Catalytic moieties for treating cancer

Abstract

The current invention relates to nucleic acid expression vectors such as therapeutic viruses, or mRNA vaccines, encoding catalytic fucosidase moieties for use in treating cancer. Further aspects of the invention relate to fusion proteins comprising a catalytic fucosidase moiety, and beneficial therapeutic combinations of the above with administration of a sialidase, and / or a checkpoint inhibitor agent.

Description

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,,n vnr - -nmmznn, . nrnmr: - m, - m,n n zn . nmrmmn,nvnn nrnnrrvn,mrrnnrn nr n. mmrrnnnnnnnnnmnn mn,,nrnnmrnnnn m nnmn nn ,r n - - m , nnnn. m nn mr nmrrn nnnvnn nr nr m.n,n,nmrn mn nr,rn m mr rn mnnnnnrm wnnn r r.rnrn,m-r mnnnn m mrn mrnn. n, mr nmm ,nn nnmnnn n nn m mrnnnnnn,r r rrnr.nnr-r mmmnn,nmmn nnmnmnnnrnmmn, mnrn,nnnnn mnnn r-nn r mr. rm , , , ,-,n -. mrnn n nrnn , nnr rmmrmnnn vn mnn w mnr vrnnmnnnnnmnnmrn,rnn rnnnnmn r ,r r rvnnn mn r ,n mn nvnnn nnnnnnrnrnmmmnnmrn,rnn, mmrnr.nn m mr n m v nn n vrnmnmmnr, nnrrnmr nnrn,rxm. nn , w n r nnr n, ,n mn rmmn nrn rnnxnn-v. mrnrnn .r rmmnnn r nrn rn nvnn r mrnrnn v r nrrmn . nvnnrrnm r rmmn nr,rnrrn rm m. mrnrnn .nnr rnvmnn r r nrnmr mn, r r - r . nvnn ,nrmrn nrrmn nrxrnnr rmmnnrnm,r m rnm. nrn, nnrn,r xr n vrnn w nmmn n,rrmr,r nr zn zn n . nr.n mrr rmmn, mrnw rm n rr mnmr,rmr n n vnxrnn vr rnn.n nx nw mnmr v n mnnvnn, n n nrn nr , .,vr,n-,nrn n n vw, - vr n,nr nn mm m rnr r n mn mnrrn,rrmxrmnn,. vr n .nrnmmn n rn nr mr mnn nrn, rrz rr v nrn.n n nn rn v n nn vrnn rnmmn nrn,rxr n mr n r nrn rn nvnn, nrn rn v n rrz rn nr mr m n nnnmznmmn rnn,nnr n. n xr n. vnr, mmn, mrn rn n n rn,nn r.nnr rmmn, rn,mrnwmrz mnm mmr n , xm r, mr.nnnzm rnnn nrnwnrnnxr nnmr nrn , ,n v r mnrnnn vv mnxmnr rmmn, nrn,r m rnr. nrnnrn n,rrvnnnr v rnmmmn n xr n v rrrrrn. n xr n vrmr n rn. nvnn, vnnrrnmnmn,nr. xrr nr vnr,nrmr rvnrrnr r m vrnn nr. rrnmmnn,r rmxvrrnnn vr,r nrnr nr,nnr,rv nr,nnr,rr,vnrr,nnr, mr nr,nrnr rmmn, n xr n vrn nm. rmnrnr nr n ,rnr nvrnnr. nrmn, n xr n vrnn ,rnmmmnn nr nrnxrnnr. mnn m m n vrr rn nvnn,r mr,rx n, n xr n vr mnr r n mmn,m n v m,xrrnn vn,rr mnrnrrnnrvnn.nr rn rmmn r rrnmrnnvnn. mnn m mn, rv r m mnrn,nr xm,n nrnnn rm.n mmn r rr n rm nrnmrn mrrn m, rnzm v mr mrnvrnm , r -nnmmn wmn rvnxr mn vmnrmrrnrnn. ,nvnn rv r n,r rnn rn -,-,- nr nn r m mn ,r - mnn rnnmnnr. m wn rnnrnrrn, wn nn nx nrn n vrm mrrrrnn r n, mn rnnr nr . m vr mnn m m wnmmnmrmnn,nnmnrn mnrr,nnrrrrv,r nmnn nzm.nmmmn, rv r nmr r xr n vr nn w n rr nn mrn m, nn,mrnr n nzvm. nn m r nrmn r,n r-rn.n r , rvv vnmmmmmn n nzm .n r nn, nrnmrn m,n nznm.rvrnrn,vn. nn-mmrn wxrm nrnnnnnmrmnnm,mn, mn nrnmnr rnvnrmnznnz vr.nm rmmnn xn m nrmn r w rrm.nrnvmmn,n nrvnrmn nnmmnzn mmnn rn mmmn rrnvmxnmnnnzrn w mrnmmmn, ,r nrnm . m,n n xr n vr,nx rn rn nmr .nmmm r rnn rxr rnnrm mxr n, nnmmmn,nmm n vr. r vr nn vr v n xr n vrrm vnnr nrnrn,rn m vn,nnxnmmn rvm.mnn, n n nn-rrnn vmrrr. nrnrnnr n, wrr-rnn nrmn,nrnn.rxr nnmn m wnrnnmmnn,,,mn,,n.r, xr rmrnn rrnv ,,, ,r nrmn . xm n . nur nnmzn nr nnnz : znr::_ . nnnz nr: nnnz nr: nnzz nr: nnz nnr: nnz nrr: nnz ::_ . vnr rrmmrnn nvnn, rnvrnr,rnxrmn vrnn r nrmn .nr r nn wnnnznnz n mmn, n rmn rnnr . rvrnn rrnrvnn,n rnrnmnnn m mnr nrmn,rn mnmnn,n n m mnx rn r .nvnnmr, r r r n vrnn rn mrn nvnnxn mn. v,r r nrn nzmmnn m mnrrmr m ,r n xr n v,r nrnmrn nvnnrrnm mnn mrnmn . rvnn rrr nr n rmn,rn - n n,xrnrnn vrnmrn: rm nn rn nn - mn,rr