Analiza mutacji punktowych i dużych rearanżacji genu NIPBL u chorych z zespołem Cornelii de Lange (CdLS)
Pełen tekst
(2)
(3)
(4) !
(5) "#$%& '()
(6) *
(7) !+)*,-. /0123054551 6107 58. 905954: 14545 4656;502;3<5 =5523;>3121?333@;4;6: 3 @55A7 3;?1B434;07:6;67C;5:924;?1 D
(8) EF301GH50I5JH4HK;5HL54772M3K14. N O'PQRR .
(9) 34565789 5 5
(10) 65 8 69598
(11) 55745 00 0.
(12) 2342567894.
(13) 252
(14) 9265
(15) .
(16) !"#"$% . & 2'($%)*+,"%-" .. 1 2,(),-)$/- .. 0 1()2) 3. 4 3$%)2$"/% 5 & 256729747 & & 625695 0 1
(17) 2573 1 $!/29"#8)9 1. )+)")%"$%)$!2'9"#8)9 . 1 & :#$!2'9"#8)9 &0 1 & ,!$+ &4 1 & 6)2)"#2;9<=%"'%'")>)%)?+",$,$@ &. 1 & & 4 ()2),!$' &5 1 & 1 )$)#'*-),!$'+ 1. 1 & 0 :#)%-'*,!$'+ 10 1 & 4 7%)('"),!$'+($"--)'+"+ 9#82 1 1 1 1ABCDEF 1. 1 1 1 BCDEF*9!"#'%()2- 1. 1 1 & ;'%)*BCDEF)%!$/(+"+ 13 1 1 1 69')*)$!"$*9/-!!"()24368<-%")* ,!$,+@ 15 1 0 ;'%)*9/-GHIJGHIK-$!9"#8)9 01 1 4 :'L")")L)*9- 01 1 4 :'L")")L)*9'BCDEF 0. 1 5+,')"-"$%-)-!$'-)','%)* 03 1 . 3#$',-) 4& 1.
(18) 123454678392222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222 1. 2 8
(19) 47 89 4
(20) 9222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222. 22 22222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222. 22 222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222 . 222822222222222222222222222222222222222222222222222222222222222222222222222222222222222222 . 222!!"2222222222222222222222222222222222222222222222222222222222222222222222222222222222222 #. 22$2%" &'&&"(&!)!*22222222222222222222222222 +. 2212 *,-8 *./'&"&0&&,222222222222222222222222222222221. 22 2 *,7-82222222222222222222222222222222222222222222222222222222222222222222222222222222222. 2222!-82222222222222222222222222222222222222222222222222222222222222222222222222222222. 22#28.*/",("&!,",3,4!5678922222222222222222222222222222. 22:24*"/4&22222222222222222222222222222222222222222222222222222222222222#. 22+2%("(&!!,3).4/&;653:. 22122"&!,!&!"'&637222222222222222222222222222222222222222222+. 222<!&&.,&.,("!(!((!( ("!.7-82222222222222222222222222222222222222222222222222222222222222222222222222222#1. 2224*"/*"*.&222222222222222222222222222222222222222222222222#. 22$2<!=)!=,22222222222222222222222222222222222222222222222222222222#. 22126'&!&)0,4!.&.". >3?;22222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222#. 22 2<!"(44,! &"(!.)!";65322222##. 222-@ABCDAEAFG22222222222222222222222222222222222222222222222222222222222222222222222##. 22#28!*((!2222222222222222222222222222222222222222222222222222222222222222222#: 2%9- H 222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222222#+ 228!*.,!"&)4!5678922222222222222222222222222222222222222222222222222222#+ 222<! .3;653("&!,!&!22222222222222222222222222#+ 222<!!.-82222222222222222222222222222222222222222222222222222222222:$ 22$2I(&!.,!"&)222222222222222222222222222222222222222222222222:1 22$22!0!/.!.,.!(!(22222222222222:. 2212%/", .!&("&!,)!&!) 0" !2722222222222222222222222222222222222222222222222222222222222222222222222222222222222:# 22<!"(44,!'&,!'&222222222222222222222222222222222222222222:+ 1.
