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WO2024154061A1 - Compositions and methods for stabilizing rna - Google Patents

Compositions and methods for stabilizing rna Download PDF

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Publication number
WO2024154061A1
WO2024154061A1 PCT/IB2024/050424 IB2024050424W WO2024154061A1 WO 2024154061 A1 WO2024154061 A1 WO 2024154061A1 IB 2024050424 W IB2024050424 W IB 2024050424W WO 2024154061 A1 WO2024154061 A1 WO 2024154061A1
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Prior art keywords
nrn
rnn
nnn
nnr
rnr
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PCT/IB2024/050424
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French (fr)
Inventor
Eric Matthew Bennett
Amendra Fernando Hewa DEWAGE
Laura Lin LOHSE
Raghav Raj POUDYAL
Liliana Wroblewska
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
Pfizer Corp SRL
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Publication of WO2024154061A1 publication Critical patent/WO2024154061A1/en
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    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/67General methods for enhancing the expression
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12PFERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00Preparation of peptides or proteins
    • C12P21/02Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00Vector systems having a special element relevant for transcription
    • C12N2830/50Vector systems having a special element relevant for transcription regulating RNA stability, not being an intron, e.g. poly A signal

Definitions

  • w rnnmrrrr rrnnwnnnr :.n, r n. , mnr,nr .rvn n . , n ., n..rvn n n rn n .nxmnrmnnnn n n n w nm , nm “ nrn.xnmrr rnnnr. .xm nz. ”, wr nnr, ,n r,.
  • rnv,nr n “ ” rmmnx mr r xr n n n vrnrn nn’r n “ ” , r r n n’ r nrrr n.,nnm ,nz,- m: -n ., , : .rn n. r rrnr nnnn n n n mn rrmz- m nvrn n rn r rm . r n ,:- n rn mn.
  • n r n nn n.rxm, r mn -nnn mnnn ' rm vr r n w n, mn rr. r vrnn mn rv . . rm nn mnrnnr v m rrn w mrnnn,:n ,n nrrmnn r rnmm-r m mnrrnnnr m rmnn .wvm m r ,n wn nrnrn w nrnrn.
  • n.nr wr “nr”r nnv r vrr “nrn ” n “ ” n mmr rr.nmnn,rn,n mmr r v wnnw ,,, mn nn, nn,r m nn, m,rrr mmr r v rr. ,”r “n ”n n “mr,” “n n r n,nnrnnrx rr rwr n.
  • nnrm mrn “mr”n “mr”, “,vn w”rn “nmrrn” vn, “v”n “”, “nn”n m n “n ”r “nn nrmnn, “n ” rnvrn-nnnnn wnrnmrnnnm, n “nnn”n “nn” mnrr rmn n x nn r rmnr r rmn.
  • nm r rm “ r rnn nx “nnmrnn” m.”mmnmnn mn “nnxn nrm “n”nn”r wnrn nr mr m n nv rmr mr r wr “nn”nnrm nn, “n m r. mnnn,nm , wvrw r ”n “n ” “nn”n mnr rr “rnn.” , r mn m mnr,n n r r rmrnrn mr.
  • n “nmmn,” “nmmn,” “ mmn,” “rn,r” “m rmn,”m “mmnm,” “rnmmn,” “n n r r ,” “ mn”, “n ,” “n ,” “ ,” ,” r ,” “rn ,” “n n ,” “rr r “m ”rmnnr mn r r r,rrrr rnr rr.
  • rv w n “nr,”r “nr” r v m,r v nmrrnmrr wrm. rrrnxm,,nnr,rn,nr, n, n,m,r v nr.
  • nrr-m mn mn r n w r, mmmrnnrm rrrv,n v nnm mrv wrnr nnn n.nnrnn, mn n, wn rrmmr nrvrnnwnvnr mn.rnnnrrn nr w rnn m r v ′ , r mnrn r m v .n n-,′-w n n n , w rnn ,nnzm rv r mr r r r .
  • n,nrnv nn-n.rxm '- zn r'--m n nr n rn ,nnvr mn,n nrnv n - ,'-,'-,r rn m - rn..,-m rn..,-mxrn, ..,-m - rn,nr- n n-mnm.
  • n nnn nnnn rrmn r- ’ r mrrmr, r-n nmx n nr rnnrmrmx, nn rr mrn r m m -n nrnm mxn nrm r m. rrnv n , n , n , mr m ..,r n nnn n m nrrrmn,nn r.
  • r n n vnnr r rn rnn r rn rnmmr .,nr rmnnr r nnrnrn -, -, nmmmn, m m n. n m mrnr mr rnv rnv nr n. n. rn nv n nn n nn n rmnr rvv r. n m rnnnn ..rnr nn,r,mn,n n.
  • n n n nrnv nn.xmrnnm wnm,v mnnw mnmnnnn,-m- wnm, w n ,rxw nm,-,mrxw-wnm-, nrm rxw n *,- n , x n , - n , z-nn, n , -z-nnr ,-mnm--z- mnn- nmn,-n- z--z-nn,--nn,---nnr,r n+,- nn,-m-nnm,-- z-nn,---z---z- nn,-m-nnm -m-nn,---z--z- nn,-m-nnm -m-nn,-mx- m,,-m-nnm,,-m,
  • n rrnv nrrvv r ,,,r, r rr ..,-z n ,..,n nnrnn , n mn. nv m mn '- rr. '- rr m nnvrn nnrxrnnrn n nnn nrn nmnr, w rnn r wn-n n rm mr m m m . rr rmvn'-rrnnrn rmv r xm '-r nnnnn m wn n.
  • rvnn nn nrn n -.z rrrr mr rrr v '--' r rn ,rnv n n n n r n.rxm n nnzmrmw mnn rr'nw, m w--nn n rn n rnvrnnn nr r n n n '-- '. n- n . n mrnn , -mr nmn,n m n r r '-rmnnr'-nnr '-- n n '-rxr r.
  • n-nnnrr.nn m n m m n r rmn - rn r '-nn rnv n '- nr .rn nxrmnn n n n rvn n n nr-rnnnn.
  • nn-mnxm,rr,n rn,xrmrn mr, nv nnnnrnnrn r nn n r m rn nnn n.
  • n r r nrnrrr,rn. mn mxn, ,v ,r r r nr n ,x, r rrm n m r mr mn.mr,,rxm, nx rrr r nrr rnn r rm n m rmnn mnrm.
  • nr nnrmn mmnn nnr mn n n r mr rm n.rxm, nnr mn n m ,nr mrvn xnr rnrn , n r v n, , rn m, n, rn, nn, nnn,rmmrn mrn ,n n r,,r ,nr nrv nmv,n ,r, nnrrm.
  • rrr ....,, v x, xn rnn mrnn mr , x n rn , rn mn r n,rnr ,rn mnm , rn mn , x rn r,..,r mn , mn r n , x n x n , xm rn r, x r r..,r,n ,,xrn r r, n r r , vn-rrn, n,.., x nrnmn , m , m , , mrnrm r,, , , rmnmrm, r.
  • nznm r m,nrmnn nxmn,rr rrvvv mnnr,n,mrr nrmrvv,,nnxnn, rxmrvv,nxnrnrv,v,r nrmrvv,,nr rrvv.
  • n rn “r ” rr rn r .nmmmn, ”rrr r rr nn mmn, rr r.nmmmn, .nm nn r.nmm rr n mn, rr - r. r rvmmnmmmnn, rr m nn m v rnn.rnn, nn r mrrnrn .
  • nnnmnr m nn-mnr,r nn n, m,rm nnn-m,nn rn, ,- x rnnmnn.r , m mr n, m ,r m ,m ,r , r , , ,n , -nn ,r nnn,r,n ,rxn , nn , n , n mmrn.nmmmnn, .r r n mr nv r mmnrn.. nnr wnr mmrn.
  • n .nnrr rmmn mn n m n , m , nn n . m . m rr , .nrmmn .nmmmn, m r r. , m - nr rr m m n,mrnr nrr nnrr n m nn z, w n rr r n,rrrrrr nnr n n n m nn z,r .rxm, mn . rvmn r nrnr,n rrr n n rmn.., n m v ..
  • nr n rn nrnmn r m nn m r zn m n mr rvn m vn m, m vnnr n mrnn -r n n nr n r n m n . nrn,. nrvn m nn n nm , m r nr ′ n nr.
  • vrnn.nm , -m .,nn vrrn n.nm m n .n., m r rn mn nr mr m rn. rn,-m nn,- m n,- ′ nr mn n nn-rrrn , rr,r′nnnnnn n r nr. r nr. ,nrr ′nnnnnnnn rrrn ′n nr.nm , n nn- rr, nnrn nn,r m mr n.
  • n vr nnzmn mmrn nn nr n r n.nmnwxnn. nr,nrn w n r rn r n rnr n. n r vr rnn m m rn -n mn-- mrn. m n nr vvrr r-,n.n.,mrnmrn.rn mm , rn n n, r vr r n nrnv.
  • nnmnr n
  • nn--mnzmrnr wn z m r n rnrn,-mnnrnr n rr. rr nmrn rn mnn m m m . ′ n nrn n '-- m m rr m , w mrnr w r n nrn rrm m '- nmrrnr,rn mn m.
  • rrrnn mnnr ′ n r ′′r n nrn n m mrr.n .,n n mrr n r n nn n nr ,r rr m m-n, wn ′- n n n w ′- m n.nm , ′rmn rnm n,rxm,′rmn mn nnnn.x n n n n , r nm ,nn,-m-nn mr nn z-nn,-x-nn, ,′r-nn,- nnn.
  • nnnnnnn vvnrn′ nrr .nm n vn m n .nm
  • m nnr mr rn wn n .n nn rm m , m m nn , rn r,nnr mm nn . rrm w. n rnnnn nzm ′ n r mr , , m , m , wn: , m, mnnnn m r.n . m ,. m-n- r m , n r nn r n wn.
  • z nn rvr nnnn mn nz n .., n nw m nz ,..,rn v.n .n vr xr n nr mn n m n mn n.rn wmr.mmnn m nz ,..n m r n n nnmmnm n, ,rn n m n nz n,.., m .., . nn n m m r n m n n,..,nrrn-.
  • r r,.., r -n m rv nrn m nrr rnrnm,..n nr. n r r , nrn ,,r,n , v,nm, mmnrn , n, mr ,nr r mmrn rn m r r ,n mn wnmmrn w n, rrrnnvnr. nnn w nn v nr n n n n rn nr,n..nr r n n nm , m n ,nnn.
  • rnmr n n rm r nnrn :,,n. n : m r wnnnnm.mn-, wrn r n n w m nnn mnmn-,rrmrn: n m mmn,. n nr mrn wrn n n mr n . v n nnn n rn n m ’nnn m mmn r, wrn n m m nnn rnnmmn. m-,rrmmrnrn: ’.
  • nn n n w, wnrnr : nrn r r’- n wnn , w nnrnr,nrm ’n n r r r rrnn w nrn n n, - nn ’-nrn ,, n rnrmmr r n nn n :-,n-, n m-,-, nmnm-n.,n wrn n’-nrn rnnmr r nn :, rm m mmn,,-,-,n-.
  • n w n n rnn rn rn ', mm - r,n rnz m n n,rvrm rn, n 'n. n rn r w m rnm mn rn m ,r .
  • wrrvrm rw w n n. n w _rrr rnrn nrn,n n n n wn n nw n n nx wrnr, w n w nr _nrrr vn. rrnr w r rnn nn r nrn. nn m rn n r n n m , r r mnmn : nm. .
  • nrrr w nrn w mzn rmv nrn,nn m n r r rn, w n r rn. ,n r n m n r .
  • r mznr mm w m n nnn:n.nn rn,n nn r w rrxm n.wr nm rw nrn,r n rnrnn r r m n, n.n n, mz vn mznrm r n n m nwn n rn rn wr nv n n n n w n rn nnnnnn r, rn . r mzn, n nnn ,rn rrrn w.
  • n' nrn wr n w n rn mzn.nn n wr rn,n w rnnw rrnnrwn,nnnnn, mmn r .n v rn w w -. nznnn mnr rn w w . rwr nn.rn rrn ,w-r.
  • nr nwr r mrn w rnnn vr mznrn rnnn wnn mnn r .n m n r . vr n wr nrnrn.nrmnrn.mzn rn, n rm rn mzn w nr n :n rr v .. xrmn . : – n r m w r rr mrv n ,,n n nv n n. n ' mzn.
  • nr n rn vrxr n -n nmnnmnnnmxrrnn nnmnnr .' nr - wnnrvmnnvmr nr ..rxm, n.nrn,n n 'n' nnnv r' : - r m' n nm n,nxr rmr n mr r -- . n , wr n xr n, r w rn n vr ru -u:n.
  • xrrm wn r.n rmnnrrmn ' n n w rv n ,.., xr nn xrmn nr -r- m-_- __ r_rm.mnrn, xwrxmrn.n mnnr , nv nr rrm rn n w ,x r wxrnnr, w w nmr rr wr nrnrrrrrmm n n.
  • wrr w mxr n nvrn wr nnmmnnrxnrTMnn.nnnvnr rvnr w r m mrmn rnnn r w. nnr mnr r xr nr ,mr wmn w mr.mr , _ :, w v rrrmnnrn -xr n wn mrmrr rnnmxrr, wn m.r.
  • nrrmn wvrr mr wr wrr.nr nrnznnrmmnwnnw nmn m. r m nnr mmrn m vnr w nn.m- - -r -rmn nrm nw rn wr rmnn vn m n , mr nr r nnr mrnn .

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Abstract

Described herein are compositions and methods for stabilizing RNA molecules. Also described herein a 5' and 3' untranslated regions for use in therapeutic and vaccine applications.