vn n,rmrnr, w mr nn xr n vrnnnnnz r nr r r r wrn - mnnnrmrnnnz. nr n nrrn n wnvn rnn n rv,x rrvnn vrrmnn wn ,rvrmnrnr w ,r n ,r w r rv . xr n vrnn n rnr w w rnnvn rnv, n , r xr n vrnn ,r n n rv nnrmnx wr,rn w vrrn rnvrmnrnrxrm wr. , w,nvr w,n,r wnnr mmnr wn m rvn wnw,nmrnnrmm,n nv,nn rn rxnr nmr.nn m mn,r- r nrmn .nr r vrn ,nnnz m mn,r -mnr mmn n mnnrmnnz nr . n rm nrmn rv vnmnvmnn,mnn, xrxr rmrn nnrmxrmnx vrrn vrnr nz mm m. ,rxnmrm nzm ,r nrnmrn ,n rmrmrmrn nrn,n rv ,rx mn.nmmmn, m r n nmm m, mmr nrnmrn , mn r nrnmrn .nmmmn, nrnnm mmmnn, mxr nrmxr n vnr,rnn rm n. nrn,rxm n mr wr mrn n nzm.nmmmn, ,r nrnn n n xr n vr,nxr rnnnrnr, nnr. nvnrn n r xmrnnn v mrmnmrnr mnn r n xr n vrnn nnnn n, n rnr vnrnn. m nvnn r nn rnr n n -nxnr wn v r m rnn ,r nrnmrn -nx n mn v.rnn ,r nrnmrn n-rnrm.nmrn,rmmnnn, rn rmnn--,-,r nrnrrm mmn nn rnnn r rn m rn - w r r-,nr-.nnn m . rm nvn,mmmrn-rnn rn --r,mmrnzmvr .. --, zm . --,zzm --,--,vm r . --,mm . zm rm . --, zvm . --, . --. --,rm . --,nrmnrxrmnm,mm. mn,rvmmn .nn--r.nnn r -, vr nvnnnrnn mn m vrvrn mrnmrn, m ,rn n.nmmmn, mnn mn xr n vr,nr nrnr mnrrn.r n mr,n nn r rv rnrnnmnmmn,,nmnn m mn,mrmr nrnrmxrrvnr v,r nmnmnnmnr,nr nn ,mm nnn mr mmnvmr ,r. w n nxrnn vr rm rnr rn nr mr vr. rmn w nvn,nn r rnnnnnnn,r nrn rvn nvnn n v. wnmr mmnnvnn: nm . - nn rnr n n rvnrmn w - m,n . - nn,r mnr. n n rvnrmn w: - .n . vrnnnn:rnr n n rvnrmn wnxr n - ,n . - vrnn. nn rnr n n rvnrmn wnxr n - : - m m,n . mnn,rr. , rn nn m,m , wrn n mn nr n, . nn rnrnr,rnzn . nn rn nn r nn m , wrn rnr- vnn -rm n w nn . n nnnr rmnr-n. rrvrmrn nn m , wrn n , mrr r nnzn nnrzm vnr,rnrr nr.mn v. nn rmnnr ,rrnrnn mm , wrn r n , mr. r nnnnrrnnrn mnrrn wnn. wn m , wrn nv mn, , m,nr . . nrrnm n r nwnrmm:n,rn rvnn rrrn, . rn n. mr,rn rn m, wrn . mn n mnn r,n-- r mr., wrn -- . mrr,n n.n r nm, wrn , rn n ,r nvn m , , ,r . n , . r n wrn rnn mrn,rn .r nm, wrn . rn mrn, wrn . .mr,rn nr-n- nnnr nmmn,n . , , , ,r ,r, wrn r ,n . n . mr nn r .mr,rn rn nm,,r, wrn. rnn r . mr,rn r m, wrn - r r -- ,r r rr - rm mrmm, ru , rmru rrn rnvu, mnn , mnum,z n . n rrn mm,rn. , , ,r . r,mrn , vn mr nn rn r . ,n v. rn nn m,r, wrn. mr,rrnnn rn r n . nr, mrnnn m, wrn mn nnnn mm mrnnn, n mnnn ,rnn - m nnnn n ,r n - m , nnnnmnn. rnnnnn rmnrnn. nn m, wrn mn n m n, n - mrnnnnr,n m mrnnnnrnn,nmmrn: rnn - m , nnnn nnn , n - m nn mrnmn nn ,r -nmmn nn m mrnn nn rnn - m nnnnmnnn , m n , nnnnmnnn , n - m n nmmn nn,r r wrn. mn r m rn mnr wr. rm , , , ,-,n n mrnn. vrnn vrnnnm mrn nnmnrn-. - m nn vnm r nmn, wmrnnmrn nnn n rmr - n n ,r nr vmmnn vrnnm mnnmr nn vnr nmnmnmrn nn n n r rr r wrn ,r r mr n n.n. rn nn r n r,, mrrrr wrrnn wrnznz m, wrn nr n , zn nmmnn mnnrrmn mrr r wrn zn n n nn,.n . rm rmrnnrnn nr nxmr, wn vrnr, n v nrxrnn vrmrn n nn. r rmrrrnn mmmmn. nn mr n, wrn n xr n vr n rm nn ,mr,n,,r,nn ,,r. ,,,.xr n vr rr vr vrnrm rr,m wrnn n rmnn m vr vr, v rm v n vr,nn- vr r vr, vn vr xr n ,rnvr,r r wrn n . vrn vrn r vrr.nmr, wrn n xr n. m m .rrv rrnnnmnnn wr nm, wrn r n xr n v , r r wr rnn , r r wrn nnnz nrmn , mr. n r rnnnnnz nrmn . rv r nmnnn wr nm, wrn n,r r wrn nn rnr wn nn r - n -,nr-, mrr rnnnnnnnnr.nnn nn -. nr nrr rn nn r nm, wrn nr,r nr,,nrr rnr, nnrnr, rmvrnnr,vr r nr,n mnm, mrr rvrnnrr,vrnnrn,nnr,. r rn nn r nmr., wrn nrm mnrr n mr,r r mnr. rn n.r rn nn m , wrn nrm mr mn nrnn,n wrn m . rnnnn m nnn. m rn nvnn n w nr,mrnmnrn .n v ,r r nnn rnnnm. m n, n mn nr, mrnnnnn v mnmnrnnnnnnnnmnnn ,rnn - m , m mn nn ,r n - m nn . rn,n. m n r r nnn mr,n:n mn nr, , -rmnnrn-nn mn m mrnnnnnnmnnn , n - , nnnnmn nn ,r -nrmnmnn m -n mn mnn ,mrnnnnnmnrnnnnnmnnn , n - m nn nnmn nn ,r wrn nmmn nn,r r . mmn rrn m m r wn . rm , , , ,- rn mrnn . r ,n -. - n m , wrn rnmrnnnrnn mv nmr nn nnmnmrn, ,r nn n vr mn nn n -mmnnn nrn mvmrrnn nnmnmrn,r n nn n vr mn r rn n n r r wrn , mr n . r r . m ,n ,rznr , n m nn r r wrn zn n n nr, mrr mmn nrrmnr, r r wrr wnrnznzn n n nn,n mr . . nr. rn nn m ,r nrnnxrrnn vmr rnmnnvn nn, n xrxnr vnr vnrn r v,rn vrr v vrmr, vnn vrn v rr,nmnnn- m v vr vr, v rm vr m mmn vrrrnnrv rnvr. wvr,rnnnr, r wr rrm. m rr nmrr rrrn.r w rm m rn mrrvrmrw ,rrxnm, vnr m m nrrnrnmmn nr. n vr, w nnn xxrrnn vrr rvr,nrr,nnnrrnnmn. vmn, n xr n vrr r nnr,n nrn r w nn xr n ,rnnmrnm. mmmnn,, vr r rmmnn . vrnnnnr nn vr, w w mnr n nnxr nn rn nr nn vr,nnm-mmrmnn mr nn m xrnrn vrvrrrmrnrn n.vn. r vr vrmr vrxr nmn nn, , wrnrnn r n mrnrnnnn xr nn mm rmr n nrrnrnn n mn .nr rmmn, rmr n mr r rrmrm mvrvnmm rrmr. r , rr xr nmn mrn - mnnn -rnrmr ,nrmr nr rmr,rnrn r -, n-rn ,mnrr w rn r , , n ,- r , r n, mn , xn nr n n. , , ,rnmrnnn ,rnrnmmn, n xr n vrrrmrrnr,rr rnrn r mn , n , wn m rrrrnnnxr n. n mmn n .r nr xr n n vr vr vr .,x mnn.:n–.n 'nrrnr r rnr mn m wmmmnmx,r ,nn , v nnn.nr m nrn . nrrrnrmnmnmvnnn, n n xrxnr vn vrnn r nr nvnn r m vrn m m . nrrmn, m nnrm mnrn , n r,r vr ,n , vn,nrr wrn, rvnr ,n n rn, m n m. mn v.r rv rnnm “ ” nvnnnururrnnm rmn rn nvnn vr n rn, ,n n , n xr n xr n v n v,r n m mn r nr rnn ,r nrnmrn ,r mmrn,,rrvnn nr. w nr.nv mnnnnmmn mrn rmnnn vnvn n n xr n vrnn r nrn mn n n , n rn. m mrn nn r nnrrrvn rrrn n mn,nnmrmnmrnn xnrvn vr.rr rn nvnn,r rvr nn, mnrr n mr. nr rnvrrnnv mr mrnrr rrmnr “mmmn”nvnn r mn mnvnn rrn.r wnxm n r,rm w rr nmnmnvn. nrwn. xm r mn r nvnn .rn ur nmxrnmn - wr n n rn . -n mn n.: : : : . w wrrrnr w rm ., wr n r r. n rn nrxmn r rn v mr . mrnnr n wrrn w wrnnn nn vx mr . xrn nnnr ,mrrwnrvv wr rv nn mrn w3-.mr wr mnnzvrnmnmrn n w . n wr-n w m wrrn n vxr wrr-n w rn v-rv mnr r w.. n z w 10-r mn. m3,n n m, wn nmrmn w wrnn- mr r nrm vrr r. mr wr mrnnnz3vr- . -. vr wnn mmnrvv wn w rrm. r v-wnr ,mnn nn nmnn w nr nrn w.- mmnrn w mrr m wr r n w mr,nnnn n, m r n n v n nn - rvmmn nnr. vr w r ,mnn n-. mn w rrm . -,mnnrn w- rxrn vrn m--. -, --n r , wr n °vrn mwn -wrn m . nn wr wn ..rr. n mnnmr w mr rmr -,-m r n, r- rzmrm , r r :z---, n nzmxr n n wmrn n-r . mn mn -rv mr wr-r m- --,mn-n,r--x,rnnrrn r- vrn w , r-:, .r w nnrr x wrrn . n- .m wr . r - r nr -n rn r w r, n-nnr,r nn- : n mr n rrm-r, -n w.n w- v -rnrn . vn -n w - - . n wn mr, n xm xmm:xrrumn nu xr n vrnnu -, ,,-nrn wr n n rnn , -. wrmrnr mn nrn wr n w r r. r r wn r n m, r , r r n n n r xm r n n mr.n.nr n wrrn wnvr w m xrn v xr ,r nrn -. rwn n r - wrn n n m,mr mr wrrvvrv wrnnnnnnzr mmm3rnn w .-. n wwrn mrrn w - n w . mnvrnnr wrrn n vx. n w mn -rv mr r r n wr-r v wrnx w n . . wrr w-n wr nr.vnnrnn wn rmn w - vmm-n rn.r. n rvvn wn-mnnn vv m xrmn, n rmn m r rm r n mr .-. v wr rmn rn xm rrm:nu w r m nmnn ,nrvrr nn rmr w m wrr rn, vr mn nrrmnrmn n-mr nrxmrn wnr vxrm wnnnnnmnnr m. xrnnnnz nr: ,n wrn ,nrr rr n mn n rn .-. n -,mnmnrr..mmn,vrv, w n,xrmn w -n nrmn. mnnvr rrmrvmn nn-mr rnr, wmrr v nn m wnrmmnrnr w. rnvnrwn wr.