAGGAGAA GCTGTGTGCC

GTGCTGGTCG GACACTCTUT GGGCATCCCC

GCCCTGCAGC TGGCAGGCTG CTTGAGCCAA

CTCCTGCAGG CCCTGGAAGG GATATCCGCC

CTGGACGTCG CCGACTTTGC CACCACCATC

TGGCAGCAGA TGGAAGAACT GGGAATGÇCC CCTGCCCTGC AGCCCACCCA

968

TAGCQATCTG CAGAGCTTUC TGGAGGTGTu GTACCGUGTT CTACGCCACC

1034

TCCTGGTTGC

TTGCGCAGCC

CTGATAA

1027 (2) INFOHMATIRES BY SEQ τ $ J? _{O: 1δΣ;} (1) SEQUENCE CHARACTERISTICS:

ÍA> LENGTH; 155 arci.nu acids (2) TYPE; asúno acid

371 ° C; STRANDEDNE51 single (D) TOPOLOGY: linear in; MOLECULE TYPE: prntain 'xi · SEQUENCE DESCRIPTION'. SEQ ID NO: 1S1:

Set ' Pro Allah Pre- Pro Aia Qys Asp Read Arg 10 Go Read To be Lys Read 15 • ueu Arg. Asp To be Hl 3 20 Go Jjeu Laugh Sep- Arg 25 Read To be Gin Uys Pro 30 Glu Go His Pro Read Pre- Thr Pro Go Read 4 0 Le « Pro Allah Go Asp 45 Phe To be Read Giy Glu 50 Trp Lys Tax Gin Met 55 Giu Glu Thr Lys Allah 60 Gin Asp Ils Read Giy 65 Allah Go Thr Read Read uc Read Giu Gly Go Men 75 Allah Allah Arg Qiy Gin 80 Read Gly Pre Thr Cys 85 Read To be To be Read Read RD Gly Gin Read To be Gly 95 Gin Go Arg Read Read 100 Read Gly Allah Read Gin 105 To be Read Read Gly Thr 110 Gin Read Pro Pro Gin 115 Gly Arg Tax Thr Allah 120 His Lys Asp Pro Ran Xyh lie Phe To be 130 Phe Gin His Read Read 135 Arg Gly Lys Go Arg 14 0 Phe Read Met Le> _ Go 14E Gly Gly To be Thr Read 150 Cys Go Arg Phe 155

(2) INFORMATION FOR SEQ ID ND: 152;

iii SEQUENCE CHARACTERISTICS:

(A) LENGTH: 309 amine acids (B; TYPE: amrno acid {0) STRANDEDNESS: single

ID.3 TOPOLOGY: linear iii) MOLECULE TYPE: protein (Xi) SEQUENCE DESCRIPTION; SEQ ID NO; 162;

Ser Pr & Ale Pre Pro Ala Cys Asp Leu Arg V&I

Leu Ear Lys Leu Leu bis Val

Hrs Pro Leu Pre Thr

Gly Glu Trp Lys Thr

ONLY

Gly Ala Val Thr Leu

6.5

Leu Gly Pro Thr Cys 85

Val Arg Leu Leu Leu

100

Prr Pro Gin Gly Arg

115

Read Ser Phe Gin His

150

Val Gly Gly Ser Thr

s

Be Pro Wing Pro Pro

165

Arg Asp Ser His Val

180

His Pro Leu Pro Thr

5

Gly Glu Trp Lys Thr 210

Gly Ala Val Thr Leu

225

Leu Gly Pro Thr Cys

245

Val Arg Leu Leu Leu

260

Arg Thr Thr Ala Hrs

275

Leu His Ser Arg Leu Fri

Pro Val Leu Leu Pro Wing

Gin Met Giu Glu Thr Lys 8S

Leu Leu Giu Gly Val Met

75

Leu Ser Ser Leu Leu Gly

Gj.y Ara Leu Gin Ser Leu: 1QS

Thr Thr Ala His Lys Asp 120

Leu Leu Arg Gly Lys Vai .135

Leu Cys Val Arg Glu Phe uSC IS5

Cys Wing Asp Leu Arg Val

170

Leu His Ser Arg Leu Ser

185

Pro Val Leu Leu Pro Wing

200

Gin Met Glu Glu Thr Lys 215

Leu Leu Giu Gly Val Met

235

Leu Ser Ser Leu Leu Gly

25Q

Gly Ala Leu Gin Ser Leu

............................ a: 6: 0 ......

Lys Asp Pro Asn Ala lie

280

Gin Cys Pro Glu Val

V <a „Asp Pne Sex 'Leu

Wing Gin Asp He Leu

Ale A * to Arg Gay Glx;

Gin Leu Ser Gly sir

Leu Gly Thr Gin Leu

Pro Asn Ala He Phe .128

Arg Phe Leu Met Leu 14 0

Gly Gly Aen Met Ala

160

Leu Ser Lys Leu Leu

175

Gin Cys Pro Glu Val

190

Val Asp Rhe Ser Leu

205

Wing Gin Asp He Leu

220

Wing Wing Arg Gly Qin

248

Gin Leu Ser Gly Gin

255

Read Gly Thr Gin Gly

270

Phe Leu Ser Phe Gin

285

373 laughs x> me Ls :: Arg Giy Lys: Vai Arg Pne Leu Met Leu Val Gly Gly Ser 29f 2 »5 -'OC

Thr Leu Cys Val Arg

Í2; ZNFORMATIUN FOR SEQ XD NO: 162:

f s> CíJ ^ i.TTÍT ^ Y *** 'Γ * ti * Ώ ft Τ Γ *> τ \. . ·, Λ. i ‘. . . Χ ^ ΨΧ ^ ς ”♦, U> wv. S * Xvitítew ^ jT ^ v · Arax «^ x \\ X-k«> .4 *. *> · Xw.ua *. ».

LENGTH AREAS; 312 sign aoiòs (Η) ΤΥΡΕ-, sign arid

X · STRANDEDNESS: single (D) TOPOLOGY: linear iii: MOLECULE TYPE; pretexts txis SEQUENCE DESCRIPTION: SEQ XD NO: 163:

To be *1 Pro Allah ⁵ ro Pro 5 A ^ a Cys Asp Read Arg 10 Val Read To be Lye Read it. IS Read Arg Asp To be His Go. Read His To be Arg Read To be Glr Cys Pro Glu Val ge 36 Prg Read Pro Thl Pro Val Read Read Pro Allah Val Asp Phe To be Read 35 40 45 Gxy Glu Trp Lys ..... AaXA, Gin Met Glu Glu Thr Lys Allah Gin Arp lie Read 56 55 66 Gly Allah Val Thr Read Read Read Glu Gly Val Met Allah Allah Arg Giy Gin 65 70 75 ONLY Gly Pin ♦ mi-r Ά Awvt · Cys Read To be To be Read Read Gly Gin Read To be Gly Gin 85 96 95 Val Arg Read Read Read Gly Allah Read Gin To be Read Read uly Thr Gin Read 106 105 .110 Pre Pre Gin Gly Arg Thr Thr Allah His Lys Asp Pro Asn Allah Ila Phe 115 120 ά> 2 a Read To be Phe G-.n His Read Arg Gly Lys Val Arg Phe Met Read 130 135 140 Val Gly Gly To be Thr wow Cys Val Arg Glu Phe Gly Asn Met Allah To be 145 .150 155 ISO ho Allah Pro Pro Allah Cys Asp Arg Val Read To be Lys Read Read Arg

156 wool

374

Asp Set Hiss Vai Leu His Ser Arg Leu Ser Gin Cys Pro Glu Vai Hus ISC · IS.: IK;

Γ & Leu Pre Thr Pre. · Vai Leu Leu Pro Ala Vai Asp Ph® Ser Leu Glv 195 209 * pgs ihi Trp uys Tnr Gin Met Glu Glu Thr Lys Ale Gin Asp lie Leu Gly ^ e · ..: Aja *., Vaj . het Ax.a .Ala Am Glv Qin Lev ²²¹ 239 .238 “*

Gly Pre Thr Cys Leu Ser Ser Leu Le Gly Qin Leu Ser Glv Gin γ: & 2

24S .25: 0. ” pgg

Arg ueu Leu ueu Gly Ate Leu Gin Ser Leu Leu Glv Thr Gin Leu p ~ - _r .

269 2Ô5? 7C

Pro Gin Gly Arg Thr Thr Ala Hie Lys Asp Pre Asn Ala lie Phe Leu 275 280ips

Ser. “‘ Hi: Qm ace Leu Leu Arg Gly Lys Vai Arp Ph® Leu Met Leu Va '2 $ C 295390

Gly Guy Ser: Thr Leu Cys V & l Arg

30? 310

Í1) INFORMATION FOR SEO ID NO; 164:

ÍÍÍ SEQUENCE CHARACTERISTICSc {A; LENGTH ’. 313 amino acids

OB) TYPE. ·, Aninc acid

IC · STRANDEDNES *: single

CDS TOPOLOGY: linear (m; MGLECVLE TYPE: protein

IKi) SEQUENCE DESCRIPTION: SEQ ID NO: 154:

Be Pre Ala Pm Pre Ala Cys Asp Leu Arg Vai Leu Be Lys Leu Leu * ^ ...................... ΊΌ ........ te _t

Arg Asp Ser His Vai Leu His Ser Arg Leu Ser Gin Cys Pro Giava ^ ²⁰ 2530

Hus Pro ueu Pro Thr Pro Vai Leu Leu Pro Ala Vai Asp Phe Ser Leu 3S 40

Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp Ila Leu 55 fie ·

375

Gly Ala Val Thr Leu Leu Leu Glu Gly Val Met. Wing Wing Arg aiy Gin

S5 72 7580

Leu Gly Pro Thr Cys Leu Ser Sez Dec Leu Gly Gin Leu Ser GlyGin

SC91

Go Arg Leu Leu Leu Gly Ala Leu Gin Sex Leu Leu Gly Thr Gin Leu 105 105115

Pre Pro Gin Gly Arg Thr Thr Ala Hrs Lys Asp Pre? Asn Ala lie Phe 1X5 125 125

Leu Ser Phe Gin His Leu Leu Arg Giy Lys Val Arg phe Leu Met Leu 1R 13514 Õ

Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn MetAla

145 152 155160

Be Pro Wing Pre · Pro Wing Cys Asp Leu Arg Vai Leu Ser Lys LeuLeu

185 170-gr. «Arg Asp Ser His Val Leu Bis Ser Arg Leu Ser Gin Cys Pro Glu Val 180 185ISO

His Pro Leu Pro Thr Pro Val Leu Leu Pro Ala Val Asp Phe «Ser Leu 155 .200 ·: 205

Gly Qlu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp lie Leu 210 215220 ^Gi X AÀ® ... V * .l Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg GlyGin

225 230 155 '

Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin Leu Ser GlyGin

245 250255

Val Arg Leu Let Leu Gly Ala Leu Gin Ser · Leu Leu Gly Thr Gin Leu 250 285no

Pro Pre Gin Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala lie Phe 275: 285285

Leu Ser Phe Gin His Lau Leu Arg Gly Lys Val Ara Phe Leu Mat Leu 290 295300

Val Gly Gly sex Thr Leu Cys Val Arg

... MS .... ............. 310 ...... ...... ........

ill · INFORMATION FOR SEQ ID NO: 185t ii) SEQUENCE CHARACTERISTICS:

iA) LENGTH: 318 amino acids (5} TYPE ·, anino acid ίχι · SEQUENCE DESCRIPTION: SEQ ID NO: 165:

To be

Arg

His ^ss:) SLO:

Go

Read

Go

...... .. 14 5

Asn

Lys

Phe

Asp

228

Pre- Wing Pre Pre Wing

Asn Ser Mis Vai Leu

Pre Leu Pre Thr Prn

Glu Trp Lys Tur Gin

Ara Vai Thr Leu Leu

Gly Pm Thr Uys Leu

S: 5

Arg Leu ueu uet Gay

100

Pro Gin Gly Arg Thr

Ser Phe Gin His Leu

130

Gly Gly Ser Thr Leu

150

Mat Ala Ser Pro Ala

165

Leu Leu Arg .Asp Ser

180

Glu Vai His Fro Leu 195

Be Leu Gly Glu Trp lie Leu Gly Ala Vai

230

Ser Arg ueu Ser Ti S ’.

Var Leu Leu Pro Wing 40

Met Glu Glu Thr Lys 55

Leu Glu Gly Vai Met ge.

Being Ser Leu Leu Gly

Wing Leu Gin. Be Leu

105

Thr Ala Hi® Lys Asp to o

Read Arg Gly Lys Vai

1.35

Uys V & l Arg Glu Phe

155

Pro Pro Wing Cys Asp

170

His Vai Leu His Ser

185

Pro Thr Pro Vai Leu

200

Lys Thr Gin Men Glu

215

Thr Leu Leu Leu Glu

235

Asp Leu Arg Vai CVs

Leu Ser Lys Leu Leu> í SÍ

Gin Cys Pre- Glu Vai

Go Asp Phe Ser Leu 45

Wing Gin Asp lie Leu ·, 6δ

Wing Wing Arg Gly Gin

Gin Leu Ser Gly Gin

Leu Gly Thr Gin Leu

110

Pro Asn Ala lie- Phe

125

Arg Phe Leu Met Leu

140

Gly Gly Asn Gly Gly

160

Leu Arg Vai Leu Ser

175

Arg Leu Ser Gin Cys ISO

Leu Pre Ala Vai Asp 2Φ5

Glu Thr Lys Ala Gin

220

Gly Vai Met Ala Ala

240

Arg Gly Gun ueu Giy Pro Tpr Cys Leu Ser Ser Leu Leu Gly .Gin Let * ί λ s '· χ rx ** ^z ' * -'.......... 3 ·. ^. 2 &>

Be or’y Gx.n Ve. Arg Leu wow «you Guy Aua Leu Gin Ser Leu Leu Glv

2 «aes; -t

Thr Sir. Itt Tro M-o sir. sly teg Thr Thr Wing ax »Xys Asp Pro Asn

275ISO

Wing Xie Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys Val Arc Phe

2H0 39Í3oc

Leu Met Leu Val Gly Guy Ser Thr Dea Cys Val Arc?

305 310 ·; t «· * ·, · * ·, * ·.» >. ·

INFORMATION FOR SEQ ID ND; lob;

{i; SEQUENCE CHARACTERISTICS - (A) LENGTH: 302 aausc; acids <S; TYPE; «Nuno acid

IC; STRANDEDNESS; single (D) TOPOLOGY; linear ¢ 11 j MOLECULE TYPE; protein

SEQUENCE DESCRIPTION: SEQ ID NO: 166 .;

Asn cys To be He Met Asp . λαΙ.Ο He He 10 His Read Lys Arg 15 Pre Allah Pro 20 Read Asp Pre Asn Asn 2S Read As i: Asp Giu Asp 30 Val iSer He Read Met Asp Arg Asn Read Arg 40 Read Pro Asn Read Giu 45 To be Phe Val Arg Allah ONLY Val Lys Asn Read Giu. . £ -. , Ί ^. . Asn THE"" To be Gly lie ONLY Giu Allah He Read Arg 65 ώ, Crx Read Gin Pro cys 70 Read Pro To be Allah Thr 75 Allah Allah Pro To be Arg 80 His Pro He He He 85 Lys Allah Gly Asp Trp 90 Gin Giu Phe Arg Giu 95 Lys Xj & L Phe Tyr ύ r <n dx M X. “ Read Val Thr Read Giu 105 Gin Allah Gin Giu Gin 110 Gin Tvr Val Giu Gly Gly Gly Gly To be Pro Guy Gly Gly To be Gly Gly Gly To be

If

Aaa Leu Gin Leu Ala Gly Cys Leu Ser

365

Gars Leu Has Ser Sly Leu pne seu tyr is ^ n uty

180

Giy Pro Thr Leu

T> ^ - r * ‘J Λ. , · Ή ^ * χλλ sv A55f A .4.-. : <y -Λ.-Χ3 • á Xw //. .

Fro Thr Gin Gly

Gly Gly Val Wing

Ser Tyr Arc Val

260 way & erGan Set

Gin Gly Asp Gly

W.. . V>. . . . Jvi. 'Λή Λ.

Asp · Thr ueu

Ata Leu Git

185

Gin Leu Asp

Glr _: Met Glu

Met Pro Wing

G

Leu Vai Aaa

245

Leu Arg His

Tire Leu Leu

Wing Wing «U Gly

Aiks Phe Au a

Ser His Leu

2 <vf $ peu Gan Wing

265

Lys Ser Leu

286

Sin Glu Lye

Gay Xue Ser

Val Ala Asp ns;

Met Ala Pre

Ser Al Phe

235

Gin Ser Phe

Pro Ser Gly

Ga U 'u? An Vaa

28S

Leu Cys Ala

300

Pre Gau Leu

190

Rhe Ala Thr

Wing Leu Gin

Gin Arg Arg

24: 0

Leu Giu Val

255

Gly Ser Gly

Arg Lys lie /ί'£>.·ΛΧ· (2: INFORMATION FDR SEQ ID NO: 167:

(i · SEQUENCE CHARACTERISTICS:

ÍA) LENGTH: 217 sign acids {EJ TYPE; asu.no acid (C) STRANDEDNESS: single (0? TOPOLOGY: Imear ~ di; MOLECULE TYPE; protein

UU SEQUENCE DESCRIPTION: SEQ ID NO; 16:

Asn Oys Ser ale Met He Asp Glu He He His His Leu Lys Arg Pro 16 _{i £}

Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Sa

2Q ........ ^ 'C ........................

379

Arg Ala

Arg Asn £ 5

Hrs Pro .lx

Vai Qlu

Thr Cl®

0

Met A is

145

Fri 'Leu

Read Gin

Tyr Gin

Pro Thr

210

Tie Trp

225 * r <\ ~ f i „

Gly Gly

Iff Arg

Being Gin

290

Gly Asp

He ~ la

Phe Tyr

100

Qty Gj.y

125

Asn Pro

Gly L «

Go Read

260

Go Read

275

Ser Phe & * y Ale

Met Asp

Va1 Lys

Leu Ala

ISO

Gly Leu ^s »

Read Asp

Gin Gin

Gly Ala

Arg Asr;

Asn Leu

Pre Cys

He Lys

Leu Vs1

Gly Gly

Be Pro

Read Cys

150

Pro Trp

165

Gly Cys

Read Gin

Thr Leu

Met Glu

230

Met Pro

245

Go Ala

Arg His ueu Leu

A <1 to Leu

310

G lu Asr:

Leu Pro

A: .a G2y

Thr Leu

Be Pro; go (0 /

Pro Ser

His Pro

Pro Wing

Leu Ser

Wing Leu

200

Gin Leu

Glu Leu

Phe Ward

Ser His

Leu Ala

280

Lys Sex

295

Gin Glu

Leu Pro

Ala Ser

Be Wing

Asp Trp

Gau Qin

1:06

Gly Glu

Lys Glu

Gj.u Glu

Leu Ser

170

Gin Leu

185

Gjlu Gly

Asp Vai

Gly Met

Ala Ser

250

Leu Qin

265

Gin Pro

Leu Glu

Lys Leu

Asn Leu

Guy Ire

Thr Ala Gan Gau Ai «Gin Pro Ser Ser His

140

Leu Vai

155

Be Cys

His Ser He Ser Ala Asp

220

Pro Wing

235

Phe Ward

Ser Phe

Be Gly

Gin Vai

300

Cys Ala

315

Oj <«Be

Glu LI · Ale Fro

Phe Arc

Glu Gin

Gly Pro

12.5

Lys Sez

Pro Ser ** ♦ ·>,, r _M , v ^ -hy

19Q

Pro Glu

205

Phe Ala

A.xa Leu

Gin Arg

Leu Glu

7Ti

Gly Ser '285

Arg Lys

Thr

Pne Va ..

le net

Ser Arc

SC

Glu Lys

Ils Ser

Pro Asn

Gly His

160

Gin Wing

Phe Leu

Read Gly <τ ^

..... Α * αλ '

Gin Pro 240

Arg Ala

255

Val Ser

Gly Gly

He Gin

SO * M ?, 7I0N FC · ?. SEQ ID NG: i6c;

SF ‘5’ EM :? AND CHARACTERISTICS ·.

(a .: LESSTH,. · 332 amino acxás; E: TYPE ·, amino acid (C; STRANDEENES5: single

CO; TOPOLOGY; linear

MOLECULE TYPE; protean: xil SEQUENCE DESCRIPTION; SEQ IE NO: ISS:

Asn Cys Ser He Met He Asp Glu

He He Hrs

His Leu Lys Arg Pm t-'re Ale Pro Leu Leu Asp lie Leu Met Asp Arg Asn

Arg Ala Val Lys Asn Leu 5 (;

Arg Asn Leu Qin ProCys

6570 hrs Pro lie He lieLys

................ 85

Leu Thr Phe Tyr LeuVal

IOC

Val Glu Gly Gly g ^ y

Pro Asn Asn Leu Asn

Leu Arg Leu Pre Asn 4 δ

Gru Asn Ala Ser Gly

S5

Leu Pro Ser Ala Thr .................. 75

Wing Gly Asp Trp Gin

Thr Leu Glu Gin Wing

105

Be Pro Gly Gly Gly

120

Asp Glu Asp Val Ser

Leu Giu Ser Phe Val

He Giu Ala He Leu

Wing Wing Pro Ser Arg '80

Glu Ph® Arg Glu Lys

Gin Glu Gin Gl.n Tyr HO

Gly Gly Gly Gly

125

Asn Met Ala Pro Glu

130

Val Ala Asp Phe Ale

145 ........

Met Wing Pro Wing

165

Ser Wing Phe Gin Arg

ISO

Gin Ser Phe Leu Glu

195

Leu Gly Pro Thr Leu Asp 135

Thr Thr He Trp Gin Gin

150 lag

Gin Pro Thr Gin Gly Ala

170

Arg Ala Gly Gly Val Leu

Val Ser Tyr Arg Val Leu

200

Thr Leu Gin Leu Asp

140

Met Glu Glu Leu Gly

160

Met Pro Wing Phe Wing

175

Val Ala Ser His Leu

ISO

Arg His; jsu Ala Gin,

205

Phe Leu

Read

Read it.

To be

Read, ne

AJ.si> ys

L> hey

Read

Lfeu

To be

Lt? I

If.

4x £ & U

285 le

SEQ XD NO; 169. ·

At:

(D;

soft:

u-me

LENGTH: 327 ajoino acids TYPE: anino acid STHAES3EXJNESS; single TOPOLOGY; linear

DE TYPE. · Protein descr:

“ONSe:

Me

Val

Leu i-le

Phe

Xh lie

G1 lie re »15

Read

Lex

Asp

Fro

Asn

Lev

Asp

GXu

Asp

Arg

Read

JuX & U ^fc ro 'Leu

G.

G.

If.

lie

Read

To be

A ^ a

Allah

Allah

Ila

Allah

Glu

Allah

105

Asp

To be

Pro

Val

Phe ner

Phe Arg Glu «re.

To be

Val

Read

Met ilil Al & Pro Glu Gly Allah Asn Aia tire 15 S .......... <A Pre Wing Leu GLr; Pre Phe Gin Arg 195 Arg Allah S «sr Phe 212 Read G »« Go To be Per 'JI Guy Gly Ser Gxy Gly 23 v Gin Go Arg Lys lie 245 Gin Allah Thr Ty * 260 Lys Let His To be Leu Gly lie ^ 3 ^ · »* χ Allah Read 290 Ax.a & Ây Read γ ns. »* W -w Tyr Gin Gly Read 11.2 ..

there . wk '. .% ¼ - -. ΛίΛ'.Λ Qk 'A. ^ K * X ^s

Tnr l.U Asx * Fu. Be Pro

130

To be '' Sf: -J f '; ' «> A < XffXkt Pro Ser x X X Pre lie Fri· Lr & To be Lys .. \ S.w.'M ·. Ser Hrs x.4: Ο Lys To be Pro Ait Pro Thr Read Asp The Leu 156 Gin Asp Go

Xie Try Gin Gin Met Glu Glu Leu Gly Me ::

1 ^ 0 *

Th- ' Gin Gly 185 Allah Met Phe 190 Allah Gly Gly Go Read Go Allah 205 Ha s Read <xXo ^, * ^! yv Arg Go Read Arc His 220 Read Allah Pro Ssr GLr. To be Phe Read 235 Read Lys To be Read Sxu 240 Gly Asp Gly Allah 250 Allah Read τ \ Glu Lys 255 Xa> ^? \ Ú Cys His Pro 2S5 Glu Glu Read val Read THERE: / v? Lev Gly Trp Allah 280 Pre Read To be To be Cys 285 Pro To be xy JLJi Cys Read To be Glix Read His To be Gxy V & u Rhe

2S5 3 0, _the

QXXa A, l & I ^ & u Gjlu G.ly XXis S <s.r

3X5 il) INFORMATION FOR SEQ ID NO: 170:

Ú} SEQUENCE CHARACTERISTICS:

(A) XiENGTH: 322 asarnc acids ÍS) TYPE: andnc acid (Cj STRANDEDNESS ·. Single ÍD) TOPOLOGY: linear iii · MOLECULE TYPE: protein

ÍXií SEQUENCE DESCRIPTION: SEQ ID NO: 170:

383

At

Met

His

Asn

Read

Asn Asp

To be

Arc

His me

Met

Aar.

wow

Asn ueu

-¾

Gl

If

Ph®

Asn

Pre

Pre

To be

Allah

AXh

Allah

Arg

Pre

Asp

Phe

Arg

Read

Phe

Read

Go.

Th:

Le

100

Allah

THE

Gru

Gin

110

Gist

To be

Pro

Gly

Gly

To be

Gly

125

Asn

Met

Ο

Allah

Met

Allah

135

Read

Gin

Thr

Gin

0

Gly

Allah

Met

Pro

Allah

Ph®

Allah

If

Allah

Phe

ISO

Gin

Arg

Allah

Go wow

Go

Ara

160

To be

Read

To be

Phe

Go

To be

Go

His

Read

Allah

Glr

Prc <

ISO

If.

Gly

To be

Gl:

185

To be

Phe

ISO

Read tys

To be

i / me

IS 5

Go

Arg

Lys

200 iiS

Asp

Gly

Allah

Allah

Read

Go

Cys set

Glu

210

Lys

Read

Gly

Gin

Cys

His

245

Allah

To be

Read

Read

Gly

Lys

Read

Hrs

Pro

Glu

Gru

Leu lie

Allah

Gly

250

Cys

Allah

Pro

To be

To be

240 eu

To be

Gin

Read

255

His

Gl)

Read

Phe

260

Read

U

26S

Read

Gin

Read

Gl '.

Gly lie

Read

Gly

Pro

Read

280

Asp

Read

Gl.

Read

285

Asp

Go

Allah

384

Asp Pne Ala Thr Thr lie Trp Gin Gin Met Glu Glu Leu Gly

OS, w * · V * '·>' lfc> Λ * Μ, · V> V V, ·

INFORMATION FOR SEQ ID NO: 171:

id; SEQUENCE CHARACTERISTICSt {Aj LENGTH: 317 amino acids (S> TYPE: amino acid

IC> STRANDEDNESE t single

ID- TOPOLOGY: linear iiii MOLECULE TYPE ·. protein (xi} SEQUENCE DESCRIPTION: SEO- ED ND; .17

• Asn Pro Cys Axa Ger Pro Lêii 20 Met s Read He Asp He Read Mat 3 S Asp Arg Asn Arg Ale 50 Val Lys Asn Read »\ Rg 65 Asn Read Gin Pro Cys 70 His Pre· lie He lie 85 Lys • Thr Phe Tyr ISO Read Val Go Glu Giy 115 Gly Gly Gly Thr ru Ί 3 ft Ά- «Λ 'V- Asn Pro To be Pro Met 145 Allah Met Pro Allah 150 Phe Allah To be Phe 165 Gin His Read Gin To be 180 Phe Read

Asp Glu Ila He His Hrs Leu Lys Arg Pro

Fro Asn Asn Leu Asn Asp Glu Asp Val Ser 25sc

Leu Arg Leu Pro Asn Leu Glu Ser Phe Val M45

Giu Asn Αψ & Ser Gly He Glu Ala He Leu 556Q

Leu Pro Rar Ara Thr Ala Ala Pre Ser · Arg

7580

Wing Gly Asp Trp Gin Glu Phe Arg Glu Lys

Thr Leu Glu Gin Ala Gin Glu Qin Gin Tyr 105HO

Ser Pro Gly Glu Pro $ er Gly Pm He Ser * 25 125 .................

Pro Ser Lys Glu Ser His Lys Ser Pro Asn 135140

Leu Gin Pro Thr Gin Gly Ala Met Pro Ala

155Igo

Arg Arg Ala Gly Gly Val Leu Val Ala Ser ¹⁷⁰ 175

G «u Vau Ser Tyr Arg Val Leu Arg His Leu

190

385

Ara Gzi ’; Pro sax 'Gay G * y —Si' Gly Gty Sex · Gir. Be Poe Lou L®u LY- ’?

191 2002 35

Ser. Leu Glu Gin Val Arg Lys He Gin Gly Asp Gly Ala Aa Leu Gin '2X0 215 ......... 22c

Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His pre Glu Glu Leu Val 225 230 ’235

Leu Leu Gly Hxs Ser Leu Gly lie Pro Trp Ala Pro Leu Ser Ser Qys 245 250255

Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser

350 26527Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Π® Ser 275 2®02SS

Pro Glu Leu Gly Pre · Thr Leu Asp Thr Leu Gin Leu Aar Val Ala Asp 250 295300

Phe Ala Thr Thr lie Trp Gin Gin Mat Glu Glu Leu Gly

395 310315

Ϊ2; INFORMATION FOR SEQ ID NO; 172;

(i; SEQUENCE CHARACTERISTICS;

(A) LENGTH: 302 axaino acids {Bi TYPE; axainc arid (Ci STRANDEDNESS; single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein <x.i) SEQUENCE DESCRIPTION; SEQ ID NO: 172;

Asn Bill Cys To be lie Met: 5 He Asp Glu He He 10 Mis His Read Lys Arg Pro Pro Allah Pro Read Read Asp Pro Asn Asn Read Asn Asp Glu Asp Val To be 20 ** »£ 30 lie Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu. To be Phe Val 35 40 45 Arg Allah Val Lys As.n Read Glu Asn Allah To be Gly He Glu Allah He Read 50 55 60 Arg Asn Read Pro cys Read Pro To be Allah Thr Allah Allah Pro To be Arg §5 70 75 80

386

Pre Ils Lie Ils Lye Ala Gly ?? ................................ 111-1 ...... ............ '

Leu Th:. · 'Pte Tyt Lea Val Thr Leu IOC .........

Val Glu Gly Gly Gly Gly Ser Pro * M ¢, <A ΛΧ ft

Asn Met Ara Tnx Gin Gly Aaa. Met 1: 3 2 £ 13

Art Ax g ax to G. ». And Guy Vat ueu Vax .............. ........ ': | g | _L ............

Glu Val Sex 'Tyr Arc Val I <I Arg

Ser Guy Gly Ser Gin Ser Phe Leu

182

Lys Xie Gin Gly Asp Gly Wing Wing

195202

Tyr Lys Leu Cys His Pro Glu Glu

2101X5

Gly lie Pre Trp Wing pro Leu Ser 235230

Leu Ala Gly cys Leu Ser Gin Leu

245

Gly Leu Leu Gin Alu Leu Glu Gly

....... 262

Leu Asp Thr Leu Gin Leu Asp Val

27 ^c 280 Gin Gin Met Glu Glu 250 Leu Gly Met 2 55

Asp Trp Gin Glu Phe Arg Glu Lys SO §5

Gru Gin Ala Gin Glu Gin Gin Tyr 195 2X0

Guy Gly Gly Ser Gly Gly Gly Ser

For the Phe Ward Ala Ser Phe Glr Ward.

^S :: 11ÍE '.....

Ala Ser His Leu Gin Ser Phe Leu

LSI: 1'60

Hxs Ar-a Gin r.m Ser G, xv Gly

£ HO27

Leu Lys Ser Leu Glu Gin Val Arc 185

Leu Gin Glu Lys Leu Gys Ala Thr

205

Leu Val Leu Leu Gly His Ser Leu

0

Ser Cys Pro Ser Gin Ala Leu Gin

235240

His Ser Gly Leu Phe Leu Tyr Glr252255 lid Ser Pro Glu Leu Gly Pro Thr 255270

Asp Phe Wing Thr trr xie Wing Trp

285

Pro Wing Wing Leu Gin Pre

300 <2; INFORMATION FOP, SEQ ID NO; 173 _:

11? SEQUENCE CHARACTERISTICS r (A; LENGTH: 317 amino acids

ÍH; TYPE: amino acid

IC) STRANDEDNESS; single

ÍD) TOPOLOGY; linear (in MOLECULE TYPE; protein

Gy'S

Xà & Asp GXu Xis XXí ?! Hxs

h..Xk 4rf <? «ο x ^ ys Pi *

Pre Wing Pre · Leu Leu Asp Pro

Asa Asn Leu Asn Asp Glu Asp Vai Sex lie Leu Met Asp Arc Asn Leu

Arg Ale Ve.l Lys Asn Leu Giu.

S p; ^: 55

Arg Asn .u-eu Gin Pro Cys Leu

Hrs Pro He He n _€ Lys Ala Gly

Leu Thr Phe Tyr Leu Vai Thr Leu

X v c '/ as Glu Gly Giy Qiy QXy Ser Pro

Thr Ila Asn p _rcs e ^ _r p _ro p _{ro Ser}

130 135

Met Ara Thr Gin Gly Ala Met Pro ¹⁴ 5 ISC

Aurg Ala Gly Gly Vai Leu Vai Ala

165

It will be Tyr Arg y _a i Leu Arg His

ISO

Uiy Guy Ser Gin Ser Phe Leu Leg

200 xus uiU Shy 'Asp Gly Ala Alu Leu 210 215

Lys Leu Cys His Pro gi _u g.1u Leu ^22s 230 lie Pre- Trp Ala Pro Leu Sex Ser 24s aj.a uly Cys Leu Ser Gin Leu His

260

Arg «I Pro Asn Leu Giu Ser Pne Vai 45

Asn Snr Giy lie Glu Ara He Leu SO> Ser Tnr Ala Wing Pro Ser Arg <5 80

Asp Trp Gio Glu Ph® Arg Glu Lys 90 gg

G * .u Gin Ala Gin Glu Gin Gin Tvr 105 no

Gly Glu Pro Ser Gly Pro Ih Ser 125

Lys Glu Ser His Lys Ser Pro Asn 14: 0

Phe Wing Ger Wing Wing Gin Arg Wing 155 160

Ser Hrs Leu Gin Ser Phe Leu Giu

170 175

Leu Wing Glr> Pre Ser Gly GIv Ser 185 χ «Α

Lys Ser Leu Glu Gin Vai Arg Lvs 2 05

Qin Glu Lys Leu Cys Ala Thr Tyr

2.20

Go Leu Leu Gly His Ser Leu Gly ^23s 240

Cys Pro Gar Gin Ala Leu Gin Leu 250

Ser Gly Leu Phe Leu Tyr Gin Glv ·> «k

388

Lsu Leu Wing Leu · Sb »L x < Sb - He To be / · £ <>. sb — U Gly Pro Tnr La 285 Asp Thr 4J * SU 0 m Leu Asp Go ΑΙΑ: Asp Fh & Ala ThT · Thr lie Ire Gl. 290 295 * A Λ * * »* < Gin Met Gxu Gru Leu Gly Me:: * · V. Λ <L & Pro Als Leu Gin Pro 3C5 32 0

INFORMATION FOR SEC ID NG: 174 ·.

it; SEQUENCE CHARACTERISTICS;

(As LENGTH ·. 3C2 amino acids (R) TYPE; amine acis (C) STRAKX3EDNESS: Single {»; TOPOLOGY: linear (ii · MOLECULE TYPE; protein

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174:

Asn Cys To be He Met lie Asp Glu lie He 10 His His Read Lys Arg * IC Pre Pro Allah Pro . i <me Asp Pro Asn Asn Read Asn Asp £ lu Asp 30 Go To be lie Read Met 35 .Asp A ^ g Asr Read Arg 40 Read Fro Asn Read Gj.u 45 To be Phe Val Arg Allah SQ Go Lys Asn Read Glu 55 Asn Allah To be Giy He 68 GxlU Allah He Read Arg 65 Asn Read Gin Pro Cys 70 Read Pro  ** * er Al 3 Thr Allah Allah Pro To be Arg ONLY His Pro lie lie He 85 Lys Allah Gly Asp Trp 90 Gin Gut · Phe Arg z · »y» < M1U 95 Lys Read Thr Phe Tyr 200 Read Go Thr Read Glu 105 Gin .Allah Gin Glu Gin Gin Go Glu Gly 115- Gly Gl ^ Gly To be Pro 120 Gly Gly Gly To be Gly 125 Gly Gly To be Asn Met 130 To be Ouch Phe Gin 13 5 Arg Arg Allah Gly Gly 140 Go Read Val Allah To be 145 His Read Gin To be Phe 180 Read Glu Go To be Tyr Arg Go Read Arg His 160

$ 38

If:

If:

Phe

Read

Read

To be

Glu ύβ · rc

1.8

Le

Pro

200

Read

Read

To be

Trp

Net wing

To be

5er

Allah

Read

Read net.

Phe

Read

Read

Le

Allah

Read

Fri

Pre g:

^ me

260

Gly ueu

Asp

Asp

Wing x and

Trp

Gin

280

Men

Read

285

Met

Allah

PreAla

390

Read

Thr

Allah

Met

255

Phe Ala

INFORMATION FOR SEQ ID NOr 175:

SEQUENCE CHARACTERISTICS;

LENGTH

TYPE. · Amine acid

ETOANDEDNESS: single

TOPOLOGY: linear (A ·

IT;

(D) amine acids

MOLECULE TYPE; protein

ixD

SEQUENCE DESCRIPTION: SEQ ID NO:

Asn Cys To be He Met He 5 Asp Gru lie He 10 His His Lys Arg 15 Pre Pre Allah Pre Read 20 Read Asp Pro Asn Asp 25 Read Asn Asp Glu Asp 30 Go To be He Read Men 35 Asp Arg Asn wow . . . 40 Read Pro Asn Read Glu 45 To be Phe Go Arg Allah Go Lys Asn. Read <** x „> KS4rU Asn Allah To be Gly He GXu Allah He Read

to / ή). «. χί

THE;

Si

Met

Read

Glu

Read

Pte

At;

Fri

Axa

If

182

Pro

If

Phe

Allah

2S0

Read

G1 i 9

Read

Cvs

His * au £ · «£> O Ò

Thr

Pro lie

Read .9

TV

To be

Phe ^& he

Gly

Wing »e.

Read

Pre re

Thr

If.

To be

Ser i?

P.

Allah

Gly 15 ';

Read

If

At:

160

Glu

Tyr

215

Go

Gly

185

If:

Lys

Read

Cya

Go

To be

Pr

Le

Step

Allah

Al®

Read

Read

Xie

To be

To be

Read * ua

Gly <- ys

Read

Qin ueu

His

G1

Read

Read

A & a

Read

Git lie:

Thr izfòtl

Asp

Thr

Met

Glu

Gin

Gly

Allah

Met

Gin

Go

Allah

G.

BO

Sly ueu

Go

240

If.

To be

Asp

Pro

Allah

Phe

Allah

FORMATION FOR SEQ XL NO

EQUENCE CHARACTERISTICS ~ (A) LENGTH; 305 amino acids (E? TYPE; antino. Acxd .391

L?: · STRÀKDEDNESS ·. sm

TOPOLOGY, linear

MOLECULE TYPE; protein ixli SEQUENCE DESCRIPTION: SEO ID NG-. 176.

Art Cys

Pro Am

He Leu

Arg A * .a

Arg Asn

His Pro

Leu Thr

Val Glu

Asn Met

Ç

His Ser

145

Allah

Leu Tyr

Gly Pro

Thr He

210

Pro Thr

225

Ear He

Pro Leu

Ret Asp

Val Lys

Read Gin.

He lie

Phe Tyr

100

Gly Gly

115

Wing Tyr

Leu Gly

Gin Leu

Gin Gly

ISO

Thr Leu

IPS

Trp Qin

Gin Gly

Her He

Read Asp

Arg Asn

Asn Leu

Pro Cys

He Lys

Leu Val Gly Gly Lys Leu He Pro

150

Wing Gly

165

Leu Leu

Asp Thr

Gin Met

Met Wing

230

Asp Glu

Pro Asn

Leu Arg 4G

Glu Asn

Leu Pro

Am Gly

Thr Leu

Be Pro

120

Cys His

135

Trp Ala

Cys Leu

Gin Ala ueu Gin

200

Glu Glu

215

Pro Wing

Ire He .25

Leu Pro

His His

Ale Ser

Her Am

Asp Trp

Glu Gin

105

Gly Gly

Pro Glu

Pro Leu

Being Gin

170

Leu Glu

185

Read Asp

Leu Gly

Phe Ala

Asn Leu

Gly He

Ths Ala

Gin Glu Ala Gin Gly Eer Glu Leu

140

Ser Eer

155

Leu His

Gly He

Val Ala

Met Ala

220

Be Al. A

235

Leu Lys

Glu Asp <3 ’V *

Glu Ear

Glu Ala

Pro Wing

Phe Arg

Glu Gin

HO

Gly Gly

Val Leu

Cys Pro

Be Gly

Sex Pro

190

Asp Phe

205

Pre Wing

Phe Gin

Arg Pro

Val Ser

Phe Val

He Leu

Ser Arc

Glu Lys

Gin Tyr

Guy Sex

Leu Gly ne r Gm

ISO

Leu Phe

175

Glu Leu

Thr Wing

Read Gin

Arg Arg

240

Λ, Χέί Giy V & ~ * mu Vai. Ala Ser 25C Glr. Ser Phe Leu Glu Go $ w Tyr A: g Val Leu Arg His Leu ........ 261 ..... ............. AX & Pro Τήχ · Ρ * ό • Goky . X C \. ·. Ã ’X Ax khan Ser Ser Leu Pro Gin Ser Phe 2 it 280 Read Lys Be Leu 285 GxL GLr; 1 a. Arg Lys lie Gin Gly Asp Gly Ala 29-0 Allah Gin x? l> * Ly * :; 300 Read Uys;

_r 3GS

INFORMATION FOR SEQ ID NO; 177;

ii <SEQUENCE CHARACTERISTICS:

(A) LENGTH: 320 amino acids ίΒ · TYPE; antnc acid iCi STRANDEDNESS: single (D> TOPOLOGY; linear dii MOLECULE TYPE: protein (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 177:

Asn Uys Ser He Met He Asp Glu lie He Mis His Leu Lys Arg Pro

5. 10 '4

Pre Wing Pro Leu Leu Asp Pro Asn Ann Leu As π Asn Glu Asp Val He20 2.E '-d

He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Ph® Va · M 40

Arg Am Val Lys Asn Leu Glu Asn Ala Ser Gly He Glu Ala H «Leu ³⁰ 5560

Arg Asn Leu Gin Pro Cys Leu Pro Ser Wing Thr Wing Wing Pro Ser Arg ^{/ C 75}

Has Pro lie He He Lys Ala Gly Asp Trp Gin Glu Ph® Arg Glu Lys ^8is 90gg

Read Thr a. Tyr U »Val Thr Leu Siu Sih Ala Glu Glu am qm Tvr ¹⁰⁵ 1.10, ^{V & 1} ..., ® ^lu ....? Jy ... 9 * y .. ^G1 X. ^G1 y Ser pro Giy Glu Pro Ser Gly Pro He Ser

............... ** ”......... .............. ......... .............................

393

Thr Tie Asr. Pro

Ser Pr

Met Tyr Lys Ward

145

S & r Leu Gly He ύ € ΐ Gir »« me. Ai a

0

Tyr Gin Gly Leu

195

Pre Thr Leu Asp u

Tie Trp Gin Gin

Read Cys Hie Pro

150

Pro Trp Ala Pro

165

Gly Cys: «I am« I uur Ala «I

Thr Leu Gm Leu

Thr Gin Gly Ala

Gly Gly Val Leu

26C

Tyr Arg Val Leu

275

Be Ser Read

Met Glu Glu Leu

230

Met Pro Ala Phe

245

Val Ala Sei 'His uys · rie Gm Gly

Arg His Leu Als

280

Gin Ser Phe Leu '295

Asp Gly Ala Ala

310

Gm Leu H, xs Ser

Glu Giy He Ser

Asp Val AM to Asp

Gly Met Ala Pro

Ala Ser Ala Ph®

250 «I Gin Ser Phe

265

Gin Pro Thr Pro

Leu Lye Ser Leu

00

Leu Gin Glu Lys

Lya Ser Pro Asr

Lou Leu Glv Has

ISC

Pre Ser Gin Ala

Guy ueu Pae Leu u

Pro Glu Leu Gly

Phe Ala Thr Thr

Wing Leu Gin Pre ·

Q

Gin Arg Arg Ala

Leu Glu Val Ser

Leu Gly Pro Wing

285

Glu Gin Vai Arg

Leu Cys Ala Thr

320 {2 · INFORMATION FOR ESQ IL NO ·. · 178;

(1) SEQUENCE CHARACTERISTICS;

(Ai LENGTH; 305 amino acids> H) TYPE; amino acid? C ·; STRAKDEDNESS; single (D) TOPOLOGY: linear iii) MOLECULE TYPE.- protein ixi? SEQUENCE DESCRIPTION; SEQ ID NOt 178:

Asn Cys Ser He Met Ila Asp Glu lie He Hrs His Leu 1

394

Read As:

Be.

THE:

Read

Asp

Asr. Leu Am

Read

Be ‘he Va

Ala Vai

Am

Asn

Allah

Be • i »6

8r

Pro

Sa:

Auk &

Ph a

Ph® ueu

Go.

101

al ae.

Pro

Gly

To be

Met

Glu «et

Pro

Thr w <& ll I will

Phe

Ala her

Glu

Gly

160

Het

A ^ a

Pro

Allah

Read

Gin

Pro

Allah

Pro

Phe

Allah

To be

Ph®

180

Arg

Gl

Go

Go.

Allah

Read

Gin

To be

Phe

195

Glu

Go

If.

Arg

Go u $ 0

200

His ueu

Gin

Thr

210

PTi x> me

Pro

Allah

To be

To be

Gin

Phe

Read

Read

Lys

Fri'

Read

Glu

Go

Lys lie

Gin

Asp

Gly

Read

246

Gl

Glu

Lys

Read

Cys

245

Wing uys

Read

Go wow

Gly

250

If

Read

Gly

Pro uet

270

To be

To be

Pty Ser

Gin

Read

Read

280

Allah

Gly

Cys

Laser

Read

His

Ph®

Gly

Read

Read

Gin

Allah

Read

395

To be

305 (2? INFORMATION FOR EEQ ID ND: 1? S:

T13 SEQUENCE CHARACTERISTICS: (A; LENGTH: amthc aSids 32C, ^r: Tire, amino sole ^FC: STRANDEDNESS: single (D; TOPOLOGY; Imear Till · / MOLECULE TYPE; pretetn

ixi .; SEQUENCE DESCRIPTION: SEQ ID ND: 179-. Asn 1 Cys Ser He Met Ila Asp Glu He He Hxs His Leu Lys; Am Pro - is ‘'is Pro Aia Pro Leu Leu Asp Pro Asn Asn Leu Am. Asp Glu Asp Val Ser 10 25 30 He Leu Met Asp Arg Ann Leu Arg Leu Pre Asn Leu Glu Ser Phe Val 35 40 4S Arg Wing Val Lys Asn Leu Glu Am Wing Ser Giv He Glu Wing Ils Leu ^5C 55 60 Arg 65 Asn Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing Pro Ser Arg Wing 70 ”5 His Fro Ils lie lie Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys 85 gg g _S Read Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tv * 100 105 ÚÜ Val Glu Gly Ely Gly Gly Ser Fro Gly Glu Pro Ser Gly Pro Ils Ser 115 120 125 Thr He Asn Pro Ser Pro Pro Ser Lye Gin Ser His Lys Ser pro Asn 130 US ₂ 4Q Met 145 Wing Rm Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val 15u 155 jgQ Allah Asp Phe Ala Thr Thr lie Trp Gin Gin Met. Giu Glu Leu Gly Met 170 17 ^

Pro Wing Wing Leu Gin Wing Thr Sin Gly Wing Wing Fro Wing Phe Wing

396

I know ’Phe Leu. Glu

21 (Thr Pro Leu Giy

Ser Leu Glu Gin

Giu Lys? Read Cys

2L0 ueu Leu Giy Hrs

Pro Ser Gin Ale

292

Gly Leu Phe Leu

305

Arg AL® »Giy Gly

Ford Ser Tyr Arg

Pre Ara Ger Ser

Go Arg Lys He

s

Aia Thr Tyr Lys

Ser Leu Gly He

280

Read uuuís A »eu Ala

295

Tyr Gin Gly Leu

3X0

V & x Lt & v AX &

Go Leu x ^ rg His

I> <u £ ro Clr S & r

X3 £ kyXX'i CXXv

250

Read Cys His Pro

Pro Trp Alss Pre

Gly Cys Leu Ser

300

Leu Gin Ala Leu

315

191?

Ser Has Leu Gl ~

Read Aia Gin Pre

Ph s? Leu Leu Lys

Ç

Au, Ana Leu G «r

Giu Glu Leu Vai

Read Ser. Ser Cvs δ S

Gin Leu Hrs Ser

Glu Gly He Ser

320 í2 · INFORMATION FOR REQ ID NO; 180?

(ii SEQUENCE CHARACTERISTICS:

(A) LENGTH; 305 amino arias (S; TYPE; sign here (C; STRAKDEDNESS; single (LU TOPOLOGY: linear (it; MOLECULE TTPS: protein

(Xi) SEQUENCE DESCRIPTION; SEQ CD _KQ . , gA.

Asn Cys To be T Met He Asp CaU Ils He Hrs His Read Lys Arg Pro : - »1 J 10 - <£ · Pro Allah Pro Read Read Asp Pro Ask Asn Read Asn Asp Giu Asp . · * · <A · ' Go To be 20 25 30 lie Read Met 35 Asp Arg Asn Arg 40 Read Pro Asn Read G _w V 45 ner Phe Go Arg Allah Go Lys Asn Read tflU Ast. Aia To be Gly lie Giu Allah He Read 50 55 «Η

7

At Asn Leu Gin Pracc Le_ Set Ala Thr A la Al a Pro Ser Arg 65 70 75 SO 'is Pre He He He Lys Ala Giy Asp Trp Gin Glu Pue, rç G / „; Lys

90 Ç

Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tvr

Val Glu Gly Gly Gly Gly Ear Pro Gly Gly Gly Ser Gly Gly Gly Sex

...... ...... ...... Ί.2Ό i 7 <1

Asn Met Ala Met Als Pro Ala Leu Gin Pre Thr Gin GJy Ala Met Fro

—... · .. · r · 14 C

Al Phe Ala Ser Al Phe Gin Arg Arg Ala Gly Gly Val Lar Val Val

14O 150 155ISO

Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu ArgHis .165 170iaLsu Ala Gin Pro Thr Fro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser iao issiso

Ph® Leu Leu Lys Ser Leu Glu Gin Val Arg Lys He Gin Glv Ast Glv

195 200 “QOS

Wing Als Leu Gin Glu Lys Leu Cys Wing Thr Tyr Lys Leu Cys His P ^ o

219 215 ‘220 ulu G * .u Leu Val Leu Leu Gly Has Ser Leu Gly He Pro Tro AlaPro225 230 235‘ -240

Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys LeuSr

245 250255

Gin Leu Hrs Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu & 0 265270

Hi Gly He Ser Pre- Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Le ' ¹ 275 280285

Asp Vai Ala Asp Phe Ala Thr Thr lie Trp- Gin Gin Met Glu Glu Leu 250 29Õ300

Gly

OS (2} INFORMATION FOR SEQ ID NO; 181 _: <i) SEQUENCE CHARACTERISTICS .;

(A # LENGTH; 320 aaino acids (B <TYPE: aninc acid (C) STRANDEDNESS; single

39?

(x.ii SEQUENCE DESCRIPTION; SEQ ID NO: 181;

& sn Cy «.; * ·‘ 4 · * - * · X7j> «A. & v

Arg Ala

C. Λ '

Arg Asn

È 5Hit Pro

Leu Thr

Val Glu

Tnr lie

130

Met Ala

145

She Ala

His Leu

Wing Gin

Leu Leu

210

Wing Leu

7-55

Ser lie

Pr0 Leu

Met Asp>

Val Lys

Leu Gin lie He

Ph® Tyr

150

Gly Gly

Asn Pro

Met Wing Wing

Gin Ser

180

Pre Thr

195

Lys Ser

Gin Glu

My 11®

Read Asp

Arg Asn

Asn Leu

Pro Cys

He Lys

Leu Vai

Gly Gly

Be Pro

Pro Wing

150

Phe Gin

155

Phe Leu

Pro Leu

Leu Glu

Lys Leu

230

Asp Gxu

Pro Asn

Leu Arg

Glu. Asn

ÇK

Leu Fro

Ax to Gly '

Thr Leu

Be Pro

126

Pro Ser

133

Read Gin

Arg Arg

Glu Val

Gly Pro

20C

Gin Val

215

Cys Ala

Ha XI®> Γ

Leu Pro

Ala Ser

Be Wing

Asp Trp

Glu Gin

105

Gly Glu

Lys Glu

Pro Thr

Axa Glv

170

Ser Tyr

185

Ala Ser

Arg Lys

Thr Tyr

Hla His

Asn Asp

Asn Leu

Gly He

ONLY

Thr Ala

Gin Glu

Wing Gin

Pro Ser

Ser His

140

Gin Gly IS

Gly Val

Arg Vai

To be

He Gin

220

Lys Leu

771 ♦ X L «'W

Leu Lys

Glu Asp

...................

Glu Ser

Glu A1 &

Al a Pro

Phe Arg

Glu Gin

HO

Gly Pro

125

Lys Ser

Met Wing

Leu Val

Leu Arg ί an * K vk 'V'

Pro Gin

205

Gly Asp

Cys His

Vg1 Ser “‘ he Va „

He Leu

Ser Arg 80

Glu Lys

α. ·: Κ.

Z -Λλ?

He Ser

Pro Asn

Pro Wing

ISO

Ala Ser

175

His Leu

Ser Phe

Sly Ala

Pro Glu

240

399

Read

INFORMATION FOR SEQ IE ND: 1B2:

ii j SEQUENCE CHARACTERISTICS. ·.

(A! LENGTH: 305 axnino acids <Si TYPE: atru.ro acxd (Ci STRANDEDNESS: sxngle (D) TOPOLOGY: linear iit) MOLECULE TYPE: protein (Xi; SEQUENCE DESCRIPTION: SEQ ID NO: 182:

Asn Cys To be Xle Met X * He Asp Glu lite Xle 10 His Mis Read Lys Arg Pro Pro ίίΑΙΑ Pro 3.Í & U 20 Read Am Pre· Asn Asn ·> Χ ·. «* · Zo nSSU Asn Asp G.x u Asp 10 Go To be II® Read Met  SL Asp Arg Asn X4BU Arg 40 Read Pro Asn Read Qiu 45 To be Phe Go Arg Allah 50 Go Lys Asn Read Glu S3 Asn Allah To be Gly lie 60 Glu Allah He Read Arc Asn Read Gin Pro Cys 70 Read Pro To be Allah Tnr 7 * 3 Allah A », a Pro To be Arg ONLY His Pro lie lie He 85 Lys Allah Gxy Asp Trp §0 Gin Glu Phe Arg Glu 95 Lys Read Thx Pne Tyr ISO Read Lax Thr Read Gru 105 Gin Allah Glu Qin 110 Gin Tyr Go Glu Gly '1 Gly Gly v *, y To be Pro 130 Gly Gly Gly Fri' Gly uly Gly To be

400

Asn Met Wing Thr Gin s_y Wing Met

130135

Arg Arg A) to Gly Gly Val Leu Val

1 «'150

Glu Val Ser Tyr Arg Val Leu Arg xss

Gly Pro Ala Ser Ser Leu Pro GH * jfir

ISOX8S

Gin Val Arg Lys He Gin Gly Asp Gly

IPS200

Cys Ala Thr Tyr Lys Leu Cys His Pro HO21 «

Hrs Ser Leu Gly Ila Pro Trp Ala Pro Π5236

Wing Leu Gin Leu Wing Gly Uys Leu Ser 24S u> eu Tyr Gm Gly Leu Leu Gin Wing Leu

HO2g5

Gly Pro Thr Leu Asp Thr le Gin Leu .275:

Thr He Trp Ghs Gin Met Glu Glu Leu 290295

Pro

65

To the Phe Ale Wing. Ser Al Phe Gin

........ 14 C ...... ...........

Wing Ser Has Leu Gin Ser Phe Leu 156 '

Leu Ala Gin Pro Thr Pre Leu licii .................... <nl | ir ................. s ........ 7 “Igf ^:::

Phe Leu Leu Lys Ser Leu Glu

0 '

4> aa ^ xaa ueu ulr> Gau Lys Leu

205 uilu ulu a> su Vaa Lex; Lao Glv

220

Read Ser Ser Cys Pro Seo Glr _; ²³⁵ 240

Gin Leu His Ser Gly Leu Ph® 25C 25.5

Glu Gly He Ser Pro Glu Leu

270 ............

Asp Val Ala Asp Phe Ala Thr

285

Gly Met Ala. Pro Leu Gin Wing

C2) INFORMATION FOR SEQ ID NOx 183;

(1 - SEQUENCE CHARACTERISTICS;

(A # LENGTH; 320 ammo acids · ÇB) TYPE; amino acid

ÍC) STRANDEDNESS: single

ÍD) TOPOLOGY; imear iii) MOLECULE TYPE; protein (xi I SEQUENCE DESCRIPTION: SEQ CD NO: 183;

Asr, Cys Sto 11. Met Xie Asp clu U. lie al. His Leu Lvs ⁵ 10 'xc

401 eu Asp

Asp

Val

He Leu

Arg Ala ^:: ÍS: OS

Arc Ast

Hxs X'xo

Leu Thr

Val Grr

Thr lie

130

Het Ala

X. 4 t?

Arp Ala

Val Ser

Pro Wing

Ai Arg

210

Thr Wing

223

Being Leu atsu Qin

Tyr Gin

Pro Thr

29C

Met Asp

Val Lys

Read Gin

Ire He

Phe Tvr

100

Gly Gly

V $ 5 *

Asn Pro

Thr Gin

Gly Gly

Tvx A.y $

182

Ser Ser

195

Lys lie

Tyr Lys

Gly He

Leu Ala

260

Gly Leu

275

Read Asp

Arg Asn

Ast · ^ eu

Pro Cys

He Lys

Leu Val

Gly Gly

Be Pro

Gly Ala

150

Val Leu

1H5

Go Read

Leu Pre ·

Glu Gly

Read Cys

230

Pro Trp

245

Gly Cys

Read Gin

Thr Leu

Leu Arc ’

Glu Asn

SB

Leu Pro

Wing Gly

Thr Leu

Be Pro

120

Pro Ser

5

Met Pro

Val Ala

Arg His

Gin Ser

20D

Asp Gly

215

Hi s Pro

Pro Wing

Leu Ser

Wing Leu

280

Gin Leu

295

Leu Pro

Ala Ser

Be Wing

Asp Trp

Gru Gin

105

Gly Glu

Lys Ciu

Phe Ward

Ser His

170

Leu Ala

185

Phe Leu

Wing Wing

Glu Glu

Leu Ser

250

Gin Leu

265

Glu Gly

Asp Val

Asn Leu

Gly He

Tnr Ala

Gin Glu

Wing Gin

Ser to be

Ser His

140

Ada Ser

155

Leu Qin

Gin Pro

Leu Lys

Leu Qin

220

Leu Val

235

Be Cys

His Seine Ser

4wx> Asp

300

Glu Ser

Glu Ala

Pro Wing

Phe Arg r- 1 x. <- X ...

X9Í.Uii:

110

Qly Pro

125

Lys Ser

Phe Ward

Ser Phe

Thr Pro

190

Be Leu

205

Glu Lys

Leu Leu

Pro Ser

Gly Leu

270

Pro Glu

2S5

Phe Ala

Phe Val

-1e Leu

Ser Arg

ONLY

Glu Lys

Gin Tyr

He Ser

Pro Asn

Gin Arg

160

Leu Glu ΐ 75

Leu Gly

Glu Gin

Read Qys

Gly Hrs

240

Gin Wing

255

Phe Leu

Leu Gly

Thr Thr

4'2

Xie Trp Gin Gin Met Glu Glu Leu Gly Met Wing Pre Wing Wing Gin Pr:

305 310 315 32 (

INFORMATION FOR SEQ XD NO: 184:

(if SEQUENCE CHARACTERISTICS '.

(A) LENGTH; 305 amino acids ι άίπΐ3.τιο aoisi

ÍC ·· STHANDED ^ ESS: single

D! TOPOLOGY ·, linear (ii} MOLECULE TYPEi pratein (Xi; SEQUENCE DESCRIPTION; SEQ ID NG: 184:

Asn Cys Gar He Met Tie Asp Glu lie He His Hus Read Lys Arg l ^c - Pro Pro Allah Pre Read .20 JwSítw Asp Pro Asn Asn 25 Read A®n Asp Glu Asp 30 Val To be 1.1a Les Met 3 5 Asp Arg Asn Read Arg 40 Read Pro Asn Read Glu 45 To be Phe Val Arg Awi. S9> 50 Val. Lys Asn Read Glu 55 Asn Allah To be Gly He 60 Glu Allah He Read Arg 65 Asn Read Gin Pro Cys 70 Read Pro aer Ara 7 5 Allah 9 * 270 To be. Arg 80 AA ^ S Pro Xie lie 85 Ly® Aus Gly Asp Trp 90 Gin Phe Axg Glu $ 5 Lys Read Thr Phe Tyr 100 Read Val Thr Read Glu 105 Gin Allah Gin Glu Gin HO Gm Tyr Val Glu Gly 115 Gly Gly Gly To be Pro 120 Gly Gly Gly To be Gly 125 Gly Gly To be Asn Met 130 Allah To be Allah Phe Gin 135 Arg Arg Allah Gly Gly 140 Val Read Val Allah To be 145 His Read Gin To be Phe 150 Read Glu Go To be Tyr 155 Arg Vax Read Arg Mis 160 Read Allah Gin Pro Thr 165 Pro Read Gly ”Ro Allah 170 To be To be Read Pro Gin 175 To be Phe Read Read Lys To be Read Glu Gin V & 1 Arg Lys He Gin Gly Asp Gly

403

ISO 185 19v

Allah A.> and \ - Gàh ^: Ç> ¢. Lys Lev Cys Ale Thr Tyr LV3 Lev 1533 Ηχδ'- • * iL * »' Ο x 7 · O * . . **. • V · χ < S> LU Gru Lea Val Read Read xxi.y His Sat Leu Giy lie P ^ STx * Aàk XJ · ve / v .. 210 225 220 bet To be To be θ '/ s Pre To be Gin Αα · ΐΐ Read Gin Leu Allah Gly Cys L «ív Know 230 235 240 Gin Read His To be Gly Read Phe Lev Tyr Gin Gly Read Read Gin Allah Read 241 250 255 Glu Gly He To be Pro Glu Read Gly Pro Thr Leu Asp Thr Read Gin Read 280 26 S 270 Asp Go Ara Asp Phe : A1 <: Thr Thr Xie ί ^ ΐΛ · »>. * Λ A jyí. Gin Met Glu Glu Read 275 2 80 285 Sly Met Allah Pre Allah Read Gin Pro Thr Glu Gly Allah Met Pro Allah Phe 2.00 235 300

Allah

305 (2) INFORMATION FOR. SEQ ID NO; 185 '.

fl} SEQUENCE CHARACTERISTICS:

(A) LENGTH .: 320 amino acids (B> TYPE: amino acid fCj STRANDEDNESS: single (D) TOPOLOGY; linear iii) MOLECULE TIER: protein (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 185:

Asn 1-'" Cys To be Ils Met O He Asp Glu He He 10 His His Read Ly® Arc 15 Pro Pro Allah Pro ^: Read 20 Read Asp Pre Asn Ahti 25 Read Asn Asp Glu Asp 20 Val To be Tie Read Met 35 Asp Arg Asm Read Arg 40 Read Pro Asn Read Glu 45 To be Phe Val Arg Allah 50 Val Lys Asn. Read Guu 55 Asn. * 25 ·. To be Gly He 60 Glu Allah lie Read Arg Asn Lev Gin Pro Cys Read Pre To be Allah Thr Allah Allah Pro To be Arg

* ^? D 583

Hxs Pro Tie XI »He Lyss Ala Gly Asp Trp Qin Giu Phe Arg Giu Lye

509S

Leu Thr Phe Tyr Leu Val Thr Leu Giu Qin Ala Gin Giu Gin Gin Tyr 10U 105HC

Val Giu Gly Gly Gly Gly Ser Pro Gly Giu Pre Ser Gly Pro lie Sac

1 * s \ “7Λ 7 r> jr ervfcv · -.« Es ·> 1á> L

Thr He Asn Pro Ser Pro Pro Ser Lys Giu Ser Hie Lys Ser · Pro Asn 130 .135140

Met Wing Ser Wing Phe Gin Arg Arg Wing Gly Gly Val Leu Val AleSer

145 150 155ISC

His Leu Gin Ser Phe Leu Giu Val Ser Tyr Arg Val Leu Arg HisLeu

165 170175

Wing Gin Pro Thr Pro Lay Giy Pro Wing Ser Ser Leu Pro Gin Ser Phe

180 .135190

La * x x ^ eu Lys Ser ueu Giu Gm Vai Arg Ly.a uae Gin: Gly Asg Guy Wing: 195 · 200: 2C5

Ala ueu Gin Giu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Giu 210 215220

Giu Leu Val Leu Leu Gly His Ser Leu Gly Tie Pro Trp Ala ProLeu

225 230 .135240

Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu SerGin

245 250255

Leu Hus Ser Gly Leu Phe Lêu Tyr Gin Gly Leu Leu Gin Ala Leu Giu 250 265270

Gly He Ser Pro Giu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp 275 250285

Val Ala Asp Phe Ala Thr Thr lie Trp Gin Qin Het Giu Giu Leu Gly 2 ^ 0 295300

Met Wing Pro Wing Leu Qin Pro Thr Gin Gly Wing Met. Pro Ala Phe Ala 205 310 315320 {2} INFORMATION PGR SEQ IT Nd 186;

(i) SEQUENCE CHARACTERISTICS:

{A} LENGTH: .421 anu.no adds (SI TYPE: atnino acid

IC) STRANDEDNESS; single

05 i D; TOPOLOGY; 1 mea r (ii! MOLECULE TYPE: protein (Xi) SEQUENCE DESCRIPTION: SEQ ID NO; 186;

Leix Asp Pre Asn Asn Leu Asn Asp Glu Asp Will be lie Leu Mec

Arg Asn Leu Axg Leu Pro Asn Leu Glu Ser Phe Vai Arg Ala Vai

XÍ'Âs · + ►W V. '

Asn Leu Glu Asr. Ala Ser Gly lie Glu Ala lie Leu Arg Asn Leu 35 404S ’

Fro Cys Leu Pro Sex Wing Thr Wing Wing Pro Ser Arg His Pre Ila

S360

He Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe

7C75

Leu Vai Thr Leu Glu Gin Ala Gin Glu Glu Gin Gly Gl? / Gly Sex '

90§5

Cys Ser II® Met He Asp Glu Ils lie His His Leu Lys Arg Pro

10C 105110

Ale Pro Leu Tyr Vai Glu Gly Gly Gly Gly Be Pre Gly Glu Pro

115 ISO125

Gly Pro II® Ser Thr lie Asn Prc <Ser Pro Pro Ser Lys Glu Ser

130 135140

Lys Ser Pre- Wing Met Wing Thr Gin Gly Wing Met Pro Wing Phe Wing

145 150155

Wing Phe Gin Arg Arg Wing Gly Gly Vai Leu Vai Wing Be His Leu

165 170tvs

Ser Phe Leu Glu Gonna Be Tyr Arg Vai Leu Arg His Leu Ala Gin

ISO 165Igo

Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu

195 200205

Gin Vai Arg Lys He Gin Gly Asp Gly Ala Ala

210215

Lys

Gin

He

Asn

Pro

To be

Hrs

To be

160

Gin

Pro

Glu

Read

Leu Gin Glu Lys

22C

Cys Ala Thr Tyr Lvs Leu Cvs Hie

225230

Pro Glu Glu Leu Vai

235

Leu Leu Gly

240 v 6 * ueu Gly 1.1 a Pro Ti ^ .. · Ala

Pro Leu

Ger Ser Cys

Pre; Being Gin

Aim η © ;, Qm .'.- ex; Giy Ward

Λ <3 V

L-su Tyr Glr: Gly ^ eu L®u

Gly Fxo üsu Asp T & x * ·

FJYm. VT «jAV ifYvwA / v} · * SF * VS ^, IlXcv V * *; _ΛΛ Llv v i. p> ιϊαΠ \ 5άχ ^ _ν rS ^ Si.