Description

w rnnmrrrr rrnnwnnr:.n, r n. , mnr,nr .rvn n . , n ., n..rvn n n rn n .nxmnrmnnnn n n w nm , nm “ nrn.xnmrr rrnnnr. .xm nz. ”, wr nnr, ,n r,. m., mzn,,n mm nrn mn n mr rn r m n mn rn, m.,-mn ,n m m mnnrn rn n r n nnn r nnrnvnvnr mmnr r r nxr n.' r nn' rnmmm nwnnrnnnn'rmn n ' n n. ' nn r n nn rnxr nn ' rmn w rnn nxr nn r r rn -rnrn nn,n m -. v mnxmrzrrnxrrm.nrn m vn v,nrrrrv,nmrn nr r mn rrnrnnr n nm mnnmwm mn .wvr, m- r n rrm r n,nwrnnnrnn.n,,r - mnr m n m n wmrv nrn n nr,n nn mn rmrrv r mnxrnnn mzvn xrnnn mrrrnr'nrnnrn rnn. '-nrn rrnnr r nn mn nmrrnn ''rn, '-nrn rn, wrn rrnn n n n '-nrnn rnrmr n :-,-,-,,-,- m r nn '-nrn r ,n-.nmmmn, n nrmmr r nnn n :, n n .nmmmn, ' ,-,-,n- n n -nrnn rnrmmr n n :,,-,,,,n.nm r nn mr n n mmn, '-nrn rnrm r nn :,n-, n,,, n mmn, '-nrn rn n.nm n , n n mrr n n ,, m r nn :, n,n.nrmmmrmnn,n'-nrn r:,n,mnr n mmn, n nr nn :-,.nm ,-,-,n- r wnn -,-, n nr nn :n- .nmmmn, n- r w n ,-,-,,-,-, mr n n.n wmmmn, m rr mmn, n n mr nnnrn.nm n nnn n rn n .nm mrn v n m nrrmr ''n m .nmmmmnm,n, mrn: nn nrnr m . n wnn, w rnnrn m nrn rn n n nrm r, r'- n w, wnrnr, r rr 'n n n n, wrn '-n nn rnrn n n n rnn rnrmmr r nnn '-nrn : r-n,-m,r-, n,-,-,nn-.nmnmmn n, .nmn rm r nn :,,-,-,n- nmmn, '-nrn rnmr n n :,,-,, n,,n.n rm r nn mr n n nmmmn, '-nrn rnrmmmnr, n'-nn :,n-, n,,,nn.nm n rn rnmr n n ,,, n,n.nmn rm r nn :, n rmmmn, '-nrn rnmr n mmn, n rnrnn :,,n.nm ,-,-,n- r w nn :-,-,-, n nr nn n:nn- .nmmmn, n- r w n .n ,-,-,,-,-, mr n n n wm, wmnmn, m rr nrn rn, 'n n n wrnr, r '- r rrn.nmmmn , wnrnr, n n 'n n, m nr wr,m wrn n r'-n rnr, nmrnm rmn. rnnn m n,n mrnrmr nrn n n w, wnrnr, r'- n: nn n nrm 'n n nrn rn wn, wn n r rrnn rnrn n n,nrnr, nrn r wrn '- n nrmr n n n n -,n-.nmmmrmnn,n'-nrn : r-n,m-r,-,,-, n n n n rm r n :,,-,-, nn rnmr n-.nmmmn, '-nrn rm r n nn n :,,n-,, n, n mmn, '-nrn rnm ,n.nm n n,n.nnmmmrrm n n -,,, n,r'-nrnnn rnmr:, nrnrnnnn :,n,,, n,n.nmnmmnr,m'- : r,n,mnr.n nmmmnn, n rm r nnn :-,-,-,,- nr n nn .nm ,-,n- r wn :-,-,-,m,m-n,,- n,n- r n wr nnn. n. rm nr wrwrmzn nmr rr n wn .n . :nrmwn v nrvn nrrr nr ..n-nvrvrwm:. wwnr rrnvr r m . xr n -wrvr vr .. , wxr n nrmz mnrnnnnrnr nnnmrn nv rnmnmrnn ,- rm n nm xnmnnr , x-x.r m nrm nnmrrn **n * r v.nxrn -.-n n n.rznrrm mn w mn r rvn rn. mnn r . w rn . w nmrnr w'' n -x. r n xrxrn nnn -rxn nnrr. w xr nxr rn nmr .n n r rnxr nn. -xn-xxrn rnr n nnn n. -x nr w n rrr n wr nmn . nr nmr n n rn vv nn m. r *. r n n. nnmrrn .- - nrzn rrm mn w m xr.n -rvn rn mnn r nmr nrn wr'' w .. w _ _ nr. m mrn r wrrnnrm r n w - r m - mmnz n . .n w nv , ,r w , n w r r n m w r nrzn . rzn r. m rrn.rrnmnnv.nmx.rrznn nrzn mr mn rrn .r rmrr. nr ' nzn rn n mnr. ' n nr w r-n nmx. mxn wn' wr r , wr m w mx. ., r nn r, r mrrn n rm xrn.v--rvn -r n. nrznmrnrm mn w m nnn . n w-n. xnrmr w w'' w rn r n.nmrnrmmnznrm n.m m r wr n .r .nn w - r m - w nv r nrzn . rz w , ,rm w xr n nrznr. m rn r r n rzn rn rrmnnv nm. . rrn mrm mnnr r. n vrn n nnn mnn rxr n nnmr mnnr . n wxr n nrmz r rv n nmr . r r n r rr.n wrv nrmz nrnnnwvnrnr_wr_ rnn vn nvnrwr v. rrm nn nr w n .nr ' ... rznnmmn wnr mrmnnnrrvmn m vr vnn w m m.- mn nvnnn vr . . wv mn n mnnn xr n.rn w nn nn n r rnnrm nn mr nnn m nn vn n.. n _ :nr mn r r vr. _ : . m vr nn mx rrnv m. nn nv n' n m r . _ :n _ : . n r v. mnnrn vrn nnrnnrnn.rnm mmmnm,rn m nrn rrnrm n ',' ,' ,n - .nm mr m rnmr nr mr m nmmn, mmn, m rnrmx w .nm rm wnr mr ,nr ,n n,r m rvnn,rn,rmrmnn nnnrn, ,.rnnrnr vmnrn n vmnn m , -n rnmmnnm n r rn. m , m , - m ,nrmmnn rnr vn. m n r rn nn vv. mrnvvr mv v vrnrr x,rmrrnr mnxmznr vr xr n mn rrnrnnrn n mn .mzn m xr r rm mnm mnn m n rrmrvmn vr n “nnr m . m nr n rnn n ”.,n 'n ’nrn rn . r n rnrnr n n , r nrn n nnr.n'r ,nnn m -mn nrr, wnnmmmmn m r n, m nn wnrm ’ n rn. r r 'nrn rnr rr.n rr mnnrnn nnrnnnnnxrr n. nnn r m r n n r mx ' r mx .. r- , w nnr w r-n n n mnn-nnnm wx r rm ' 'n rn mnx m mr n r n, w rrn rnn m n rn rr zrnnzn . m n, :- .n n nn- .,rnn m . rnv,nr n “ ” rmmnx mr r xr n n n vrnrn nn’r n “ ” , r r n n’ r nrrr n.,nnm ,nz,- m: -n ., , : .rn n. r rrnr nnnn n n mn rrmz- m nvrn n rn r rm . r n ,:- n rn mn. rnv,m mn r m nrr rn mn rnn m r r n rm nn rnrmz' ,nn rn . w nnr r r m n,rmr nrnrnrrnr'n rr w r. rn n m xrm nr n nrrr,n,n. ,nnr n nn , ' m nn., :- . mn w r m nrr nr nr nrrr rnr. n r,: n nn n.rxm, r mn -nnn mnnn ' rm vr r n w n, mn rr. r vrnn mn rv . . rm nn mnrnnr v m rrn w mrnnnn,:n ,n nrrmnn r rnmm-r m mnrrnnnr m rmnn .wvm m r ,n wn nrn w nrn. n r, rr n vr,n r n n mrvr,nxr r m rnr nrn .v' r rnrr n m mzn nnrr n v xr nvrrrn n vrn nn rrxmmnn rnvr n m nnnnm. v m m rm “m ”r nn mnn nxm rn rv vn. rn r nnwn rv nwnmrv n- n m n xr n,n-n,n,-nn rr r m nn nrz rxrnn -r wrrn r xm,n vn n, nrn r nm m .r rnnnn rnmrn,rrn rn rn . rm rn - vr nn,mmn. :-nrnn - rnxr nnrn r-rnnrnx,r.,nn mv ,w– . ,rnn v-rwvn n .n w vr - n - v n nmrrw r rn,mnmrn n vr r ., xmrmnn,m . wn r m v n n m r rnnr rvn,mnnr -rvnxr n rnvvnmmn r rn r w wrwr -r n. r rmn vr n.. vr rn n ' wrr nwn rn n xm w. nr nr wnr nr rn n n m w w r -n-rnn'n'm nn w n rrnr,nnn n ,r. m n n nv n r rmr nxr n w n rrr nv n.r n,rnrnn wrrnnn wz n rnrrrnn v. mrrnrrmnrr .r vr n m nrmnn , m wr nnr n.nrn mnmrnnn mn xr nv r.nrm' wrxr n w n nr m,n m r wrrnr wn nn- n mrn w nmr, n v n nnrn. r r xr n rn m nnnnxnr n wr n -rn rrrn vr , -rn , nm , ,r. m. -rrmn m w v rmn vr nnnrrr n mn wr n. wn nmn rr r nnrm n. r r nn n m n rr rn r n, rm “ ” rn nnnrrn m vrnnn r n m r n v n nm nrrnmnrv vn.rrrxrmr,n mmrmn,rnr n m nm rn v r wn , , , , m “ ” m , , , ,,,,,,,,,, , , , , rn n. r mrmn m m wr “”r “n” wn nnnn w rm “mrn” n “nnr “ mnr,” nn w mnn “nr mr,” “ n,” rnn.” n, n, n “,nmr” mnnn “n”nr “r,”. r,,,nrn : n,rmnn,, mnn n,mnn r. n.nr wr, “nr”r nnv r vrr “nrn ” n “ ” n mmr rr.nmnn,rn,n mmr r v wnnw ,,, mn nn, nn,r m nn, m,rrr mmr r v rr. ,”r “n ”n n “mr,” “n n r n,nnrnnrx rr rwr n. nnrm mrn, “mr”n “mr”, “,vn w”rn “nmrrn” vn, “v”n “”, “nn”n m n “n ”r “nn nrmnn, “n ” rnvrn-nn”nn wnrnmrnnnm, n “nnn”n “nn” mnrr rmn n x nn r rmnr r rmn. nm r rm “ r rnn nx “nnmrnn” m.”mmnmnn mn “nnxn nrm “n”nn”r wnrn nr mr m n nv rmr mr r wr “nn”nnrm nn, “n m r. mnnn,nm , wvrw r ”n “n ” “nn”n mnr rr “rnn.” , r mn m mnr,n n r r rmrnrn mr. n “nmmn,” “nmmn,” “ mmn,” “rn,r” “m rmn,”m “mmnm,” “rnmmn,” “n n r r ,” “ mn”, “n ,” “n ,” “ ,” r ,” “rn ,” “n n ,” “rr r “m ”rmnnr mn r r r,rrr rnr rr. n,nnn wrn rnnn n rr r r,rnrr n,r nrrr r mrrn r mnmn v nn.rrrmr,nnr mr mnnr mr rrm “. rnmn”rn “rnn”rn vrn rmn n “rm,”r v r r. rm “mrv,” v “rnr r”rn vrn rmn n mr nr rnr,r rmn “rrrnr m . rv w n,” “nr,”r “nr” r v m,r v nmrrnmrr wrm. rrrnxm,,nnr,rn,nr, n, n,m,r v nr. rrn,nr n, , rmn n mn nr w n,rrnrr m nr nn, , n,m,r v nr mnnnr r rrznrmr nnrr nr m rmnr m,r v nrnr mn.mn n, , n, xrn rm r “,” nrnn, mn n m n ,nn nrmn .rxnm, n nn, n xrn r . rn, rmnnn,r mr , n n rxr ′ n “--rxrrn ” mn nmn, nnm rn ,nnn,nr.rn , rm, “n , rmnnr ,n m . rn r ,” nnnrn, m nn n m n nn nrr r--m rn nn, n, r mr, rn r . .rxm, nnn, n w rxr rn, rm “rn ” mn n mnr m ′ n --rrn r.nn , rrn. nwn rn nr rnr w n nrn rn′- , n r , m nr nn ′ . nmn, n,n ′nrn rn′- n rn , ,nnnm , rn r ,nn , rr., mnnr , m -mn , ,n m m rnnmr rn, w nmn, n r nm mrvrnm nnmrrnnnn mmrm,rnnn mmmmn., nn- mn.rxm,nn , m r n n mnnnnmn vn n r nrzn n n rr mn - rn vr vmmnzn w . m vn . mnr rr n vrrnr n n “rm n”mn n m n rmnnr m ,.., n . “m ”r “m ” rr n nrr n m m ,vn n n, n, n, rnnnnr mr n mr nr rrn . ′n rr n nn-n mr nrn n ,r n ,r′nnr.nnn , m nn n m n n r nr mrrn n .rxm, m r mnn rrvr nr n n .rxm, n rrn r nn rnnr nn n,r n n nnn nnn-r n n . rn nr n rxn .rxmnr, n , m nz w-m rnnn n. rnrn nr n r n r. r rnrn n nr-rnrwn .nm , r n vrrnrnn mrn, wrn r rrn n nn xrn .nm , . r n,nr r-r n ,r-mn rmrrnnnwrmn, vn “r rn rn,” “ m. ,” rrr nn “,rrm” r n “wr nr-n” m mr “nv” , w- vrn rnr rm ,wvr.nm r, m rn ,n mnmmn r r m nr n rn”r “n. rm r v m nrn . “m m rmr ”r “vrn” rr rnr w rnr,r.rnmmn n, r w r w- n m vrnnr,nz mn vrnrnr m v rnn. nmrnr m vr mnrv r m r w r n v n vr rnn rn w- mnnnrnn r r , mmnn. r rn r n,nnr rrn nvw- r rmnnm rn. rn m r rm rnm w nv,r nmnn,rxrnn xr n m ,r - mnn rmn vnr m .nr r ,rr n ..,nnnr vrrnrrn n n n nnn w mnr. rm “rmnn” m n r rmr n nm m ,nn mnnr rr r nr m . n vrrr r mrm “r,”rn r mrr, n vr mr,rr r m n r rmnn n rr rn,r m.., wn rm .., wnm nz.r m rrrr n n mnr n vr,mnnnmrn rr mn m nm n wr,n r “ ” r mnrm nnr .rvr,n “ n rmn”r “ ” nrnrnnrmnnr n nrrr rrrn rmnnr n mn mvrm nr r nnrvnn.,rrxm,r r nmr rnrnvrnmnmx nn “ mr,” rn nxrn nn “-nv.”nvnrnm n nxn n r rm, nv n ,rxm, n w n nr. rrr rnr,n n n, r n,n n . rr rrnnrnr w r r “mr” r mr,r m m rn rm n nn rn-nn n rnrm , nn ′n′nrn rn ,n n -mn n