-.n - xmxr:rnrmnnumrrnu vrn rnzm nn wrrnrrrr n r w rn-nn nrrn nxm ,xnn mnnzm v, rrnv, , m , nm rr rm rrn n v w rnvu , . n vr nr. mr v n rmn xn mr - xr m,rnrwnn rn vrnnn mmn -.m, nvwrm vrn rn n, vrn w nnr nmr.r mr - ,n n v v n, vrn mr n.mrnn nnw n r mn rn nrv mmn m. wm mmnvnr rn mr ,x - wnn w r, nzm vrnnn .. r nzxr rnrn wrnnrn r mr n mxvr nr rrn wnrn m n mmn m' rnmn mxrrn. r r x n-m: n mmmnrnwnn nrrmrnnu nmmrrunnn-.nnw mvrnnmmn - mn r nrnwn mrn mm, mr x z mnn x-rmvn nn . nvnr mmn nr wrv mrwr zm m w - r n mnnr. wr nr r r-n. r w- nw m wr wnnr mrnn- r n .rxrmn rmn w rrn m mrn,n-r nrrnn nzm nn n .nrm -r nn w w n n- -nn w ,rrrnm nxr ., .rrn n - - w -rn , nnr rnrrn , wr rrm .. r mnrn n n-n - v mr nn n .. ,-r nr wr. n. v wn n wn v r un u PPRRYTPDWP:rn LD , nr: YADF RPLPAWFDEAKFVFIHWVFVPAWEWFWWHWERPYRFMRDNYPPF KRNIRPYFLTYAHRFLFLHEPWEFEHWPALDYLLFLDAKAKNAKFYKVTVLHTFTVKHAHKETMFPTENLWYPDLPVVWNWNKDVPHRDLVELTALR FLWLYNDPVKDEVVVNDRWN HHYYNEDK NYKPDLIWDEWEPDTYWNTN TEEEIIELVTVLNYLLNIPTKD FKPLPDHKWEMTIDKFWYRRDMALDV WYTKAVVKYAIFLHWP LIVPIFERLLAVKWLINEAIYAKPWRVWEKNTTV WTIKLT ENVLNLEPITTTTKITMLIDLKWTDPDKLFILPLPPAVPAEFA MRAPMRRPA:PALLLLLLFL,AnAErVnRRAPnPRRYTPDWPnv nr WEWFWWHWERPYRFMRDNYPPFYA LDRPLPAWFDEAKFVFIHWVFVPA TNWPPVWNWNKDVPH DFPFTARFFHPEEWADLFAAAKYVVLTTKHHEF ELYD RDLVELTALRKRNIRYLYHLLEWFHPLYLLDKKNFKTHFVAKTMP PLLPVDNHKYWKEPMDLTIWIDDKFEWWEYPRDRTDYMWANLTDNVFTLEEWLEYINIDEPLVVKDTEVVVLVNDNRYWLLNNIPTHHYYNEDKFK LAVKWLINEAIYAKPWRVWEKNTTVWYTKAVYAIFLH KDLIVPIFERL DLKWTDPDKLFILPLPPAVPAEFAWTIK WPENVLNLEPITTTTKITMLI MAFLWLLWAL:LTTFPPR,RYnTPrDWnPLDnLTVK RPLPA mrnn- nr RPYRFMRDNYPPFYADFPFTAR WFDEAKFVFIHWVFVPAWEWFWWHWE KIDWVDPHERWDELVPDETLYWTNALTRNKFRLNIWRLYYNLDYHF PVLF KLH DEP EWE VFE VHW VPA NLD DYL RLF WLDAKA NKNAKFY HKV HTVLHT YFT YVKH NAH EKE DTKMF FPT KEN PLWYPDLLP PVVNWYNKWPNDL IDKFWYRRDMALDVTEEEIIELVTVLNYLLNIPTKDLIVPI DHKWEMT IYAKPWRVWEKNTTVWYTKAVYAIFLHWPENVLN FERLLAVKWLINEA LFILPLPPAV LEPITTTTKITMLIDLKWTDPDK :PAnEFrAWTIKLTVK ERPYF,LRFFFm MLn n n RDVNTYTPPVHFYPAPDRFRYPTPFDWPnmrnmmn nv nn nr MEWWV LDrRPLPAWFDEAKFVFIHWVFVPAWEWFWWHW KDVPHRDLVELTALRKRNIRYLTYAHRFLFLHEPWEFEHWPALDYLLFLDAKAKNAKFYKVTVLHTFTVKHAHKETMFPTENLWYPDLPVVNWYNWN LIWDEWEPDTYWNTNFLWLYNDPVKDEVVVNDRWN HHYYNEDKFK KPD TIDKFWYRRDMALDVTEEEIIELVTVLNYLLNIPTKDLI PLPDHKWEM AIYAKPWRVWEKNTTVWYTKAVYAIFLHWPEN VPIFERLLAVKWLINE LFILPLPPAVPAEFAWTIKLTVK VLNLEPITTTTKITMLIDLKWTDPDK v n : -, unrn nnr nr nrn mrn MEWWVFLFFLVTTVHPPR - . ER RYTPDWPLDRPLPAWFDEAKFVFIHWVFVPAWEWFWWHW KDPVYPHRRFDMLRVDNEYLPPTAFLRYKARDNFIRPYFLTYAHRFLFHPEEWADLFAAAKYVVLTTKHHEFTNWPPVWNWN LIWDEWEPDTYWNTNFLWLYNDPVKLDEEWVFVHVPNLDYRLWLDKNKNFHKHTHYFYVNAEKDTKMFPKELYDLVNYKPD TIDKFWYRRDMALDVTEEEIIELVTVLNYLLN PLPDHKWEM AIYAKPWRVWEKNTTVWY IPTKDLIVPIFERLLAVKWLINE LFILPLPPAVPAEFAWTTIKKLTAVVKYRATIAFELPHKWSPPEDNKTVHLTNCLPEPCPPITTTTKITMLIDLKWTDPDK TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEYNSTYRAVPVESLVLLGTGVPLSHVFDLWFLPPKPKDTLMISR ALPSADPGISEFKFTLIYSSKKALKTGVDPKRSERPWVYGTNLVPFPSSCRSD NGKEYKCKVSNK LD VEMLHTEKANLHVNSHLYTTCLKVSKLGSFLYSPPSGDKIAVEWESNGPENNYKTTPPV u :unn: ATAA T Arn n n TAAA T AAA T A TTTTTTTTTT A TT T TTTTAAAATAATTTAATTATTAATTAAT TA TTATAAA T A ATTTTT AT A A T TTTA T TT TA AA AAAAATAAAATTATAAA AAATTATTAATTTTTAATA ATTTAAT ATTAA AATTTTA TAA AAATT A TTTTAATTAAATTAATATTTAAAAATAAAAAAA TT AT A T AA AATATAATA T ATTT A TTTATTA TAAA TTAATTTT ATTAATTAAAAAAAATAAAAA TTTTAAAA AATTTT AAAAT T TAATATAAAAAAATTTTTTATTTAATTAATTAT A AT AAT TA TTAAAAAT AAATAT ATAT ATATTAATATTATAAAAATAATT TAA T AAAAAAT AATT ATTAA AAT AAATAAATTTAT TAAAA AATATTATAAATATA ATAAAAAAAATATTTATTATTAA TT T T TT AAAT TAATAA AA ATTA ATTTAAAAATTTTAAATAAATT TAAAAAAAAAATATAAATTTTAAAAAA TT TTTA ATTTTTAT A AATTAATATAAAAA TAATAAAATTAAAAAAATAATT TATT T TATT