(21) 234356789
(22) 9 66
(23) 333333333333333333333333333333333333333333 23433 8 533333333333333333333333333333333333333333333333333333333333333333333333333333333 2343356!
(24)
(25) 8 "8 66
(26) # $%&'333333333333333333333333333( 23)3*6+,66 +,9+ 33333333333333333333333333333333333333333333333333333333333333333333 -3./012033333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333) 345670163333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333( 356869556$:47333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333333. 1.
(27) 12345678681492 63
(28) 7 1. !"#$%&'(%')*+',+#-." / 0123 "45 6789:28;9<=>?:<9@;6232@A ! 87;1=:3B C @;DE?<7?3989F?=398G:3B H 3?;1 H) 37<I;2 -" @?6I<:2 J >?:<9@;62?<KA3I L 198;M>?:<9@;62<2N7DO72?8?6;1AOK<?09 C 3?02=PQ " 6789=PQB , :?OA=PQRP % O?<;A=PQRS H 3787=PQRB T 37619=PQR ) <2<9=PQRU * N769=PQRPS .
(29) 12345678681492 63
(30) 7 1. !"#"!$ % &'()*)& %+, &'()-./)-01*2-32-1&) 4 5/0-./)& 6678 9-'&:-'9;<)*('(30/=-9&)& 6>+, '(-?3/)@?=(-0/'/A&'()*)-9/BC@&)*)-9/B0/D*)-9/*5/0-./)-9/E 66>+, '*'(-?3/)@?=(-0/'/A&'()*)-9/BC@&)*)-9/B0/D*)-9/*5/0-./)-9/E FG+% ?9&3(0/=()-'*&D*)-0(01&-50-9/AHIJKLMNMOPQRPNMSTMIUQQVMIPVSWVPXE Y C@&)*)& Z748[ 9-'-1-9\C=&):-0&3@ ]^4_ 5`=-1(?D&C)(.@ >4_ 5`=-1(?3-'@ >7a4_ 5`=-1(?&D-)@ bc4 d@2-1'-=*./(1/01-5/0;9AeMXSfLggXShMLLSLKiPiSjkllMUE G '-'(5/=-3*&15.&)3-'@AmgXPkRSOgXMVKLSmkLnJQIME + 0/D*)& +%F d@2-1'-(=(?01-2-1(./.?9&3(D-50-9/DAoUPiSpSWVMIQIMSpSqrstE +cF d@2-1'-(=(?01-2-1(./.?9&3(Dd-1)/DAoUPiSpSfgUQIMSpSqrstE +bu vw&D*)-wvw`/'1-?3/D(0/=-wxByw:1-:&)-'*-= [$"_"z#{# %|%_} &=&)*)& ]|]} D(0*-)*)& 4|4$} 5/30(*)& >|%} &3:&1&C*)& G|%~} ?9&3&3:&1&C*)-9/ ,|,!"} :1-=*)& F|Y_} ?9&3C=@0&D*)-9/ |Y_} C=@0&D*)& |,} 2()/=-&=&)*)& b|%!^} &1C*)*)& Y|Y_$} C=*5/)& |!} 3(1/)& 7|7} `*30/'/)& +|+!} 01(-)*)& u|u_} *.-=(@5/)& |_} 9&=*)& Z|$} =*./)& |+!~} 01/:0-2&) |} =(@5/)& |+$!} 0/1-./)& .