v′rrnrrrnv m′. nn-.n mr mr r mrrn r n rm m nnnv mz m mn ,rnnnrrn,nmmnn. “nrr-m mn” mn r n w r, mmmrnnrm rrrrv,n v nnm mrv wrnr nnn n.nnrnn, mn n, wn rrmmr nrvrnnwnvnr mn.rnnnrrn nr w rnn m r v ′ , r mnrn r m v .n n-,′-w n n , w rnn ,nnzm rv r mr r r . w n n m rn n v nnrnnrrnrnn m n n , rr v n vmn “ n-nnr m m.nxmnr n ”.r, m xr nn rn nrn nnmznn n m,rnn nrr ,r n nrn-v m m .rm n “-mn m”nr. n rv mn nnvr n nnnnn vrn r . r rrvnnnrnrrm r wn ,vrrr mnnnnvr nmnmnnxr nnr.r m. wn-rvr m nnnr rr rnn ′n, m mn,m rnr m nn,nn r m. r wr r rn nn n r,nnnrrmrv n n r r n nmmn rnnvrm,x. n mrrnmrvr,r, rmn m rrnn zn m w nrn n . nr r r n,r r n w mnnrmnn,nnnx.r mnn mmn , rnrmmn- m nrr mr rnmr n m n -m nn nrrn m.n r rn n '-rmn r r .., n rn,rnn rn '-rmn r r n..,’- , nnn rn zn r n..,’- , n'- rn,n '- rnrn.nmmmn, m rnrrn - rn mz nnn ..,n '- .nm , m m x rm n n.nr mmrmnrnm n n nn ' rr, nrmnn nn, m, m m rn nr n nn.nn rn n , mn nnr, m rrn mrnvnnmnnnrnv.. n,nrnv nn-n.rxm, '- zn r'--m n nr n rn ,nnvr mn,n nrnv n - ,'-,'-,r rn m - rn..,-m rn..,-mxrn, ..,-m - rn,nr- n n-mnm. nr mr ,m,n, nnr n nr mr ,n r. : r mnmnn rrr m mr rv : mr nmr r nn . rnn nrnmnnr rrr. nr mr , ,nmn r,wr: r : rrm : :, :,:,:r,: m rvn :,:,:,:,:,:,: ,: ,r:.nrn,:m,:,m:n,:,:,:, m rm : :.nrmmn, : r rm, : r :.rxm, : r m .: , .:, .:,: .:, mnn m.:, ,n mr .:.rxm nn nnrn, n mn: r mnnr mnr, n.r:. nnrr,n n n,mrn,r mn.nnmmn, r n n ,nrnnmn'-n,,,,nr rnvrmmr, nr'-r,rn mnn n nn, nn, n, rn,r mnn m. , m rn mn nr mr rv nr rnrnn, w mr rrnnnr n nr .rnxmnnmmn rn n w m vr xr ,r nrn-mn v mnr m mx r r nn n w mrnnn vv. rv rrnnnr m. rnv mnr , n rnr n,nr r rnn n ,nrn n , w r mmn v xrmn n. mzn m x nn mrvmn vr mnn m m .n ’r m nrn rnn n “nnr”,n nn ’rnnrnn rn . rn n , w mmn m rnrn. ’ nn -m n ,nnmmn rn. rn r ,n m n rr ’ . ’ nvvnn,r m nn wnrmn nmx. n nn nnn rrmn r- ’ r mrrmr, r-n nmx n nr rnnrmrmx, nn rr mrn r m m -n nrnm mxn nrm r m. rrnv n , n , n , mr m ..,r n nn n m nrrrmn,nn r. m r,r nrn n , n rn .., nn r m n.nrnmmn,rn..,nr nr.rnrrnn n , r,n nrn ,..r,n rnn rn r m rn rn , n '-, r nrn rn,'-,r n n ,r nrn mr mr. m .rxmr,nn mr mrr mr n n nrm r..,n rrmn,rnnr mrr ,,, m rn m,rn vnr rmn r m n nrm rn n n m rnvn nn rnr.nmnn, nn n ,,,,r rnr r r, wrn m +,+,+ nn mnn+,+,+,+, r+n,++r,+r+nr+n+r. rr mx vr nn nnrn . n .., n w r n n rnr n r n n n r rrn m n r .nrn m '-rn'-rmn n n n n n nrn '-rn rn.nmmmn, rnv n mnr.n r nnv m nnrm rn r nnr mr n ,.., r n nn,nrvnnrn . nnr mr ,,rrn ,rm ,r.,rm ,rm ,rm ,rmrm ,rmm ,r,rm ,rm ,rm ,rm ,rm ,rmm ,,rrm ,rm ,rm ,rm ,rm ,rmm ,,rrm ,rm ,rm ,r m ,r m ,rm ,rm ,rmm ,r,mr ,rm ,rm ,rm , ,rm m,nrm,rm . ,rm ,rm rn n r rn n wn nnr . n rmnn n m nn mnmm zrn .,,,,r. n ,rnnrvnnrn mxmm rnv rnv n , , rnv n ,rnv n rn, n , rnv n ,r v xm, rnv n .r r nn m nnnrnvrmn nrnvr ,.nmmrmn,rn,n , r w, , r ..,- r. rnvr n r nmrnv vn nrn..,,r,rr mrrn n rnr n rrr.nmrnnm,n v,n n, r, wn,rnv,n..,-r nnn rnv nn r mnv . r r m n nn rrrn rr. n vn rnrr..,,,r mrn rnnmnn wn, n n n.. n n nnnmmnn nn mmn rnn nr, mxrnr . r n n, vnnr r rn rnn r rn rnmmr .,nr rmnnr r nnrnrn -, -, nmmmn, m m n. n m mrnr mr rnv rnv nr n. n. rn nv n nn n nn n rmnr rvv r. n m rnnn ..rnr nn,r,mn,n n. n n rr w,nn, rv n m vnnn r r r n n . r,..,nr r mr nr mn-nn r m mn ,rxm,n rx, x,nr nnnnn nm ,r, ,x, r n. r mr rn rnx nnr n nnm nmmnvn,n nrnvrnn rnvr.xmr -n rn ,-z-r,-z-r rn,rn- r ,-- rn, ,---z-r,--r ,- mn -r,--r -- rn, -rx -r ,- m ..,--r r-rm-r,-m-rm,- mmx-,r-mr,r -x m,r -x m r rxrxmx-m-r m, -rxm rn,- mm,-mxrr m,-rxrxm-r m r mm ,- nm-rmm,-mxrnm---r m mnmmn--m-r---rmnnmm,,-m-mmnmmnm-r-mnm,- mnm ,-rmm-r nm,-rx -n-r mnm,-rxm mnm---r m mnm-r rn- r,-rnm mnm,-rn-r,- rnm--- -r xm,-rnm- rn,- m,..,vn r nxm ,x-rmnnm,-m---- rrnn,m-m,-m-r-- -m-r-mr,-m--- rnm ,---m- rn, rn, n--m-m,----m- rn, -m--z- r rn,,- rr-,-zm--rrnr,m,rr , - r rn, -mx -- rr, m -r, -mx---r, - mn-x- rn,-mx--- rn,-m- rn,-- ,-rxnrnrmnm ,-m---mn--rxr rn nm ,,'--m-rnrmnm,- nnmnm --r mxrnm-'--m-r m,--'--m-rn m,- m rnnmm,-rxmnmmmm, -rmm-'-- ,'--m-rnmm, nm-'--m-rnmnmm, --r,xmn - nnmnm -'--m-rnnmm, r,-rmm--,--rmxvn-r,-rm rxm - -mx---r -r,-rxm---r,-nm-r, n nnm nm,nm-n- v,--r nn nnmnr rnv n. nrnv n.xmr n, n, n -z- n,-z- n ,-m--mnm-,-nmm-,n- - n ,-rm- - n,-rxm- n m,-mm,- nn,.rr.,- n,rr- n,-- n , - n, -- ---m- n,-- n,-m---mz- - n, zn,r---m--z- m-z rn,-z---z rn,- n,-z-z rn,- -m- n,-mx nz,-rn,-mx- n,-mx- n ,,'--m- nmm,-m-x'----mm- n, ,'--m nmm,-rm-'--m- n -m,n m,rm- nmm,-- n,-rx- n,--zr ,,'-- n--z - n, n nnm- nmnm.nvn,n nrnv nnnrnv nn.xmr r n -mn-rn,-mn- rnn,.,.,--mnr-rnrn,,--mmnn----m-r-nr..,-mn--r-rn,-- -z--z-nn,-z n,-z-nn,-z-nn, ,- --mn-rn,-z--z--mn-rn,-z- nnmnmr,n,-m-z---nzn-,m-m,n-mrn,--m-m--nnnnmm,m-m,-- rnxn-nnnnnn,-m -- nn-nn m , -- m ,-nrm-n,n-m,--rn--rx nn nn m--rnrm-nnm ,-m -r-rmn-nn ,- m ,,-m-nnm ,-rxnrv rm-rmn-nn --mm--nn-,r-mxnrv-rnnm,--mnnx-mnnn,,---n-n,n′nnn,, nn m, ,′--m-nnmm, ,,′--r --m- mm,,′--m-nnmm,′--r nn m-rnn mn--m-rn,--nn,-z-nn,'-- ,- '--r-nn, --mn-n r-nn,'--nn, -rm-nn,n-rx xnn -nn,,-m-nn, nmmmn,m n-nn. n n n nrnv nn.xmrnnm, wnm,v mnnw mnmnnn nn,-m- wnm, w n ,rxw nm,-,mrxw-wnm-, nrm rxw n *,- n , x n , - n , z-nn, n , -z-nnr ,-mnm--z- mnn- nmn,-n- z--z-nn,--nn,---nnr,r n+,- nn,-m-nnm,-- z-nn,---z--z- nn,-m-nnm -m-nn,-m-nn,-mx- m,,-m-nnm,,-m, -nnm,,-m-nn nn,-m--x-nn ,,-m-nnm,,,-x- ,-m---nn ,-m---nn, -m---nn, -m-nn ,--nn,′--m-nnm,-m-′- ′--m-nmm,,-m-′--m-nnm m,-m- m-nnm,n,′-m-mm,-n,-nmmm-,′-n-m---nnnn,-m-m,m-,n′-- n′--r n n, rn r. rm nv n n n nnn rn, nnn,,rnnr,rmnn.rxm, n nnrnv n n nn,nr,xrm,,r xnn.nnrmmn, ,nn rz,-rmn n,-rm-rrnnnn rvv n, xnn, xnn,-mnnn,- -m-,-rxm nnn nn,-r n r rmvvn nrnnrvnvn,- rn,n-mnm,n-rn- rn,,--rrn,-r n.. n,-zr, ,- ,-rxn r ,-rm,-mn,- -rm,-rrm - nnn nn,- r r -m nn,-znnnrn--znnr,nznnn,,--mznnnnn znn,znn,-znn, -zn ,-mz,-,,rz n,rz,-rmn, rmn,rzn--nnn,,,,--rzzrn,mz,-rzn, z,- n r n rnn,rznr,,rzn. n rrnv nrrvv r ,,,r, r rr ..,-z n ,..,n nnrnnn , n mn. nv m mn '- rr. '- rr m nnvrn nnrxrnnrn n nn nrn nmnr, w rnn r wn-n n rm mr m . rr rmvn'-rrnnrn rmv r xm '-r nnnn m wn n. n mrmn m '-n nrn'--rnr n n n n.n '- r n '-rmn m nr n-m-n r . rn r m rmn nrnrmnrn n '- r n 'n n m n rr m-mr .'n- n mr ,r n v n rn n m nrn m nn- mr ,rr n. rvnn nn nrn n -.z rrrr mr rrr v '--' r rn ,rnv n n n n r n.rxm, n nnzmrmw mnn rr'nw, m w--nn n rn n rnvrnnn nr r n n '-- '. n- n . n mrnn , -mr nmn,n m n r r '-rmnnr'-nr '-- n n '-rxr r. nmn'- nrr n nrn'-, w n mrnr m r. ,m n ,rrrrnrrn n n ,m nn, w- n , rrm nr.., nn ,r '- nrm rr, w rnn nz.nnn mn m.r.x.,m nn-,nzmn-vrrnzm nnw nnn '-'-r r, w n nnnnn-m r w '--m rnn nn-'-r -'-nn, m-'m-, wr m..,,'v--m- n '--m' '. '- m r,n n mn '-rmn n n r..,,nn -n'--m nnrv rm n m . n .., m .nrxmr m, wn m '--m mmr nnn..,,' mr nn, --m-nn-'-r -'- n m-. n mn m nr.n nn-mnxnm, rn r r r n r w r n n.,,, rr w rnrn n rrn. nrr n rnnv,nwnnnr mnr r--rrn.nx --rnx n nn-mnnxm-- nrn,x..,- vr 'n --rnx -m'- ' r n n m nzn n rrn wrr.rrn n mr :- n n nnrr rrn.n rnn, n n. rn r -rrm nx vrrnrn rnn, wr nmn n n nnn rr r mrnr n rmnn . , w r nnn,n rrmnn '- rr nrn nmn rnrn mnr, m r rnv nn r mr . -rnrn,n "mnzrm,nnr"r rrnr mrr n'- mrrrrrr m.m, rn, r nn,nnn r w r. , "mr nrrr r rrnv nnn, w-, nrr "rnr r rr mr n rrn rrr,r w n,nr rrnnnn, w-, nr,r rn rrm r .n-mnxm mr n '- rr nr mr n rn rr w,m n nn n n rn,vnn nr r 'nrn,nr -, r '-nn , w-,- n, mr n '- rrnwnn rr r n nnrzmrn rmn '-n'-r-mr.rnrxrm,n rzmmnnn n nn '- '-r n wn '-rmn n nr n'-rnn n wrn nnnnn-m nn rmmn nrr. n r nn '--m. rr ,n r vn rrn-n rrn n-mn, r r' n rrnw mmr n, mr,.., m' ', ,m'nn'r. rxmr rrn ,n m m,,'m'm'm ,m'- 'mm rnv n mm,' . r mr -rnrn,n nr rxm wnn, nrn n m mn . n nn vrrnrn r n.'-rmn m n r n .'-rmn mn nnn.n nnnn rnn,-m-nn,'-r-nn,- n n mn-nn, z-nn,-x-nn,- nn m -'nn,n-z-nn.nm , n nn ,rnnr-. m n n- nn . m n'- m ' ,nnr nr nr m - mn , nm , nnrr wn m, n: m n '-nr'- n r rn w m n r mmn, mr rnnxn r m rr,r m n r r '- m rv nn n m. m rr n rnn rnn n m..’- m'- mrnn nnn rnnn, rnnnn m nn, m mrnmrznnnn. mnnrnnnmnznnnr mr rnrrrm rn, rnr n rnrn. n mr mr mrrnnrn m.,'- w r r , rrnmn m rn mv, mzn mnr mr v n,nr- m m. n r '- m vn r rmrn '- m z wrnnr mr n r rvnn mnnrmn,nn,,r.'