TAA A TTTATA T TAT A AT : ,nrnATAAmTrAnnT-AAn n A TTTTTATTTTTATTATATTATTAATTT AAATT A T AATA TATAT TTTA T TTTTATATTTTTTATAT AAATATTTA ATATA v AATATAAAAATAAAATTATATTTAATATAAAATAAATATTA TTATA ATTT TTTAAAA AT ATTTA AATA AAATT ATAAAAAAAA TTAAATT A TTTTAATTAAT TTAAA TTTAATTTTTTAATTTTA T AA AATATAATA AATTTT AAAAT TATTAATTAAAAAAAA TTTAAAA ATTT A AT AAT TATAATATAAATATAAAATAAA TAT TAATAT TTAAAATTTTAAAAAT AAATTTTTT TTA ATATAAATTAAATAATTAA TAA T AAAAATAT ATAT AATAAATTTAT TAAAA AAT TA AATAAAAT AATTA ATTTATTAA TT AAA AAT TA T AATATTAAAT TAAAA ATTATATT AATTTAAAAATT TT AAAT TAATAA AA TT TTTTAAAAATTTT TAT AAAAAAAA TTTAAAAAA ATTAAAAAAATATTAT TAAAA TTAATAAA TATAA TTTATA T TAATTT TATATA ATATTATATATA A AAA TAA ATT TAAATAATA ATAATA:T TTT,nrn mrnn n ATAA TAT TATTTTTTATTTTATAATA TTATTTA T A TTTATAT TTTA TTAATATTTTAT TTTAA AAATTT AA AAAAATAAAATTATAAATAATAT ATTTTT AT A A ATTAA AATTTTA TAAAAT TAATTTTTAATA ATTT ATTTAAAAAAAA TT AAT TA AAATT A TTTTAATTAA ATAAATTTTAAAATATAAATTT AT A T AA AATATA AAA AATTTT TAATTTTA TTTATTAAAAAAAA TTTA TATTT A ATAAAAATATTTATTAATTAAATAAA TA TATAATAT TTAAAA ATAATATAAAAAAATTTTTT T AT ATATAAATTAAATATTTTAAAAAT AAATAT AT AAATAAATTTAT ATATTAAA TAA T AAAAAAT AATT ATATTTATTAA TT ATA AATAATATTATATA AAA A A TATT AATTTAAAAATT TT AAATAATATAATTAAA ATTA ATTAAA T TAT AAAAAAAA TTTAAAAAAAAA TT TTTA ATTTTTAT TA A AAT AAA TTAATAAA TATA TTTTAAAAAAATAATT TATTA AATTAATATA A AAA A TATAAA T TAT A T TATT TAAATAAT :rnn n, wnr, v AATTAAAATATATTTTTTATTTTTTATTTTTATAATA TTATTTA T A TTTATAT AAATT T TTTAA AAATTT AA AAA TTTA T TTT A ATTTTT AT A A ATTAAAATAAAATTATATTTAATATAAAATAAAATATTA TTATA ATTT ATTTAAAAAAAA TTAT ATTTA AAT TAAATT ATA AATT A TTTTAATTAA ATA TTAAA TAATATAATTTTTTAATTTTAATTTAAAAAAAAAAATATA AAA AATTTT AAAAT TATTA A TTTA TATTT A AT AAT T ATTAAATAAA TA TATAATAT TTAAAATTATTATAAATAATAAAATAAAAAAAATTTTTT T AT ATATAAATTAAATAATT TAT AT AAATAAA AA TAA T AAAAAAT AATT ATATTTATTTTTAATA TTATAATA AATAATATTATAAATATA ATAA A A TATT AATTTAAAAATT TT AA AAA ATTA ATTAAA T TAT AT TAATAA AA ATAT TTTA ATTTTTAT TAAAAAAAAAATATAAATTTATAAAAAATATAAA TTTTTAAATAAAAATATATAATTT TATATA ATATTATATATA A AAA A TAACGTACGGCAGAGCCCAAATCTCCGGACAAAACT ATT TAAATAAT CTGAACTCCTGGGGGGACCGTCA CACACATGCCCACCGTGCCCAGCAC ACCCCTGAGGTCACATGCGTGGTGGTGCTTGTGCACCTGCTTGTACGCCCCCACCCGAAAAAGAACCCCCCATAGGACACCCTCATGATCTCCCGG GGACGGCGTGGAGGTGCATAATGC GAGGTCAAGTTCAACTGGTACGT T CAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGG GCCACGCCTGCTCCCCATGCCACCCCCGCTACTCCTGGACGAACACAAAGCGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA CCTGCCCCCATCCCGGGATGAGCTGACCACTACATGCACAACACAAGGCGCTACAAAGGCGCGTCGAAGCCCCTCGCGAGAACCACAGGTCTACAC CCAGCGACATCGCCGTGGAGTGGGAGAG CCTGGTCAAAGGCTTCTATC CTGGA CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CGTCTCTTCCTCCGAATCGGCGTCCTCCGCTTGTACTTGTCCACTTGCATGAGCAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAA CGGGTAAA CTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTC AATAATT:ATTAAAAATTTTAAArATTArTnTrATTnTTAATArmn ATTATA TTTTAAT TTTTATATTATTTT TATTTTTTTATTTTTTTTTA T TTATAAATTTTTTTTTTATAA TTT ATTTTTTA AA A TTT TTTA AAT TTT TTT T T TTT ATT AATTATTTT ATTT TTT ATAATAT A AATAT T TT TTAA T TT ATATTTATT TATTTTTTTTTAAATTATTTTTTTAAATTATTATTTT v TTTTT TT TT TTT TTT TT TAAAT ATT A :Tmn T , nvn TTTT TAAATA AAAATAATTTTA TTTTTTTTTT TA TTTTAA TAAATT ATTTATAATTAATATTAT AAAT T ATTTTTTAT AAAAAAAAT AATATTAATTTA TATT AT TATTTTTAATATAAATTT TTTTA AATT TAAAAATA AATTTA A A AATAATTTAAAAAATTAAAA AATTTAAT A ATAATAATAAT ATT TT AT