(31) 12345678681492 63
(32) 7 1. ! @! CDE TUTV aOb! cd@e! aOst! wxyz! {|ET }~ {~ txt! @! CD yz yst! ys! E~E sxO! st!. "#$%&'()$&*+,$(-(.(%,#-/,01234567819:;<5=1>? "#$%&'()$&*+,$(-(.(%,#-/,A234567819:;<5=1B? (FGHI,$(/H-&J,+K(2LMN;5!O5=PQ!RSPQN;? G,(W.&H+K#/)$,+KX+#J-#"HF(+Y,)-($/.-Z%+Y,2[[[\[]SN;^N;_18=6;7<=N`8NL;6R1 N;7PR68L=1`=L85N;? "#$Z.&'HYX+#G,(W.(K-&'K,$Zfg82hi86SRN7jQ5;81Lk19lj57NL;?m H+K#/)$,+KX+#JH)-KZI($,H.&n#KY,mJZ-op$,(/,q.,F.(-&'K(YoJmn&I&F&" r7Lmr<L> "#$.&'HYX+ZG,(W.&/#%(-Z$qmn&I&F&"r7`>u1[P8>u1v75 "#$.&'HYX+Z"F#Y&%&+n&'$Z+KZ$$,.JK-&/)H$#-JoJ '#(+#)ZF(KZn,/)&$&J#mJZ-op$,(/,q.,F.(-&'K(YoJ G,(W.&I&'#FHYX+#+n-&I()Z$q2585=L<j=LQ68N;1=L85N;1>? "#$.&'HYX+Z-#+#%)&- "#$.&'HYX+ZG,(W.&4A2n6. ?G,&-X+#H'K,(WJ-#"HF(+Y,.&n#KY,m n&I&F&"v<<mv7R G,(W.&K(($"(p&J($#J$(%-(Jq%&'JoY$Z+n%q.$,q94mJ+n&'K,J/.W(' .&I%F#./H
(33) 9K$,G-Z$X,
(34) 4 G,(W.&$,G-Z$(K(($"(p&J($#J$(%-(Jq%&'JoY$Z+n%q.$,q94mJ+n&'K, J/.W('.&I%F#./H
(35) 9KG,(W.,#I
(36) f00,
(37) 4 "#$/H%-#/&-&JZm.&'HYX+Z$#H-&,G-&I,$q "#$.&'HYX+Z'#F($",$q29]G,(W.&$,%%#']]F,.#?mn&I&F&"v<<BmN7m N``5^] "#$.&'HYX+Z$H.F#&%&-Z$q&I(/,#+KX/)#+K.&J#Y0.( &/&+K&J#G,(W.&+,Xp&J#42E]-#"$($+ZE//&+,()#'F(/I(-&)#,$? "#$.&'HYX+ZG,(W.&6G,&-X+#H'K,(WJ-#"HF(+Y,.&n#KY,2=5<L<NLP71 N77L<N685^1Lk1iN785=? "#$.&'HYX+Z.,$(Kq30H+K#/)$,+KX+XJH/HJ($,H.&n#KY,m2LRL N¡51 ¢N;6751>?n&I&F&"v^<u1£RL>u1£LRL1 .
(38) 12345678681492 63
(39) 7 1 56789 HIJKL V6 W9X8Y Vbb W9XcY Vef96g Vif W9XjY nHo q6e. !"#$%&'()*+,-./012-.)34 !:#:(:;<=>3?13@A.+BA+313CB.2,D%&'(EFF,% GF*, !: MN NO#N$ONP&O$$QR94%N&:N"! 'O("S
(40) 9:!'S
(41) TUU# ! :#:"Z#' (;[1\@4?].=A13^BAD%:674_% N#PM"$( #:PN%&'(`\\,%)+Fa #PM! : MN N&:$;[3+1B\.bd\@4?13*. b@dB+3@AD !:#:T447hZ#"O#Z#(Z' ! &#'"'NON:(: #:$ Z#(kQ&#'"'PN;[1\0F10\?].l?3A1BA?AFB.@m.bd\@4@+@4B+D% N#PM"$( #:PN! ! #(O#""!'