- m n-mz,r m mrnr rmn. m , nm , nm. n. mn n n r n n rmn nm m '-rv n rn.., '- '-n n rn. nn-mnxm, m m nm .., r rn.nm ,n m n mrn n .wm nn-m. m m n nrmn rn nrn rn..,' nxm, m m wnnn nm- n nrmn rn.nm , m w '- zn rn m z n '- zn rn.., n r,nnn nnnrmnn n . wn rr n, m,n w nn nnnrnrmnn- n mn w.n '-r m m z nrnn rn, mn, w n nrvnnrn n . nn n rmn n'-nxnm m,', z '--mn ,--n ,'-rn '- xn n nwnn rnr r rn ,n r rnv rn r mn nm,.n- rmnnn, m n m m rnrr - r,nr'- rr. nnn rnmrn.nnr- rn n mnn. nnrmnn mn nn, n rn r nm ,nm n'- rr. '- rr mn , m rn mnr mrnnnrnwnrn rr.nn.m nn-m,nnxmrv, nmr nn-m rnn mxmn, m rnn mn m mn- r rnn..n n mn mn.n n n m- n - rnr n - rnrnrnn n, n nnr nm r.n r , n n m r nnnrrmn rnr n nn m nrnrr n m n - n nnr n m n - rrnn.nm , n m rmrnnrrmnr.n r n n nnr nm n - rnr rn,nnn rnrnnnr m n n mmn nn. n m m mmrnnr nnr n nn. rvv r. n mr m nn nn 'rn r rn n .rn r n,n n nn nrn rn nrm m n - m . nr m m nr ' mm rrnrn, '-n rnr v r r-r,x.n-nmr n nn n . n.n - rnn,n - rn wn n r n rn mr.rnv rnvn rnv rn r n nrn,.nnnr - rn rn n nn.nnrmmnmmn, - nmmn.,nnnrmmn, n n , .nnrm nn mn,.nnnr mm n .nnrmmn, n n .nnr nn, n.n n .nnrmmn, n mmn, nrmmn, n n .nnr n n.nnr n .nnrmmn, n nrmmn, n mmn n, n n .n n .nnrmmn .nnrmmn, n nrmmn, n n, .nnn n .n n .nnrmmn, n rmmn, n nrmmn, n n .nnrm n .n n .nnrmmn, n m nn, n.n nrmmn, n n .nnrmmn, n nrm nm .nnrmmn, n n .n n n, nn .nn n .nnrmmn, n .nnrmmn, nrmmn, nn mmn, n n .nnrmmn.nnr n .nnrm , n nr mn, n n .n n mmn, nn . n .nnrmmn, n .nnrmmn,nnrmmn, n mmn, n nn .nnrm n .nnr n n .nmnn, - rn m mn n, n, rn.n, n nn nnrnv n m r n nrnnn, - rn m ,,,,, r , - rnnnrnv n m r rn.nm n . n m n rnvn nn r vr rnv n , n r r rr rn rnnv nrnv n m.rn rn n mr xr rm rnv m rn w nv n r rnv n ..,rn ,,,,r r - rn - rn m ,,,, n rnrnnrnnv n r. - rn m nx, - rn m ,,,,,n w n.n n nrr n nr, mn,,r-r mr nrn ,nnrnn nr n n r mn. nnrn m nnxr n. nnrn r- nr n w nr nn rn mnrnvr m m. nn-mnxm, m mn n nmn nn r nnn -nnrn nnnnrr nrrn nnnrnn mnr nnn. n-nnnrr.nn, m n m m n r rmn - rn r '-nn rnv n '- nr .rn nxrmnn n n rvn n n nr-rnnnn. nn-mnxm,rr,n rn,xrmrn, mr, nv nnnnrnnrn r nn n r m rn nn n. n .nrn , - rn m rr w nrnnnr wn n r, - rn n rrnn .n wrn nn nmxn m r r n'-'xmn , - rn m n rn nmnn,n n. r m mn - r. -r nnnn nrr .rnn n n rm -r n - rn. r nn mmn, -r nrr n rrmrnn - m v m r ,rnr n - r r nrnr nrvmnn. n vr - rn n n.nm , m mn n- rnn mn m z n '- zn rn. m w - rn mrr wn -'--rrr m.nrrrn, m'- mrnr.nm-- r. '-rzn.n rnr w m, '- zn rz mn wn m - w rnr, r-n- '-xrrnn, '-nxrmnn,n n'-xnn',-xnn r n, xn , ','- '-xmn, ','- x xnn,','- xrn,','- -mnn,',.'-nxrn,n m,','- xmn,'-xn ,rn - r m z nrn w 'n-rn rnr -- rvnnrn n .n rnn, mn w n - rnr -n ,''---- rxnnr n rmn n m ,n,','- z rrnxnv n ’--nmn nnn ,'- r rn. wnn rnr nnnnmmnr,rm n mnr m. nnrnmr . rm nnr nr n nnr m n nnr . mnn, r nnr mnnnnr mr n mr nrr. rmn. m m n rnnr vr r,rrnrrr,nnrr mrmnn.mr,x,xn, , m r r r nrr,rnr rrm n nx r rmnn mn. ,rxm, rm n m r n r nnr m n m n. r.rxm, m n rnr mr nr n r r, ,rn,rvr r nrr . mrr rn mmm' vrrmr rrr.rn nnr m rnrrnr nrnz rnrn. n,r z m n m n rrvrnrrrrr.n n r nrr m rr rn n,nrxm,rrrnrrvr r r, , n, , .., zr vr rn,r mrr rnn n .nrnmmn, mn n m r nr. rm n mnrnn wn rvr vrrr mn.mnmmnvmr.nmmn,mmmn,n m n vr m n.nmmmnm, n m n vr m m n m n mn mnmn n.mmn r mr mnn r rn.nm mnn., n rm n rn n nnr mn nr mn mnnnnr mr n nn,rnr mrr nrr , n . m n r r nrnrr,rn. mn mxn, ,v ,r r r nr n ,x, r rrm n m r mr mn.mr,,rxm, nx rrr r nrr rnn r rm n m rmnn mnrm. nmmmn,rxm, mr m n.nm .rrmr mn rm., nmrm mn n , mnrnr , nrr, mm, r, rm, r, rn, rn, n,,n, rn, n, n, nmn, xm, r , m r , rnr,n r .r , mr mn, - r n,, n vn mr -- , - -- , , , - , ,- - ,- r n- , ,- -- -r n, ,- -- --, , nr,--,- , ,- -- rxr m r , n ,r-n, --n , , nr, r r, rm,-mm , rx rn, n , r r, n , nn r n, n r nvnr ,,vnvnnx ,,vvnnrr, vn vnrrn n r , ,,rxxn, rn, rn,rvz ,rxr ,rxm , , r, r, nr m m r , mr r , m r m r , m r , rm r ,, nmxmrr,,m m r , r,, xnnnr ,mr, rr r , r r x nn,mrrnn mmxrr xm n, xmr, xmn, r r, , vr , --r n,rm n rn,r , rmrn , -m--xzn , -- - , -xz -xzn r nrn ,n r. v n mn , r nm ,nnrn.., mn rmmmmn, rn .., n rn n ,mrn..,mrrmn,, rnr,rnrvxv .., xrn, .., n, mwr,rmn, n,rnrm,rmmrx,n m,r nn rznn, mn,mrx,rr, , mn m, n, rnn,rnn, n, r r,nrnn m, nnxn, wnnr nnnr,nnrn..r, r . .., n, mrn,vnn,r rr . m nn mrnr mrnnz .rxm, r n z wnnr , wnx nznrrr n nn, mnr n r n.nr r, r m rnzn n wnr mrr n n mmrn wmnn, r rnn,rmn. r m n vr,mr mnr,n mmnrn.rmnnnrr wnnwnnn r. nr nnrmn mmnn, nnr mn n n r mr rm n.rxm, nnr mn n m ,nr mrvn xnr rnrn , n r v n, , rn m, n, rn, nn, nnn,rmmrn mrn ,n n r,,r ,nr nrv nmv,n ,r, nnrrm. rrr ....,, v x, xn rnn mrnn mr , x n rn , rn mn r n,rnr ,rn mnm , rn mn , x rn r,..,r mn , mn r n , x n x n , xm rn r, x r r..,r,n ,,xrn r r, n r r , vn-rrn, n,.., x nrnmn , m , m , , , mnrr,, mrnrm r,, , , rmnmrm, r. nznm r, m,nrmnn nxmn,rr rrvvv mnnr,n,mrr nrmrvv,,nnxnn, rxmrvv,nxnrnrv,v,r nrmrvv,,nr rrrvv. r m, rxn, rx n,r m,nr , m m ,rn , r, m m r , m r, m , nmnr,nr m,r.xm m n nn m , ,mr , m ,nrr,,mm ,, rr nrm,n,rrnznmmr.x,mnznnmmrr,rnrvvn , rm, rnmr,rxn,r z ,rn,r, , rn,xn, n,rr,rxn, ,nmrr nr, mr,n,nx n,n rrvvn , r n ,nrmr.xm nn r rn, r nm , rn, m rn, rn, mnz,nz ,rxnz , mnz, mr,n , r n mrn,nrr .xm rrvv mn, nm,,rn, n ,nz ,n,n xm rrvvnn, rxnz,nr n . , - , r nm , vmn, vmn, vmn nrrn,.rrr, , r r , r ,r , , rxm m ,rvvn , r nm , r, r n , nmn,rmm,r rxn, , rx , m , m m , mr r , , m rnm , m m , ™, ™,nr .nxm,rr r ,vn , rx n r rx n rn xm r rrxmn. r n, n nrn ,n,r nm ,r r n, mr, mr, m nmmnmr, mrn, - n , m r , m, m, m,nm,rn, , mvn,nn , n m , mr m , r ,r m n, mx mxr, , mm, ,m mr, m , m mxr, m n m r, mr , mrn, m , m , mmxr,r,mmn m , mn , mnmrx,mn ,mn-n r.., n n,nr mrx,n ,rn-r wr, nmm'mnn,, r,nrmnnr. r .nmmmmn,nnrn mrrn ,n r r.nmmmmnnn,nr m rrnrn rnr n mrm, r mr m nrr r .nm vmmnmn..,, vmn mr vmnrr r.r r mn m r.., n m n..n, nnrvvnn r. rr rr m vmrnn r.rxm, nn r rr . rn,nrm “rrrr n n rn nnnr m . n rn, “r ” rr rn r .nmmmn, ”rrr r rr nn mmn, rr r.nmmmn, .nm nn r.nmm rr n mn, rr - r. r rvmmnmmmnn, rr m nn m v rnn.rnn, nn r mrrnrn . rrr mr vrn nn wr mr nn rrn nnr.nnr,nnn m n m nnr mr mr ,rxm, m . m n nmnr,m nn-mnr,r nn n, m,rm nnn-m,nn rn, ,- x rnnmnn.r , m mr n, m ,r m ,m ,r , r , , ,n , -nn ,r nnn,r,n ,rxn , nn , n , n mmrn.nmmmnn, .r r n mr nv r mmnrn.. nnr wnr mmrn. n mmrnn , rrnr r r n -nnnm wnr mrmn.., mmrnrmn,..,v n.., r nn nrr nr w mrmn r .n-nr rnn,x n, zn,n m nn nnn n nnz wnrr nm .nmmmn, nr n w n r-n nr mr n ..,n rr r nnrn m,r n r w r n.nr nnxr nnz.n rr nnr r- z r nnr m n n mmnrnrnnnzn rnnrnn n nnr m n mmnr r rnrmn m .., . n , rn nnm , r rn, n, -nmn, n n , r,n . mmn, rnn ,n rnnnvmn.nm r vrn . nnnn mr .., nrnnmrn mrn mrrrz vr m .rxm, xmn mr nz r rnnnn rn mr m nmr.., nmrrn m . mnm rnr nm rn m z rmnr z.nrr zm n. zrn vrnnrmn ,vrn,r rr n mr m rr , r , m n z n z, rnx, mr n. mnz m wn nmn nm,.., nm m nm, rn n.m,rx nmm,, nm, m nnm,z n mm, nrm,m m n,m, nm, nm, nm, nm, nm, n nm, nm, nm, nm, nm, nm, rm nm, n nmm, nm,r nm n,m.rnmmm nmmn, m nmnz m nm,rm nm nm,rm n,rm nm nm nm,rm nm nm,rm nm,rm nm,rm nm nm,rm nm m n nm nm nm,rm nm nm,rm nm,rmrm nm nm,rrm nm m nm nm, mmn, mnz m rm nm .n nm.rn r rmmn, mnz m nm.nrmmn n z m , mn m nm. n rv mn. rnx m m ..,mn ,.., r z r n nnr . r n. mn.v rnxnrn nrrwr z .,.,.,.,.,.,.,r.,n.x,r.m,.,.,.,..,,.., .,.,.,.,.,.,.,r ,.,nx m ..nmmmn, r z rnm . .. nmnrn. wrx rmv, z m wrn, mn vrr nv,rrn rnrr n r., m mnrn r. mnr nr w , ,n r m + mn,rmmmmn, z n m rm - + m,rm - m + - m m + m,rm - m m - m,rm - m,rm - m m,rm - m,rm - m + m, + m,rm - m + m,rm m r +m m - m + m,rm - m m + m,rm m,rm + m m + m,rm + m,rm + m + m,rrm ,rm + m n n n + m + m. mn r n r nrr r rrrn, rrvr n mnnr rrw w xmr, .., . n vn.nn m mnrn,r nmrn mn r nrr n nnnn rn vnr rn rrn nnr wnr mr r nnrrrrn..rn m mr mnr rn, n n n., rn nn.r nnr r rxm , , , , , , , ,rr, , m, , , , , ,r .nmmmn, n n , , , .nrnmmn n m m n m, n n n m . rm n ,m, rnr mr n.rxm, m m n r rn mr vvn n. ,m,r nn rm nmr n z,n rn,rn,rn. rm n w rnr nrmm mrn nnr m mn nr mrm mrmnnn.rm m n xm, rm m n mn nr mr nnr .r nr mr nnr nnn r mrm mrn r .rm m n mrrr mnr rn r nr n rxnrmrnnr mnnrn nr mrr rrmn.nr rv r rm m nn n xn,.,.rnnxrm,nnm,nnm' nn,nmrr,, .rmnv,n rnnnnvnrnnrxnn m nn r rnnnrnrm m nmm n w,xn r mrmrnn r nr mrm mrn rm n r.nmxnrm rnrn m nm w mnn rm mr m r nrn rm n mnn w mnn . nr rrw r rrnnmmmn m,nrr v mrmxnrmr rnmrnn mn m .rxm, nr mrxnr rnrn m m n , , , ,r mr rm nvnn.nmmm , rm xn , , ,n, m,nnr v,rrnr r..nnmmmmn,nxn rvr n nr mnrn.nmmmn,nxn rv n r.nmmmn,nx mmn,nxn rm rm , r n m nr n nr n rm , r rm , mr,nrnnn rm . vmn nr mrm xn,nrnr mr nnr , nr mr rm w rn r wn vrnrnn rm m nn rn r nrr n,nnnn rn n,z,nrnn mnr. w xm, rm m wn m mmr wn n w w nr mr nnr . nrxm, rn. m n m mr wn. m mr n wv nr mrm n..,.r,n,m.,, ,r. wv. m n rmrn r,rr rr nnr nr rm nr mrr °rw znrr nrmn.., n °rwn - °nr, - °mrrwn - ° - °, - °, - ° .., - °, - °, - °, xm, rm, - °, -m °, -n °,m -r °n, -n °r, - °, - °r - °.r nr mr nnr nr .., v mrm mrn rr nrmn,rxm, - °, zn rrr °,r - °.n - °, - °, - °, - °, - nrnnmr mn,nn rv r m nrn rn nnr nrrm mmnnnmr mrn °rwr, mrr wn - °n °mrrwrn °, - - °, ° -n °, - - °,.., - °, - °, - °, - °, - °, - °, - m °, -r °,r - °, - °r, - °. m n,r