A AA TAA AATTAAAATA TTTTATAAAAAAAAA ATAATT TTATAA TTTATTTA T TAATTATAAATTTTAAAAAAATTTTTTTAAA T AAT TAAAAAAATTTATATTATTTATTTT A A ATTATAATA AAAT T TTATTTAAAA AAATTTTTAAAT A TTAAAAT ATT AAAT AAAATATAAATAAATTAATATATAATAAA AATTA ATATAATAA AAA A ATTTAAATTAAA TTT AA ATTTTTATTAATATAA AATAT AAATA TTTTTAAA T A ATA TATTATTAATAA A ATTAAA AATAT AAAATATA TAA ATTTT AAAAAATAAAAAAAATTTA ATTTTTAAT A A TAATATA TAAAAATTTATATTAAAAAATTAATT AAAT TTTAAAT A TATAAT TTAAA T TT TTAAATAT A A :mAnATATTAA rn, , nv ERWPn FWEWLYPWRLKAn EFKPIL, n M PLKLYLVLELFL, MLKLDPNPYPPPPPn FAKHr YEA, DTFRFPDLPFTTWAEKFLFDNAARNLWPAADWIFFDAAKFAKIYFIIVHLWTVKFHHVEPF EYWNWNAIDEPKRDIVKELEVAIRNRTDLRF FTLW YELVNNY LYYLFEWFHPLFLEDE FHKRFPVKTLPEL HLLPHKWEPNEVMLTWIDDKLDWAYPRDREYAWNITDYFLLTAWLYNEPVRTVVTNDRWAIKHFYTDRYNP MWLKVNEAIYETHTWRNDTVTPDVWYITEEKLPVKKEKLLVVEYTAVIFLKNLLMNIPTLDTIVVFEERLR HPLNWILENIMVELPL WPT LFLHPKAILATEVKLL : -TIH,MPK,W nWALALTNVI HHHHHH AT TAAT AA v TTT AA AATAATTTTA TATTTATATTTATTTTAT TA TTTTAA TAAATT ATTTATAT ATTTA T TAAATTTATT v TATATTTTTTTTATTAT AAAAAAAAT AATATATTATAAAAATA AATTTAATAATAAAATTTAATAATTTTTTTAAAAATTTTAA AAAT A ATAATAATA AAAAAA TTTA TT AT AT ATTAA TAA AATTAAAATA TTTTAATAAAAATAAAAAAAATTTTTAATT TTATAA TTTATTTA T TAATTAAAATAA TAATAATATAATATTTATTATTAAAATTTAAT TAAAA TTT T TTATAAA ATAATA AAAT T TTATTT TTAT A TTAAAAT ATT AAAT AAAAAATAAATAAATTTATAAAATTAATATATAATAAA AATTA ATATAATAAATTTA AAA ATTTATAAAT A AATTAAA TTT AA AT TT TAAATAAATAATATATAAATAAATATATTTTAAAAT AAT A ATA TATTTATAAAA TA AATATA TAA AT AAAAATTTA ATTTTTAAT A A TAATTTTATAAATAAAAAAAATTTATATTAAAAAATTATATT AAAT TTTAAAT AT TT TT ATAAT AAATT AAAAATAA AAATAT TA AA TTTTT AAAA AAAATA ATATTATTAAATAATTATTAATATTATTT AAAATAAA AAAAAATAATATAAAAATTAAATTTATA TATATAAT A ATT TAAT AAAT A TTTA TTA TTAA A AAATAATTAAAAA T A ATAAAAA AATAAAAAATAAAATAAT ATAATAAAAATTTTATAA T AT ATATA AAAT A AAAAATAA T A AAT TAT A TAAAATA AAA T TTAT A TTTTTT A TTAAAATTAAAAAAAAAAATTATATTATATTTTAATATT TATAT : - rn, , nv ATA MRPnELPRLAnFPL,LLLLLL,LLPPPPPnAr, EWFWWYWKEKIP HATRFDPTWELDARLPAWFDAKFIFIHWVFVPF EYWNWNAIDEKYPVKERFDMIKVDKNEYLPEPVAFIKRYNERDTFDLPRLFFTLAYKYFFLNFAENWFWADIFAAKYIVLTKHHEFTLW YELVNNYPEVLWDDAPDYWNTFLA HPLFLEDE FHKRFPVKTLPEL HLLPHKWENMTIDKLWY WLYNEPVRTVVTNDRWAIKHFYTDRYNP MWLKVNEAIYETHTWRRRNEDATVITPDDYVLWTYITEEKLPVKKEKLLVVEYTAVIFLKWNPLTLMNILFPLTLHDPKTIVVFEERLR HPLNWILENIMVELPLTIHMPKWWALALTNVIRT AILATEVKLL FLFPPKPKDTLMISRTPEV AEPKSPDKTHTCPPCPAPELLGGPSV DWLNGKEYKCKVSNKALPATPCIVEVKVTDIVSSKHAEKDGPEPVRKEFPNWVYYVTDLGPVEVHNAKTKPREEYNSTYRVVSVLTVLH SNGPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWGNVFPSSCRSDVEMLHTEKANLHVNSHLYTTCLKVSKLGSFLYSPPSGDKIAVEWE v n : , , rrn rnvu, mrn n ATAATAAATATATTTTTTTATATAATTTATTTTTAATATATTAAATATTAATAATAAATT TT AAT TATA AAAAAAATA TAAATATAAATAATTTATTT ATTAAATAAAT AAAT AATT A AA AAT AAAAA ATAATA TTT A T AAAATATAT TTATATTTTTTTAA TA ATAAA AAAAAA TTA TATAT AATAATAAAATTTAAAAAATATTAAAT ATTA TA TAAAAAAAAATAATTTATAATATAATAAT A TATAA AA TTAAAATA AATAATTTTTTATTATAAAAAATATTTAAAA TAAA AAAATATAAAT AAATA A T AAAA TATATATATAA TA ATATTATAATAAAAATATATTA AA AAAATTAA AATTT A AAATAAAAAT TATTAAATAAATAAAAAAAATAT TT ATT TTTATTTTAA AAATTTATTAATTAAAAA AAATATTAAAA AAAA AAAATTAAAT AATATTAAAATAATATAAAA AAAT T ATTTATAATAA ATTTTAA AT TAT TAA AAAA AAAATTA A TTTAATAAA TTTAATAATA TTAT ATA TAAT TAAATAAAT T T AAAA TTTATATAATATTTATAAATAATATTAA AA TTT TAAAA ATT A A AA TTAAATA : rn,A,AArrATnAArTAA WrnWVFLnFFLVTTnVH,NEIWN. nvu ME RTnvu, nr, . DPTDYNPREWARLAKKAMKYAVLTAKEHWHFDRKFERLFFDMFAILHTWDYLYAIPALEWVMEKRMTVEEYEKYFEF