205 310

Uys Leu Ssr Gin

255

Gin Alu Leu Glu '280

Read Gin Read. Asp

85

Gru Glu ueu Gly

Leu Hi.x Ser Glv Leu Poe

Gly He Ser Pro Glu Leu .285

Go Ale Asp Ph® Alt Thr 3 00

Met Wing Pro Wing Leu Gin

3X5 sin

Pre · ili INFORMATION EOF. SEQ ID ND: 187:

SEQUENCE CHARACTERISTICS;

(A} LENGTH: 321 amino acids (S? TYPE; amino acxd (Ci STRANDEDNESS: single (D) TOPOLOGY: linear iii) MOLECULE TYPE: protein txi? SEQUENCE DESCRIPTION-. SEQ ID NG: 1.87;

Pre Ser Wing

• Gly Asp Trp 3 5 lf®U GaU 50 Gin Me t SS Xie Asp L-au Asp Pro Arg Asr Read

Asn Ala Ser

S X> ^ xy He r Glu Allah lie Leu v AMv 20 Allah Allah Pro To be Arg Gin Glu Phe Arg Glu 4 δ Lys Allah Gin Glu Gin 55 15 .Ul Glu Glu He He * 3 Q HiS His Read Ann Asn 85 Asn Asp Glu Arg .100 Read Pro Asn Read Glu 105

Arg 10 Asn Read Gin Pro Cys Me His Pro XI® Ή®. He 30 Lys TO 1& iXâií Tar Rhe Tyr 45 Read Go Thr Gly Gly To be 6.0 Asn Dy® To be XI® Lys Arg 7 ^c . Pir Pro Allah Pro Read 80 Asp 90 Go To be He ivíãkl Met 95 Asp To be Phe Go Arg Allah 110 Go Lys

07

Asa Leu Giu Tyr Vai Sxy Giy G * y Giy Ser Pro Giy Gm Pre Sec

Gly i - ', r «lie Ser Ire He Asn Pre Ser Pre Pre Ser Lyu Gru Ser Hrs

133 13514C leys Ser Pro Asn Met. .Ala Thr Gin Gly Ala Met Pro Ala Phe AlaSer

145: 153 155lEc

Phe Gin Arg Arg Ala Gly Gly Val Leu Val Ala Ser Hrs Ward; LeuGin

165 170i? *

To be Phe Leu Glu val to be Tyr Arg Val Leu Arg His Leu. Wing Pro Gin

ISO 18519C

Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Lev Lys Ser Leu Glu IPS 230205

Gin Val Arc Lys He Gin Gly xAap Gly Ala Ala Leu Gin Glu Lys Leu 210 2.15220:

Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Glv

Hrs Ser Leu Gly He Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin

Alu Leu Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe ISO 26: 5270

Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Tie Ser Pro Glu Leu 275 280285

Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr 290 295300

Thr He Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gin

305 310215

Pro

INFORMATION PGR SEQ CD NG: 188:

(1} SEQUENCE CHARACTERISTICS:

(A) LENGTH: 321 amino acids (B) TYPE; amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear ill; MOLECULE TYPE: protein

Pro I *. <S Ixi: Ils Lyss Ala

Asp. Try νχπ -u.x-U

Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu Gin Ala Gin

2530

Glu Gin Gin Gly Giy Gly Ser Asn Cys Ser Xle Mat Xle Asp Glu lie .3..7 .. 494 5

He 1US Hxs Leu Lys Arg Pro Pro Wing Pro Leu Leu Asp pre Ash Asn SC 5 £ 5C

Leix Asn Αερ Gru Asp Vai Ser H® «su Met Asp Arg Asst Leu AroLeu

H go _{? 5} - Pro Asn Leu Glu Ser Phe Vai Arg Ala Vai Ly® Asn Leu Glu AsnAla> 85 .9'09 $

Ser Giy 11® Gly Ala Xie Leu Arg Asn Leu Gin Pre Cys Leu Pro Ser 209 ICS 'no

Ara Thr Ala. Tyr Vat Giu Giy Gly Gly Gly Ser Ser Gly Glu Pro Ser 115 129- ^ 2 5

Gly Pro 2.1® Sex Thr He Asn Fro Ser Pro Pro Ser Lys Giu Ser »i _s 130 135140 ^ ys Ser Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Ph® AlaSer ¹⁴⁵ ISO 155160 * la Phe Gin Arg Axg Ala Gly Gly Go Leu Go Ala Be His LeuGin

185 170175

Ser Phe Leu Glu Vai Be Tyr Arg Vai Leu Arg His Leu Ala Gin Pro ISO 1852.90

Ser Gly Gly Ser Gly Guy Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu ^1SS 200205

Gin Vai Arg Lys Xle Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu 210 215220 uys Tnx Ward Tyr Lys Leu Cys His Pro Glu Glu Leu Vai Leu LeuG'y ^22s 230 2352 <

Hrs Ser Leu Gly lie pro Try Ala Pro Leu Ser Ser Çys Pro SerGin ²ⁱⁱ⁵ 250255 nla ^ eu Gin Leu Ara Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe u6C 265 οτπ

409

: v Read Leu Glu At a Leu 2 8 0 Glu Gly TXe To be 285 Pro Glu Read Gly Frc T ^ go Asp- Thr Leu Gur ueu Asp Go Aa & Asp Pne Alt Tap 29C 295 3 0 C TJixr 1X «- Trp Gin Gin Met Gin G1u Leu Gly Net AX ?? Pro Allah Read Gin 305 HO 315 3 C <

Pro (2} INFORMATION FOR SEQ ID NO; 189:

<1: SEQUENCE CHARACTERISTICS:

JA.J LENGTH: 321 ffstnc · acids {£) TYPE: amino aoxc (C> STHANDEDNESS: single! D) TOPOLOGY: linear (ii) MOLECULE TEPE: protein ixi; SEQUENCE DESCRIPTION: SEQ ID NO: 189:

Ward Gly Asp Trp Gin Glu Ph® Arg Glu Lys Leu Thr Phe Tyr Leu Val

Thr u & u Glu Gun Wing Gin Gun Gin Gun Gly Giy Gly Ser Asn Cvs Ser

2S * 30 ux® 'Met Le Asp Gin xle lie His Hrs · Leu Lys Arg Pro Pro AlaPro

3540

Leu Leu Asp Pre Asn Asn Leu Asn Art Glu Asp Val Ser He Leu He * 5C 55 ¢ 0

Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arg Ala Val «vs Asn Leu Glu Asn Aua Sex · Gly He Glu Ala He Leu Arg Asn Leu S5 9C §s

Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His pro He 100 iQS no

He He Lys Tyr Val Giu Gly Gly Gly Gly Ser Pro Qly Giu ProSe115 120 “125

Oxy pro He Ser Thr He Asn Pro Ser Pro Pro Ser Lys Glu SerHis

13 ° 115140

410

Lys Ser Pro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ala Ser, -, 50- Ito160

A'a Phe Gin Are Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin 165 270 ·:? Ε

ΛΚ- ^f * »'

Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro 180 18519c

Set 'Giy Gly Ser Gly Gly «Ser Gin Ser Phe Leu Leu Lys Ser Leu G” ^: u 195 200205

Gin Vai Arc Lys He Gin Gly Asp Gly Ala Ala Leu Gin Glu Lvs Leu HO 215220

Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu LeuGlv

225 23δ 235240

His Ger Leu Gly He Pro Trp Ala pro Leu Ser Ser Cys Pro SerGin

245 250255

Alw- x »ea xsln lsu Ara Gly 0y & Leu Ser Gin Leu His Ser Glv Leu Phe 200 265270 ajsu Pyr Git Giy Leu Leu Gm Az © Leu Glu Gly He Ser Pro Giu Leu 275 280285

G ~ y rro Thr Leu Asp Thr Leu Gm Leu Asp Val Ala Asp Phe Ala ’’ ’hr 299 295308

Tnr ale Trp Gin Gm Met Glu Glu Leu Gly Het Ala Pro Ala Leu Gin ^ 2 310 325220 (2) INFORMATION FDR SEQ IQ NO ;. ISO;

£ i) SEQUENCE CHARACTERISTICS:

ÍA) LENGTH: 329 amine «« ids (B) TYPE: anmo acid (C; STRANDEDNESS-, single (Di TOPOLOGY ·. Linear

III. 'MOLECULE TYPE; protein (xi) SEQUENCE DESCRIPTION; SEQ ID NO; 190 ·.

ueu Asp Pre Asn Asn Leu Asn Asp Glu Asp Val Ser lie Leu Met Asp ^{1 5} 2 0 is

Arg Asp Let Arg

Asn Leu Glu Asn · ^s.

Pro Cys Leu Pro

He Lys Ala Gly φ 5

Leu Vai Thr Leu

Gly G * y Sex ^- Gly

LOG

Xie His His Leu.

Gly Gly Ser Pro

Leu Pro Asn Leu

Ala Ser Gly Xia

Ser Ala Thr Ala

Asp Trp Gin Glu

Glu Gm λχδ Gin

Gly Gly Ser Asn

Lys Arg Pro Pro

120

Gly Glu Pre · Ser

Glu Ser Phe Vai

Ui.lu j ^ la kkie net

Wing Pre Ser Arg

Phe Arg Glu Lys

75 '

G * u Gin Gin Gly so

Cys Ser lie Met

105

Pre Wing · Leu Tyr

Gly Pre He Ser

140

Arg Ala Vai Lys

0 ·

Arg As: Leu Qin

His Pre He He

Leu Thr Phe Tyr

Gly Gly Ser Gly eg

Xie Asp Glu He HO

Go Glu Gly Gly

125

Thr He Asn Pre?

Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Met Ala Thr Gin

145 1.30 135 igg

Gly Wing Met Pro Wing Phe Wing Wing Ser Wing Phe Gin Arg Arg Wing Gly Gly

155 1.70X75

Vai Leu Vai Ala Ser His Leu Gin Ser Phe Leu Glu Vai Tyr Arg ISO 185190

Pal Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin 195 200205

Ser Phe Leu Leu Lys Ser Leu Glu Gin Vai Arg Lys lie Gin Gly Asp ²¹⁰ 2152GQ uil ¹ 'Ala Ala Leu Gin Glu Lys Leu Cys Ala Thr Tyr Lys Leu evsHis

2u5 230 235240

Pro Glu Glu Leu Vai Leu Leu Gly His Ser Leu Gly He Pro TrcsAla

243 2502.55

Pro Leu Ser Ser Cys Pro Ser Gin Alu Leu Gin Leu Ala Gly Cys Leu

260 265270

Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Wing 280

Leu Glu Gly Ha Ser Pro Glu Leu Gly Pre Thr Leu Asp Thr Leu Gin ²⁹⁰ 295300

Lsu Asp V & r Aáa Asp Pt »and Tar Wing

Thr He Trp Gin Gin Met sm

Leu Gly her Wing Pro Wing Leu Gin Pro

325

INFORMATION FOR SEQ ID ND; 191:

ίί; SEQUENCE CHARACTERISTICS;

Í A; LENGTH: 329 amino ani ds> Bj ΤΥΡΕ ·, ammo acid (C · STRANDEDNESS. · Single (D; TOPOLOGY; linear • ii) MOLECULE TYPE; protein ixi: SEQUENCE DESCRIPTION: SEQ ID NO; 191;

Asn Ala Ser Gly Π®

Giu Ala Ila Leu Arg

Pro Ser Aia Thr Ala δ

Gly Asp Trp Gin Glu àz & u Gm Gm Ala Gin ED

Gly Gly Gly Ser Asn

Read Lys Arg Pro Pro

Glu Asp will be lie.

Glu Ser Phe Vai Arg

115

Gly Gly Ser Pro Gly

0

Ser Pro Pro Ser Lys

145

Gly Ala Met Pro Ala

W.

Wing Pro Ser Arg His .44

Phe Arg Glu Lys Leu

Glu Gin Gin Gly Gly 55

Cys Ser He Met He 70

Wing Pro Leu Leu Asp

.. 90

Read Met. Asp Arg Asn

105

Ala Vai Lys Asn Leu

120

Glu Pro Ser Gly Pro

135

Glu §er Hrs Lys Ser

ISO:

Phe Ala Sex Ala Phe

170

Asn Leu Gin Pro Cys

Ί G V · *. -s**

Pro He He He Lys

Thr Phe Tyr Leu Vai

Gly Ser Gly Gly Gly

Asp Glu He He His

Pro Asn Asn Leu Asn

Leu Arg .Leu Pro Asn

HO

Glu Tyr Vai Glu Gly

He Ser Thr He Asn

140

Pro Asn Met. Thr Wing

155

Gin Arg Arg Ala Gly

175

Read

Allah

Thr

To be

Has

Asp

Read

Gxy

Pro

Gin

160 ciy

413

Val Leu Val Ha Sac Hxs Leu Gin Ear Phe Leu Glu Val Ser Tyr Arg

180 18S19C val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gay Gly SerGin

155 2CC ^:: 205

Ser Phe Leu Leu Lyss Ser Leu Glu Gin Val Arg Lys He Gin GlyAsp

210 21.5220

Gly AX «Wing Leu Gin Glu Lys Leu Cys Wing Thr Tyx Lys Leu CysHis

225 23S 23524?

Pro Glu Glu Leu Val Leu Leu Gly HA® · Ser Leu Gly lie Pro TrpAla

245 252255

Pre Leu Ser Ser Cys Pro Ser Gin Ala Leu Gin Leu Ala Gly Cys Leu 280 2652 ~ 0

Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Wing 275 2802S5

Leu Glu Gly He Ser Pre Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin 250 295300

Leu Asn Val Ala Asp Phe Alb Thr Thr Xie Trp Gin Gin Met Glu Glu 305 310 315220

Leu Gly Met Wing Pro Wing Leu Gin Pro

325 ^ FORMATION FOR SEQ XD RO: 192:

> i; SEQUENCE CHARACTERISTICS:

(A) LENGTH: 329 amino acids

ÍE) TYPE: amino acid í C: STRANDEDNES S. ·. s ing 1 e

CD) TOPOLOGY: linear ii; MOLECULE TYPE: protein

XÍ: SEQUENCE DESCRIPTION: SEQ XL RO: 192:

Wing Pro Ser Arg

His Pro He

Xie lie

Lys

Aaa

Gly

Asp

Gin *; ft

Glu

Phe Arg Glu Lys Leu Thr Phe Tyr Leu Val

25

Thr Leu Glu Gin Ala Gin

Giu Gin Gin Gly Gly Gly Ser Gly Gly Gly Ser

40

Gly Gly Gly Ser Asn

414

Oys Ser lie Maa II® Asp Glu He 11 «His His Leu Lys Arg Pro Pre 56 £ 560

AH · ^; 'Χ': · Leu jeu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val SerXie

70 75SC

Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe ValArg

S5 9095

Val Lys Asn Leu Gau Asn Wing Ser Gly II® Glu Wing Leu Arg 100 Wing 105110

Ann Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing Tyr Val Glu Gly Gly Wing 11- '120125

Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro He Sat Thr He Asn Pro 13 0 .135140

Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro Asn Mei Ala ThrGin

5 156 155160

Gly Ala Met Pro Ala Phe Ala Ser Al Phe Glr Ala Arg Arg Ally GlyGly

165 170175

Leu Val Ara Ser Hrs Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg 180 105190

Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin 1B5 2602 OS

Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys He Gin Gly Asn 210 3X5220 u- * y A-i.a Ala Lau an Glu Lys Leu Cys Ala Thr Tyr Lys Leu OyoHis

225 230 235240

Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly He Pro TrpAla

245 2502.55

Pro Leu Ser Ser Cys Pro Ser Gin Ala Lev Qin Leu Ala Gly Cys Leu

250 26527Q ^> er Gin n & u His Ser uay ueu Phe ueu Tyr Gin Gly Leu Leu Gin A ^ 275 280285

Leu Glu Gly Xie Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin 290 295300

Leu Asp Val Ala Asp Phe Ala Thr Thr He Trp Gin Gin Het G'u Glu ³⁰⁵ 31Q 315 ~ 320

Leu Gly Met Wing Pro Wing Leu Gin Pro

325

415 ί2 ·; INFORMATION FOR w * YK * x: «» w »: t \ txv: ww: TW C ·>

w4b K> WXbWÍ ^ A «tt». A * jC ^ aAvA. - A - K> ώ s (A? LENGTH; 299 aisino acids (H) TYPE. · Amino acid {<?} STRANDEDNESS; single r D; TOPOLOGY: 1inear

JU; MOLECULE TYPE, protein

; xi? SEQUENCE DESCRIPTION: SEQ IT

Li.y - i ’ Gly vs - y Gly SB ’ Asn * k His Read 23 Lys Pro Pro Read A & rs Asp 38 GiU Asp Go To be Ila 4C Pxc Asri Read GiU To be Pee Go Arg Know 5 " Gly lie Allah He 73 Arg Aa a /***.*> Allah Allah Pro S3 To be Arg His Gly Gly Gly Gly IOC Ear Pro Gly Uflu Asn Pro To be Pro Pro To be Lys Glu Thr Gin 1". Gly A ^. The Met Pro Ax a 135 Phe 148 Gly Go Read Go Allah 150 To be Hrs Tyr Arg Go Read Arg 165 Ms . <M ^ w Allah £ »<» 22 Gin To be Phe ISO Lreu Read Lvs To be Cly Asp Gly 1H5 Ax a Allah Read Gin Glu 200

) ND: 193;

Cys Ser '0 He Met He Asp Glu Ire Al to 2 ^i; Pro Read Read Asp Pro 3 0 Asn Asm Read Met Asp Arg Asn 45 Read Arg Read Allah Go Lys Asn SC Read Glu Asn Allah Asn Read GvA * 4 * ΐ w Pro Cys Read Pro To be 80 Pro He 90 He lie LvSc Tyr val Glu Pro Ί 05 To be Gly Pro lie To be 3.10 Thr He To be His Lys To be Pro 125 Asn Mat Allah Allah To be Allah Phe 148 Gin Arg Arg Ale Read Gin To be 158 Phe Read d.U Go Be ISO Gin Pro 173 To be Gly Gly To be Gly 175 Gly Read 185 Glu Gin Go Arg .uys 130 He Gin Lys Read cys Allah Thr 205 Tvr Lys Read

416

Çys. , ^ ικ, 9ro wwü Glu. x ^ eu Va ·; x ^ me

Ήρ Ala Pr s i + u Ser Ser Cys Pro I * ... · jsju

Cys Deu Ser Gin Lsu His Ser Gly

41

Gin Ala Leu Glu Gly lie Ser Pro: '2s0l · ......

Leu Gin Leu Asp Val Ala Asp Phe

OH :::: 280

G * .u Glu Leu Gly Met. Ara Pro Ala

290295

Leu Gly His Sar Leu Gly He Pre

Ser Glr: Ais Leu Gin Leu Ala Qlv

235240

Leu Phe Leu Tyr Gin Gly Leu Leu 250255

Giu Leu Gly Pro Thr Leu Asp Td

Thr Thr He Trp Gin Gin Met Ward

285

Leu Gin Pro

Í2; INFORMATION FOR SEQ ID NO: 194:

ii; SEQUENCE CHARACTERISTICS:

ÍA) LENGTH: 329 aru.no acids (ES TYPE ·, sure add (C; STRANDEDNESS: single

ID <TOPOLOGY: Xmear (ii) MOLECULE TYPE; protein id SEQUENCE DESCRIPTION; SEQ ID NO: 194:

Met Asn Wing Cys To be Ila Met He Asp Giu 10 Xie Xie His His Read <S: C. Lys Arg Pro Pro Ara Pre- Read Read Asp Pro Asn Asn Read Asn Asp Glu Asp 20 25 30 Val To be He Read Men Asp Arg Asn u & u Arg Read Pro Asn Read Giu To be „„ 40 45 Phe Val Arg Allah Val Lys Asn Glu Asn Allah To be Gly He Gw'w The 50 55 60 He Read Arg Asn Read Gin Pro Cys Pro To be Allah Thr Allah Pro 65 <V 75 80 To be Arg Hrs Pro lie lie lie Lys Allah Gly Asp Trp Gib Giu Phe Arg 85 90 95 GwmU Lys Read Thr Phe Tyx Val * * 4u4x Giu Gin Allah * Ά S -'- uvl · Giu Gin 100 105 X. Λ

417 m Tyr Gíu Gly w — y Qy Gly ¹ Ser

Pro Gly Gau Pro Ser Gly Pro lie Ser The lie Asr Pro Sex Pro Pro Ser Lye Gau Sex his Lyr Ser 130 13514C

Pro Asn Met Ala Tyr Lys Leu. Cys His Pro Glu Glu Leu Val LeuLeu

145 150 1SSISO

Gly His Ser Leu Gly He Pro Try Ala Pro Leu Ser Ser Cys ProSex '

165 17017S bit Ala Leu Άπ ueu Ala Gly Cys Leu Ser Gin Leu Has Ser Glv Leu

180 1..85190

Phe Leu Tyr Sir, Gly Leu Leu Gin Ala Leu Glu Gly He Ser Pro Glu

Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Aw Phe Ala HO 315220

Thr Tar He Trp Gap Gah Her Glu Glu Lev Gly Mei Ala Pro AlaLeu

Â25 _: 23 _: Q 235240:

Gin Pro Thr Glu Gly Met Met Wing Phe Wing Ear Wing Phe Wing GinArg

245 256255

Arg Ala Gly Gly Vai Leu Val Ala Ear Els Leu Gin Ser Phe Leu Glu 250 255270

Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Gly Gly Qlv Ser 275 280285

Asp Met Ala Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gin Ser Phe 296 25Ô300

Leu Leu Lys Ser Lav Glu Gin Val Arg Lys He Gin Gly Asp Gly Ala Tk TV FT. wa *

Wing Leu Gin Glu Lys Leu Cys Wing Thr

325 (2) INFORMATION FOR SEQ Hi NO: 195:

(1} SEQUENCE CHARACTERISTICS:

(A) LENGTH; 329 amino acids

ÍB} TIRE: amino acid

IC} STRANDEDNESS: single (D) TOPOLOGY> linear (ii} MOLECULE TYPE: protein

418

Met Ala Hr Cys Ser le Met Ha Asp Giu lie lie His Hl a Leu

Arg Pre

Ρχ <

Let

Let Asp · *> £

Asn

Read Ast. Asp Glu Asp

It Will Be He Leu Mat Asp Arg Ast Leu Arg Leu

Pne Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala

SO '55

Ila Leu Arg Ast Leu Gin Pro Cys Leu Pre Ser «5 70VS

Ser Arg His Pre He He He Lys Ala Gly Asp

8590:

Giu Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu. «Ou105

Gin Tyr Vai Giu Gly Gly Gly Gly Be Pro Gly

He Gar Thr Xie Ass Pro Ser Pro Pro Ser Lys 130135

Pro Ann Met Ala Pro Glu Leu. Gly Pro Thr Leu

145 ISO25 «

Asp Vai Ala Asp Phe Ala Thr Thr He Txp- Gin 165170

Gly Het Ala Pro Ala Leu Gin Pro Thr Gin Gly XaO185

Ha Ser Ala Phe Gin Arg Arg Ala Gly Gly Vai 195200

Read Gin Sex Phe Lay Giu It Will Be Tyr Arg Ual ............ ............ .......... ..... -> «<· ...........

** · * · ^ <$ χ · 3 · ................ ............ .......

Gin Pro Giy Gly Gly Ser Asp Met Ala Thr Pro 335 230 230

Ser Leu Pro Gin Ser Phe Leu Leu Lvs Ser Leu

245258

Gin Gly Asp Gly Ala

260

Wing Leu Gin Glu Lys

265

Pro Asn Leu Glu Ser

Sar Gly He Giu Ale v

Thr Wing Wing Wing

Trp Gm Giu She Arg «5 uln Aia> Gm Qm Gm

Glu Fro Ser Gly Pro 3 2 5

Glu Ser Hit Lys Ser

24G ........ ..............

Asp Thr Leu Gin Leu

160

Qin Met Glu Glu Leu

175

Met Pro Wing Phe Wing

X90

Leu Vai Ala Ser His 205

Read it. Arg His Lsu Ala

Read Gly for Ala Ser

240% suu · «· <« * <. var .Arg Lys .255

Leu Cys Ala Thr Tyr gyn

419

Pr

Val eu

If

Le

Ria / s Leu Ser

Read u. 7 3 5

Phe uet «xa

Being ”<o

SEQUENCE CHARACTERISTICS;

LENGTH. · 328 amino at TYPE; asuno acis STPAKDEDKES5: single TOPOLOGY: linear (S

CD} ‘RIPTIQNc SEQ ID NO

196;

Met * UA

Asn

Cys

If.

Xle

M®

Asp

Glu

ID

Xie

Hxs

Read

Lys

If

He

Phe

Val

Allah

Fruit® u

Asc

Atn

Read

Asn

Asp

Asp

Read

Asp

Arg

Asn

Asn

4?

Read

Allah

Val

Lys

Asn

Le;

Glu

Asn

To be

Gly rxe

Glu

Allah

* le

Leu neu

Pro

Cys

Read

To be

Allah

Allah

Allah

Pro

If.

Pro lie

He

Allah

Gly

Gin

Phe

Read

Thr

IOC

Phe

Read

Val

Read

Glu

Allah

Gin

110

Gin

Gin

Glu

Sa:

TO

G1

To be

120

Gly

Pro

125

He

To be

Thr

Pro

To be

135

Pro

Pro

Be x> y $

Glu

140

If.

His uys

To be

Pre Asn Mee Ata Set Ata Pae Gm Arg Axrg Ax Guy '· Guy Val LeuVal

U5 IS 8 XS5 ~ 180

Αχ »Ser Hxs Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val LeuArg

..................!> y .. --7. ^ 5 .. .......

His Leu Asa Gm Pro Guy Guy Gly Ser Asp Met Ala Ttr Fro Leu Glv .180 M5190

Pre Ale Ser Ser Leu Pro Gin Ser Phe Leu Leu Lys Ser L «u GluGlr

Val Arg Lys He Gin Gly Asp Gly Ala Wing Leu Gin Glu Lvs LeuOys

215 'HE 220

Aua Thr Tyr Lys Leu Cys Hus Pro Glu Glu Leu Val Leu Leu GlvHis

225 230 235 242

Ser Leu Gly He Pro Trp Ala Pro Leu Ser Ser Cys Pro Set GinAla

245 256 255 * x> su Gin ueu Aus Gly Cys Lev Ser Gxn Leu Mis Ser Gly Leu Phe Leu

2S0 365 * 276

Tyr Gun Leu ueu Gin Ala Leu Gxu Gly He Ser Pm Glu Leu Gly 275 280285

Pro Tar ueu Arp Thr xeu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr 290 295SOQ

He Trp Gin Gin Het Glu Glu Leu Gly Met Ala Pm Ala Leu Gin Pro 310 315320

Thr Gin Gly Ala Met Pro Ala Phe Ala

325 {2} INFORMATION FOP SEQ XL NG: 197;

(i? SEQUENCE CHARACTERISTICS-.

(A · LENGTH: 329 autino aci & s • E; TYPE: amine atad (CJ STRANDEDNESS; single w · TOPOLOGY: linear (ii> MOLECULE TYPE: protein

ÍKÍ · SEQUENCE DESCRIPTION: · SEQ XD NOr 197, -.

Ax a axsn Cys Ser xue Met Xue Asp Glu He He Els His Leu Lys ¹ s 10 1 «

421.

.I

L> ®u

Asn

Go

To be

Me

Read

Read

Phe

Allah

Go

Read

Allah

If

Fri'

Read

Pro

To be

Allah

Allah

Pr>

He

A. À.-δ

Phe q 5

Arc

Phe

Read

Go

Read

Gl:

Go

Gly

To be

145

Asn

Allah

Phe .Be

Á1®.

195, and

Asn

Pro

Ser * ς

Pro

To be

Lys

Glu

140

To be

H1.S

Lys

Me:

150

Pro

Read

1H5

Allah

To be

Phe

Arg

Arg

170

Allah

Read

Gin

Glv

Th

Gin

Gly

Met

160

Go

Read

Go

Phe

Xj & U

Go

Go

190

Read

He

Asp

Met

Allah

Th

Allah

HC

To be

Xie

Read

Pro

215

To be

Phe

Read

Read

Lys

120

To be

Read

Gin

Gly

Asp

Wing x «

Glr

Glu

Lys

Read

240

Allah Tin Tyr Lys Read 245 Cys Hrs Pro Gru GXu 250 Go Read Read Gly 255 His To be Read Gly He 260 Pro Trp Allah Pro Read 265 To be To be Cvs Pro To be 270 Gin Allah Read Read 275 Allah Gly Cys Read To be 280 Gin Read His To be Gly 285 Read Phe Read Tvr * «Κ «Ly Read Read Qin Allah Read Glu Gly He To be Pro Glu Read Gly

290

295

300

Pro Ών Leu Asp Thr Leu Gin Leu

Asp Val Ala Asp Phe Ala Thr Thr

215 320

He Trp Gin Six: Max. Glu Glu Leu Gly (2; INFORMATION FOR SEQ ID KO: 198:

(i? SEQUENCE CHARACTERISTICS:

(A; LENGTH: 329 amino acids; B} TYPE: ammo acid i'C; STRANDEDNESS: Single! D: TOPOLOGY; .linear ii? MOLECULE THE-. Protein (Xij SEQUENCE DESCRIPTION: SEQ ID NO: ISE:

H........ uA Allah Asn Cys To be 5 Met lie Asp Glu 10 • Í * * X *. He .33m Has Lys Arg Pre Pro Allah Pro Read Read Asp Pro Asn .Asn Read Asn Asp Glu Asp 25 30 ’Val He "I Met Asn Arg Asn Read Arg Lc & V Pres Asn Read Guu. To be 35 40 45 Phe Val Are Allah Val Lys Asn Read Glu Asn Allah To be Gly He GUU Allah 50 55 66 lie À ^ fèvi Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro 65 T Q 75 80 To be Arg His Pre He lie lie Lys Allah Gly Asp Trp Gin Glu Phe Arg 8.5 90 95 Glu Lys Read Thr Phe Tyr Read Val Thr Read Glu Gin Allah Gin Gm Gin 100 106 HO Gin Tvt Val Glu Sly Gly Gly Gly To be Pro Gly Glu Pro To be Gly Pro 115 12.0 125 II® To be Thr i * ϊΧΧ He Asn Pro To be Pro Pro To be Lys Glu To be His Lys To be 130 135 140 ^ Χ ^: Ο Asn Met Au. The Thr Gin Gly Allah Met Pro Allah Phe Allah To be Allah Phe 145 ISO 155 160 Gin Arg Arg Allah Gly Gly Val Val Allah To be His Read Gin To be Phe 155 170 175

423

Leo

Gly

Ser ^- '

Giy

225

Pro

Pro

To be

Lt & u

Read

305

Read

Glu Gonna Be Tyr Ary

180

Ser Asp Met Ale Thr

195

Phe Leu Leu Lys Ser

210

Wing Wing Leu Gin Glu

230

Gru Glu Leu Vai Leu

245

Read Ser Ser Cys Pro

260

Gin Leu His Ser Gly 275

Glu Gly He Ser Pro

230

Asp Vai Ala Asp Phe

310

Gly Met Ala Pro Ala

325

Go Leu. Arg Ht «, Leu

5

Pro Leu Gly pro Ala _s J

Leu Glu Gin Vai Arg

215

Lys Leu Cys Ala Thr

235

Leu Gly His

350

Being Gin Wing Leu Gin

265

Leu Phe Leu Tyr Gin

280

Glu Leu Gly Pro Thr

235

Thr Thr He Trp Wing

315

Leu Gin Pro

Pro Gly Gly

190

Being Ser Leu Pro Glu

205

Lys He Gin Gly Asp

220

Tyr Lys Leu Cys His

240

Gly Xie Pro Trp Wing

255

Leu Ala Gly Cys Leu

270

Gly Leu Leu Gin Ala

285

Leu Asp Thr Leu Gin

300

Gin. Glu Her Glu Glu

320 (2; INFORMATION FOR SEQ ID NO; 199:

: i> SEQUENCE CHARACTERISTICS:

(A; LENGTH: 318 amino acids (B; TYPE; asuno acid fC) STRANDEDNESS: single (D; TOPOLOGYr linear ire! MOLECULE TYPE; protein

(Xi) SEQUENCE DESCRIPTION; SEQ ID NG : IPS: Met Wing Asn Cys Ser Asn Met Xie Asp Glu Xle lie Thr His Leu Lys 1 5 m 15 Giu Pro Pro Leu Pro Leu Leu Asp Phe Asn Asn Leu Asn Gly Glu .Asp 20 25 30 Gin Asp »lie Leu Met Asp Asn Asn Leu Arg Arg Pro Asn Leu Glu Ala 35 40 45

424

Phe Asn Arg A, la Val Lys Ser Leu Gin Asn Ala Ser Ale He Glu Ser SO: ss gr lie Leu Ly * Art Leu Leu Pre Cys Leu Pro Leu Ala Thr Ala Ala Pro

70 75go

Thr Arg His Pro lie His He Lys Asp Gly Asp T'rp Asn Glu PheArg

90 ~ 95

Arg Lys Leu Thr Phe Tyr Leu Lys Thr Leu Glu Asn Ala Gin Ala Gin 10.0 205HO

Grp Tyr Val Glu Giy Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro 115 12C125

He Ser Thr He Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser HO 135140

Fro Asn Met Ala Thr Gin Gly Ala Met Pro Ala Phe Ale Ser AlaPhe

145 ISO 155ISO

Gun Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gin SerPhe

165 17017 «

Leu Glu Val Ser Tyr Arg Vai Leu Arg Hi® Lev Ala Gin Pre Ser Gly 180 185iso

Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Í95 ............. .................... ......................................

Arg Lys lie Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Ala ²¹⁰ 215220

* .hr Tyr rys ve Cys His Pre Glu Glu Leu Val Lav Leu Gly His Se ^ ^22S 230 235 '' 24Q

Leu Gly lie Pro Try- Ala Pro Leu Ser Ser Cys Pro Ser Qin Ala Leu

..2.45 .. 250255

Gm Leu Aaa Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr

260 265270

G * n Gly Leu Leu Gan Ala Leu Glu Gly He Ser Pro Giu Leu Glv Pro ²⁷⁵ 280285

Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr He 29D 29330Q xtp Gin Gin Her Glu x ^ ru Leu G * y Met Ala Pro Ala Leu Gin Pro

305 Jigy 4 {2? INFORMATION FOR SEQ I © NO; 200:

fi) SEQUENCE CHARACTERISTICS;

425 (A? LENGTH: 322 anino acids

ÍB? TYPE; amino acid (C) · STRANDEDNESS: single? D; TOPOLOGY -. linear (ii; MOLECULE TYPE: protein (Síií SEQUENCE DESCRIPTION; SEQ ID NO-. 200;

Het &THE& Ast Cys Set Asn Met lie Asp G-ix He He His Read Lys · * * Ç ..... * .;. Xi Pre Pro Read Pro Read Read Asp Phe Asn Am Le « Asn Sly Glu Asp 2u 25 30 Gin Asp Xie wow Met Glu Asn Asn Read Arg Arg Pro Asn Read Glu Allah **!. · ?. 40 45 Phe Asn Arg Aa © Val Lys To be Lieu Gin Asn Allah To be TO 1& lie G »u To be 50 S3 60 He Read Lys Asn Read Read Pro Cys Read Piro Read Allah Λ <K4u4v Act Pro ¢ 5 20 7 &; 80 Tnt Arg His Pro Xie lie He Arg Asp Gly Asp Trp Asn Glu Phe Arg 85 90 95 Arg Lys Read Thr Phe Tyr Read Lys Thr Read GXu Asn. Allah Gin Allah Gin 100 105 110 Gin Tyr Val Glu Gly Giy Gly Gly To be Pro Gly Glu Pro To be Gly Pro HS 120 125 lie To be Thr He Asn Pro Her Pro Pro To be Lys Glu To be Hrs Lys Her 13 C 13 5 140 Fro Asn Met Ara Thr Gin Gly Allah Met Pro Allah Phe Allah To be Allah Phe .X4z> 150 155 160 Gin Arg Arg Allah Gay Gly Val Read Val Allah To be Hrs Read **? ·· * · To be Phe 155 X? 0 1.75 Read Glu Val Her Tyr Arg Val Read Arg His Read Allah Gin Pro Thr Pro ISO 185 190 Read Gly Pre* Allah To be To be Read Pro GJLn To be Phe I »me Read Lys To be Read 195 200 205 Gzu Gin Val Arg Lys He Gin Gly Asp Gly Allah Allah Read Gin Glu Lys 210 215 220

426

Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu '7 7 *> 0 3: 7:

C, ly Hi® Per wow C-ly lie Pre Trp Ala Pre Lau Sar Ser Cyg ProSex245 250255

Sirs Ale Leu Gin Leu Ala Gly Cys Leu Ser Sir Leu Hus Ser Civ Leu

265 2S5270

Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly lie Ser Pro Glu

275 2SO285

Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala

290 295300

Thr Thr Xle Trp Glx: Gin Mat Glu Glu Leu Gly Met Ala Pro Ala Leu

305 310 315320

Gin Pro ...... .... ......

•2? INFORMATION FOR SEQ W NO ·· 201 ·.

(ij SEQUENCE CHARACTERISTICS:

(As LENGTH; 319 amino acids

ÍB: TYPE: amino acid (C! STRANDEDNESS; single> Ds TOPOLOGY: linear iiii MOLECULE TYPE; protein ixi) SEQUENCE DESCRIPTION t SEQ ID NO: 201:

Met . «K: Allah Asn Cys To be 5 Asr Met He Asp Glu 10 He He *> h * · His Read Ί ff. Lys Pro Pro Lr & u Λ. Λ * u Pxc Read Read Asp Phe 25 Asn Asn Read Asn Giy 30 Glu Asp Gin Asp lie 35 3X ^ 14 Met GvixU. Asn Asn 40 Read Arg Arg Pro Asn 45 Read Giu. Allah Phe Asn 50 Arg Allah Val Lys To be 55 Read Gin Asn Allah To be 60 Allah He Glu To be He 65 Read Lys ASTi Read Read 70 Pro Cys Pre Read 75 AL a Thr Allah Allah Pro 80 Thr Arg His Pro Ila 85 Xie He Arg Asp Gly 90 Asp Asn Glu Phe OR Arg

42?

Arg Lyu ^ eu Thr Phe Tyx x ^ eu uys Tnr ul.u Am Ala Qtn Ata Qin

100 105lie

Gin Tyr Vai Glu Gly Gly Gly Gly Ser Pro Gly Glu Pre Ser Gly Pro

115 125. „29 lie Ser Thr He Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser ã» v. <. u 5 .λ 4 v ‘

Pro Asn Met Ala Thr Gin Gly Ala Met Pro Al Pha Ala Ser AlaPhe Ala

14.5 150 - 155160

Gin Arg Arg Ala Gly Gly V & À Leu Vai .Ala Ser Hrs Lew Gin SerPhe

165 170175

Leu Glu Va.1 Ser Tyr Arg Vai Leu Arg His Leu Ala Gin Pre Ser Gly

180 185190

Gly Sar Gly Gly Ser Gin Ser Phe Leu Leu Ly »Ser Leu Glu Gin Vai IPS 200205

Arg Lys lie Gin. Gly Asp Gly Ala Ala Leu Glrs Glu Lys Leu Cys Ala 210 215220

Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Vai Leu Leu Gly HisSer

225 210 235 “240

Leu Gly He Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin AlaLeu

245 250255

Gin Leu Ala Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr

260 285270 xsun Gxy Leu Leu Qtn Ala Leu Glu Gly He Ser Pro Glu Leu Glv Pro 275 280 285 ......

Thr Leu Asp Thr Leu Gin Leu Asp Vai Wing Asp Phe Wing Thr Thr He 290 295300

Trp Gin Qin Mat Glu Glu Leu Gly Met Wing Pro Wing Wing Gin Pro

305 310315 * 2) INFORMATION FOR EEQ ID ND; 202:

: i; SEQUENCE CHARACTERISTICS:

(A; LENGTH: 322 aaaino acids (Bi TYPE: amno arid (G) STRANDEDNE.SS; single (Π TOPOLOGY ': linear (ii; MOLECULE TYPE: protein

428

Read

Read

Phe

At

Lys

Ass er

Pre

Met

Read

Hit

Pre is

His

Arg

Lys

Thr

100

Phe

Tyr

Giy

Pro

145

Read

Read

Read

Gly

Gin

To be

110

Asn

Pro

Asn

Met hr

150 '0

Allah

Gly

Glu

Gly

Gin

210

Go

Fri

Allah

Go

Allah

To be

Read

Arg

Ils

Lys

245

Allah

Read

Pro

Read

Gly

If:

Go

Go

Read

Gly

D NO 7 δ u c Xle Asp Glv f !. lie lie Thr Hi.® L & u Asp Phe 25 Asn Asn Read Asn Gly 3 0 Asr 40 Read Arg Arg Pro Asn 4S j G Lxf & U Gin Asn Ara To be 6G a Λ ~ Xle Xi <U! <> cyr Read Pro Read 75 A j. The Th. ** Allah Allah Lys Asp Gly «0 Asp Trp Asn Glu Phe 9 5 LT® Thr 105 Read G a. Asn Allah Gan 1X0 Allah Gly .120: To be Pre Gly Glu Pro Fri Gly Pre Pro To be Lys Glu 140 To be Mrs Lys Allah: Met Pro Am 155 Phe Allah To be The «.a Read Go Allah 170 To be His Read Gin To be 175 Read Arg 105 His Read Allah Gin Pro 190 Thr Pre 200 Gin To be Phe Read Read 205 Lys To be Gly Asp Gly Allah Allah 22 Q Read Gin G. »u Cys His Pro Glu 235 Glu Read Go Read Txp Allah Pro 250 To be To be Cys Pro 255 Cys 265 To be Gin L-me His To be 270 Gly

Lys

Arc

Pro

To be

Phe

Read

Lys

Only:

Read

Phe l§v

Read

24Ü

2"

Ph® Leu Tyr Qin Gly Leu Leu Gin Ala Leu Glu Gly Ha Ser Pro Glu

375 280285

Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Va. ‘Wing Asp Phe

290 295360

Thr Thr: 1a Trp Gin Gin Met Glu Glu Leu Gly Met Ala Pro Ala Leu

395 31C 315320

Gin Pro

2; INFORMATION FDR EEQ ID ND: 203:

(tj SEQUENCE CHARACTERISTICS;

ÍA) LENGTH: 306 amino aeida (B) TYPE.- astino acid (C: STRANDEDNEES: single

ID; TUPGLOGY: linear iiiJ MOLECULE TYPE; protein (xi) SEQUENCE DESCRIPTION; SEQ ID ND: 203:

Ai & Asn Cys Ser Ixe Met He Asp Glu He He Hxs His Leu Lys Am :: 1 ........ ::: 5 :: .......... 1CTC

Pro Pro Wing Pro Leu Leu Asp Pro Am Asn Leu Asn Asp Glu Asp Val

257 ·: ·

Ser He Leu Met Asp Arg Asn Leu Arg Leu Prc <Asn Leu Glu Ser Phe

35 .............. 40 45

Vat Arg Ala Val Lys Asn Leu Glu Asn Ala Sex Gly H® Glu Ala He

SO 55SO *

Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Ot 7075

Arg Kia Pro Ila He He Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu

.......... .......... 85 ........ ........ ........... .. .......... 9C · α ς

Lys Leu Thr Phe iyr Leu Val Thr Leu Glu Gin Ala Gl _n Glu Gin Gin

100 105 ng

Tyr Vax glu G * y Gty Gly Gly Ser Pro Gly Glu Pm Ser Glv Pro He

115 120 125

Ser Thr He Asn Pre »Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro $ W - ·» c «........... ............ ... .....

430

Aar; Met Glu Val His Pre Leu Pro

i.sp Phe Let Leu Gly Glu Tx ~ - Lys

Thr Pro Val Leu Leu Pro Ala Val

.................................................. ...... <yg |

Thr 'Git Met Gm Gm Tnr Lys Ala

Gin Asp lie Leu Gly Ala Val Thr 180

Wing Arg Gly Gin Lsu Gly Pro Thr 195208 '

Leu Ser Gly Gin Vs I Arg Leu Lex: q 28 5

Gly Thr Gin Leu Pro Pre Gin Gly 225230 • Asn Ala He Phe Leu Ser Phe Gin _ ..

Phe Leu Met Leu Val Gly Gly Ser

260

Gly Asn Met Al® Ser Pro Ala Pro

275 280

Ser Lys Leu Leu Arg Asp Ser His 29C 295

Cys Pro

305

Leu Leu Leu Gru Gly Val Met. Act a

185 190

Cys Leu Ser Ser Leu Leu Gly Gin -> fre. <& · V

Leu Gly Ala Leu Gin Ser Leu Leu

220

Arp Thr Thr Ala His Lys Asp Pro

23524G

His Leu Leu Arg Gly Lys Val Arg

250255

Thr Leu Cys Val Arg Glu Ph® Gly

26527Q

Pre Wing Cys Asp Leu Arg Val Leu

285

Val Leu His Ser Arg Leu Ser Gin

300 (2) INFORMATION FOR SEQ ID NO; .204.-.

i; SEQUENCE CHARACTERISTICS:

{A) LENGTH; 306 amino acids (E) TEPE; amino acid (C) STRANDEDNESS; single (Di TOPOLOGY: linear (ii) MOLECULE TYPE: protein

X) SEQUENCE DESCRIPTION: SEQ ID NG; 204:

Wing Asn Cys Ser lie Met lie Asp Glu He He His Hás Leu Lys Arg

Pro Pro Wing Pro Leu Leu Asp Pro Asn Asn Leu Ann Asp Glu Asp Val

25 30

31

Ser He Leu Met / Sy /

Go Arg Ala V & l

Cl · rh

M

Leu Arg Asn Leu

Arg His Pro lie

Asn «.rg .Asn · ueu

Asn Leu G.a u

Gin Pro Cys Lev

Arg Leu pm Asn

Asn Ala Sex Gly

Leu Glu Sex · Ph®

He Glu Ala HeLys Leu Thr Phe

100

Tyr Vax Glu Gly

113

Ser Thr He Asn

0

Asn Met Leu Pro

145

Gly Glu Trp Lys

11½ He Lys Ala

........

Tyr Leu Vai Thr

Gly Ala Vai Thr

ISO

Leu Gly Pro Thr

195

Go Arg Leu Leu

Gly Gly Gly Ser

120

Pro Ser Pro Pro

Thr Pro Vai Leu

ISO

Thr Gin Met Glu

165

Leu Leu Leu Glu

Pro Ser Wing Thr

Gly Asp Trp Glr

x.eu ulu Gm aua

105

Pro Gly Glu Pro

Pre SaOO Wing

Glu Pne Arg Glu

Gin user Gin

Pro Pro Gin Gly

225

Read Ser Phe Gin

Go Gly Gly Ser

260

Be Pro Wing Fro

275

Arg Asp Sex Sis

290

Cy & Leu Ser Ser

200

Leu Gly Ala Leu

215

Arg Thr Thr Ala

230

His Leu Leu Arg

245

Thr Leu Cys val

Ser Lys Glu Ser

140

Leu Pro Ala Vai igs.

Glu Thr Lys Ala

170

Gly Vai Met Ala

185

Leu Leu Giy Gin

Be Git 'Pro He .1.25

His Lys Sex Pro

Pro Wing Cys Asp

280

Go Read His

...... .......

Gin Ser Leu Leu

220

His Lys Asp Pro

235

Giy Lys Vai Arg

250

Arg Glu Phe Gly

285

Leu Arg Vai Leu

Asp Phe Ser Leu

160

Gin Asp He Leu

175

Arg Gly Gin Ward

190

Read Ser Gly Gin

205

Gly Thr Gin Leu

Arg Leu Ser Gin

300

Asn Ale He Ph®

240

Phe Leu Met Leu

25.%

Gly Asn Met Ala

270

Sex Lys Leu Leu

285

Cys Pro Glu Vai

His Pro

305

432 (2; XNFDRKZ.TXON FOR SEQ ID NG; 205;

t i; SEQUENCE CHARACTERISTICS;

(A; LENGTH: 3C £ ammo acids <!> · TYPE: amine acid {C} STRAtW-EDNESSL single (D.j TOPOLOGY: linear (it> MOLECULE TYPE; protein

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO : 205; Allah | 1! ........ · Asir: Cys To be Ils Met He Asp Glu He 10 He His His Read Lys Arg Pro Pit Allah Fra 2G Read L&U Asp Pro Asn 25 Asn Read Ann Asp Glu 3 0 Asp Val To be Ila Read 35 Met Asp Arg Asn Read 40 Arg Read Pro Asn Lau 45 Glu Fri- Phe Go Arg SC Allah Go Lys Asn Read 55 Glu Asn Allah To be Gly 60 lie Glu Allah He Read 65 Arg Asn Read Gin Pro 70 Cys Read Pro To be Allah 75 Thr Allah Allah Pro Fri* ONLY Arg His Pro He lie 85 He Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg $ 5 Glu Lys Read Thr Phe 103 Tyr Read Val Thr Read 105 Glu Gin Allah Gin Glu 110 liB Gin Wyj, Val Glu Xii Gly Gly Gly Gly To be 120 Pro Gly Glu Pro To be 125 Gly Pro He To be Thr ISC- He Asn Pro Set Fro 135 Pro To be Lys Glu To be 140 His Lys To be Pro Wing 145 Met. Val Read Read Pro 150 Allah Val Asp Phe To be 155 Read Gly Glu Trp Lys ISO Thr Gin Met Glu Glu 165 Thr Lye Allah Gin Arp 170 He Read sly Allah Val 175 Thr Read Read Read Glu 180 Gly Val Met Allah Allah 165 Arg Gly Gin Read Gly 190 Pro Thr Cys Read To be- 135 To be Read Read Gly Gin 200 Read To be Gly Gin Val 205 Arg Read

433

Wing Leu Gin Ser Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly ............ 210 215 23c Arg Thr -? 2 ^C. Thr Ala Hxs Lys Asp Pro Aar Ala He Phe ucu Ser Phe Sir. 330 235 240 Hrs Leu Leu Arg Gly Lys Vai Arg Phe Leu Met Leu Vai Gly Gly Ser 245. 25Ô 285 Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Met Ala Ser Fro Ala Pro 360 265 .27 g Pro Wing Cys Asp Leu Arg Val Leu Ser Lys Leu Leu Arg Asp Ser Hie 375 286 285 Go Read 2 SC His Ser Arg Leu Ser Gin Uys Pro Glu Val His Pro Leu Pro 295 30Q

Thr Pro

305

INFORMATION FOR SEQ · ID NO: 206:

(1) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 306 amino acids (E; ΉΡΕ: amino acid

 f; * K J STRANDEDNESS; single <D) TOPOLOGY; linear

(il) MOLECULE TYPE: protein (Xi) SEQUENCE DESCRIPTION: SEO ID NG: 206:

Asn Cys Ser He Met. lie

• S 71 ................................................ .... _:::: 5 Read Read Asp Pre Pro Allah Pro 20 To be lie Read 35 Met. Asp Arg Asn Val Arg 50 Allah Val lys Asn Read 55 Read 65 Arg Asn Read Gin Pro 70 Cl'S

Asp Glu He He His His Leu Lvs Arg

1015

Pro Asn Asn Leu Asn Asp Glu Asp Vai

30

Leu Arg Leu Pre Asn Leu Glu Ser Phe 4045

Glu Asn Ala Ser Gly lie Glu Ala He

Leu Pro Ser Ala Thr Ala Ala Pro Ser gg

Arg His Pro lie He He Lys Ala Gly Asp so

Gin Glu Phe Arg Glu

434 uys Lex: Tnr pne Tyr Leu v & _ Thr nex; Gm Gm axa Gin Glu Gin Glr ^K > 0 .............. ............ liii ............. ......

T-'r Va? ' 71u G; \ Gly Gly Gly Ser Pro Gly Glu Pro Ser Gly Pro Xie 115 '120 2.25

Ser Thr Ire Asn Pro Ser Pro Pro Ser Lys Glu Ser Hie Lys Ser Pro

Asn Me ”Ala Vai Asp Phe Ser Leu Gly Glu Trp Lys Thr Gl ~ Meo Gin 145 ISC ISE

Glu Thr Lys AU Gin

155 v & sL

ΚΑ »χ · Ψ * ϊ '« γ.χ λ,

Hrs Lys

225

Gly Lys

Arg Glu

Leu Arg Vai Leu Ser

Her

Ara

Gly Gio Leu

.............. ^::

Asp Xie l- <uu Gly Ala V & .1 Thr Leu Leu Leu Glu

170 HE

To be

Goy

Gin

20C

Read

185

Go

Leu Leu Gly Thr Gin Leu Pro

.................................... 2 * 5 ........... ............

Asp Pro Asn Ala Xie Phe Leu

230

Go Arg Phe Leu Mat Leu Vai

245

Phe Gly Gly Asn Mat Ala Ser

Gly

Thr

190> be

Arg Leu Leu

Leu Gly Ala

THE

Read

Pro Gin Gly Arg Thr Thr Ala

Ser Phe Gin His Leu Leu Arg

235 240

Sly Gly Ser Thr Leu Cys Vai 25C ....... 2 ^sa : ........

Pro Wing Pro Pro Wing Cys Asp

Lys Leu Leu Arg Asp Ser

280

Hrs ‘Vai Leu His S & z

288

Arg Leu Ser Gon Cys Pro Glu Vai His Pro Leu Pro Thr Pro Va ' ¹ Le *' ²⁵⁰ 295 300

Leu Pro

OS (2) INFORMATION FOP; SEQ XL NO: 207:

U) SEQUENCE CHARACTERISTICS;

(A) LENGTH: 3S6 amino acids (S) TYPE: acid ardao C) STRANDEDNESS: s ing1e

CD) TOPOLOGY: linear iii) MOLECULE TYPE ·, pro is in

435 (Xi) SEQUENCE DESCRIPTIONSEQ ID KC

Wing Asn Cys Ser He Her. He Asp Glu He He, - ’xs Hrs Set Lyr Ary

5 1015

Pro Pro Ale Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu AspVal

2Q 2530

Ser He. Lea Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Pue 35 .4045

Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly He Glu Ala lie SO 5560

Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Wing Thr Wing Wing Fro Ser 65 7 07 5

Arg His Pro He lie Ila Lys Ala Gly Asp Try Gin Glu Phe Arg Glu 85 90§5

Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105T10

Tyr Val Glu Gly Gly Gly Gly Ser Fro Gly Glu Pro Ser Gly Pro He 115 120 125

Ser Thr He Asn Pro Ser Pro Pro Ser Lys Glu Ser His Lys Ser Pro 130 135140

Asn Met Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin Met Glu GluThr

145 150 155150

Lys Ala Gin Asp He Leu Gly Ala Val Thr Leu Leu Leu Glu GlyVal

165 37Q175

Met Wing Wing Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu 180 185190

Gly Gin Leu Ser Gly Gin Val Arg Leu Leu. Leu Gly Ala Leu Gin Ser 195 200205

Leu Leu Gly Thr Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala His Lys 210 '215.220

Asp Pro Asn Ala He Phe Leu Ser Phe Gin His Leu Leu Arg Gly Lys 226 230235

Val Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu 245 250255

Phe Gly Giy Asn Met Ala Ser Pre Ala Pro Pro Ala Cys Asp Leu Arg

260 265270

€ 43

Vâi Leu Ser Ly® Leu Leu Arg Arp Set ’Hrs Vau Leu Hrs Ser Arg Leu

271 272 285

Be Gl «Cys Pre Glu Val His Pre Leu Pre Thr Pro Vai Leu Leu Pre

296 .295 300

Val Wing ..................

305 (2; INFORMATION FOR SEQ ID NO; 208;

{i} SEQUENCE CHARACTERISTICS:

(A) LENGTH; 396 ammo arid® (Bi TYPE ·, aaàno arid (C · STRANDEDNESS; single (D · TOPOLOGY: linear (ii) MOLECULE TYPE .; protein (X.X.) SEQUENCE DESCRIPTION: SEQ ID NO; 205:

Wing Asn Cys Ser He Mat

5

Pre Pre Wing Pre Leu Leu 20

Ser Ils Leu Met Asp Arg ......................... Bil ....... .....

Val Arg Ala Val Lys Asn 50

Leu Arg Asm Leu Sin Pro

70

Arg His Pre He lie lie

S5

Lys Leu Thr Phe Tyr Leu

103

Tyr Val Glu Gly Gly Gly

115

Ser Thr He Asn Pro Ser 130

Asn Met Gly Glu Trp Lys

145 ISO

He Asp Glu He 10 He His Has Read Li's Arg Asp Pro 'ί ε X X Asn Lev Asn Asp Gxu 30 Asp Val Asr Read 40 Arg Read Pro Asn Read 4S Glu To be Phe Read 55 Glu Asn Allah To be Gly 60 He Glu Allah lie Cys Read Pro To be Allah 75 Thr Allah Allah Pro To be 80 Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 95 Glu Val Thr Read 305 Glu Gin Allah Gin Glu 110 Gin Gin Gly To be 12 C Pm Sly GxU Pro To be 125 Gly Pm He Pro 135 Pro To be Lys sst To be 1¼ x> His Lys To be Pro Thr Gin Met Gru Glu jL5 5 Thr Lys Allah Gin Asp 153

437 lie Leu Gly Ala Vai Tor Leu Leu Leu Glu Gly Vai «et Ala Ala Arg

Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser Leu Leu Gly Gin ueu Snr

180 18-5 190

Gly Gin Vai Arg Leu Leu Leu Gly Ala Leu Gin Sas: Leu Leu Gly Thr

195 200 205

Gin Leu Pro Pro Gin Gly Arg Thr Thr Ala Hrs Lys Asp Pro Asn Ala

Pne Leu Ser Phe Gin His Leu Leu Arg Gly Lys Vai Arg Phe Leu

2'7 «730 / V · λ. ··.

Met Leu Sal Gly Gly Ser Thr Leu Cys Vai Arg Glu Phe Gly Gly Asn

245 250 255

Met Ala Ser Pro Pro Pro Wing Cys Wing Asp Leu Arg Vai Leu SerLys

Leu Leu Arg Asp Ser His Vai Leu His Ser Arg Leu Ser Gin Cys Pro

275 .3502SS

Glu Vai His Pro Leu Pre Thr Pro Vai Leu Leu. Pro Wing Asp Phe

280 295300

Be Leu

305 .................... ........

(2 i INFORMATION FOR. SEQ IP NO: 209:

ilj SEQUENCE CHARACTERISTICS:

(A) LENGTH: 30 $ ax & ino aciüs (Hi TYPE: amino acre (C? STRANDEDNESS: Single fD) TOPOLOGY: linear ixj.) SEQUENCE DESCRIPTION; EEQ ID ND: 209:

A * a Asn Cys Ser He Met He Asp

Pro Pro Wing Pro Leu Leu Asp Pro

Ser lie Leu Mat Asp Arg Asn Leu

40

Glu lie He His His Leu Lys Arg

IS

Asn Asn Leu Asn Asp Glu Asp Vai 25 30

Arg Leu Pro Asn Leu Glu Ser Phe

Read

Thr

Me * hv

.•I

Pha jw®: U

Phe

195

168

Gin

Leu val

If:

Read

P:

Pro

Allah

His

Go

Val

Pro

Read Gxy Gx? <I 275 T ** r> ^τ Tnr ΓΠ *> Wt-k.AÀ Net 290 Read Gly Ala Val Thr Ifeu Read 290 295

Lea

Fr

Sss

Allah

Th:

Val

60 He ^ Ά · Χ <·. A.JL & He Pro Sax ’ A..L & THr / kw- A Pro Wing Ge * ' 80 Gj.y Asp 90 Trp GU * -> Glu Phe Arg Glu Read 103 Glu Gin > 4 * · ίλ · * ψ GXv Gin -5 £ f> ΛΛ, ^ Γί Pro Gj.v Glu Pro To be 12 <' Gly Pro He Sar Lys .ki ¥ * Λ · fcul. Ss r 140 His Lys Ser Pro To be Read Read 155 Gly Gin. Àyc & U Gly 26 0 Read Gin 170 Sax Read Read Guy Tar 3 © 5 His Lys Asp Pro Aan Ala ISC He Gly Lys Val Ax? G 205 Phe Le.u Met Val Arg G1 Phe 220 Gly Gly Asn Met At'p Read Arg t? Val Ser Lys Read 240 To be Arg 250 Read To be AM usln Cys Fro 255 Clu He gave 285 irf ^ Ü Pro Allah Val Asp Phe 270 To be Glu GvA \ 4 TJir Lys Allah 285 Gin Asp He Glu Gly Val Met Allah Arg Wing Gly

2? information for

J NO;

HARACTERISTI

439 ai LENGTH. 3 06 jaaino acids! B; TYPE; amino acid

IC5 STPANDEDKESS; single (Di TOPOLOGY; linear

Uii MOLECULE TYPE; protein

ÍXX5 SEQUENCE DESCRIPTION: SEQ ID ND; 210;

Wing Asn Cys Ser lie Met He Asp Glu He He His His Leu Lys Arg

Pre Pro Wing Pro Lsu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val .......... 20 25 ..30

Ser He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 35 4045

Val Arg Ala Val Lys Ann Leu Glu Asn Ala Ser Gly XI · Glu Ala lie SO 556θ

Leu Arg Asn Leu Gia Pro Cys Leu Pre Ser Ala Thr Ala Ala Pro AlaSa 70 70go

Arg Hi® pro He He He Lys Ala Gly Asp Trp Gin Glu Phe ArgGlu

9095 '

Lys Leu Thr Phe Tyr Leu Val Thr Leu Glu Qin Ala Gin Glu Gin Gin OO 195no

Tyr Vau Glu Gly Gly Gly Gly Sei Pro Gly Glu Pro Ser Gly Pro He H5 129 125

Ser Thr He Asn Pro Ser Pro pro Ser Lys Glu Ser His Lys Ser Pro 230 135140

Ass Met Gly Thr Gin Lsu Pro Pro Gin Gly Arg Thr Thr Ala HisLys

145 150 1.55ygg

Asg Pre Asn Ala He Phe Leu Ser Phe Gin His Leu Leu Arg GlyLys

165 ............... ......... ............. 170 175

Va: Arg Phe Leu Met Leu Val Gly Gly Ser Thr Leu Cys Val Arg Glu 180 185

Phe Gly Gly Asn Met Ala Ser Pro Ala Pro Pro Ala Cys Asp Leu Arg 195 2002Q5

Val Leu Ser Lys Leu Leu Arg Asp Ser His Val Leu His Ser Arg Leu 210 215 229

440

A® '

He;

Pr

Pre uet

Le uu weu mu

To be

85 mu

Go

If

INFORMATION FOR SEQ «mrs.no acios

LENGTH: 30

TYPE: amin

STRANDEDNESS: single

TOPOLOGY; linear (xi) SEQUENCE DESCRIPTION: SEQ ID NQ; 211;

Asn Cys Ser He Met lie Asp Glu He He H15 Ria Leu Lys Arg 5 1815

Pre Pro Wing Pre Leu Leu Asp Pre Asn Asn Leu Asn Asp Glu Asp Val 20 253Q

Ser He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe 35 4045 \ a .; Arg Ala Val Lys Asn Leu Giu Asn Ala Ser Glv Hs Glu Ala He SO 556o

Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Wing Thr Wing Wing Pro Ser 70 7580

Arg His pro He He He Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu 85 $ 0g

Lys Leu Thr Ph® Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin IOC · 10511 $

441

Tyr Va- Gau Gay Gly Guy Giy Ser Pro Gly Glu Pro Ser Gly Prs li © (<v 'Iflfillfl _{: K} ' ................ ........ ..... iliif '............ ............................... .