nn, z m .nmrm n rn r m rrz vr rmr mmn, rr .., r rr r m nr .., rvr rmr m xmn mn. nmmmn, nr , nn, z r r,,r rrm n rn r r r, r, r r, r, r rr r, r r, r r r, r r, , r rr, r, r r, r,rrr, r r, r r, r rr, r, r mnnm,rmrmr rmn.,n nrrn r, rnnn,nz , nn, z m n r mr ,r rm nr r mr m, r r, r mr, r mr, mr, r mr,r mr, r mr,r mr, r mr,r mr, r mrr r mr, r mr, r mr, r mr, r mr, r mr, r mr, r mr, , r mr, r mr , mr , r mr, r r mr r mr, r mr, r mr, r , r m r mr, r mr, r mr, m nn,mmrm.n, , nn, z mnrrnr,rm mnnrrnnr, r mnr mnnr,rnr m, rnr, mnrnr, mnrnr n mnrnr, mnr , mnrnr, mn,rnr, m nr, mnrnr, rnr nrnr, mnrnr, mn m nn,rm mmn rmmr nnn,r. rn r,nrnnn, z , m nn, rz m n,r rm nr mr r m r, r mr, r mr, r mr, r mr, r, r mrr, mr,r mr, r mr mr, r mr,r mr,r mr,r mr, nm r, r mr. m n,r mrmmnn, , nn, z mnrnr, m rn r mnrnr, rnr nrnr, mnrnr, mn nr,, mn mnrrnnr,r, mn mnrnrrn,r, m mn r mnrnr, mnrnr nrnr, mnrnr, mnr , mnrnr, nmmmn nr. m n , , nn, z n,rn, rmz n rn r nrn , m r r,m nr, mr rm nr mr r mr, r mr r, r mr, r mr, r mr, r, mr , r mr, r mr, r mr , r mr, r mr, r mr, rn, “x” rrr mr, r mr .., m nr , mnnnm r n nr rm n r nnr, z n m..n,r r rrn , n , m r n, z m n,rnmrn rm..., mrxmn,“r ” rr, mnnn,mz rm n n,r r rnrrn nnr n .., m rm n.rnr , nn, z m n,r nr.. xm, “” rr mn m r n r rm ,n m nr , nn, z m n, m r rrrn , nnnnr n .., r rm , z m n, mnn, nn.nrr mnnrr mnnnnr mr n nrnr mr nrr,. nmn . m m xn, n,rvr,rnrrrr,nnrr mrnmn.m,x, r rrm n m rr r nrr rr, ,rxm, nx r rmnn mn n n r rm n m . mnn m rm n. nnr ,..,n ,rxm, n , . mn mnn m rrv , ,n rr mmn, rrmr , n rn.nm mnnr. , ,nr,rr ,rn rn rr r r m nmm rr rn. , ,mnn,rr m.nn n n , nnr n mnrnmmn, mnn m , . m n , m m m . m rr ,n .nmmmn m, m,rv m nx m nn nnr n , m mn n , m m m . mnr rm mmnrr ,n m n , m ,, . mmnnrnr , m . m .nnrr rmmn, mn n m n , m , nn n . m . m rr , .nrmmn .nmmmn, m r r. , m - nr rr m m n,mrnr nrr nnrr n m nn z, w n rr r n,rrrrr nnr n n m nn z,r .rxm, mn . rvmn r nrnr,n rrr n n rmn.., n m v .. rm ww r mnn r r.nmmmn,rm : :, :,:,: nrr n m :,:,:,:,:,:,: ,:,:,:,:,:,:,:,:, ww r mnn ,r:,:,n:r,r:,n m:.rrmxm,: r n:.rnrrnmnmn m,, wrwx rm, m:. mn r ..,rv-v r . r n rn nrnmn r, m nn m r zn m n mr rvn m vn m, m vnnr n mrnn -r n n nr n r n m n . nrn,. nrvn m nn n nm , m r nr ′ n nr. n, “ -” rnrn n nnnnn, n.., ,.n mm, , ,,,,,,,,,,, r ,, ,,, ,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,, n nn,rn rn ,,,r nn m n nr v rv rn.nrrr , m n n nnnn..nrrr , n n m. nm , m nzm n r , m nnrmn w. mr.nm , mnmm ,mm r wnrm n nn m.n nn r rrnnn nrz nrzn mn m rnrn r r. nrrmvn,..,, wwr,nnr,znn, .nm m rnn , mr,. ,. m ,n . rrr , vn rn rn r v,..,rrn, n.,rnnmw mrrnrrnr.rnr m rn vr nn.rrxmn., nr m m r rmr r rnrrm “,-nnmr mr” wnr m rnr m m .xmr mr n r rnr,,n mrrm,r vrmn.r, wm mr rrrnnrrm m r-mnrnrn. mr v n r mnr rv rr n n vr.nm ,nr mn r mmr, w rr mnmr r -n r r mr z rmn n ′′rn. w- mrn mnmr.. m mr nmw mrn vrmn , mr n nnnr mnm′ ′m, , nmv v rrrn nwnrn vrrvnnrrn.rrnxm, rrr n m rrn n ..,n ,n -m nn rn m r m n “n wvnrr mrn n”′---mrn′rn′n “ ”,r m′ ′, wrn n n nr n ..,n n. ′ nr n nrnrnrnrnrnr rrr m n ′n m r rmr m nnm7n rn nr . rrn - ′-′r r. n rnr “-” n v r mn ,rxm,n,wr mr mn r r nnrrr n. m m rrn rnn r nnn m m m,rnzmn mrnr. rw mr. nnr n m. nrn-n m r rn m nn- m nrn n rn m.n-nn nn rn nnnnnmrn rnr m mn xm, r , w n , mr , ,n , m nn nn n .nrrr , m n m r “m m m n rn rrr “m m ” mn m m.”.nmrrr , m - r n .nnm n,nn m m rn n rnrm nr n r m. nn mn mn n .nmnnrn m,w mrn mr mrnmr mrn mn rnrm m r-mn m , rrr r n, vr m n m .rr, nr mr m. m. rnvn,r mnrnn,nnnn m,..,w m,r,r,v, mrnnnn,.., rn,r n rn nn. rrn m n rn xr nn rn, mm m nmzr-mz rnr nxr mn m. m r,rxm r r n r n.nr r n ,rrv n n ,rxm,rxm, n m m w r nm , nr mrn mnn nn - . m m nrrn w m r mrrrnrnn,nm , nrn nrrnn n n w n nr . rn, “mmn rn m nnn w wr mrn rr” rrnvr r rnmz n rnr, , , n mv.nn mm wn nn m m n rr m n,r w n r rnn rrm r m m n.wr m nr m nrnn n n . vr,rr m n w r n rn m “-m-” rxm, n “ ” m m “ ”.r . m n m rr m rm “ ” m n , n “” nnr, r nn rrn nm n, . m mn nr mr m n r.nn′ rr. r rrn n m nrnwnn r nrnmn ,rm m, mr,r n vrrn,rn r n , n ,rn rnr v rv r m,r ,rm ,rm ,rm ,,rmn.,.,r,mrm ,,rm,rm ,,,,rrmm ,,,rrmm ,,,rrmm ,,,,rrmm ,,rm ,,rm ,,rm ,,rm , ,,rmrm ,,rm ,,rm ,,r ,rm ,, ,,rm ,,rm ,,rm m ,,rm ,,rm ,,rm , ,,rm ,,rmrm, ,,rm, ,rm ,,rm ,, ,,r ,,rm, ,,rm, ,,rm, ,,rmm,, ,,,,rrmm,, ,,,r,mr,m,,,,,rm,rm, ,,rm, ,,rm rm, ,, , ,,rm, ,, , ,,rm, ,,rm ,,rm rm, ,,rm, ,,rm, , , ,,rm, ,,rm, ,,nrm, xm,n.nmrrr, , m n n .r wn, n, n wnn,wnn,n n, n , n, n wn wn , , n, n wn, n n, n n .n.mnrr, n wn , n r n vrrnrnr r n,r r mn n .nm , n nnrn n m rrn ′ n′ . nnr, nm,wr, mr m m m n n n rn n ..,nnnrn wnn rn w n. n xr nmn n r rm m m m n r n.nrrnnrrn mnnr r n r r n r , m m m n n “-r nnmrr. ,”nrr “r n, m . “-mn ,” mn m m r” rr n w r nmn r .- vr,n n rr vr w rvrm,.., nn nr. - n n rn m m mn m v- rv n -nnr mrn rvr ,n rn nrnrrm vr . rv w nr nnnn r . r , wr nr nmrrnrn, m m rnnn,r mmvrnrrvnrvxr nnn nnr,.., vr vr w rrn rrrrnr w mn r n rnrnvn xr n nn. vr n n n nnrm, nn nmr nr r .., vrnn, m mr nm ,. rmnn vr -mn n nr mrn nnrr vr r , vrr , vr n r '-n rn.nm , -mn m n ′-n rrmvn r n n,n n r n n r n ..,nnnnr. nmrmr nx,r nr r n m n n -mn . rrmnn rnn -mnn..,nnnr mnnrnr m nr nnrnmrn vr- nr rr.rr . -mn, m-mnr mrn m nn n m -mvn,r mxm,nnmnnnrr mrn vrnn vr rn. rn r n r r vrr n - nnrr wn -mn m nn m v n .rxm, ,m r vrnnzn n r, n vr nnn vrrrr n vr ,nr mr m. n, nrnv rn, m -nnnm m,r-m mnr m r rnn n m n nr,.n.,r rm -mn mr m n vr r . vrnn.nm , , -m .,nn vrrn n.nm m n .n., m r rn mn nr mr m rn. rn,-m nn,- m n,- ′ nr mn n nn-rrrn , rr,r′nnnnnn n r nr. r nr. ,nrr ′nnnn nnn rrrn ′n nr.nm , n nn- rr, nnrn nn,r m mr n. n vr nnzmn mmrn nn, nr n r n.nmnwxnn. nr,nrn w n r rn r n rnr n. n r vr rnn m m rn -n mn-- mrn. m n nr vvrr r-,n.n.,mrnmrn.rn mm , rn n n, r vr r n nrn nv. nn- r nmn rr vrnrnn n m nrrn r vrr ,nm , -mn m r n nmrrn.nm n, -mnnr nr n vrn m vrnn.,n n w-n vrr,r m, n -nm, m nn r nn rm. vrrrmrn w r n rrr nn w- vr r nrm n nr,rn rnnmrrnrnn nmmnnnn rm- rmmnn nn rr rm.nv rmr vrn ′ n r,rn. nr-mn m m vw n rnrmn mrnmnnn r n′ n rn v n..,wnrm nnr.nm m n n rnrm,..,n rrnnr n rnr n,-m.n m r rn m n vrr n vrr r n r vrn,rr nrvr vrnr rn, - nn n. r n m r rnrmnrnm mrr m . -mn m r rn rvmrnn,n rn nrv n -nn mr w nr r nrm vr ,r nr rn r n m r . m xrnn rvnr v,rr m rnn mr rnrv rmrrvnrr wvn mnrn vr w rrn rvn xr n nn.m,rr,, m vr- . vr n vr m.xm nr r rr-rn vr n vr,m r vr n vr wn vr nn vr r vr, vr vr,nnzn nn rv. , -mn r rn mnrr n r n rm vrnn,m-vrr vr vr ,r,nr vr vr n,nnznn m.nm , -mn r rn mnr vr rvrm mnr w- vr n,.. r n n n , n mn vr ,v wr-. rnrn+-r rn r r m-rnrrn r r rrnnm--rnrn w +- . w -rvn vrrv r. n--mrxrnr m mv rnr vrr +-rn n n v nmrn rn rn r w n r nr . r nn nm.rnrv n xr n r n vr, m r vr,n rnr m r rmn n vr,r mn nn vr, nzn n vr rnnmn vr, vrn ,rr-mr. ,nv- mrn rvrmr n rnvr,vvr, vr,n mrrr w- vr rnvrr, w-vrnw,nnvrrv, vr,rrnvr. mrn r n, v,.rmrnn r, vr n r - vxm , - , r vr -, - rnnn m v,r nn vr -, - , -, vr -, --,,z - ,r-rn -, r vr - , r - , r -, m vr -,, v-r v, m -,xn vr -, -, - ,nr vr --,, --,m r ,rn -,n -,nzn n,nn m- nrn-,m -, -,- -,- ,-,-,-rn, nm-,,n-- -. nr -mn m r rnrrr rnn .., m.r.xm,, --mmnn m m r m,r ,,,,, , n , v ,r r mr,rn rnr ,rv rn.nr,nxm, -m,n , , , , , , , , , , , , , , , , , , , , , , , ,r . , , nnmnr, n,,w-rm mrn mn mnnn rn w n rn n ..,nn n nmn n. nr r wnxr r n rn rm -mn m n r n nrn mnnr r n r mr nmnn,. n-m rnn r.rrn mn nr n r r- rnr x- r r m ′ , ,r nnr.nm , m ′n . mvnnn r , m . m mrrn rmr r- n.., nr′n. nn n v nn r nnm m , ′ r rr, m n n v nn r . m n v nn r n v nn r nn n v .nmrrr , mn n v nnn r .nm , mnnnnrn n nnn r rn. n m m r nrr rn xrmrn.nrnn r r- n n, m nr r n. m rrn .nm , wnrm nnn.n rnn nmm r nrm , m r n vrrnrn r n rn,r,n..,nrn,..,wnrnrnrnrn m. r v,..,rrn, r nrnmrr, m nn m r zn m n m n nn m nn -nrnr,-n w--mnnn r n,nmn, wr n n,nn′- mm rn,r,′nnnmnnr, wr m m .n rr m ′ ′ rn wnrr rn rrr rvv r, w mrnrn.n n r m nzm nnr r m rnm vrrrnn , ′n m w n rr zm r nr rnrn.nm , nxmmrrnzrmn r,..,nnrnnw mrnn, mn. nn--mnzmrnr, wn z m r n rnrn,-mnnrnr n rr. rr nmrn rn mnn m m . ′ n nrn n '-- m m rr m , w mrnr w r n nrn rrm m '- nmrrnr,rn mn m. n n nrnr,nnr nzm ′n rr.nnvr n-n--mnn r.rnv, ′-m nn v ′′r rr wr --m rnr w n nrnr nm n .n- n rr, ′- r m nrnr rn.n n--mnn rz m n r n.nmrrrrrr ,,nzmn rn n rnnn nrzmrm nrnn v n- mmxnn.nxnmr ′,r mrr n w-r,nmrnnrn., ′nnnn nnnr rnn ,nr -, r nwnn rr w-,′- n, mr n ′ rr rmnn n r nnrr ′ rr.rxm, nzm m nzmn rmnn′--m rnr n m r nn ′-′-r n wn ′-rmn n m nnn ′-rnmnn n wrn nnn n rr rm r nr. r mnnr ′--m. n r n r vn rr-nrmnmrn-mn mr,.., r′ n rrnwnn r. n, r nmm ,m rrn , - ′ ′, nm′ ′m . rrrnn mnnr ′ n r ′′r n, nrn n m mrr.n .,n n mrr n r n nn n nr ,r rr m m-n, wn ′- n n n w ′- m n.nm , ′rmn rnm n,rxm,′rmn mn nnn.x n n n , r nm ,nn,-m-nn mr nn z-nn,-x-nn, ,′r-nn,- nn. -mn-nn, -nn,n-z- n nrmmn .,n n rn mn rn n r r , m,r ,,,,,,, n m rm ,.., ..,-,-,-,-,-,r ,,r,rrw nr n ,rnn rnn.nr v rn, n. m , .., n,m m,r,,r,,n,,,n,,r,n, rn m rnrm , ,,,,,,,,,, ,,,,,,,,, rnr v rv ,,,,,,,,r n ,rn rnrnnn m mr,rnn,..,n-,-r,n,rr n,,rnrr mwrr nnnr ..,n-mmn. n,n.