FTLIDWHHPDYPKYNDMHHPMRNEAYKDENINFDRYLEYMHKATVNETEKLAVTRNDYLVKRLEFLDAFRAELKVLY WKAEELIRMVRKHPDVIIDNRLE EK DILWFDFYDNMEDT TMNNHW NIVTDHPNIYDFAPEMIIPPMKDLNKPIPWELA IEYDYKPYEYWDHRTYYTKTKNTTIVIYRAKHLIVYEETVPLKALNFLIYLNIVPDAKRIPKEEILTVEWMENELYE VALENPVFYPLPDEID PEVTITFL AVREAWNTAMYDTPF : TVLKIELKK HHHHHH ATTATTAAATAAATTTTTTTTTTTTTT TTTTATTTAATAATA ATTTA T AAAA AAATTTAA A TATTATATAAATAAATTTTTATTAATTAAAAT AATTAAT TTTAATAAATA TTAAAATATATTTATAATATT T AA AAAA AT TAATT AAAAAATAATAA TAAATATTAAATAAAAAATT v ATTATAAAT AATTATAAAA TATTTAATATTA TAA A ATAAATAATTTAATAA TTTTTTATATAAT TAAAA T AA A TA ATAATTTTATTAATAAAAAATAAA AATTTAA TT TTTATTTTT AAAAAAAAAATATATATTA T TTTAA A AAAATAATTTA A ATATAATTAATTAATA ATATTAT AAAATTATTAATATAAAAATTATTAAAATTATTAAAAA ATATAAATTAAATATA TA ATAT ATATATAA TAAA TAAAAATTAAAAAATTTAAAAA A TAAAAATAATTTA TATTTAATTA TAA AATTTTTTATATT AATATAAAA TAATTTATATATTAAATATAAATAATTTT TA ATTA T A TAAAAATAAATATATATATAAATTAAAT T ATATT T AAAA AT TAAAATATTAAATATTTTTAATAATTTAAA TTA A A AAATTTATTTAAATAATTATAA AATTTTAAT TAATTATTAATTAAATTTAATT AAAATAAATTAATAA ATATTTATTATAT TTAATTAAATAAATAT A TATTA T ATTATTTTTATTAT AAATTT TTTATAT ATTTTT T T AATAATTA T TTTTTA AAT AAAA TAATAAAATTATA AAT ATTTTAATTATTAATAATTATTA TAATTTTTA T TTATAATT TT TTTAATTAATAAATATTAAAAAAAA A TAAAT AA TAAAAAAAATATATA TTTAAAATAATATT TTA TTTATTAAAAAAA TTTAAA AATTTA AAAAATAT TATTAATTTAAATAAA AT TATA ATATTA A AAAT ATT TTTAAATAATAAAAAAATTTTT TTAAAATA TAAAAT AA TATTAATTT AAATTTTTAA AATATAAAT AAAATT AAAAT TTTAATAAAT AAATTAATATAAATTTTT TAA T AAAATTATTAATTATA AAAA AAATATT ATTAAATT TT T AAT TTTATTAATAAAAAATATTTTATTTTAAAA T AAAAAATAAAT TTTAAAAAA TTTATTTAA TTAATA AAA ATTAATTAT ATAATAATAAATAATATATATTAT ATA ATTAATTTA A TA ATT A TTT AA TTTTATT T TAT A AAAATTTAATTT TAATAATA TAAA A TATATA - :ATA r mn,ur nrr,nn- vnn nn vrunm,n,n- nr,nn v-r v nvr,n vr, mn, nr,n- n vr mn, MLAILYPDVATANLLLVLPLIAPLPLx RLFHAARPDITDLTPALAVLRATIKA VDYDDYLNWYIPPPKL VL AELVRP VKFITLNKIAHPVYEAKFVDAATYH TEDPWTF TKLEIK KATLTADE TAYMLLAEDAVYF YWMNWVKRP LEWIIWPDDTNYNKFK AELARPAVKMKTYTFTRYTM ARRETTTVRYYYAMDYW TTVTV DIKL YMLLTEDAVYYA HWVKRP LEWIYINPRYTNYNKFKDKATLTTDK TA PEKVTMTRA VYRMYNYWDYDHYKLDTYW TTLTVVE VDDILTPAIMA YY WNPLTFATKLELK PKRWIPYPDTKVAVPYRF TYLTIMEAEDAAT AWGSEWFWWHWGEGRPYRFMRDNYPPGFSYADRFRGYPTPFDTWAPRSFLFDHSPREPELWPAADWLFFDEAAAKGFAGKVYFIHWGVFSVP FTNWPSPVSWNWNSKDVGPHRDLVGELGTALRKRNI VVLTTKHHEG PELYDLVNSYKP RYGLYHSLLEWFHPLYLLDKKNGFKTHFVSAKTM KPSLPDHKWEMDCLTISWISDDKGFESWWEGCYPRDRTDYMWANLSSTDNVFTLESEWLYNDSPVKDEVVVNDRWGNCSCHHGGYYNCEDKF LLAVGKWLSINGEAIYASKPWRVWEKNTTSVWYTSSEKIGISSAEVLYVAITFVLSHLWGPGENNYGLVLLNNILGEPSTPKDGLIVPIFER IGDLKWSTDPDKGLFISLPLPPSAVPAEFAWTIK ITTSTTKITMLG : LTGVKAHHHHHHHH AATAAATTTTTATTTTTAATTTTATATTTTAAATAAATAAAAATAA AATTTATA TTAATA AATAAAAA TATAATT AT TATTAT AAAAAATATTATTTTTAATAAATTAAA TATAAAAAAAAAT TTTA TAATAT TA TAAATT TTT A A A TTAATT AAAA ATAT AAAATAAT A AATTA ATAATAA A ATTAAAATT A ATATTAAAA TAATTTA TAAAA T AAAATTAATTAAATATAAAATTAATTTTTTAAAATTAT T T TAAAA T AA A TAA ATAATTAAATA TAAAATTATAATTATAATTATAAATTTAA AT TTATTT AATAAAATT A ATTTA AATAATAT AAA A ATATTAT AAAA AA TATT TAATATTAAT ATTTTAATAATAATTTAAAATAAAAATTAA TA A TAAAATAATAT ATAAT ATAT A ATA TAA AATT AA AAA TAAAAAT TTA TAA AATAAAAAATTAATAATAAAAAAATAATATAAAATAATAT TAT AA AAAATA TTTT AA A TAT TA TATTATTAAATTT AATA AA AATT A TAATTTAA T AATAATATTTTAAATATAATTATTAAATAAAA TAAA TAAAATATTAAAATAAT A T A T AA T AA ATTATTTAA TTTAATTTT AA ATTAAATTTAATTTTAATA