(42) 94;[B\3ABp?\^3A3AB.<3FdD !14r4s;14rsD#:!N#(&:%;t3A^+. =u?\1vw3xB.,D&'(y?*z,-.{|],-.{?|] .. }~K~o o~o o Io IHo no Jo Jo Jno. O#PNN: &#:'N '#' #:;=\\?. f@4|?\?13CB.BA@43F.\3*3+?13@A.D "NONZP#:%o#Z#Z#"O:oo "NZN47;b@dB+3Av=++@F3?1B*.<B^3@A+DN"Z$O#MM :"OP! #(s (Z##: M(&:#Z': Z#;7BA?10\3A^. \?*3BA1.B].]BF1\@|d@\B+3+D Z# N""O#NkN &#' Z#:N ;7BA?10\3A^. 3^d.B\m@\4?AFB.e303*.fd\@4?1@^\?|dD O$$R94;7@0]BvV1\?A*.\B?x .
(43) 12345678681492 63
(44) 7 1 6789 6H8IJ8 TUV 9] 9_]I 9qr A A UwUx Uwqx U7V_ |}~} rU] V]9q V9_ VU8 Vr VI. !"#
(45) 94$!$!!% &'()*+,-.*+*)/,)01)+234 !"5!"#
(46) 94$!$!!% &'()*+,-.*+*)/,*.2)+234 :$;!<%<5<#<*),=*>?&@.?(32=+2)+2,A),*>?,BCD3*E*F1>*()G !KL#"$<<%M<!&@N3O,>1..*)/, 1)E,PQR-.1>2,S*>+0*)/4 !5"9WXYZ5![M<[$;M\ $%M!#;$K&B2>23(E?-.2',^)1.C=*=G #!<#$[<5;#!$!!M<%!MK`!K &abcdeG!#!#$MKf<5"&B?)>*)/>()g, .()/1>*(),h1+>(3ig,>02,jklmn^,=?D?)*>,(h,jjop,1)E,>02,.*-*E,O*)1=2,P(34 #M;s94<!!#$!t&B*/0,u2=(.?>*(),v2.>*)/G !"#
(47) 94$!$!M!% &A)>3()*+,-.*+*)/,)01)+234 !"5!"#
(48) 94$!$!M!% &A)>3()*+,-.*+*)/,*.2)+234 $!K!<!#!$:!5$MK&yCR-0(D.1=>(*E,z2..,y*)2=4 <!%!!$![ M<M<&y(S,z(-C,u2-21>=G #";[ !!!#!&y()/,A)>23=-23=2E,{?+.213,.2R2)>G f< $f!#$[<"`;%!!$<&v?.>*-.2',y*/1>*() E2-2)E2)>,3(D2,^R-.*h*+1>*()G $$$!5%!!$![&{()^..2.*+,B(R(.(/(?=, u2+(RD*)1>*()4 %!!$!["!`K&{()B(R(.(/(?=,)E(*)*)/4 #!!#!#$#"!<M!M5"!\#! &{?+.2?=,y(+1.*=1>*(),*/)1.G #[##"![!
(49) 94&{()=2)=2v2E*1>2E, 2+1CG !t:"#;![!cM!<5#;6"!#; .
(50) 12345678681492 63
(51) 7 1 "# '()# '@(@# 'GHGI# "Q# R# TU#VU## )'W# @(]^# @^# @]fg# @f'# @@('# klT# q@r#. #. ! $%$$& *+&%!$,-./012345637895:;7<35=>:/;? %%$,,%AB.43=/=:/C67D:6>347 894/25>:E7D3F545>:/;? $,*9JKLM&$N!O,!*$ KP , $*&S%$$& N, *,$X!-<5>:/7.4/Y37Z2F0:[:=5>:/;?,,,, %\MK4 N_*N,`-D3a34378/2Y:;3E7b22C;/c3[:=:3;=1? ,%$S!,,-D3d23;>507eCF0:=5>:/;? !!O-D9/4>7b;>346F3463E7hC=03547i0323;>? !,$&,-D:;d037hC=03/>:E37./012/4F9:62? X$!!,,%j94BD:;d037D>45;E78/;[/425>:/;7 ./012/4F9:62? +`m$%$$&-nop2:;50? &SXP,!_$S,. .
(52) 123415654784.
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
(54) 123415654784.
(55) !