-m mnnn mn vvrnrn rn.nvm′ n , vn-m mn n mn.nn nn′ rrnr mr rn w m , m n nn rm, nr n ,n.nm , m m .., nm , m m mr m rnrnnv. ′ ,-m m n mn. mn mnnnnn vvnrn′ nrr .nm n vn m n .nm , m nnr mr rn wn n .n nn rm, m , m m nn , rn r,nnr mm nn . rrm w. n rnnnn nzm ′ n r mr , , m , m , wn: , m, mnnn m r.n . m ,. m-n- r m , n r nn r n wn. rmrm.n, n, r n r nrn vwn w ,.., , m,r -,- n- n- ,r n ,-,-,-,-,-,r- r. r n.nm , r n wr .nm ,r r mnnrrmnw r n, n . ,..,,,,,,, n , m,r r v rv rn. ,,,r ,rn rn .,.,n.,nr.,n.,.wn ,,n n .,.,,., m.,,, .r2n ,.,.., m.,., m,-..,.r,r.,., v rv r m,rn rnr n rn. r m w,rrnr , wn n n r n. nr r n r-r r,.n.,m, m, . ,rn r,n n nr °r mn ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,r, m,n,,,rn, rn,r v,,rv,,r,n.n,m, °, n r n n mrrrrn°n n r,r..,,,°,.,,,,,,,,,,,,,,r°,n , mn,mr ,, , , n n m r n , , , , , , , , , , , ,, , , , , , , , , , , , , , , , , mrmn rnn, rn,,, ..rrn rnr v mrv rn.r m rr n mr , v rvr r nzr - . ,.., r -n m rv m nnm w ,n m nzmr mm rwrnn vrrnrn r n.nm 2, n v m rn, r n m rn r r n vm n nrmn w nrnn . n n w zmr,. mnm m n n ,n rn m w r m nm , m r rn nn nn mr wn mn vr r rn w nzm nm , nrrnrmn r n r. r n m, mvrmn vrrnrn rmr.nrxm, m r rm m v m wrm n, rmv m n nn r w n r n r n..nrxm , r-mmz rvz rmr m, mn n m rzn rn. mnm r n mnvv m w nn.nrr m n n, wrn r rvrnrrn rr, m nn w nn n rm rnn vrrnrn m n rnnrm w n rnrmznx wwnrnn nr.r-mnv nn nmnnrn nrn,rn. n mrr m nnrr rvrnr mrmr r r r rnnrnn , , mmnrnrn r r mrrr, r,n mr , , , , , m vrrnrrrn,n rr r. rn ..,nnnx mn mrmnr nr n , nzn n m vn n rrm.nrrr n . r- m rn, rm “r ” rr r n n vrnrnrrrn r mrnmrnr,rnrr rrrn-rm.nm , rr, r r m rr m rnrn.nm. r,r r r r rrmr rn w mnnr r mmrrv n,n,n- rrn w n nn rnnrmn,rn r mnnr , rv,r nn rrr wrr w r nrrmmzn r mm n rmnv rnnn w rnrmnr r.nm , r r , -w,r m vn n,rr nr , m rrnnznrnrn r r m, w n r n m r n vrrnrn r nn n-mz rrn n vr rn rnr m r n mx, r m rmrr mnn r n mx ,n nr m rnrn nn rn mmrn n r n m . r n m rr n mnnr rn n rm r n mx,n nr mr nnr r n mx nr m n rn n . w n, rm “r r” rr mrr rmn rrnrn mn vrrrmnr rn r n rr nr nn. w mnn r mrr, °.nn°n°.nm , r r mnn mrr ,m , r r mnn mrr °.nm vmrmr r, m,nn,,m,rr, ,°,.,,r,r, m, rn,n, ,,rr, rr mr,,rnr vm.nnwn.nm , vm .nm , m , vm r rw rrrr rm m rwnrn n rw r r nrn rrmn mnvm.n, nnn n r r m n v rn nm.nm, ,rrwn r6 8rwmn m,r r r x x6m 8m,n m.n x7vmr,n x7nm, x x m n v n mvnr,n r mrwxnmr r w vn r w rwn n m rw r.rxm, ,,,n,r,,r,m n v r v n ,,, n.n ,,,,,,,,,r rn mxm n ,m, ,,, ,rrwnn n nnr mr r.nm , r,rw,,,,,,, r r n r r.nm nn r wn rw nrnr mr m.rxm, nnn rnnnrn rn rnrnrw r , m rwnr,,,,,, n ,,,,,,,, r mr , ,,,,,, m r nrn r .nrmr r r.r nrr rrn n. r r m rr- wrvnr vr r ,n.,nm,, , r rmr n n ,,, m , r,,,,,,,,,,,r, .n r rmr nrmrnn n.nm .n,m , mr n n . r r r r r n m nr wnnw mmr nnxr.nmrrr , r rn rn rnn nr r,nrmnrn mrwrm r n mx,nr rr r . m r w mnnrm r.,nr mmrrnnn ,w n mm,rrxmnn rrnr mxn. mmnr n r rn m r w mnn, ,..,rn, m nrr n.n,rmw m r w mnn, n n m, mm, rn mmrn v rnnmmz r n m wrrmnr m nz n m n m r rr rrnn mmmrrmnnn. nr mnrnrmrmn r n m ,.., r n n r nnn m n mr,rxm, rnv, n nnr w m r w mnn. nn mxn rnr m mr nnn m. n nnrnrn mw r-m mrmn n vr n vrrnrn r n mnr rr zrnrn r n. n rrz mn vr mr .n m m rrrmrnr m nz rnv,n m rrm rr r rr n. r n.nnr ,n m rrm r r- n r n ,..,nnxn rmr n r r n m m rmn n nzr- .rrxm,nm ,rmnnzr m nnrr m.rmnnzrnnmnn m r rr . r , m r n n .n r v. z nn rvr nnnn mn nz n,.., n nw m nz ,..,rn v.n .n vr xr n nr mn n m n mn n.rn wmr.mmnn m nz ,..n m r n n nnmmnm n, ,rn n m n nz n,.., m .., . nn n m m r n m n n,..,nrrn-. m -nrnr,rr, mrn m, r n , , , , , , , , , ,, ,r, , , , , , , , , , , , , , , , , , , , , ,r -nrnr,rn r , , , m rmn r rn, nr v rv rn.r rr n m .., v rvr r nzr- . r,.., r -n m rv nrn m nrr rnrnm,..n nr. n r r , nrn ,,r,n , v,nm, mmnrn , n, mr ,nr r mmrn rn m r r ,n mn wnmmrn w n, rrrnnvnr. nnn w nn v nr n n rn nrvr r r,n..nr r n nm , m n ,nn. rr n rnrnnn rmrvnrnmrvrn wn w rrr n,n m mm,n mn n rmnn,n m rn rm m m, r mr r,zn,n m n, n, nr, r,rrn nn,,rvr, mn, m rm ,r r ,rr r vrrr, rr n,rr ,r n,r m,nvr m , n rr r ,r ,r r vr r m,r r m,rm,mm,mnmrn,n n,n , m nn, rm nm,nr, m , rn,nr rrnn, rm m , rmrrnn, rm rn rm r,,xrrm n, ,rnvr, r nr n,rmn-n mrr vr vr, -, - mn,r rmn, m vr ,n vr n,r, -nn,-,nm r , vr ,n nr n,nrvrr wn,r n,nm , nrvr , n,nrvr, mn x vrn :, n :,rmrn,mn-rrr , r n, rn,r rmr,nvvrn,, n rmn, rmnm,rnn,nrn rn, rn, nr vr, m r, m nnz, m , nvr nr v r r, r r vr, r, r , -, ,m rm,, r,r mx vr n -n mn vr , mnmmn n vr,r wrn, mn mn mnrvr -nmnrvr -, vr mvr ,mn mvr ,mnrnnz rnm,,rrnn,n vr, vrn, vrn,mnn v,r,mnnnn,, r n, ,zr m,nrrn vr,,m vrmnn vr , vr, m r, nm w,rr rmmrn m vr ,m vr, rmrn mnmnm,,rwrm r , rm rn, r mnn , r r, rmrn, r nrr , m,rmxvr r , r ,n r vv,rn rnm ,rnm wrm nnz, r r n, n,nm r mn,rvvr , r n,mm nvr, v, vr, vr, rrn vr , r , rnvr,, r,vr n, rwz, mn n,r , vr, vr, vr, vr, n,nmr vr,nv rnvr, m n, n,r r, r,rrx n,nmn, n, vn,rn rr,n n,n m,-rnrn rrn ,rx,rrmnn vrnx,rr,xnm,rnr,rrrnm m, r,rnmrz,r mr m, ,rnm zr vr ,r mrrr m r zr vr ,r n vr,r r, nr, v rn,nzn n rrnr, wvr vr, rn nn vr, r . vr,rnnr ,rn ,nrn nrrmmnr,,nn m nr rn rn vr rr x n vr rrnrnnr vrn r, mr rnvr n.mnn.nm , vr n vr rrrnrmm vr, vr. nmr nmr - nm , vr rnvr,nmrr,mn m- . r,nn nrrn rr nn vrn r.nm , m rn rnrrnnr vr rrmnr,nn nr rrnr nn vrn r.n nnr - m , m rn r nn nnr - vr rrmn r,nn nr rrnr n vrrnrr., m rn rr n r rrnx rnr nrnvrrnrmnx.nmn , m , m rn vrnmn.nm --nmn. rr n rr x n nm , m r rnn nr mr rnn rm , w.nm , m r nmrnrr mr n n n n m rmrr nn :-.nm , n n nnmrnr mr n n .nm , m rmr r nn :- n n n rnmrnr mr n nn :-.nm , n m rm r mr nr mr n n n r rn n rm r nn :-.nm n , n m r rnmrnr mr n n .nm n , n m rmr rrnmnrnnr mr n:- nnn :-n.n n n rm r mr nr mr m , m r rn n rm nr nnn :-n. n m r rnmrnr m nm , n.nm n n rmr nr nnn :- n , n m nr rnmrnr mr n nn : n rm r mr n -.nm , m r rn n r mrrm nr nnn n n m r rnmr :-.nm , r nn :-nr mr n n rm :- r w .nm , r n nn w n “ nnn.rxm, _ : :- r”n w “ .”nnm.rx,m,r n_ nn: w n “:”n “.” _ : __ __ __ _ _ __________ _v- _rn _vr- _n rrn- ______ _ _ _ _ ____ _ rr_ _n _ _________________ rrn_ ________ ___________________________ _________________________ __________________ __________________ __________________ __________________ _________________ _ _____ ________ _ ____ rrn_ rrn_ rrn_ __ __ _ _ _ __ _________ ____ _ _ ___ _____________ _ _ _ _ ____ rnmrmr m n nnnmmn-,n wrn n’-nrn n mr nnnn mm:n,-,, w,r,n,n’-. rnmr n n rm r nnrn :,,n. n : m r wnnnnnm.mn-, wrn r n n w m nnn mnmn-,rrmrn: n m mmn,. n nr mrn wrn n n mr n . v n nnn n rn n m ’nnn m mmn r, wrn n m m nnn rnnmmn. m-,rrmmrnrn: ’. nn n n w, wnrnr,: nrn r r’- n wnn , w nnrnr,nrm ’n n r r r rrnn w nrn n n, - nn ’-nrn ,, n rnrmmr r n nn n :-,n-, n m-,-, nmnm-n.,n wrn n’-nrn rnnmr r nn :, rm m mmn,,-,-,n-. n wrn ’-nrn rnmr r nnn :,,n n n rm m mmn, w-,,,,n. n n rn ’-nrn rnmr r nn :,n-,, n n rm m mmn, wrn,’,n. n n n n-nrn rnnmr r nn :,,,,,n. rm n mnmmrnm, wrrnn’-nnrn rn:mr m nn mmn-, w ,,n. : r rn r n m m wnnn. w, wnrnr, mnr,’-nrrnrmr rn n n n n w, wnrnr n, ’n n m mmn,,rrr rrn. ’n n n w,m wrn n n n nrn rn nrnr, r’- m mmr. nrn. n rnn m n xm rwrrxrmrvr nrrrn rnnvnn. rnnvnn ,nr nnn m nmr ..,mnnn w,.mrrrv, n m nr r w r , r, ., mxrmnrrrnvn nvnn mr wr. rnrmnrnv,nnm wrm, r,mnnn rwnn , rm , wn r. n w nnr wrrwr n m n nmr v .. n rn n rrmnzn nnmr rnr.nnxm,nn . n :, w n n rnn rn rn ', mm - r,n rnz m n n,rvrm rn, n 'n. n rn r w m rnm mn rn m ,r . n n “rzn”nn n m m, n n r wn r ,r r mn nr mmrnn mn rnr wmnnnnm.n, wr n r n m r,v r mn n w w nnn rmnnrn ww w r nnr v rrnr.mnrxm, r rn r rrnn rvnnr n :..n.... r nr r, ,w r nn“rzn” m .n , r n . r r,z r rr r n ' rn z nn n, n rn m r wn m m. nrn r , r nvn r n w xm,n n. n,n wn n .n n. nnmr r nnn.xm n nrn n. n w rr rrn nw rnr nwnrn. r nr v n xm rmn r. rr nmr m n r nrn, m n r n r m n ,r nrr .n n rn-n wr m n mnxmr r mz, n n mrv rn nm n, m mrv n w r n. r, m n r r . w nrn. r mn r nmr nrn, n rv rnrr v nn r rxm, : w rr r rr nr. n n n mnn nr m v nvr n n n, nrrrn,r m nr.xm, rr mn wvr,rm r.n xrm, v r m n wn r rn wrnn. rw ,,n n n w <. nnwnrm n m, w: mr rr n vn rrn w r.. n w n n r xm n r rn,rnnn nn mn n m n m n n vr n rrmn r, n,n m n w nmr m n m nm n rn. wr n x<m,, n :rmxm ,vnn m n r r, mmznv r . rnrn w rn wn n rnnr wrn, nrw nnrrnn. 