Ser Thr He Asn Pro Ser Pro Pro Ser Lys Giu Ser His Lys Ss: -. ^v Pro Ί a Γ. â * · a A * *> · · Λ .V *, · Λ <*, U

Aen Met Gly Arg Thr Thr Ala His Lys Asp Pro Asn Ala He Phe Leu

145 150 155ISO

Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met LeuVal

IAS: 170175

Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Gly Asn Met Ala Ser

180 185150

Pro Αχκ, ίι Pro 195 Prt. ills Cys Asp Read 200 & ν'-ιΓΎ: ιΠμ »: $“ [·? Val Read To be Lys 205 Read Read Arg Asp To be His Val His To be Arg Alrêíiw. To be Gin Cys Pro Giu v His *? t r 216 A * x · Pro Read Pro Thr Pre V®1 Read Read Pro Val. Asp Phe To be Read Giy 23 0 235 240 Glu Lys Thr Gin Met Glu Glu Thr Lys Gin Asp Tie Read Glv 245 250 _{to the} 2HB Allah Val Read Read Read Glu Gly Val Met Allah Allah Arg Giy Gin Read 260 265 270 Gly Pro Thr Cys Read To be To be Read Read Gly Gin Read To be Gly Gin Go 2H 2 & 0 285- Arg Read Read Gly Allah Read Gin To be Law Read Gly Thr Read Pro 230 <5 0 «Ws · ¹ D 300

Pro Gin

305 (2} INFORMATION FOR SEQ XL NG; 212:

(!) SEQUENCE CHARACTERISTICS;

(A; LENGTH: 306 asiino acids (3; TYPE: amino add ÍC) STRANDEDNESSt single (Df TOPOLOGY: linear iic) MOLECULE TYPE: protein {Xi} SEQUENCE DESCRIPTION: SEQ ID NO: 212:

2

Asr. Cys Ser He Met He Asp

Glu He He His His Leu Lys Arg

Pre Pro Ria Pm Leu Leu Asp Pro ................. 20 ........

Ser Xle Leu Met Asp Arg Asn Leu 3540

Val Arg Ala Val Lys Asm. Leu Glu SO «5

Leu Arg Asm Leu Gin Pro Cys Leu 6570

Arg Hie Pre lie He lie Lys Ala 85

Lys Leu Thr Phe Tyr Leu Val Thr .......... 100 .......

Tyr Val Gru Gxy Gly Gly Gly Ser

H5120

Ser Thr He Asn Pro Ser Pro Pro '130135

Asn Met Ala Hie Lys Asp Pro Asn 145ISO

Leu Leu Arg Gly Lys Val Arg Arg Phe .................... 165 .......

u Cys Val Arg Glu Phe Gly Gly 180

Wing Cys Asp Leu Arg Val Leu Ser

185200

Leu His Ser Arg Leu Ser Gin Cys

210215

Pro Val Leu Leu Pre Ala Val Asp 225230

Gin Met Glu Glu Thr Lys Ala Gin 245

Leu Leu Glu Gly Val Met Ala Ala

260

Leu Ser Ser Leu Leu Sly Gin Leu

275 280

Asn Asn Leu Asm Asp Glu Asp Val

3 0 · ......

Arg Leu Pro Asn Leu Glu Ser Phe

Asn Αλ. & Ser Gly He Glu Ala lie

Pro Ser Wing Thr Wing Wing Pro Ser

80

Gly Asp TryGym Glu Phe Arg Glu 90

Leu Glu Gin Ala Gin Glu Gin Gin 3 05 ho

Pre Gly Glu Pro Ser Gly Pro He

125

Ser Lys Glu Ser His Lys Ser Pro

140

Ala He phe Leu Ser Phe Gin His

155iso

Leu Met Leu Val Gly Gly Ser Thr 170175

Asn Met Ala Ser Pro Pro Pro Wing 185igo

Lys Leu Leu Arg Asp Ser His Val

205

Pre Glu Val His Pro Leu Pro Thr

220

Phe Ser Leu Gly Glu Trp Lys Thr ................. «fc’ Mi * ·

240

Asp He Leu Gly Ala Val Thr Leu 250 255

Arg Gly Gin Leu Glv Pro Thr Cvs

265 ’270

Being Gly Gin Val Arg Leu Leu Leu

285

443

Gly All Leu Gin Gar La- Leu Gly The Gin Leu Pre Pro Gin Gly Arg 290 295 300

The Thr

305 {I'j INFORMATION PGR SEQ IQ ND; 313:

Í1Í SEQUENCE CHARACTERISTICS;

(A · LENGTH; 301 ammo acids (Bi TYPE: amino acid

IC; STRANDEDNESS: Single iD} TOPOLOGY: linear

Ul) MOLECULE TYPE; protein txi; SEQUENCE DESCRIPTIONi SEQ ID NG: 213:

Allah 1 Asn cys To be ..He. Met Xle Asp Glu lie 10 He His Hrs Lys 15 Arg Pro Ere Ara Pre 28 Read :: LeU ': Asp Pro Asn 25 Asn Read Asr Asp Glu 30 Asp Go To be lie Read 35 Mat Asp Arg Asn Le- 4.0 Arg Read Pro Asn wow 45 Glu To be Phe Go Arcs 50 Allah Go Lys Asn Read k; .r Glu Asn Allah To be Gly 60 Giu Allah He Read 65 Arg Asn Let QXrs Pre Cys Read Pro To be Allah 75 Thr Allah Allah Pro 80 Arg Hrs Pro " "AND 11 « 85 He Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 95 Glu Lys Read Thr Phe 100 Tyr Read Go Tnr Read 105 Glu Gin Allah Gin Glu 110 Gin Gin Tyr Go X ^ Gly Gly Gly Gi y To be 126 Pro Gly Glu Pro To be 125 Gly Pro lie To be Thr 130 11 « Asn Pro To be Pro 135 Fro To be Lys Glu To be 140 His Lys Ear Pro Asn 145 Met Asp Pro Asn Allah ISO He Phe Read To be Phe 155 Gin His Read Read Arg 16Ό Gly Lys Go Arg Phe 165 Read Met Read Go Gly 170 Gly To be Thr Le: Cys 175 Go

Arg Glu Phe Giy 180 Giy Asn Met. To be Pre Allah Pro Pre Allah 190 Cys Asp · Xy'ijV- Arp Val li & U To be Lys Read Read Hoop Asp To be W 4: - <t Val Read His Fri- _c M 200 205 Arg wSu sS-êjr Gin Cys Pro Glu Val His. Read Pro Pro Val Read c * X S-: 215. 2.20 Kv Pro Wing Val Asn Phe Fri' Read Gly Trp Lys • Uk Glx: Met Guu · <&> · Χ ·. ** ·· 23 0 235 240 Glu Thr Lys Allah Gin Asp He Read G1Y Allah Val Read Read Read Glu 245 250 2 Gly Val Met Ale Ara Arg Gly GuTi Read G ^ y Pro .’P'fct-y » & · *> · & · & Cys Read To be 260 265 270 Read Leu Gly .Girt Read To be Gly Gin Val Arg Read Read Gly THERE& Read 'y-tj: 5 ^ 290 285 αλ1Χ1 ·. Ser Lau Read Gly Thr Gin Read Pro Gin Gly Arg Thr Tnr Allah 293 295 300

Hus Lya

305 (2} INFORMATION FOR SEQ ID NG: 214:

¢ 1} SEQUENCE CHARACTERISTICSt {A · LENGTH: 308 amino acids! E; TYPE: aau.no acid {C; STRANDEDNESS; single (DJ TOPOLOGY: linear tii: MOLECULE TYPE: protein ixi) SEQUENCE DESCRIPTION: SEQ ID NO: 214:

AX & 1 Am Cys To be 7> gWi: Í Met He Asp Glu He 19 He Hrs K.1 & Read Lys 15 Arg Pro Pro Allah Pro 20 Read Read Asp Pro Asn 25 Asn Read Asn Asp Glu 30 Asp Val To be He Read 35 Met Ast? Arg Asn uea 40 Arg Lau Pro Asn Read 45 Glu To be Phe Val Arg Allah Val Asn Read GxU Asn Allah To be Gly lie Glu Allah He

arg aaa vaa Lys Asn ueu Giu Asn Ara Ser G1 SC 55

445

Cv

Pr ^ vla rhr

Allah

If

Air·

His

Pro

SS aer

Glv

Asn _:

145

Me

Allah

Phe

Read

Read

To be

Lvs / sec

Vax

Asp

Phe

Asp

Allah

Sin. «I

To be

Sly

290

Pro

305

Phe

100

Gly

To be

He

Phe

Met

Met

ISC

Read

To be

260

Gin val

Fri

S & 3

Phe

Read

10ft

Pre

To be

Gin

Gly

To be

Pre

To be

Let

Gly

Lys

Read

185

Val

Gly

To be

Read cys

Val

Arg

Glu

175

Pne

Allah

Read

Val

Read

Lev

If.

Allah

Pro

185

Pro

Cys

Asp

ISO

Val

Arg

Asp

Pro

215

To be

His

Val

Read

If

Be.

Pro

Lys

Gly

Read

Gly a j.

Pro

Thr

Val

Read

Read

Met

Glu

Glu

Lys

Val

Pro

Thr

Arg

Read

28C

Read

G1

295 «2? INFORMATION FOR SEQ ID NO; 215:

ii) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 305 amine acids

5E} TYPE: amino acid (C? STRANDEDNESS: single

Read

250

Cys ueu

Lew

Read

Thr

Read

Glu

Gly

Val

Het

To be

Allah

Thr

300

If:

Read

285

Allah

Read

270 jLriSU.

To be

Read

446

ID) WPÇiQGY; itnear it! MOLECULE TYPE: protein ixii SEQUENCE DESCRIPTION: SEQ ID NO. · 215;

Asn Cys Ser Wing

Ils Met He Asp Glu He

He His Hie Leu Lys Arg

Pro Pro Wing Pro

Leu Leu Asp Pro Asn Asn

Ser Ils Leu Met

Go Arg Ala Vai

Leu Arg Asn Leu

Arg Bis Pro He

Lys Leu Tar Phe

100

Tyr V & l Gru Gly

Ser Thr Ils Asn

130

Asa Ker Glu Vai

145

Asp Ph® Ser Leu

Gin Asp lie Leu

ISO

Arg Gly Gin Ward

195

Read Ser Gly Gin

210

Gly Thr Gin Leu

225

Asp Arg Asn Leu Arg Leu

Lys Asn Leu Glu Asn Ala 55

Gin Pro Oys Leu Pro Ser 70 lie He Lys Ala Gly Asp

90

Tyr Leu Vai Thr Leu Glu

105

Gly Gly Gly Ser Pro Gly

120

Pro Ser Pre Pre · Ser Lys

135

His Pro Leu Pro Thr Pre ·

150

Gly Glu Trp Lys Thr Gin

165 170

Gly Ala Vai Thr Leu Leu

155

Leu Gly Pro Thr Cys Leu

200

Go Arg Leu Leu Leu Gly 79 K.

Pro Pro Gin Gly Arg Thr23 0

Read Asn Asp Glu Asp Vai

0

Pro Asn. Leu Glu Ear Ph® 45

Ser Gly II® Glu Ala lie SO

AL® Thr Ala Ala Pro Ser

80

Trp Gin Glu Phe Arg Glu

S5

Gin Wing Gin Glu Gin Gin

110

Glu Pro Ser Gly Pro He

......................... · κ. ♦ * ·. · ** ............... .......................

Glu Ser His Lys Sex 'Pm 140

Go Leu Leu Pro Ala Vai

155 160

Met Glu Glu Thr Lys Ala

175

Leu Glu Gly Vai Met Ala

190

Being Ser Leu Leu Gly Gin

205

Wing Leu Gin Ser Leu Leu 220

Thr Ala His Lys Asp Pro 235 24Q

7

Asn THE- & —— & Phe Read Ear $ 4 & Σ2 Pnu Gb. X; Leu Leu Arg Gl „, Lys Go 255 Ara Phe L & u M <s ~ Read 260 V ci l G — y Gly S&X Thr 265 Lsu Cys Zi * Arg Gà.U Pile G — 5 Asn Met To be Pro Wing Pro Pro 280 Allah Cys Asp Read Arg 285 Go Read To be Lys Read 2 S Ο Read Ara A & p. Sn & ST · 23 V & l Read Hls Ser Arg 300 Read To be Gin CA - '. S;

Pro

305 (2; INFORMATION FOR SEQ ID NO: 2X6:

Ji) SEQUENCE CHARACTERISTICS:

(A · LENGTH; 305 asLi.no acids

ÍS) TYPE: aisino acid (C; STRANDEDNESE; single (D; TOPOLOGY: linear (ii · MOLECULE TYPE .; protein txi} SEQUENCE DESCRIPTION; SEQ ID NO: 215;

Wing Asn cys To be He 5 Met Tie Asp Glu He 3.0 There is His His Read Lys 15 Arg · Pro Pro Allah Pre Let Read Asp Pro Asn Asn Read Asn Asp Glu Asp Go 20 > 4 ax · *. · ' .10 To be lie àb ^ vlnl Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe 35 40 45 Go Arg Allah Go Lys Asn Glu Asn X Λ _w Wing To be Gly He Glu Allah lie 50 60 "I Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro To be 75 SC Arg W *. . <£ · XXmK jo Pro He He He Lys Allah Gly Asp Gin Glu Phe Arg Glu 85 ONLY 95 Lys Read Phe Tyr Read Go Thr Read Glu. Gin A, xa Gin Glu Gin Gin 100 105 110 Go Gl ^ Gly Gly Gli Gly To be Pro Gly Gm-. Li Pro To be Gly Pro He 15 120 125

448

Ser Thr He Asn Pre Ser Pro Pro Ser Lys Glu Ser Sis Lys Ser Pre

130 135 140 Asr. J-4 £ Met Leu Pre. Thr Pro Val Leu Leu Pro Ala Val Asp Phe Ser Leu ISO 155 '~ 160 Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp lie Leu Its 170 175 Gly Aia Val Thr Leu Leu Leu Leu Glu Gly Val Met Ala Ala Arg Glv Gin 180 185 19Õ Read Gly Pro Thr Cys Leu Ser Ser Leu Le Gly Gin Leu Ser Gly Gin 195 310 205 Pal Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Glv Thr Glr Leu 220 215 220 Pro ~ c. • Pro Gin Gly Arg Thr Thr Ala His Lys Arp Pro Asn Ala He Phe 230 05 240 Read Ser Phe Gin His Leu Leu Arg Gly Lys Val Arg Phe Leu Met Lsu 245 250 255 Val Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Asn Met Ala Ear 260 255 270 Pro Wing Pro Cys Wing Asp Leu Arg Val Leu Ser Lys Leu Leu Arg .275 2S0 285 A & p Ser His Val Leu His Ser Arg Leu Ser Gin Cys Pro Glu Va7 290 295 309

Pro

305 (2) INFORMATION FOR SEQ ID NO: 217:

• SEQUENCE CHARACTERISTICS; (A) LENGTH; 305 amino acids (8) TOE: mtw acid (C; STRAMDEDNESS: single (D) TOPOLOGY: linear (hi; MOLECULE TOE; protein

(xi} SEQUENCE DESCRIPTION: SEQ ID NO: 217; Allah Asn Cys Ser Ila Met He Asp Glu He He His His Leu Lys Arg £ v Λ 15

449

Pro Pro Wing Pro Leu

Le- Asp Pro Push Asn Leu

Set lie Leu Met Asp f \

Val Arg Ala Val Lys

Arg Asn Leu Arg Leu Pro

Lav Arc Am Leu Gin

Arg His Pro He He .... 85

Lys Leu Thr Phe Tyr

ISO

Tyr Val Glu Gly Gly 11B

Ser Thr 1.1® Asn Pro

1.3.0.

Asn Met Val Leu Leu

145

Thr Gin Met Glu Glu

165

Leu Leu Leu Glu Gly

180

Cys Leu Ser Ser Leu

195

Leu Gly Ala Leu Gin

21Q

Arg Thr Thr Ala His

225

Hrs Leu Leu Arg Gly

245

Thr Leu Cys Val Arg

260

Cys Wing Asp Leu Arg

275

Leu His Ser Arg Leu

290

Asn Leu Glu Asn Ala Ser 5 5

Pro Cys Leu Pre- Ser Ala 7 (5 75

Xie Lys Ala Gly Asp Trp

Leu Val Tnr Leu Glu Gin

105

Gly Gly Ser Pre Gly Glu 12G

Ser Pro Pro Ser Lys Glu.

Pro Wing Val Asp Phe Ser

150 165

Thr Lys Ala Gin Asp He

170

Val Met Wing Arg Gly Wing

185

Leu Gly Gin Leu Ser Gly

200

Ser Leu Leu Gly Thr Gin

215

Lys Asp Pro Asn Ala Xie

230 235

Lys Val Arg Phe Leu Met

25Ü

Glu Phe Gly Asn Met. Allah

265

Val Leu Ser Lys Leu Leu

280

Be Gin Cys Pro Glu Val

295

Asn Asp Glu Asp Val

Asn Leu Glu Ss; Ph ~ 45

Gly He Glu Ala Xie

Thr Ala Ala Pro Ser

Gin Glu Phe Arg Glu 95

Wing ksin Glu Gin Gm HO

Fro Ser Gly Pro Xie ’16

Ser Hxs Lys Ser Pro

L4Ü

Leu Gly Glu Trp Lys

160

Leu Gly Ala Val Thr

Gin Leu Gly Pro Thr

190

Gin Val Arg Leu Leu

205

Leu Pro Pro Gin Gly

220

Phe Leu Ser Phe Gin

240

Leu Val Gly Gly Ser

255

Sex Pro Wing Pro Prc270

Arg Asp Sex His Val

285

His Pro Leu Pro Thr

300

450

INFORMATION FOP. SEQ ID NO; 21S:

ti) SEQUENCE CHARACTERISTICS ·.

ÍAÍ LENGTH: 305 amino aexds ÍB) TYPE: amino aris

IC; STRANDSDNESS: single (D? TOPOLOGY; linear <<<$. Ρ * 'τντ ^? - ****** <*> ΛΑΡ Ί v IW'Wm'-w VwL 1 JVL s · A * · * · tv «LaL.va txii SEQUENCE DESCRIPTION: EEQ ID ND; 218:

Asn Uys Ser Ila Met. He Asp Glu He Ils His His Leu Lys Arg

5 1019

Pro Pro Wing Pro Leu Leu Asp Pro Ast. Asn Leu Asn Asp Glu Asp

2530

Ser He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Lsu Glu Ser Phe 33 4045

Vai Arg Ala Vai Lys Asn Leu Glu Asn Ala Ser Gly He Glu Ala He SO 55eo

Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing ProSer Wing

S5 70 75so

Arg His Pro He He He Lys Ala Giy Asp Trp Gin Glu Phe ArgGlu

9095

Lys Leu Thr Phe Tyr Leu Vai Thr Leu Glu Gin Ala Gin Glu Gin Gin 100 105

Tyr Vai Glu Gly Gly Gly Gly Her Pro Gly Glu Pro Ser Gly y-rr, He

115 128 125

Set Tax Ire Asn Pro Ser Pro Pro Her Lys Gru Ear His Lys Ser Pro * 30 135 HQ

Asn. Met Ala Vai Asp Phe Her Leu Gly Glu Trp Lys Thr Gin Met. Glu 145 150 155 igg

Hu Thr Lys Ata Gin Asp lie Leu Gly Ala Vai Thr Leu Leu Leu Glu

................ ...... 165 17Q ........................ 175. ........

Gly Vat Neu Ala Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ser

W ISE 190

451

Leu Leu Gly Gin Leu .- ..

1Á5

G.iy uxr. Va «Arg ** eu Leu

Leu Guy Ale Leu

205

Gin Ser Leu Leu G.ly Thr

210

Hrs Lys Asp Pro Asn Ala

225 230

Gly Lys Vai Arg Phe Leu

245

Arg Glu Phe Gly Asn Met

360

Arg Will Read Be Lys Read

Leu Ger Gin Cys Pro Glu

S C

Gin Leu Pro Pro Gin

He Phe Read Ser Phe

Ί «Λ

Λ · »<. *> '

Met Lev Goes Gly Gly

25C

Ale Ser Pro Ala Pro

285

Leu Arg Asp Ser Has

280

Go His pro Leu Pro

295

Gly Arg The Thr Als .χ <ο · η ·

Gin Hus Leu Leu Air

Being Thr Leu Cys Vai

Pro Wing Cys Asp Leu) i <ί V

Go Read His Ser Arg 38 x

Thr Pro Vai Leu Leu

300

Pro

305 (2} INFORMATION FOR SEQ ID NO: 219:

U; SEQUENCE CHARACTERISTICS:

(A? LENGTH: 305 asu.no acids

ÍBJ TYPE: amino acid (C) STRANDEDNESS: single

ID} TOPOLOGY: linear

Hi; MOLECULE TYPE; protein ixii SEQUENCE DESCRIPTION: SEQ ID NG: 219 ·.

Asn Wing Cys To be He Met He Asp Glu rue 10 11a His His Read Lys H Arg Pro Pro Allah Pro Read Read Asp Pro Asn Asn Read Asn Asp G * .u Asp Go 20 25 30 Ser He Xrôfcü Met Asp Arg Asn Read * Arg Read Pro Asn Read Glu To be Phe 35 40 45 Go Arg Allah Go Lys Asn Read GH Asn Allah to see Gly He Gau Allah He ONLY S5 60 Leu Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro Ear £ 5 70 $ 7 80

Asn

Met ue

Asp va

Η:

.huh

If .:

To be

Pro

Pre

Fri

Met

To be ",

Axe

Arg

If:

wow

Val xeu

Le *

Phe vax

Gly

200

Read

Read

Read

Read

Allah

Li Λ> ν ^ ί

To be

Read

A »and’

Pro

Thr

At.

Phe

To be

Phe

Gin

Read

Read

240

Phe

Go me

Gly

Let

Asn

Ms

If

Cys

Asp

Val i * eu

Ahp

If:

Read

His

To be

To be

Val ueu

Pre

Thr

Fro

Val

Read ueu

300

V & l

305 • (li INFORMATION PGR SEQ ID NO: 220;

(i} SEQUENCE CHARACTERISTICS;

(AJ LENGTH; 305 aaiino'wids (B; ΉΡΕ: amino acid

IC) STRANDEDNESS; single í D} TCPCLOGY; 1 inear {XX? SEQUENCE CESCF.XPTTON ·. EEQ n NO: 22 5;

«J.â Asn Cys Sec ale Met Xue Asp Gib lis He Hxa His Leu Lvs Arc

-5 xq1s

Pro Pre Ale. Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu AstVal

* .V 2c> £ 3

Ser Xie Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Ser Phe

Val Arg Ala Val Lys Asn Leu Glu Asn 50.5.5

Leu Arg Asn Leu Gin Pro Cys Leu Pre

6; 570

Arg His Pro Xie 11® He Lys Ala Gly .......... 85

Ly * Leu Thr Phe Tyr Leu Val Thr Leu

108105

Tyr Var Glu Gly Gly Gly Gly Ser Pro XIS120

Ser Thr He Asn Pro Ser Pro Pre Ser

130135

Ala Ser Gly Xie Glu Ala Xie 65

Ser Ala Thr Aaa Ala Pro Ser ⁷ 5 gc

Asp Trp Gin Glu Phe Arc Glu

95 iKT.w there, Gan Ala Gin Gin Gin Gin

110

Gly Glu pre Ser Gly Pro Xie ιος ............

........ aiwíLLC uys Glu Ear His Lys Ser .Pro

140

Asn Met Gly Glu Trp Lys Thr Gin Met Glu Glu Thr Lvs

145 150155

Au a

X6G

He Leu Gly Ala Val Thr Leu Leu

Gly Gin Leu Gly Pro Thr Cys Leu

ISO uly Gin Va * Arg Leu Leu Leu Gly IOS, ~ <Λ A * vu

Gin Leu Pro for Gin Gly Arg Thr

218215

XI® Phe Leu Ser Phe Gin His Leu

225230

Met Leu Val Gly Gly Ser Thr Leu

45

Leu Glu Gly Vai Met Ala Ala Arg

170

Her Sex Leu Leu Gly Gin Leu Se ^ 185iso

Wing Leu Gan Ser Leu Leu Glv Thr * 1

Thr Ala His Lys Asp Pro Asn Ala

220

Leu Arg Gly Ly® Val Arg Phe Leu * 3 $ -US

Cys Val Arg Glu Phe Gly Asn Mat

2SO JkJ

454

rvl-S. Lii / i Minutes Pre Pro jbii <t> K ·· ¹ Asp .2 6 5 Leu Arg Go Leu Ser 270 Lys Read Luu Arg À-sp Eaj Hrs Go Len His 220 To be Arg Lar To be Glr. Cys 288 'Pm Ό G r a Go His 290 Pro Lau Pro Thr Pro 295 Go L · · ^ u Leu Pro Allah 300 Go Asp Phe To be

Read

305

INFORMATION FOR SEQ ID NQ; 221;

ii) SEQUENCE CHARACTERISTICS;

fAi LENGTH: 305 ssunc acids tB) TYPE: amino acid (Cj STRANDEDNESS; single (d; topology; linear

Hi: MOLECULE TYPE; protect fxii SEQUENCE DESCRIPTION; SEQ ID NO: 221:

Allah Asr Cy® To be He 5 Met He Asp Glu He 10 He Hrs His Read Lys 15 Arg Pro Pro Allah Pro 20 Read Read Asp Pro Asn 25 Asn Read Asn Asp Glu 30 ASP: Val To be He Read 35 Met Asp Arg Asn Read 40 Arg Read Pro Asn Read 45 Glu To be Phe Go Arg 50 Allah Go Ly® Asn Read «7 Glu Asn Allah To be Gly 60 lie G1U Allah He Read 65 Arg A®n Gin Pro 70 Cys Pro To be Allah 75 Thr Allah Allah Pro To be ONLY Arg His Pro lie He 85 He Lys A Ài & Gly Asp 90 Trp Gin Gikc Phe Arg 95 Glu Lys Read Thr Phe 100 Tyr Read Go Thr Read 105 Glu Gin Allah Gin Glu 110 Gin Gin Tyr Go Glu 115 Gly Gly Gly ” Gly To be 120 Pro Gly Glu Pro To be L.a »Σ * Gly Pro He To be Thr 130 He Asn Pro To be Pro 135 Pro To be Lys Glu To be 140 HIS Lys To be Pro

455

Asr. Met G.ly Pre Thr Cys Leu Ser 145 ISO

Gm Vax. Arg xueau oeu Leu Gxy Asa 1.65.

Lsu Pro Pro Gin. Gly Arg Thr Thr .180

Phe Leu Ser Ph® Gin Hi® Leu Lev

195 200

Leo Va ~ Gly Gly Sex: Thr Let Cys

8®- * ο-Όλ * Gly ox.n Ger ^ xy IS 5 ιό; ’;

Leo Glr; Ser Leu Leo Glv T

Aus His Lys Asp Pro Am Ala 21® 1 ^ 5 290

Arg Gly Lys Val Arg Phe Leu Mat

Val Arg Glu Phe Gly Asn Met Ala

Ser Pro Ale Pro Pro Ala Cys Asp

Arg Asp Ser Hus Val Leu His Ser

245

His Pro Leu Pro Thr Pro Val Leu

260

Gly Glu Trp Lys Thr Gin Men Glu

275260

Gly Ala Val Thr Leu Leu Lsu Glu

290295

Read

305

Leu Arg Val Leu Ser Lys Leu Leu

235 '24Arg Leu Ser Qin Cys Pro Glu Val

250255

Leu Pro Ala Val Arp Phe Ser Leu t * ** / 0

Uti.fi Tar Lys Ala Gin Asp lie Leu

285

Gly Val Met Ala Ala Arg Gly Gin

300 information for seq id no.- 222. · ii) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 305 amino acids iS) TYPE: asaino acid

ÍC) STRANDEDNESS: single! D) TOPOLOGY: linear lx) MOLECULE TYPE: protein xi) SEQUENCE DESCRIPTION: SEQ ID ND: 222:

AU Am Cys Ser He Met He Asp Glu lie He His His Leu Lvs Arg ^{1 5 10} 15

Pso Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Am Va ’

456

Ser He Leu Men Asp Arp Asn Leu Arg Leu Pre Asn Leu Glu Se

i.v 4 C 4: 5:

Ly?

Am Leu

Glu Asn

Ala Ser Gly He Glu Ala He

Leu Arg Ass Leu Gin Pre Cys Leu Pro Ser Wing Thr Wing Wing 65 70 75

Fro Ser

Arg His Fro He

lie He Lys Ala

Tyr Leu Val Thr

Asn Met Gly Thr

145

Asp Fro Asn Ala

Val Arg Phe Leu

ISO

Phe Gly Asn Met .195

Leu Ser Lys Leu

218 .....

Gin Cys Pre Glu

225

Val Asp Phe Ser

Pro Ser Pro Pro i 7 ss

Gin Leu Pro Pro

150

He Phe Leu Ear

155 ................

Met Leu Val Gly

Ser Lys Glu Ser

140

Glu Phe Arg Glu

Gun Gau. Gm Gin

Being Gly Pro He

Hrs Lys Ser Pro

Wing Gin Asp lie

26Ό

Wing Wing Arg Gly

275

Gin Leu Ser Glv

290

Wing Be Pro Wing

200

Leu Arg Asp Ser

215

Val His Pre-Lav

230

Leu Gly Glu Trp

245

Leu Gly Ala Val

Gin Gly Arg Thr

155

Phe Gin Has Leu

170

Gly Ser Thr Leu

185

Pro Pro Wing Cys

Gin Leu Gly Pro

280

Gin Val Arg Leu

295

Mrs Val Leu His. U-ΖΌ

Pro Thr Pro Val

235

Lys Thr Gin Met

250

Thr Leu Leu Leu

265

Thr Cys Leu Ser

Thr Ala His Lys

160

Leu Arg Giy Lys

175

Cys Val Arg Glu

190

Asp Leu Arg Val

205

Be Arg Read Be

Leu Leu Gly Ala

300

Leu Lieu Pro Wing

240

Glu Glu Thr Ly _s

255

Glu Gly Val Met

270

Ser Leu Leu Gly

285

Leu Gin Ser Leu

Read

305

SEQUENCE CHARACTERISTICS · (A: LENGTH.- 305 am no acids (S 'TYPE; asrj.no acid? C) STRANDEENESS: Single (D? TOPOLOGY; linear

KOLECULE TYPE; protein (Ki J SEQUENCE DESCRIPTION; SEQ CD NO; 223:

Act Asn ς-ys ser lie Het. lie Asp Glu 11 «He His Has Leu Lys Arg * i '...... 10j5

Pro Pm Am Pro Leu Leu Asp Pro Asn Asr. Read Asn Arp Glu. AspVal

2C -................ 'PA ......................... 57 .... ...... ~ .......

Be at Leu Met Asp Arg Asm Leu. Arg Leu Pro Asn Leu Glu Ser Phe Ά “4 Q * ' ^ai Arg Aa Vat Lys Asn Leu Glu Asn Ala. Ser Gly Be Glu Ala lie 30 5: 5g.

Leu Arg Asn Leu Gin Pm Cys Leu Pro Eer Thr Wing ProSer Wing »5 70 7«, „~ '* ΛΡgo

Arg His Pro Ire He He Lys Ala Gly Asp Trp Gin Glu Phe ArgGlu

90 »c ays ve Thr Phe Tyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin QH ¹⁰⁰ 105

Tyr Val Glu Gly Gly Gly Gly Ser Pm _{sly GIu Pro Sfôr C1} * _χι ^ * 25 12C-12 A uec Thr He Asn Pro Ser Pro Pm Ser Lys Glu Ser His Lys Ser Pro ¹³⁰ 235140

Asn Met Gly Arg Thr Thr Ala His Lys Asp pro Asn Ala He p _{he Leu} ^iSC 255

Ser Phe Gin His Leu Leu At G-Xv v »'?».

^ y _S #urg Rhe Met Leu Val ^{1S &} 270

Gly Gly Ser Thr Leu Cys Val Arg Glu Phe Gly Asn Mei Ala Ee- Pm ¹⁸⁰ US190

AU Oro Pro Λ1. Cys top toe Val l « _{u s <k} :? Ftr,

458

Trp. · Lys Thr Gin Met

Va ~ Τ'Ώ.:. · Iieu Leu Leu

Cys Leu Ser

Leu Leu Leu Gly Wing

2 & 0 $ &. ??

Leu Leu Prc230

Glu Glu Thr

Glu Gly Val

Be Leu Leu

SO ueu Gar: Be

Be Glu Cys Pro

Ç

There. Vaa Asg Ph®

235

Lys Ala Gin Asp

Met Wing Wing Arg

£ 2 E

Gly Glu Leu Ser

Leu Leu Gly Thr

300

GXU. V: ®X Has Pm uex ueu Gly Gau

0

He Leu Gy Ala

Gay Gm Leu Gly

Gly Gin Val Arg 285

Gin Leu Pro Pro

f2s INFORMATION FDR SEQ ID NG: 224:

EQUENCE CHARACTERISTIC. ia:

{SB {D>

LENGTH: 305 amino acids

TYPE: amino acid STRANDEDNESS; sangle

TOPOLOGY; fling

MOLECULE TYPE:

<xi? SEQUENCE DESCRIPTION:

Asn Cys Ser He i s wing

Pro Pro Wing Pro Leu

Ser lie Leu Met Asp -¾ 8

V & .1 Arg Ala Val Lys 50

Leu Arg Asn Leu Gan

Arg His Pre Ha He

SEQ ID NO: 224

Met He Asp Glu He

Read Asp Pro Asn Asn

Arg Asn Leu Arg Leu

Asn Leu Glu Asn Ala

Pro Cys Leu Pro Ear

He Lys Ala Gly Asp rie His Has Leu Lys Arg

Read Asn Asp Glu Asp Val

..36 ...

Pm Asn Leu Glu Ser Phe

Be Gly He uiu Ala He SO

Thr Wing Wing Wing Pro Ser ^{75 75}

Trp Gin Glu Phe Arg Glu 95 *

459 it Pre Tyr Va

χ. * s'X · 'Λ «. * V * Vv’ <v .χ -v ** ‘« «·>« -ei »uaU« —η λ— a> j «r, Uiiu«:!>

To be

As to er

Ser 'n:

Asp

Rm aS:

* er i & U

Let

Tnr

Go uys

Met w «~.

Las

Read

Read

Read

9?

Cys

Sly

Aà &

Read

To be

Read

Sa

Read

Read

SIS if »

Gs. wow

Go

Phe

Arg

Allah

Go

Th «ye

Allah

Go

Led

ONLY

To be

Me

Read

INFORMATION FOR SEQ ID ND; 325:

(X) SRQUENQZ CHARACTERISTICS '.

1a; LENGTH: 305 attánís acids (H; TYPE; asaino acid (C; STRANDEDfiESS; single

CD: TOPOLOGY; linear (ii; MOLECULE TYPE: protein

Arc

Asp

Allah

Ph®

Asn

Ph®

Asp

Arg

Set

Thr

300

Ή®

Pr «:

Go Pre & ΛΜ-ν-ϊ Pre ·

Be Gly Lo

A A. ··.

-xivL-S 'ÍaX ^ ÍEí

Ala He Phe

Leu Met Leu

Met Ala Ser

196 u®u «I Arg

Glu Vai His

Ser Lau Gly Glu

240

—.—. And ueu xy — .y A. ^. A

25 ^

Gly Gin Leu Gly

Gly. k> - «<· Va.«. Arg

28S

Gin Leu Pro Pro

60

IXX? SEQUENCE DESCRIPTION: SEQ ID NO: 225:

fua A'sn uys S3- ue Met He Asp Glu He He Hus Sts Leu Lys Arc

..............: I, 171 ..........

Pro Pro Ale Pro Leu Leu Asp Pro

Ser He Leu Met Asp Arg Asm Leu

3540

Val .Arg Ala Val Lys Asn Leu Glu

50H

Leu Arg Asn Leu Gin Pro Cys Leu

657-3

Arg Hrs Pro lie He He Lys Ale

Lys La xx Phe Tyr Leu Val Thr

10c

Tyr Val Glu Gly Gly Gly Gly Ser

115120

Ser Thr He Asn Pro Ser Pro Pro

730135

Asn Met Asp Pro Asn Ala He Ph® • 745;, 5Q

Gly Lys Val Arg Phe Leu Het Leu

165

Arg Glu Phe Gly Asn Met Ala Ser

180

Arg Val Leu Ser Lys Leu Leu Arg

795

He read Ser Gin Cys Pro Glu. Val His

210215

Pre Wing Val Asp Phe Ser Leu Glv

225230

Thr Lys Ala Gin Asp He Leu Gly

245

Val Met Ala. Wing Arg Gly Gin Read at 0,,: 10 ,. " I Q........

Asn Asn Leu Ann Asp Glu Asn Val 22 30

Arg Leu Pro Asn Leu Glu Ser Phe

..... 45 ..............

Wing Wing Wing Gly He Glu Wing Wing

...... 60 .........

Pro Ser Aaa Thr Ara Axa Pro Ser

7580

Gly Asp Trp Gin Glu Phe Arg Glu 9095 'sjlu Ala Gík Glu Gin Glr.

105iic

Pro Gly Glu Pro Ser Gly Pro He

125

Ser Lys Glu Ser Hrs Lys Ser Pro

140

Leu Ser Phe Gin His Leu Leu Arg

155loc

Val Gly Gly Ser Thr Leu Cvs Val

770175

Fro Wing Pro Pro Wing Cys Asp Leu

185190

Asp Ser His Val Leu His Ser Arg

205

Pro Leu Fro Thr Pro Val Leu Leu

220

Glu Trp Lys Thr Gin Met Glu Glu 235240

Wing Val Thr Leu Leu Leu Leu Glu Gly ..... 2 SO ......... 2go

Gly Pro Thr Cys Leu Ser Ser Leu 265270

461

LSI ,. * ut; v'au Arc ueu Leu oeu Gly Ala Leu G1

Ser Leu Leu Gly Thr Gin Leu Pre- Pro · Gin Gly Arg Tnx TÁr Ala Hi 390 195 joe l / V S

305

INFORMATION FOR SEQ ID NO; 226 x ix; SEQUENCE CHARACTERISTICS;

(A? · LENGTH; 305 amine acids (S: TYPE; iffiinc acid

IC · STRANDEDNESS; single

ÍD) TOPOLOGY: linear ilii MOLECULE TYPE; protetn (Xi; SEQUENCE DESCRIPTION: SEQ ID NO; 226:

Al® Asn Cys Ser He 5 Met He Asp Glu Tie 10 lie His His uSk. Lys Arg Pr » Pro Pro Leu Read Asp Pro Asn 25 Asn Read Asn Asp Glu 30 Asp Go To be lllh ;: Read 35 Met Asp Arg Asn Read 40 Arg jUíSU Fro Asn Read 45 Glu To be Phe Saw Arg 50 Allah Val Lys Asn Read 55 SXu Asn Allah To be Gly 60 He Glu Allah Read 65 Asn Read Gin Pro 70 Cys Read Pro To be Ax & 75 Thr Allah Allah Pro To be 80 Arg Hus Pre lie He 85 lie Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 05 Glu Lys Read Thx Phe Tyr 100 Val It & v 105 Glu Gin Gin Glu HO Gin. Gin Tyr Val Glv 115 Gly Gly Gly Gly To be 120 Pro Gly ' Glu Pro To be 125 Gly Pro lift To be :: * -X-Â * S- ':: 130 He Asn Pro To be Pro 135 Pro To be Lys Glu To be 140 His Lys To be Pro Asr 145 Meg Allah lie Phe The 150 To be Phe Gin His Read 1 see Lftu Arg Gly Lys Val 160

62

Phe Leu Met i S + fiiw Gly Sly Sen * n> r «. Read 13 ^ · * Arg Gl'j Phe ciy .As r. Met Ala ÍS ^J ** Í ' Pro Wing Pm pro . . . _x , X. . Asp Lifêu Arg V ^. £ Read ISC IPS ISC To be Lys Leu Leu Asp Ser Hrs Go Read Hrs To be Arg Read To be Gin 198 200 2Q5 Cys Pro· Ole Vai -.?$ 5 «· S’ Pm Leu Pre Thr Pro Go x # me Read Pro Go" <·. *} -¾ zy 215 220 ASp PLe Being bet Gly Glu Trp Lys ’T'Ht- 0λ2α · Met Glu Glu go*. 1-. Lys Allah ν ' 230 235 240 > * V ΤφύίΆΆ'Χ ·: Asp He Leu Gly Allah Va * * Γ * ··· ~ Read Read Glu Gly Go Me τ íkÀ <Λ 245 Χύ’ν Á & á · Arc Gly Gin Read Gly Pro Thr Cys Read To be To be Read Read Giy GÃr> 280 7 £ K W W A? 4 0 Liêsu To be Gi.y Gin 'Go Arg Lt €? V iz & V Gly Allah Read Gin To be L-STd L & 'J. 275 200 285 G dy Thr GIn Leu Pro Pro Gin Gly Arg Thr Thr Axa His Lys Asp Pro 23 0 295 3Ü0

Asn

INFORMATION FOR SEQ

ND.

I Al (B;

ID *

NCR CHARACTERISTICS:

LENGTH: 309 amino acids

STRANDEDNESS: sxnglg

TOPOLOGY; ii _near prote.

(Xi5 SEQUENCE DESCRIPTION: SEQ ID ND: 227 ·.

Allah. Asn Cys To be He Met He Asp Glu He He His Mis Leu Lys Arg X 10 15 Pro Pro tt »a Pro Read Asp Pro Asn Asn Read Asn Asp Glu Asp Go 2C 25 30 To be He Read Mat Asp Arg Asn Read Arg Read Pro Ann Read Glu Ser Phe

4 _S

x.yí λϊγ, «I Giu Asn Ala Ser * 1 y x. 1 and Gx · „. Wing XÍe O «a ** Ax / χΛ,» · «eu

65 .....:

Arg His Pro He

«VS Thr Pne 100 Tyr Glu Guy To be HO He Aan Asn 145 Met Read Pro

Gly Glu Try Lys

Gl; -. Pro Cys Leu

Ise ula Lys Aia

TyrLeu Val Thr

Gly Asp Trp Gin

90 '

Leu utlu Gin Ara

Wing, ΐχέ Pro Ser

SC

Glu Phe Arg Glu §5

Gm Glu Glr; gin

Gly Allah val Thr 180 Read Gly Pro 195 Thr Val Arg 210 Lav "I Pre · ?; ç. Pro Gin Gly Read To be Phe Gin val Gly G.ty To be 250 Asn Lys ’Ro Met Read 296 Glu Allah 275 Read Val To be Arg His

3C5

Gly Gly Gly Ser

12C

Pres Ser Pro Pro

1.3 5

Thr pre Val Leu

ISO

Thr Gin Met Gig

165

Leu Leu Leu Glu

Cys Leu Ser Ser

2CD

Leu Gly Ala Leu

215

Arg Thr Thr Ala

230

His Leu Leu Arg

245

Thr Leu Cys Val

P «o.-.- a Pro Pre

280

Asp Ser His Val

295

Pro

Pro Gly Giu Pro

Be Gly Pro ’k

Ser Lys Glu Ser

146

Leu Pro Ale Val i§ <

Glu Thr Lys Ala

170

Giy Val Met Ala

185 «au Leu Gly Gin

Gin Ser Leu Leu

226

His Lys Asp pro

235

Gly Lys Val Arg

250

Arg Glu Phe Gly

265

Gy.® Wing Asp Leu

Read His Ser Arg

300

His Lys Ser Pro

Asp Phe Ser Lao

160

Gin Asp He Leu t 7 «

Arg Gly Gin Ward

190

Read Ser Gly Gin

2G5

Gly Thr Gin Leu

Asn Ala He Phe

240

Phe Leu Met Leu

25 ^

Gly Asn Gly Gly

270

Arg Val Leu Ser

285

Read Ser Gin Cys

12; INEOEMATIQN FOR SEQ X © NO: 2281 ί 1; SEQUENCE CHARACTERISTICS ·.

64

TvPCLOGY. linear di} MOLECULE TYPE; protetn

. DESCRIPTION: SEQ ID NO: 22

Set lie Met lie Asp Glu He

Pro Leu Leu Asp Pro Asn Asn

Tyr Va *. Gru

115

Ser Thr He

130

Asn Met Leu

145

Gly Glu Trp

Met Asp Arg Asn Leu Arg Leu

4G

Val Lys Asn Leu Glu Asm Ala

S; '™ | ^: gg ¥ · ................

Leu Gin Pro Cys Leu Pro Ser

7G

Xie Lie lie Lys Ala Gly Asp

90

Phe Tyr Leu Val Thr Leu Glu

100 in. «

Gly Gly Gly Gly Being Pro Gly

Gly Ala Val

Leu Gly Pro

195

Val Arg Lav · #; I · 6

Asm Pro Ser Pro Pro Ser Lys

135

Pro Thr Pro Val Leu Leu Pro

150

Lys Thr Gin Met Glu Glu Thr no

Thr Leu Leu Leu Glu Gly Val

ISO i§5

Thr Cys Leu Ser Ser Leu Leu

200 uu mu Gly Ala Leu Gin Ser

215

He His His Leu Lys Arg

Read Asn Asp Glu Asp Val

Pro Asn Leu Glu Ser Phe

Be Gly He Glu Ala Ila SO

Thr Wing Wing Wing Pro Ser 75 go

Trp Gin glu Phe Arg Glu

.................. ....................

x> ln A. * a ^ a uXu Gin Gin

............. 118

Glu Pro Ser Gly pro Xie

Glu Ser Bis Lys Ser Pro 140

Wing Val Asp Phs Ser Leu

3-55 160

Lys Ala Gin Asp He Leu

17.5

Met Wing Wing Arg Gly Gin

IPO

Gly Gin Read Ear Gly Gin

205

Leu Leu Gly The Gin Leu

228

465

Pre Pro Gin Gly Arg Thr Thr Hello FHH · s _{:: ':::} ^{......................}

Leu Ser Phe Gin His Leu Leu Arg

245

Val Gly Gly Ser Thr Leu Cys Vai

SC

Asn Met Ala Ser Pro Pro Pro Wing

375285

Lys Leu Leu Arc Asp Ser Hrs Val

290295

Pro Glu Val His Pro

05

His Lys Asp Pro Asn Ala lie Phe

23-5240

Gly Lys Vai Arg Pae Leu Met Leu

SC-Q55

Arg Glu Phe Gly Glv Asn Glv Glv 265270

Wing Cys Asp Leu Arg Val Leu Ser

285

Leu Hxs Ser Arg Leu Ser Gin cvs

306

INFORMATION FOR SEQ ID NO; 225:

• i! SEQUENCE CHARACTERISTICS;

(A; LENGTH: 309 anu.no acids (£>} TYPE.- anino acxd {C) STRANDEDNESS: single (D> TOPOLOGY: linear {ri- MOLECULE TYPE: pratein (Xi) SEQUENCE DESCRIPTION: SEQ ID NG: 229:

Allah Λ Asn Cys To be He 5 Met Xie Asp Giu He || · | lie His His Read Lys 15 Arg Pro Pro Allah Pro 20 Read Read Asp Fro Asn 25 Asn Read Asn. Asp Glu 30 Asp Val To be He 35 Met Asp Arg Asn Read 40 Arg Read Pro Asn Read 45 Giu To be Phe Val Arg 50 Allah Val Lys Asn Read 55 Glu Asn Allah To be Gly ONLY He Glu Allah He Read 85 Arg Asn Read Gin Pro 70 Cys Read Pro To be Allah 75 Thr Allah Allah Pro Ger SO Arg His Pro He He £ 5 He Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 95 Glu Lys Read Ths Phe io Tyr Read Go Thr Read 105 Glu Gin Allah Gin Glu 110 Gin Gin

466

To be

Ser His Ly.

AT-

Asr; Met Val Leu 145 Read Pro A-hiK Val Asp Phe To be 158 Leu Gly Glu Met Glu TΛ * <w. Lys Aia Gin Asp He Leu Gly Ara Val 1 έ 3 170 7 * 7 CL. Read Lr & li Leu Glu G ^ y saw Met Allah Allah Arg. Gly Gin Leu Giy Pro 180 185 190 cys Read Ser Ser Gly Gm Read To be Giy Gin Val Arg 195 200 2 Co Read Gly Wing Leu Gin To be *"I Read Gly Thr Yes Leu Pro Pro Gin <L À 0 220 Arg Thjr Thr Ala Hm Lys Asp Pro Asn Allah He Phe Leu To be Pne <sL :: 230 235 Illláz Read Leu Arg Giy Lys Val Arg Phe Read Met Leu Val Gly Gly 245 250 255 Read Cys Val .Arg Glu Phe Gly Gil ' Asn Gly Gly Ann Met Allah ISO 265 270

IA'S

Read

240

Set *

Asp

Go

Read

Be £

Let

Read

280

Lys

285

Asp

To be

His

Val

Read

To be

05

Arg wen

Gin

Cvs

300

Val

Pro

05

Read

Pro

SEQUENCE CHARACTERISTICS:

LENGTH; 3Q5 amino acxds TYPE: aaxso acid STRAHDEDMESS: single TOPOLOGY; linear (A, (D (ix

SEQ

467

Wing Asn Cys Ser He Mot H®. As Glu Ha Tl «His His Uu Lye Arg

1Λ ........ 13 ........ .H ............ sgA _s

Pre Pro Ala Pro Leu Leu Asp r x u Wing Asn Lav Asr2 * 5

Asp Glu Asp Vgl

Ss-x. Aw® úSü Met Asp- Arg Asn Lae Arg Leu Pro Asn Leu Glu Ser Phe 35 4 045

Vai Arg Ala Vai Lys Asn Leu Glu Ann Ala Ear Gly lie Glu Ale Lie ^2C 35SO

Leu Arp Asn Leu Gin Pro Cys Leu Pro Ser Thr Thr Wing Pro Fri Wing · * 7Λ _$ v. , χ? Λ ·> .C5 & V

Arg Hxs Pro lie He He Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu

Lys Leu Thr Ph® lyr Leu Vai Thr Leu Glu Gin Ala Gin Glu Gin Gin W 103lie

Tyr Vai Glu Gly Gly Gly Gly Be Pre Gly Glu pro S® ^ · Gly Pre-He

115 123ns'

Gar Thr He Asn Pre Ser Pre Pro Ser Lys Glu Ser His Lys «er Pro HO 135Kg

Asn Mat Ala Vai Asp Phe Ser Leu Gly Glu Trp Lys Thr Gin MatGlu ¹⁴⁵ Í5C .15.6iso xjIu Thr uys Ala Gin Asp He Leu Gly Ala Vai Thr Leu Leu LeuGlu

165 17017 «

CL \ - Va * Het «la Ala Arg Gly Gin Leu Gly Pro Thr Cys Leu Ser Ear HO 185 igg

Read

Read

Read

To be

Qlv

Go

Read

Read

THE

Allah

Read

cser

Le

Read

Read

Pro

Pre?

Gin

Pro

216

Arg

Thr

Wing i, ae

Phe

Read

If

Phe

233

Gl:

Read

Read

Hoop

240

Arg

Glu

Allah

Go

Arg

Pae

245

Read

Met

Lex

Go

Gly

To be

Read

Go

Phe

Gly

230

Asn

Gly

Asn

265

Me

Allah

Ear

Pro

Allah

270

Read it?

Read

To be

280

Read

Read

Asp

2SS

Pro

Hxs

Pro

Go

468 «au Hls Ser Aro Leu Ser Sin cys Pro Siu Val Hxs ^2SG 293 300

Fro Leu Pre Thr

Pro Ví. Read .l: ’ru

05 ': ...

2J INFORMATION FOR SEQ XD NO: 231;

{i; SEQUENCE CHARACTERISTICS:

IA; LENGTH; 3G8 amine, acids

CE; TYPE: amine acid

IC; STRANDEDNESS: Single Dj topology; linear '11? MOLECULE TYPE; protein ixij SEQUENCE DESCRIPTION: SEQ ID NO; 231Aia Asn cys Ser n ₈ Met He Asp Glu 11 «n _e His _Kis Leu *“ -1: 04 e

Pre Pro Wing Pre Leu Leu Asp Pro Asm Asp Leu Asn Asp Glu AspVa ²⁰ 2530

Ser Ise Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu Glu Phe 35 4-G

Val Arg Ai _{a V} & 1 Lys Asn Leu Glu Asn Ala Ser Gly U _and Glu Ala _IIe 55go

Leu Arg Asn Leu Gin Pro Cv® Leu c ^ av δ; mu * x »x„ „ ^u -> ^s ** - Q Ser Wing Thr Wing Wing Pro Ser ^w - 7C-? s <Sgo

Arg Hrs Pro He He lie Lys Ala Gly Asp Trp Gin _Giu p _h * Arg Glu ^{85 90} 35

Lys Leu The · phe lyr Leu Val Thr Leu Glu Gin Ala Gm Glu Gin Gin 290 105

13¾ Val Glu Gly Gly Gly _S ly Ser Pro Gly Glu Pro _{Ser Qlv r} ^XiS 229125

Ser Thr lie Asn. Pro Ser Pre Pro £ »* ϊν« · «

-m Glu Ser Hrs Lys Ser Rro 23u

Asn Met Asp Phe Ser Leu Gly Glu Tm ->

. _rft ^{y ixp} ^ ys ihr Gin Met Glu Glu Thr ^{âC 1SS} 160 to Al. Gin> xp n. your «y _{Ma VaJ Tte}

163 * i TA

Me;

Pro

Phe

Asp «®u

Fri

AT!

at

Arg

Read

Arg 180  * "I Gly Pro Thr Cys 185 Read To be To be ISC- Read Read Fri Giy Gin Go Art IOC Leu Leu Leu Gly Pls wow Gia Set Thr Gin Read Pro 213 Pro Gin Gly Arg Thr 2x * « Thr The Has Lys Aus lie Phe 230 Read To be Phe Gin His 235 Read Read Arg Gxy Lys 240 Read Met 24 5 Go Gly Gly Ser Thr 230 Read Cys Go Arg 253 Glu Asn 250 Gly Gly Asn Met Ala Ser Pre · 265 Allah Pro Pro 270 Allah Cvs Go Read To be Lys Read 280 Leu Arg Asp To be His 2S5 Go Read His To be Gin Cys Pre Glu Go Mis Pro Read Pro The ML. Pro Go

295

300

Pro

Allah

Go

INFORMATION FOR SEQ JQ nq _x 232:

{THE}

ÍB)

IDJ

LENGTH; 309 amine »acids

TYPE; amino acid

STRANDEDNESS: Single

TOPOLOGY; linear

MOLECULE TYPE: protein

SEQUENCE DESCRIPTION: SEQ ID NG:

Asn Wing Cys To be He 5 Met He Asp Glu He 10 lie His His Read Lys 15 Arg Pro Pro Allah Pro 20 Read Read Asp Pre 2S Asn Read Asn Asp Glu 30 Asp Go To be He Read 35 Met Asp Arg Asn Read 40 Arg Read Pro Asn Read 45 Glu To be Phe Go Arc "HERE Allah Go Lys Asn Read Glu Asn Allah To be Gly He Glu Allah He

470

Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ale Tnr Ala Ala Fro Ser tO * 7 Λ ** · *

Arg Hi 4 Pro lie Xie He Lys Ala Gly Asp Trp Gin Glu Phe Arg Gl <> S5 90

Lys Leu Thr Phe lyr Leu Val Thr Leu Glu Gin Ala Gin Glu Gin Gin X0 0 XOSt

Tyr Val Gau Gly Gly Gly Gly Ser Pro Gly Glu pre Ser Glv Pre He

Ser Thr He Asn Pro Ser Pre Pro Ser Lys Glu Sex His Lvs Ser x> r « ¹³ ₁₄₀ ” - '~

Asn Met Gly cm -p Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asp

ISO 155 me Leu Gay Ala Val Thr Leu Leu Leu Glu Gly Val Met Ala Ala Arg

ItS 170i? «;

* you

Gly Gin Leu Gly Pro Thr Uys Leu Ser Ser Leu Leu Gly G _in Leu se ~ 180 185

Gly Gin Vai Arg Leu Leu Leu Gly Ala Leu Gin Ser Leu Leu Gly Thr ^{1S £} 20C

Gin Leu Pro Pro Gin Gly Are Th »· The rm sn -« κ ^ - ₀ « ^xs pys Asp Pro Asn Ala

220

XI. Fba to sex Fhe air. His _{toB siy Va} , ^2M 235 - ₂ „

Met to Val Gly Gly Ser Thr to cys Val Ar _S Glu Fh «Gly Gly to

245 ΐίΛ * J? ** ^ ⁵⁵¹⁵

255

Sly Gly to Mt Ma Ser Fro Ma Fro Fro * 1 »Cy® Asp to te _a Val

270 to to Ly, Leu to tag Aap to Hi. Val to _Ser

2H0 285

Sin Cys Fro Siu VM His Fro to Fro ftr Fro Val to to Fro Ala

300

Val Asp Phe Ser Leu

305

(2) XmWATIGN FOR SEQ ID NO: 233:

¢ 1) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 309 artxno acids

ÍB) TYPE; amino acid íul STRAISfDEDNESE> single

Λ Ο ‘5

Irne-sr <xi · SEQUENCE OF

Ale Asn Cys Ser

SCRIFTIDN: SEQ I

He Met He Asp £ NO: 233:

Glu He He His

His Leu Lys Arg

Pre · Pro Ala Pro

Asn Asn Leu Asn

Iuδρ Ajiu asp Va <j.

Ser Π® Leu Met

Val Arg Ala Val

Leu Arg Ast; Read

Arg His Pro He

Lys Leu Thr Phe

Tyr Val Glu Gly

115

Ser Thr He Asn .130

Asn Met Gly Pro

145

Gin Val Arg Leu

Leu Pro Pro Gin

180

Phe Leu Ser Phe

195

Leu Val Gly Gly 21C

Gly Asn Met Ala

225

AjTC? AS-Γ *

4ΰ i ^ ys Α & Π GLu

Gin Pro Cys Leu lie He Lys Ala

Tyr Leu Val Thr

Gly Gly Gly Ser

120

Pro Ser Pro Pro

5

Thr Cys Leu Ser

150

Leu Leu Gly Ala

165

Gly Arg Thr Thr

Gin His Leu Leu

200

Ser Thr Leu Cys

215

Be Pro Wing Pro

3: 4 V

Arg Leu Pro Ann

Asn Ala Ser Gly

ONLY

Pro Ser Wing Thr

Sly Asp Trp Gin 90

Leu Glu Gin Wing

105

Pro Gly Glu Pro

Ser Lys Glu Ser

140

Ser Leu Leu Gly

155

Leu Gin Ser Leu

170

His Lye Asp Wing

185

Arg Gly Lys Val

Val Arg Glu Phe

220

Pro Wing Cys Asp

235

Leu Glu Ser Phs

He Glu Ala He

Wing Am Pro Ser

Glu Phe Arg Glu

Gin Glu Gin Gin

Ser Gly Pro lie 125

His Lys Ser Pro

Gin Leu Ser Gly

ISC

Leu Gly Thr-gin

175

Pro Asn Ala lie

190

Arg Phe Leu Met

205

Gly Gly Asn Gly

Leu Arg Vai Leu

240

472

If

Eer .oe

Phe

If

Lys

Gin

Asp

4-Í-Ô

Allah

Read

He

INFORMATION FOR £ EQ {A} LENGT-

STRANDEDNEES: si

TOPOLOGY; linear

MOLECULE TYPE ', protein

234;

Allah Wing cys To be He 51 Met He Asp Glu He 10 He Hrs Hrs Read Lys • t , Ax * g Pro Pro Allah Pro 20 Read Read Asp Pro Asn 25 Asn Read Asn Asp Glu 30 Asp val To be Ils ajísu %AND: Met Asp Arg Asn Read 40 Read Pro Asn Read 45 Glu To be Phe Val Arg S3 AX & Vax Lys Asn ueu Glu Asn Allah To be Gly 50 He Glu Allah Ire Read 65 Arg Asn Read <*** «.. 'uSlTí Pro Gy $; 70 Read Pro Fri Allah 7 s Thr Allah Allah Pro To be 80 Arg His Ila He 85 lie Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 95 Glu hys Read Phe IOC- Leu Val Thr Read lv5 Gru Gin Als Gin Glu *? y λ. Gin Gin Tyr val Glu 115 Gly Sly Gly Gly To be 120 Pro Gly Glu Pro Ser • α ^ άΙ w ¹ Gly Pro He

473

Ser Thr Xie Asr. Pro Se:

Asn Mot Qly Thr Gm Leu

34 * 150

Asp Pro Asn Ala He Ph®

15'5

Va „Arg Phe Leu. Met Leu

180

Pii® uly viy Asm Gly Gly

.........................

Asp Lifei Arg Va χ Leu Ser aer Arg Leu Ser Gin Cys ²²⁵ 230

Leu Leu Pro Ala Vai Asp

245

Glu Glu Thr Ly® Ala Gin

280

Gru Gly Val Met Ala Ala

7 ^C

Ser Leu Leu Gly Gin Leu 290

Lav Gin Ser Leu Leu

0 5

Pik. ' To Gar ^ ys Gau. Ser Hrs Lys Ser Pr ·: Ú3Ô

Pro Pro Gin Gly Arg Thr Tnr Wing EraLys ~ ^S “ ^! IS;

Lav Ser Phe oln Has Leu Leu ArgLv *

170my

Val Gly Gly Thr Leu Cys Val Arc Glu ISoISO

Asn Met Ala Ser Pro Ala Pro Pro Ala Cvs 200205

Lys Leu Leu Arg Asp Ser His Val Leu Has ^ • 5220

Pro Gau Val His Pro Leu Pro Thr Pro Val

Hu

Phe Ser Leu Gly Glu Trp Lys Thr Gin Mar 250

Asp H® Leu Gly Ala Val Thr Leu Leu Leu ....... 265270

Arg Gly Gm Leu Gly Pro Thr Cys Leu Ser 280285Ser Gly Gin Val Arg Leu Leu Leu Gly Ala ^2S5 300 <2; INFORMATION FOR SEQ ID NO; 235;

d; SEQUENCE CHARACTERISTICS:

{A} LENGTH; 309 amino acids (B.! TYPE; amino acid (C) STRANDEDNESS; single (D) TOPOLOGY: linear di! MOLECULE TYPE; protein (Xi; SEQUENCE DESCRIPTION; SEQ ID NO; 235u «ten Cys S« r 11 «Met _{: 11} * « _{p elu Ile Ile Bis} ⁵ 10 ·> e

4’’4 fro> ~ r. Wing Pro Leu Leu

At:

Asp Gi

Nst Àup Arg

Ase Leu Arg Leu Pro Asr Leu Glu p® 4C 45

Go Arg Ala Val Lys Asn Leu

55

Glu Asn Ala

Ser Gly He ksUt

II®

Read ueu

Pro

Allah

Thr

Allah

Arg hxs Pro He He Ha

k.ys

Allah

Asg gn

Trp

Phe Arg Glu

Lys Leu Thr Pne Tyr Leu Val

108

Tyr V & l Glu Gly Gly Gly Glv

Thr Leu Glu Gin Ala Gin Glu Gin Qir a η, _A „

Being Pro Gly Glu for Being Gly Pre He

120 ........ 125 ..........

Ser Thr Xle Asr. Pro Ser Pro Pro 12 0 735

Asn Met Gly Arg Thr Thr Ala Hus 1 * 2 150

Ser Phe Gin Mis Leu Leu Arg Gly

Ser uys Glu Ser His Lys Ser Pro

140

Lys Asp Pro Asn Ala Ile Phe Leu ⁱ⁵ 5 ~ isc

Lys Val Arg Phe Leu Met Leu Val

170

Gly Gly Ser Thr Leu Ca

0 ϊϋ r -í hex. Wing Pro Wing Wing Pro

195

Leu Leu Arg Asp Ser Ris 2X0 iu Val His Pro Leu Pro ²⁵ 230

Ser Leu Gly Glu Trp Lys

245

He Leu Giy Ala Val Thr

260

Gly Gin Leu Gly Pro Thr

275

G * y Gin Vau Arg Leu Leu

290

Val Arg Glu Phe Gly

185

Pro Wing Cys Asp Leu

200

Ford Leu Bis Ser Arq

215

Thr Pro Val Leu. Read

235

Thr Gin Mag Glu Glu

250

Leu Leu Leu Glu Gly

265

Cys Leu Ser Ser Leu

280

Leu Gly Ala Leu Gin

295

Gly Asn Gly Gly Asn

0

Arg Vau Leu Ser Lys 205

Read Ser Gin Cys Pro

220

Pro Wing Val Asp Phe

240

Thr Lys Ala Gin Asn

255

Go Met Ala Ala Arg

270

Leu Gly Gin Leu Ser

285

Ser Leu Leu Gly Thr

300

SEQUENCE CHARACTERISTICS;

(A; LENGTH; 3 08 «» flC atxds iB; TYPE; amine acid

C> STRANDEDNESS. ’Single

ID; TOPOLOGY. · Ixnear

MOLECULE TYPE; protein

Xi) SEQUENCE DESCRIPTION; SEQ XL NO. 23 £ Wing Asn Cys Ser lie

Met lie Asp Glu lie He

Has Hrs Leu Lys Arg

Pro r’m Ata Pro Leu. ::: 2: 6: ......