TAAAATTAAAATTAATAATATTAATATA v ATTATATATTAAATATATTTATAAATTATA ATT A TATTTAATT T ATTTTTT AT A AATAATAATTAATATATTATAATTTATA TATA ATT TTTTA TATTTAAATTAA A ATTA ATTTAATTATAAT TTTTTA AAT T TT TATAATAATAATAATATTAAAAAAAAAATATATTTTAATAAAT A TAAAAAAAAATAATA TTAA AT ATTATAAAAAA A TTATTTTA TTT ATTAATTAAA TTTAATATAATATAATTATAAATAAAATAAT ATTA AATAAATTTTTTT TTATAATAT A TTAAAATT TAAAATTTTAATAA TTTATAAAAATATTAATATATAAATAATATAAAT AAAATTTAA TAA TTTATTAAAAA AATATATAAAAATTTTTTATAATTATATAAAAAT ATTAAAT TAAAAAT TATT AAAT AAAT TTTATAA TATTTAAAATT T AAAAA TTTAATAAA ATATATTTTTAAAATTTTTATATAT AAAAAA ATTAATTAA TATAAAT TAT AAA TAATTT AAAAAAATAAATT ATA A TTAATTTATAAATAATTAATAAATAATTTTTATAA T TAT ATA TTT ATA A T TATATAATAATAT ur : rn vnnn vrun,n- n vr mn, nr,n- nr,n- mnn, v nr,n- v n vr mn, MEWSWVFLFFLSVT r mn, nr, ,x LIYWATR TGVHSELVMTPLTVTAEKVTMK LLNNKNYLTWYKPPPKL EVELLEVPDRAFET TDFTLTIVAEDLAVYYNDYYPLTFATKLEIK KATL LVRPTVKIKAYAFTNYWLWVKRPHLEWIDIFP NIHYNEKFK KPATVAKDVKKATAYYMTFLTRYLTTMFHEWDVRAVAYPFARLLERWNIWDYEIPNMPDYRWYTNTYTAVDTVVKRFTITDTVDLV AEVK LREDTATYYARYYDDHYLDYW TTVTV ETT ADDIVLTKPTTAYMEL RATLRA VYMNWYKPKAPKRWIYDTKVAVPARF TDYLTIN ATLLPE WNPLTF TKVEIK PPRRYTPDWPSLDSRPLPAWFDE LEAEDAATYY EWFWWHWGEGRPYRFMRDNYPPGFSYA AKFGVFIHWGVFSVPAWGS PSPVSWNWNSKDVGPHRDLVGELGTALRKRDNFIGRPYGFLTYAHRSFLFLHEPWEFEHWPALDYLLFLDAAGAKYVVLTTKHHEGFTNW DLVNSYKPDLIWSDGEWECPDTYWNS KKNGFKTHFVSAKTMPELY LP TNFLSWLYNDSPVKDEVVVNDRWGNCSCHHGGYYNCEDKFKPS GKDWHLKSWIENMGCETASIIYDAKSFKSPWWGRYVRRWDEMKANLSDVTEESEIISELVTVSLGGNYLLNIGPTKDGLIVPIFERLLAV LKWSTDPDKGLFISLPLPPSAVPTATESFVAWWYTTISKKLGTSGAVVKYAIAFHLHHHWHPHEHNHGHVLNLESPITTSTTKITMLGIGD v r rrnrrum n r nn:n n mn n rn nrnrr ,n. , ,, , , ,

Claims

vm.r nvn xr n vrnn r n rmn,rn . m nn rr n xrrn,n vnrrnr n.rn m, wrn . n n -- --xr nn v.rr mrnnn m,rr, wr.n .r nn xr n vr rnn m, wr,nr r mr, r r r , , , ,r,n . n nn ,r r vn, rmr . n xr n vrr rn v. xr n vr m, wrn n nn nn mr n mrn,r - n: nn nn n ,,, - ,rn ,nn nrnmrn r, nn n . n x n v,nrr. rn m, wrn . r nr x-r-n v. rr - rr rn m, wrn rrn rnv-u,rmrm mrm, ur, rrm num,z n mnn um . n xr n ,n r mrn. rr -- vrrrm rrrnn mrnrv, wrn . u nn n . wr nn nxr nx vrrnr vrrnn nnn rrnnm, - n,r r wrn n rrn ,vn r mn -- nn n - rmrnn-n nn n .v . wr nn xr nn v,rrn mrnnnn nrr, nzm, ,r r wrn zn nmmn nrn rmn,r, mrr r wrn zn n nn mrnr r wrn. zn n . wr nn xr nn v,rrn mrnn nnnr,rmnrnm, nn m mrnnnnnnmnn n m , nnnnmn n n ,rnn - n n ,r n - m. nn mrnn. w xr n vrr rn nn r n m, nrnr nm,rnn mn nr, -rmnnrn-nn mn m,m: nrnnnnnnnmnnn , n - m nn nmnrmn nn ,r -nmmn nn m mrnn nnn rnn - m , nnnnmnnn , n - m nn nnnnmn nn ,r wrnmmn nmmn nn,r r. n xr n vrr mr rn mn . nn rm , , , , r, wrn mr. n xr n vrr rn -,n -. - mrnnnn m mr m, wrn rnn r v nn nnmnmrn, mmnn , nn n vr mn nn n - n nr rn mvmnrnr nnnn vrnnmmnnmrn,r nn r nrnr r wnrn n n xr n vrmr n . ,r r . wr nn xr n vrr rn nn r n m, nn n rmxnrn mn v vrr vrr, v vr vrrm vrrmv vr, vn vr vr,nn- vr ,rnvr,r r. wr nn nxrxnr vnr vrrnrn n vnr. wrn n xr n v r n m,. n xr n vrrrn m m . wrn n xr n vrrrvn nnrnnmrnnnm, r rr w wrrnn,r n xr w r n v nnnr nznnnnz nrmn , mr. n xr n vrr nrmn . wrn n xr n vrrrvn nnrnnmrnnnm, nn rn,r r wrn n w nnnn - n -, n rnnn n nr-, mrr r wrn. n n xrnnn nn -. wrn nrr n vnrrr,r rrn nnnr r n m, nr,vrnr,r nr,nr nr,nnr rmvrn nr,r nr,n mnm, mrr rvr ,rv nr,n. w n xr n vrr rn nnnnr,rrnnnmr., rrnr w nrn nxr nx vrr mnr r n mr, n n n vr mnr nrmr.m m. nrnnrnv n nvn nxn w nr,mrn nnn r n m.r n vrnn

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