'mzrmnn,nn'rmn rm ,vrvr n :n. wr nrxrmn n r : .. . n v n rn . vnn.rrmxmn, mzn, m vnnx mn n n rrmn, : xm nn rmn v .n rm m nrvn n : w mn m rmv , w ,r nn nrrr m . n, n vrrnnrrnrnm.n w m rrr wr n nn r m w vr r r n n.xm n r nrm :..r w :vrnrvn:nnrrr: rwn r:n v :..-.n, rmrnr w m.r, v :. n v rr nrn m wr rnnm nr nwr m r rnnnrnm n.r nwr m wr nnrn n www.nrw.r wnr.vrnn.’., w:rnv.r wnnxr-wnvrn.n.,, xr’nnwn- mnmmw: r mm wnrmrm ,n r m r, r n - n mn w n rrn , w m z n. v mrnnv n- nnnrnrm r w r - - rmzn-r .x rnznr rm ,n, nmr rn v r wr n mxrnmnrnn r. n r w n rm w m,nn vrn rm mn. r. r n -mnn v wrnn n w w n,wn vnnr wr rr nn r r, n n w ,nn n. r n mn wrr n r rn n nrn rr mnrm n rnr.mr m , nr nwr m w n rm nrx,rrnn mnn. nm r vr r . -rn nr nwr v - r mrrrn r xrmn n n v mr nrvnn nm n rv v ,n rrr mn v . , rnrvn w mr xrmn rv rnn nm m wr r w rr rwr vmrrrn nr v , n mz rr v _rrn . rvn, n w v r xrmn rv m r r nmz mn nm mmr. n,n rrmn .n vr r rnn,mmmznn w wrr-rmmzn n_rr v r _rr r r nv . nn r rn n ww _rr, w_rr n w n mznr nrn, w n rnrn, nn mz r r .n m n r w nnn m n r ,n rn, nvr,n w nnrn. n r zmznn. nrn, wn r n m m rn rnr wnrn,nnrnr m n r w m rn rn mzn.rnnn, r r r n.vrr,nrnn. wr nrn n nr, n w mz r n r n m n r . rnrn, wnnnn mrn.n r 'rmn vnr'rmnn,nnn wr:, w rn. mzn. n w n rn n nr nwr m xm wr mmn wr rrnn'n,rnmxmnm'nnnn .z : wr n w n rn m m, w n n nrnmznz n wn. wrrvrm rw: w n n. n w _rrr rnrn nrn,n n n n wn n nw n n nx wrnr, w n w nr _nrrr vn. rrnr w r rnn nn r nrn. nn m rn n r n n m , r r mnmn : nm. . mznn m rnn r n nmmnn n m nr n mzn _rr v.,mmznn w v wr rnn,n r n n :. r nw m wn x v nrrrn ' nr xr n mnmrmnnr. rr,mzn wrnr nr ' w rr rrnn.r wr n, wrn.nnrnnnnn rrnn vr vrnm nrrrr nr w.rmr rnnn, rn m r . vmn rn. mwnnnnr.rnnmrzn wnrr n m wxmn rn m vr nr z n w ,r n ' n n wrvnnnm n r w ,nr wn rr. xmvn, wr w.nnr ,m 'rmn,r z ,rrn r nr vn n n wr nr mr rnrrn n. nrrr w: nrn w mzn rmv nrn,nn m n r r rn, w n r rn. ,n r n m n r . r mznr mm w m n nn:n.nn rn,n nn r w rrxm n.wr nm rw nrn,r n rnrnn r r m n, n.n n, mz vn mznrm r n n m nwn n rn rn wr nv n n n w n rn nnn nn r, rn . r mzn, n nn ,rn rrn w. ,n r mrnn v m wnzm rnn rn mzn r n :,n w rr w.n nrn wnrr r vr rnrrn mnr. n v mrrn r r r nrmn n.n mn n r rn,r rr vr n n n r. n vrrrnn nrrr :,,,,n wrnr wn n . m . :, n nxm,r mn w :. ' n' nrn : wr n w n rn mzn.nn n wr rn,n w rnnw rrnnrwn,nnnnn, mmn r .n v rn w w -. nznnn mnr rn w w . rwr nn.rn rrn ,w-r. mzr mnr w r,n,,r r r mr wr n w n nnn,vvnrm r wnnrn rnm:r.r w nrnn xmnrv nn:vv -n,rmzn n nrrr nv n nrrr n r n r nn . nr w , , n ,n m wrvn x n : wr m wrrz rn mzn w r m wr nn n w n. n ’n z rnrnnrzn. wnnn w. mz r nrn w n nrn m n r n. m n r r n.rnv mznnnnn wrnrn v, rrn nw nrm mzn wx rn n. rr v r m x r n nvr n rr r v r m nn rnnxm. -.. wm nrxmv rm nv nr m v. n. n , nr nwr m w mz nv n rn mz'nn. mzzn m w r wrrznn n w n m n r . n w.n m n r nrn. r nrn,n n r n.nn - w rr n mr nv n wrmmrv mrrzn, vrr n nn :,,, r rm : wr rxrmn . n rnn nv n. n , nr: nwr r mrn w rnnn vr mznrn rnnn wnn mnn r .n m n r . vr n wr nrnrn.nrmnrn.mzn rn, n rm rn mzn w nr n :n rr v .. xrmn . : – n r m w r rr mrv n ,,n n nv n n. n ' mzn. zn m wr wrrrrznnvn n w n rn mzn, nv n rnn wrmmzzn.rn rn rn w n rnrn. n m rn, r . n m n r n r w .,n nvrn r w nnrn w . r n r n n wr rm r rn r rn mznn.mzn.r mrmr wr r rmnn rn . -. wr r rnn rn wn. -.. n n nnnxm m - nr: nn , : w n 'n z m wr m w r n. mzn. mzn w rn w wr.rznnn n w n rn r . r nrn m n r n m n mz ,n n rnrn.rm :nn, vr: nnn wnr rrnrxrmnn -. n nmr nv n r v. :r rr v .n rr v .r :. : wn xmnn nrrmnrrrmxmn. _,: w nn mxm mzn rmr nxnnnrxmn.,n nnr r rmv rm w rn rmr nr w :.nrmnn m rn rrr w w n m mr.., , ,nrn n r znr . m rmr wr n w w wr rrnz wnnn n.nwmznr m n rn, n mrnn mz'nnr . zm mzn n n rnrn n r . r nrn, mn wnn: w .n n :, w n nr w rn n n rm . : - wr rr :n. n v nvvn r nr w w n ,rnn v wr mznr n n ::nn : w:r. vn , mz rnr rn w mzn r v. :.:wr n n :r . v n:n : w wr nn nr n v w w. rv w ,,n mzn , n m v w rrn n . :- wr n w w nr :. mr wrnmz wn n w r w mz mm r nnrr n v . : rrmr n n w rm r :w rr rr n rv r:.nrn m nr : wr n . n m r mxmzn mn w w n mz rv rn r wr n mn wnr r n n:-. : w mr nr r :.wv rm rn, nrrrnrn wr nnrn nrn,n w:. :, - m vrn vrnn v mv wrwm w.rn' wnr -rnn n vrnr rnrrrmrnwn r.mn , n mxmz vr n rr, w znrr mrxmzn' rn wr n . m r m mvrr-nr m wr n rr.mr,x' n' wrnr wnrxv' . vrn. wn n m, mnn wnn –n n r n nmr n –n n :r v . __ .._ .._ .._’ .._’ _ ._ ._ _ ___ . . . . . . . _____ . .. . . . . __ . . . . . . . .. nr n rn vrxr n -n nmnnmnnnmxrrnn nnmnnr .' nr - wnnrvmnnvmr nr ..rxm, n.nrn,n n 'n' nn nv r' : - r m' n nm n,nxr rmr n mr r -- . n , wr n xr n, r w rn n vr ru -u:n. s -a vv - name nce consru-cner aenm. sze.n.u conc nncasuao -- -- - . . . .. . - - _ --. . .. .. . -- - - -- - c_ - . . . . -_ .. . . .. ... : v x - - v -- x - -- .. . -- - . . -- - . . -- _ - . -- - . . ---- _ -_- .. . . .. nm rrm nr n nrr wn nnrr nn v ,n_nr_n, v,r wnr ‘ ’ n nn v w nr n :,n wn n n nr. nr v x n n , wr r nrxr n .rr n n m, nrm m n w v . r wr ,rnn mn r m n, wnrv rn rnx vrn,nn -rnnn n m nr vxrmn . ' rrm mr nr nmr w,r.. w rv n - nr w ., xr n : - .mr nmrnr - n n rr-.mwr,mnr rrmnnmr' -rn n mmn rn n n rr. n n nr : - n vmrn wn vvrnrr :n-,vrr mnr rr-m n mn vrrmn. wrrmn . nmmn wrnw mn -r,nw nvrnxm,n rr nv' n wn nn n n nv' wrnr rrrr. ' wr rr n m .mn m, rr r xr nn n n m , w rnnv. wnn . n wr n rxrmn ': ' __ __ . . _ _ . _ _ . _ _ . _ _ . . _ . _ _ _ _ . .. _ __ . . __ _ .. .. _ __ . . _ _ . . _ . _ _ _ _ . .. _ __ . . __ _ .. .. _ __ . . __ _ .. .. _ __ . . _ _ . . _ . _ __ . .. __ _ . ._ __ . .__ _ . .._ _ . ._ __ . ._ _ .. .__ _ . .._ __ . ._ _ .. .__ _ . .._ __ ._ _ . ._ ._ _ _ _ .._ __ ._ _ .. ._ _ . ._ ._ __ . .__ _ . .._ _ . ._ __ ..__ __ ._ _ .. ._ _ . ..__ __ . .__ _ . .._ __ ._ _ .. ._ _ . ._ ._ __ . .__ _ . .._ _ . ._ __ . .. __ _ . ._ __ . ._ _ .. .__ _ . .._ _ . ._ __ . ._ _ . ..__ __ . ._ _ .. .__ _ . .._ _ . ._ _ _ _ . .._ _ . ._ __ . ._ _ .. ._ _ ._ _ .__ _ . .._ __ ._ _ .. ._ _ ._ _ .__ _ . .._ _ . ._ __ . .__ _ .. .._ __ ._ _ .. ._ _ ._ ._ _ _ _ . .._ __ ._ _ ._ ._ __ . ._ _ .. .. __ __ .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ . ._ _ .. .__ _ . .._ _ . ._ __ . .__ _ . .._ _ . ._ __ . ._ _ ._ ._ _ _ _ .._ __ . ._ _ .. .__ _ . .._ __ ._ _ .. .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ . .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ . ._ _ ..__ __ . .. __ _ . ._ __ ..__ _ . ._ __ . .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ ..__ _ . ._ _ _ _ .._ _ . ._ __ . ._ _ .. ._ _ ._ ._ __ .. .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ . ._ _ .. ._ _ ._ ._ __ .. ._ _ ._ ._ __ . ._ _ .. .__ _ . .._ _ . ._ __ . ._ _ ._ ._ __ . .. __ __ ._ _ .. ._ _ . ..__ __ .__ _ . .._ __ ._ _ .. ._ _ ._ ._ __ . ._ _ . ..__ __ .__ _ . .._ _ . ._ __ . ._ _ .. ._ _ . ._ ._ __ . .__ _ . .._ _ . ._ __ . .__ _ . .._ __ .__ _ . .._ __ ._ _ .. ._ _ ._ ._ __ . ._ _ ._ ._ __ . ._ _ ._ ._ __ . ._ _ .. .. __ __ .__ _ . .._ _ . ._ __ . .__ _ . .._ _ . ._ __ . ._ _ . ._ ._ _ _ _ .._ _ . ._ __ . ._ _ ._ _ ._ _ .. .__ _ . .._ __ .__ _ .. .._ _ . ._ __ . ._ _ .. .__ _ . .._ _ . ._ _ _ _ .._ _ . ._ _ _ _ . .._ _ . ._ __ . ._ _ .. ._ _ . ._ ._ __ . .__ _ . .._ _ . ._ __ . .. __ __ ._ _ .. ._ _ ._ ._ __ . ._ _ .. .__ _ . .._ __ .__ _ .. .._ _ . ._ __ . .__ _ . .._ __ . .__ _ . .._ __ ._ _ .. ._ _ . ._ ._ __ . .__ _ . .._ __ .__ _ .. .._ _ . ._ __ . .__ _ . .._ __ . .__ _ . .._ _ . ._ __ . ._ _ ._ _ .__ _ . .._ _ . ._ __ . ._ _ .. .. __ _ . . _ __ . . __ _ . .. _ _ . . _ __ . . _ _ .. . __ _ . .. _ __ . . _ _ .. . _ _ . _ . _ __ . . _ _ .. . _ _ . _ . _ _ _ _ .. _ __ . _ _ . . _ . _ __ . . _ _ .. . __ __ . . . .. : ' neeannsuorescennce eanuorescencenens _ '_ n __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ ' rm rrrnmvnm wnn., wr ' wrr w . ' wn n nmrrmnr rm . w' - w. n' mnr mr v nnnn nn wrmn rrmrnn rn n nr, wrrnnxr n,nr mxrrnnrrrr,r. n,mr mr nmrnn nr .,nr r, n mn _ . rrmn n wr vr nn rnnn nx nrnnr, - ., r n n ' rm . rr m r r w vr' , rrrm'n w n- m rrr nmnnn nrrn, x m mr n ' .n nnnr w n’mrrn_n vnnnn.nnr :-nnm.n - r - wzr r-rrrmn vr r rn nnx rn vrr nrn,, vr r r r n, n nr rm m rmrrn wr n-xr nn mnmrn n n mn -rx n m . rrnv nr wr r rnr n .n n , w n rrmrrm n,.