Ser He Leu Met Asp

Vai Arg Ax Vai Lya SC

Leu Arg Asn Leu Gin

Arg His pro, H © xíj »

Lys «I Thr Phe Tyr

108

Tyr Vai Glu Gly Gly

Ser Thr Ila Asa Pro

130

Asn Met Ala His Lvs

145

Leu Leu Arg Gly Lys

155

Leu Cys Va.1 Arg Glu

ISO

Arg Asn. Leu Arg Leu Pro

4C ·

Asn Leu Glu Asn. Ala Ser s: sj: g ::: 2

Pro Cys Leu Pro Ser Ala

He Lys Ala Gly Asp Trp .90 *

Leu Vai Thr Leu Glu Gin

105

Gly Gly Ser Pre Gly Glu

120

Be Fro Pro Sex Lys Glu. 135

Asp Pm Asp Ala lie Phe ^1S0 155 »ax Arg Phe Leu Met Leu

170

Phe Gly Gly Asn Gly dy

185

Leu Asp Pro Asn Asn Leu

Asn Asp Glu Asp Vai

Asn Leu Glu Sei phe

45 .............

Gly He Glu Ala He SO

Thr Ala Ala Pro Ser

Gin Glu Phe Arg Glu

ACPC ^::: 1 ^:::: C ............ 7 ^:: 1 ........ ί | §§ · '| ·: · 7' .... .........

Wing Gin Glu Gin Gin

110

Pre Ser Gly pre · He

Being His Lys s _er p _ro

140

Read Ser Phe Gin His

160

Go Gly Gly Thr

175

Asn Het A.xa Ser Pro

190

476

ΛΑά rxo 'ίτε Ai # Cys Asp Lew Arg

Val Leu Ser Lys Leu Leu Arg Asp

Γ-er Hus - = 1 Lag hls Ser Arg Leu

Leu Pre Thr Pro Val Lev Leu Pro 22? 23 C

Trp .Lys Thr Gin Met Glv Glu Thr

245

Val Thr Leu Leu Leu Gig Giy Val

6 C

Pro Thr Cys Leu Ser Ser Leu Leu · * '<- .2SO

Lev Leu Leu G.i.y Alu Leu Gin Ser

290 2 ^ 5

Gin Gly Arg Thr Thr

305 i2> INFORMATION FOR SEQ r © NO; 237;

(i? SEQUENCE CHARACTERISTICS: (A? LENGTH: 30§ amino acids ΐΒ> TYPE; amino acid (C; STRANDEDNESS; single

ÍD} TOPOLOGY; linear sii; MOLECULE TYPE; protein

Wing Val Asp Phe Ser Leu Git ¹ · Glu

335240 «ys ..ala osm Asp Lie Leu Glv Ala

250255

Met Wing Wing Arg Gly Qin Leu Gly

265270

Gm «I am Gly Gm Val Arg

285

Leu Leu Gly Thr Gin Leu Pro Pro

300

5Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 237;

φ Ala Asn Cys Ser lie Met He Asp Glu lie He His His Leu Lys Arg ~ 102A

Pro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Am Glu Asp Val ^{50 2S} 30 ^{Ser Met} keu Arg Leu Pro Asn Leu Glu Ser Phe

Val Arg Ala Val Lys Asn Leu Glu Asn Ala Ser Gly He _{SXu A} la _Xle

55s «so Arg Asn Leu Gin. Pro Cys Leu Pro Ser Thr Thr Wing Pre Wing of ⁷⁰ scT

Glu Phe

7, d ί

Hi

Let

Ger it

If.

t> r

Fri

Sa: 1 <SY.

Me

Asp

Lex:

If:

Phe

Ph® íz3? H

Me ”« ®X1

Put

As ” ⁴

Met

Allah

To be

X9C

Cvs

Read «V®

Read

Arg

To be

If.

wow

Cys

Go

Hie

Pro

Read »

Thr ueu

There

Go.

Asp

Phe

Only

Read

Guy

Thr

240

Gin

Lex

Gly

Allah

Go naked

Allah

Met

Guy

Gin

UHE

Thr

2δ

Leu Ser To be 275 Read Read Gly Gin Read S & x Giy G-XH Val Arg 285 Read L®u. Lsu Gly Ala 29G Lsu Gin To be 295 Gly Gin Leu Pro 300 Pro Gin Gly Arg

Ala (2) INFORMATION FOR SEQ XL NO; 238;

(i) SEQUENCE CHARACTERISTICS;

iA; LENGTH; 308 sign acids

IT; TYPE; amts acid {0; STRANDEDNESS: single CD? TOPOLOGY: linear ’ill; MOLECTLE TYPE: protein

478

Asn ae:

lie Met

Met Asp

Arc lie ASF

Ast

Leu wSk

Asn Ale

His

Asn

Asn

Gly

Let

Asp

He

Au. The

Vahe

Leu »®r

Allah

Thr:

Allah

Allah

Pro

To be

Lys

Read

Phe

Ger

Go

Gru

Thr

Asn

-ie

Phe

Met

Arc

Read

210

Ann

Val

ÀzfôU.

aer

Gin

Val

Lys

Ala iae

Lys

Gly

Asp

Glu

Phe

Arg

Phe «me

165 • be

Asp

24t

Read

Read

ISO

Val

Lys

Pro

Ph *

230

Asp

Val

Gly

Pro

135

To be

Met

Read

T * p% V «me

105

Gin

Allah

Gin

Glu

Sa.

Pro

Ph®

Giy

200

Val

Read

Read

To be

To be

To be

Gly

Glu

To be

125

Gly

He

Lys aer

140

Lys

To be

His

155

Read

Val

160

Thr

Read

Cys

Val

Arg

Glu

Phe

Pro

Asp

Pro

Allah

2S0

If.

Read

Val

His

Val

205

Pro

Lys

Th:

Th

Let

Ax a

193

Asp

His

If :;

Pro

Val

Read

Gin

Read

Me

240

Read

1®

Ly

INFOHMA

To be

N:

479 íA LENGTH: 302 SEi & C acids {B} TYPE: amino acic (C · STRANDEDNESS: single (E; TOPOLOGY, · linear

Pr mu

Aua

MOLECULE TYPE: protein

AT THE:

239:

SEQUENCE DESCRIPTION: SEQ IE

Allah >> X · >> Asn cys To be He 5 Mat He Asp Glu He He His His Read Pro Pro Wing PX‘Q Read La> _ Asp Pro Asn 25 Asn Read Asn Asp Glu 30 Fri lX <s Leu 35 Met .Asp Arg Asn Read 40 Arg wow Pro Asn Read 45 Glu Val Arg Al® 50 Val Lys Asn Xa> ^ $> A $ 5 Glu Asn Allah To be Gly ONLY He Glu Read Arp Asn Read Gin Pro 70 Cys Read Pro To be Wing *? Thr Al® Allah Arg His Pro He He 85 He Lys Allah Gly Asp PRAÇA Trp Gin GsiU Phe Lys Leu Thr Phe ISO Tyr Read Val Thr Lav 105 Glu Gin AsAkál Gin Glu W Tyr Val Glu MS Gly Sly Gly Gly To be 120 Pro Gly GIl. Pro To be 125 Gly To be Thr Xie Asn Pre To be Pro Pro To be Lys Glu To be His Lys

To be

Arg

To be

140

Arg

Val

Phe

To be

ONLY

Gin

80

Asn Sfe :; Asp λ <Λ * ^: Pre Aar; He Phe Ward: L> yx ^: Go. Arg Phe Leu Met Leu

Arg Q_.u Phe Gly Gly Asn Met: Ala 18 ·;

Ser Phe Gin Hie Lee Leu Arg

15 5 150 Go Gly Gly Be Thr Read Cys Vai 170 •: »iL '· I'« 5 Be Pre Pre Wing ·· Allah. Oys Asp 185 on.

Read Arg Go 195 To be Lys Read 280 sArp Lau To be Cys Pre· Qx v Go Let ·· pry Allah Go Asg Phe 23 0 To be Read Glu The Lys Allah Gin 245 Asp lie Read Gly Go Met TO 1& 280 Minutes Arg Gly Gin Read Read .χϊ 1 y 275 Gin Read To be Gly Gin Rar 298 Read Read Qly Thr Gin EPS Gly

Arg Asp Ser Hrs Vai Leu Has Sex

£ 2V _:

His Pro Leu Pro Thr Pro Vai Leu

Gly Glu Trp Lys Thr Gin Met Glu

335240

Ut «y ^ -x.a Vax. Thr Leu Leu Leu Glu

2582 § 5

Leu Gly Pro Thr Cys Leu Ser Ser

255 ->? R

V & j. Arg Leu Leu Leu Gly Ala Leu

85

Arg Thr T.hr Ala His Lys

300

Í2 í INFORMATION FOR seq _{is w} . 240:

ili SEQUENCE CHARACTERISTICS:

£ A; LENGTH: §1 Hase pairs

E) TYPE; nucleic acid (Ci SWtfJDEmESS: single (D) TOPOLOCT:

vii: MO ^ SCUuE TYPE; ether nucleic acid <Ai DESCRIPTION: Zdes * ® * DNA (synthetic) 'ixi) SEQUENCE DESCRIPTION; REQ ID NO: 240:

TTu-LTCG, AAAv «GAC- ttctatgtga aaaccttgga gaacgcgcag gctcaacagt

ACGTAQAGGG CGGTGGAGGC T ^ · (2) INFORMATION FOR SEQ NO: 241

481 ('ll' 'DRARACTCTÍST ~ 23;

(A: LENGTH- Si nase parrs

ÍB} TYPE: nuclerc sere (C; STRANDEDNESS; single

CD: TOPOLOGY-, linear iix: MOLECULE TYPE: other nucleic acid (A? DESCRIPTION; / dasc «* DNA (synthetic;

(Xi; SEQUENCE DESCRIPTION; SEQ ID «> Π

CGGGGAGCC TCCACCGCCC TCTACGTACT GTTGAGCCTG CGCGTTCTCC AAGTTTTCAG

ATAGAAGGTO AGTTTACGAC GG (2: · INFORMATION FOR SEQ ID NO; 142;

{i i SEQUENCE CHARACTERISTICS; (A, i LENGTH: 8 amino acids ÍB) TYPE; ajainc acid (C) STRA1WEDNESS .: single (D) TOPOLOGY-, linear (ii; MOLECULE TYPE; prqaeir.

(Xi; SEQUENCE DESCRIPTION; SEQ ID NO; 242;

Giy uly Gly Ear Gly Gly Gly Ger

5 (2; INFORMATION FQR .SEQ ID NO: 243;

(i) SEQUENCE CHARACTERISTICS;

(A) LENGTH: 12 anino acids {E; TYPE; amino acid (C; STRANDEDNESS; single (DI TOPOLOGY: linear '(ii) MOLECULE TYPE; protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 243;

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

482

INFORMATION _{F0 ?;} - _r , _KC; .

ii; SEQUENCE CHARACTERISTICS:

(A) LENGTH; ? wno © cads (B) TYPE; anu.no acid

ÍU; STRANDEDNES'S; single {R; TOPOLOGY ': linear (ii? MOLECULE TYPE; prctsit ixi) SEQUENCE DESCRIPTION; SEQ jq NO; 244-.

Ser Gly Gly ger Gly Gly S®r (2 / INFORMATION FOR SEQ ID ND: 245. ·.

(ij SEQUENCE CHARACTERISTICS; (Rs LENGTH: £ attino acids (B) TYPE: amino acid (C) STRANDEDNESS; single ÍD} TOPOLOGY; linear (xâ.> MuL & CULE TYPE: protein

(XXX) SEQUENCE DESCRIPTION: EEQ ID NO: 245 ·;

Glu Phe Gly Asn Met Ala (2.J INFORMATION FOR SEQ ID NO; 246:

ii) SEQUENCE CHARACTERISTICS:

(A) LENGTH; 7 amxnu acids (B) TYPE: amino acid (C) STRANDEDNESS: single (0} TOPOLOGY; linear! Ii) MOLECULE TYPE; protein iXl) SEQUENCE DESCRIPTION; SEQ ID NO; 246;

Glu Phe Gly Gly Asn Asn Ala: nforma

LENGTH; 10 arunc acid TYPE. amino actd STRANDEDNESS: single topology:: linear (xi? SEQUENCE DESCRIPTION

Asn Gly Gly Asr. Met.

Allah

INFORMATION FOR SEQ ID ND: 248;

SEQUENCE CHARACTER! STX (A;

(B?

LENGTH: 30 $ amino ac

TYPE: amino acid £: single ineax

TDPDLCC

MOLECULE TYPE: protein ids

SEQ W NO:

245:

AaS Asn Cys Ser He 5 Met He Glu He 10 Xie His His Read Lys Arg Pro Pro Pro Wing and the Read Asp P ^ ÍJ Asn Asn Read Asn Asp Glu Asp Val uw 25 30 To be He Leu Met .35 Asp Arg Asn 40 Arg Read Pro Asn Read 45 Glu To be Phe Go Arg Val Wing Lys Asn Read Glu Asn Allah To be Gly 11 « Glu Allah Xie sC 55 50 Read 65 Arg Asn Leu Gin Pro 70 Cys Pro To be Wing *? The; Thr Allah Minutes Pro To be 80 Arg His Pro He He 85 Read Lys Allah Gly Asp 90 Trp Gin Glu Phe Arg 95 Glu Lys Read Thr Phe Tyr Read Val Read Glu Gin Allah Gin Glu Gin Gin

484

Gly Ser Pro Gly

Pro Ser Gly p _rc χχ

Ser Thr Ila Asm Pro Ser Pr »Pro Ser Lys Glu Ser Hi ^{13 C} 13 £ _X4C

Asm Meo Leu Pro

Thr Pro Val Leu

Gly Glu Trp Lys

Gly Ala Val Thr

Thr Gin Met Glu

165

Leu Leu Lao Glu

Leu Pro Ala Val

138

Glu Thr Lys Ala

Asp Pne Ser Let

Asn Asp He Leu

Leu Gly Pro Thr .195

Val Arg Leu Leu

........ Ill | l ........ ^a

Pro Pro Gin Glv

225

Leu Ser Ph® Gin

Val Gly Gly £ _er

260

Asn Meo. Ala Ser

Cys ueu Ser aer

200

Leu Gly Ala Leu

215

Arg Thr Thr Ala

230

Mos Leu Leu Arg

245

Thr Leu Cys Val

Gly Val Met. Allah

185

Leu Leu Gly Gin

Wing Arg Gly uys Leu leu Lys

290

Fro Ala Pro Pro

280

Asp Ser His Val

255

Gin Ser Leu Leu

220

Hrs Lys Asp Pro

...... 235 .........

Gly Lys Val Arg

250

Arg Glu Phe Gly

265

Wing Ser Asp Leu

Leu Ser Glu Gin

205

Gly Thr Qin Leu

Read His Ser Arg

300

Asn Ala Ixe Phe

240

Ph® Leu Het Leu

255

Gly Asn Gly Gly

270

Arg Var Leu. To be

285

Read Ser Gin Cys

Pro Glu Val His Pro · *? V V »

U) XfcrDRMATXON FOR SEQ ID NO: 249-.

ii? SEQUENCE CHARACTERISTICS:

(A) LENGTH: 458 base pairs (B) TYPE: nucleic acid (C) GTRANDEXWSS: single

ID) TOPOLOGY ·: linear

i. *, · MOLECULE TYPE: ocher nuclei c acid (A; DESCRIPTION: / òesc »DNA (synthetic

4SS iXl; SEQUENCE DESCRIPTION. SEQ “I NO: 24 9:

GTCCTTCACA GCAGÀCTGAG CCAGTGCCCA. GAQGTTCACC CTTIOCCTA ^ '

CTGCCTGCTG TGGACTTTAG CTTGGGAGAA

18C

CAGQACATTC TGGSAGCAST GACCCTTCTG

240

CTGGGACCCA CTTGCCTCTC HTHC ^ C ' ¹ ''* ?! · 3C0

CTTGGGGCCC TGCASAGCCT CCTTGGAACC

360

CACAAGGATC CCARTS SCAT CTTCCTGAGC

420

TTCCTGATGC TTGTAGGAGG GTCCACCCTQ

459 iG ^ «AAAuCC AGATGGAGGA GACCAAGGCA u.iG \» Asjx3 <aAG TGAIUGCAGC ACGGGGACAA GGGQAGCTTT CTGGACAGGT CCGTCTCCTC CAGCTTCCTC CACAGGGCAG GACCACAGGG TAGCAGC

Í2- INFORMATION FOR SEQ ID NO; 250:

Í1? SEQUENCE CHARACTERISTICS:

v. LENGTH; 447 has® paxr®

ÍE} TYPE; nucleic aois (C) STRANDEDNESS ·. single (D) TOPOLOGY; linear wm; MOLEC1AE TYPE; ether nucleic acid (A? u? £ SCR »PTIOK; / desc» ’DNA {synthetic}

SEQUENCE DESCRIPTION: SEQ ID NO; 250;

TuTuCCGCTC CGCCTGCTTG TGACCTCCGA QTCCTCAGTA. AACTGCTTCG TGACTCCCAT

CTCCTTCACA GCAGACTGAG CCACTQCQCA GAGGTTCACC CTTTGCCTAC ÀCCTGTCCTG Á. J & - U

ΙβΓ ”^ '” CTTSGSAGfiA * ^ SGMAACCC: ASATGGAÜOA GACCAAGGCA

CASGACAMC tGSGAKAST CWCCCTTOT, CTOGAOms TCATOSCAGC ATOSSGAC »

81

CTGGGACCCR CTTGCCTCTC ATCCCTCCTG GGQCAGCTTT CTGGACAGGT v; ....... C.Tjjww-v '. Tw.ÀwAuCOT CCTTGGAACC CAGGGCAGGA CCACAGCTC ¹ · CAAG ”

360 “'“ * “^ ·

AATGCCATCT TCCTGAGCTT CCAACACCTG CTCCGAGGAA AGGTGCGTTT CCWG '’’'

420

GTAGGAGGGT CCACCCTCTG CGTCAGG • 2? : mromiATrok = foe sec io no; 2si?

Í1> SEQUENCE CHARACTERISTICS:

(A} LENGTH: 45 $ base pairs (3) TYPE; nucleic acid (C; STRANDEDNESS: single

:to 1; KOuECCLi TYPE; other nucleic acid

IA; DESCRIPTION; / desc ® “DNA (synthetic)“ (xii SEQUENCE DESCRIPTION: SEQ ID NO: 251;

TCCCCAGCGC CGCCTGCTTG TQACCTCCCA

GTCCTTCACA GCAGACTGAG CCAGTGCCCA

120

CTGCCTGCTG TGGACTTTAG CTTGGQAQAA 18G

CAGGACATTC TGGGAGCAGT GACCCTTCTG

240

CTGGGACCCA CTTGCCTCTC ATCCCT ^ CTG 3GC

CTTQQGQCCC TGCAGAGCCT CCTTGGAA ^ C

360

CACAAGGATC CCAATGCCRT CTTCCTGAGÇ

420

GTCCTCAGTA AACTGCTTCG TGACTCCCAT

GAGGTTCACC CdTGCCTAC ACCTQTCCTG

TGGAAAACCC AGATGGAGGA GACCAAGGCA

CTQGAGGGAG TGATGGCAGC ACGGGGACAA & AAAJSCTTT CTGGACAGGT CCGTCTCTTG CaGCTTuCTC CACAGGGCAG GACCACAGCT TTCvAAuAtC TGCTCCGAGG ÀAAGGTGCGT

TTCCTGATGC TTGTAGGAGG GTCCACC »* ^

45.S

TGCCTCAGG; 2) INFORMATION FOR SEQ ID NO; 2H246 7 ii. · Sequence iA; LENGTH; 2.-3 amino acids; is; TEPE: amnc aciu (C? STRANDEDNESS ·. Single> D; TOPOLOGY; linear ill; MOLECULE TYPE; proteir.

(XX! SEQUENCE DESCRIPTION ·, SEQ ED NO; 252:

Be Pro Wing Pro

Arg Asp Ser Hrs <* t 0

His Pro Let; Pre 35

Gly Glu Trp Lys

Gly Ala Vai Thr g 5

Leu Gly Pro Thr

Go Arg Leu Leu IOC

Pro Pro Gin Gly

Read Ser Phe Gin

Pro Wing Cys Asp

Val Leu His Ser

Thr Pro Val Leu

Thr Gin Met Glu «I« I «I Gru

Cys Leu Ser Ser

Leu Gly Ala Leu

Arg Thr Thr Ala

120

Hrs Leu Leu Arp

135

Leu Arg Val Let;

arg «I Be dn

Leu Pro Ala Val

Glu The Lys Ala

Gly Val Met. Allah

Leu Leu Gly Gin ...... 90

Gin Ser Leu Leu

105

His Lys Asp Pro

Gly Lys Val Arg

140

Ser Lys Leu Leu

Cys Pro Glu Val

Asp Pne Ser Leu

Gin Asp II® « _eu

Arg Gly Gin Ward

Read Ser Gly Qin $ 5

Gly Thr Qin Leu

Asn Ala Tie phe

125

Phe Leu Met Leu

Val Gly Gly ger Thr

145

Leu Cys Val Arg

ISO (2) INFORMATION FOR SEQ ID NO: .353;

i i; SEQUENCE CHARACTERISTICS; (A; LENGTH: 149 amino acids ÍB} TYPE; amino acid <CJ STRANDEDNESS: single (D; TOPOLOGY: linear (ii; MOLECULE TYPE: protel

4B8

Ser Pi '; - Wing

Pro Pro Ala Cys Asp .Leu Arg Vai

Leu Ser Lys Leu Leu

Arg Asp Ser Ms Vai

Leu Ha s.

To be

Read

Glu

H * s .ro Leu Pro Thr Pro Vai Leu Leu Pro Ala VM Asp Phe Ser Lev <045 _ui y «it Trp Lys Thr Gin Met Glu Glu Thr Lys Ala Gin Asr- He Lesv 55

Gly Ala VM Thr Leu Leu Leu Glu Gly Vai Met Ala Ala Arg Gly _Gln ⁷⁵ SC

Gly Pro tte Cys L «u _{Ser s <r ely G. R ser} ^Ss sc ^Leu ** eu Gin Ser Leu Leu Gly Thr Gl- q-> _v

IOC _{10 £} - _u „~ ->

«Rg Thr Thr Ala His Lys Asp Pro Asn Ala Xle Phe Leu Ser Phe Gin« me «me Arg Gxy Lys Vai Arg Phe Leu Met Leu Vai Glv g ^ 'g®

Thr Leu C'ys Vai Arg

145

ÍH INFORMATION FOB SEQ XL NO; 254:

U) SEQUENCE CHARACTERISTICS;

ÊA3 LENGTH; 153 amino acids ÍB? TYPE; asnmo acid (CS STRANDEDNESS; single ί> TOPDLDGy; 1 inear iiii MOLECULE TYPE: protein (xi) SEQUENCE INSCRIPTION; SEQ ID NG; 254;

Sa

Pro Al® Pro Pro Ai _{a C} ys Asp Leu Arg Vai

.......... ft.

Leu Ser

Lys Leu

15 ...

«<Me

Arg Asp Ser Hia Vai Leu H

Ser Arg Leu Ser Gin Cys

Mo Glu Vai

489

Hit Pro Leu Pro Thr Pro Val Leu

Phe

4.3

Gly Glu Trp Lys Thr Gin Met Glu

Lys

Αλ £

Asn le Leu

Thr Leu Leu Leu Glu

Allah

Aua

Lex:

SiPhe

Val and t

Lex

To be

Read

Gin

Read

If;

Lex?

Thr Cys Leu Ser Ser 6 5 &> i Leu Gly Ala Leu

IOC u »ly Arg Thr Thr Ala Hrs Lys Asp Pro Asn Ala 11« Phe 120 125

Gin Hrs Leu Leu Arg Gly Lye Val Arg Phe Leu Met Leu 13S 14Q

Ser Thr Leu Cys Val Arg

150 ...................

i'l .; INFORMATION FUR SEQ ID NO: 283.> i? SEQUENCE CHARACTERISTICS:

{A) LENGTH c 64 base pairs (S) TOE: nucleic acid (C) STRANDEDNEES: single (D? TOPOLOGY: linear; i _.; MOLECULE TYPE: other nuclexc acid (A) DESCRIPTION: / dese ® “DNA {synthetic * *

ÍXt) SEQUENCE DESCRIPTION; SEQ ID NO: 255:

GGATCCÀCCÀ TGAGCCGCCT GCCOG ^ CC ^ G ~ wv «A» .u..w UvshXLvw ^ ACTCCTGGT CCGCCCCGCi

ATGG (2? INFORMATION FOR SEQ ID NO; 25 S _: ii) SEQUENCE CHARACTERISTICS: ί & Σ LENGTH; 153 amine acids ÍB) TYPE: «mino acid {C) ETRANDEDNES $, · unhnown

490 iix) FEATURE:

»As NAME / KEY: Modified-site (Si LOCATION: 112

₅ OTHER INFORMATION / note »« position 112 is delete

Axa.VA—. u _rs: Pre. Phe, Tm o— Me— (xxl FEATURE · (A? NAME / KEY: Mt> dirisd ~ si te (B? LOCATION ;. 113

OTHER

Pre

INFORMATION:

, Phe. Allah..

mute »’ posmom 113 is deleted or

Vat, read. He. Trp or Met *; ix.i FEATURE;

(A) NAME / KEY; Modified-si us (Si LOCATION; 114

IB) OMSK IWoraATXON./to^. • ixwiUen 114 _{ia eelettó} „

Phe4 M.ta, Vat, Lau> lie. Trp or Met ’(XX) FEATURE ;.

(A) NAME / KEY; Modxfied-sxt® (Bi LOCATION: 115 iL; OTHER INFORMATION; / note = “positop 115 is deleted cr

Gin, Gly, Ser, Thr, Tyx _f or Asm '(xi! SEQUENCE DESCRIPTION: SEQ ID NO: 256:

Be Pro Wing Pro Ara Cys Asp Leu Arg xo Val Read To be Lys Read 15 . Read Arg Asp Ser His 20 Val Read His Ser Arg Read To be Gin Cys Fro V Val 3C Hus Pro Leu 3 5 Pro Tin Pre Val 40 Pro Allah Val Asp 45 Phe Eer Read Gly Glu Trp 50 Lys Thr Gin Mat 55 \ 3 «A.xí> ΤαχΓ Lys Allah 60 Gin Asp lie Gly Ala Val 65 .. · μΆ ·. . Read Read Read L.JL: ^ T Val Met 75 Allah Allah Arg Gly Glh 80 Leu Gly Pro : <ψ eew- :: Cys 85 Read To be Be Leu Read 90 Gly Gin Read To be Gly 95 Gin Val Arg Leu Read 100 "I Gly Allah jw> me Oxxi 105 To be Read Read Gly Thr no Gin Xaa Xaa Has Xaa Gly Arg Thr Tjfir Allah Lys Asp Pro Ann Allah X ^: '-L ^: ii e Phe

91 already. j-’n-s Gii, His Leu Are Qty Lys Vai “Γ Phe Iox Me · Le .1.3; · ..

w · »v, λ ** <: v

Go Gly uly & er Thr Leu Cys Val Arg

-4S iso

INFORMATION FOR SCO ID NO; 257;

ii SEQUENCE CHARACTERISTICS;

ia) LENGTH; 454 hs.St hovers; S ·; TYPE. · Nucleic acjc (¢, - STRANDEDNESS; Single (0? TOPOLOGY ·, linear in, MOmEuJLE TYPE; ether nucleic acid <: A; DESCRIPTION.- / desc - · »(synthetic) 'ixi; SEQUENCE DESCRIPTION: SEQ ID NO; 257;

CCATGGCTAA CTGCTCTATA ATGATCGATG AAATTATACA TCACTTAAAG AGACCACCTG ^ uA AACCTCAATG ACGAAGACGT CTCTATCCTG CTTTGCT LGACCCGAAC the ATGGATCGAA '.,. I.UA, J ^ AAAuCTG GA5AGCTTCG TAAGGGCTGT CAAGAACTTA gaaaatgcat CAGGTATTGA GGCAATTCTT CGTAATCTOC AACGATGTCT GCCCTGTGCC the ACGGCCGCAC> $ 4 · V ^^ κ.0Α. "Α TCCAATQATC ATCAAGGCAG GTGACTGGCA AGÀATTCCGG GAAAAACTGA Um-v ^ As. GGTTACCCTT GAGCAAGCGC AGGAACAACA. GTACGTAGAG GGCGGTGGAG QCTCCCCGGG TGAACCGTCT GGTCCAATCT CTACTATOAA GCCGTCTCCT CCGTCTAAAG

AATCTCAT / sA ATGTCCAAAC ATGTAAGGTA CCGCATGCAA GCT ^

464 .............................................. * (2 ) INFORMATION FOR SEQ ID NO; 258;

ii; SEQUENCE CHARACTERISTICS;

(A) LENGTH: 419 base pairs (E) TYPE; nucleic acid (C; STRANDEDNESSrsingle

492 fD. TOPOLOGY: Linear ill; MOLECULE TYPE; other nucaexc acid {A-v ~ ECFIFTION, / dese = DNA {synthetic: 'ixi) SEQUENCE DESCRIPTION; SEQ ID NO: OSS;

CCATGGCTAA CTGCTCTATA ATGATCGATG

.................................................. .....................................

CACCTTTGCT GGACCCGAAQ AACCTCAATG

ACCTTCGACT TOCAAACCTG GAGAGCTTCC ·

ISO

CAGGTATTGA GGCAATTCTT CGTAATCTCC

24C

CCTCTCGACÀ TCCAATCATC ATCAAfflSCAG

300

COTTOTATOT GGTTACCCTT QAGQAAGCGC

360

GCTCGCCGGG TGGTGGTTCT GGCGGCGGCT

419

AAATTATACA TCACTTAAAG AGACCACCTG

ACGAAGACGT CTCTATCCTG ATGGATCGAA

TAAGGGCTGT CAA.GAACTTA GAAAATGGAT

AACCATGTCT GCCCTCTGCC ACGGCCGCAC

GTGACTGGCA AGAATTCCGG GAAAAACTGA

AGGAACAACA GTACTTAGAG GGCGGTGGAG

CCAAUATGTA AGGTACCGCA TGCAAGCTT

Claims (41)

1. Hematopoietic protein comprising; an amino acid sequence of the formula: RuL: “R _2> Ra-Li-Rt R-Ri ·. OR Rz-Rt 5 where R ₅ and Ra are independently selected from the group consisting of: (I) a polypeptide comprising; a sequence of modified human G-CSF amino acids of the formula. Xaa Xaa Xaa Gly Pro Allah To be To be Read 10 Fro Gin To be Xaa Read Read Xaa Xaa Xaa Glu 20 Gin Val Xaa Lys Xaa Gin Gly Xaa Gly Allah 30 Xaa Read Gin Glu Xaa Read Xaa Allah Thr Tyx 40 Lys Read Xaa Xaa Xaa Giu Xaa Xaa Val Xaa 50 Xaa Gly His To be Xaa Gly Ile Pro Trp Allah 60 Pro Read To be To be Xaa Pre To be Xaa Allah Read 70 Xaa Read Allah Gly Xaa Read To be Gin Read His 80 To be Gly Read Phe Read Tyr Gin Gly Read Read 90 Gin Allah Read Glu Gly He to be Pro Glu Read 100 Gly Pro Thr Read Xaa Thr Read Gin Xaa Asp 110 Val Allah Asp Phe Allah Xaa Thr He Trp Gin 120 Gin Met Glu Xaa Xaa Gly Met Allah Pro Allah 130 Gin Pro Thr Gin Gly Allah Met Pro Allah 140 Phe Ara To be Allah Xaa Gin Xaa Xaa Aia Gly 150 Gly Val Read Val Allah To be Xaa Read Gin xaa 160 Phe Read Xaa Xaa Being Tyr Arg Val Leu Xaa Xaa Leu Ala Gin Pro (SEQ XD KQtl) where Xaa in position Xaa Xaa Xaa Xaa Xaa

Xaa Xaa Xaa Xaa Xaa Xaa Xaa

Thr, Pro SAW. > Phe, Lys, Ser, Arg, Tyr or L®U; Arg, Tyr or Ser To be, Pro, To be, Thr, Tyr, Pro, 'Gly; e, Leu To be; To be; position po & tçàíj position position position position position position position position position position position position xg, Cys in position Trp, GÍFa n 3 na na na Xaa í Xaa 'Xaa í Xaa | Xaa i Xaa i Xaa t Xaa i Xaa i Xaa t Xaa f Xaa i Xaa i Xaa | Aiâktà ... j Xaa ^; Xaa Xaa Xaa 'Xaa Xaa Xaa Xaa or is it is Leu, Arg, He, Asp, Allah, Lys Cys or Cys $ _er His, Thr, Behold, Ser, Gly, Pro, Ser, Thr pro; Thr or His; Ala, Ile, Tyr (i x e or Cy a, * Thr o »Ala; j Read; Go, Lys, Trp è è è is Leu; â4 ^is Pro, OR «M.- .. Í15J position 46 ã Glu, Arg, Phe, Arg, i le or Allah; position 47 ã Read or Thr? at position 49 ê Leu, Phe, Arg Ser: at position 50 ã Leu, lie, His, Pro or Tyr; at position 54 è Leu ^Oü Hia, - at position 64 o Cys or Ser; ns position 67 is Gin, Lys, Leu ^or Cys; at position 70 2nd Gin, Pro, Leu, Arg or To be; at position 74 ^is Cys or Ser; at position 104 is Asp, Gly Val; ns position 108 and Leu, Ala, Vai, Arg, Trp, G ln oíj at position 115 & Thr, His, Leu «« Ward rss position 120 & Gin, Gly, Arg, Lysou His Hey position 123 is Glu, Arg, Phe «« Thr at possession 144 Φ Phe, Hia. Arg, Pro, Leu, G ln ^cü at position 146 &: Arg ^Oü Gln; at position 147 is Arg «« Gin; nat position 156 & His, Gly or Ser; us position 159 and Ser, Arg, Thr, Tyr, Go oü Gly; at position 162 is Glu, Leu, Gly or Trp at position 163 is Go, Gly, Arg or al & laugh position 169 <? Arg, Ser, Leu, Arg or Cys; at position 170 His, Arg ^Oü Ser: where optionally 1-11 N-terminus and 1-5 C-terminus amino acids can optionally be deleted from said modified human G-CSF amino acid sequence; and where the N-terminus is linked to the C-terminus directly or through a linker capable of joining the N-terminus to the C-terminus and having new C- and N-termini in amino acids; 38-39 59-80 99-100 39-40 60-61 123-124 40-41 61 -62 124-125 41-42 62-63 125-126 42-43 63-64 26 ~ 127 4 44 64-65 128-129 44-45 65-66 129-130 45-46 66-67 130-131 46-47 67-68 131-132 47-48 68-69 132-133 48-49 69-70 133-134 49-50 70-71 134-135 50-51 71-72 135-136 51-52 91-92 136-137 52-53 92-03 137-138 53-54 93-94 138-139 54-55 94-95 139-140 55-56 95-96 140-141 56-57 96-97 141-142 57-58 97-98 or 142-143 58-59 98-99 (H) a paipeptide comprising; a modified human IL-3 amino acid sequence of the formula: •Bad Pro Met Thr Gin 5 Thr Thr To be Read Lys 10 Thr To be Trp Val Asn 15 • Cys Xaa Xaa Xãa Shah& 20 Xaa Xaa Xaa Xaa Xaa 25 Xaa Xaa Xaa Xaa Xaa 30 Xaa xaa Xaa Xaa Xaa 35 Xaa Xaa Xaa Asn Xaa 40 Xaa Xaa Xaa Xaa Xaa 45 to ^X § £ $ ^v <id Aria shah Xaa Xaa Xaa Xaa .Xaa Xaa Λ Lisi Xaa Xaa Xaa Xaa <S ¢ ^. 60 Xaa Xaa Xaa Xaa Xaa Xaa Xa.a Xaa Xaa xaa xaa Xaa Xaa Xaa "S 70 Xaa x> a a Xaa Xaa Shah Xaa Xaa Xaa Xaa. Xaa Xaa Xhe Xaa Xaa Xaa 80 85 90 Xaa Xaa Xas Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa X> as Xaa Xaa 53 1st xos Xaa Ph® Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa Ί (> Αΐ. ^. 110 115 120 Xaa Xaa Xaa Gin sin Thr 7J-W 4-ΛΑΛ. Read Rar Read Allah Ils Phe 12S 130 'REQ XL ¹ NO: 2) : n is Sap, Ly> _r Xaa napwçee 18 è tes, His, Lee, i _Uj Pha, _<H , Shah" Aa p <> '$ 19 è Met, phe. Xl «, Xa <a in position 34 0 He, Cys, Gl », Xaa in the piece 21 6 Asp, Phe, Lys, Thr, s «r ^ alf Xaa in pasfçâa • 4-2 Glu, Trp, Fra, Lay, go 0Ü í Sly; Xaa ,in position 23 è lie, Vaj, A1 &> Lae, s * r, »U Arg? Xaa A3 pGS-taa 24 it's Xle, Gly, Go* Xaa the posigàs 2S »Thr, His, Gly, Xaa Γίδ position 26 6 Ris, Thr, Phe. Xaa: faithful position 27 ® Leu, Gly, AXS, Xaa AS pSS.iç4 <> 3 « 6 Lys, Arg, Leu, Xaa the paaiçàu 29 is Sln, Asg, Leu, Xaa A3 pasiç ^ A 36 ^s pye, His, Thr, Xaa in position 31 is Pro, Asp, Giy, Xaa A3 pass 32 it's Lep, Go, Arg, Arg. Gly, Ala, or ty _s; Glu, Arg, Fro, on Ala; Arg, Ala, g> y, Glu, Gl _n , S «i ·., Ala. His, Asp, Asn, Cln, Oly, Tip, Lys, Fhe, Arg, Ser, Fhe. or Leu? Glii <Arg, pro, ua Ala; Gly, Arg, Ala, or Txp; Star, Ser, or AU; Qla, Gly, Prss, Vai or Trp · Fra, Arg, or y _to i _; Gly, Asp, Gin, Ser, Leu, _or Ala, Arg, Leu, Oü si '; ^ Ifi, Asp, Gly, Ala, OR Glu5 Xas in position 33 8 Pre. Read it. Gin,. Allah. Thr, Xae _na pasiçà » 34 is Leu, Go. Gly, Lys. Glu. Gin, Thr. Arg, Ale ,, Fhe, 11 «or Met; Xaa ft * position 35 4 Leu, Aj ^ a., Gly, Am, Pro. ίχ.Ϊ Γΐ, <Jy Val; Xaa n »position 3 δ φ Asp, Read, OR Go; Xaa position 3? is Phe, Ser. Pro, Trp, OR He; Xaa in position 38 is Asr. _f GÜ Wing; Xaa ft * Bread 4S θ Leu, ^ P'Oli Arg; Xaa in position 41 is Asn. £ ys _f λχ £ & ,. _and H.às _f Mat, βϋ Fro; Xaar.a portion 42 è Gly. A $ p _f Ser _z Cys, Asr: _x Lys, Thr, Leu, Go. Glu .. Phe .. Tyr, lie. Met _δί ι Ala; X ^ Ana position 43 is Glu, Asn, Tyr. Leu, Phe, Asp. · Ala, Dy a, Gin .. Arg, Thr, Gly or To be; Xaa ft * position 44 8 Asp, Ser, Lev, Arg. Lys, Thr, Met, Trp, Glu, Asn, Gin. Wing _or Pre; Xaa _n3 pasíçâo 45 is Gin, Fro, Phe, Vai < Met. Leu, Thr, Lys, Trp, Asp, Ma, Arg, Ser, AU, XI®, GluOU His; Xaa o »pesuçaa 46 4 Asp, Phe, To be, Thr, Cys, Qiu, Asn, _Gln Lys, Xis, Allah, Tyr, He. Come on Gly; Xaa rta position 4? and He, Gly, Val, Ser, Arg, Pro., Or xi _S; Xaana position 48 is Illustration, Cys, Arg, Ila, His, Phe, Glu. Ly®. Thr, Allah Met, Vai _Oi j Asn- Xa »in position 49 è Met, Arg, Allah Gly, Pre, Asn, His, or Asp; Xaa at position To be G * .u, Laws, Thr, Asp, Tyr, Lys, Asn, Ser. Allah. He, Go, His, Phe, Met or Gin; position 51 is Asn, Arg, Met, Pro, S & r, Thr, OR Mi§ _; Xaasa position 52 8 Asn, Ris, Arg, Law, illy, Ser, or Thr; Xaa os possção 53 ê Leu, Thr, Allah, Gly, Glu, pro, Lys, S «r, Qll Met Xaa os position 54 _is Arg, Asp. He, Fri, Go, Thr, Gin, A «n, Ly «, His, Wing 0 U Leu; Xaa ns position 55 is Arg. Thr, Go, Ser, Leu, or Gly; Xaa o the position 56 is Pio. Gly, Cys, Ser, Gin, Glu. Air _a , yo. _{s <} Thr, Ala, Tyr, Phe, Leu, Go or «Ys; Xaans position S? 4 AenGM g | y _f Xaa roa position $ 58 Read <Ser, Asp, Arg, Gin, Val, hi Cys;

Xaa ns position "9 and G1V Tyr, Hi®, L®u, Pre, I Arg; Xaa in position £ 6 * Allah, Fri, Fro, Tvr> Asn, ® ü Thr; Xaa in position SI is Phe, Asn Glu.  < Lys. Arg, Oü Ser; Xaa in position 53 AT", HLS, Val, Arg, Pr ', Tht, Asp, nu lie; Xaa in position «2 is Arg, Tyr Trp, Lys, Ser, Xis, Pro, or Val; Xaa the position 64 is Allah, Asn, Pro, To be, OX Ly®; Xaa ns position € 5 is Val, Thr, Pro, Uis, Leu, Phe, ^ft Ser; Xaa in position 66 is Lys, He, Arg, Val, Asn, Glu, osj Ser? Xaa ns position 67 is To be, Allah. Phe. val. Gly, Asn, lis, Pr ', os; Xaa ns position a® Read Val, Txp, S®r < 11®, Phe, Thr, or His? Xaa ns position 68 ^is Gin, Allah, Thr, Glu, Arg, Trp, Gly, o® Xaa in position 70 Asn, Leu, V & l Trp.jí Pro., Or Ala; Xaa in position 71® Allah, Mat. Leu, Pr », Arg, Glu, Thr, Gin, Sis: Leu,

Trp. or Asn; Xaa in pssnection 4 SOS, Glu, Met, Allah. His. Asn, Arg ,. _{s (J} Asp; Xaa in position ’N and Allah, Glu. Asp, Leu, To be. Gly < Thr, oo Arg; Xaa in position 7th and TI® , Mat, Thr , Pro, Arg, Gly. . Allah; Xaa in position 7S is G1U, Lys, Gly, Asp, Pro, Trp, Arg <Ses Gl & ir .0 · ^ Leu; Xaa in position 7th O To be, Val, Asn, Trp, Glu.,: Pra, Gly, _or Xaa in position 77 is 11®, Ser, Arg, Thr, on Leu; Xaa fia position 79 is Read it. Illustration, Glu, Phe. Gly, OR Arg; Xaa ™ f ' ^osí ? ^to 79 O Lys, Thr, .Asn, Met, Axg, Ile, Gly, Oü Asp, Xaa in position to is Asn, Trp. Val, Gly, Thr, Read Glu.ou Arg, Xaa in position 81 is Leu, Gin, Gly, Allah. Trp, Arg, Go, or ' lys, - Xaa «the possession S2 is L «u, Gin, Ly®, Trp, Arg. Asp, Glu, Asn, Hi®, Thr, To be, Allah, Tyr, Phe, II®. Met _i5iJ t Val 't' Xaa pa position S3 and Pr », Ala, Thr, Trp, Arg, o Met; Xaa in position 84 O Cy * _f Glh, Gly, Arg, Met, Gü Val.- Xaa n «position at is , Asn, Val, Í> U £ In; Xaa ™ position 86 The Pr », Cys, Arg, Allah, αο Lys; Xaa in position 87 is Read, · Ser, Trp .. Hi.1 G. ly; Xaana position 68 and Allah, Lys, Arg, Val, OR Trp; Xaa® «position 89 and Thr, Asp, Cys, Leu, Val, Glu Hi®, Asn, OR and Xaa ⁱⁿ position. 80 Allah Fro To be, Sly, ASSp, Ils, 0y Met; Asp; To be; Xaa r> 3 position 514 A1 &, Pro, Ser , Thr, Phe, Leu, Asp, or His; Xas in positions . 83 is Pr », Ph®, Arg , Ser, Ly &, His, Ala, Gly, He Lew; Xaa os position S3 is i Thr, Asp, Ser, Asn, Pro, Illustration, OR Arg; ix ns position , §4 Á Arg, lie. To be, Glu, Leu, V <1. Gin. Lys, His, A * a, uu Pro> Xaa in position 9th is Η1§> Gin, Pro, Arg, V <1, , ΌΧν> · Thr, Asn, Lys. Sox , Wing, Trp. Phe, He, çu Tyr; Xaa ⁰³ position Healthy 6 Pro <Lys, Tyr, Gly, lie. OR Thr- Xaa m position 97 is lie, Val, Lys, Ale, or Asn; · X & a in position SB is Hrs, He, Asn, Leu, Asp, Ala, Thr, Gio, Qin > Being, Phe, Met, Go, Lys, Arg, Tyr oil Pro; Xaa in position $ 9 ê He, Leu, Arg, Asp, Val, Pro, GXn, Gly, Fh «. or- His. *** rm χ _Οβ position _is Lys, Tyx, Uu, _{ai <<} Arg, _{n <<} Xaa ns paaição 301 B Asp. Pro, Het, Lys, His, Thx ₄ V <1, Tyr <Glu, Asn, Ser, Ala, Sly, Ile, Leu, m; Gin.; Xea in position 1P2 is Gly, Leu, Ly®. To be, Tyr, gü Pro; Xisa in position 103 and Asp, Pü S «r; Xaa n »position 104 0 Trp, Val, Oys, Tzr < Thr, Met, Pro, Read it. Gin, Lys, Ala, Phe, me Gly; Xaa , -in ics & Aam, Pre, Allah Pne, & ®r Trp, Gin, Tyr, Leu, Lys, Xis, Asp, or His; Xaa in position, £ 13 is G.1U and To be, Ale, Lys, Thr, lie, Gly. OR Fro; Xaa ns _l3g position is Arg, Lyss, Asp, Leu, Thr ,, Xie, Gin, His, Ser Wing ^Oü Pro; Xaa m3 request Xaa _: n $ position Ser, nude 109 is. lie ê Trp; Arg, Lys, Thr, Allah, Pro. Asn, Glu. · Thr, Tyr, Leu, Leu, Arg, To be.. Gin, or Giy; His, Glu, Xaa ns position 111 è Leu, He, Arg Asp □ u Her .; Xaa _the position . 112 .is Thr, Val, Gin, Tyr, Glu, His, Ger, ^or Phe; Xaa in position 113 ή Phe, Fri, Cys, His, Gly, Trp, Tyr, Asp, Lys, Leu <He, Val OR Ακη. ' Xaa.:f;e position 114 is Tyt. cys. His, To be, Trp, Arg, or Leu; Xae in position 115 ê Leu, Asn, Val, Pro Arg, His, Thr, Pm, OR Met: Xaa H £ is Lys, Lay, Pr ©, Thr, Met, Asp, Vel> Glu, Axg, T-p, To be - Asn, Eis, Ala, Tyt, Phe, S In. OR There is; xaa in position 0 Thr, Ser, Asn, lie < Trp, Lys, OR Pro; xaa in position 118 O Leu, Ser, Pr & < Ale, Gj.U, Cys, Asp, OR Tyr; Xaa in position 119 is Glu, Ser, Lys, Pro, Leu, Thr, iyr, OR · Arg; Xa & in position 12G 0 Asn, Ala, Pr », Leu, kís, Go. OR Gin; Xa & POSiCtion *2· * is Ala, Ser, He, Asn, Frc-, Lys. Asp, OU ’Gly ,; Xa.a in position 122 it's Gin, Sar, Met, Trp, Arg, Pne, Frr-, Mis, ’1«, Tyr, OR Cys; Xaa in position 123 is A1 &, Mat, Glu, Mis. To be, Pr «, Tyr, OU 'Lau: where from 1 to 14 amino acids can optionally be deleted from the N-terminus and / or from 1 to 15 amino acids can optionally be deleted from the <nO'C terminus of said modified human IL-3 amino acid sequence; where 0 to 44 of the amino acids called Xaa are different from the 5 outstanding amino acids of native human intedeucin-3 (1-133; and where the N-terminus is linked to the C-terminus directly or through a linker (L ₂ ) , able to join the N-terminus to the C-terminus and having new C and N termini in amino acids 26- 27 27- 28 50- 51 51- 52 85- 86 86- 87 28-29 52-53 87-88 29-30 53-54 88-89 30-31 54-55 89-90 31-32 64-65 90-91 w4Í. 65-86 9V92 33-34 66-67 92-93 34-35 67-88 97-98 35-36 88-69 98-99 36-37 69-70 99-100 37-38 76-71 100-101 38-39 71-72 101-102 39-40 72-73 102-103 40-41 82-83 I 103-104 41-42 83-84 49-50 84-85 (Hi) a polypeptide comprising; a modified human c-mpl iigant amino acid sequence of the formulaAfc g. * hrTh.rGi.y x & rulyX * euXíevLy sTrpGrnG.inGlyPheAxxf AlaLygi ~ ePr o • 1'35 2GG2Q5 GlyLeiiL & uAs nu loThrSer ArgSerLsuAspG 1 nil © proG lyiyrLe'uAsnArg 2X0 2X5 225225 j.ieHissjlu.ueuLeuAsnGlyThrArgGlyLeu.phePrpG.lyProSerArgArgThr ²³⁰ 235 240245 LeuG ly AlaProAspXleSerSerG 1 yThrSerAspThrGlys erLeuProProAs n ^2SC 255 260255 LeuGi nProGlyTyrEer ProSerProThrHisProProThrG lyG XaiyrThrtsu ²⁷⁰ 2 ^? 5 280 rheProLsuProProThrLeuProThrí> TovaXValGlnx.euHisProLsuLeuPrí3 298300 AspProSerAXaProThrPrcThrProThrSerProLeuLeuAsnThrSerTyrThr «Ή 3X0 3 * 5320 K i sSeru j.nAstu, eiis & rQlnGluG. * Y (SEQ XD NO: 3} 325 330333 153 where Xaa in position Phe, Trp, 112 is detected or : Met; Allah, val, lie, Pro, xaa in position lie, Trp, 113 He is deleted or ’Pro, Phe, Ale, Val, Leu, Xaa in the lie position, Trp, 114 MS is denounced on  Fro, Phe, Allah, Val, Leu, X && in position . 115 Gin, sly, To be, Thr, Tyr, Asn, or Asn: o where the N-terminus is connected to the C-terminus daily or through a linker (U) capable of joining the N-terminus to the C-terminus with new C and N terminations in amino acids; 26- 27 27- 28 28’29 29-30 30’31 32- 33 33- 34 34- 35 ML36-37 W 37-38 38-39 40-41 41’42 42- 43 43- 44 44- 45 46- 47 47- 48 48- 49 50-51 5 51- 52 108-109 52- 53 109-110 53- 54 110-111 54- 55 111-112 55- 56 112-113 56- 57 113-114 57-58 114-115 58- 59 115-116 59- 60 116-117 78- 79 117-118 79-80 118-119 80- 81 119-120 81- 82 120-121 82- 83 121-1'22 83- 84 122-123 84-85 123-124 85-86 124Ί.25 86- 87 125-126 87- 88 126-127 88-89 or 127-128; (IV) a polypeptide comprising, an amino acid sequence modified human IL-3 acids of the formula ' Allah • Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Val Asn 5 10 15 Xaa x & a Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 2.0 ’25 30 Shah& xaa xaa Xaa Xaa Xaa xaa Xaa Asn Xaa Xaa Xaa Xaa Xaa Xaa 35 40 45 Xa a Xaa Xaa X & At Xsa Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa 50 55 &S xaa .Xaa Xaa y · \ & Xaa Xaa Xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Xaa € 5 70 75 Xaa Shame Xaa X && Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa X.aa 30 gç 90 Xaa Xaa Xas Xaa xa.a Xaa Xaa Xaa Shah Xaa Xaa Xaa Xaa Xaa Xaa 95 100 105 Xaa Phe Xac> X && Xaa xaa Xaa Xaa Xaa Xas Xaa Xaa Xaa Xaa Xaa .110 115 12Ü Xaa Xaa Xaa GIxí Gift Thr Thr Leu To be Read Allah He phe 12 5 130 ISSEQ ID NO: 2) in q ^ i? xaa ne pOSi çâe 1? Xaa in position there is Xaa, Xâô in the potion 19 8 Met, X && in position and 11a, Shah" in position 21 l? Aap Tbr. s «r OÜ Val; Xaa f? the position 22 and Giu. Read it. Val ^su Gly; Xaa in position 23 and 11®, Read it. §Er. - OU At £ r; Xaans position 1 24 is 11 «, Xaa in position 2S and Thr, Xaa the pssition 2"! and Mia, Xaa in position 27 8 L ««, Xaa in position 28 is Lys, Xaa in position 29 & Gin. Xaa in the po & içèa 34 and ?: r>, It was going to be, Lys. Sly, Aap, SI ', _or α _γ§ . His. Leo, Ils, Phe, Arg, su -Tin; 9ha, 11 «, Arg, Gly, A.U, £ j <i Cys? Gys. · Gin, Glu, Arg, Fro, ^ 5.3 .. Phe, Lys. Arg, Ala, Gly, Glu, Gift, Asn, Trp. P.te, S »x \ Ala. Ki. &, Asrjs. & sj &, Gln> Val sia, Gly, Trp. lys, yfe ', £ * ly <V <'i' _v Arg, Asr, Fh «, _Gy l« su _; His. Gly. Gin, Arg. Pro, _or Ala.- Thr, Fhss, ^ .ly <Axçj _y Gly, Ar§. Thr, s * r, or au _; Xrjj. Leu, Gm, Gly, Pro, v & j go Trj>_; Wing. Lssu, Pro, Arg, * 8 Val; His. Thr, Giy. Asp. Gin, Ser, Leu, m lys X ** at position 31 is Fro, _{ÃJ5P (AU> cln} . ΚΛΒ at position 32 is Leu. Val, Arg, Gin, Asn, ci _{y <Ma} , _{QU Giu} Xaa naposíÇB » ₃₃ and Pro, Leu. Gin, χι _& , W. _or Glu; Xaa at position 34 § Leu., Val, Gly, Ser, Lys. Giu „« i _n . AFg <Ala, Fh® <lie çsy Met .; Xaa rsa position 35 is Read it. Allah. Gly, Asa, Pro. Gin. _ΛΜ Val; Xaa ns position J $ è Asp, Leu, ^üu Val; Xaa in position 3? ^is Phe. Ser. Pro, Trp. _or Χ1 _βί Xaa in position 38 is ΛλμΓι, φ tj àía, í Xaa in position 40 ê L «U, Τ? Ρ _Λ oíj Xaa o the position 41 is Asn. Cys. Arg, Leu. His, Met. çy p * o Xaa bss position 42 is Gly, Asp, Ser. Cys ,. Asn, Lys, Thr. Leu, Val. Glu ₍ Phe, Tyr, Aunt. Met. Allah; Xaa we pos-ation «3 is Glu, Asn, Tyr, Leu, Phe. Asp. Ala, Oys, Sip, Arg. Thr. Gly!) «Being; Xaa o the position 44 Ó Àsp, Ser, Leu, Arg. Lys, Thr. Met. Trp, Glu, Asn, Gin, Wing or Pre; Xaa in possession 45 is Gin. Pro, Ph®, v »l. Met, Leu. Thr, Lys, Trp, Arp, Asr Arg. Ser. Ala, XXe. Gluoil His; Xaa in position 46 is Asp, Phe, ger. Thr, Cys, Glu, ^ sr>. Gin, Ly s, Hrs, Allah, Tyr, Ile, Val Gly; Xaa in position 4? is 11 «, Gly, Val, g ^ r, Arg. Pro.or His, - Xaa in position 40 § Read it, Xar. Cys, Arg. He, His ,. ? he. Glu, Lys. Thr, Ala, m «*. Val OR Asn; X. «position„ _{is MM} , _teB , _{Ale 01y ffC} 'fc. , »P» W » _M ♦ <.„. Ala, Ils, Val, His, Phe, Met oíj Gin; Xaa at position 51 is Asn, Arg. Met, Pro, ger, Thr, ^until His ^X ** at position 52 is Asn. His, Arg, _{Gly <Serj or} ...... nap S3 è Lou. Thr, Ala, Gly, Glu, Fro. Lys. _S « _r , _or Xaa nspos ^ o _S4 is * »ys, Al & ç? Ií X # <& U7 n. pomsso ₅₅ d _Μβ> „. _{ti Vali s <r} , IB „· poslçíp M 4 I». Oly. cys. sx, _clu , Thr, Ala. Tyr, phe, L® _{and <} Val py Lys; Xae frog pPSiÇ.80 57 Λ Α & Γ, OR G1 yr aaa ns P0S-I0O ss and Leu, Sssç ·, Asp, Arg, · Git ;, Val, or Cys; Shah" f $ a BUSION $ 5 & Giu Tyr, Sits, Leu, Pro, ot; Arg; Xaa at position 60 ⁷ èj Illustration, Pre, Tyr, Asn, or Thr; Xaa at position £ 1 and Phe, Asn. GIU, Pro, Lys, Arg, or Ser; Xaa at poSiÇâ » 82 & Asn, His, Go, Arg, Pro, Thr, Asp, _{CJJJ e;} Xaa ns position uan and Arg, Tyr. Trp, Lys, Ser, Sí.is, Pro, or Val; Xsa POS: TION 64 £ í Ala, Asn ,, Pro, S «.r, nu Lys; Xaa ns potion 65 is Val, Thr, Pro, His, Leu. Phe, or Ser; Xaa at position o6 and Lys, lie. ** »< Val, Asn, Glu, or Ser; Xas position 67 <is Illustration, Phe, Val, Gly, Asn, lie, Pr ', or Hus Xaa at position 68 ç Leu, Vai, Trp, Sex, He, Ph ', Thr, nu Has; Xaa at position £ 6 Λ Gin, Pro, Thr, Glu, Arg, Trp, Gly, _cy Leu Xaa ns position 76 £ Asr., T, «u, go. Trp, Pr ', or Ala; Xaa P3 position 61 5¾ Ala, Hot, Law, Fro, Arg, Glu, Thr, Gi _n , Trp <OR Asn; Xaa i · ^ POSITION 72 is Glu, Met, Ala, His, Asn, Arch, üil Asp: Xaa at Possession 71 is AjvS Giu, Asp, Read, Ser, Gly, Thx, o6 Arch: Xaa at position 74 is XI®, Mat, Thr, Pr », Ar§, Giy, Allah; Xaa Π3 position 75 è Glu, Lvs, Gly, Asp, Pro, Trp, Arg, To be, Gift, <3U Lets; Xaa o® position 76 is To be, Val, Ale, Asn, Trp, Glu, Pr », Gly. <U Asp; Xaa in position ?; € lie, S®r, Arg, Thr, <su Leu _; Xsa in position 78 O Leu, Ala, Ser, Giu, phe, Gly, At  s; Xaa. «The position $ 7 is Lys, Thr, Asn, Met, Arg, 11 «, «Ly. OR Asp; Xaa sa position LOL and Asn, Trp, Val, ciy, Thr, Leu, or Arg; X && in position 61 is L> & u j. Gin, Gly, Ai *, Try, A _rgíí Val, or Lys; Xaa position 82 is w & Vl * Gin, Lys, Trp, Axg, Asp, GiU, Animal, Hi®, Thr, to be y. Allah, Tyr, Phe, Ha, Met õü Val; Xa * o® position 61 is Pro, Ala, Thr, Trp, Arg, or Met; Xaa h3 position 84 is Cys, slu, Gly, Arg, Met, Val _; Xaa λβ position 8S is G & u, Asn, Val, nu Gl _ftí Xa * in position 85 is Pro Cys, Arg, Ala, or Ly '; 2a® in position 87 is Leu, Ser, Trp, gç Uly- Xaa in position 88 is Allah, Lys, Axg, Val, or Trp; Xaa ΠΟ position 89 is Thr, Asp, Cys, Leu, Go, 01u. Mis, Asn, Xas in position 90 is Allah. Pr®, Ser, Ttir, Gly, Asp, He, Met; Xa <in position 91 o Allah, Pro, Sex, Thr, Phe, Leu, Asp. Hxs, Xaa in position §2 is Pro, Phe, Arg, Ser, Lys, Mis, Allah, G -l y, H Read; Xaa Xaa in position in position Wing, in position Lys. To be, Thr, Arg, Asp, He, Ser, Asn, Glu, Pxc, Read, Leu, Arg?  Hiss Gin, Lys Mrs, Gin, Ρχα, Arg, Go, Leu, Gly, Thr , Asn 13 » Allah Xaa in position ss i i Pr®, Lys, Tyr, Gly, Xaa in position 9? < 5 He, Go, Lys, Ala, Xaa in position $ 5 Pis, Xle, Asp, Leu, Glu, Gin, To be,  Phe, Met, Go, Lys, Xaa in position 99 ( 3 11 «, Arg, Asp, Gly, be. Phe, Hi » z Xaa in position 100 is Lys, Tyr, Leu, Pis Kaa in position 191 Asp, Pre, Met, Lys Giu, ASIA, Sax, Ala, Gly, He, Xaa in position 182 0 G ly, Leu, Glu, Lys Xaa in position 103 Aep, To be; Xaa in position 104 to Trp., Go, Cys, Tyr Gia, Lys, Allah, Phe, Gly and Xaa in position 195 is Asn, Pr®, Ala, Phe Read, Lys, He, Asp, His í Xaa in position 106 Glu, S »x, Ala, Lys. Xaa. in position 308 is Arg, Lys, Asp, Leu, Ale ox pro; Xaa in position 189 is Arg, Thr, Pro, Glu, Xaa in position HC and Allah, Asn, Thr, He Asp, Ala Arg, Tyr Thr Go Pro Pro? Gin. Arg, His Read I know,. · Thr, To be, Th. Thr Xle, Sex, Gin, Thr, Go, Gift; Met *. rp, He He Tyt, Leu, Leu, Arg, Fro; Fro Gin, To be Gin, Frc, Leu, Fro His, Ser Ser, or in position Xsa in position Xaa ΠΟ POSITION Gly; His> Glu. Xs.a is Leu He Go Lye, Leu, Lie.3 is The lie Vai To be Arg, Asp, din, Tyr, cys, His, or Met; Glu, KU, Gly, Trp, Tyr, top To be Phe; Asn; Xaa Π9 position 114 and Tyr, Cys, Bis, to be Trp, Arg, OR Read; Xaa in position 115 and Leu, Asa, Val, Prcu Arg, · Allah. His. Th Trp, Met; Xaa in position 116 is Lys, Lau, Pro, Thr, Met, Asp, Val, Glu, Arg, Trp, To be, At tft, R is. Ala, Tyx, Phe, Gin, or II®; XãA in position 117 is Thr, Ser, ASii, 11®, Trp Lys, the pro; Xaa in position 118 is Leu, Ser, Pro, Allah, Glu, cys, Asp, OR Tyr. · Xaa in position 119 is Glu, Ser, Lys, Pro, Leu, Thr, Tyr, OR Arg; Xaa in position 12 0 is Asn, Wing, Pro, L®u, Mis, Val, OR da; Xaa in position 121 and Allah, Ser. 11®, Asn. Pro, Lys, Asp, OR Giy; Xaa in position 123 is Gin, Ser, Met, Trp. Arg, Phe, Pro, Hi Sy XI®, Tyr, OR Cys, Xaa at position 123 is Allah. Met, Glu, Xis, Fri , Pre Tyr. GU Uu; where from 1 to 14 amino acids can optionally be deleted from the ~ N terminus and / or from 1 to 15 amino acids can be optionally deleted from the C-terminus of said modified human IL-3 amino acid sequence; and where 1 to 44 of the amino acids called Xaa are different from the corresponding native interleukin-S gumana amino acids (1-133); and (V) a colony-stimulating factor; where L _? is a ligand capable of binding R ^ to Ry with the proviso that at least one R _s or R? is selected from the polypeptide of formula (l) _; II) or III); and said hematopoietic protein may be immediately preceded by (methionine ^). (alanine ¹ ), or (methionine '*, alanine' ¹ ). 2 .. Hematopoietic protein comprising; an amino acid sequence of the formula R _r L _r R _a , Rrfó-Ru RrR ₃ , or R _r R: where R, s R ₂ are independently selected from the group consisting of; (I) a polypeptide comprising a modified human G-CSF amino acid sequence of the formula: Xaa Xaa Xaa Giy Pro Leu Xaa Xaa Xaa Ata Xaa Leu Gin Giu Ala Ser Ser Leu Pro Gin Glu Gin Val xaa Lys Xaa Xaa Giu Xaa Xaa Val Wing Pro Leu Ser Ser Xaa Leu Xaa Thr Tyr Ward Xaa Xaa. Giy H.is Ser Xaa Xaa Leu Ser Gin Leu Leu Gin Alu Leu Glu Xaa Pro Ser Xaa Ala Leu His Ser Gly Leu Phe Leu Xaa Thr Leu Gin Xaa 120 Gin Gin Met Giu xaa Gly Xle Ser Pro Glu Leu 110 Asp Val Ala Asp Phe A * la Gin Gly Ala Met Pro 150 Gty Gly Val Leu Val Xaa Gly Met. Wing Pro Wing 140 Ala Phe Ala Ser Ala Xaa Being Tyr Arg Vai Leu Ala Ser Xaa Leu Gin Xaa 170 Xaa Xaa Leu Aia Gin Pro Ser Xaa Gin Giy xaa Giy Lys Leu Xaa Xaa Gly Xie Pro Trp Xaa Leu Ala Gly Tyr Gin Gly Leu 100 Gly Pro Thr Leu Xaa Thr Xie Trp 130 Leu Gin Pro Thr Gin Xaa Xaa Aia 160 Phe Leu Xaa Xaa (SEQ XL NO: 1; Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Thr, Ser,, Pro or Leu 08 POSITION IN POSITION at position 3 ^è Leu, Arg, Tyr c u Being; at position 13 is Phe, To be, His, Thr Pro; position 16 « Lys, Pro, To be, Thr ot His; at p 0 ν 'Ϊ ç â 1? is Cys. To be, Gly, Wing, Ile, Ty position 3 ^ θ φ Leu, Thr, Pro, HIS, lie or ns position 22 « Arg, Tyr, To be, Thr or Ala; Π8 position 24 4 Ile, Pro, «TH» wXfXΟ λ or Leu; position Arg, na na in position position ã è © O Read OR Asp, Ala> Ile Lys ou Cys o « Cys ^me Read To be; To be; To be'; r, Gly, Val, Lys Trp, Ala, position on Arg, cys Xaa in position 44 is Pro, Trp, Gin, ⁰ⁱ Thr Xaa at potion 45 s Glu, Xaa at position 47 2nd Léu í Xaa at pos-ç & p 49 « JLrfêtl :? Xaa at position 50 is Read Xaa at POSITION 54 è Read ¹ Xaa ns position 64 ® Cys < Xaa at P0SÍÇ30 67 is Glu, Xaa at position ? 0 © Gin, xaa at position 74 ^and Cys < Xaa at position 104th Asp Xaa at position 105 » Read Xaa at position 11.5 ^è Thr Xaa at position 120 ã Gin Xaa at position 123 * Glu Xaa at position 144 è Phe Xaa at position 146 » Arg Xaa at position 147 ê Arg Xaa at position 156 6th Hís Xaa ns POTION 159 8 To be Xaa Π3 position 162 2nd Glu Xaa at position 163 ^is Val Xaa at position 169 is Arg Xaa at position 17 G is Hís Where optionally 1 Gly, Arg, Asp, Arg, val Wing, His Arg, Phe, or Thr; Phe, Arg Ser: Ile, His, pro ow HIS; uu Ser: Lys, Leu Pro, Leu Ile Ala; Cys; To be; Gly Allah, His < Gly, Arg, His, val; Val, Arg, T Read 0 «Ala; Arg, Lys or Hís Phe «tí Thr Arg, pro, Leu, Gin Gin; ΊΡ Gly or Arg, 'Leu, <Gly,> Ser,: Arg « ^u ; To be; Thr, Tyr, Val Gly or Trp; Arg 9 ^u . Allah; Leu, ArgCys; To be; Gly; ^or Glu; -11 amino acids from the N-terminus and 1-5 from the C-terminus can be deleted from said modified human G-CSF amino acid sequence; and where the N-terminus is linked to the C-terminus either directly or through a linker capable of joining the N-terminus to the C-terminus and having new C termini and Nor amino acids; IS 38 ^ 39 62-63 123-124 39-40 63-64 124-125 40-41 64-65 125-126 41-42 65-66 126-127 42-43 66-67 128-129 43-44 67-68 129-130 45-46 68-69 130-131 48-49 69-70 131-132 49-50 70-71 132-133 52-53 71-72 133-134 53-54 91-92 134-135 54-55 92-93 135-136 55-56 93-94 136-137 56-57 94-95 137-138 57-58 95-96 138-139 58-59 96-97 139-140 59-60 97-98 140-141 60-61 98-99 141-142 61-62 99-100 or 142-143 (II) a polypeptide comprising; a modified human IL-3 amino acid sequence of the form. Allah Pre Met Thr Gm Thr Thr To be Read Lys Thr To be Trp Val Asn 1 5 10 15 Cys Xaa Xaa xaa Xaa Xaa Xaa Maa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Aan Xaa Xaa Xaa xaa Xaa Xaa 35 40 4S IS) X «sa Xaa Xaa Xaa Xaa 50 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa OC- Xaa .Xaa Xaa X ’a Shah" Xa a Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xs 3 Λ * 70 Xaa Xaa Xaa Xaa X & 9 & shah xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa Xaa 80 85 '3D Xss Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa. Xaa Xaa S5 100 105 Shah Phe Xa <j Xaa xaa Xaa xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Χ-άίϋ 110 .115 120 Xaa Xaa Xaa Gia Cln Thr Thr * j8U 5 & Γ Read Allah Xis Phe 125 130 ISSEQ XL ND: 2 ...... ê <r qua xaa ns position 17 would be, * > ys. sly, & sp, Met, Sin, _0L ; Arg; Xaa our positions i8 is Wing, Ks.s. Lau, 13 «, Pha. Arg, or Cln; Xaa in position 13 á Het. Ph «. 11®, Αχ-g. · Gly, Aia, qjj Cys; Xaa in position 2ϋ ΰ 11 », Cys, sin. Glu, Arg, Pr®, ₀ ; _} Wing; Xaa in the visit 21 is Asj? Ph «, tys, Arg. Ala, Gi.y, Glu, sin, A _SK , Thr. g «r Or go; Xãã n «position 22 ^is Glu, Tsgs, hs. Gar. Ala, His, Asp, Asn .. Gin, Lsu, go PU Qiy _; . Xaa ns position 23 is 7 t » go there", Gly, Trp, Lys, Ph «, Ser, Arg; X * «» after i 24 £ _{IU <aiyi Val} sar, «». _oy Leu; Xaana position 25 è Thr, κ _{Αδ (aXy>} Gin, Arg. Pre, u »: X ^ aa ^ çSo _{2β is} Kia, _phe>Ciy> OUR naposíçào 27 è l «u, Giy, Arg,« Jfcg .. _{Ser <or Ai <{} Xaa in psis ^ So 28 is Lys, Arg, l # u, Qin, sly. P _r «, _{Val or} Xaa nspcsiçàc 2§ is Gin, s. _sn .. Lau, pt «, Arg. _ôu V _fti · Xaa «3 position 33 to _{M <} _ -„ * e .ro. Kia, Thr, Giy, _{cijS / Ser U} u, or Ly Xaa at position 31 is Pro; Asp; Cty; Allah; Arg; Read; or Gin; Xaa at position 32 is Leu; Val; Arg; stage; Acn; Gly; Allah; or Glu; Xaa on pc & ation 3 3 X- ' Pro. Read Cln, » or x «« n «position Γϊ Lsu, · Go. Gly. Lys ,. Qlu Arg, AH, lie ti Met; Xaa ns ps & içse S0 4 Leu, Allah. Gly. ÀSÍTi,. Pro, Gin Xaa the positions 36 £ Asp. or ^v «l; Xaa p <js <çâi3 I? 4 Phe, S «mr. Pro, Trp, Xle; Xaa in our positions 3S ώ Asr. , Oü Ala ,: Xaa a pasigio 4S 4: Leu, Trp, or Arg; Xaa na pn & içâs 41 Ç1 Asn, Cys. Arg. Leu, His, Met, Xaans weight 42 is Gly, Àsp, S4? X ‘y cys. Xsr>. Lys, go *. u i u. She t Tyr, 11®, Kat Oi j Wing Xaa _{η; ΐ} position 43 Glu .. Asn * / * < Leu, Phe, Asp, Gin, Arg, Thr < Gly or To be; Xaa ns posto 44 4 Asp. Fri. Leu, Arg, Lys, Thr, Τη Met,. · < Xaa Qin, Pro. Phe Go Met, Trp, Asp, Xas as positSo Asr Arg Ger, Ala, He Lys, ô è Asp, Phe Thr, cys At Allah, He, Vaio ·; ly; He Go Pro. Xaana pcsiçâo 48 is Leu, Ser, Cys, Arg, lie. His. Fhe, Gly, «Ya. Th *. Allah, Met, Vai or As Xi; Xa »AB position 49 § Met. Arg, Ala, «Ly. Pro, Asn, His, on Asp; Xaa at. posit inn 5'3 is Glu. Leu, Thr, Asp, Tyr, Lys, Wing, per, Ala, lie, Go. His, Phe, Het on Gin XAe. <$ J position Si Asn. Arg, Met, Pre, Ret, Thr, »« His; Xaaas position 52 4 Asr ,. His, Arg, Leu, Qly, To be, OR Thr; Xaats ps & ion 5.3 is Leu, Thr, Ala, Gly, Glu, Pro, Lys, Ser, or Xaa pçríçãe $ 54 AX £ L Asp, lie, To be, V »l < Thr, Gin, Asn, Lys .. Sis < Wing Gi Met, Read; Xaa ns pssiçâí Go, To be. Xea ns position 54 « Read it. or Gly, Ala ly < Y » Ser, th.n, Glu, AX'S, His, Phe <Leu, Va.l õ u Lys ,: Xaana p Xaa us pas χ So Ser, Asp. Cln, Val, <ju _; Xaa in position and G1U Tyr. His, Read, Fro, u Arg; Xaa es position SO is Allah, to be. PXP, Tyr, Asm, Thr, · Xaa 03 POST 3'3 61 ê Phe, Asn, Glu, Pre ·, Lys, Arg, 0 «Being; Xaa in position 82 is Asn, Kia, Val, Arg, Fro, Thr, Asp. <s u 11a; Xaa in position 61 is Arg, Tyr, Trp, Lys, his, pro, ομ Val; Xaa nss position 64 è Allah, Asn, Pre, Ser, QU Lys; Xaa laugh position 65 is Val, Thr, Pr », His, Leu, Phe. ^or Being; Lys, lie. Arg, Val, Asn, Glu, or Ser; Xaa ns Sé position Xaa at position 87 is Xaa os position 680 Xaa na position SS ^è Xaa ng position 70® Xaa na position 71 ê Trp, or Wing; Xaa os position 72 The Xaa in position 73 is Xaa in position 74 is Xaa in position • SC ’W and Gin, OR Read; Xaa in our positions : <5 * ·: is Xaa in position w ....... 7 < is Xaa in position 78 and Xaa ^M position 78 is Xaa in the poãiçàô 85 and Xaa in position 81 is Xaa in poauçâo 62 and Ser, Ala, Phe, Val, Gly, Asn, 11®, Pro, or His, · Leu, Val, Trp, To be, Ile, Phe. Thr, αιι His; Sln, Allah, Pro, Thr, ulu Arg, Trp, Gly, hi Leu Asn, Leu, Val, Trp, ? r <s. 0 U A. A.à * Allah, Met, Leu, Pre, Arg, Glu, Thr, Gin, To be, Glu. Met Allah, His, Asn, Arg, _or Asp; Allah Glu, Asp, .My, To be, Gly. Thr, or Arg; 11 «, Met, Thr., Pro, Arg, Gly, Ala: Glu, Lys, Gly, Asp, Pro, Trp, Arg, To be, Val, Allah, Asn, Trp, Glu, Pro, Gly, çií A «p lie. To be, Arg, Thr, o u Le u; Read it. Allah, To be, Glu, Phe, Gly- Oil Arg; Lys Thr, Asn Met, Arg. Gly, OR Asp; Asn, Trp, Val, Gly, Thr, Read it. Glu, or Arg; Leu, Gin, Gly, Ara, Trp, Arg, Val, or Lys; Read Qln, Lys, ¹ Tx * p _# Arg, Asp, Glu, Asn, His, Thr, Ser, Ala, Tyr, Phe, Ile, Met _0L Val; Xaa na position S3 ú Pre, Ala, Xaa na position 84 is Cys, Glu, Xaa «s position 85 and Leu, Asn, Xaa * « position 86 is Pro, Cys, Xaa na position 87 , ά Illustration, Xaa na position 88 is Ala, Lys. Xaana pasiçâo S9 and Thr, Asp, Xaa ^na pasiçâc . 80 is Wing, Pro, Thr, Trp, Ar ', or Met? Giy, Arg., Et. or v <l; Val, Gin; Arg, Ala, ç Lys: Trp, or Gly; Arg, Val, or Trp; Cys, Leu, Val, Glu, His, Asn, 00 Ser; Ser, Thr, Gly, Asp, Ile, _0Li Met; Xaa in the pieces 91 4 Ala, Pro. Set, Thr, Phe, Leu, Asp, U His; Xaa ns position Is au; $ 2 4 Pro, Phe, . Arg, To be, Lys, ds, Allah, Gly .. Xie at S j 4 <Thr, Asp. To be, Asn Fro. Ale. wfiU, OR Arg; Xaa in position 94 Ala, OU Pro; 4 Arg, He, To be, Glu. Go, Qin, Lys, His, Xaa ns position Lys, Set, 95 ê & I & _v His, Gin, Trp. Phe. Pre, Arg, Xie, eg Ty Val. Leu. r · Gly, Thr. Asn, Xaa at 9ó ® Pr », Lys, Tyr, Gly, Ils. FU Thr; Xaa position S3 4 Xie, Go ,. Lys, Ala. (St; Asn; Xaa at position 98 4 Ηχβ, Xia, Ash. Read it. Asp, Ala, Thr Glu. Gin. Ser. Phe, Met, Val, Lys, Arg, Tyr in Pro; Xaa n heading 99 4 IX '. Read it. Arg, Asp, Go, Pro, Gin, Gly. Ser. Ph e, t> v His; Xaa in position 104 4 Lys. Tyr, Leu, His, Arg, He To be, Gin, or Pro Xaa ns position ΐδΐ 4 A&P, Fro, Met, Lys. Mis. Thr. Go, Tyr. Glu, Am <Gr l y,> s O < ¹ Qin z Xaa in position 142 «Gly. JL & u> Lys. To be. Tyr, ου Pro; Xaa, ~ i8 postion 103 is Asp. GV Ser; Xaa in position XÔ4 6 Trp, Go, Cys, Tyr, Thr. Net. Pro, Lx € 8U < Gin, Lys, Allah, Fhe ,. or _Gly:; Xaa ins position ICS ® Asn, Pro, Wing, Fhe, Ser, Trp, Gin. Tyr. l> ®üí Lys, He Asp, ου His; Πδ ICS it's Glu. £ er, Ala, Lys, Thr, He, Gly, p U Pro; Xaa ** position 14 & 4 Arg, Lys. Asp, Leu, Thr, Tie, Glu. ! hs. To be, Wing ^{i) U} Pro; X & ns X & â positions 349 114 Trp; £ and Arg, Lys. Thx, Pro * A. A <J? ViS Xi, Glu. Tyr, Thr, Leu < Leu, Arg, To be, Gin. or Gly; His, Glu Being, OR xV & â. in position 111 4 Read it. H «<Arg, Asp. g y Met; Xaa ns PO5ÍÇ3G . 112 . Sf Thr, Go, sir. Tyr, Glu. His. Set, Phe; Xaa laughs 133 & Phe. Ser. Cys, KU, Gly, Trp, Tyr. Asp. Lys, Leu, 11®, Go OR Asn; Xaa r · ® pCSiCtion THERE IS and Tyr, Cys, His, Ser, Trp. Arg, Oh Leu; Xaa in position 115 2> Read it. Ahn. Go, Pro. Arg, Allah, Sts, Thr,