(56) !"#$ !%&9'
(57) (
(58) )*9'+,'-./" 01$2 )93./"(
(59) 456789:458;: )<99./"$
(60) )<-./
(61) ($
(62) $ 2
(63)
(64) )<=./
(65) (
(66) "
(67) $> %
(68) &
(69) 0 >$ ! !(2
(70) ( ? ( &@A2
(71) (0#1
(72) ! B.(%2
(73) $ (0#
(74) (
(75) ! ! 2
(76)
(77) !0(#1
(78) !
(79)
(80) ( ( 2 !
(81)
(82) (
(83)
(84) ($?
(85) ! % 2$ ! (
(86) $( %
(87) $
(88)
(89) AA
(90) C$(& (
(91)
(92) & D:4EFGF
(93) (6$H1A>%1 ( (>(
(94) %(I( ! J
(95) 2(
(96) $ !
(97)
(98)
(99) A KLMNO(
(100) > !PHCJ (
(101) &
(102) (
(103) $(
(104) A == ! !(2 (> (#
(105) > >A AQ$ !
(106) (2
(107) (? 6$H1$(
(108) 0
(109) &A
(110) 222?
(111)
(112) !(
(113) ((
(114)
(115) 6RS
(116) (
(117) &
(118) ">$2 !'TAC(
(119) ($2 %
(120) &
(121) %(
(122) &9"BP (" %AKLMNO(2
(123) 2(
(124) >AUVOWXYZ[4\O]XZ^Z[4K_MX``[4abcde
(125) (fbK\ gA
(126) $2
(127) "2# h"'P ("%
(128) &
(129)
(130) ((KLMNO4(A4)\O]XZ^Z[4 K_MX`` (0#1abcdeij ! %
(131) $
(132) I $(
(133) >> (0#1$ !
(134)
(135)
(136) A !($(
(137) &KLMNO4 ! !(6$H1j4. 9.
(138) 123415654784.
(139)
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
(141) 123415654784.
(142) !!"8 !!!!#$%&'( !!" 8!)!!*((!+ "2 !!(!!#$%&', (-.,/010!621!" 2!((!!#$%&',( !(3245!(66!*! !!!! #$%&'("2!!#$%&'(+" 27!)!! ! 689"2! (!!7!9"
(143) 3!7(:;'<=>?*#$%&'* @'A=?B?*#C%=DD*EFGHI*JF#@"2(!!K"L 3 !#$%&'*@'A=?B?*#C%=DDEFGHI("2! +((!(!!#$%&'(( 621!". 9.
(144) 12345. 89
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
(146) 12345. 89
(147)
(148)
(149) 9 9 !"## !
(150) 8$%& 8 9$& 8 9'(2 # 9 8!
(151) !
(152) 88 8 8)*
(153) 9 +( #,- 6./0 16629 9
(154)
(155) 8 8!'
(156) ( # 38)'
(157) ( #8$!
(158) % 8"
(159) 89
(160)
(161) 94# 8$ 8 9 8 656 65/%
(162) " 9$867 8 &8 % 9
(163) 8
(164) 9
(165) 89 8
(166) 8! ! 9) 8 8
(167) 899. 89 38) #!8$
(168) ) 99$8699!"!91
(169) )& 8$8 9 98!5 899
(170) 9%$ 8
(171) 9$&
(172) "#!
(173) #9+
(174) !9
(175) #$! 89 8
(176) 8$" )9
(177) "9 :
(178) )& 8$8 7 !
(179) 9 99 9 6
(180) 9 1 8$%&
(181) 6999 88 9
(182) 9)% $ 8 "!
(183) "8
(184) ! 8$ "!
(185) 9 8 %
(186) !
(187) # $68 #
(188) ! !
(189) #'
(190)
(191) 8989
(192) #!%&
(193) # 8!8 89$8!&$989899 " ) 9 8$ 9 8$!
(194) 9%
(195) 98 $%
(196) 8#! ;<=>?@A=?BC%! #$
(197) 6$"
(198) ;?DEFG<>D?C%!#
(199) $8%98$9 9 &!9 $
(200) 8
(201) 9 H9 ; 9$69#)
(202) 9 C4
(203) 8 8$ %9 & !