- mrrn,n n nv n' n ___ _nnr mnmrxr nmr nmr, n n rmrr n ___ _ n rrmn nr n rnn rv rn n nmmnnxnr nnnrznn n n r,n. nnr w-rnnnrn n m rn rnn. nrm n n m - wr w. w-rrmn , ___ _ m :rmxm, wn w-xr nn' nrn n r rmn vrrnx r,n v nr.r r nn vvmmnn ., nr w n nnrnmnrr w nr r n : w n r: n n_rr _,r, : ,n nr :,nn n ,nrn mrn v:-, vnnmnrvm mn _, :n _, : . _n _,r :n ru su:sance vv cons-ruc- consru sze -c ne.r aenm nu concncasuaon -- - . .. .. .. --- _ - . . . .... -- _ - . . . .. --- __ - . . . .. m-- _ - . . . .. m-- _ -- . . . .. m-- _ _ . . . .. m - _ _- - . . . .. m m - -- _ m - - _ __- - .. .. .. .... m--- _ _ - .. .. .. .... - -- _- _-.. .. .. .... n m ,nn n w wrn n w > n , w rrmr nr w rnx . . vrxr n m w n n ame: v x consruc - xearevseson xeave - run resson --- _ _ -- __ . . -- _____ _ . . -- ___ __ .. .. m---- ______ __ . . m-- __ . . m-- _ _ _ . . m- __ _ . . m - ___ _ . . m---- ______ __ .. . m-- ___ . m-- _ _ _ . . -- ___ _ .. .. xrrm wn r.n rmnnrrmn ' n n w rv n ,.., xr nn xrmn nr -r- m-_- __ r_rm.mnrn, xwrxmrn.n mnnr , nv nr rrm rn n w ,x r wxrnnr, w w nmr rr wr nrnrr rmm n n. m m rv - m -nn r nn m.r n nrm rn n .r nrnn rn n wr r nrz , w n rn. r r , mrvn v nrrznrrmrnmrrmvnr vrrnnn rr mnm n _ _, _nm_r, nn vn m nmr w n nnrn mr v- r r, _ :n _ :r r nr.z. rv n n nm n nn r, n nn. : w n vr:xrwn rw,rvwx nrnnr _ nm rznn r. nwr r.r r_nn m_ w wnvn mwrrnv- v_n mw-rrmn nrznn rrnn,mrr n-rrmn ,nr n-v .n xm,m _ : .r w n nmr _, : :r nnrznn rn nv- n _ n - , __n w:rm.mnn rn wn,rv nrvnnn v vrr rnnmrr rnrrznr mr nn vv n.rn-rmnr, mnn mr r rnv nr- nr.wvr, r mnn xr n -rn rm xr nn ’ rrm w r m n nr, n nw vr r nmmnn r n. w .,vr n nv _nn :rnmmn_n n m.:rxm,_ :nr nrnn.mwr r, m_mnn n m: wn mr-n -nnrnn_w-mmn:n. nn m_. w m , wnm-nnrrmr m_r m_n nnrmzrn rr-_ . wrv.r- v m - n - rn v- :,rvrnmr _ _. nw nr _ n nxm wmn rrmr wvr- r nrznrrnmrnn - nmr. _ w r n- r rmr nn nrn rn , n nrm rrmnwnrm z n. _ nrrrn, rmr m-rmnwrnn.mnwvr,n nrrnnrmnn. r nmwr vrnn wr rmnv._ nn m_ wr.n,xn w n vrn nn mn _ n _ _ n _,n nxm .n , n , - m n- nr nxm r nrzn rn rn _ _nmr_n . w r rxnmxm ,mnnrrv r mxnmrznnnrnrrn ' vrnn vv.rxm, v .- _ n n mr nmr n : w -, w w n rv n : . nnrnr xrrn n .,v r n z m,n nnn,'n_, m rm rn. r xr -rnn vrn rrnn mmn_ rnn m:.rn wr _nnn m _ : n v nmz nrrr r r nrzn rnn m , _. r, n nr rn n m nr nrvxr n mrm m nmmn rn rrnnrn m m.mnnn mn r m nrn n n n n n xnm vn nrn nr n ' n n rrmrr xrmn v nn rn rn mrrnr-nn.rrnxmr,nn :n wr, n wrmr rrmr w wn n nrrnr mn mr , nr nn xr n -r - ., . , -m-- nn v m nn vrn . , _ mn rnn m .-nnn m'-. nn n w rv rnxr nn n- n -rrr r. wrw r rn mnr n.rr mn rnxr nr m vr nnmnr,, :n : rmn rm rn n w rnn xr nv mr v r wr .n mrnrnn mnnrrrrm'z.n n - . vr:-rnrm-nn wn rm -mmnn .n .- : wr n nrv m nnr n - m. rmrrnr nr xrn rnn v rn vr , m xrn mrn wr nrmz xr nnrn n rnn n n r m rr nnrn n:nw rm, mrr,. w +r mnr n rm n r wr n rrr. - rnn mm -- mm. n n-m . wrr w mxr n nvrn: wr nnmmnnrxnr™nn.nnnvnr rvnr w r m mrmn rnnn r w. nnr mnr r xr nr ,mr wmn w mr.mr , _ :, w v rrrmnnrn -xr n wn mrmrr rnnmxrr, wn m.r. nrrmn, wvrr mr wr wrr.nr nrnznnrmmnwnnw nmn m. r m nnr mmrn m vnr w nn.m- - -r -rmn nrm nw rn wr rmnn vn m n , mr nr r nnr mrrnn . rrn nx nrv'znnr'- w'r rnrn mvnnn rv wn vr , n rm nn ..nn v nrznr n -mr - nmnr r r _ :, w vr r nmr. w mr nmr . rznr n .vrxnn mnr rv mmnn n m wxr nn . m nr n,vr wr _ :n _ :rn wrnnr n' nwr mnnn w n rvn.v n n nrzn rnrn - m mnn rvnn-nr mrnnxnnvn,rrz.. m n vrn rn nn rnnnr. m wrnr n r r r wrrmx nm r rrr n nr rr .xr nn m nn nnr n mrnv n w w nrm rn n r rnn ..nn wv nr nrn - r m nnrn- r m.nn r nrzn vr r w mr nn m w, .. xr n r rr wrn nrvn n m v wr vrv rn rmxrnn r . w rv xr m vr m mn wnn vv .. w rv rnnmrv rr rnn rn m rmnnmmn. :w . -nnn w vrn .,. nrn r,, r vm wnrrmr r w nn nr m rnrn. rxr n r r nv n r n wxm nr nv. vrn rv xr n m n . n mnnn n.n vv n rnnm . xrmnn m,rmn m n ..n -n - rrmn nnn , nr rn wrrrm. n nrmmm-n rnn- wrr rnr. n m-rrnnr .rnrnxr n., r vxr nvrrnr xnm vnn n. n vr m nrmmn r rnrrrvr n wn rnrvwn nnrn nnrrm.n

Claims

. rn '-nr m mrnn ''rn: n n r '-nrn rnn nr rrnn wrn '-nrn rnn, n n n mr ,n-rm n . r nn -,-,-,,-,- n :. mn m, wnrn '-nrn rnmr n r nn :,,- n n rm. m nn m,--,n-. mr , wrn '-nrn rn rm nr nnn n n n. m nn m-, w:,rn,-,'-n,,,n. mr n n n nrn rnn. r mm r nnnn m-, w:r,-,,,,n. mr n n n '-nrn rn rm r nn :n,, n n. m nn m-, ,,,n. m wrn '-nrn rn ,r,n n n rm r nn :. m. : rnn nn wm-, wrn n nr. m nm-nn, wr.n n nr. m : rnn w mn-,. n w n n rrmrn: n . m m, wrn. n n mr nn.nr mrn v n nnn n rn . m’ nn mr, wrn n n . m nnn mm-.,rrmrn: '.
. m nrnnnnn n rn n w m, wnrmnrrn:, r'- nn r w, nn wnrnrnrm 'n n rnrn n ,n r rrnn wrn '-nrn rnm , -n,-, n-,,-,n r -,n-rm n . r nnn :. mn m, wnrn n'-nrn rnnmrr n nn :,,-,-,n m r. m m, wrn '-n -. n n nrn rnnmrr n nn :,,-,,,, m r. m m, wrn '-n n. n n nrn rnnmrr n nn :,-,,,,n m r. m m, wrn '-nr . n n n n rnnmrrm n n mn :,, r. ,,,n. n mrm, wrrnn'-nnrn rn:m,r n. m nn m-, wr ,n. m : r n n nr . wnnn. : rnn wm-n, w.rn n nr . wn mrnr,m,rrr'-nmrnrn rnn, n'n n w, n w, wnrnr, r rrn. n. n m n m,rnr wmr, wnnrn n n ' rn. nr, r'-nrn
. m.rrn n rnn m n m
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025074292A2 (en) 2023-10-06 2025-04-10 Pfizer Inc. Immunogenic compositions
WO2025186725A2 (en) 2024-03-06 2025-09-12 Pfizer Inc. Improved lnp formulations and uses thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050147621A1 (en) * 2003-10-10 2005-07-07 Higgins Darren E. Use of bacterial 5' untranslated regions for nucleic acid expression
US20060148033A1 (en) * 2002-12-11 2006-07-06 Takara Bio Inc. Cold-induced expression vector
US20080312179A1 (en) * 2004-01-20 2008-12-18 Insight Biopharmaceuticals Ltd. High level expression of recombinant human erythropoietin having a modified 5'-UTR
US8519110B2 (en) 2008-06-06 2013-08-27 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College mRNA cap analogs
WO2014132064A2 (en) * 2013-02-27 2014-09-04 University Of Newcastle Upon Tyne Cells and methods for fatty acid synthesis
WO2022081764A1 (en) * 2020-10-14 2022-04-21 RNAimmune, Inc. PAN-RAS mRNA CANCER VACCINES
WO2023283600A1 (en) * 2021-07-08 2023-01-12 Fred Hutchinson Cancer Center Method for analyzing an ability of target nucleic acid sequences to impact gene expression

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060148033A1 (en) * 2002-12-11 2006-07-06 Takara Bio Inc. Cold-induced expression vector
US20050147621A1 (en) * 2003-10-10 2005-07-07 Higgins Darren E. Use of bacterial 5' untranslated regions for nucleic acid expression
US20080312179A1 (en) * 2004-01-20 2008-12-18 Insight Biopharmaceuticals Ltd. High level expression of recombinant human erythropoietin having a modified 5'-UTR
US8519110B2 (en) 2008-06-06 2013-08-27 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College mRNA cap analogs
WO2014132064A2 (en) * 2013-02-27 2014-09-04 University Of Newcastle Upon Tyne Cells and methods for fatty acid synthesis
WO2022081764A1 (en) * 2020-10-14 2022-04-21 RNAimmune, Inc. PAN-RAS mRNA CANCER VACCINES
WO2023283600A1 (en) * 2021-07-08 2023-01-12 Fred Hutchinson Cancer Center Method for analyzing an ability of target nucleic acid sequences to impact gene expression

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
A. R. GENNARO: "Remington's The Science and Practice of Pharmacy", 2006, LIPPINCOTT, WILLIAMS & WILKINS
CAO ET AL., NATURE COMMUNICATIONS, vol. 12, 2021, pages 4138
FERREIRA ET AL., APPLIED BIOLOGICAL SCIENCES, vol. 110, no. 28, 2013, pages 11284 - 11289
HERNANDEZ ET AL., TRENDS IN BIOCHEMICAL SCIENCES, vol. 44, no. 12, 2019, pages 1009 - 1021
KORE ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 21, 2013, pages 4570 - 4574
KOSE ET AL., SCI. IMMUNOL., vol. 4, no. 35, 2019, pages eaaw6647
LEPPEK ET AL., NAT COMMUN, vol. 13, 2022, pages 1536
LEPPEK ET AL., NAT REV MOL CELL BIOL, vol. 19, 2018, pages 158 - 174
LIM YITING ET AL: "Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer", NATURE COMMUNICATIONS, vol. 12, no. 1, 9 July 2021 (2021-07-09), XP093023532, Retrieved from the Internet <URL:https://www.nature.com/articles/s41467-021-24445-6> DOI: 10.1038/s41467-021-24445-6 *
ORLANDINI VON NIESSEN ET AL., MOL THER, vol. 27, no. 4, 2019, pages 824 - 836
SAMPLE ET AL., NATURE BIOTECHNOLOGY, vol. 37, 2019, pages 803 - 809
SEGAL ET AL., PNAS, vol. 116, no. 27, 2019, pages 13701
THERYAMIGORENA, CURR OPIN IMMUNOL., vol. 13, no. 1, 2001, pages 45 - 51
TRAINOR ET AL., SCIENTIFIC REPORTS, vol. 11, 2021, pages 2461
ZENG ET AL., ADV MATER, vol. 32, no. 40, 2020, pages e2004452
ZHANG ET AL., METHODS MOL BIOL, vol. 2586, 2023, pages 15 - 34

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025074292A2 (en) 2023-10-06 2025-04-10 Pfizer Inc. Immunogenic compositions
WO2025186725A2 (en) 2024-03-06 2025-09-12 Pfizer Inc. Improved lnp formulations and uses thereof

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