>; «« - Arg, Trp _t 116 is Lys, Leu, Pro. Thr, Met, Asp, Go, Glu, To be , Asn, KU. Allah. Tyr, Rhe, Gin. THE 11® i in position 1Π and Thr, s®; ·, Asr „He, Trp, Lys, OR Pro; in position 118 The Read, Ser, Aro, Ala., Glu. < Cys, Asp, OR ly _r; Shah in position 119 and Glu <Ser. Lys, Pro, Leu, . «T ^ v ** ** 7 Tyr, OR Arg xaa in position 120 and Asn, Ala, Pro, Ley, His, Go. OR Gin; in position . , γ. r · is Wing, Ser, Tie, Ace », Pro, IjVSfr _f Asp, or- Gly; Xaa in position He, Tyr, 122 ê OR Çys; Gin, Ser, Met, Trp. Arg, Phe, Pro, Ris, in position 123 Al *, West, Glu, His, To be, Pre, Tyr, OU · Leu; where from 1 to 14 amino acids can be optionally deleted from the ~ N terminus and / or from 1 to 15 amino acids can be optionally deleted from the C-terminus of said modified human H .. - 3 amino acid sequence; and where from 0 to 44 of the amino acids called Xaa. are different from the amino acids corresponding to native human interleukin-3 (1-133); and where the N-terminus is linked to the C-terminus either directly or through a limestone (U) capable of an N-terminus to the C-terminus and having new C and N termini in amino acids; 26-27 50-51 85-86 27-28 51-52 86-87 28-29 52-53 87-88 29-30 53-54 88-89 30-31 54-55 89-90 31-32 64-85 90-91 3.2-33 65-66 91-92 33-34 66-67 92-93 34-35 67-68 97-98 35-36 68-69 98-99 36-37 69-70 99-100 37-38 70-71 100-101 38-39 71-72 101-102 39-40 72-73 102-103 40-41 82-83 or 103-104; 41-42 83-84 49-50 84-85 (III) a polypeptide comprising: a modified c-mpl linker amino acid sequence of the formula: ArgThrThrGlySerGlyLeuLeuLysTrpGlnGÂnGlyPheArgAlaLysiiePro 195 200205 Glyt ^ LeuAsnGlr * rhrSerArgSerLeuÀspGinXleProGlyTyrLeuAsnAr $ f 215 215 220225 XleHí sG luLeuleuAsnGlyrhr ArgGlyLsuPheProGlyPrcSarAr gArgTfcr 230 235 £ 40245 LeuGlyAlaPrQAspxieSerSerGlyThrSerAspThrGlySerLeuProProAsn 250 255 260255 LeuGlnProClyT'yrSerProSérProTh.rHisP ^! roProThrGlyGlnTy ^f rThrLeu ^AíU * ·· '> 2 »0285 rhePrcLeuP'r OProThrLeuProThr'ProValValGinijeuHisPz'QLe'ULeu.Px'o 290 295300 XspProSerAlaPrcThxProThrProThrSerProLeuLeuAsnThrSerTyrThr 305 310 315 320 .HisSerGLnAsnLeuSerGlnGlu.Gly {SEQ TD NO : 3) 1 <· ·> $ ** 330 332 15 3 on what Xaa in position 112 is denounced or Allah, Val, lie, Pro, Phs <Trp, r Met; Xaa in position 113 is denounced or Pro, Phe, Allah, val, Leu, He, Trp, Met; xaa in position 114 4 detected or Pro, Phe, AXsl ₊ Val, Leu, Xle, Trp, Met; Xaa in position 115 Gin, Gly. To be, ΤΉϊΓ, Tvr Asn; or Asn, and the terminus N is connected to the C-terminus directly or through a linker (U) capable of joining N-terminus to the C-terminus or having new C and N termini in amino acids; 52-53 53-54 54-55 55-56 56-57 57-58 58-59 59-80 78-79 79-80 80-81 81-82 82-83 83-84 84-85 85-86 86-87 87-88 88-89 108-109 109-110 110-111 111-112 112-113 113-114 114-115 115-116 118-117 117-118 118-119 119-120 120-121 121-122 122-123 123-124 124-125 125-126 126-127 or 127-128; (IV) a polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Allah 1 Pro Met X Gin 5 Thr Thr To be Read Cys Xaa Xaa Xaa X && 20 Xaa Xaa Xaa Xaa Xaa Xaa Aââl Xaa Xaa 35 Xaa Xaa Asn Lys Thr Ser Trp Val Asn 1015 Xaa Xaa Xaa xaa xaa xaa 2530 Xaa Xaa Xaa Xaa Xaa Xaa 4045 Xaa Xaa xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Xaa xaa Xaa 60 Xaa .Xaa Shah"" ^v * a Shah" US xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa xaa Xaa 75 Xaa Xaa Xaa Xaa Xaa a> 3 Xaa Xaa Xaa Xaa Xaa ES Xaa Xaa Xaa Xaa Xaa 93 Xaa Xaa Xaa Xaa Xaa 95 Xaa Xaa Xaa Xaa Xaa 2ÕC Xaa Xaa Xaa Xaa Xaa 105 Xaa Phe Xas » xaa Xaa lie Xaa Xaa Xaa Xaa xaa 115 Xaa Xaa Xaa Xaa Xaa 120 Xaa Xaa Xaa Din Gin 125 Thr Thr Read To be Read 13D Allah (SEQ 11® | Bi; Phe ND: 2) in <iijs x && na portion _{1? s <t> /} Lys, Gly, Asp, _{Het sljif} Xaa «the Xasí position? ^osi 0 ^o IS is Asn, Sts. L * 8, XI®, Phe, Arg, <su Gin; IS 8 Met, Phe, 11 «. Arg. Qly, _{A1 <i or £ ys} . Xaa ns position 20 ê Π « ₍ ays. Gift, Siu, Arg,? Χ _ο , _ου Ma, - Xa.a in position 23 è Asp, Phe. uy®, Arg, Ala, Gly, «Ju, Gin, Asm, Tnr. Shsx 0 L Val; .................................................. ........................ Xaa in position 22 '· <3Li, Trp. i? ro, _Se r, _AU His, Asn, Let. Go QU Q.ly _; Xaa in position 23, Lie, Val, Al *, giy. Trip, Lys, Phe, . Ser, (j y Arg; Xaana position '2 «$ Ils, Gly, Val, Arg, Ser, Pho, _otJ Leu _; Xaa in position Xaa in position Xaa ns position 25 and Thr, the _Si, y _{cl (Frs alnj> hi} _ _{f r;.} * HXA Thr Pn®, Gly, Arg, Ala _{Οί <ϊυ Ρ;....} 27 and L 'u, Gly, Arg. , Thr, Ser. Or Ala _; Xaa ns position 2nd is Lys, Arg, Leu, Gin, Gly. p _ro , _or ^, _rp . Xaa in position 29 and Gan, Asn, Leu, Pr ', Arg, ots Val; Xaa ns pssição è Pre, His, Thr, Gly, _Asp , _G1 „. Xaa at position 31 is Pro; Asp; Cly; Allah; Arg; Read; or Gin; Xaa at position 32 is Leu; Vat; Arg; stage; Acn; Gly; Allah; or Glu; Xaa ne peg-can 33 6 Pro, Leu, Gin, Ala, Thr. <s u. <GlU; X »the _n3 position 34 is Read, Go, Gly, Ser, Lys, Glu, Gin. Thr Arg, Ala, Fh®, He or Met; Xaa n s POSITION 35 2nd Leu, Ara, Gly, Asn, Gin, _GU Go; Xaa r, a position 3S is Asp, Las, Vai, * Xaa ,, g. psion 3 *? O Fh © _} Ser <Fro, Trp, or I 1"; Xaa na position .35 R A® i; í · Μ Αχ Λ ί Xaa r> ³ position £ 40 L & uí χ Ajtçí ψ Xaa m position 41 ã Asn.- Cys, Arg, Read, Hxs, Met, or Fro; Xaa os position 42 is Gly, Asp, Ser, Cys, Asn, Lys, Thx , Le u Go,. Glu, Phe, Tyr, He, Met qu Minutes; Xaa po & ation 43 ès Glu, Aso. Tyr, Read it. Phe, Asp, Ala . Cys. Gin, Arg, Thr, Gly o.u Ser; Xaa na position 44 o Asp, Ser, Leu, Arg, Lys, Thr, Mat > Trp. Pro; Ala qq X.aa _ng position 4S _is Gia, Pro, Phe, Met, Read Thr, Lys, Trp <Asp, Asn, Arg, Ser, Ais, He, GluOu SUs í Xaa o the position £ 4 is Asp, Phe. To be, Thr. cys, Glu, Asn, Gin, Lys, His, Al < s. Tyr, He. Veiled Gly; Xaa in position 4Q is X.X & * .. V&X x To be, Arg, Pro, His; Xaane position 48 and Lati, Ser, Cys, Arg. 11®, Hrs, Ph®, Glu, Lys, Thr, Allah. Met, Vai _au Asn t Xaan »position 43 is Met, Arg, Ala, Gly, Pro, Asn, His, Or the Xaa at position 50 and GLu. Leu, Thr, Asp, Tyr, Lys, Asn, To be, AX &> ,: Χ1.; & _Ζ Go Hxs, Phe, fistou GlA; X * My position 51 & Wing. Arg, Met, Pro, SfôXH Thx CU Xi $; Xaa _fsa po $; çào 52 ά Asn. Hrs, Arg, Leu, Cx Λ, ^. Χ To be, or Thr; Xaa in position S3 and Leu, Thr, Ala, Gly, Glu, Pro, Ly®, To be, Xáana position S4 is Arg, Asp, li®, To be, Go, Thr, Gin, A «h, Wing OR OR Lys, His. Met, Ley; Xaa in position 8S is Arg, Thr, Vai, Xaa os position SC and Pro, Gly, Cy _S , Thr. Allah. * by; Phe, Leu, Vaiou Xaans position 5 ” ÀK & 0V Gly? Xaa in position 58 and Read, Ser. Asp, To be Lys; Arg, Gin, Va.j ,,: OR Gys; L®U, Q (J Gly; □ in, Glu, Arg His Glu Ty Xaa a position Mis, Lev, Pro, OR Arg; X * «ns position 6C is Illustration, Pro, Tyr. Asn, ^su Thr; Xaa n the position 81 is Phe, Asn, Glu, Pre, Lys, Arg, 0V Ser; Xaa in position »2 is Asn, Ens, Val, Arg. Pro, Thr, Asp ,. cy 11 »; Xaa in position S3 is Arg, Tyr, Trp, Lys, Ser, Hrs, Pro, eu Val; Xaa position 44 á Ala, Asn. Pre, Ser, su Lys; Xaa «OOSsÇãc 85 is Val, Thr, Pro, His, Leu, Phe, ^oy Ser .; Xaa in position 46 is Lys »Ile, Arg, Val, Asn, Glu.or Ser; Xaa 0 3 position ãl é Illustration, Phe, Val, Gly, Asn. He, Pr ', or Xaa ³³ potion 68 is Leu, Val, Trp, Ser, He, Phe, Thr, or Xis; Xaa in position The? ^is Gin, Ala. Pro. Thr, Glu, Arg, Trp, Gly, or Xaa fjg position 70 ^έ Asn, Lsu. Val, Trp, Pro, Alga; Xaa pa position 71 θ Ale. Jtet, Read, pre, Arg, Glu. Thr, Gin, Trp, or Asn; Xaa o «position 72 & Ser. Glu, Man, Ala, His. Asn. Arg, _{0) J} Asp; Xaa in position 7 ₃ is Ala, Glu, Asp, Leu, Ser, Gly, T.hr, gu Arg; Xaa in position 74 is He, M «t, . Thr, Pro. Arg, Gly. Allah; Xaa f> the potion 75 4 Giu, .Lys, Gly. Asp. Pro, Trp, Arg, Ser, Gin, or Read; Xaa in position Ser, Val, Ala, Asn, Trp, Glu, Pro, Gly. gy Xaa os position 77 is He, Ser, Arg, Thr, 08 Leu; Xaa «* position 78 is Leu, Ser, Glu. Phe, Giy, OR Arg; Xaa ^ ⁴ position 7? & Lys, Thr » Asn, Met. Arg, He. Gly, or Asp; Xaa in position SO ^is Asn, Trp, Val. Gly, Thr, Leu, Glu.gy Arg; Xaa in position 81 is Read, Gin, Gly, Ala. Trp, Arg. Val, OU 'Lys; Xaa ns position 82 ê Read, Gin, Lys, Trp, Arg, Ακρ, Glu, Asn, Read it. Asp; Kia, Thr, To be Ala, Tyr, Ph®, 8th 11 «, Mat _or Val Xaa in position Pro, Wing, Xaass position 64 is cys. Glu, Gly, Arg. Met, <? U Val: Xaa o »position 85 Leu, Asn, Val, '^{:> υ} Glu; Xaa in position 86 is Pro, Cya, Wing, or L ys; Xaanã position 87 and Illustration, Trp. 0U Gly; Xaana position 88 and Ala, Lys, Arg, Val, or Trp; Xaa ^! · ³ position 89 6 Thr, Asp, cys, Leu, Val, Glu, Xis, Asm, oü sar; Xaa ^na 46 and Wing, Pro, To be, Thr, Gly, Asp. H®. 0U Met; Xaa in possession! » Xaa in position 91 is Sê ê Ala, Pro ,. Pro _f Phe, Thr, Phe * Uu, Àjgp, cu Ris; Xrçj · *: X * v®; íki & .t CSày * XClís ;chest; Xaa in position 9.3 è . Thr, Àsp, Ser, Asn, Pro, Ala, Leu, ç.;, Argr Xxjíà in position §4 è Arg, lis. Ser, Glu, ueu. Val, Gin. Lys, Lo, Ala, I Pro; XSS. in position 95 is H * s, Gin, Pro, Arg, Vai, Leu, «ly, Th.r _f Asn, Lys. To be, Allah, Trp, Phe, 1 ! ♦> or Tyr; Xaa in oos-çâo §5 is Pro, Lys, Tyr. «Ly, lie, tu Thr; Xaa in position 97 è lie, Val, Lys, Ala, y;>. Y Aan; Xaa in position Healthy is Mis, He, Asn, Uu, Asp, Ala, Thr, Glu, Gin, To be, Phe, Hat, Val, Lys, Arg, Tyr or Pro; X &. & in position is He, Leu, Arg, Aap, v * l, Pr ©, Gin, Gly, Phe, en Hís; iaa in position yo ã Lys, Tyr, Read, Hls, Arg, Ile, Ser, Qin, _or p _rcs . Xaa in position 181 is Asp, Pro, Met. Lya, His, Thr, Val, Tyr, Glu, Asn, Ser, Ala, S ly, 11®, Leu, OR «In; Xaa in position 103 is Gly, Leu, Glu, Lya, Ser, Tyr, nü Pros; X. &. & at pcj & içàa 103 è Asp, su Ser; Xaa in position 174 is Trp, Val, Cys, Tyr, Thr, Met, Pro, Leu, Sin, Lys, Allah, Phe, or Gly ? Xaa jo® position 175 è Wing, Ala, Phe, Sar, Trp, Clu, Tyr, L «u, Lys, Ils, Asp, or His f Xaa in position 155 è Qlu, Ser. Ala, Lys, Thr, H., Gly, Pro; Xaa n <3 position 108 is Arg, Ly ', Asp, Leu, Thr, lie, «. '. A, Pis, s« y, ÂU ^OR Pro; Xaa ns position 179 is Arg, Thr, Pro, Glu. Tyr, Leu, Ser, »r Gly; Xaa in position no is Lys, Al ', Aan, Thr, Leu, Arg, ln, Xis, gi. _u . Ser, you * $? Ypr Xaa Π3 position ui is Read, 11 «, Arg, Âsp, or Met- Xaa in position .112, yeah : Thr, Val, GLn, Tyr, Glu, His, Ser, ^or Ph® _? Xaa. in position 113 ê Phe, tys, Sis, Gly, Trp, Tyr, Asp, Lys, Leu, lie, Val ^ot! asiü; Xaa in position 114 è Tyr, Cys, Xis, Ser, Trp, Arg, nu, l »u; Xaa in position 115 is Leu, Asn, Go, Pro, Arg, Ala, H1i, Thr, '30

Trp, QU Met; Xaa H € is Lys, Leu, Pre, Thr, Mst, Asp, Go, Siu, Arg. <Trp, Ser, Asn, His, Ala, Tyr, Phe, Clr ·, or He, * Xaa in position you? and Thr, Ser, Asn He, Trp, Lys. OR Pro, Xaa in position 118 O Leu, S®r, Fro, Allah, Glu, · Cys, Asp, OR Tyr; Λ & * in position lis is Glu, Lys, Pro, Leu, Thx, Tyr, OR Arg; Xaa in position 120 is Asr ', Ala. Pro, Leu, His, Go, OR Cln; Xaa in position 121 ã Ala, S®t. Ils, Asr ,, Pro, Lys, Asp, OU 'Oly; Xaa in position Photography, Met, Trp, Arg .. Ph®, Pro, His. 11®, Tyr, OÍJ Cys Xaa in position 121 is Wing, Met, Glu, His, Ser, Pro, Tyr. or Leu, * 1 to 14 amino acids can be optionally deleted from the N-terminus and / or 1 to 15 amino acids can be optionally deleted from the C-terminus of said modified human IL-3 amino acid sequence; and where from 1 to 44 of the amino acids called Xaa are different from the corresponding 5 amino acid teeth of native human intedeucin-3 (1-133): and (V) a colony stimulating factor; and where L; it is a linker capable of binding R <to Rl with the proviso that at least R; or is selected from the polypeptide of formula (I), (II), or (III): and 10 said hematopoietic protein may be optional immediately preceded by (methionine (alanine ⁵ ) or (methionia ' ² , alanine' ¹ ). Hematopoietic protein according to claim 1, wherein the polypeptide of (IV) is selected from the group consisting of; Allah Ash Lys To be Ils Met lie Asp Glu He He His Has Read Lys Arg Pro Pro Allah Pre Read Read Asp Pro Asn Asn Asn Allah Glu Asp Go Asp He Read Met Glu Arg Asn Read Arg Read Pro Asn Glu To be Phe Go Arg Allah Go Lys Asn Read Glu Asn Allah To be Gly lie Glu Allah lie Read Arg Asn Read Gin Pro Cys Read Pro To be AX â Thr Allah Allah Fro To be Arg Mis Pro He lie Xie Lys Allah Giy Asp Trp Glu QXjU Phe Arg OXix Lys Read Thr Phe Tyr Read Go Thr Read Glu Gin Allah Gin • G-X Qin Gin (SEQ ID NG: 225}; Allah Asn Cys j> er He Met He Asp Glu He He His Hxs Read Lys Arg Pro Pro Asn Pre Read Read Asp Pro Asn Asn Read Asn To be Glu Asp Met Asp He Read Met G1U Arg Asn Read Arg Thr Pro Asn Read Read Allah Phe Go Arg Allah Go Lys His Read Glu Asn Allah To be Gly He GXu Allah lie Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Al * Allah Pro To be Arg His Pro lie He lie Lys Allah Gly Asp Trp Qin Glu Phe Arg Glu Lys Read Thr Phe Read Go Thr Read Glu Gin AU Gin Glu Gin Gin tSEQ ID NO; 226); AX & Asn Cys To be He Met He Asp Glu lie lie His Hxs Read Lys Go Pre Pro Allah Pro Read Read Asp To be Asn Asn Read Asn To be Glu Asp Met Asp lie Read Met Glu Arg Asn Read Arg Read Pro Asn Read Allah Phe Go Arg Go Lys Asn Read G1U Asn AX & To be Gly He Glu Ala 11® Leu Arg Asn Leu Gin Fro Cys Leu Pro Ser Ale Thr Ala Ala Pro Ser Arg His pro He He lie Lys Ala Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Ph »Tyr Leu Vai Thr Leu Glu Gin Ale Gin Glu Gin Gin {SEQ ID NO: 227 3.2 Ayat Pro Cy® ' Pro Know Allah lit Met He Read Asp Glu He He Asn His Hl® Leu Lys Arg Asp Pro Read Asp Pro Asn Read Asp Asp Glu Val Sat life Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe Go· Arg Allah Val Lys Asn Read Glu Asn Allah. To be Gly Xia Glu Allah He Read Arg Aso Read Sin Pro Cys Read Pre To be Allah Thr Allah Allah Pro To be Arg His Pro Xie He Xie Lys Allah Gly Asp Trp Gin Glu Phe the rg Glu Lys Read Thr Phe Tyr Read Val Thr Read Glu Gin Allah Gin G.1 u Glr * (SEQ ID NO: 228J 4. Hernatopoietic protein according to the claim where the polypeptide of (IV) is selected from the group consisting of: Asn Cys Ward Ger He Met lie Asp Glu Xie He His His Read Lys Arg Pro Pro Pro Leu Read Asp Pro Asn Asn Read Asn Allah Glu Asp Val Asp He Leu Met Glu Arg Asn Read Arg Read Pro Asn Read Glu Ser Phe Val Val Lys Asn Read Glu Asn Ger Gly He Glu Ala Xie Leu Arg Asn Read Gin Pro Cys Read Pro Ger Allah Thr Ala Ala Pre Ser Arg His Pro He Ila He Lys Gly Asp Trp Gin Glu Phe Arg Glu Lys Read Thr Phe Read Val Thr Read Glu Gin Wing Gin Glu Gin Gin {EEC ID NO: 225); Asn Cys Ward . $ er. He Met There is Asp Glu 11 » XI a His His Read Lys Arg Pro Pro Asn Pro Leu Read Asp Pro Asn Asn Read Asn To be Glu Asp Met Asp He Leu Met Glu Arg Asn Read Arg Thr Pro Asn Read Leu Al Phe Val Wing Arg Ala. Val. Lys His ... , <LeM ... Glu Asn Allah .&air Gly He Glu Ala Xie Leu Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Ala Ala Pro Ser Arg His Pro Xie He Ils Lys Allah Gly Asp Trp Gin Glu Phe Arg Glu Lys Read Thr Phe Tyr Read Val Thr Read Glu Girt Wing Qin Glu Gin Gin iSE? ? ID NO: 226): Asn Cys Ward To be He Met There is Asp Glu Xia lie His His Lys Val Pro Pro Allah Pre · Read Read Asp : To be Ast t Asn Lex. i Asr t be  Glu Asp Met Asp He Read Mat Glu Arg Wing Read i Arg Let . Pre > As n . Read

Read Allah Phe Val Arg Allah Val Lys Asn Read Glu Asn Allah Scr Gly read Glu Allah 11 « Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah A & a Pro To be Arg Hi® Pro He He you Lys Allah Gly Asp Try Gin í ** '* Λ v xjc Lm Phe Arg Glu Lys Read Thr Phe Tyr Read Val Thr Read Glu Gin A.x.a G ^ .S Glu Gin Gin (SEQ ID NOxZ27>. ί end Asn Cys To be Huh Mat wool® Asp Glu He He Sis His Read Lys Arg Pro Pro Allah Pro Read Read Asp Pro Asn Asn Read Asn Asp Glu Àsp Val To be Ile Read Met Asp Arg Asn Read Arg Read Pro Asn Read Glu To be Phe Val Arg Allah Val Lys Asn Read Glu Asn Allah To be Gly He Glu. Ale He Read Arg Asn Read Gin Pro Cys Read Pro To be Allah Thr Allah Allah Pro To be Arg Hiss Pro He He He Lys Allah Gly Asp Trp Gin Glu Phe Arg Glu Ly® Read Thr Phe Tyr Read Val Thr Read Glu CS X ϊ < Allah Gin Glu Gin Gin <SEQ ID NO; 1 (28). 5. Hemopoietic protein comprising; an amino acid sequence of the formula: RrLrRj, Ra-UR., R, -R _2; or R ₂ -R, wherein R <is a polypeptide comprising; a sequence 5 of human G-CSF amino acids of the formula:

as a Xaa Xaa siy Pro Allah To be To be Read Pre Gin To be Xaa Read Read Xaa Xaa X && Glu 20 Gin Val x && Lys Xaa Gin Gly Xaa Gly À-L & 30 Xaa Read Glh GX.ú Xaa Lev Xaa Ala - Thr Tyr 40 Lys Read Xaa Xaa ^ 2, X% a Xaa Xaa Val Xaa 50 Xaa Gly His To be Xaa Gly Ile Pro Trp Allah 60 Pro Read To be To be Xaa Pro To be Xaa Allah Read 70 Read Allah Gly Xaa t> QU To be Gin Read His SO Ser Gly Read Phe Read TyT Gin Read Read only Gin AXs LíSU Glu Gly lie To be Pro Glu Read 100 Gly Pro Thr Read Xaa Thr Read Gin Xaa ASp 110 Val Allah Asp Phe Allah Xaa Thr Ile 130 where Xaa o® position 1 and 2 is Thr, Ser, Arg, Tyr Gly; Xaa in position Pro oo Leu; V s ja r <the position there is Leu, Arg, Tyr cu ser; Xaa in position 13 is Phe, Ser, His, Thr «ο ρχ- _Ο; Xaa in position reads 8 Lys, Pro, Ser, Thr or His; Xaa in position 17 4 Cys, Ser, Gly, Ala, lie, τ Xaa in the pass 18 4 Leu, Thr, Pro, His, lie or xaa in position 22 4 Arg, Tyr, Ser, Thr or Ala; Xaa in position 24 ® lie, Fro, Tyr or Leu; Xaa ns position 27 ê Asp,: Gly; Xaa ®s position . 3D * Ala, XIe. Read the Gly; Xaa in position 34 4 Lys ser; Xaa in position 38 is Cys au Ser; Xaa Π3 position 42 is Cys a being; Xaa in position Arg, Cys, 43 is His, Thr, Gly, Val, Lys, T ^or Leu; Xaa in position Trp, Gin, 44 è "O Pro, Gly, Arg, Asp, Val, A ^w * ./ xaa in position 46 is Glu, Arg, Phe, Arg, lie or Xaa in position 47 is Leu or Thr; Xaa in position 49 4 Read it, Phe. Arg ^or Ser; Xaa in position 50 ê Read it, Xie. Ris, Pro or Tyr; Xaa in position 54 is Leu ⁰⁰ His; Xaa. in position 84 is Cys or be; Xaa in position 87 is Gin, Lys, Leu ^or Cys; Xaa f3 a POSITION 70 è Gin, Pro, Leu, Arg or Ser; Xaa ns position 74 ^is Cys or Ser; Xaa 83 position 104 4 Asp, Gly ^DU Val; Xaa r <the position 108 4 Read it. Ala, Val, Arg, Trp,> Xaa the position 1.15 4 Thr, His, Leu or & χ ₃ . Allah, Gin 120 123 144 & é é è & na na Fan Xaa Xaa Xaa Xaa Xaa Gly, Arg, His, posjçáe pssíçâa position position His Arg, Lysou His Phe Thr Arg, Pro, Leu, Gin 147 na. Glu Glu Phe Arg ⁰⁰ Gin; Arg or Gin; Xaa in position 158 is His, Gly or Ser; Xaa in pa & i tion ... 1.5.9. and Ser, Arg, Thr, Tyr, V Xaa Π3 pGSITION 182 $ Glu, Leu, Gly oo Trp; Xaa 8® position 163 is Val, Gly, Arg Ala, - ? Ϊ3 pGSITION 169 Arg, Ser, Leu, Arg or Xaa Π3 position 170 and His, Arg «ü Ser; Cys; N-terminus amino acids and 1-5 amino acids where optionally C-terminus can be deleted from said modified human G-CSF ammoacid sequence; and where the N-terminus is linked to the C-terminus either directly or through a 5 ligand capable of joining the N-terminus to the C-terminus and having new C to N termini in amino acids; 38-39 65-66 126-127 39-40 66-67 128-129 40-41 67-68 128-129 41-42 68-69 129-130 42-43 69-70 130-131 43-44 70-7 ^ 131-132 52-53 71-72 132-133 53-54 91-92 133-134 54-55 92-93 134-135 55-56 93-94 135-136 56-57 94-95 136-137 57-58 95-96 137-138 58-59 96-97 138-139 59-60 97-98 139-140 60-61 98-99 140-141 61-62 99-100 141-142 62-63 123-124 Or 142-143 63-64 124-125 64-65 125-126 and Rj is a polypeptide comprising; a modified human 11-3 amino acid sequence of the formula; Wing Pre Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Vai Asn 15 1015 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 2530 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 4045 Xaa Xaa Xaa Xaa Xaa 50 Xaa Xaa A3a Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa 50 Xaa Xaa X * a Ajcí <5. 55 Xaa Xaa Xaa Xaa Xaa 7C Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa SQ Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa 92 Xaa Xaa Xaa Xaa Xaa 95 Xaa Xaa Xaa Xaa Xaa 100 Xaa Xaa Xaa Xaa Xaa 105 Xaa Fhe Xac * Xaa Xaa 110 Xaa Xaa Xaa Xaa Xaa 115 Xaa Xaa Xaa Xaa Xas 120 Xaa Xaa Xaa Cln Gin 125 Thr Thr Read To be Read 130 Allah I5SÇ Ile  ID Phe NO-.2 } in q-Je X && ns pcaiçâo _{n s <r} - _t u / _Sí « _Λ γ _γ Asp, Met, Gin. qjj Ar <? r Xaa in pssiçâã U è Asn, Si », Leu, II®, phe, OR Gl '; Xaa ^na ^ ^S! ^ ° 15 is ãfest, ph «„ μ *, Arg, Ma, CU Cys; Xaa in position Sü is * 1 $, du _F OR Wing; Xaa 0 $ poasção Λ.1 è Asp, The, Lys, Arç, Ala, Gly, Glu, Gin, Asn, Thr, $ «r 8) .l ' Ial; Xaa in position 22 is Glu ₊ Τϊτρ, Fro. 3er, A1 &, Ri _Sí A »P, & sr„ Gin. Read, Go Hi; _; 31S ', - Xaa os position 23 è lie, Val, Ala, Gly, Trp, Lys, Rn®, Leu, S-er '’u Alg; Xaa in pos: tion i 24 t lie, Gly, Val, Arç. · £ © #, S> he < ; χ; Read; Xaa in position ..... 2 $ ã Thr, Kr ', Gly, Gltí, Arg,? ro, OR Al *; Xaa Π® position 25 ^{ 'Ris, Thr. Fhe, Gly, Arg _} Ma, <$ u Try; Xaa in position 27 ^is Leu. Gly, Arg, Tht, 5ar, _cr Ala; Xaa ns position 25 ¢: A, ys, Arg .. Leu, G1t * _f Gly, Fra, Val CU Trp; Xaa in position 25 is Gin, Asn, Leu,? r <-, Arv, or y, Xaa ns position 30 is Pro, Ms, Thr, Gly, Asp, _Ginf Ser, Leu, _Oi j Lys Xaa at position 31 is Pro; Asp; Cly; Allah; Arg; Read; or Gin; Xaa at position 32 is Leu; Val; Arg; glo; Acn; Gly; Allah; or Glu; Xaa ns ps & ição 33 ê Ptí>. Read, Gin, Allah, Thr. 0-U 'Glu .; in position Ή is Read, Go, Gly, To be, Lys, Glu, Qin. Thr, Arg, Α.Ή. Phe, XI® <30 Met; Xaa in po &; tion 35 è Leu, Ala, Gly, Asr Pro, Gin, _DlJ Val; Xaa ns position Mê Xse in position 37 ê Phe, Ser, Pro, Trp, 00 1: 1 «; Xaa os position 38 ê Mr., ου Ala; Xaa '> «pooição $ 4 Read, Τχρ, _οΐ! Ms; Xaa in position 41 ç Asn. Cys, Arg, Leu, His, Mfitijt QI-Í £ 1'0; Xaana position 42 ê Gly, Asp, Ser, Cys. Asn, Lys, Thr, Leu, Va-í <Glu. Pne, Tyr, Xle. Met _or Wing * Xaa _r , _s position 43 is Glu, Mrs, Tyr, Leu, Ph®, Asp, Ala. Cys „ Gin, Mg, Thr, Gly du Ser; Xaa ns position 44 is Asp, Sex ', Leu, MS, Lys, Thr. Met, Trp, Glu, Asn, Gin. Fro Wing; A® ^a in p & sjçâo 4S is Girt, Pre, Ph®, Go, Met, Read, Thr. Lys, Trp. Asp, Μη, Arg, Ser, Ala, 11 ». i Glu OB Kis; Xaa. the position IS is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Lys ,. His, Allah, * iy r, Xle, VA1 o; Gly and Xaa in position 4? is XU, Gly, Go, To be, Arg, Pro, or His _; Xaa in position 48 is Read, Ser, Cys, Arg. Xle, His, Phe, Qlu, Lys ,. Thr, Allah, Met, Vai .-. U Μη The....... Xaapa position 48 ê Met, Mg, Ala, Gly, Pro, .Asn, Hrs, or Asp; Xaa to pusifcior; $ 8 is Glu, Leu, Thr, Asp, Tyr, Lys, Asn, Sex, Ala, Eu. Go, Hie, Ph «, Met go Glu Xaa position _tía 51 is Asn, Mg, Mee, Pre, To be Thx, 00 Hi _s; Xaaoa position S-2 is Mn, His, Mg, Lev Gly, Ser. <Jç Thr; Xaa in position S3 is Leu, Thr, Ala, qiy. » Glu, hrs>, Lys, Ser, du wet Xaa in position 54 _and Arg, Asp, lie, To be·, Go. Thr, Gin, Asn, Lys, His, Leu Wing; Xaa in position 55 to ¹ Arg, Thr, Vai, To be, Read, Gu Gly; Xaa in position 55 ® Fro, Gly, Cys, To be, Gin, Glu. Arg, His, Thr, Ala. Tyr, Phe, Leu, Vaiou Lys; Xaa in position 57 0 Asn00 Gly: Xaa fia position 58 is Lsu ,. Ser, Asp, Arg, Gin. Va1.0u Cys; Xaa ns position look Glu Tyr, His. Read it. 7r <? <> ç u Arg t Xaa rsa position fiíi é Allah, Ser, Jtq. Tyr. Asn, OR Thr; Xaa us position? si is Ph «< Asm, Glu. Pro. Lys, Arg. ^GU s »r; Xaa in position S2 is As you, Bis .. Val, Arg. Fro, Thr, Asp, Ile; Xaa sts position »3 á Arg, Tyr, Trp, Lys, to be. Hxs, Pro.OU Val; Xaa in position 54 8 Allah. Asn, pros, To be, t u Lys. ' Xaa the position £ 5 P Val, Thr, Pros, His. Iz $ M * Phe, ^0υ Ser; Xaa r> ã pOOiçàü 5® ® Lys, 1a, Arg, Go, .Asn, Glu, op sort Xaa in position € 7 is To be,. Ala, She, Val, Gly, Asn, He, Fxc ·. «V Bis Xaa ns position 58is Leu, Val, Trp. To be, 11 «. Phe, Thr, pu His; Xax & in position 55 ® Gin, Ala, Pre ,. Thx, . Arg, 'trp, Gly '> ^{0 L:} Leu Xaa in position 7S « Asn, L «u <Val, Trp, Pr®, cu Ala; Xaa in position 71 yo Allah, Het, Leu, y ^ y? £ j Arg. Glu, Thr. Gin Li .. Trp, or Asn - Xaa in possession 73 is Sax> Glu, Met, Allah, Bis. Asn, Arg, _hello Asp; Xaa in position 73 è Allah, Gin, Asp, To be, Gly. Thr, or Arg; Xaa na 74 is 11 « , Met , Thr , Pr® , Arg, Gly, Allah; Xaa i ' ^a Qlr., OR L «u; <s Glu, Lys, · Gly, Asp, Pro, Trp. Arg. To be, Xaa na position 78 and sax, Val, Allah, Asn, Trp, Glu, Pr®. Gly, Asp; Xaa os position 7? and 11 «. S «r, Arg, Thr, C U Leu y Xaa na position 7S is Leu, Allah. To be, Glu, Phe, Gly, or Arg; Xaa position 7θ and Lys, Thr, Asn, Met, Axg. He, Gly, Oh Ksp _; Xaa na P <1 Si Ç 3.Ϊ3 85 THE Asn, Trp, Val, Gly. Thr, Leu, Glu.PU Arg; Xaa ns Possibilities 81 £ Leu, Gin, Gly. Allah, Trp, Arg, V «l, Vü 'Lys; Xaa na position 82 and Read it. Gin, Lys, Trp, Arg, Asp, Glu. Asn, Kis, Thr, To be, Allah, Tyr, Phe, lie, Met _β u Xaa na position 83 is tr®, Allah, Thr, Trp, Arg » p <. · Met; Xaa at position 84 is Cys, Glu, Gly, Arg, Met, Ou Val; Xaana position SS is Leu, Asrt, Val, «« Gin; Xaa ^í? the potion 85 ^ê Pro, Cys, Arg. Ala, or Lys; Xaana position 87 is L «u < To be, Tpp, S U Gly; Xaana position 88 is Allah, Lys, Arg, Val, · or Trp; Xaa / 1st position 8 $ « Thr, Asp, cys, Bait, Val, Glu, Mis., Asn, or be; Xaa ^r ' ^a P8S = Çàa . 80 Allah, Pro, To be, Thr, Gly. Asp, He, _C3, Man; Xaa in position Si é Allah, Pro ?, Ser, Thr, Phe, Leu, Aep, Vii His; Xaa r.e people . 82 t I pre, Phe, Arg, Ser, Lys, His, Ais, Gly, Xle Read; Xaa 03 position 9.3 is . Thr, Asp, Ser, Asn, Pm. Allah, Leu, or Arg; Xaa in position . 84 is Ar g, 11 «, Ser, Glu, Leu, Val, Glu. Ly®. Hxs, Wing, or .Pro; Xaa o the position 85 is His, Glu, Pre, Arg, Val, Leu, Gly, Thr, Asn, Lys, Ser , Wing, Trp, Phe, Xle, py Tyr; Xaa position $ & ê Pro, Lys, Tyr, Gly, Π®. or Thr; Xaa in position 9 and Xle, Val. Lys, Aia, hi Asji; Xaa r; po & .ção 88 è His, lie, Asn, Leu, Asp, Ala, Glu, Glr, . To be, Phe, Met, Val, Ly & ,, Arg, Tyr or Proj; Xaa in position 00 ê Xle, Read, Arg, Asp. Val. Pro, Glu, Gly, Ser , Phe, 00Hi S; Xaa at position 100 è Ly ». Tyr, Ue, Bis., Arg, n '. s «r, Gin, _or p _ro Xaa in position jg: »Asp, Fro, Met, Lys, Hi® ,. Thr. Val, <Lxlu.í ÃjS ^, y AJ.A, QXy. XIj ^ v i OR OXíi; Xaa ΠΒ pG & jao 102 ^it's Gly. Leu, Glu, Lys, Ser, Tyr, or Pro; X.-vJ-Ã í> S ιοί is Asp. or Being; Xaa at pG & ection 104 is Trp, Val, Gy®, Tyr, Thr, Met., Pro, Leu Sln, l> y $. Allah, Phe, the u Gly; Xaa ; position 155 and the", Pru, Als, Phe, Ser, Trp, Gin, Tyr Uu, Ly # / XÍ $> Asp> nu HÍS; Xaa na position 3Õ6 is Glu, To be, Xaa S3 potion XU8 and Arg, Wing <* ^iJ Pr u * <· Xaa na position 108 and . Arg, Thr. XaA r.g position 118 and Lys, Allah, Ser, or Trp; -: ·: · «Λ ·: ·: ··· / ν. ·. >»<·· ^: · <·· γ .... Xaa na position 111 and Leu, 71 ». Xaa, ·. £. position 112 is Thr, Val, Xaa ns position 112 is Phe, To be, Lys, Leu, Xle. Val AT"; Xaa ns position 114 and Tyr. Cys, Xaa the «position 115 0 Leu, Asfi, AU. Lys, Thr. II®, gi _{y> QlJ Frs} , A »P, Leu, Thr, lie. Gin, His, Ser Pre, Glu, Tyr. yours, Ser, »r Gly; Asn, Thr, Leu, Arg, g _{ia> GJu} Arg, Asp, or Heç _f Glib T / r, Glu, His, Ser, ^Oü Phe; Cys, His, Gly, Rry ^ Tyr, _Asspj Eis, Ser, Trp, Arg, or Leu, Val. Pre, Arg, Ala, His, Thr. T-y, OU Het; kaa 116 is Lfâu, Pre, Thr, Met Asp, Val, VsÃUy Arg, Trp, To be , Asn, H is, Ala, 'r, Ph®, G ln, or XI® i Shah* in position 117 is Thr, To be. Asn. Λ, _f **> < Lys, OR Pr »; Shah in position 118 O Leu, Be < Vr ©, TO 1&, Gáu _t Dys, Asp. Tyr; Xaa in position XIS and Glu, To be, Lys, Pro, Az ^ fU _t Thr, Tyr, OU- Arp; Xaa in posiTion 126 is Asn, Al *, For < His, V * X, OR G ln .; Xaa. in position hey »4 · i and Al *, Fri, Ile, Asr>, Pr o, Lys, Asp, OU 'Giy; Xaa in position 222 is Gin, To be, Met, Trp, Arg, Phe. Pro, Hls. Xle. Tyx, OR i 2ys <; & · && in position 127 and Allah, M®r, Glu, Mis, To be, Pr », iyr. OR L®u; where from 1 to 14 amino acids can optionally be supernruded of the N-terminus and / or 1 to 15 amino acids can be optionally deleted from the C-terminus of said modified human intedeucin-3 ~ amino acid sequence: and where from 0 to 44 of the amino acids designated by Xaa are different from the corresponding native human intedeucin-3 amino acids (1-133); and where the N-terminus is linked to the C-terminus directly or through a ligand (L ₂ ) capable of joining the N-terminus to the C-terminus and having new 10 C and N termini in amino acids; 26-27 50-51 85-86 27-28 51-52 86-87 28-29 52-53 87-88 29-30 53-54 88-89 30-31 54-56 89-90 31-32 64-65 90-91 32-33 65456 91-92 33-34 66-67 92-93 34-35 67-68 97-98 35-36 68-69 98-99 36-37 69-70 99-100 37-38 70-71 100-101 38-39 71-72 101-102 39-40 72-73 102-103 40-41 82-83 or 103-104; 41-42 83-84 49-50 84-85 where Lt is a linker capable of joining Rt to R ₂ ; and said hematopoietic protein optionally can be immediately preceded by (metiania ¹ ). (alanlna ' ¹ ) or (methionine' ² , alanine ' ¹ ), 6, Hematopoietic protein comprising; a sequence of 5 amino acids of the formula: RrLrfta, RrU'R _; Ri-R _2: or R ₂ ~ Ri where R; it is a polypeptide comprising; a sequence of amino acids 10 modified human G-CSF of the formula: Xaa Xaa GXy Pre AH To be To be Read 10 Pro Gin To be Xaa Read Read Xaa Xaa Xaa Giu 20 Gin val Xaa Lys Xaa Gin Gly Xaa Gly Allah 30 Xaa Read Giíi GXu Xaa Read Xaa Allah Thr Tyr 40 Lys Read Xaa Xaa Xaa QXli x * && Val Xaa S0 Xaa Gly His To be Xaa Gly He Pro Trp Ai a 80 Pro Read To be To be Xaa Pro To be Xaa Allah Read 70 X & â Read Allah Gly Read To be Gin Read His 80 To be Gly Read Phe Read Tyr Gin Gly Read Read 93 Sir Allah Read Glx * Gly Ile To be Pro Glu Read 100 Gly Pro Thr Read Xaa Thr Read Gin Xaa Asp 110 val Allah «Isp Phe Allah Xaa Thr Xie Trp 120 Gin Met u xU xaa üly Met Allah Pro Allah 130 Leu G-jua ·· It was Thr Gin Gly Allah Met Pro Allah 140 Phe Allah To be Α-λτΰ Xaa Gin Xaa Xaa Allah Gly 150 Gly Val Read val Allah To be xaa Read Gin Xaa 160 Phe Read Xaa Xaa Ser Tyr Arg Val Leu Xaa Xaa Leu Ala Gin Pro (SEQ ID NO: 1). 30 Xaa in position Xaa in position Xaa in position Xaa the position Xaa f? í3 position Xaa in position Xaa ns position Shah in position Xaa 88 position Xaa in position Xaa in position Xaa in position Xaa in position xaa in position Xaa in position Arg. Cys, Xaa 88 position Trp, Gin, Xaa in position Xaa in position Xaa ns position Xaa in position Xaa 83 position Xaa in position Xaa pGS-ion Xaa 83 POSITION Xaa in position Xaa in position Xaa in position Xaa in position Xaa in pGsttion Xaa in position Xaa δ 0 Xaa 88 position Xaa in position Xaa ns position Xaa in position Xaa 83 position Xaa 88 position Xaa 88 position Xaa 83 position ό é é ® Thr. Tyr Ser .. Λ or Leu; Arg. Tyr or Ser; Thr ου Thr eu Wing, 1 Read it. Arg Phe <Ser, His, Lys, Pro. Ser, Cys. Ser, Gly, Leu. Thr, Pro., Arg, Tyr, Ser. Pro; His; le, T ‘hr naked Read; Xie, Pro. Tyr 'Gly; Ala, II®, Leu Lys or Ser; Cys co Ser; Cys «ο Ser; Hrs Asp 42 ^is 43 is « ^υ Leu M ® Pro Thr. Gly, Go Lys Go. 46 ã Glu. Arg, Phe, Arg, I 47 4 Leu or Thr; 49 ® Read r Phe. Arg ⁰⁰ Ser: 50 è Read ,. Tie, His, Pro or 54 is Read ⁴ His; 64 o Cys «the being; 67 è Gin, Lys, Leu ^or Cys; 70 is Gin, Pre, Leu, Arg eu 74 ^and Cys or Ser; 104 « Aap, Gly ° u will; 108 ^έ Leu, Wing, Go, Arg, ¹ 115 ® Thr, His, Leu «o & i _a 120 è Gin, Gly. Arg. Lys or 12 3 ⁶ Glu, Arg, Phe Thr 144 is Phe, His, Arg, Pro. 146 * Arg ° ⁴ Gin; 147 and Arg ^or Gin; 156 è His, Gly or Ser; 159 o To be, Arg, Thr, Tyr, ’ 162 is Glu, Leu, Gly ou- Trp 163 έ Go, Gly, Arg or Ala 169 is Arg, Ser, Leu, Arg or 170 and Hi $, Arg o ^ Cys; To be; Trp Val <31 le ° u Ala; Leu, Gin Trp a Allah. His, Gly; where optionally 1 -11 amino acids of the N-terminus and 1 -5 of the C-terminus can be deleted from the said modified mo5 human G-CSF amino acid sequence: and where the N-terminus is attached to the C-terminus directly or through a capable of linking N-terminus to C-terminus and having new C and N termini in amino acids; 38-39 65-66 126-127 39-40 66-67 128-129 40 * 41 67-68 128-129 41-42 68-69 129-130 42-43 69-70 130-131 43 .... 44 70-71 131-132 52-53 71-72 132-133 53-54 91-92 133-134 54-55 92-93 134-135 55-56 93-94 135-136 56-57 94-95 136-137 57-58 95-96 137-138 58-59 96-97 138-139 59-60 97-98 139-140 60-61 98-99 140-141 61-62 99-100 141-142 62-63 123-124 or 142-143 63-64 124-125 64-65 125-126 R ₂ is a polypeptide comprising; a modified human IL-3 amino acid sequence of the formula: Wing Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Vai Asn 5 1 5 1015 Cvs Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 2530 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 4045 Xaa Xaa Xaa Xaa Shah& 50 Xaa Xaa xaa Xaa Xaa 55 Xaa Xaa Xaa Xaa Xaa 50 xaa .Xaa. Xaa y 's. Xaa 55 xaa Xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa 75 Shah Xaa Xaa Xaa Xaa 80 Xaa Xaa Xaa Xaa Xaa 85 Xaa Xaa Xaa Xaa Xaa 90 xaa Xaa Xaa Xaa 55 xaa Xaa Xaa Xaa Xaa 100 Xaa Xaa Xaa Xaa Xaa 105 Xaa Λ & c * Xaa Xas Xaa Xaa Xaa \ aa Xaa 115 Xaa x & a Xaa Xaa Xaa 120 Xaa Xaa Xaa Hello Ci in 125 Thr Thr Read Ear Read xa 0 Ward 11 « (SEC? ID Fhe AT THE;. 2 ? 7 hello Wed Xaa πa position 17 is Ser, Ly ', Gly, Asp, M & t, Gin, çn. í * rs Xaa in the pasture hello Asn, Kís. L «u, 13 « Arg, u u-m; Xaa n <$ position IS is Wer, Phe, He, Arg, Qly 4 Ala, 0 Gys; Xaa we p & siçáe 20 is 11 «, eys. Gin, Glu, Arg, R * », OR Al»; Xaa in position 21 is Asp, Phe. Lys Arp, Allah Gly, Glu, Gin, Asn, Thr. To be. »« Val; Xaa in position 22 Glu. Trp, Fro, To be, Allah, Xis, Assy ,. Asn, Gin, Leu _t ValOU Gly; Xaa ns position 23 í Flight> A1.ã> Tfcpj Lyn. Fhe, Illustration, or Ars; Xaa in position " 24 £ 11 », Gly, Vai, Arg, Ser, çj jj L ^ &U; · Xaa in position 21 0 Thr, 'is, Q.ly, Gin, Arg, ? ro, Ç.y Ai »; · Xaa in position ££ & Hie, Thr, Ph®, Qly, Αχ-g, Ãl <i OR Trp; Xaa in position 27 and Lwu, Gly, Arg, Thr, Ser, air wing, i Xaa íl® $ 3 £? 8ÍÇ-àO $ 3 and ^ ys ·, Cly, ? re> <Vai OR Trp; Xaa na pü & içáü 25 is Gin, Asn, Leu, Fro, Arg, 0 0 Val, · in position 30 O Pr *, Kis, Thr. Gly, Asp, Gin, S'r, Leu, gu Lys; Xaa at position 31 is Pro; Asp; Cly; Allah; Arg; Read; or Gin; Xaa at position 32 is Leu; Val; Arg; stage; Acn; Gly; Allah; or Glu; Χλ® ns position Al * Thr Pro. Read it, Gin Xaa pes: tion 34 ê Leu, Val, Gly, To be. Ly *, Glu, Gin. Thr, Arg, Al®, Phe, Xie 00 Met; Xaa Π8 position 25 & Leu, Ala, Gly, Asn, Pro, Gin, OR Val; Xa® ns position 3 € § Asp * i Xvtôti> o l í X * a in position 37 is ? h «, Ser, Pro. Trp. or Ha; Xaa ns position 38 ê Asn, OU Al®; Xaa * 3 weight 40 ê Leu, Trp, _ot . Arg; Xaa pa position 41 è Asn, Cys ,. Arg, Leg, Hit, Met, 00 p _ro . Xaana position 42 is Gly. Asp. To be, Cys. Asm. Lys, Thr. Leu, Val, Glu, Phe, Tyr, 11 «. Met _I Wing; Xaapa position 43 is Glu, Asn. iyr, Read, Phe, Asp, Ala, Cys, Gift, Arg, Thr, Gly Oã Ser; Xaa ns position 44 è Asp, Ser, Leu, Arg, Lys, Thr, Met, Trp, Glu, Asn, Gin, _Alô Pre wing; ^ 3 to ^our position 4S is Gin, Pro, Phe, Val, Met, Leu, Thr, Lys, Trp, Asp, Wing, Arg, Ser, Ala,: 11 «. Gluou Hi » £ Xaa ns position 45 is Asp, Phe, Ser, Thr, Cys, Glu, Asn, Gin, Ly®, Hi®, Allah, Tyr, 11®, Vaiou Gly; Xaa pa position 57 8 11®, Gly, Go. Ser, Arg, Pro, 0 «Hit; Xaa o »position 4B is L «u, Ser, Cys. Arg. He, Mrs, Phe, Glu < Lys, Ths, Allah, Met, Valjy Aap; Xaapg. position 4 $ o Het, Arg, Ala. Gly, Pro, Asn, Ηχβ, ρρ Asp. Xaa until posit lor; 5 (5 is Glu, Leu, Thr, Asp, Tyr. Lys, Asn. To be. Wing, XI®, Val, Mis, Phe, Met or Gin; ^ * ^the position 51 is Asn, Arg, Met, Pm, Ser, Thr, The «HiS; Xaa π the position 52 è .Asn, Mis, Arg, Read it. Gly. To be, or Thx; Xaa ns position S3 is Leu, Thr, Ala, Gly, Glu. Pro, Lys, be, or Xaa pg. position 54 _is Arg, Asp, lie. Ser, Val, Thr, Gin, Asn, Lys, His, Wing o Xaa in position 55 is Arg, Thr, Go. Ser. Leu, _O o Gly, - Xa * in position 56 is Pro, Gly, Cys, Ser, G.ln _f Glu, Arg. His, Thr. Allah, Tyr. Phe. Leu, Vaiou Lys; Xaans position 57 is ASiIFcU Gly _; Xaa in position "& is Read it. Ser, A-sp, Arg, Gin, Val.i J U Oy®; Met; Xaa in position 5% is Glu Tyr, His, Leu, Pro, gu Arg; Xaa in position £ <j o Allah, pne. To be. Asm, Pro, · Tyr < Glu, Pro, Asn, ^{9 <i} Thr; Lys. Arg, Ser; Xaa in pssition 81 is Xaa in position £ 1 and Asn. Hl ». V & l, Arg. Pro, Thr, Asp, or Π '; Xaa in position 53 i Arg. Tyr> Trp, Lys, Ser. Xis, Pro.or Vai; Xaa cia position & 4 & Allah, Aso., Pro, Ser. OV Lys; Xaa in position $ 5 and Go, Thr, Pro, His, Read it, Phe. To be; Xaa in position 6C 0 Lys, He. Arg. Go. Asm, Glu, or Ser; Xaa n-s position 51 and To be, Allah, Phe. Go, Gly, Asn, He, Pro, or Xaa «the position ege Read Go Trp, He, Phe, Thr, 00 Exs; Xaa in position and Gin, Allah, Pro. Thr. Glu, Arg, Trp, Gly, the « Xaa fja position 70 and Asn, Leu, Go, Trp, Pro, or Ala; Xaa in position Trp. or 71 Asr; is Allah, Meo, Read, Pro, Arg, Glu, Thr, Gin, Xaa in position AND To be, Glu, Met, His, Assn, Arg, _o ,. Asp; Xaa at pOBíçáa 73 0 Allah, Glu, Asp, Leu, Gar, Gly, Thr, or Arg, - Xaa in position 74 4 11 « , Met, . Thr, Pro? _f Arg. Gly, Ala; Xaa in the post » ΟΙ®, or $ 7 Read; 4 Glu, Lys Gly, Asp, Pro. Trp. Arg, Xaa in position ? £ is To be, Go, Ala, Asn. Trp, Glu, Fro, Gly, or Xaa os position 77 4 1'1 «, To be Arg. Thr, OR Read; ............... Xaa in position 75 is Leu, Allah, Glu, phe, Gly, or Arg; Xaa ^rfa F ^IJ »ICAO $ 7 is Lys, Thr, Asn. Met, Arg, He, Gly, or Asp; Xaa ns postoão SC 4 Am. Trp Go, Gly, Thr, Leu, Glu, c g Arg, - Xaa in the post 81 δ Leu, Gin. Gly. Allah, Trp, Arg, Val, OR Lys; Xaa «the position 82 4 Leu, Gin, Lys. Trp, Arg. Asp, Glu, Asn, Xis, Thr, Hxs; Read; Asp, Ser, Ala, Tyr, Phe, II ', Met q _; j Go; Xaa in position S3 is Pro. Wing. Thr, Trp, Arg, <m Met; Xaa in position 54 4 Cys, Glu, Gly, Arg, Met, or v * l; 85 is Read, Asn, Go, ^or Gin; Xaa «the position £ 8 Pro, Cys. Arg, Ala, or Lys; Xaa in position 87 is Read it. Ser. Trp. or Gly: Xaa in position 85 4 Ala, Lys, Arg, Go, pu Trp; Xaa ns position 89 O Thr, Asp, Cys, Read it. Go, Glu, Xis, Asn, c u Xaa in position . 58 4 Allah. Pro. Be, Thr, Gly. Asp, He, 0U Met; To be; Xaa in position SI is Allah, Pr », To be, Thr, Pne, Leu, Asp, OR Behold; Shah* in position S2 ê Pro, Phe Arg, To be, Lys, His, Ala, Gly, .tie ^aL Read; X ** in position . SfJ is: Thr Asp, Asn, Pr », Allah, L «u, or Arg; Xaa in position 54 è Axg, He, Glu, Leu, Go, t * lh «. Lys, Axé, Ãla, a:> Pr ©; X ** in position 95 ê Hrs, Gin, Pr ', Arg, Go, Leu. Gly. Thr, Àar ,, Lys, Ara, Trp, Phe, He, o; j Tyr; Xaa f »pssiçàa 9 is Pro. Lys. Tyr, Gly, He, or Thr; Xaa in position is η ·. Come on, Lys, Ala. OR As'; Xaa in position 98? His, 11 «, Asn, L» u, Asp, Ala, Thr, Glu. Gin, To be, Phe,. Met, Val, Lys, Arg, Tyr or Prot Xaa in position 99 is lie, Leu, Arg, Àsp, Go, Pr ». Olis, Gly, Se »·, Ph®, CU 'Ria; Xaa in position 100 it's Lys , Tyr, Leu, His, Arg, Bs, s «r, Sir ,, _or p _ro Xaa in position 10 * is Asp , Pro. Met, Lys, His, Thr, Go ... Tyr, Glu. Asn. Ser, Ala, G ly, X le, leu, or Glh-; Xaa in position 182 it's Qiy. Leu, Glu, Lys ,. If », Tyr. © U Pr ©; Xaa η the position 143 4 Aap, <3 d Being; Xaa in position 204 is Trp, Go, eys. Tyr. Thr, Met, Pr ©, Deu, Gin. Lys. Allah. Phe, CD Gly Λ .Xaa <ns position 102 and the". Ps ^- ©, Allah, Phe, To be, Trp, CIk, Tyr, Read, Lys, 11 », Asp, Gc His Xaa in position IS 6 δ Glu, To be, Allah, Lys, Thr, He. Gly, or Pr '; Xaa © to Possession 108 is Arg, Lys Asp. Leu, Thr. 11 », Gin, His, Set Wing ^{0: J} Pr »; Xaa in position 109 is Arg, Thx, Pr © ,. GXv _? Tyr, Leu, To be. or Giy; Xaa in position 116 ê Lys < Allah, Asr, Thr, Leu, Arg, Gin, HiS. Glu Ser, 0 0 Tr. ©; · in posfção * 4 * Leu, ..Iley. Argf, Asp, OR Wc; Xaa in position 112 • is Thr. Go, Glu. Tyr, Glu. His. To be ^or Phe; Xas ns position 113 is Phe, To be. Cys. Kis, Gly, Trp, Tyr. Aep, Lys ,. Leu, lie. Go 40 As ©; Shah" in position 114 Tyr, Cys Hia, Know, Trp, Arg, 00 Leu; aaa "the position 115 ® Leu, Asn. Go, Pro. Arg, Allah, Sis, Thr, i ^ p, OR Me Xaa Arg, T * p, 115 To be is Lys. , Asn, H Lau, Pr ', Xte, Met. is. Ais. Tyr. Phe, G Asp. Ln, OR Go, *1" Glu. < Xaa in position 117 is Thr. Ser. Asn, 21 «, Trp, Lys. OR P xo. Xaa in position 115 is Leu, Ser. Pr », Allah. Glu. Oys. Asp, OR Tyr; Xaa in position 1.18 and Glu, S «r. Lys., Pro. Thr. Tyx. OR Arg. X && Π3 POSITION 12 (3 and Asn, Allah. Pre, Read it. Hls. Go, OR G In. · Xaa in position 121 and Allah, Ser, lie, Asn. Fro, Lys, Asp or Gly * Χ & α in position 122 is Gin, Ser, Met, Τχρ. Arg, Phe, Pro, Sls Ile, Tyr, OR i Cys X Xaa in position 133 is Allah, Met. Glu ,. sir, To be, Pr «s. Tyr, or Leu, where from 1 to 14 amino acids can optionally be deleted from the N-terminus and / or 1 to 16 amino acids can be optionally deleted from the C-terminus; and where 1 to 44 of the amino acids designated by Xaa are different from the corresponding native human interteukin-3-amino acids (1-133); where Lí is a ligand capable of binding Ri to R ₂ , and additionally said hematopoietic protein can be immediately preceded by (methionine '), (alanine ^) or (methionine' \ alanine ' ¹ ), 7 Hematopoietic protein comprising; an amino acid sequence of the formula; where Ríê a polypeptide comprising; a sequence of 15 modified human G-CSF amino acids of the formula; Xaa Xaa Gly Pro Allah Fri' To be Read 10 Pro Gin To be Xaa Read Read Xaa Xaa Xaa Glu 20 Gm Val Xaa Lys XoLcS Gin Giy Xaa Giy Allah 30 Xaa Read Sin Glu Xaa Read Xaa Allah Thr Tyr 40 Lys Read Xaa Xaa Xaa Glu Xaa Xaa val Xaa 50 Xaa Gly Hie To be Xaa Gly xie Pre Trp Au.a 63 Pro Read To be To be Xaa Pro To be Xaa Allah Read 70 Xaa Read Allah Giy xaa Read To be- Gin Read Mis SO Ser Gly Read Phe Read Tyr Girt Gly Read Read 90 Gin Allah Read Glu Gly Xie To be Pro Glu Read 100 Gly Pro Thr Read Xaa Thr Le « Gin Xaa ASp 110 Val Allah Asp Phe Allah Xaa Thr He Trp Gin 12'0 Gin Mat Glu xaa Xaa Giy Met. Allah. Pro Allah 130 Read Gin Pro Thr Gin Gly Allah Met Pro Allah 140 Phe Allah To be Allah Xaa Gin Xaa Xaa Allah Gly 150 Gly Val Read val Allah To be Xaa Read Gin Xaa 160 Phe wow xaa Xaa To be Tyr Val Read Xaa 170 Xaa Read Allah Gin Pro (SEQ ID • AT THE; 1)

Xaa in position 1 ê ¹ Xaa Ft <3 pÜSÍÇãG 2 ê Xsa in position 3 ®: Xaa in position 13 ® Xaa in position 16 is Xaa in position .17 is Xaa in position 18 ê Xaa in position 22 è Xaa position 24 is Xaa in position . 27 ê xaa in position 30 ^is Xaa in position 34 is xaa in position 36 « Xaa H <1 pCSí 42 * Xaa in position 43 è Arg, Cys, ^{0 <i} Read Xaa ns position 44 ® Trp. Gin, ^or Thr ns position 46 is Xaa in position 47 è Xaa nç position 49 « xaa ns position 5Q is Xaa ns position 54 is Xaa in position 64 è Shahist tísí pot & içãü 67 0 Xaa 03 position 70 is Xaa in position 74 ^â Xaa in position 104 è Xh ^ in position 108 » Xaa in position $ 115 Xaa in position 120th Xaa in position 123 « X-Ha in position 144 is Xaa in position 146 is Xaa in position 147 is Xaa in position 156 is Xaa in position 159 o Xaa in position 162 á Xaa ns position 163 is Xaa in the country 169 à Xaa in position 170 is ends optionally 1 -11 Th: Read To be, Tyr Gly; Read < Phe, Lys, Cys, Leu, Arg, Ile. Asp. Allah, Lys or Ser, Cys or Ser; Cys «<> Ser; Ris, Thr, Tvr His Know Gly. Pro. Ser. Gly; Ile, Leu Pro, Arg a S er; Thr »<< Thr or Ala, Xle, I Hrs, Zre or Thr or Ala; Read; His OR ciy, Arg Phe Come on, Lys. Trp, Al A & p, val. Allah, Glu Read or Read it. phe, Arg ^{C! i} Read it. Ile, His,] Read ^OLÍ His; cys <> «Ser, Gin, Lys, Leu ^or Gin, Pro, Leu, Arg ° ^u Ser; Cys & u Ser Gly Allah. Hís, Gly. Arg. His, Gin; Arg, He Alã; To be; o or Tyr; Asp, Leu, Gin Glu Phe Arg ^or Arg o · His Ser Glu Vai ^otJ Vai; Go, Arg. Trp Leu or Ala; Arg, Lys Phe or Thr Arg _t Pro, Leu. Gly; His Gly _or Arg. ¹ Read, i Gly. . Arg, Ser,: His, Arg or> Ser; Thr, Tyr, val ^or Gly _; Gly or Trp; Arg or. Read it. Arg au cys; To be; amino acids of the N-terminus and 1-5 of the C-terminus can be deleted from said modified human G-CST amino acid sequence; and where the N-terminus is linked to the C-terminus directly or through a linker capable of linking the N-terminus to the C-terminus and having new C and N termini in amino acids: 38-39 60-61 123-124 39-40 61-62 124-125 40-41 62-63 125-126 41-42 63-64 126-127 42-43 64-65 128-129 43-44 65-66 128-129 44-45 66-67 129-130 45-46 67-68 130-131 46-47 68-69 131-132 47-48 69-70 132-133 48-49 70-71 133-134 49-50 71-72 134-135 50-51 91-92 135-136 51-52 92-93 136-137 52-53 93-94 137-138 53-54 94-95 138-139 54-55 95-96 139-140 55-56 96-97 140-141 56-57 97-98 141-142 57 -58 98-99 or 142-143 58-59 99-100 59-60 122-123 is a polypeptide comprising; a sequence of modified human ammo-acids with modified formula: SerPrnAJ.aProFrnAlaCysAspLeuArgValLeuSarLysLeuLeuArgAspSer 1 S 1015 HisValLeuHi & SerArgLeu £ erGlnÇysProGluValííísProX * euProThrPro 20 25 3035 valLeuLsuProAlaValAgpPheSerLeuGlyGluTrpLysThrGlnMetGluGlu 40 45 5055 ThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeuLeuGluGlyValMetAla 60 65 7075 WingArgGlyGlnLeuGlyProThrCysLeuSerSerLeulieuGlyGlnLeuSerGlv 80 $ 5 9095 Glnv alArgLeuLeuLeuGlyAlaLeuGlnSerLeuLeuQlyThrGlnXaaXaaxaa * 00 105110 XaaGlyArgThrThrAlaHisLysAspProÀsnAlallePheLeuSerPheGln.His 115 120 125130 LeuLeuArgGlyLysValArgPheLeuMetLeuValGlyGlySerThrLeuCysval * 3c 140 145 ^ 50 Arg (£ EQ IL NO: 256) 153 where Xaa in position Phe, Trp, 112 is deleted or ; Met; Leu, Val, Xle, Pro, Xaa in position 1 ^ 3 is denounced or Pro, Phe, Allah, Val, Leu, 11®, Trp, Met; Xaa in position ..... 114, .is reported or ’Pro, Phe, Allah, Val, Leu, He, Trp, Met; Xaa in position 115 Gin, Gly, To be, Thr, Tyr, Asn; where the N-terminus is linked to the C-terminus either directly or through a linker (U) capable of linking the N-terminus to the C-terminus and having new C to N termini in amino acids; Μ — Μ— ₁ 1111 ιι ιι ιι ιι ιι 11 ιι ιι mu mnrrrrr I r I r 26-27 50-51 27-28 51-52 28-29 52-53 29-30 53-54 30-31 54-56 32-33 56-57 33-34 57-58 34-35 58-59 35-36 59-60 36-37 78-79 37-38 79-80 38-39 80-81 40-41 81-82 41-42 82-83 42-43 83-84 43-44 84-85 44-45 85-86 46-47 86-87 47-48 87-88 48-49 88-89 108-109 109-110 110-111 111 -112 112-113 113-11A 114-115 115-116 116-117 117-118 118-119 119-1.20 120-121 121-122 123-124 124-125 125-126 where L ~ 1 = is a ligator capable of binding R <to R ?; and 5 additionally said hematopoietic protein can be immediately preceded by (methionine ' ¹ ), (alanine ⁴ ) or (methionine' ^2. Alanine ''). 8 Hematopoietic protein comprising; an amino acid sequence of the formula; R _r L _r R _s , R _r Rs. or R ₂ -R, 10 where R ₅ is a polypeptide comprising; a modified human c-mpl linker amino acid sequence of the formula: SerPvoAlaPruPicAla-OysAspLeuArgValLeuSerLysLeuheuArgAspSer *. , - ·. „5; . 1015 Hi. SValLeo & isserArsLeuSerGlnCysProGluVaXHí sProLeuP ^ GTh ^ ro 20 25 3035 ValLeuLeuProAlaVa lAspPheSerLeuGlyGluTrpLy sThrGl nMeoGluGlu 4S 45 5055 ThrLysAlaGlnAspXleLeuGiyAlaValThrLeuLeuLeuGluGlyvalMetAla 60 65 70 * 75 Al aAr gGly g InLeuGlyProThrCysleuS erSerLeuLeuGly G InLeuS * »r G * v 30 gg §Q * 'gg * G rhV at Ax gL euleuLeuG XyAlaLeuG Ids erLeuLeuGlyThrGlnXaaXaaXaa 100 105 XaaGlyArgThrThrAlsHisLysAspProAsnAlaxiePheLeuSerPbeGlnH.is ** ⁵ 170 125130 leuLeuArgGlyLysValArgPhaLeuMeíiLeuValGlyGlySerThrLeuCvsval -35 140 145 Arg LSEQ XD NO: 256) 153 where Xaa in position 112 is deleted or Leu, Val, Xie, Pro, Phe, Trp, : Met; Xaa in position 113 is deleted or • Pro, Phe, Allah, Val, Leu, He, Trp, My xaa in position 114 isdetached or  Pro, Phe, Allah, Val, Leu, · ^: · ^: · ^: · ^: · ^: · '<· 2 ··; ·; ν. ... Xle, Trp, Met; Xaa in position ...... ^: ™ 2 ............. ............................ ^.... Gin, Gly, To be, Thr, Tyr, A ^ n; where the N-terminus is connected to the C-terminus directly or through a linker (L _s ) capable of connecting the N-terminus to the C-terminus and having new C and N termini in amino acids; 26-27 48-49 109-110 2 / -28 51-52 110-111 28-29 52-53 111-112 29-30 53-54 112-113 30-31 54-56 113-114 31-32 55-56 114-115 32-33 56-57 115-116 33-34 57-58 116-117 34-35 58-59 117-118 35-36 59-60 118-119 36-37 79-80 119-120 37-38 80-81 120-121 38-39 81-82 121-122 40-41 82-83 123-124 41-42 83-84 124-125 42-43 84-85 125-126 43-44 85-86 OR 127-128; 44-4c? 86-87 40-47 87-88 47-48 108-109 where R ₂ is a polypeptide comprising, a sequence of amino acids Modified human IL-3 of the formula: 5 Wing Pro Met Thr Gin Thr Thr Ser Leu Lys Thr Ser Trp Vai Asn 1 5 1015 Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 2530 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 10 35 4045 Xaa Xaa X && Xaa Xaa 50 Xaa Xaa XS- & Xaa Xaa 5S Xaa Xaa Xaa xaa Xaa 50 Xaa .Xaa XâSí r -a Xaa 55 Xaa xaa Xaa Xaa Xaa 70 Xaa Xaa Xaa Xaa Xaa 75 Xaa xaa Xâsâ: Xaa Xaa 80 Xaa Xaa Shah& Xaa Xaa Ô5 Xaa Xaa Xaa Xaa Xaa 90 Xaa Xaa Xaa Xaa Xaa 55 Xaa Xaa Shampoo Xaa Xaa 100 Xaa Xaa Xaa Xaa : Xaa 105 Xaa Fhs Xa <i Xaa Xaa 110 Xaa Xaa X && Xaa Xaa 115 X.aa Xaa xaa xaa Xaa 120 Xaa Xaa Xaa Gin Gin 125 T ^ *! · Τ Thr Sar Lau 130 Allah (SEQ He Phe NO: 2? ONLY qu® Xaa ns position 17 is s «r. ly _B> Gly, _{Met {} Xaa ns χ $ ρ position Asn. His, Leu, 11 ', Arg, or Gin; Xaa our position ^and IS and mt. Ph «, n «, Arg. Gly, Ala, _G g Oys; Xaa ns jp g position xie, cys. Gin, Glu, Arg, pre, _{or λ} ι _β; Xaa in the gl pssition it is Asp. Phe, Lys. Arg, Ala, Gly, Giu, ₆ ln, Asp, TM, S «p OUVél; Xaa ns position jç Glu, Tsp, Fra ·, Ser, Ala, sis, Asp, Am, Ql _n , Leu, Vai OR gly, - Xaa in position _{23 is} 21 «,. Go, Allah. Gly, Trp, Lys, pp®. Uu. S* Xaa n pos-ation Xaa in the potion ..... 2S position Xas Λ3 Xaa. Γ53 Xaa ns D0SÍÇ3Ü Xaa na Xaa in the gosíçáü position Arg; è 11 «® Thr. Ki®, Gly, Gia, Ms, Pro. Sis. Thr. Go Fha, Mg. fc ?, Sar. Fhs, Lys> Arg, Gin, Am. Fro, His L®u i4ij OR Lev; OR. Allah; Gly v Arg, Ale.,: _GG : Typ; Mr. or Ala; Gly. Fra. I go Trp; Arg, hi; VaiAsp. Gin. S * r. Lav, OR Lys _; Gin, Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa: Xaa Xaa xaa Xaa is 0 Xaa Xaa Xa «i xa, Xaa Xaa> aa Xaa Xas Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa Xaa Xxa Xaa Xaa Xaa & 5 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xae · .100 Xaa Pha xaç, Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa .5 Xaa Xaa Xaa Gin Gin Thr Thr Leu Ser Leu Phe wing ¹² .5 130 <SEQ ID NQ; 2i where Xaa. ua portion _l? i® S «r, _{Ly # <sly <} Asp, K» t, Xsa in position 18 is Asn, Xis, Leu, üe, phe. Xa® position .15 6 Mat, Ph®, 11® ,. Axg, Gly, Ala, or Cys; Xaa in position 2S is Xle, Cys, Gin, GÂu, Arg, Pre-, orj AI «.; Χ & Λ BS pOSiÇSÜ 21 is Asp, ph®, Lys, Arg, Ala, Gly, Glu, Gin, Asn, Thr, Ser ^HH 'Vai; Xaa r; s position Glu, Trp, y _{rCíf S (S. R} , _{A1 <j} His, Asp, Asm. Gin, Read, v * i «Ü Giy; X *. _s in position 23 is He, Val, &; «. gly, <prp, Lys. Phe, Read, s «r / OR À®S; Xaa in position ⁴ 24 ® 11 », Gly, · Val, Àrg. s «j ?, Phe, _tni Leu; Xa »rua postç-Sa ···· 25 is Thr, Pis ,. Gly, Qln, ... Arg, .. XCO ..> .; 0 A ¢: .-: Xaa sa position 26 is Hxs. Thr, ph®, Gly, Arg, Ala, or Trp; Xa «in position 2? £ Lau, Gly, Asg, Thr, Ser, or Ala; Xaa in position 26 is Lys, Arg, Leu, Gin, Gly, Pro, Vel or Trp, · Xe® ns position 23 is Gin, Asn, Leg, Pro, Arg, OR Val; Xaa na ps & rçàe 36 è Pre, His, Thr, Gly, Asp, Gin, Ser, Lav, or Lys Xaa in position 3 3 4 Fro, Read, Gin, Allah, Thr, _or: - Glu; Xaa ns position 34 4 Leu, Go. Gly, To be, Ly.e. Glu. Din, Th Arg, Ala, Phe, T1 & 0 • J Met; Xaa in position IS A Leu, Ala, Gly, Aso, F: ro. Gin, or Val; Xaa n® position 4ό 4 ....,, .f & u, 0 'U' 4hs 1; ..... Xaa ng position 37 is Pho, Ser, Pro, Trp, »U He; Xaa os position 3rd is Aen, «« Ala; Xaa position 4 δ φ Read, Trp. _CÍJ Arg; Xaa o the position 41 is Asn. Cys, Αχ-g, Leu, His. Met, ^ου Pro; Xaana position 42 ê Gly, Asp, Ser, Cys. Asn, Lys, Thr, Leu, Var. GλΙι, Phe, Tyr, na »Mat _O u Ala > Xaane position 43 is Glu, Asp, Tyr, Leu., Phe, Asp, Allah, CX &, Gin, Arg, Thr, Gly nude Ser; Xaa os position 44 and Xsp, Ser, Lsu, Axg, Lys. Thr, Met, Trp Glu, Asn, Gin, Pro Wing, - Xaa ^ g pc & jçâo 4S g Gln, Pre, Phe, Val, Met, Leu. Thr, Lys. Trp, Asp, As a, Arg, Gar, Ala, XIe, Glu OU His Xaa ua position 46 4 Asp, Phe, S »r, Thr, Cys, Glu, Aen, Gin, Lys, His, Allah, Tyr, Ile. Veiled Gly: Xaa n «position 4? is He, Gly, Val, Ser, Arg, Pro, 0 «H; is; Xaa ns position 48 4 Read, Ser, Cys. Arg, XI®, His. < Fhe, Glu, Lys, Thr, Allah, Met, Val _Cy Asn; Xaana position 4.9 4 Man, Arg. Ala, Giy, Fro. Asn, Ris, CHI Asp Xaa at posit ion 5 C> yeah Glu. Leu, Thr, Asp, Tyr, Lys. To be, Al®, Xie, Val, His, .Phe. Meteu Gl »; position Si 4 Asn, .Arg, Met, Pro, Ser, Thr, or gj _# , Xaana position 52 4 Ass, Hi *, Arg. Read it. Gly, Ser, _cu Thr; JUaaapos ^ .... _S3 is Thr,. Ma. Gly, Glu, p _riS , Lys _{,? <R} , _{O <J Het} Xaa _in position Si _á Arg, Asp, 11 «, $ _{and £ (V <i <Tkr} Lys, His, Ala or Leu; Xaa ns position 55s Xa «oa jgé position Thr, Ma, Tyr. Xaans' position 4 Arg. Thr, Val, Sex, Leu, _or Gly; Pro, Sly. cys, Ser, Gin, Glu, Arg, His, Fh® »Leu, Val ^: PW Lys; A »» ®V Gly; Xaa ns position 58 is Read, Ser, Asp, Xrg. Gin, Val, or Cys, · Xaa o the position and Xaa t> the pos; tion 86 is Xaa ns position 61 is Xaa in position £ 2 is Xaa ns position 6'3 è Xaa «the position $ 64 Xaa 08 POSITION £ 5 is Xaa o the position 6 is Xaa in position £ 7 § Xaa position $ 6 Xaa os position 6S *   at ₇₀ è Xaa os position 71 è Trp, and u Asn · Xaa os position 2 is Xaa os position 7 3. Xaa in position ? 4 is Xaa ^ position 75 is Glu, or Read; Xaa n® position ? S ^is Xaa in position 77 & Xaa in position 78 * Xax ^ ⁸ P ^ftSi ío 78 4 Xaa in position $ 80 Xaa the position 81 is flB Xaa in position 82 is His, Thr, Ser, Xaa in position 83 is Xaa o the position 84 is Xaa Exposition 85 ® in position 86 ^έ Xaa in position 87 is Xaarts position 88 is Xa »ns position 85 8 Xaa ⁱⁿ pcsition . 9Q ^is Glu Tyr, His, Leu, Pro, or Arg; Allah, To be, Pro. Tyr, Asn, <u; . Phe, Asn, Glu. Pre, Lys, Arg, To be; Asn, His, Val, Arg, Pro, Thr, Asp, or He; Arg, Tyr, Trp, Lys, Ser, Hls, Pre, <su Val; Allah, Asn, Pro. Ser. I Lys; Val, Thr, Pro Xis, Leu, Phe. To be; l «y & í Ile. Arg, Val. Asn, Glu, at; To be: Sefc < Allah, Phe, Val. Gly, Asn., 11®, Pr o, or Leu, Val, Trp, Ser, 11®, Phe, Tnr. or Mis; Gin, Pro, Thr. Glu. Arg, Trp, G1 y. or Mb, Leu, Val < Trp, Pro, Su Ala; Wing, Met, Read Pro, Arg, Glu, Thr. Gin. Glu. Met> Ale. His, Asn, Arg. _OR Asp; · Allah Glu. Asp, Read, Ser, Gly, Thr, or Arg; Sis Leu: U®, Met, Thcr, Pre, Arg. Gly, Ala; Glu, Lys, Gly. · A * p, Pro. Trp, Arg, Ser, To be, Val, Ala, Asn, Trp. Glu, For, Glv . naked 11 «, Ser .. Arg, Thr, or Leu? Leu, Allah. Glu, Phe. Gly, OR Arg; Lys, Thr, Asn, Met, Arg, He. Gly, ass Asp; Asn, Trp. val, Gly, Thr. Read it. Glu, Or Arg; Leu, Gin, Gly, Ala. Trp. Arg, Val, ass Lys; Leu, Gin, Ly '. Trp. Arg, Asp, Glu. Asn Allah, Tyr, Phe. Xle, «♦ t or 1 Val; Fru, Ala, Thr, Trp, Arg, uu N0 & t:, í: Asp; Cys, Glu, Gly, Arg, Met, nu Val; Leu, Asn, Val .. <? U Gin; Pro, Cys, Arg, Ala, u Lys, Leu, Ser, Trp, or Gly..; Ala, Lys, Arg, Val, or Trp; Thr, Asp, Cys, Leu, Val, Glu, Xis, Asn, Oh Ala, Pro, Ger, Thr, Gly, Asp, He, 0; Me t; To be; Xaa at pcsection 91 is Hello , Pro, To be, Thr, Leu, Asp, OR His; Xaa J> S well & section Read: 91 is Pro. Phe, Arg, To be, l »y s $> v Hrs, Aia, Gly, lie ^or Xaa at 9, 3 © < Tiir, ÂSp, To be, Asn. Pro, Ale, 00 Arg; Xaa at , §4 is Ax g. Xis, To be. Giu, Lí & m.y Val .. Gin,. Lys, Si ', Wing, OR Pro; Xaa the position 95 0 His, Gin, Pre. Arg, Val, Wool, Gly, Thr, Asn Lys. To be,. Allah, Trp, Phe, 11 ', cu Tyy; Xaa in position 9 *> ® Pro. Lys, Tyr, Gly, XI ', or Thr; Xaa in position 9 and Ile, Val, Lys, Ala, or Asn; Xaa the position 93 is Lo, lie, Asn, Lee, Asp, Ala, Thr. Gru, Gin, to be, Phe, Met, Val, Lys, Arg. Tyr or Pia; Xaa in position 99 P Ile, Leu, Arg, Asn, V <1, pra, Qln ,. Gly, Phe 00 'HIS; ** «in position 10δ is Ly», Tyr, Leu, His. Ar _s , n «, s. _fex , Gin, _{oü Fr <?} Xaa bs position ιοί is Asp, p * ç>, Met, Lys, His, Thr, Val, Tyr, Glu, Asn, Se-, Ala. Gly, Xle, l 'u, or Gin; Xaa in position KX is Gly, Leu, Glu, Lys, To be, Tyr, or Pro; Xaa in position 103 O or if t y * ·> Xaa ns position 184 and Go, Cys, Tyr, Thr. Met, Pres, Leu, Gin, Lys, Ala, Phe, or Gly; Xee; o3 position 106 è Asn, Fro, Ale, Fhe, Ser Read it. Lys, II®, ÀSp, OR HIS; Trp, Cl ', Tyr, Xaa BS position i & g ç Glu, To be, Allah, Ly®, Thr, Ile, Gly. <5 u Prn; Xaa os position _{1 & s} and Arg, Ly ', Asp, Leu, Thr, 11 ', Gin, His, Ser, Ala vu Hre; Xaa at position 109 and Arg, Th-tT Pro, Tyr. Read it. To be, nr Gly; Xaa in position 1IC is Lys, Al-âi j Wing, Thr. Leu, Arg, Gin, His. Glu, Ser, or Trp; Xaa ns position m and IrôU., lie. Arg, Âsp. Or Met; in position 112 is Thr. Val, Oln, Tyr> Glu, His, ^GU Phe; Aa * at position 113 and P3> «. To be.. cys .. HIS. Giy, Trp, Tyr. Asp, Ly®, Leu, lie, Val ^0, - ⁱ A &n; Xaa at position 114 and Tyr. Cys, H & s í To be. Trp, Arg, * u Read; Xaa in position Read Asn, Val. Pre, Ax §, Ala, Fsa Thr, Trp .. QU Men; Xaa Arg, Trp, 116 is Lys. Lay, Pro, Thr, Met. Ser, Asn, His, Al *. Tyr, Phe, G Asp, V * l, Glu, In. 00 lie, · X ** in position X · ®. and Thr, Ser, Asn, H®, Trp, Lys, OU Pro; Xaa in position 1U is Read, Ser. htô <Ala, Glu, Cys. Asp ,. OR Tyr; Xaa in position ns is Glu, Lys, Pro, Leu, Thr, Tyr, OU- Arg; Xaa in position 12 C is Asn, Ala, Pro, Lee, Hie, Val, 00 Gin; Xaa in position 121 is Illustration, lie, Asn, Pro, Lys .. Asp, 00 ' Gly; Xaa in position λ ^ .Λ- j4 is Photography, Her, Trp, Arg, Phe. Pro, Hl s. He, Tyr, OR Cys; Xaa in position 123 and Wing, Met, Glu, His, To be Pro, Tyr. 00 Read it. where 1 to 14 amino acids can optionally be deleted from the N-terminus and / or 1 to 15 ammo acids can be optionally deleted from the C-terminus of said modified human interleukin-3 amino acid sequence; and where from 1 to 44 of the amino acids called Xaa are different from the corresponding amino acids of native human interleukin-3 (1 -133): where L; it is a linker capable of binding R, to R ₂ ; and said hematopoietic protein can optionally be immediately preceded by (methionine ' ¹ ). (alanine '') or (methionine ² , anianine ”). Hematopoietic protein according to claim 6 or 10 8, where R ₂ is selected from the group consisting of: Asn Cys Ser Lie Ward Met He Asp Glu H _{and Jie Kis Ly £} Arg Pro Pro Ala Pro Leu Leu Asp Pro Asn Asm Leu Asn Al * Ol _u Asp Va ~ Asp He Leu Met Glu Arg Asn L »u Arg Leu Ere Asn Leu Glu Ser Ph® _{V <} 1 Ar _S Al * _{Vai Leu qiu} Asn lie Glu Ala lie Leu Arg Asn Leu Gin pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg Ms Pro He n * n® _Gly Trp Qin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu Vai Thr Leu CUu Gin Ala Gin Glu Gin Gin (SEQ ID NO; 22S);

Allah Asn Cys To be Xie Met He Asp Glu lie He His His Arg Pro Pro Asn Pro Read Read Asp Pro Asn Asn Read Asn Asp Ker Asp lie Li ^ u Met Glu Arg Asn Read Arg Thr Pro Al a Ph® Val Arg Allah Val Lys His Read Glu Asn Allah Glu Allah lie Read Arg Asn Read Gin Pro Cys Read Pre Thr Allah Allah Pro To be Arg His Pro lie 11® II® Lys Allah Trp Gin Glu Phs Arg Glu Lys Read Thr Phe Tyr Read Val Glu Gin A * a Gin Glu Gin Gin i'SEQ ¹ ID NO: 2 : 28); To be To be To be Thr Read Lys L®U ax Al® Allah Asn Cys To be He Mat XI® Asp G * u XI® He His His Read Lys Val Pro Pro Allah Pro Read Read ASp To be Asn Asn Read Asn To be Glu Asp Met Asp He Read Hex Glu Arg Asn Read Arg Read Pro Asn Read Read Allah Ph® <al Arg Allah Val Lys Asn Read Glu Asn Allah To be Gly He Glu Allah He Read Arg Asn Read Gin Pro Cys Read Fro To be Allah Thr Allah Allah Pre To be Arg His Pro XI® He He Lys Allah Gly Asp Trp Gin Glu Phe Arg Glu Lys Read Thr Phe Tyr Read Go Thr wow Glu Asn Gin Cys Allah To be Gin He Glu Met Gin Xie Allah Pro Read Read Val lie Read

To be Phe Val Allah Allah II® Arg Read Allah Asp Val Allah If: Arg Arg Asn Gin Asp Asp Arg Lys Read ISSE ID Glu II® NO; 227) _r Xie HXS and His L®U Pro Asn Asn Gin Asn Read L®u Pro Asn Read Asn Arg Glu Read Asn Pro Allah Asp Asn To be Lys Glu Read Arg Asp Glu Qin Glu Gin Wing His the Arg Glu Lys Gin Glu Gin Gin lie II® Cys II® Read Pro To be Allah Thr Lys Read Phe Gly Thr Asp Trp Leu Glu Allah Tyh Leu Val (SEQ JO NO; 228). 10. Hematopoietic protein comprising: an amino acid sequence of the formula: RrLrRj. Ra-Lv ^ n RrRz OO R3-R1 where Ri is a polypeptide comprising; a sequence of amino acids 5 modified human c-mpl ligand of the formula: SerProAla _F ro? R _and AlaCy AspI.® ₉ LTT _t V _{≤ U} s li.e _ERI, y _{St, Eui, USA, gAstígei.} Ί-S _The HxsVa.lLeuH.isEerArgLeuEerGlnCysProGiuVaLHisPr., _The euProThrFr * .................. ™ ....................... 35 ...... ................... ^ν3 · ¹ ^^ ' ¹ »« ώ8ν «1 ^ ρρηε3βΓΐ.βπΒ; γ (31ΗΤ _ϊ ρ _ί , _Χ 3 _{ΪΜ01ηΜβω11101} „ ” ^so 55 ThrhysAlaGlnAspIlet.euGlyAlavalThri.euLeu ^ uGiueiyvalMetAla .............. ....................? · 5. Al _aA r _S Sl ^ laL _and uaiyPro ₁ .h ^ _sl , _euSerSerLe ^ _uGly , _{01rXeiiSerGiji} GlnValAxaieuLeuLeuGlyAlaLeuG ^ ertóu ^^, ^^^^^ xuà110 XjAGlyAxgThrTta-MaHiaysAspProAsnAlailePhel.euSerPheGlnHx 12513Q ^^ Ar ^ lyLy.V. ^ rgPhe ^ uMe ^ ValGlyGlySerr ^^^ ........ ...... X <O ................................. ................... Arg (SEQ XD NO: 256 ( 153 where Xaa in position 112 is displayed oo Read, Ala, Vai, lie, Pro, Phe, Trp, : Met; Xaa in position 113 is deleted or Pro, Phe, Ala, val. Leu, lie, Try. Met; Xaa in position 114 is deleted oo  Pro, Phe. Allah, Go. Leu, lie, Trp, Het; Xaa "the position ......... ...... Gin., .. Gly., Ser.,. Thr, Tyr, Asn; where the N-terminus is linked to the C-terminus directly or through a linker (U) capable of connecting the N-terminus to the C-terminus and having new N and C termini in amino acids'. 26-27 49-50 108-109 77-28 50-51 109-110 28-29 51-52 110-111 29-30 52-53 111-112 30-31 53-54 112-113 32-33 54-56 113-114 33-34 58-57 114-115 34-35 57-58 115-11 Ο- 38-37 58-59 116-117 37-38 59-60 117-118 38-39 79-80 118-119 40-41 80-81 Γ19-120 41-42 81 -82 170-12’1 A 42-43 82-83 121-122 W 43-44 83-84 123-124 44-45 84-85 124-125 45-46 85-86 125-126 46-47 86-87 or 127-128 47-48 87-88 48-49 88-89 where Rj is G-CSF or G-CSF Ser ' ^z : where Lí is a linker capable of connecting R <a R _a ; and 5 said hematopoietic proteins may optionally be immediately preceded by (methionine '). (alanine ') or (mationin ^). alanine ’). Hematoposetic protein according to claim 1> 2, 3 ₍ 4, 5 _: 6, 7, 8, or 10 _t where said ligator (U) is selected from the group consisting of: GlyGl / GlySer (SEQ ID NO: 12); GlyGiyÜlySerGlyGlyGlySer (SEQ ID 80: 2421; GlyGlyGiySerGlyGlyGlySerGlyGlyGlySer (SEQ 10 80: 243); SerGlyGlySerGlyGlySer (SEQ ID NO: 244H GluPheGlyAsmetAla (SEQ XD 80: 245); G lu PheGlyGlyAsnMetAla (SEQ ID 80: 246); GluPheGlyGlyAsnGlyGlyAsnMecAla ('SEQ ID NO: 247); and GlyGlySerAspMetAl aGly (SEQ XD 80: 248}. 12. Hematopoietic protein according to claim 9 wherein said hgador (L ·) is selected from the group consisting of: GlyGlyQlySer (EEQ ID NO; 12); GlyGlyGlySerGlyGlyGlySer (SEQ ID 190: 242); ^ lyulyGlySerGlyGlyGlySerGlyGlyGlySer (SEQ ID NO: 243) SerGlyGlySerGlyGlySer (SEQ ID NO: 244}; OluPheGlyAsnMetAla (SEQ ID NO: 245}; GluPheGlyGlyAsnMecAla (SEQ ID NQ; 246); uluPheGlyGiyAsnGlyGlyAsnMetAla (SEQ ID NO: 247); GlyGlySerASpMatAlaGly (SEQ ID NO: 248). 13. Homatopoietic protein according to claim 1 where said protein is selected from the group consisting of: Asn Cys Ser He Met He Asp Glu lie Xie His His Leu Lys ArgPro Pro Ala Pro Leu Leu Asp Pro Asn Asn Leu Asn Asp Glu Asp Val Ser He Leu Met Asp Arg Asn Leu Arg Leu Pro Asn Leu. Glu Ser Phe Val Arg Ala Val Lye Asn. Leu Glu Asn Ala Ser Gly lie Glu Ala He 'Leu Arg Asn Leu Gin Pro Cys Leu Pro Ser Ala Thr Ala Ala Pro Ser Arg His Pro Xie Xie Xie Lys Wing Gly Asp Trp Gin Glu Phe Arg Glu Lys Leu Thr Phe Tyr Leu val Thr Leu Glu Gin Ala Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly Gly Ser Pro Gly Gly Gly Ser Gly Gly Gly Ser Asn Men Ward Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly He pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gin Ala. Leu Gin Leu Wing Gly Cys Leu Ser Gin Leu His Ser Gly Leu Phe Leu Tyr Gin Gly Leu Leu Gin Ala Leu Glu Gly Xie Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gin Leu Asp Val Ala Asp Phe Ala Thr Thr He Trp Gin Glu Met Glu Glu Leu Gly Met Wing Pro Wing Wing Gin Pro Thr Gin Gly Ala Met Pro Ala Phe Ala Ser Al Phe Gin Αχ-g Arg Ally Gly Gly Val Leu Val Ala Ser His Leu Gin Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin Val Arg Lys He Gin Gly Asp Gly Ala Ala Leu Gin Glu Lys Leu Cys Thr wing (SEQ ID NO: 166); Asn Cys To be Xie Met He Asp Glu He lie His H1S Read ..Lys .. Arg Pro- Pro Allah Pro Leu Leu Asp Pro Asn Ash Read 'Ash' Asp Glu Asp Val To be lie Read Met Asp Arg Asn Read Arg Pro Asn Read Glu To be Phe Val Arg Allah Val Lys Asn Read Glu Asn Ara To be Gly He Glu He Arg Asn Read Gin Pro Cys Read Pro to be Allah Thr Allah Pro To be Arg His Pro lie lie Xie Lys Gly Asp Trp Gin G1U Phe Arg Glu Lys Read Thr Phe Tyr Read val Thr Read Glu Gin Allah Gin Glu Gin Gin Tyr Val Glu Gly Gly Gly Gly To be Pro Gly Glu Pro To be Gly Pro He To be Thr lie Asn Pro To be Pro Pro To be Lys Glu To be His Lys To be Pro Asn Met Allah Tyr Lys Read Cys KÁ & Pro Glu Glu Read val Read Read Gly His To be Read Gly He Pro Trp Allah Pro Read To be To be Cys Fro To be Gin Allah Read Gin Read Allah Gly Cys Read To be Gin Read His To be Gly Read Phe Read Tyr Gin Gly Read Read Gin Read Glu Gly Xie To be Pro Glu Read Gly Pro Thr Read Asp Thr Read Gin Read Asp Val • AjJà Asp phe Allah Thr Thr lie Trp Gin Gin Met Glu Glu Read Gly Met Allah Pro Allah Read Gin Pro Thr Gly Allah Met Fro Allah Phe Allah To be Phe Gin Arg Arg At. Gxy Gly vai Leu vai Ala Ser His Leu Gin Ser phe Leu Glu Vai Ser Tyr Arg Vai Leu Arg Kxs Leu Ala Gin Pro Ser Gly Gly Ser Gly Gly Ser Gin Ser Phe Leu Leu Lys Ser Leu Glu Gin val c * rg Lys 11ê Gxn u? Jy Asp Gly Ala Ala Leu Gin Glu Lvs Leu ^ * vs Ala Thr {SSG ID NO: 167i; Asn Cys Ser lie Mee Xle Asp Glu Pro Pre Ala Pro Leu Leu Asp Pro Vai Ser Xle Leu Met Asp Arg Asn Ser Phe val Arg Ala val Ly® Asn Glu Ala lie Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg His Pro Tie Gin Glu Phe Arg Glu Ly® Leu Thr Gin Ala Gin Glu Gin Gin Tyr Val Gly Gly Gly Ser Gly Gly Gly Ser Pro Thr Leu Asp Thr Leu Gin Leu Thr He Trp Gin Gin Mee Glu Glu Gin Pro Thr Gin Gly Al Met Met Arg Arg Ala Gly Gly val Leu Val Leu Glu Vai Tyr Arg Val Leu Gly Gly Ser Gly Gly Ser Gin Ser Gin Val Arg Lys Xle Gin Gly Asp Leu cys Ala Thr Tyr Lys Leu Cys Leu Gly His Ser Leu Gly lie Pro Pro Ser Ala Leu Gin Leu Ala Ser Gly Leu Phe Leu Tyr Gin Gly Xle Ser ISSEQ id NO1I68); Xle He His His Leu Lys Arg Ann Asn Leu Asn Asp Glu Asp ueu Axg Leu Pro Asn Leu Glu Leu Glu Wing Ala Ser Gly He Pro Cys Leu Pro Ser Ala Thr He Xle Lys Ala Gly Asp Trp Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Asn Met Ala Fro Glu Leu Gly Asp Val Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu Ala Phe Ala Ser Ala Phe Gin Ala Ser His Leu Gin Ser Phe Arg Mis Leu Ala Gin Pro Ser Phe Leu Leu Lys Ser Leu Glu Gly Ala Ala Leu Gin Glu Lys His Pro Glu Glu Leu Val Leu Trp Ala Pro Leu Ser Ser Cys Gly Cys Leu Ser Gin Leu His Leu Leu Leu Glu Gly Asn Cys Ser He Met Xle Asp Glu Pro Pre Ala Pro Leu Leu Asp Pro Val Ser Ha Leu Met Asp Arg Asn Ser Phe Val Arg Ala Val Lys asp Glu Ala Xle Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg His Pro He Gin Glu phe Arg Glu Ly® Leu Thr Gin Ala Gin Glu Gin Gin Tyr Val Gly Glu Pro Ser Gly Pro He Ser Ser Lys Glu Ser Hi® Lys Ser Pro Pro Thr Leu Asp Thr- Leu Gia Leu Thr * lie Trp Gin Gin Met Glu Glu Gin Pro Thr Gin Gly Ala Met Pro Arg Arg Ala Gly Gly Val Leu Val Leu Glu Val Ser Tyr Arg Val Leu Gly Gly Ser Gly Gly Ser Gin Ser win Val ^ rg Lys lie Gin Gly Asp Leu Cys Ala Thr * Tyr Lys Leu Cys Leu Gly His Ser Leu Gly Xle Pro Px “o Ser Gin Ala Leu Gin Leu Ala Ser Gly Leu Phe Leu Tyr Gin Gly He Ser (SEQ XL Xle He His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ala Ser Gly He Pro Cys Leu Pro Ser Ala Thr He He .Lys Ala Gly Asp Trp Phe Tyr Leu val Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Thr · He Asn Pro Ser Pro Pro Asn Met Ala Pro Glu Leu Gly. Asp Val Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu Ala Phe Ala Ser Ala Phe Gin Ala Ser His Leu Gin Ser Phe Arg His Leu Ala Gin Pro Ser Phe Leu Leu Lys Ser Leu Glu Gly Ala Ala Leu Gin Glu Lys His Pro Glu Glu Leu Val Leu Trp Ala Pro Leu Ser Ser Cys Gly Cys Leu Ser Gin Leu His Leu Leu Gin Ala Leu Glu Glv Asn Cys Ser lie Met Xle Asp Pre Pre Al® Pre Leu Leu Asp Val Ser He Leu Met Asp Arg uei Phe Val Arg Ala Vau lys Glu Aua He Leu Arg Asn Leu Wing Wing Pre Ser Arg Hus Pre Gin Glu Phe Arg Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr G ^ y 'Guy Giy Ser Gly Glv Glv Read Gin Pro Thr Gin Gly. Gin Arg Arg Ala Gly Gly Val Pne Leu Glu Val Ser Tyr Arg • Ser Gly Gly Ser Gly Gly Ser Glu Gin Val Arg Lys lie Gin Lys Leu Cys Ala Thr Tyr Lys Leu Leu Gly His Ser Leu Gly Cys Pro Ser Gin Ala Leu Gin Hus Ser Gly Leu Phe Leu Tyr Gly Xle Ser Pre Glu Leu Gly Asp Val Ala Asp Phe Ala Thr Leu Gly (SEQ lb HQ; 170): Glu lie Xle His His Leu Lys Arg Pro Asn Asn Leu .Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Asn A.ia Ser Gly He Gin Pro Cys Leu Pro Ser Ala Thr Xle -.le ule Lys Ara Gly Asp Try Thr Phe Tyr Leu Val Thr Leu Glu Val Glu Giy Gly Gly Gly Ser Pro Ser Asn Met Ala Met Ala Pro .Ala Met Pro Ala Phe Ala Ser Ala Phe Leu Vai Ala Ser His Leu Gin Ser Vai. Leu Arg His Leu Ala Gin Pro Gin Ser Phe Leu Leu Lys Ser Leu Gly Asp Gly Ala Ala Leu Gin Glu Leu Cys Hus Pro Glu Glu Leu Val Xle Pro Trp Ala Pro Leu Ser Ser ueu Ara Guy Cys Leu Ser Gin Leu Gin Gly Leu Leu Gin Ala Leu Glu Pro Thr Leu Asp Thr Leu Gin Leu Thr He Trp Gin Gin Met Glu Giu Asn Cys Ser Xle Met Xle Asp Pro Pro Ala Pro Leu Leu Asp Val Sex Xle Leu Met Asp Arg Ser Phe Val .Arg Ala Vai Lys Guu Ala xle Leu Arg Asn Leu Ala Ala Pro Ser Arg His Pro Gin Giu Phe Arg Glu Lys Leu Gin .Ala Gin Giu Gin Gin Tyr Gly Glu Pro Ser Gly Pro lie Ser Lys Glu Ser His Lys Ser Leu Gin Pro Thr Gin Gly Ala Gin Arg Arg Ala Gly Gly val Phe Leu Glu Val Ser Tyr Arg Ser Gly Gly Ser Gly Ser G ^ u uln \ <ai Arg uys Xue Gin uys Leu Cys Ala Thr Tyr Lys Leu Leu Gly His Ser Leu Gly Cys Pro Ser Gin Leu Leu Gin Hus Ser Gly Leu Phe Leu Tyr Gly Xle Ser Pro Glu Leu Gly Asp Val Ala Asn Phe Ala Thr Leu Gly (SEQ rb NO: 171): Glu Xle He His His Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn ueu Glu Asn Ala Ser Gly Xle Gin Pro Cys Leu Pro Ser .Ala Thr Xle lie xle Lys Ala Gly Asp Trp Thr Phe Tyr Leu Val Thr Leu Glu Vai Glu Guy Gly Gly Gly Ser Pro Ser Thr lie Asn Pro Ser Pro Pro Pro Asn Met Ala Met Ala Pro Ala Met Pro Ala Phe Ala Ser Ala Phe Leu Val Ala Ser His Leu Gin Ser Val Leu Arg His Leu Ala Gin Pro Gin Ser Phe Leu Leu Lys Ser Leu Gly Asp Gly .Ala Ala Leu Gin Glu Leu Cys His Pro Glu Giu Leu Val Xle Pro Trp Ala Pro Leu Ser Ser Leu Ala u> ly Cys Leu Ser Gin Leu Gin Gly Leu Leu Gin Ala Leu Glu Pro Thr Leu Asp Thr Leu Gin Leu Thr He Trp Gin Gin Met Glu Glu Asn Cys .Ser Xle Met xle Asp Glu Pro Pro Ala Pro Leu Leu Asp Pro Val Ser He Leu Met Asp Arg Asn Xle Xle Kus His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Ser Phe Val Arc Ale Val Lys Asn Glu Ala He Leu Arg Asn Leu Gin Ala Ale Pro Ser Arg His pre He Gin Glu Phe Arg Glu Lys Leu Thr Gin Ale Gin Gin Gin Gin Tyr Val Gly Gly Gly Ser Gly Gly Gly Ser Me * Pro λ1λ Phe Ax Ser Ala Phe Leu Val Ala Ser His Leu Gin Ser Val Leu Arg His Leu Ala Gin Pro Gin Sei * Phe Leu Leu Lys Ser Leu Gly Asp Gly Ala Ala Leu Gin Glu Leu Cys His Pro Glu Glu Leu Val He Pro Trp Ala Pro Leu Ser Ser Leu Ala Gly Cys Leu Ser Gin Leu litíií uln .Ala Leu Glu Pro Thr Leu Asp Thr Leu Gin Leu Thr Xie Trp Gin Gin Men Glu Glu Gin Pro 'SEQ ZD MO: 172i; Leu Glu Asn Ala Ser Gly He Pro Cys Leu pro Ser Ala Thr He He Lys Ala Gly Asu Trn Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Gly Ser Pro Asn Met Ala Thr Gin Gly Ala Gxn Arg Arg Ala Gly Gxy Val Phe Leu Glu Val Ser Tyr Arg Ser Gly Gly Gly Gly Ser Glu Gin Val Arg Lys He Gin Lys Leu Cys Ala Thr Tyr Lys Leu Leu Gly His Ser Leu Glv Cys Pro Ser Gin Ala Leu Gin Has Ser Gly Leu Phe Leu Tyr Gly Xie Ser Pro Glu Leu Gly Asp Val Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu Asn Cys Ser He Met He Asp Glu Pro Pro Ala Pro Leu Leu Asp Pro Val Ser Xie Leu Met Asp Arg Asn Ser Phe Vai Arg Ala Val Lys Asn GXu Ala He Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg His Pro He Gin Glu Phe Arg Glu Lys Leu Thr Gin Ala Gin Glu Gin Gin Tyr Val Gly Glu Pro Ser Gly Pro Tie Ser Ser Lys Glu Ser His Lys Ser Pro Met pro Al® »he Ala Ser Ala Phe Leu Val Ala Ser His Leu Gin Ser Val Leu Arg His Leu Ala Gin Pro Gin Ser Phe Leu Leu Lys Ser Leu G-iy Asp Gly Ala Ala Leu Gin Glu Leu Cys His Pro Glu Glu Leu Val He Pro Trp Ala Pro Leu Ser Ser Leu Ala Gly Cys Leu Ser Gin Leu Gin Gly Leu Leu Gin Ala Leu Glu Pro Thr Leu Asp Thr Leu Gin Leu Thr Xie Trp Gin Gin Met Glu Glu Gin Pro (SEQ XD NO; 173 J; He He His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu A ^ eu Glu Asn Ala Ser Gly Tie Pro Cys Leu Pro Sex * Wing Thr Tie Tie Lys Wing Gly Asp Trp · Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Gly Ser Pro Thr rle Asn Pro Sex * Pro Pro Asn Met Ala Thr Gin Gly Ala Gin Arg Arg Ala Gly Gly Val Phe Leu Glu Val Ser Tyr Are Ser Gly Gly Ser Gau Ser Val Gau Lys Tie Gin Lys Leu Cys Ala Thr Tyr Lys Leu Leu Gly His Ser Leu Gly Cys Pro Ser Gin Ala Leu Gin Hrs Ser Gly Leu Phe Leu Tyr Gly He £ er Pro Glu Leu Gly Asp Val Ala Asp Phe Ala Thr Lêü Gly Met Ala Pro Leu Wing Asn Cys Ser lie Met He Asp Glu Pro pro Ala Pro Leu Leu Asp Pro Val Ser He Leu Met Asp Arg Asn Ser Phe Val Arg Ala val Lys Asn Gru Ala He Leu Arg Asn Leu Gin Ala Ala Pro Ser Arg His Pro He Gin Glu Phe Arg Glu Lys Leu Thr Gin Ala Gin Glu Gin Gin Tyr Vai He Tie His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ala Ser Gly He Pro Cys Leu Pro Ser Ala Thr Xie Xie Lys Ala Gly Asp Trp Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Gly Gly Glv Ser Gly Gay Gly Arg Arg Al® Gly Gly Vai Leu Leu Glu Vai Tyr Arc val Gly Gly Ser Gly Gly Ser Gin Gin val Arg Lys xle Qin Gly Leu Cys Ala Thr Tyr Lys Leu Leu Gly Hie Ser Leu Gly lie v $ 6 »G .. * no. ueu Gin Leu Sex 'Guy Leu Pne Leu Tvr Gin Xle Ser Pro Glu Leu Gly Pre val Ala Asp Phe Ala Thr Thr Gly Met Ala Pro Ala Leu Gin Phe .Ala I SEQ XL NO : 177ϊ Ser Asn Met Ala Per Ala Phe Gin osSx. Hxs Leu Gjw-Γι Sex * Pile Leu Arg His Leu Ala Gin Pro Ser Ser Phe Leu Leu Lys Ser Leu Glu Asp Giy Aia Ala Leu GinG'v Cys Has Pro Giu Glu Leu VaiLeu Pro Trp Pro Read about SerCys Ward Gly Cys Leu Ser Gin LeuHis Gly Leu Leu Gin Alu Leu GluGlv Thr ^ su Asp Thr Leu Gin Leu Asn o »le j-X'P Gm Gin Met Glu Glu Leu Pro Thr Gin Gly Wing Met Pro Wing Asn Cys Ser Xle Met Pro Pro Ala Pro Leu Vai Ser lie Leu Met Ser Phe Vai Arg · Ala Glu Am Xie Leu Arg Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu Gin Ala Gin Glu Gin Gly Glu pr> 'Ser Gly Ser Lys Glu Ser His Arg Arg Ala Gly Gly Leu Glu Vai Tyr Gly Gly Ser Gly Gly val Arg Lys ne Leu Cys Ala Thr Tyr Leu Gly His Ser Leu Px u Ser Gm Ata Leu Sax- Gly Leu Phe Leu He Ser Pro Glu Leu Vai Asp Phe Wing Giy Met Wing Pro Wing Wing Phe Wing (SEQ id no; 1 Xle vslu Xue r <e Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg 'Vai Lys Asn Leu Giu Asn Leu Gin Pro Cys His Pro Xle ih He Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Gly Pro Xle Ser Thr He Lye Ser Pro Asn Met Vai Leu Vai Ala Ser Arg Vai Leu Arg His Ser Gin Ser Phe Leu Gin Gly Asp Gly Ala Lys Leu Cys His Pre Gly He Pro Trp Ala Gin Leu Ala Gly Cys Tyr Gin Gly Leu Leu Gly Pro Thr Leu Asp Thr Thr Xie Trp Gin Leu Gin Pro Thr Gin 75 j His Hie Leu Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly Ha Leu Pro Ser Ala Thr Lys Ala Gly Aso Tro Leu Vai Thr Leu Glu Gly _ü ly vly Ser Pro Asn Pro Ser Pro Ala Ser Ala Phe Gin His Leu Gin Sex * Phe Leu Ala Gin Pro Ser Leu Lys Ser Leu Giu Ala Leu Gin Glu Lys Giu Glu Leu Vai Leu Pro Leu Ser Gin Cvs Leu Ser Gin Leu His Gin Ala Leu Glu Gly Tnr Leu Gin Leu Asp Gin Met Glu Glu Leu Gly Wing Met Pro Wing 8ropro Ala pro ^V & 1Ser He Leu Ser Phe Vai Arg Giu Ala He Leu Ala Pro Ser Gin Glu Phe Arg Gin Ala Gin Glu Gly Gly Gly Ser His Pro Giu Trp Ala Pro Leu Gly Cys Leu Ser Leu Le Al Gin Met He Asp Glu Leu Leu Asp Prp · Met Asp Arg Asn Ala Vai Lys Asn Arg Asn Leu Gin Arg His Pro Xle Glu Lys Leu Thr Gin Gin Tyr Vai Giy Gly Gly Ser Leu Vai Leu Leu Ser Ser Cys Pro Gin Leu His Ser Leu Glu Gly He He He Hrs His Asn Asn Leu Asn Leu Arg Leu Pro Leu Glu Asn Ala Pro Cys Leu Pro Xle Xle Lys Ala Phe Tyr Leu Vai Glu wly Gly Gly Asn Met Ala Tyr Gly His Ser Leu Ser Gin Ala Leu Giy Leu Phe Leu Fri- Pro Giu Leu Leu Lys -Arg Asp Glu Asp Asn Leu Glu Ser Gly Hg Ser Ala Thr Gly Asp Trp Thr Leu Giu Gly Ser Pro Lys Leu Cys Gly He Pro Gin Leu Ala Tyr Gin Gly Gly Fro Thr Leu Asp Thr Leu Gin Lay '· Asp Vai Trp Gin Gin Met Glu Glu Leu Gly Thr Gin Gly Ala Met Pre Ala Phe Ala Gly Gly Vai Leu Vai Ala Ser Vat Ser Tyr Arg Vai Leu Arg His Gly Pro Ala Ser Ser Leu Pro Gin Glu Gin Vai Arg Lys Tie Gin Glv Lys Leu Cys Wing Thr (SEC XL NO: 1 Ala Asp Phe Ala Thr Thr Xle Met Ala Pro Ala Leu Gin Pro Ala Ser Ala Phe Gin Ara Ara His Leu Gin Ser Phe Leu Glu Leu Ala Gin Pro Thr Pro Leu Ser Wing phe usu net, Lys Ser Leu asp uiy Ara Ala Leu Gin Glu 7); Asn Cys Ser lie Meo Pro Pro Ala Pro Leu Val Ser xle Leu Met Ser Phe Vai Arg Ala • Glu Ala Xle Leu Arg Ala Ala Pro Ser Arg GW ulu Pne Arg Glu Gin Ala Gin Glu Gin Gly Glu Pro Ser Gly Ser Lys Glu Ser Has Has Pro Glu Glu Leu Trp Ala Pro Leu Ser Gly Cys Leu Ser Gin Leu Leu Gin Ala Leu Leu Asp Thr Leu Gin Trp Gin Gin Met Glu Thr Gin Gly Ala Met Aia -Gly Gly val Leu. It will be Tyr Arg Val Gly Pro Ala Ser Be Veil .Arg Lys Lys Leu Cys Ala Thr ** 8 Asp uxu xle Xze Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pro Xle He χχ§ Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Glv Pro lie Ser Thr Xle Lys Ser Pro Asn Met Val Leu Leu Gly His Ser Cys Pro Ser Gin Leu His Ser Gly Leu Glu Gly Ils Ser Pro Leu Asp Val Ala Asp Glu Leu Gly Met Ala Pro Ala Phe Ala Ser Val Ala Ser His Leu Leu Arg His Leu Leu Leu Pro Gin Ser Phe Xle Gin Gly Asp Glv (SEQ XL NO: 177} · His His Leu Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly lie Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Val Thr- Leu Glu Gly Gly Gly Gly Ser Pro Asn Pro Ser Pro Ala Tyr Lys Leu Cys Ser Leu Gly Xle Pro Ala Leu Gin Leu Ala Phe Leu Tyr Gin Gly Glu Leu Gly Pro Thr Phe Ala Thr Thr He Pro Ala Leu Gin. Pro Ala Phe Gin Arg Arg Gin Ser Phe Leu Glu Gin Pro Thr Pro Leu Leu Leu Lys Ser Leu Ala A.i.a Leu Gin Glu g | Asn cys Ser Xle Met Xle Asp Glu 'W'Pro Pro Ala Pro Leu Lep Asp Pro Vax Ser xle Leu Met Asp Arg Asn Ser Phe Val Arg Ala Val Lys Asn Glu Ala Xie Leu Arg Asn Leu Gin ............ A.t a .... Aia ... Pro Ser Arg Hi s Pro Tie 'Gin Glu Phe Arg Glu Lys Leu Thr Gxn Ala Gin Glu Gin Gin Tyr Val Gly Glu Pro Ser Gly Glu Pro Ser Ser Lys Glu Ser His Lys Ser Pro Pro Thr Leu Asp Thr Leu Gin Leu Tnr lie Trp Gin Gin Met Glu Glu Gin Pro Thr Gin Gly Ala Met Pro Arg Arg Ala Gly Gly Val Leu Val Leu Gin val Ser Tyr Arg Val Leu Leu Gly .Pro Ala Ser Ser Leu Ser Leu Glu Gin Val Arg Lys Xle Gin Glu Lys Leu Cys Ala Thr Tyr lie Xle His His Leu Lys Arg Asn Asn Leu Asn Asp Glu Asp Leu Arg Leu Pro Asn Leu Glu Leu Glu Asn Ala Ser Gly Xle Pro Cys Leu Pro Ser Ala Thr ^e »OB ^: & Gly: igr β · Phe Tyr Leu Val Thr Leu Glu Glu Gly Gly Gly Gly Ser Pro Thr xle Asn Pro Ser Pro Pro Asn Met Ala Pro Glu Leu Gly Asp Val Ala Asp Phe Ala Thr Leu Gly Met Ala Pro Ala Leu Ala phe Ala Ser Ala Phe Gin zuta s? Er His Leu Gin Ser Phe Arg His Leu Ala Gin Pro Thr Pro Gin Ser Phe Leu Leu Lvs Gin Gly Asp Gly Ala Ala Leu Lys Leu cys His Pro Glu Glu Leu Val Leu Leu Gly Ser Ser Cys Pro Ser Qin Leu His Ser Gly .ueu U-xu uly xle Ser Asn Cys Ser Xie Met Pro Pro Ale Pro Leu Vai Ser Xie Leu Met Ser Pne Val Arg Ala Glu Ala lie Leu Arg Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu Gin A.xa Gin Glu Gin Gly Glu Pro Ser Gly Ser Lys Glu Ser His Leu Gin Pre Thr Gin Gin Arg Arg Ala Gly Phe Leu Glu Will Be Thr Pro Leu Gly Pro Lys Ser Leu Glu Gin Leu Gin Glu Lys Leu Glu Leu VaS Leu Leu Leu Ser Ser Cys Pro Ser Gin Leu His Ser Ara Leu Glu Gly Tie Leu Gin Leu Asp Val Met Glu Glu Leu Gly Tie Asp Glu Xie Zle Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Vai Lys Asn Leu Glu Asn Leu Gin Pro Cys Has Pro Xie lie Xie Lys Leu Thr Phe Tyr Gin Tyr Vai Glu Gly Pro Tie Ser Thr Xie Lys Ser Pro Asn Met Gly Ala Met Pro Ala uj.y Vai Leu Vai Ara Tyr Arg Vai Leu Arg Ala Ser Ser Leu Pro Vai Arg Lys Xie Gin cys Ala Tnr Tyr Lys Gly His Ser Leu Gly Ser Gin Ala Leu Gin Gly Leu Phe Leu Tyr Ser Pro Glu Leu Gly Ala Asp Phe Ala Thr (SEQ XD NO: 181); His Ser Leu Gly Tie Gin Ala Leu Gin Leu Leu Phe Leu Tyr Gin iSEQ TP NOcl7 $} _? Pro Trp Ala Pro Leu Aue Gjy Cys Leu .Ssjt ^^ Ijí AJ.S- 5 **. τ ^, -j- J * Has His Leu Lvs Arc? Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu .Asn Ala Ser Gly Xie Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Vai Thr Leu Glu Gly Gly Gly Ser Pro Ann Pro Ser Pro Ala Met Ala Pro Ala Phe Ala Ser Ala Ala Phe Ser His Leu Gin Ser His Leu Ala Gin. Pro Gin Ser Ph.e Leu Leu Gly Asp Gly Ala Ala Leu Cys Hxs pro Glu Xie Pro Trp Ala Pro Leu Ala Gly Cys Leu Gin Gly Leu Leu Gin Pro Thr Leu Asp Thr Thr- Xie Trp Gin Gin Asn cys Ser zle Met xle Asp Pro Pro Ala Pro Leu Leu Asp Vai Ser Xle Leu Met Asp Arg Ser Phe Val Arg Ala Vai Lys Giu Ala Xle Leu Arg Asn Leu Ala Ara Pro Ser Arg Hrs Pro Gun Gru Phe Arg Glu Lys Leu Gin Ala Gin Glu Gin Gin Tyr Guy Gly Gly Ser Gly Gly Gly Met pro Ala .Phe Ala Ser Ala Leu Vai Ala Ser His Leu Gin Vai Leu Arg His Leu Ala Gin Ser Leu Pro Gin Ser Phe Leu Lys Tie Gin Gly Asp Gly Ala Thr Tyr Lye Leu Cys His Pro Ser Leu Gly Xle Pro y _rp Ala Ax a Leu Gm Leu Ala Gly Cvs Phe Leu Tyr Gin Gly Leu Leu Gxu Leu Gly pro Thr Leu Asp Phe Ala Thr Thr lie Trp Gin Pro Ala Leu Gin Pro {SEQ XL Glu Xle lie His His Leu Lys Arg Pro Asn Asn Leu Asn Asp Glu Asp Asn Leu Arg Leu Pro Asn Leu Glu Asn Leu Glu Asn Ara Ser Gly Tie Gin Pro Cys Leu Pro Ser Ala Thr Xle Xie Xle Lys Ala Gly Aso Trp Thr Phe Tyr Leu Vai Thr Leü Glu Vai Glu Gly Gly Gly Glv Ser P ^ o Ser Asn Met Ala Thr Gin Gly Ala Phe Gin Arg Arg Ala Gly Gly val Ser Phe Leu Glu Val Ser Tyr Arg Pro Thr Pro Leu Gly Pro Ala Ser Leu Lys Ser Leu Glu Gin Val Arg Ala Leu Gin Glu Lys Leu Cvs Ala Glu Glu Leu Val Leu Leu Gly His Pro Leu Ser Ser Cys Pro Se ¹ 'Gin Leu Ser Gin Leu His Ser Gly Leu Gm Ala Leu Glu Gly Xle Ser Pro Thr Leu Gin Leu Asp Val Ala Asp Gin Glu Glu Leu Gly Me * Ale NOI182); Asn Cys Set Ils Met pre Fro Ala Fro Leu Val Ser lie Leu Mao Ser Phe Val Arg Ala Glu Ala Ils Leu Arg Ale Ala Pro Ser Arg Ua · *; kx.u. U For aX * g ulu Gin Ala Glu Glv Glu Gly Glu Pio Ser Gly Ser Lys Glu Ser His Met Pro Ala Phe Ala Leu Val Ala Ser Sis Val Leu Arg His Leu Ser Leu Pro Gin Ser Lys Xie Gin Gly Asp Thr Tyr Lys Leu Cys Ser Leu Gly He Pro Aia ueu Gm Leu Ala Phe Leu Tyr Gin Gly Glu Leu Gly pro Thr Phe Ala Thr Thr He Pro Alu Leu Gin Pro He Asp Glu He He Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Val Lys Asn Leu Glu Asn Leu Gin Pro Cys His Pro Tie Xie Xis Lys Leu Thr Phe Tvr Gin Tyr Val Glu Gly Pro He Ser Thr Xie Lys Ser Pro Asn Met Ser Al Pha Gin Arg Leu Gin Ser Phe Leu Ala Gin Pro Thr Pro Phe Leu Leu Lys Ser Gly Ala Al Leu Gin Has Pro Glu Glu Leu Trp Ala Pro Leu Ser Gly Oys Leu Ser Gin Leu Leu Le Ala Leu Le ~ A Thr sp Read Gin Trp Gin Gin Met Glu (SEQ XL NO: 183); His His Leu Lys Arg L eu As n ® ^ sp G u. u sp Leu Pro Asn Leu Glu Asn Ala Ser Gly He Leu Pro Ser Ala Thr Lys Ala Gly A $ p Trp Leu Val Thr Leu Glu Gly Gly Gly Ser Pro Asn Pro Sera Pro Ala Thr Gin Gly Ala Arg Ala Gly Gly Val Glu Val Ser Tyr Arg Leu Gly Pro Ala Ser Leu Glu Gin Val Arg Glu Lys Leu Cys Zula Val Leu Leu Gly Hrs Ser Cys Pro Ser Gin Leu His Ser Gly Leu Glu Gly He Ser Pro Leu Asp Val Ala Asp Glu Leu Gly Met Ala Asn Cys Ser He Met Pro Pro Ala Pro Leu Val Ser He Leu Met Ser Phe Val Arg Ala Giu Ala lie Leu Arg Ala Ala Pro Ser Arg Gin Glu Phe Arg Glu Gin Ala Gin Glu Gin Gly Gly Gly Ser Gly Arg Arg Ala Gly Gly Leu Gau Vai Tvr Pro Leu Gly for Ala Ser Leu Glu Gin Val Gin Glu. Lys Leu Cys Leu Val Leu Leu Gly: Ser Ser Cys Pro Ser Gin Leu His Ser Gly Leu Glu Gly He Ser Gin Leu Asp Val Ala Glu Glu Leu Gly Met Met Pro Ala Phe Ala He Asp Glu Tie He Leu Asp Pro Asn Asn Asp Arg Asn Leu Arg Val Lys Asn Leu Glu Asn Leu Gin Pro cys His Pro Xie He He Lys Leu Thr Phe Tyr Gin Tyr Val Glu Gly Gly Gly Gly Ser Asn Met val Leu Val Ala Ser Arg Val Leu Arg His Ser Ser Leu Pro Gin Arg Lys He Gin Gly Ala Thr Tyr Lys Leu His Ser ... Leu Gly He Gin Axa Leu Gin Leu Leu Phe Leu Tyr Gin Pro Glu Leu Gly Pro Asp Phe Ala Thr Thr Ala Pro Leu Gin Ward (SEQ TD NO: 184); His His Leu Lys Arg Leu Asn Asp Glu Asp Leu Pro Asn Leu Glu Asn Ala Ser Gly He Leu Pro Ser Ala Thr Lys Ala Gly Asp Trp Leu Val Thr Leu Glu Gly Gly Gly Gly Ser Pro Ala Ser Ala phe Gin His Leu Gin Ser Phe Leu Ala Gin Pro Thr Ser phe Leu Leu Lys Asp Gly Ala Ala Leu Cys His Pro Glu Glu Pro Trp Ala Pro Leu Ala Gly Cys Leu Ser Gly Leu Leu Gin Ala Thr Leu Asp Thr · Leu Xie Trp Gin Gin Pro Pro Gin Gin Gly Allah MetAlaAsnCysSerHeMetXieAspGluHeHeHisHisLeWsArgP-oP-oAla ^ X ^^ S ^^^ Í ^^^ P ^^ PValSerXleLeuMe ^ AspAÍÍAsn GlvT ί Sr? ·, * I ° J-snueuw * uSer. neValArgAlaValLysAsnLeuGiuAsnAlaSer uiyXleGla ^ l ^ leLeaArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro I SerArgH sProX leXlell eLysAlaG lyAspTrpGlnGluPheAr aGluLvsDeuThr PheTyr LeuVaXlhrDeuGluG InAlaGlnGluGlnGlnTyrValGl uG lyGl yGlyGlv 3βΓΡΤ © 01ν3'1ηΡΓθ3 1γΡΓθΧ1β3 £ £ £ Γ ΓΤΚχΣ1βΑ5ΠΡΤθ ££ ΤΡΤθΡΕθ5 Γΐ @ <? · ΛΒ31Ζ SerHXsLysSerPrGAsnMePAlaTyrLysLeuCysHisProGluGluDeuvilDeuLisu GlyHisSerLeuGlyllePrairpAlaProLeuSerSerCyoProSerGlnAlaDeoGlr LeuAlaGlyCysLeuSerGlnLexxHxsSerGlyLeuPheLeu '^' rGlnGlyLeuLeuGln A oaLeuGiuG I1eSer ProGluLsuG ly ^ ly ProThrLeuAspThrLeuGlnL uAspVa i Α1 & Α & ρΡρβΑ1ΗΤΗΓΤΠΕΧ1βΤΓρ31ηα.1ηΜ «ρ01 ^ 1υ1Χ6π81γΜ $ ΕΑΐάρί _Ο Α1Η ₄ βΰ Glr; Px'oThrGlnGlyA.laMet.ProAlaPheAlaSer? ilaPheGlnAraArqAla ^? valLeuValAlaSarHislaeuGXnSerPheLeuGluValSeriyrAríValLeiiArÍHis ΕουΛΧ ^ '^ χπ.Ρχο01νθ2Λ'ο1ν2 & χΆ5ρΜόΑ1ΗΤΑ, τΡοοΟβπ61γΡ * ΧθΑ1α4 ProGlnSer PheLeuLeuLy sS erXeuGluGlnVal ArgLvs 11 eGlnG lyAspG lyA a AlaLeuGlnGluLysLeuCysAlaThr (SEQ ID NO: 194); R 1 MetAxaAsnCysSarlieMet leAspGluIIel eHisHi sLeuLy sArgPraProAla The ProLauijeu sp Pr oAsoAsnL euAsnAspG luAspVs.1 s sr I leLeuMe The p and Ar π π The "Gy-euArgLeuPjOAsaLeuGiuSerPheValArgAiaValLysAsnLeuGluAsnAlaSer LeGluAlaIx LeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaPro h ^ £ ~ rArgHrsProXleilexleLysAlaGlyAspTrpGlnQluPheArgGltiLvsLeuTbr beXyrLeuValThrLauGluGlnALaGlnQluQlnGlTiTyrValGluGlvGlyGlvGlv be ProGlyGluProSerG ly proxies erThr I leAsnProSer Pro Pros eriy sG lU-HiSLysSerProAsnMetAlaProGluLeuGlyProThrLeUi ^ and ^ ^ Jl DThrLeuGlnLeu AspVaxAlaAspPneAiaThxThrlleTrpGXnGlnMetGluGlüLeuGlyMetAlaPro suGlnPreThxGlnGlyAlab cProAlaPheAlaSerAlaPheGlnArgArgAla ^ ^ «£ i u.ijeuValAlaSex'Hx.sLeuGlnSeTPheLeuGluValSerTyrAroVaiLev Arg EUAL ag ts INPR oG lyGlyG Lys AspMe t er al ly aThrPr oLeuG ProAlaS ether serLeuProGInSer PheLeuLeuLysS erLeuGluGlnValArgLvs lleGlnGlvAsm • SlyAlaAlaLeuGlnGluLysLeuCysAlaThrTyrLysLeuCysHisProGluGluLeu Va- ^ euLeuGlyHxsSerLeuG lylleProlrpAlaProDeuSerSerCys ^ mSerG * n AlaLeuGlnLeuAlaG lyCysLeuSerGlnLeufíi sSer GlyLeuPheLeuiv ^ GlrGlv LsuLeuGlnAiaLeuGluGlyileSer (SEQ ID NO: 195); ' ⁴ “ Meta aAsnCysSerZleMetllôAspGlullelleHísHisLeuLysAraProProAia ^ ^ ^ oLeuLeuAspProAsnAsnLeuAsnAspGluAspValSerlleLeuMe AspArQAsn LArgL ^ ^^ r ^ ^^^^ ProAsnLeuGluSerPheValArgAlaValLysAsnLeuGluAsnAlis' ^ o ^^ uAiaiieLeuArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaP 2SíCí ^{g? 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(SEQ W NO: 198) λα-s Asn Cys Ser Xxe Met lie Asp Arg Pro Pro Ala Pro Leu Leu Asp Asp Val Ser Xie Leu Met Asn Arg Glu Ser Phe Val Arg Ala Val Lys lie Glu Ala Xie Leu Arg Asn Leu Thr Ala Ala Pro Ser Arg His Pro Trp Gin Glu Phe Arg Glu Lvs Leu Glu Gin Ala Gin Glu Gin Glu íyr Gly Glu Pro Ser Gly Pro lie Ser Ser Lys Glu Ser His Lys Ser Pro Ser Ser Leu leu Gly Gin Léu sèr Gly Ala Leu Gin Ser Leu Leu Gly Glu Xie lie His His Leu Lys Pro Asn Asn Leu Asn Asp Glu Asn Leu Arg Leu Pro Asn Leu Asn Leu Glu Asn Ala Ser Gly Gin Pro Cys Leu Pro Ser Ala lie He lie Lys Ala Gly Asp Thr phe Tyr Leu Val Thr Leu Val Glu Gly Gly Gly Ser Pro Thr xle Asn Pro Ser Pro Pro Asn Met Gly Pm Thr Cys Leu Oly t »ln Vai Arg Leu Leu Le Gin Thr Leu Pro Pro Gin Glv Μ Arg Thr Thr Ala His asd Pro Gin His Leu Leu Arg Gly Lys Val ^G ? ^y f? ^{r Thr} Leu Cys Val Arg Glu Px ο A-.a Pro Pre Ala Cys Asp Leu arg Asp Sax ^- His Val Leu His Ss * 'Vac Hrs Pro Leu Pro Thr Pro Val Sex ~ Leu Gly Glu Trp Lvs Thr Gin Asp He Leu Gly Ala Thr Val Leu Ala Arg Gly Gin Leu (SEQ ID _NO::; Asn Ax a <uo Phe Leu Ser Phe Arg Phe Leu Met Leu Val Glv Phe Gly Gly Asn Met Ala SexArg Vai Leu Ser Lys Leu Leu Arg Leu Ser Gin Cys Pro Glu Leu Leu Pro Ala Val Asp Met Glu Glu Thr Lys Ala Gin Leu j ^ eu Glu Giy Val Met Ala 09> ·

Asn 2Ή. Pro Asp Vac Glu To be He 've seen> Ll Allah Gin Gru Gly Glu To be Lys Pm Gin Read To be i.eu val Met Allah Lys Read Cvs Pm Val ASp Lys Allah Val Met Read Read Read Gin Cys Ser xie Met He Asp Glu Pro Wing Pro Leu Leu Asp pro Ser lie Leu. Met Asp Arg Asn Phe V & l Arg Al a Val Lys Asn Ala He Leu Arg Asn Leu Gin Ala Pre Ser Arg His Pro He Gru Phe Arg Glu Lys Leu Thr Axa Gin Glu Gin Gin Tyr Val Pr.> Ser Gly Pro lie Ser Thr Glu Ser His Lys Ser Pro Asn Gly Arg Thr Thr Ala His Lys Phe Gin His Leu Leu Arg Glv Giy Gly Ser Thr Leu Cvs val Ser Pro Pro Ala Pro Pro Ala Cjt Leu Arg Asp Ser His Val Leu Glu Val Hrs Pro Leu Pro Thr Phe Ser Leu Gly Glu Trp Lys Gin Asp He Levs Gly Ala Val Aua Ala Arg Gly Gin Leu Gly Gly Gin Leu Ser Glv Gin Val Ser Leu Leu {SEQ lb MO _; 210) _; ile lie His His Leu Lvs Asn Asn Leu Asn Asp CPu Leu Arg Leu Pro Asn Leu Leu Glu Asn Ala Ser Gly Pro cys Leu Pro ser A ^ a Be lie Lys Ala Gly _Λ ίρ Phe Tyr Leu Val Thr Leu Giu Gly Gly Gly Ser Pro xle Asn Pro Ser Pro Pro Men Gly Thr Gin Leu Pm Asp Pro Asn Ala He Phe Lys Val Arg Phe Leu Me * Arg Glu Phe Gly Gly Asn Asp Leu Arg val Leu Ser Hxs Ser Arg Leu Ser Gin Pro Val Leu Leu Pro. Wing Thr Gin Met Glu Glu Thr Thr Leu Leu Leu Glu Gly Pro Thr Cys Leu Sex 'Ser Arg Leu Leu Leu Gly Wing The 5 Λ .Asn Ovs Arg Pro Pro Asp Val To be To be Pne He Glu Wing Thr Wing · Wing * ~ Gin L u Glu Gin Allah Gly Glu Pro To be Lys Glu Hi s Lys Asp Arg Gly Lys Cvs Val Arg Allah Cvs Asp Ws; ΐ IS * Read His Pro Thr Pro Trp Lys Thr Ax a Val Thr Ser He Met Ala Pro Leu He Leu Met Val Arg Ala Xie Leu Arg Pro Ser Arg Phe Arg Glu Gin Glu Gin Ser Gly Pro Ser His Lys Pro Asn Ala Vai Arg Phe Glu Phe Gly Leu Arg Val Ser Arg Leu Val Leu Le Met Met Glu Leu Leu Leu He Asp Glu Leu Asp Pro Asp Arg Asn Val Lys Asn Asn Leu Qin His Pro He Lys Leu Thr Gin Tyr Val Xie Ser Thr Ser Pro Asn He Phe Leu Leu Met Leu Gly Asn Met Leu Ser Lys Ser Gin Cys Pro Ala Val Glu Thr Lys Glu Gly val He He His Asn Asn Leu Leu Arg Leu Leu Glu Asn Pro Cys Leu He HeLys Phe Tyr Leu Glu Gly Gly Xie Asn Pro Met Gly Am Ser Phê Gin Val Gly Giy Ala Ser Pro Leu Le Pro Argu Glu Val Asp Phe Ser Ala Gin Asp Met Ala Ala His Leu Lys Asn Asp Glu Pro Asn Leu Ala Ser Gly Pro Ser Ala Ala Gly Asp Val Thr Leu Gly Ser pro Ser Pro Pre · Thr Thr Ala His Leu Leu Ger Thr Leu Ala pro Pm Asp Ser His His Pro Leu Leu Gly Glu He Read Gly Arg Gly Gin iâ Asp Glu

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Il sriv SueuSerGlnLlLiHH nT ρ * ιγίr- »ί -, _t λ-Λ? ^ iJS ^er ^ f ^3G ^ ^{uLfôuGiy? roT} ^ ^rL “ ^uAs P ^T hrLeuGlnLeuAspValÃH.AJnPhe ^ ^etGlu81u ^ ^{uelyMetAla!? ro} ^^^ S ^ SPGL MetAlaAsnCysSerAsnMetIl _{ea u el} i _eThrHisLeu ii, j _{iysQlnf> roproLeu} π ís RTN '^ i' ^yS? R? ^OAs ™ ^etAia ' ^{rhr <31nG1} y ^AlaK eK? Í ° AiíPhÍÂiS; -Ay5? S' vrAr ^ va? F'Í? XÍ? 2 | í ^/ í4T ⁱ y? ⁱ í ^ia 2j ^1: ' ^ai ' ^Leusln S «rt ^> heLeuGlÍvals · '?; ^Γ ^ Γί ^ ^& ^ ^δ ^ ^{εδβΓΐ #} ® ^{αί3ΐαα1ην} ^ Α3Γ0 ^ 8Χ11αΐη ^ νΑ ^ ϊν'1? Ϊ? yHrSSer euGiy ^ ^^ ^^ ^ eproTrpAlaProLeuSerSerCvsPr Zr-ri ^?: ^δ ^ ^^ ^ ^^^^ 'ΓαΐΓώβπΗίδ5όΓδ17ΐ _<6πΡ1ι ΐπ'Ρνχ51 £ ^ ^^ 1ν Ιη-η e r ^ s ^ ^a ^ ^{GloGiMetGiuetoe} S2i? ^"i ^^ ™ iE: e n ^'s X ^ ^^^^ H2i ^THEN * ^{v' ^;} * ^The ^ s ^ ™ 'v ArgG Íyl * vsValÀrgPh & LexlMet. l «mir * T * ^e ^^ J ^Uto ^^ ^eG ^^ xsLeuLeu ArgAspSerHisValLeuHis ^ iraL ^ i & lLeuSerLy sLeuLeu Thr? RaValLeuLeuP _TO ÃlavÈAiSh ^ e-? Í ^ ví? ^O 2 ^lu y ^{aXHisFroLeuPrc} GluThrLysAlaG'i nAsr ^ <p> t ”a ??? _y ^e ; ^ ^dGlyw ^ ^uT ^ ^L ysThrGlnMetGlu MaArgGÍ ^ íH ^^^^^^^^ euOÀuGlyValMetAla L ^ e ^ D ^^ «5 ^Ile ^ ^luIleIle8í ^ 8 ^ WBAr _and FroProila« - _n ~ ÇLü ^ Frõ4nl, ftü-jn <orPh ^r ' ⁱ v ^S V? ^ ^LjA f ^' ^Si “ ^er ' ^:: ' ^eije ' ^Í1 ^ ^et AspArgAsnL < ^í u ^ _eu v _alBiy01 ; ss ^^ ^T1 ^ ãl-euSers' «rLeuL2íei ^ _Q í ^ g ^^? 5íf * ^? ^« ^G1 y ^Q L> I- «uaiyI> ro I * euGlnSerLeuLeu {SEQ ID NO.222) · '' * ' ^yw ^ ^va ' ^ ^r ^ ^eu ^ ^{, and} ^ ®UG.lyAla r ^ í? Sip ^er t ¹ ^ ^{eCXiôASpG1UXieXieHisH} -isLeuLvsAraPr ^ PA>; L ‘« UX’6dA ^ pP ^ OAsilnSHLeiL? * ^ Rü & csnft lu & er ^ va i ^ 9γΓ ^ Κ AXBLeuFroAsnI, euGlus _e rPheX'aÍAr _e AiaV / alülíÍh'H ?? ^t í ^spA f ^SÀSr * ^Leti y ^ l ^ ín ^ uArsAanLeuGinPr ^ aieu ^^^ Sh ^^ í - ^^ y ^A ~ gHusProXue x le x XeLysAlaGly Asn'4inr in ·, JS'V ^ 2? ^ ^15iI a ^ oSer TyrLeuValThrLeuGluGl nr ¹ rn ·, p ^ ^P Xr ⁿ X ^iU? ^ ^eÂr 9GuuLíysLsuThrfche ϊ ^χ , ^aG ^ ^nGxuGInGíln ^ ZrValGluGlyG3vmvr <A2 .. uüxj «^ Pro ^ eruuyProHeSsrThriieAsr ^ _o g« ríÍ ^ ÍÍ® T ^{yi> er} '^ _suysSerP'r . _Gi p _{roTferí? V} ® ^r * - o © Seruy5u.luSer uunValArgLauLeuLeuG? vAlaLeuG NSP-τ ^ a *> * '^ r ^ y ^{UWR Ui2} ® ^L * nLeuSerGlv slyArSTh ^ t ^ toAlaHis ^^ ^^ T ^ ii ^ i ^^ FroGXÕ gMyLysvalArgPheLÍuHeLiuvXifevIeS: -: ^ e * ⁿ yPheSlnHisLeuieu SIVs? ' ^{£ y} ? ^{lyAsia4etAiaS8rI> roA1} ^ õp-õÂiÍ ^ sAÍhi ¹ ? ^rs !: ⁱ Y ^, ' ^he _: e _t s ^ e ^ euArgAspSerHisValLeuHisSe-A- ^ í ?? ^s J ^ P ^ vArgValLeu. nr ^ unMetG luGluThrLvsAlaGlnAsni '1 Σ, 7 ~ ?? Χ? ^β ί ^ ^LeuG WluTrpLvs ^ yVa ^ «tAmiaAr _S GlyGlnLeÍHÉ5 S Y '^^ euLeuGlv A-aAsnCysSerXleMeí “il» A «'n **' 3 ~ 3tó * ''« v λ _β1 Λ6 ^ ρΡΓΟΑ3ηΛ3 ^ Β ^ ώ ^ ϊ2ίίί5ϊ ?? ¹ ! Ί '? ^{! Λ} ' ^{5, ίΑΓ9ϊ} ' ^ΓΟΪ '- »1ΒΡΓΟ Ars ^ euProA _S ni .. _euGluSsr p _hv ; P -Se. ^ XeLeuMetAspirg ^^. xxeGiuAlallaLeuArgAsnieusiX ^ iyi ^ As ^ uSluAsnAlaSarGlv í52: yP'OIleIleIl _and i, y _SA l _aG i _vAso § ₁ ^ ₁ ^ ^p S® ^ 3 ^ ta-AlaAlaProser </ _ ueu v'alTnrLetiGluGlllGeP PrQGlyGiuProSerGlyProlleSerThrrÍAsnpí ^ S ^ ¹¹¹ ? ¹ ^ ¹ ^ ¹ ^ ¹ ^^^ ntsuysSerProAsnMetGlvThrGkuL.euP-oP? ^^? ^r ? ^ROI> I ^{oSerL, ysGiuS} ROAs ^ ^ ^ ^ • lailaPheLeuSe;!! S M ^ro - ^{'ll' roi 'ro} AlaCysAspi, euAr5valI, "i;e; l I ^is xyu ^ ^ ^ ..- yAsnMet? aLeuHisSerArgLeuSerslnCvsFrÕG-vvíÍH® '· ⁵ ^' y ^ ^^^^ SAspSer LeuLeuProAiaValAspPheSerLeurilvGl.lThyv ThrProVal ^^^ ^ bye-unAspX XeLeuG 'ave va »* φ>.Λ" * _T "^ ®Thr l.nMte tGluGluThriv® G? ®T. ^ .- 1 * ΣΖ £ X * - ^ ^Axa7axT ^ keuLeuLeuGluGXvVa'-ma® ait X “- ^ ^fe « ^ yProTnrcysLeuSerserLeuL ^ mv ^ í ^ Z ^^ ^tA1 ^ -sArgGly -eu ^ auuxyAlaLeuGlnSerLeuLeu ÍSEQ χ5 ^ νο? 234? ^ ^Λγί3 ” ^πνδ1ΑΓ 9 ^ υ TA, »* _Λ it ry.-X jL T} <S? T? * J '**' * K «iT». · * ^ * ^ StUspProA ^ nAsnLéuà <snA® ^ ”f7XÍ ^? ^à SA ^^ euLysArgProPrMãp ^ o ^ gLeuProÀSnLeuGluSerPhivalAroÀlívítf ^ F ^^^^^^ SAsnLeu ^ ^e ^^ laTleLeuArgAsnLeuGint> y-3 ^r vieupÍíc ^Sn í '? ^UG ' ^IuAsnAlaSerG * y ^Ar 9HisProlleTiexieLysAlaGlvîn5 ^? ^U ? F ^oSarAia ^ AlaAlaProSeÍ ^ yrLeuValThxXeuGluGltiA> «ri X? T ^P ®f ^pw J ⁿ ^ ^xuPhe ^ 9GluLysiseUTh _r ®h« ProGlyGrLuProSerGiyp ^ j ^ g ^^^^^ ^ ^ Jygs ^ ^ ^ = q ^ sr -euCy _S va ^ ArgGiuPheGlvGi _yAsr . _GivG1 ^ _Aq . ^ J ^ f ^t J ^euVa XGlyGlj ^ SerThr -e ^ inCysPrQGluValHisProLeup-r ^ íSJS ^ValLeuHxsSe -ArQLeu S® ^ euSly _G l _uTr p _{LysThr51nIJa ta} ; S er s er L euL euG 1yG 1 iiL e us e r G lyGlnValArgLeuheuDeuG lyAl aLeuGlns * »r LeuLeuGiyThrGlnLeuProProGln (SEQ ID NO: 235); AúaAsnCysSerlleMecIleAspGlullelleHisHisLeuLysArgProProAlaPro LeuLeuAspPrDAsnAsnbeuAsnAspGluAspValSerlleDeuMetAspArgAsnLeu ArgLeuProAenLauGluSerPheValArgAlaValLysASHLeuGluAsnAlaSerGly IleGluAial 1 eLeuArgAsnLeuGlnProCy sLeuProSerAlaThrAlaAlaPr Oser ArgHi s Prollell ellehy sAlaG lyAspTrpGlnGluPhaArgGl uLysLeuThrPhe TyrLeuValT hrLeuGluGlnAl aGlnG luGlnGlnTyrValGluGlyG LYG lyGl vSer FroGuyGluProSerGiypralleSerThrxleAsnPrQSerPrQPrDSerLysGluSer HxsLysSerPraAsnMetAlaHisLysAspProAsnAlallePheLeuSerPheGliiHis EUL euArg 'ly Ly sValAr gPheL® UME t 1 LeuVa Gly GlyS erThrLeuCy s VALAR GluPheGlyGlyAsnGiyGlyAsiüíetAlaSerProAlaProproAlaCysAspLeuArã VarLeuSerLysLeuLeuArgAspSerHisValLeuHisSerArgLeuSerGlnCvs g ^ ro GiuValHi s ProLeuProThrProValLeuLeuPr oAlaValAspPheEerLeuGlvGlu ^ rpLysTiirGlnMetGluGluThrLysAlaGlnAspIleLeuGlyAlaValThrLeuLeu "· £ ^ | ^ & 01νν 1Μ" ΕΑι & Α1ΜΑτ $ α1γΏ1π υ0 ^ ^ ΡΕθΤηχ £ γ £ ^ & υ £ £ βτ & Ε ^ ®υ1>β''υί G ^ • ^^ © yu 'unierGj.yuitnValAr gLeuLeuLeuGlyzilaLtSuGlnSerLex iLeuG ** v * ^r 'l · * GxnLeuProProGlnGlyArgThrThr (SEQ ID ^ 0: 236) .- ~ ~ A * ^& .aAsnCyeSer.IleMsrIleAspGluIleIleHisHisLeuLvsAraPrG roA3 r * a ^ <^ uLeuAspProAsnAsnLeuAsnAspGluAspValSerileLeuMeEAspÃÍgAíSLiu '? F ^ ^g ^ C ^{uPro euGiuSerPheV? iArgAiaVa} ^ ^L VSAsnLeuGluAsnAlaSerGly r ue ^ rtiAlau j. '^''DArgAsnLeuGlnProCysLeuProSerAlaThrAlaAlaProSer Air gHxs proline ellel Lely SAlaGlyAspTrpGlnGluPheArgGluLy sLeuThr Phe Tyr uValThrLeuGluGlnAlaG ^ ⁱ Prc nGluGlnGlniyrValGluGlyGlyGlyGlySer - ^^ yGruPro erGú.yProIIeSerThrIleAshProSerProPro $ * $ erLvsGluSe ^ · ^ sLys erPrcAsnMetAspProAsnAlallePheLeuSerPheGlnHi; Leul1euArG' ~ ly-uyEvaxArgPheLeuMetLeuValGlyülySerThrLíeuCi''sValArgGluPheGlv ^T ^ * yAsnGlyGlyAsnMetAlaSerProAlaProProAlaCysAspLeuArgValLeuS '· YS ~ er Hi LeuLeuAr gasps sV the ILeuHiss erar gLeuS ERG Incy s ProG 1 uValHi s ErojweuPraThrProValLexiLfôuProAlaValAspPhe.serl euGlyGluT.rpLysThr ^^ _e' 2 R e ^^ ^a ^^ ^{s XU} i ⁱ f ^{plieLeuGlyAlaVal aGlnA} J3 ^{<rhrLeuLeuL 'uQ1} ^ ly; ^? r ^ Í ^ t ^ ^rg ? ^Ay ^ ^ln t ^íeuG t ^yP F ^cThrC y ^sLGU SerSerLeuLfôuGlyGlnLeu 2,!: ~ ^ < ^/ - | ^η ^ ^± ί5 ^ ί ^? ' ^αί ' ^βυί3 · ⁾ ' ^γΑ · ^{ΐ £ ίΙ <βπί31η £ βΓ1} '· ⁶ ' ^α ^ « ^ν ^ ΐντηταιΐιΐ; βαΡΓο Pio ^ lnGlyArgThrThrAlaHxsLys {SEQ XD NO: 237) Ao. art, $ nCy s S er I x eMe til. aAspG 1 ul 1 e 11 eHi sHi eL euLy s Ara P ^ o ^ r oAl aPr o ^ euL ^ uAspProAsnAsnLeuAsnAspGluAspValSerlleLeuMet.AspArqAsn £ eu ^^ LSaProAanLeuGluSerPheValArgALaSHaLaGsLaGHaLaGHaSHaLaGaLaLaGaLaGaLaGaLaGaLaGaLaGaLaGaLaGaLaGaLaLaGaGaLaLaGaGlHgGlHgGlHgGgHgGgHgGgHgGgHgGlHgGgGgGgggggggggggggggggggggggggg ^J tf ^S ? ^S: í '? ^UG } ^nProCysI ' ^{euprDSerAlaThrAlaAla} ^'> Ser ^ ?: ν:? Ίί “1 * Ξ, ^ί ^ ϊ ^ ^β ? Ί ^γ ^ ^ρΓ Π ^{, 01Σια1} '^{1Ε> ί1} » ^Α Γβ <31υΙΫ5Χ.β «τίΐΓΡηβ ^ 0G? vSlÍirls ^? í'v ^ íí'ií = ^J ' ^: ' 2Í ^U ? í ' ⁿ ? ^{lnTyrVaiGluG1YGlyG1 SSi} · y y ^G1 OGJ-ul-YGI · x ^ L ^ o If yProxleSerThru.leAsnPrQSerProProSerLvsGluSer HrsLysS erPraAsnMe t AlallePheLeuS ether PheGlnMisLsuLeuArgGi ytysVa 3 ^ ^'w ^ f ^ ^^^ ^et euMecLeuValGlyGlySerThrLteuCvsvalAraGluPheGlyGÍvAsnGlv - ^A i ^{and? PROOAXaProFrOAiaCysAspLôuAr} ãvalLeus _e ? Lys ^ GLeu ^^ ovF '''i ^, ^^ t®v ^ Sí ^u ® ^er ? ^ln SY ^sp f ^{OGluVal8is? roieuí> ro} ~ ^ν * xo ^ -laVaxAspPneberLeuGlyGluTrpLysThrGlnMôtGlu Gd.uThrLysAlaGxnAspileLeuGlyíilaValTàrLeuLíeuúauGluGlvVaifcietAla Al * ArgQlySl ^ e _uOiyProT ^ Val ^ euLeuLeuGJyAlaLeuGX ^^ ArgThrThrAlaHxsLysAspProAsn (SEQ Π>CN;^23S1;? Θ nSSSS ^^ ^ ^{4 and} S ^ ^{X1 SP XU} M ^M ® ® ^{IE1 KiSííeWSArgFrO ROA} l ^ 0 ** - * u ~ ç.uAspPrüÀsnAsnLeuAsnAspwluAspvalSe -ilei, euJ4ecAspArqAsnLeu ArgxeuProAsnLeuGiuSarPheValArgAlaValLysAsnLeuGluAsnAliserGlv XleG XuAlal j eLeuArgAsnLauG ln ProCysLeuPr © SerAlaThr Ai AAL to Ετης # '7 ArgHisPruixexXexx ^ ysAlaGlyAspTMlnGluPheAraGluLvsri ^ issf I? ^{f r pfu} ^ f' ¹ '* ^hr ^ ^euGiuGlljA * ^ag ^ ^nGluG * ^ng l ⁿ TyrValGlUGlyGlyQlvQiySs ^ oGAyduProSerGXyProIleSerThrXleAsnPraSerProProSerLvsG u <? pηΐ ? ^ Thexetme ^ e ^ ValGlyGXySerThrLeuTysVaXArgGluPheGlv SÍtsSe? ^ ⁰ Í5alií ^{Xa? r0} r ⁰ ? ^{Was it} ? ^YSA f ^PL ' ^{eUArSValLeuSerL} > ^{? S} - ^e ^^ S ^δ Υ ^{& 1} ^ αΗι ^sSs t ArgLau ^ beGlnCysProGluValRigpr oLeuPrc I '~ - BEU rova ^ v ^ euPradaVaiAspPheSerLeuGl.yGluTrpLvsTt oGlnMetGl' ^{οΤΛχ Τ>} · αχ 'Ώ5' η3 'ΓΑ ^' αΕ 'χιθΧνθ1ηΑ & υ5δΓδχνα1Γ hÍsÊÍÍ S2 ^U ^ J J ^ | ^ ^T ^^ y ^{euGinSerLeuLeuGi} lnGlyArgThrThSl. _s 14, Hematopoietic protein according to claim 1, 2, 3. 4, 5. 6, 7, 8, 10 or 11, where said colony stimulation factor is selected from the group consisting of GM-CSF, G-CSF. G-CSF Ser ^v c ~ mpl ligand (TPO), M-CSF. entropoietin (EPO), IL-1, IL-4 _; IL-2, IL-3, IL-5 _S IL-6. IL-7, 5 IL-8, IL-9. lt-10, IL-11, IL-12, IL-13. IL-15 _; LIF _: ligand fí.i3 / fík2, human growth hormone, cell growth factor B. cell differentiation factor B eosinophilia differentiation factor, and stem cell factor (SCF). Hematopoietic protein according to claim 14. 10 where said colony stimulation factor is selected from the group consisting of G-CSF. G-CSF Ser ¹⁷ and shiny c-mpl (TPÓ). 16, Nucleic acid molecule encoding said hematopoietic protein according to claim 1, 17, Nucleic acid molecule encoding said hematic protein Matopoietics according to claim 2. 18, Nucleic acid molecule encoding said hematopoietic protein according to claim 3. 19, Nucleic acid molecule encoding said hematopoietic protein according to claim 4. 20. Nucleic acid molecule encoding said hematopoietic proteins according to claim 5. 21. Nucleic acid molecule encoding the hematopoietic protein according to claim 6. 22. Nucleic acid molecule encoding said hematopoietic protein according to claim 7. 23. Nucleic acid molecule encoding said hematopoietic protein according to claim 8. 24. Nucleic acid molecule encoding said hematopoietic protein according to claim 9. 25. Nucleic acid molecule encoding said hematopoietic protein according to claim 10. 26. Nucleic acid molecule encoding said hematopoietic protein according to claim 11. 27. Nucleic acid molecule encoding said hematopoietic protein according to claim 12. 28. Nucleic acid molecule encoding said hematopoietic protein according to claim 13. 29. Nucleic acid molecule encoding said hematopoietic protein according to claim 14. 30. Nucleic acid molecule encoding said hematopoietic protein according to claim 15 31. Nucleic acid molecule according to claim 27 selected from the group consisting of; 51 ^Ύ V 151 201 25.1 301 351 401 452 502 € 551 € 01 51 7vl 752 802 903 ATGGCTAACT ACCACCTGCA CTATCCTGÃT AGGGCTGTCÀ TAATCTCCAA C.AATCATCAT TTCTATCTGG isyiA-U ACAAGCTGTG ATCCCCTGGG AGGCTGCTTG TGCAGGCCCT CTGCAGCiGG AGAÀCTGGGA CC7TCGCCTC CATCTGCAGA GCAGCCCTCT TAGAGCAAGT CTGTGTGCCA GATCGATGÂA GCTCTATAAT CCWGCTGG ACCCGAÀCAA GGACGGAAAC CTTCGACTTC AGAACTTAGA AAATGCATCA CCATGTCTGC CCTCTGCGAC CAAGGCAGGT GACTGGCAAG TTACCCTTGA GCAAGCGCÀG TGCCCGGGTG GTQGTTCTGG CCACCCCGAC GAGCTGUTGC CTCCCCTGAG CTCCTGCCCC AGCCAACTCC ATAGCGGCCT GGAAGGGATA TCCCCCGAGT AGGTCGCCGA CTTTGCCACC ATGGCCCCTG CCCTGCAGCC TGCTTTCCAG CGCCGGGCAG GCTTCCTGGA GGTGTQGTAC GGCGGCTCTG GCGGCTCTCA GAGÀÀAGATC CAGGGCGATG CCTAATAA (SEQ W NO: 9i ATTATACATC ACTTÀAAGAG CCTCAATGAC GAAGACGTCT CAAÀCGTGGA GAGCTTCGTA GGTATTGAGG CAATTCTTCG GGGCGCACCC TCTCGAGATO AATTCCGGGA AAAACTGACG GAACAACAGT ACGTAGAGGG CGGCGGCTCC AAGATOGCTT TGCTCGGACA CTCTCTGGGC AGCCAGQCCC TGCAGCTGGU TTTCCTCTAC CAGGGGCTCC TGGGTCCCAC CTTGGACACA ACCATCTGGC AGCAGÀTGGA CACCGAGGGT GCCATGCCGG GAGGGGTCCT GGTTGCTAGC CGCGTTCTAC GCCACCTTGC GAGCTTCCTG CTCAAGTCTT GCGGAGCGCT CCAGGAGAAG 101 152 202 251 301 351 401 451 502 551 501 651 702 752 801. 852 901 ATGGCTAACT GCTCTATÀAT GATCGATGAA ACCACCTGCA CCTTTGCTGG ACCCGAACAA CTATCCTGAT GGACCGAAAC CTTCGACTTC AGGGCTGTCA ÂGAACTTAGA AAATGCATCA TAATCTCCAA CCATGTCTGC CCTCTGCCAC CAATCATCAT CAAGGCAGGT GACTG0CAAG TTCTATCTGG TTACCCTTGA GCAAGCGCAG CGGTGGAGGC TCOTGGGTG AACCQTCTGG CGTCTCCTCC GTCTÀAAGAA TCTCATAAAT CTGTGCCACC CCGÀGGAGCT GGTGCTGCTO CTGGGCTCCC CTGAGCTCCT GCCCCAGCCA GCTTGAGCCA ACTCCATAGC GGCCTTTTCC GCCCTGGAAG GGATATCCCC CGAGTTGGGT GCTGGACOTC GCCGACTTTG CCACCACCAT TGGGAATGGÇ CCCTGCCCTG CAGCCCACCC GccTCTGcrr tccascgccg ggcaggaggg GCAGAGCTTC CTGGAGGTGT CGTACCGCGT CCTCTGGCGG CTCTGGCGGC TCTCAGAGCT CAAGTGAGAA AGATCCAGGG CGATGGCGCA TGCCÀCCTAA TAA (SEQ ID NO; 95); ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC ÀATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GGACACTCTC GGCCCTGCAG TCTACGAGGG TCCACCTTGG CTGGCAGGAGCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC ÀAAACTGACG ACGTAGAGGG ACTATCAACC GGCTTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG ACACAGTGQA ATGGAAGAAGGC ATGGCTAACT 101 15Í 201 251

> C1

801 851 .901 agggctgtca TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CCGAGTTGGG GCCACCACCA GCAGCCCACC wGiaCAGGAGG TCGTACCGCG CTCTCAGAGC GCGATGGCGC CACCCCGAGG tcccctgagg GCCAACTCCA AGG GCTCTATAAT GATCGATGAA CCTTTGCTGG ACCCGAACAA GGACCGAAAC CTTCGACTTC AGÀACTTAGA AAATGCATCA CCATGTCTGC CCTCTGCCAC CAAGGCAGGT GACTGGCAAG TTACCCTTGA GCAAGCGCAG TCCCCGGGTG GTGGTTCTGG TCCCACCTTG GACACACTGC TCTGGCAGCA GÀTGGAAGAA CAGGGTGCCA TGCCGGCCTT GGTCCTGGTT GCTAGCCATC TTCTACGCCA CCTTGCGCAG TTCCTGCTCA AGTCTTTAGA AGCGCTCCAG GAGAAGCTGT AGCTGGTGCT GCTCGGACAC TCCTGCCCCA GCCAGGCCCT TAGCGGCCTT TTCCTCTACC CCTAATAA (SEQ XD NO: 9i ATTATACATC ACTTAAAGAG CCTCAATGAC GAAGACGTCT CAAACCTGGA GAGCTTCGTA ggtattgagg caattcttcg GGCCGCACCC TCTCGACATC ^ ATTxCGuGA aaaactgacg gaacaacagt ACGTAGAGGG CGGCGGCTCC AACATGGCTC AGCTGGACGT CGCCGACTT '' CTGGGÀATGG CCCCTGCCCT CGCCTCTGCT TTCCAGOGC ^r TGCAGAGCTT CCTGGAGGTG ccctctggcg GCTCTGGCGG GCAAGTGAGA AAGATCCAGG GTGCCACCTA CAAGCTGTGC tctctgggca tcccctggg ^ ^ GA gcàgctggca GGCTGCT AGGGGCTCCT GCAGGCCCTG SI 101 ATGGCTAACT accacctgca ctatcctgat 1 1

7 ^ 1 301

501 AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTA ^ C ^ GG UksGTG G AGGC CGTCTCCTCC * to 1CLCA 601 651 701 751 801 8 51 901951 CA.CCATCTGG xx Au u X AGGG GGAGGGGTCC CCGCGTTCTA AGAGCTTCCT ggcgcagcgc CGAGGAGCTG TGAGCTCCTG ctcqatagcg. gatatcctaa GCTCTATAAT GATCGATGAA CCTTTGCTGG ACCCGAACAA GGACCGAAAC CTTCGAOTC agaacttaga AAATGCATCA CCATGTCTGC CCTCTGCCAC caaggcaggt TTACCCTTGA fT f ** <** <** <** <** r * r * íT «gtctaaagaa CCTTGGACAC AGCAGATGG TGCCATGCCG GCCTTCGCCT tggttgqtag ccatctgcag CGCCÀCCTTG CGCAGCCCTC GCTQAAGTCT TTAGAGCAAG TCCAGGAGAA GCTGTGTGCC GTGCTGCTGG GACACTCTCTPCAGCCAG GCCCTGCAGC GCCCTT GACTGGCAAG GCAÀGCGCAG AACCGTCTGG TCTCATAAAT ACTGCÀGCTG aagaactggg ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT GACGTCGCCG AÀTGGCCCCT CTGCTTTCCA agcttcctgg TGGCGGCCCTGAGGGGCGAGGAGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGCGGGGCGGGGGGCGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGGCGGGGGGGGGGGGGGGGGGGGGGGGGCGGGCGGGCGGGCGGGCGGGGGGGG ACTTAAAGAG GAAGACGTCT gagcttcgta CAATTCTTCG TCTCGACATC aaaactgacg acgtagaggg ACTATCAACC GGCTCCCGAG ACTTTGCCAC GCCCTGCAGC GCGCCGGGCA aggtgtcgta ggcggctcc CCGGGGCCCCCTGGGCGA 301 ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC GCTCTATAAT CCTTTGCTGG ggaccgaaac AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GATCGATGAA acccgaacaa CTTCGACTTC AAATGCATCA CCTCTGCCAC gactggcaàg GCAAGCGCAG GTGGTTCTGG ATTATACATC CCTCÀATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC ACTTAAAGAG GAAGACGTCT gagcttcgta CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTA CTTCCTGGAÍ GCGGCTCTGC AGAAAGATCÍ GT ACC / 'CJWSWS ^ uilu AT CT ’ GAAGAACT ATGGCTAACT AGGGCGATGG CGCAGCGCTÍ AGGAGCTGGt AGCTCCTGCC TATCCCCCGA GACTTTGCCA TCAAGTCTTT GAGGAG AAGC GTTGGGTC 401 451 501 553 601 651 TAATCTCCAA CAATCATCAT * y <cr <Q jAfri CGGTGGAGGC CGTCTCCTCC CCAGCGCCGG TGGAGGTGTC TCTGGCGGCT GATCCAGGGC - »Λ3ς_ i LA WkS 801 851 GGACCGAAAC AGAACTTAGA CCATGTCTGC CÀAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA AGCCCACCCA GCÂGGAGGGG GTACCGCGTT CTCAGAGCTT GATGGCGCAG CCOGGAGGAG CCACTGATGGCCCTCT AAATGCATCA GACTGGCÀAG gcaagcgcag AACCGTCTGG TCTCATAAAT GGGTQCCATG TCCTGGTTGC CTACGCCACC CCTGCTCAAG CGCTCCAGGA CTGGTGCTGC CTGCCCCAGC gcggcctttt CCCGAGTTGG TGCCACCACC TAA (SEQ ID NO: 99); ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC aattccggga GAACAACAGT TCCAATCTCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA 951 CCGGCCTTCG TAGCCATCTG TTGCGCAGCC TCTTTAGAGC GAAGCTGTGT TCGGACACTC CAGGCCCTGC CCTCTACCAG GTCCCACCTT ATCTGGCAGC TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GGCTATGGCC CCTCTGCTTT CAGAGCTTCC CTCTGGCGGC AAGTGAG AAA GCCACCTACA TCTGGGCATC AGCTGGCAGGG gggctcctgc GGGAACAGA AGG ATGGCTAACT GCTCTATAAT 15.1 301 551 801 651 701 CTATCCTGAT AGGGCTGTCÀ TAATCTCCAA CAATCATCAT TTCT ATCTG CGGTGGAGGC CCCAGGGTGC GGGGTCCTGG CGTTCTACGC GCTTCCTGCT GCAGCGCTCC GGAGCTGGTG gctcctgcccc CATAGCGgcccc GGACCGAAAC AGAACTTAGA ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG uATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCATGTCTGC CCTCTGCCAC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG CATGCCGGCC TTGCTAGCCA CACCTTGCGC CAAGTCTTTA AGGAGAAGCT CTGCTCGGAC CAGCCAGGCC TTTTCCTCTA TTGGGTCCCA GACTGGCAAG <3u.AAGuGCAG gtggttctgg TTCGCCTGTG AGCCCTCTGG GÂGCAAGTGA GTGTGCCACC ACTCTCTGGG CTGCAGCTGG CCAGGGGCTC CCTTGGACAC acttaaagag GAAGACGTCT gagcttcgta CAATTCTTCG TCTCGACATC ÀATTCCGGGA AAAACTGACG ACGTAGAGGG AACATGGCTA CCGGGCAGGA TGTCGTACCG GGCTCTCAGA GGGCGATGGC gccaccccga GCTCCCCTGA GAGCCAACTC TGGAAGGGAT gacgtcgccg GAACAACAGT CGGCGGCTCC CTTTCCAGCG TTCCTGGAGG cggctctggc GAAAGATCCA TACAAGCTGT CATCCCCTGG CAGGCTGCTT CTGCAGGCCC ACTGCAGCTG 851 901 ACTTTGCCAC -CACCATCTGG CAGCAGATGG ÀAGAACTGGG GCCCTGCAGC CCTAATAA ÍSEQ ID NO: 100), AATGGCCC; 101 151 201 401 4 D J. 501 551 601 651 701 *? Σΐ 801 851 901 S51. ATGGCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG CTATCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACCCTTGA CGGTGGAGGC TCCCCGGGTG CGTCTCCTCC GTCTAAAGAA GGTGCGATGC CQGCCTTCGC CCTGGTTGCT AGCCATCTGC TACGCCACCT TGCGCAGCCC CTGCTCAAGT CTTTAGAGCA GCTCCAGGAG AAGCTGTGTG TGGTGCTGCT CGGACACTCT TGCCCCAGCC AGGCCCTGCA CGGCCTTTTC CTCTACCAGG CCGAGTTGGG TCCCACCTTG GCCACCACCA TCTGGCAGCA GCAGCGCTAA TAA (SEQ ΣΙ GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA ÀAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGCACCC GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACAÀCAGT AACCQTCTGG TCCAATCTC ^ TCTCATÀÀAT CTCCAAACAT CTCTGCTTTC CÃGCGCCGGG AGAGCTTCCT GGAGGTGTCG TCTGGCGGCT CTGGCGGCTC AGTGAGAAAG ATCCAGGGGG CCACCTACAA GCTGTGCCAC CTGGGCATCC CCTGGGGTCC GCTGGCAGGC TGCTTGAGCC GGCTCCTGCA GGCCCTGGAA GACACACTGC AGCTGGACGT GATGGÀAGAA CTGGGAATGG 'NO; 101); acttaaagag GAAGACGTOT GAGCTTCGTA CAATTCTTCG TCTCGACATC aaaactgacg ACGTAGAGGG ACTATCAACC GGCTACCCAG CAGGAGGGGT TACCGCGTTC TCAGAGCTTC ATGGCGCAGC CCCGAGGAGC COTGAGCTCC AACTCCATAG GGGATATTCCGCC 101 151 201 v *. 301 351 401 451 501 551 001 651 701 751 801 851 S01 GCTCTATAÂT ATGGCTAACT ACCACCTGCA CCTTTGCTGG CTATCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACCCTTGA CGGTGGAGGC TCCCCGGGTG CTGCTTTCCA GCGCCGGGCA AGCTTCCTGG AGGTGTCGTA TGGGGGCTCT GGCGGCTCTC TGAGAAAGAT CCAGGGCGAT ACCTACAAGC TGTGCCACCC GGGCATCCCC TGGGCTCCCC TGGCAGGCTG CTTGAGCCAA CTCCTGCAGG CCCTGGAAGG CACACTGCAG CTGGACGTCG TGGAAGAACT GGGAATGGCC CCGGCCTTCG CCTAATAA (£ GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA AAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGCACCG GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACAACAGT GTGGTTCTGG CGGCGGCTCC GGAGGGGTCC TGGTTGCTAG CCGCGTTCTA CGCCACCPTG AGAGCTTCCT GCTCAAGTCT GGCGCAGCGC TCCAGGAGAA CGAGGAGCTG GTGCTGCTCG TGAGCTCCTG CCCCAGCCAG CTCCATAGCG GCCTTTTCCT GATATCCCCC GAGTTGGGTC CCGACTTTGC CACCACCATC CCTGCCCTGC AGCCCACCCA: EQ TD NO; 102); ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTT CCATCTGCAG CGCAGCCCTC TTAGAGCAAG GCTGTGTGCC GACACTCTCT GCCCTGCAGGGAC GCCCTGG PMON25191 101 ATGGCTAACT ACCACCTGCA CTATCCTGAT GCTCTATAAT GATCGATGAA CCTTTGCTGG ACCCGAACAA GGACCGAAAC CTTCGACTTC ATTATACATC ACTTA ^ AGAG CCTCAATGAC GAAGACGTCT CAAACCTGGA GAGCTTCGTA

AGGGCTGTCA AGAACTTAGA AAATGCATCA GGTATTGAGC TAATCTCCAA CCATGTCTGC CCTCTGCCAC GGCCGCACCC CAATCATCAT CAAGGCAGGT GACTGGCAAG AATTCCGGGA TTCTAT.TTGG TTACCCTTGA GCAAGCGCAG GAACAACAGT CGGTGGAGGC TCCCCGGGTG AACCGTCTGG TCCAATCTCT CGTCTCCTCC GTCTAAAGAA TCTCATAAAT CTCCAAACAT TTGGGTCCCA CCTTGGACAC ACTGCAGCTG GACGTCGCCG CACCATCTGG CAGCAGATGG AAGAACTGGG AATGGCCCCT CCACCCAGGG TGCCATGCCG GCCTTCGCCT CTGCTTTCCA GG-AGGGGTCC TGGTTGCTAS CCATCTGCAG AGCTTCCTGG CCGCGTTCTA CGCCACCTTG CGCAGCCCAC ACCATTGGGC CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT TAGAGCAAGT CAGGGCGATG GCGCAGCGCT CCAGGAGAAG CTGTGTGCCA GTGCCACCCC GAGGAGCTGG TGCTGCTCGG ACACTCTCTG GGGCTCCCCT GAGCTCCTGC CCCAGCCAGG CCCTGCAGCT TTGAGCCAÀC TCCATAGCGG CCTTTTCCTC TACCAGGGGC CCTGGAAGGG ATATCCTAAT AA ISEQ ID NO: 107) CAATTCTTCG TOTC G AC AT I AAAACTGACG ACGTAGAGGG actatcaacc ACTTTGCCAC GCCCTGCAGC • X λ V? 1 'i * W CCTGCCAGCT G AGAAAG AT C CCTACAAGCT GGCATCCCCT GGCAGGCTGC TCGTGCAGGC 1 ATGGCTAACT GCTCTATAAT 51 ACCACCTGCA CCTTTGCTGG 101 CTATCCTGAT GGACCGAAAC 151 AGGGCTGTCA AGAACTTAGA 2Cl TAATCTCCAA CCATGTCTGC 251 CAATOATCAT CAAGGCAGGT 301 TTCTA ^ CTGG TTACCGTTGA 3 51 CGGTGGAGGC TCCCCGGGTG 401 CGTCTCCTCC GTCTÀAAGAA 451 TTCCAGCGCC GGGCAGGAGG 501 CCTGGAGGTG TCGTACCGCG 551 GCTCTGGCGG CTCTCAGAGC 601 AAGATCCAGG GCGATGGCGC 651 CAAGCTGTGC CACCCCGAGG 701 TCCCCTGGGC TCCCCTGAGC 7 51 GGCTGCTTGA GCCAACTCCA 801 GCAGGCCCTG GAAGGGATAT 851 TGCAGCTGGA CGTCGCCGAC .901 GAACTGGGAA TGGCCCCTGC 951 CTTCGCCTAA TAA (S £ Q II GATCGATGAA ATTATACATC ACTTAAAGAG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTTCGACTTC CAAACCTGGA GAGCTTCGTA AAATGCATCA GGTATTGAGG CAATTCTTCG CCTCTGCCAC GGCCGCACCC TCTCGACATC GACTGGCAAG AATTCCGGGA AAAACTGACG GCAAGCGCAG GAACAACAGT ACGTAGAGGG AACCGTCTGG TCCAATCTCT ACTATCAACC TCTCATAAAT CTCCAAACAT GGCTTCTGCT GGTCCTGGTT GCTAGCCATC TGCAGAGCTT TTCTACGCCA CCTTGCGCAG CCCTCTGGCG TTCCTGCTCA AGTCTTTAGA GCAAGTGAGA AGCGCTCCAG GAGAAGCTGT GTGCCACCTA AGCTGGTGCT GCTCGGACAC TCTCTGGGCA TCCTGCCCCA GCCAGGCCCT GCAGCTGGCA TAGCGGCCTT TTCCTCTACC AGGGGCTCCT CCCCCGAGTT GGGTCCCACC TTGGACACAC TTTGCCACCA CCATCTGGCA GCAGATGGAA CCTGCAGCCC ACCCAGGGTG CCATGCCGGC NO: .103); 101 151 201 251 301 351 401. 451 501 ATGGCTAACT GCTCTATAAT GATCGATGAA ru_C / iCCTuAA CCTTTGCTGG ACCCGAACAA CTATCCTGAT GGACCGAAAC CTTCGACTTC AGGGCTGTCA AGAACTTAGA AAATGCATCA TAATCTCCAA CCATGTCTGC CCTCTGCCAC CAATCATCAT CAAGGCAGGT GACTGGCAAG TTCTATCTGG TTACCCTTGA GCAAGCGCAG CGGTGGAGGC TCCCCGGGTG GTGGTTCTGG ACAAGCTGTG ATCCCCTGGG CTCCCCTGAG CTCCTGCCCC CGACCCCGAG GAGCTGGTGC AGGCTGCTTG ÀGCCAACTCC ATAGCGGCCT ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT CGGCGGCTCC TGCTCGGACA AGCCAGGCCC TTTCCTCTAC ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG AACATGGCTT CTCTCTGGGC TGCAGCTGGC CAGGGGCTCC 551 601 651 7C1 801 ® · 901 101 151 201 251 301 35 ¹ 401 451 Ί S51 601 851 701 751 801 851 901 aci 5 ^ 101 151 201 25 ' 301 351 401 451 501 551 60.1 651 701 751 801 851 901 951 TGCAGGCCCI CTGCAGCTGG AGAACTGGGA ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT bc λ vs C Cs and £ C CTGTGCCACC CTGGGCTCCC GCTTGAGCCA '-yOw CTGGAAG GCTGGACGTC TGGGAATGGC GCCTCTGCTT GCAGAGCTTC CCACACCATT TCTTTAGAGC GAAGCTGTGT GGAAGGGATA TCCCCCGAGT ACGTCGCCGA CTTTGCCACC ATGGCCCCTG CCCTGCAGCC TGCTTTCCAG CGCCGGGCAG GCTTCCTGGA GGTGTCGTAC CCATTGGGCC CTGCCAGCTC agagcaagtg ágaaagatcc CTATGTGA TGGGTCCCAC CTTGGACACA ACCATCTGGC AGCAGATGGA CACCOAGGGT .GGCATGCCGG GAGGGGTCCT GGTTGCTÂGC CGCGTTCTAC GCrACCTTGC CCTGCCCCAG AGCTT0GTGO AGGGCGATG GC: GCTCTATAAT GATCGATGAA ATTATACATC CCTTTGCTGG ACCCGAACAA CCTCAATGAC GGACCGAAAC CTTCGACTTC CAAACCTGGA AGAACTTAGA ÀAATGCATCA CCATGTCTGC CCTCTGCCAC GGCCGCACCC GGTATTGAGG CAAGGCAGGT GACTGGCAAG AATTCCGGGA TTACCCTTGA GCAAGCGCAG GAACAACAGT TCCCCGGGTG AACCGTCTGG TCCAATCT ^ T ^ Ci gtctaaagàa TCTCATAAAT CTCCAA? CCGAGGAGCT GGTGCTGCTC GGACACTCTC CTGAGCTCCT GCCCCAGCCA GGCCCTOcÃg ACTCCATAGC GGCCTTTTCC TCTACCAGGG GGATATCCCC CGAGTTGGGT CCCACCTTGG GCCGACTTTG CCACCACCAT CIGGCAGCAG OCCTGCCCTG CAGCCCACOC TCCAGCGCCG GGCAGGAGGG GTCCTGGTTG AGGGTGGCAT CTGGAGGTGT CGTACCGCGT TOTACGCCAC GGGCCCTGCC AGCTCGCTGC CCCAGAGCTT AAGTGAGAAA GATCCAGGGC QATGGCGCAG GCCACC7AAT AA (SEQ ID NO: 105); ACTTAAAGAG GAAGACGTCT GAGCTTCGTA TCTCGACATC aaaactgacg ACGTAGAGGG ACTATCAACC GGCTTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG ACACACTGCA ATGGAAGAAC GCCGGCCTTC CTAGCCATCT CTTGGGCAGC CCTGCTCAAG CGCTCCAGGA ATGGCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG CTÀTCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACCCTTGA CGGTGGAGGC TCCCCGGGTG CGTCTCCTCC GTCTAAAGAA CCTGCCCTGC AGCCCACCCA CCAGCGCCGG GCA.GGAGGGG TGGAGGTGTC GTACCGCGTT GGCCCTGCCA GCTCCCTGCC AGTGAGAAAG ATCCAGGGCG CCACCTACAA GCTGTGCCAC CTGGGCATCC CCTGGGCTCC GCTGGCAGGC TGCTTGAGCC GGCTCCTGCA GGCCCTGGAA GACACACTGC AGCTGGACGT GATGGAAGAA ctgggataat gatcgatgaa attatacatc ACCCGAACAA CCTCAATGAC CTTCGÀCTTC CAAACCTGGA AAATGCATCA GGTATTGAGG CuTCTGCCAC GGCCGCACCC GACTGGCA ^ G AATTCCGGGA GCAAGCGCAG GAACAACAGT AACCGTCTGG TCCAATCTCT TCTCATAAAT CTCCAAACAT GGGTGCCATG CCGGCCTTCG TCCTGGTTGC TAGCCATCTG CTACGCCACC TTGCGCAGCC CCAGAGCTTC CTGCTCAAGT ATGGCGCAGC GCTCCAGGAG CCCGAGGAGC TGGTGCTGCT CCTGAGCTCC TGCCCCAGCC AACTCCATAG CGGCCTTTTC GGGATATCCC CCGAGTTGGG CGÇCGAOTTT GCCACCACCA AA (SEQ ID NO: 109); ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GGCTATGGCC CCTCTGCTTT CAGAGCTTCC CACACCATTG CTTTAGAGCA AAGCTGTGTG CGGACACTCTC AGG TCTGGCAGCA

atggdtaact gctctataat ACCACCTGCA CCTTTGCTGG CTATCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA TÀATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACC-CTTGA CGGTGGAGGC TCCCCGGGTG CCCAGGGTGC CATGCCGGCC GGGGTCCTGG TTGCTAGCCA xACGC CACCTTGCGC TGCCCCAGAG CTTCCTGCTC GGCGATGGCG CAGCGCTCCA CCACCCCGAG GAGCTGGTGC CTCCCCTGAG CTCCTGCCCC AGCCAACTCC ATAGCGGCCT GGAAGGGATA TCCCCCGAGT ACGTCGCCGA CTTTGCCACC ATGGCCCCTG CCCTGCAGCC GATCGATGAÀ ATTATACATC ACTTAAAGaG ACCCGAACAA CCTCAATGAC GAAGACGTCT CTTCGACTTC CAAACCTGGA GAGC ^ ~ GTA AAATGCATCA GGTATTGAGG CAATTcitCG CCTCTGCCAC GGCCGCACCC TCTCGACATC GACTGGCAAG AATTCCGGGÀ AAAACTGACG GCAAGCGCAG GAACAACAGT ACGTAGAGGG GTGGTTCTGG CGGCGGCTCC AACATGG ^ RT TTCGCCTCTG CTTTCCAGCG ccgggcagga TCTGCAGAGC TTCCTGGAGG TGTCGTACCG AGCCCACACC ÀTTGGGCCCT GCCAGCTCCC AAGTCTTTAG AGCAAGTGAG AAAGATCCAG GGAGAAGCTG TGTGCCACCT ACAAGCTGTG TGCTCGGACA CTCTCTGGGC ATOCCCTGGG AGCCAGGCCC TGCAGCTGGC AGGCTGCTTG TTTCCTCTAC CAGGGGCTCC TGCAGGCcA'r TGGGTCCCAC CTTGGACACA CTGCAGCTGG • nCCATCTGkjL. A «AGATGGA AGAACTGGGA CTAATAA (SSQ ZD NO i110);

ATGGCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG CTATCUTGAT GGACCGAÀAC AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC CAATCATCAT CAAGGCAGGT TTCTATCTGG TTACCCT ^ GA CGGTGGAGGC TCCCCGGGTG CGTCTCCTCC GTCTAAAGAA GGTGCCATGC CGGCCTTCGC CCTGGTTGCT AGCCATCTGC TACGCCAGCT TGCGCAGCCC CAGAGCTTCC TGCTCAAGTC TGGGGCAGCG CTCCAGGAGA CCGAGGAGCT GGTGCTGOTO CTGAGCTCCT GCCCCAGCCA ACTCCATAGC GGCCTTTTCC GGATATCCCC CGAGTTGGGT gccgactttg ccaccaccat CCCTGCCCTG CAGCCCTAAT GATCGATGAA ATTATACATC ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA AAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGCACCC GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACAACAGT AACCGTCTGG TCCAATCTCT TCTCATAAAT CTCCAAACAT CTCTGCTTTC CAGCGCCGGG AGAGCTTCCT GGAGGTGTCG ACACCATTGG GCCCTGCCAG TTTAGAGCAA GTGAGAAAGA AGCTGTGTGC CACCTACAAG GGACACTCTC TGGGCATCCC GGCCCTGCAG CTGGCAGGCT TCTACCAGGG GCTCCTGCAG-CCCACCTTGG ACACACTGCA CTGGCAGCAG ATGGAAGAAC AA Ishq ID NO: 111}; ACTTAAAGAG GAAGACGTCT GAGCTTCGTA caattcttcg TCTCGACATC AAAACTGACG AC GTAGAGGG ÀCTATCAACC GGCTAGCCAG CAi ^^ AGGGGT TACCGCGTTC CTCCCTGCCC TCCAGGGCGA CTGTGCCACCT CTGGGGCTGA CTGGGCT 101 151 201 251 301 ATGGCTAACT ACCACCTGCA CTATCCTGAT AGGGCTGTCA TAATCTCCAA CAATCATCAT TTCTATCTGG GCTCTATAAT CCTTTGCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA GATCGATGAA ACCCGAACAA CTTCGACTTC ÀAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG

601 651 701 'WJ jn.', 801 8S1 901 <. <FAG ^ AGGG tlcccgggtg gtggttctgg cggcggctcc CTGCTTTCCA GCGCCGGGCA GGAGGGGTCC TGGTTGCTAG aacatggcct CCATCTGCA · AGCTTCCTGG AGGTGTCGTA CCGCGTTCTA CGCCACCTTG ^ CGCAGCTCAC ACCATTGGGC CCTGCCAGCT CCCTGCCCCA GAGCTTCCTG CTCAAGTCTT TAGAGCAAGT GAGAAAGATC CAGGGCGATG GCGCAGCGCT CCAGGAGAAG CTGTGTGCCA CCTACAAGCT GTGCCACCCC GAGGAGCTGG TGC ^ ACACTCTCTG GGCATCCCCT GGGCTCCCCT GAGCTCCTGC TCGG CCCAG u ^ V'r ^ CTvxA GGCAGGCTGC TTGAGCCAAC TCCATAGCGG ul CC '^ TTT' "^ TACCAGGGGC TCCTGCAGGC CCTGGAAGGG ATATCCCCCG AGTTGGGCT CACCTTGGAC ACACTGCAGC TGGACGTCGC CGACTTTGCC ^ ACCACTATCT GGCAGCAGAT GGAAGAACTG GGAATGGCCC CTGCCCTGCA GC ^ w GGTGTCATGC CGGCCTTCGC CTAATAA (SEQ ID NO 7-F. ~

3H1 401, * C 1 Mr T>> 601 851 CTATCCTGAT AGGGCTGTCA TÀATCTCCAA CAATCATCAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC CTGTGCCACC CTGGGCTCCC GCTTGAGCCA GCCCTGGAAG GCTGGACGTC TGGGAATGGC GCCTCTGCTT » 851 901 Q CCGGCGGCGG ACPCAGAGCT CGATGGCGCA

GCTCTATAAT A X -A UU X GGATCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG GTCTAAAGAA CCGAGGAGCT CTGAGCTCCT ACTCCATAGC GGATATCCCC GCCGACTTTG CCCTGCCCTG TCCAGCGCCGGGCTGCT GATCGATGAA ACCCGAACAA CTTCGACTTC CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT GGTGCTGCTC GCCCCAGCCA GGCCTTTTCC CGAGTTGGGT CCACCACCAT CAGCCCACCC GGCAGGAGGG GCTACACCAT GTCTTTAGAG AGAAGCTGTQ ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCÀATCTCT CTCCAAACAT GGACACTCTC GGCCCTGCAG TCTACCAGGG CCCACCTTGG CTGGCGGGGGGGTGG CAAGTGAGGA TGCCACCTAA ACT? AAAGAG GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGlagaggg ÀCTATCAACC GTCTTACAAG TGGGCATCCC CTGGCAGGCT GCTCCTGCAG ACACACTGCA ATGGAAGAAC CTAGCCATi CAGCTCCCTG AGATCCAGGG TAA (SEQ ID 251 351 451 atggctaact ACCACCTGCA CTATCCTGAT AGGGCTGTCA TÀATCTCCAA CAATCATGAT TTCTATCTGG CGGTGGAGGC CGTCTCCTCC TTGGGTCCCA CACCATCTGG CCACCCAGGG GGAGGGGTCTA CCGCGATGTA GCTCTATAAT CCTTTGCTGG GGATCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACCCTTGA TCCCCGGGTG CCTTGGACAC CAGCAGATGG TGCCATGCCG TGGTTGCTAG CGCCACCTTG CCCTGCCAGC GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT ACTGCAGCTG AAGAACTGGG GCCTTCGCCT CCATCTGCAG TCCCTGCCCC ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT tccaatctct CTCCAAACAT AATGGCCCCT CTGCTTTCCA AGCTTCCTGG CGGCGGCTCT AGAGCTTCCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GTCTCCCGAG ACTTTGCCAC GCCCTGCAGC GCGCCGGGCA AGGTGTCGTA GACATGGCTA GCTCAAGTCT 51 TTAGAGCAAG δ01 GCTGTGTGCC 051 GACACTCTCT 901 GCCCTGCAGC Ο ζ “- ^. i Λ ν'-Λωυ'οϋ NQ :. 156 /; tgaggaagat AOC ^ Ac * a αογ GGGCATCCCC CTCCTGCAGG CCAGGGCGAT x r <rv · * TGGGCTCCCC CTTGAGCCAA í ^^ A ^ m ***** a *. «Λ.

GGCGCAGCCC CGAGGAGCTG TGAGCTCCTG CTCCATAGCG GATATCCTAA ΠΛ * · *, * \ a% *> e ^ x jmt Λ ** ^. ^, *** »^^^ Xi2 1% Jf *. vJ> ** Λ. S"* ACPCAGCCÀG

51 ACCACCTG101 CTATCCTGAT 151 AGGGCTGTCA 201 TAATCTCCAA 251 CAATCATCAT 3 01 TTCTATCTGG 351 CGGTGGAGGC $ 4. * 451 TTCCAGCGCC 501 CCTGGAGGTG 551 GCTCTGACAT 601 TTCCTGCTCA 651 AGCGCTGCAG 701 AGCTGGTGCT 751 TCCTGCCCC'A 801 TAGCGGCCTT 351 IncorporaçõesCGAGTT 901 TTTGCCACC A 951 CCTGCAGCCC GCTCTATAAT GATCGATGAA CCTTTGCTGG ACCCGAACAA GGATCGAAAC CTTCGACTTC AGAACTTAGA AAATGCATCA CCATGTCTGC CCTCTGCCAC CÀAGGCAGGT GACTGGCAAG TTÀCCCTTGA GCAAGCGCAG tccccgggtg aaccgtctgg GTCTAAAGAA tctcataaat GGGCAGGAG-G GGTCCTGGTT TCGTACCGCG TTCTACGCCA GGCTACACQA TTAGGCCCTG AGTCTTTAGA GCAAGTGAGG GAGAAGCTGT GTGCCACCTA GCTCGGACAC TCTCTGGGCA GCCAGGCCCT GCAGCTGGCA TTCCTCTACC AGGGGCTCC ^1? GGGTCCCACC TTGGACACAC CCATCTGGCA GCAGATGGAA ACCCAGGGTG CCATGCCGGC ATTATACATC AGTTAAAGAG CCTCAATGAC GAAGACGTCT CAAACGTGGA GAGCTTCGTA GGTATTGAGG CAATTCTTGG GGCCGCACCC TCTCGACATC AATTCCGGGA AAAACTGACG GAACÀACAGT ACGTAGAGGG TCCAATCTCT ACTATCAACC OTCCAAACAT GTCTTCTGCT GCTAGCCATC TGCAGAGCTt CCTTGCGCAG CCCGGCGGCG CCAGOTCCCT GCCCCAGAGC AAGATCCAGG GCGATGGCGC CAAGCTGTGC CACCCCGAGG TCCCCTGGGC TCCCCTGAGC GGCTGCTTGA GCCAACTCCA GCAGGCCCTG GAAGGGATAT TGCAGCTGGA CGTCGCCGAC GAACTGGGAA TGGCCCCTGC CTTCGGCTAA TAA; (SEQ 1 ATGGCTAACT 51 ACCACCTGCA 101 CTATCCTGAT 151 AGGGCTGTCA 201 TAATCTCCAA 251 CAATCATCAT 301 TTCTATCTGG 351 CGGTGGAGGC 401 C GTCTCCTCC 451 CCTGCCCTGC 501 CCAGCGCCGG 551 TGGAGGTGTC 601 TCTGACATGG 651 CCTGCTCÀAG 701 CGCTCCAGGA 751 CTGGTGCTGC 801 CTGCCCCAGC 851 GCGGCCTTTT 901 CCCGAGTTGG 951 TGCCACCACC XL NO: 15S) GCTCTATAAT CCTTTGCTGG GGATCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT TTACGCTTGA TCCCCGGGTG GTCTAAAGAA AGCCCACCCA GCAGGAGGGG GTACCGCGTT CTACACCATT TCTTTAGAGC GAAGCTGTGT TCGGACACTC CAGGCCCTGC CCTCTACCAG GTCCCACCTTAGCT GATCGATGAA ACCCGAACAA CTTCGACTTC AAATGCATCA CCTCTGCCAC GACTGGCAAG GCAAGCGCAG AACCGTCTGG TCTCATAAAT GGGTGCCATG TCCTGGTTGC CTACGCCACC AGGCCCTGCC aAGTGagga TCGACGGGCG ATTATACATC CCTCAATGAC CAAACCTGGA GGTATTGAGG GGCCGCACCC AATTCCGGGA GAACAACAGT TCCAATCTCT CTCCAAACAT CCGGCCTTCG TAGCCATCTG TTGCGCAGCC AGCTCCCTGC GCTCCGGGGCTCTGGGGCCT ACTTAAAGAG GAAGACGTCT GAGCTTCGTA CAATTCTTCG TCTCGACATC AAAACTGACG ACGTAGAGGG ACTATCAACC GTCTATGGCC CCTCTGCTTT CAGAGCTTCC CGGCGGCGGC CCCAGAGCTT gatggcgcgAGGGGCT (SEQ 1 ATGGCTAACT GCTCTATAAT SX ACCACQTGCA CCTTTGCTGG 101 CTATCCTGAT GGATCGAAAC 151 AGGGCTGTCA AGAACTTAGA TAATCTCCAA CCATGTCTGC .201 251 302 CAATCATCAT CAAGGCAGGT TTCTATGTGG TTACCCTTGA 351 CGGTGGAGGC TCCCCGGGTG 401 CGTCTCCTCC GTCTAAAGAA 451 GGTGCCATGC CGGCCTTCGC 502 TACGCCACCT TGCGCAGCCC CCTQGTTGCT AGCCATCTGC 552 602 651 GGCCCTGCCA GCTCCCTGCC The AGTGAGGAAG ATCCAGGGGG gp 701 CCACCTACAA GCTGTGCCAC 751 CTGGGCATCC CCTGGGCTCC 802 GCTGGCAGGC TGCTTGAGCC 852 GGCTCCTGCA GGCCCTGGAA 901 GACACACTGC AGCTGGACGT 951 GÀTGGAAGAA CTGGGAATGG ID NO: .15 9) GATCGATGAA ATTATACATC ACTTAAAGAG ACCCGAACAA CCTCAATGAC GÀAGACGTCT CTTCGACTTC CÀAACTGGA GAGCTTCGTA AAATGCATCA GGTATTGAGG CÀATTCTTCCCTGTGCCAC GGCCGCACCC TCTCGACAIT GACTGGCAAG AATTCCGGGA AAAACTGA ^ G GCAAGCGCAG GAACAACAGT ACGTAGAGGG AACCGTCTGG TCCAATCTCT ACTATCAACC TCTCATAAAT CTCQAAACAT GTCTACCCAG CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT AGAGCTTCCT GGAGGTGTCG TACCGCGTTC GGCGGCGGCT CTGACATGGC TACACCATTA CCAGAGCTTC CTGCTCAAGT CTTTAGAGCA ÀTGGCGCAGC GCTCCAGGAG AAGCTGTGTG CCCGAGGAGC TGGTGCTGCT CGGACACTCT CCTGAGCTCC TGCCCCAGCC AGGCCCTGCA AACTCCATAG CGGCCTTTTC CTOTACCAGG GGGATATCCC CCGAGTTGGG TCCCACCTTG CGCCGACTTT GCCACCACCA TCTGGCÀGCA IncorporaçõesTGCCCT GCAGCCCTAA TAA; (SEQ JC ^ CTGCTQTATAATGATCGATGAAATTATACATCAOTAAAGAGACCACCTGCACC ^ i ^ CTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACC ^ ^ 3 ^ ^GCAAT1 ' ^CTTCGT ^ ^t C7CCACCGGTC C ^ t.AxCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAA ^ TGACGTTC 2 ™? Ií; ^ T ^cctcotq ^ ^ccc ' ⁱ ^ <»» ct = otgsaacccagcttcctccacas • 2rrhÃ7A'A0h2 ^ACÃAGGA ' ^rCCCAATGCCA ' ^: ' ^{CTTCCTGAGCTT CAA} CAC''T3CTC ~; 2 ^^ 2? ® ^ ÃX ^ ^{c <Kct} = TOC ^ KÍACCTCCGACTCCTCAGTAAACTG ^ JS? ^{WA T} ^ ^{CCAiGTCCT? CACAG} ^ GACTGAGCCAGTGCCCAGAGGTTCACCCm'G S ^ pi ^ SJ ^^ J ^^^^^^^^^^^^ ’^ GCTTGGGAGAATGGAAAACCCAGATG GCAGCâCGGGGACAACTG (SEQ XD NO: 124); Ex ™ SS ^^ ^a ^ ^{tgatcgatgaaattata} cacttaaagagaccacctgcaccx 7X42 ^ 'J ^ - ^^^^^ GT'TCGTAAGGGCTGTCAAGAACTTAGAAAATGCA-TCAGGT; C2 ^ n ^^ ^{CTTCOTÂATCTCCAACCATGTCTGCCCT} CTGCCACGGCCGCACCCTCT 1 ^ 21 ^ y1 p1 ™ ^{A;? GAAGGCAGGTGA} - ^^ aattccgggaaaaactgacgttc 3 ¹ ~ ^GAGC ^ ^AGGGGA <3GAACAACAGTÀCGTAGAGGGCGGTGGAGGCTCr '.E ^^^^ Z2 ^^ ^GG J ^G ^ CTCTACTATCAACCCGTCTCCTCCGTCTA

^G S ™ SZ? ^ ^T ^ ^AT ^ ^{TGATCGATGAAATTATA} 8ATCÀCTTAAAGAGAcr <ACC'PG _C A ^^ TTc _f GTGGACCCG ^ CAACCTCAATGACGAA <GACGT'C «r ^^ _AT Znl ^ ^a XI ^A 11S Ü11Á coACTTee ^^ cttgag ^ AA? ^wc ^^ ^TOTe ^ ^cc ^^^ cSESè £ ÊSèââ? A5cA2-t2 ^ v.x3AuaTuLj! * A'rCATCATCÀAGGCAGG ' ^r GACTGGr ^, A “rrj.« Λί ^ Λ <ί «- xuiUíURAw / iATTCCGG1 l <ll ?? ílr ^G * ^{1 u,?, kU} ' ^GAAGGGCAGG A4tdAACAGTACGTAGAGGGCGGT'GGAG ^< ''' Tr ^, ' ^:: ' UuurwLrlúrAACCGTCTGG ^ CPAhTf '* ©' ** '^ · ».Vru- ^ wAGvau.r i. CATAAAT-TC - AAAÍ? Ar ^ 2S: il ^ ltÍF ^^ ^{CGTCTCCTCCGTCTAAAG} ^ CT Ar, ^ “^^ S ^ SJCAwAuuAcAGCTCACÀAGGATCCCAATGCCATGTT ^^ TG ^^^^^ ÍXl ^ l ^ SJl ^^^^GG - ^^ CCTGGGG ™ lEi ;; llll HxlE ^GGCAACA ^ ^GCCTCT CCGGCGCeGCCTGOTG ^ O ^ l llíl? X ^T ^ ^TAAACTGOTcST ^^ CCCATCH ^t CC? TCACAGr ' _AGA ^ Ti: S _{ ; l? I ;; ll ™ ^^ ^AAAA ^^^ ^A ^ ^GGAG ^ ^G ^ ^GG & AGGQAQAGGACATTCTGGGACrArTar ^ l''F>'; ““? ®22 ^^ CAGCA _CSG GGACMCT ^ CCÍ ^^? M ^ r ^ íSJSSr ^^^^^^ TC ^ CTTGGGGCCCTGCAGÃGC- TcA? ACuCAGCTTCCTCCACAG (SEQ ID NO: 126); ^ ₁ 1Α1 ^ 1 ^^ 11 ^ · ^Λ · ^ΑΑ ^ * ' ^λ ^ ΑΤ0 «ίΛ» Τ0ΑΑΑΤΤΑΤΑ0ΑΤ0ΑΟΊΤΑΑΑ0ΑΟΑ ^Γ ' ΩΑ ^ ΌΤ ^Γ '' ”Α '^^ ^ΓΤ ' * i © uTGGÀCCCGAAGAArrTra ¹ CGACWCA ^^ rgtílI ^ iSiljJJ ^^^ MCCTGATeGACCGAAACCTT ^ GAC ^ '* J? 11 ^{A Cxa} ' ^AAtó ^ ^GCT < ^? 7CAAGAACTTAGAAAATGCATCAGGT Λ- - ^ A ^ wu ^ TTCTTCGTAATCTCCAACr ATGTrTGr ^ rv ^ 'Ff' ^^>, ~ .211111tl _ CGACATCCAATCÀTCATcaAGQrA ^^ rãr ^^ S,? !!! ^^^ '' ^^ '^^^^^^! TATCTGGTTXCCC ^ r to ^ ã s -X — 1111 ^Il ^ ^{CAAuAAT TC} ^ ^GGG AAAAACTGACGTTC, _Λ ílllXG ^^^^ - ^^^^^^^ CAACAGTACGTAGAGGGCGGTGGAG ^^ Tru ^ wuGtGAACCGTT CATAAATCICCAAACATm ^ - ^ -ll _TGC lllrtl ^The ZllX ^ACAAGGA ^ A · ^ CCAATGCCATCTTCCTGAGCTTCCAA-1 to SllllJ ^{AAAGGTGCGTTTG} ^ ^ ^ SATGCTTGTAGGAGGGTC Arn ^ r; ll LXs i ^ lS ^ ™ ^{OiCCCATG OTCACAG} GACTGAGCCAGT ^ ^ - ^ CAGAGG <Ti Sr??? uuTTT ^ CCTACACCTGTCCTGCTGCCTG ^ GTGGArwTar - ^; lA171r? r2 ^GGTTCAC LAGATGGAGGAGACCAAGGCACAQr ^r hr'À ^{í ¥>!} l © « ^{, r,} '^' ^ '' i \? - '/ * ® λ» ^ ^α - ^ xsGAGAATGGAAAACC GTGA-toc'A ©' · -Inlwll ™ íl ^GM * ^{Ai x à wGGAGG} ^ TGACCCTTCTGCTGGAGGGà ^^ A ^^ u ^ GACAaC4 xaGGACCCACTTGCCT ^ TCATG ^ r ^^^^ r ^ r ^ r ** TCTGGACAGGTCCGTCTCrT ^ r ^ rrn ^ r * © · ^^; lllXÍ ± ^Ai ^^^ - ^ etGGQAGCTT CCACAGGGCAGGACCACA (SEQ j | ^G ^ F ^ ^GA ^ ^{AGCvT C} ™ ^G ^ ACCCAGCTTCCT GCTAACTGCTCQATAATGATCGATGAAATT ^ TACATr a a- a ~ TTGCTGCACCCGMCAACCTCAATGASÃASÈ ^ yl ^^ t ^ i ^^ ^^ r ^ ¹ CGACTTCCAAACCTGGAGAGr the íUiíX ^ ^^ ^ ^TCC ATGGACCGAAACCTT ATTGASGCAA rirr ^ ^ T ^, 11111 ^Λ ^ J AAGGusuTGTCAílGAACTTAGAAAATGCATCAGGT CGÍSt; ^MOTCC Î ^ fS ^ ^CCATOTCTG ^^^ TGCCACGGCC AC4? R4. ^^ X ^^ TuAAGGCAGGIGACTGGCAAGAATTCCGGGAAAAA ^ TCArr ^ r lxS ^TvjTTACCCT? ^ AGC.AAGCGCAGGAACAACÀG-írrTlíÍr7Í5-SSÍF ^TTC CCC ^ GTGAACCGTCTGGTCCAAT ^ T ^ A ^ à ^ rÍS ^ Í ^ ™ í2Í ^C ^ ^GTGGAGGCTCC _vvAA1 _ ϊ _ Av CAACCCGTCTCCTCCCTGA CATAAATCTCCAA ^ C ^ ITuGATOCCAATGCCATCTTCCTGAGCTTCCAACACCTGCTCCGA GGAAltGGTvTCGTTTÇCT.GATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGGGAATTCGGC GGCAACATGGCGTCTCCGGCGCCGCCTGCTTGTGACCTCCGAGTCCTCAGTAAAC GC ^ ^'T' CGTGACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCAGAGGTTCACCCTT "RGR <* The ACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAACCCAGATGGAG GAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGCTGGAGGGAGTGATGGCA GCACGGGGACAACTGGGACCCACTTGCCTCTCATCCCTCCTGGGGCAGC AG ^ ^^ CTGGA ^GTCCGTCTCC: <\ {7CTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGGC AGGACCACAGCTCACAAG SEQ XD NO: 128); 1 ATGGCTAACT GCTCTAACAT GCCACCGCTG CCGCTGCTGG 201 atatcctaat ggacaataac 15X CGTGCTGTCA AGTCTCTGCA 201 ÀAATCTCCTG CCATGTCTGC 2 «o - c òa λ. c CATAT CAAGG ACGGT 301 TTCTATCTGA ÀAACCTTGGA 351 CGGTGGAGGC TCCCCGGGTG 401 CGTCTCCTCC GTCTAAAGAA 451 GGTGCCATGC CGGCCTTCGC 501 CCTGGTTGCT AGCCATCTGC 551 TACGCCACCT TGCGCAGCCC 601 CTGCTCAAGT CTTTAGAGCA 651 GCTCCAGGAG AAGCTGTGTG 701 TGGTGCTGCT CGGACACTCT 75'1 TGCCCCAGCC AGGCCCTGCA 801 CGGCCTTTTC CTCTACCAGG 851 CCGAGTTGGG TCCCACCTTG 901 GCCACCACCA TCTGGCAGCA 951 GCAGCCCTAA TAA SEQ { XX GATCGATGAA ATCATCACCC ACCTGAAGCA ACTTCAACAÀ CCTCAATGGT GAAGACCAAG CTTCGTCGTC CAAACCTCGA GGCATTCAAC GAATGCATCA GCAATTGAGA GCATTCTTAA CGCTAGCCAC GGCCGCACCC ACGCGACATC GACTGGAATG AATTCCGTCG TAAACTGACC GAACGCGCAG GCTCAACAGT ACGTAGAGGG AACCGTCTGÜ TCCAATCTCT ACTATCAACC TCTCATAAAT CTCCAAACAT GGCTACCCAG CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT AGAGCTTCCT GGAGGTGTCG TACCGCGTTC TCTGGCGGCT CTGGCGGCTC TCAGAGCTTC AGTGAGAAAG ATCCAGGGCG ATGGCGCAGC CCÀCCTACAA GCTGTGQCAC CCCGAGGAGC CTGGGCATCC CCTGGGCTCC CCTGAGCTCC GCTGGCAGGC TGQTTGAGCC AACTCCATAG GG- CTCCTGCA GGCCCTGGAA GGGATATCCC GACACAQTGC AGCTGGACGT CGCCGACTTT GATGGAAGAA CTGGGAATGG IncorporaçõesTGCCCT NO: 114); 1 ATGGCTAACT GCTCTAACAT 51 GCCACCGCTG CCGCTGCTGG 10.1 ATATCCTGAT GGAAAATAAC 151 CGTGCTGTCA AGTCTCTGCA 201 AAATCTCCTG CCATGTCTGC 251 CAATCATCAT CCGTGACGGT 301 TTCTATCTGA AAACCTTGGA 351 CGGTGGAGGC TCCCCGGGTG 401 CGTCTCCTCC GTCTAÀAGAA 451 GGTGCCATGC CGQCCTTCGC 501 CCTGGTTGCT AGCCATCTGC 551 TACGCCACCT TGCGCAGCCC 601 CAGÀGCTTCC TGCTCAAGTC 651 TGGCGCAGCG CTCCAGGAGA 701 CCGAGGAGCT GGTGCTGCTC 751 CTGAGCTCCT GCCCCAGCCA 801 ACTCCATAGC GGCCTTTTCC 851 GGATATCCCC CGAGTTGGGT GATCGATGAA ATCATCACCC ACCTGAAGCA ACTTCAACAA CCTCAATGGT GAAGACCAAG CTTCGTCGTC CAAACCTCGA GGCATTCAAC GAATGCATCA GCAATTGAGA GCATTCTTAA CCCTGGCCAC GGCCGCACCC ACGCGACATC GACTGGAATG AATTCCGTCG TAAACTGACC GAACGCGCAG GCTCAACAGT ACGTAGAGGG AACCGTCTGG TCCAATCTCT ACTATCAACC TCTCATÀAAT ctccaaacat ggctacccag CTCTGCTTTC CAGCGCCGGG CAGGAGGGGT AGAGCTTCCT GGAGGTGTCG TACCGCGTTC ACACCATTGG GCCCTGCCAG CTCCCTGCCC TTTAGAGCAA GTGAGAAAGA TCCAGGGCGA AGCTGTGTGC CACCTACAAG CTGTGCCACC GGACACTCTC TGGGCATCCC CTGGGCTCCC GGCCCTGCAG CTGGCAGGCT GCTTGAGCCA TCTACCAGGG GCTCCTGCAG GCCCTGGAAG CCCACCTTGG ACACACTGCA GCTGGACGTC

Xí '? · <:? c 'r »/“ Ύ φΤϊ AxwuviAftU * GCCACCGCTG ATÀTCCTGAT CGTGCTGTCA ÀÀATCTCCTG

GCTCTAACAT GATCGATGAA ATCATCACCC CCGCTGCTGG ACTTCAACAA CCTCAATGGT GGAAAATAAC CTTCGTCGTC CAAACCTCGA AGTCTCTGCA GAATGCATCA GCAATTGAGA CCATGTCTGC CCCTGGCCAC GGCCGCACCC CCGTGACGGT GACTGGAATG AATTCCGTCG AAACCTTGQA GAACGCGCAG GCTCAACAGT TCCCCGGGTG AACCGTCTGG TCCAAT ^r TCT GTCTAAAGAA TCTCATAAAT CTCCAAACA * ⁷ 'CGGCCTTCGC CTCTGCTTTC CAGCGCCGGG AGCCATCTGC AGAGCTTCCT GGAGGTG ^ G TGCGCAGCCC TCTGGCGGCT CTGGCGGCTC CTTTAGAGCA AGTGAGAAAG ATCCAGGGCG AAGCTGTGTG CCACCTACAA gctgtgccao cggacactct ctgggcatcc cctgggctc ^; AGGCCCTGCA GCTGGCAGGC TGCTTGAGCT CTCTACCAGG GGCTCCTGCA GGCCCTGGAA ^T X ^C 2 £ ^CT 11 ^G gacacactgc agctggacgt T ^ T ^ ucAGcA. uATGGAAGAA CTGGGAATGG TAA (SEQ ID NO: 116}; λ. gaagaccaag GGGATT'CA X '*' GCATTCTTAA ACGCGACATC TAAAOTGACC ACGTAGAGGG ACTATCAACC, * - *. * «: As 4. CAGGAGGGGT TACCGCGTTC TCAGAGCTTC ATGGCGCAGC CCCGAGGAGC CCTGAGCTCC AACTCCATAG GGGATATCCC CGCCGACTTT→TGCCCT

TTCTÀTCTGA CAGAGCTTCC TGGCGCAGCG CCGAGGAGCT CTGAGCTCCT GCTCTAACAT GATCGATGAA CCGCTGCTGG ACTTCAACAA GGACAATAAC CTTCGTCGTC AGTCTCTGCA GAATGCATCA CCATGTCTGC CGCTAGCCAC CAAGGACGGT GACTGGAATG AAÀCCTTGGA GAACGCGCAG TCCCCGGGTG AACCGTCTGG GTCTAAAGAA TCTCATAAAT CGGCCTTCGC CTCTGCTTTC AGCCATCTGC AGAGCTTCCT TGCGCAGCCC ACACCATTGG TGCTCAAGTC TTTAGAGCAA CTCCAGGAGÀ AGCTGTGTGC GGTGCTGCTC GGACACTCTC GCCCCAGCCA GGCCCTGCAG GGCCTTTTCC TCTACCAGGG CGAGTTGGGT CCCACCTTGG CCACCACCAT CTGGCAGCAG CAGCCCTAAT AA (SEQ ID ATCATCACCC ACCTGAAGCA CCTCAATGGT GAAGACCAAG CAAACCTCGA GGCATTCAAC gcaattgaga gcattcttaa GGCCGCACCC ACGCGACATC AATTCCGTCG TAAACTGACC GCTCAACAGT ACGTAGAGGG TCCAATCTCT ACTATCAACC CTCCAAACAT GGCTACCCAG CAGCGCCGGG CAGGAGGGGT GGAGGTGTCG TACCGCGTTC GCCCTGCCAG CTCCCTGCCC GTGAGAAAGÂTCCAGGGCGA CACCTACAÀG ctgtgccacc tgggcatccc ctgggctccc CTGGCAGGCT GCTTGAGCCA GCTCCTGCAG GCCCTGGAAG ACACACTGCA GCTGGACGTC ^TGG GAATGGC U ATGGCTCTGG u GGAC CGAAAC Au C C GAACAA CTTCGACTTC CCTCAATGAC CAAACCTGGA GAAGACGTCT gagcttcgta CTATCCTGAT agggctgtca

AGAACTTAGA AAATGCATCA GGTATTGAGG CCATGTCTGC'CCTCTGCCAC GGCCGCACCC CAAGCCAGGT GACTGGCAAG AATTCCGGGA TTACCCTTGA GCAAGCGCAG GAACAACAGG ATAATGATCG ATGAAATTAT ACATCACTTA GTACGTAGAG GGCGGTGGAG GCTCCCCGGG CTACTATCAA CCCGTCTCCT CCGTCTAAAG ATGGCTACCC AGGGTGCCAT GCCGGCCTTC GGCAGGAGGG GTCCTGGTTG CTAGCCATCT CGTACCGCGT TCTACGCCAC CTTGCGCAGC tctcagagct tcctgctcaa gtctttagag CGATGGCGCA GCGCTCCAGG AGAAGCTGTG ACCCCGAGGA GCTGGTGCTG CTCGGACACT CCCCTGAGCT CCTGCCCCAG CCAGGCCCTG CCAACTCCAT AGCGGCCTTT TCCTCTACCA AÀGGGATATC CCCCGAGTTG GGTCCCACCT GTCGCCGACT TTGCCACCAC CATCTGGCAG GGCCCCTGCC CTGCAGCCCT AATAA (SEQ CAATTCTTCG TAATCTCCAA TCTCGACATC CAATCATCAT AAAACTGACG TTCTATCTGG AAGAGACCAC CTGCACCTTT TGAACCGTCT GGTCCAATCT AATCTCATAA ATCTCCAAAC GCCTCTGCTT TCCAGCGCCG gcagagcttc ctggaggtgt CCTCTGGCGG CTCTGGCGGC CAAGTGAGAA AGATCCAGGG TGCCACCTAC AÀGCTGTGCC CTCTGGGCAT CCCCTGGGCT CAGCTGGCAG GCTGCTTGAG GGGGCTCCTG CAGGCCCTGG TGutACACal T-gcagctggac CAGATGGAÀG AACTGGGAAT XT NO: 86); 101 5 Ί Γΐ -ΐ Ku Gj wv 251 301 401 451 501 551 GUI

75 ^ 801 851 901 95.1 ATGGCTAATG TCTGCCCTCT CAGGTGACTG CTTGAGCAAG gatccatgaa ACCCGAACAA CTTCGACTTC ATACGTAGAG CTACTATCAA ATGGCTACCC GGCAGGAGGG CGTACCGCGT TCTCAGAGCT CGATGGCGCA ACCCCGAGGA SAMSTGAGCT CCAACTCCAT AAGGGATATC GCCGCCGACT CATCAGGTAT TGAGGCAATT GCCACGGCCG CACCCTCTCG GCAAGAATTC CGGGAAAAAC CGQAGGAACA ACAGGGTGGT ATTATACATC ACTTAAAGAG CCTCAATGAC GAAGACGTCT CAAACCTGGA GAGCTTCGTA GGCGGTGGAG GCTCCCCGGG CCCGTCTCCT CCGTCTAAAG AGGGTGCCAT GCCGGCCTTC GTCCTGGTTG CTAGCCATCT TCTACGCCAC CTTGCGCAGC TCCTGCTCAA GTCTTTAGAG GCGCTCCAGG AGAAGCTGTG GCTGGTGCTG CTCGGACACT CCTGCCCCAG CCAGGCCCTG AGCGGCCTTT TCCTCTACCA CCCCGAGTTG GGTCCCACCT TTGCCACCAC CATCTGGCAG CTGCAGCCCT AATAA (SEQ CTTCGTAATC TCCAACCATG ACATCCAATC ATCATCAAGG TGACGTTCTA TCTGGTTACC 'GGCTCTAACT GCTCTATAAT ACCACCTGCA CCTTTGCTGG CTATCCTGAT GGACCGAAAC AGGGCTGTCA AGAACTTAGA TGAACCGTCT GGTCCAATCT AATCTCATAA ATCTCCAAAC GCCTCTGCTT TCCAGCGCCG GCAGAGCTTC CTGGAGGTGT CCTCTGGCGG CTCTGGCGGC CAAGTGAGAA AGATCCAGGG TGCCACCTAC ÀAGCTGTGCC CTCTGGGCAT CCCCTGGGCT CAGCTGGCAG GCTGCTTGAG GGGGCTCCTG CAGGCCCTGG TGGACACACT GCAGCTGGAC CAGATGGAAG AACTGGGAAT ID NO: 87); K; 1Õ1 151 201 251 301 351 401 451 ATGGCTGCAC AGAATTCCGG AGGÀACAACA ATACATCACT CAATGACGAA acctggagag ATTGAGGCAA GTACGTAGAG CTACTATCAA ATGGCTACCC CCTCTCGACA GAAAAACTGA GGGTGGTGGC TAAAGAGACC GACGTCTCTA CTTCGTAAGG TTCTTCGTAA GGCGGTGGAG CCCGTCTCCT AGGGTGCCAT TCCAATCATC CGTTCTATCT TCTAACTGCT ACCTGCACCT GCTGTCAAGA TCTCCAACCA GCTCCCCGGG CCGTCTAAAG GCCGGCCTTC ATCAAGGCAG GGTTACCCTT CTATAATGAT TTGCTGGACC CCGAAACCTT ACTTAGAAAA TGTCTGCCCT TGAACCGTCT AATCTCATAA GCCTCTGCTT GTGACTGGCA GAGCAAGCGC CGATGAAATT CGAACAACCT CGACTTCCAA TGCATCAGGT CTGCCACGGC GGTCCAATCT ATCTCCAAAC TCCAGCGCCG

*? . /*·/* /""Saw TCTCAGAGCT CGATGGCGCA ACCCCGAGGA Ci- CTGAGCT CCAACTCCAT AAGGGATATC GTCGCCGACT GGCCCCTGCC GTCDTGGTTG CTAGCCATCT ^ / * ί *> 'Χ: Γΐ ft r * · »« *** <* »r * ft y * y. i · \ a · · * Χΐ ^ hiw ¹ Aw · x X xD \ * xO2 J.. TCCTGCTCAA GTCTTTAGAG AGAAGCTGTG CTCGGACACT CCAGGCCCTG · *. Ά Xj-Xv X · <** · X GGTCCCACCT CATCTGGCAG AATAA ÍGEQ ksiw T C CÃ.GG GCTGGTGCTG yx ft y »x U · AGCGGCCTTT‡PCGAGTTG TTGCCACCAC CTGCAGCCCT GCAGAGCTTC -CTGGAGGTGT CCTCTGGCGG CTCTGGCGGC caagtgagaa agatccaggg tgccacctac aagctgtgcc CTCTGGGCAT SAMSTGGGCT cagctggcag gctgcttgag GGGGCTCCTG AGAGGATGAC GCAGGGGA

~ '01 Ma * X »* wft 301 3 52 401 451 501 r ¢ - 531 O01 851 701 801 901 952 i SEO ATGG1TCTGG GGACCGAAAC AGAACTTAGA CCATGTCTGC CAAGGCAGGT * *. AXvXv'mt CTTAAAGAGA CGGGTGAACC AAAGAATCTC CTTCGC CTO '”' ATCTGCAGAG CAGCCCTCTG AGAGCAAGTG TGTGTGCCAC CACTCTCTGG CCTGCAGCTG AC CAGGGGCT ACCTTGGACA vsUaGCAGATG ID NO: 90); ACCCGAACAA CCTCAATGAC CTTCGACTTC CAAACCTGGA ÀAATGCATCA GGTATTGAGG CCTCTGCCAC GGCCGCACCC GACTGGCAAG AATTCCGGGA GCAAGCGCAG GAACÀÀCAGG GTTCTAACTG CTCTATAATG CCÀCCTGCAC CTTTGTACGT GTCTGGTCCA ATCTCTACTA ATAAATCTCC AÀÀCÀTGGCT GCTTTCCÀGC GCCGGGCAGG CTTCCTGGAG GTGTCGTACC GCGGCTCTGG CGGCTCTCAG AGAAAGATCC AGGGCGATGG CTACAAGCTG TGCCACCCCG GCATCCCCTG GGCTCCCCTG GCAGGCTGCT TGAGCCAACT CCTGCAGGCC CTGGAAGGGA CACTGCAGCT GGACGTCGCC GAAGAACTGG GAATGGCCCC GAAGÀCGTCT CTATCCTGAT GAGCTTCGTA AGGGCTGTCA CAATTCTTCG TAATCTCCAA TCTCGACATC CAATCATCAT AAAACTGACG TTCTATCTGG GTGGTGGCTC TGGCGGTGGC ATCGATGAAA TTATACATCA AGAGGGCGGT GGAGGCTCCC TCAACCCGTC TCCTCCGTCT ACCCAGGGTG CCATGCCGGC AGGGGTCCTG GTTGCTAGCC GCGTTCTACG CCACCTTGCG AGCTTCCTGC TCAAGTCTTT CGCAGCGCTC CAGGAGAAGC AGGAGCTGGT GCTGCTCGGA AGCTCCTGCC CCAGCCAGGC CCATAGCGGC CTTTTCCTCT TA.TCCCCCGA GTTGGGTCCC GACTTTGCCA CCACCATCTG TGCCCTGCAG CCCTAATAA 1 ÀTGGCTAATG CATCAGGTAT 51 TCTGCCCTCT GCCACGGCCG 101 CAGGTGACTG GCAAGAATTC 151 CTTGAGCAAG CGCAGGAACA CGGCGGTTCT AACTGCTCTA 201 251 301 ÀGAGACCACC TGCACCTTTG GTCTCTATCC TGATGGACCG CGTAAGGGCT 351 CGGGTGAACC GTCTGGTCCA GTCAAGAAOT 401 451 501 CTTCGCCTCT GCTTTCCAGC AAÀGAATCTC ATAAATCTCC 551 ATCTGCAGAG CTTCCTGGAG 601 CAGCCCTCTG GCGGCTCTGG AGAGCAAGTG AGAAAGATCC 701 TGTGTGCCAC CTACAAGCTG 751 CACTCTCTGG GCATCCCCTG 601 CCTGCAGCTG GCAGGCTGCT TGAGGCAATT CTTCGTAATC TCCAACCATG CACCCTCTCG ACATCCAATC ÀTCATCAÀGG CGGGAAAAAC TGACGTTCTA TCTGGTTA ° C ACAGGGTGGT GGCTCTGGCG GTGGCAGCGG TAATGATCGA TGAAATTATA CATCAC ^ TAA CTGGACCCGA ACAACGTGAA TGACGAAGAC ÀÀACCTTCGA CTTCCAAACC TGGAGAGCTT TÀGAATACGT AGAGGGCGGT GGAGGCTCCC ATCTCTACTA TCAACCCGTC TCCTCCGTCT AÀACATGGCT ACCCAGGGTG CCATGCCGGC GCCGGGCAGG AGGGGTCCTG GTTGCTAGCC GTGTCGTACC GCGTTCTACG CCACCTTGCG CGGCTCTCAG AGCTTCCTGC TCAAGTCTTT AGGGCGATGG CGCAGCGCTC CAGGAGAAG ^ TGCCACCCCG AGGAGCTGGT GCTGCTCGGA GGCTCCCCTG AGCTCCTGCC CCAGCCAGGC TGAGCCAACT CCATAGCGGC CTTTTCCTCT 851 ACCAGGGGCT 901 ACCTTGGACA - d x GCAG i 'AGAT G (S £ Q ID NO: S1); x - * '- · λ CACTGCAGCT GAAGAACTGG - ~ i GG AAG GGA GGACGTCGCC GAATGGCCCC TATCCCCCGA GACTTTGCCA 4.4, CCACCATCTG CCCTAATAA? ÍsííSÍr ™ JÍÍ? ®'SêJyÍT? Í: J ^CATCAS “AAAaASACCACCTGCACCT CGACTTCCàx, '—- ^ - GG ^ Us-u ^ AAu ^ TT? ^ TG agg ^ & ^{A CÍ} * ^wTCAAGAA CTTAGAAAATGC ATCAGGT HnnH ^ llS ^^^^^^^^^^^ '- ^^' ^^ 'CCCTCTGeCACGGCCGCACCOT ^ -r rlsHj _; Tt2jil ^ J ^{TCAAGGCAS3TGACTG} CCAAGAATTCCGGGAAAAACTGACG ^m íc Xis ^C L ^^ r ^{'oT; TGGTCCAATCTCTACTA rc} AACCOGTCTCCTCCGTC ^ AAAGAAT-t 7 N- ^{TCT 'JCA} ^ ^{CATGGGACCCACTTGCCT} CTCATCCCTC ^ TGGGG ^ Arbw ^^> CAGGTCCGTCTCCTCCy? GGGGCCCTG ^ g & rrrí? AwX-> Rix ™ l ^ACTTT ^ ^TG' '' ^A _A _, W ' -AkiAGGCTCCTTGGAACCCAGCTTCCTCC ΑΓ a · '· ^^ «^ ACuAuAGCTCACAAGGATCCCAATGCCATOTCCTGAG ^? _i - ^ 2i ^ 'X; wAGGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCA Í ^ ^ ^^ r ^ T cTnT ^ a ^ - ?? * 2 ^ £ ^ JJs ^{ATGGCGTCTCCCGGT} CCGCCTGmGTGACCTCCGAG CAG CC ^ ^ L ^ ^ í AAA- TGAGTOCCATGTCCTTCACAGCAGAC GAG ^ A ^? ^ Tro ^ V ^ zSlXÍ?! ^^ ^{0 T} There · ACCTGT ^ rTG ^ on ^{v ã} ^ ^T ^ ^Cí ~ ^CAGag óTTCAQCCTTTGCCT A. ^ GÃa3c-AàÍSS5S? ^ S2 ^ í ®S ^{GAA 'r <3S "AACCCAG} ATGGXG GCACGSGGAciÍCTHáa CTGGAGGGAGTGATGGCA ^^^ ^ l i ^ATAAa HxUAí GAAATTATÃCATCACTTAÂAGAGAC AC ^ ^' ^T 'G ^ Ar'" n * V * x -G ^ AC ^ CGAACAACCTCAATGACGAAGACGTr ^^ & Tr ^ r '** r- ~ ^ * ^A ~ n ^G ~ ^Av '“' ⁱ CGACTTCCAAACC ^ GGAnarrTT ^ r *? * ^ * TÍ ^A ^ ^C ^ ^TSA ^ ^wGA ^^ ^GAÃAC CTT A ^ TGArr ^ A; J ^^^^^^^^ '- ^^ QKCTTAGAAAATGCATCAGGT * ^^^^^^^^ CTCCAftCCATGTCTGCCCTrTGCCArrer ^ A ^ aA ^ H,''- ^u ^' ^v “ATCCAATCATCATCAAGGCAGGTGACTGCAA ^r 'Ax. ^f r »rr>r>r'r'r'iK x * lS2 ^ ^AG - TATCTQG * T * TAor> f * ~ T> rar * r * s> x H ^L ^^^^ CCGGGAÀAAACTGACGTTC ,, _r Jn: : Ix ^ ^^ sji ^^^^^^^^^^^^^^ CCTAGAGGGCGGTGGAGG -r '* ·'^{"AAACAT<3í3GAACCCA} SCTTCCTCCACAGGGCAGGACCAr Aita Arr ~ ^ '^ CCC tgccatctt ATGCTTGTAGGAGGG ^ ^^ ^^ CCAro _r? m ^ r, «^ ™ Z: ^ ™ E ^uAGGAAAGG ^ CGTTTCCTG ^^^^^^^^^ AHCGGCAACATGGCGTC ^ CCCGC ^ tSci ^^ - ^^^^^ A ^ AÍ ^ eCTOCGTGACTCCCÀTCTCcÍTclí g | GTGGÍÍRATA ? 7 ^CTGCTQCC - ^GCT ^^^ h ^ i ^^ '- ^^^^ CTGGAGGGAGTGATGGCAGCACGGGGACAA-TrorxrAA x * ^ xAusA ^ LCTQCTí? (SEQ ZQ NO ' ¹ 37 »* λsarkaMwUx, 2S3 ™ ^CTGCTC ™ ^AA ' ^rG *'! 'CGATGAAATTATACATCACTTAAArA <' ». ^ R '-, ^ m * ^» ^ ttgctggacccgaacaacctcaatgacgaãgacgtc ^ SÍÍ1SSÍS? -S ^{ctgcm: c} Ãw5S ^ ^ ^ c ^ OT TATCTGGTOAS ^ IS'Sr ^^^^ LrrcCGGGaLAACTGACTC 'b ^^ CAAGCG ^ GGAACAACAGTACGTAGAGGGCGGTGrarir ^G i ^^^ CoAACCGTCTGG-rcCAATCTCTACTATCAA ^ C-rTrírr. ^ ^CTCC CATÀAATCTCCAAACATGGGACCCACTTGC ^ TrTr; SnSSJSSE ^{GTCTAÀAGAATCT} CàGGTCCGTCTCCT- ”r ^ rrrrr ^ r'r ^ -? Íx ^ S ^CATC ' ^{CTCCTGGGGCAGGTT} TCTGGA SSCAGGACCACAGClÍA6AAGGAÍcCckÊ? ^^ S ^? ^ SJ ^G ^^ ^CCACAC ^ AGGAMGGTGCGTTTCCTGATGCTTGTAGeAGaarcSS ^ SSS 1O1 GGCGGCAACGGCGGCAACATGGCGTCCCGAGCGCCGCCTGCTTGTGACC AGTC ^ CC ^ ^ r ^ · agtaaactgcttcgtgactcccatstccttcacagcagactgagccagtgccÓgagg CACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTCxSACTTTAGCTTGGGAGAATGGAAA ACCCAGATGGAGGAGACCAAGGCACAGGACATTCTGGGAGCAGTGACCCTTCTGGTGG GGAGTGATGGCAGCACGGGGACAACTG ^ G (SEQ ΣΓ NO: 148); ttgctggacccgaacaacctcaatgacgaagacgtctctatcctgatggaccgaaacctt vtót ITU '~ ^ AAAT TGGAGAGC'TTCGTAAGGGCTGTCAAGAACTTAGAAAATG' ^/ 'ATCAGG' ^t 'ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGrrGCACCC cgâcatqcaatcatcatcaaggcaggtgactggcaagaattccgggaaaaactgaggtt- ^^ ^ ^z TATCTGGTTACCOTTGAGOAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGScTer CCGGGTGAACCGTCTGGTCCAATGTCTACTATCAACCCGTCTCCTCCGT aaAGAA CATAAATCTCCAAACATGGGAACCCAGCTTCCTCCACAGGGCAGGACCACÃGI ^ ^ I-Trkr 21 ^ 1: Χ1Γ ‘** Aw ^ TTGGG, AGAATGGÀÀAACCCAGATGGAGGAGACCAAG ^2, RI; H ^^ ^X '^{"TGGGAGCA, 3TGACCCTTCTaCTíS <3A} GGGAGTGATGGaAGCACGGGGA ^' 1 ^ '22': ^C ^^ J ^{CTCATCCCTCCTGGGGCAG DC} 2F - TTGGACAGGTCCGTCTC ^^ ^^ ^a ^^ ^ ^ IXI ^GATGAAA ^ ^A ^? ^A ^^ CTTAAAGAGACCACCTGCACCT ^ JlII ^{CCAAACCTGGAGAG} CTTCGTAAGGGCTCTCAAGAACrrAGAAAATGC ^ CASG '; íí2y ^ 7 ^ ^LAATTC ' ^rTCGTAA ' ^rG TCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT ^ ™ ^Α ^^ Ξ? ^ ^{ΑΤϋΑΑδσθΑΟ} ° ^{ΤαΑΟΤδ0εΑΑίΞΑΑ} ^ € ΟΟΟΑΑΑΑΑΟΤαΑθσΤΤΟ i2 \ lH ^^ ^T ' ^kA! '' - ^{'LTTGA: 3CAAGCGCAGC3AAC} ACAGTACGTAGAGGGCGGTGGAGGrT ^ C ^' ^ 7 ^^^^ ^{CGTCTGGTCCAATCTCTACT} CAACCCGTQTCCTCOGTCrrAAAGAAT ^ T ^ i ^ ^ I ^^^^^ rzr ACCACAGCTGACAAGGATCCCAATGCCATOTCcÍG AG ~ ^ ^ r ^ GAATx GGGuGGCAACGGCGGCAACXiTGGCGTCCCCAGOítrrr r ^ m £ ^L TSSF I ^CCGAGTCC ^ ^CAGTAAACTGG T ^f rCGTGACTCCCATGTC'OTTCACAGCAGA ^ ÍG 11 ^: 21 ^^^ ^AA ^^^ ^AAA '' ^CC ^ ^GA ' ^r “ ^GAGGA ^ CCAAGGCACAGGACATTOTGGGAGCA _wr ? Cll ^ lJ ^{1 TG} X ^{Tu, UfAGGvaAGTG} ^ TGGCAGCACGGGGACAACTGGGACCCAC ^ TGCCTC S? G ™ J? ^ "JJiy ?? ^ = jyGAAATTATACATCACrTSAAaSACa ^ CTCCACCT A ^ U ^ -rS ^ S ^^^ - ^ SAA ^ STCTCTATCCTSATSGACCOAAACCTT X ™ i XZ): ^AAA ^^ ^T ^ ^wAGA ^ ^v ' ^TTCCTA A ^í 3GSCTGTCAAGAÀCTTAGAAAATGCATCAGn ^ ^ x®x ^^^ ^C ^ ^{CGTAATCTCCÂAGGA} TGTCTGCCCTCTGCCACGGCCGCA ^ CC ^ C ^ ^ * C ^ Jí ^^ ^a J ^ga ^ ^{catcaagí3CAGG} ^ sactggcaagaattccggaaGaGaGa v. . ^l '- ^ ^v> ' ³ «^> ACuT ^ GGTTTCCTGATGCTTGTAGGAGGGTCCACCCTCTGCGTCAGG 102 GAATTCGGCGGCAACGGCGGCAACATGGCGTCCCCAGCGCCGCCTGCTTGTGACCTCCGA STCCTCAGTAAAeTGCTTCGTaACTCCCATGTCCTTCACAGCAGACTGAGCCAGTGCCCA GAGGTTCACCCTTTGCCTACACCTGTCCTGCTGCCTGCTGTGGACTTTAGCTTGGGAGAA TGGAAAACCCAGATGGAGGAGACCAAGGCACAwGACATTCTGGGAGCAGTGACCCTTfTTG CTGGAGGGAGTGATGGCAGCACGGGGACAACTGGGACCCACTTGCGTCTCATCCCTCCTG GGGCAGCTTTCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACC CAGCTTÇCTÇCACAGGGCAGGACCACA (SEQ ID NO: 1515; GCTAACTGCTCTATAATGATCGATGAAATTATACATCACTTAAAGAGACCACCTGCACCT TrGCTGGACCCGAACAACCTCAATGACGAAGACGTCTCTATCCTGATGGACCGAAACC ^ C ^ CGACTTCCAAACCTGGAQAGCTTCGTAAGGGCTGTGAAGAACTTAGAAAATGCATCAGGT ATTGAGGCAATTCTTCGTAATCTCCAACCATGTCTGCCCTCTGCCACGGCCGCACCCTCT CGACATCCAATCATCATCAAGGCAGGTGACTGGCAAGAATTCCGGGAAAAACTGACG TATCTGGTTACCCTTGAGCAAGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGrTêr CCGGGTGAACCGTCTGGTCCAATCTCTACTATCAACCCGTCTCCTCCGTCr'AAAGAA c't ^ '^ CATAAATCTCCÀAACATGGATCCCAATGCCATCTTCCTGAGCTTCCAACAC GCT GA ggaaaggtgcgtttcctgatgcttgtaggagggtccaccctctgcgtcagggaattcggc ^^' ^ _í GLAACGGCGGCAACATGGCGTCCCCAGeGCCGCCTGCTTGTGACCTCCGAGTC'r AG ^'TS ^^^ ^^ Cl ^ C ^ SGCC CACASCAaACTSASCCASTGCCCaSASGA SG ^ Ar' - & G ? ArcSr ~ ^ ^ 2 ^ SSSS ^{3SACmASCWSGGAQAATGGAAAACC} GGA ^GAG * ^ AusACOAAGu 'uAuAGk' AUiTTuTGGGAGCAGTGACCCTTCTGCTGG AGGG the IGATGGCAGCACGGGGACAACTGGGACCCACTTGCCTQTCATCCCTCCTGGGG ^ ^ ^ CCT MRTT TCTGGACAGGTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAAQCCAGCT CCACAGGGCAGGACCACAGCTCACAAG {XO SEQ NO: 152); JJE ^ lA ^ JJ ^{CTCTATAATGATCG} ATGAAATTATACAl'CACTTAAAGAGACCACCTGCACCT ij ?? ^ ^^ J ^ J ^ 2 Sj2'l ^{AATGACGAAGACGTC} -CTATCCTGATGGACCGAAACCT r ^{"wAwAv, TTCGTAAGG} ^ '* GTC AAGAACTTAGAAAATGCATCAGGT' AATC T T ^T CCAACOATGTCTGCCCTCTGCCACGGCCGCACGCTCT ^^ ^^ 1Í.1 E ^{ATCATCAAí3GCAGGTGACT} ' ^3í5CAAGa A.TTCCGGGAAAAACTGACGTTC ^^ xQuTTACCCTTGAGCAÀGCGCAGGAACAACAGTACGTAGAGGGCGGTGGAGGCT ^^ ΑΤΑΑΑΊ1X --ããACATGw CATCTTCCTGAGCTTCCAACACCTGCTCCGAGGAÀAGGTG C ^ C ^ ^ ttcctgàtgcttgtaggagggtccaccctctgcgtcagggaattcgg ggÍaacggU: Si;: EiiJJS X ^{^: The} '^ ^{T u} ®® ^{A <^ 3fte -®:} A® ®CCC * ^r ^ A ^ A SA®3TTC3tfXCTTTeCCT HTCC CA j ^ uuCTGCTGTGGACTTTAGCTTGGGAGAATGGAAAA air CCAGATrf * r ^ ^ r ^ 2i S22S ^ ^C ^ ^{CACTOCCT CATCCCTCCTGGGGGA <3CTTTCTGGACAG L} - ^L '-' ^ 7 ^ * k, CTU CTTGGwâuuCTGCAGAGCCTCCTTGGAACCCAGCTTCCTCCACAGGiG aGusACCAÇAGCTCACAAGGATCCCAAT ^ (SEQ ID NO: 153); and -S-TS ^ r ^^^ ^SAOTGGC ^ ^MWCCOTSJ ^ CTGAa ^ Ag ^^ tS 103 & CATâAATCTCCAAACATGGATCCCMTGCCATCTTCCTGAGCTTCCA CACCTGCTCCGA GGAAAGGTGCGTTTCCTGATGCTTGTAGGAGGGTCCACCCTGTGCGTCAGGGAATTCGGC GGCAA.CATGGCGTCTCCCGCTCOGCCTGCTTGTGÀÚOTCCGAGTCCTCAGTAXACTGCTT CGTGACTCCCATGTCCTTCACAGQÂGACTGAGCCAGTGCCCAGAGGTTCACCCTTTGCCT ACACCTGTCC-'GCTGCCTGCTGTGGACTTTAGCTTGGQAGAATGGAAAACCCAGATGGAG gagaccaaggcacaggacattctgggaggagtgaçccttctgctggagggagtgatggca GCACGGGSACAACTGGGACCCACTTGCCTCTCATGCCTCCTGGGGCAGCTTTCTGGACAG GTCCGTCTCCTCCTTGGGGCCCTGCAGAGCCTCCTTGGAACCCAGGGCAGGACCÀffAGCT CACAAG (SEQ ID NO: 154). 32. Process for the production of a hematopoietic protein comprising: growth under appropriate nutrient conditions, a host cell transformed or transfected with a replicable vector comprising a nucleic acid molecule, according to the conditions 5 hints 16, 17, 16, 19. 20. 21. 22. 23, 24, 25, 25, 27, 28, 29. 30, 31, in a way allowing expression of said hematopoietic protein and recovery of said hematopoietic protein. 33. Pharmaceutical composition comprising: hematopietic protein. according to claim 1, 2, 3, 4, 5 _S 6, 7, 8, 10. 11, 12, 10 13 or 14, and a pharmaceutically acceptable carrier. 34. Process for stimulating the production of hematopoietic cells in a patient comprising the step of: administering an effective amount of the hematopoietic protein according to claim 1, 2, 3, 4, 5, 6. 7,, 8,10, 11, 12, 13 or 14 to said patient. 15 35. Process of stimulating the production of hematopoietic cells in a patient comprising the stage of; administration of an effective amount of the hematopoietic protein, according to claim 9. to said patient ......................... 36. Process for selective ex vivo expansion of stem cells, 20 comprising the steps of: (a) separation of stem cells from other cells; (b) culturing said stem cells separated with a selected culture medium comprising; the hematopoietic protein according to claim 1,2, 3, 4, 5, 6, 7, 8. 10, 11, 12, 13, or 14: and (C) harvesting said culture cells. 104 37. Process for expansion ^: ex vivo 'stem cell selective, comprising the steps of ^- . (a) separation of stem cells from other cells; (b) culturing said stem cells separated with a selected culture medium comprising: the hematopoietic protein according to claim 9: and (c) harvesting said culture cells. 38 Process for treating a patient having a hematopoietic disorder. comprising the steps of: (a) removal of stem cells; (b) separation of stem cells from other cells; (c) culturing said stem cells separated with a selected culture medium comprising; the hematopoietic protein according to claim 1, 2, 3, 4, 5, 6, 7. 8, 10. 11. 12, 13 or 14; (d) harvesting said culture cells; and (e) transplanting said culture cells to said patient. 39. Process for treating a patient having a hematopoietic disorder, comprising the steps of; (a) removal of stem cells; (b) separation of stem cells from other cells; (c) culturing said stem cells separated with a selected culture medium comprising; the hematopoietic protein according to claim 9; (d) harvesting said cultured cells; and........... (e) transplanting said culture cells to said patient. 40. Human gene therapy process, comprising the steps of: (a) removing stem cells from a patient; (b) separating said stem cells from other cells; (c) culturing said stem cells separated with a selected culture medium comprising; the hematopoietic protein according to claim 1, 2. 3, 4, 5, 6. 7, 8. 10, 11, 12, 13 or 14; »05 (d) introduction of DNA into said culture cells; (e) harvesting said transduced cells; and (f) transplanting said transduced cells in said patient. 41. Human gene therapy process, comprising the 5 steps of. (a) removing stem cells from a patient; (b) separating said stem cells from other cells; (c) culturing said stem cells separated with a selected culture medium comprising; hematopoietic protein according to 10 with claim 1.2. 3. 4. 5. 6, 7. 8, 10, 11. 12, 13 or 14; (d) introducing DNA into said culture cells; (e) harvesting said transduced cells: and (f) transplanting said transduced cells into said patient.