(204) ! 7
(205)
(206) %89#)
(207) !8$ H9,-88I.%1
(208) " 8I60 5
(209)
(210) 9 8
(211)
(212) )9 8$!9999#!9 #&9 9 & ! &7!&9 8" H
(213) 9 9 99 !
(214) 8#
(215) 8% )
(216) 9 8
(217) 8$ &
(218) 69
(219)
(220) 69
(221) ;:3C1 !8$ &"&8$&" 5J55J: & $ 7%& 89 99 "8
(222) &
(223) 9 9 ) ,J
(224) "!K 8I104
(225) 89 & "9 98 L 99
(226) 9'(2
(227) 8
(228) ,2I601" 9 M2N 8
(229) 8$
(230) 69 8999#)
(231)
(232) %
(233) 67.
(234) 12345. 89 9
(235)
(236) 8 ! "#$ %&''( ) %&'66*%+ $9 , !8 ! 8 99
(237) 9-"5
(238) %&'6'*%# !898 9- !
(239) , - !9-8 !
(240) , 9 #!.2 89 9 ! . $ / 89 !,
(241) 9- - !-8 !8 % 1 9 9908
(242) ! $ -89-89 8-9 -8 ! 1
(243) 8 !!
(244) 0 80 , 9- !
(245) 9 0
(246) 8/ 89-9 0 9 90 8 89$"2 8 %&''75
(247) % &'6'*% 3! $ 9 9,!$-008 !9 898 9
(248) 89 !9 $8- 4! ! &5
(249) $67780 5'(808") % &''9 : ; %&'6'*%<
(250) 8 0 !9-0 9 $!9 . 8 9 8 9 "2 8 %&''7*%1 9 !9 09#!.2 9 -89 91!
(251) 8 99 $. 9 99 89 !9 8 9!-8 89 -0!9 8 1 9-
(252) 0-
(253) -/
(254) $ 8- %=-
(255) 9 $ 9 8, 9 8
(256) 8- ") %6((5*% : 89 8 9 $ $ 998-8! ! 65'> 6?'80 95'>67
(257) $%@ 0 ,!$- 9
(258) 89 9 9-89 6(80 89 !9 8 0
(259) 8/ ") %&''9 *% A- - 9- !9 8
(260) - -89-0 88 0 -0 8,%@ !0 8 0 $-9
(261) 8!98 ,
(262) BCDEFGHCB!$ $ 9 - -,
(263) 0 9 -0 9-0
(264) -8 8-0 !! $9-") %&''9 . %&''( *%3 989 9
(265) 8-8 989 99
(266) !9-0 8
(267) - -89-0 0 0 9-0 "I %&''(* 9 8/
(268) 8
(269) 889 8 99 9 % J !9 89 9 8!98 $9 !9 (7K 8, !$ !0 !
(270) 89 -89 - 8 !,8 9! 8((K%L - 9 -
(271) ! !9
(272) !- -8999-0
(273) . 0 8-0 %M77K8-8
(274) ,
(275) 9 9
(276) 0 $9 0 9 ! -0 9!9 0 -
(277) ! 4FGNOPHQR8 67.
(278) 12345. 89
(279)
(280) 89 88 9 7 8 8 ! 8
(281) 9!"#
(282) 89#
(283) ! 85
(284) $ $%& "89
(285) #'$!""
(286) 8 "#989' ()* 8' +&&, - .8 !
(287) 9"8 / #
(288) 0 89 '" 8 98*9
(289) ,1"
(290) 8 " # 0 !
(291) $#' "(2 8'6773- 1"'" "'' !8 0" 9
(292) 9"!4"9 1 $ $$ $
(293) "$'"9' 8 8$ # #0 8 9"8$8 ! 5 *6 $
(294) !89
(295) #'8 /"0 9
(296) ' * 7 *
(297) 9*. 6*8 " " " 4"9 9 $89
(298) #'$!"#9$' $
(299) 8 '#$ " 8 8 $"$8 " " 8$(: 8'+&&%- ;7&' $
(300) 8"" 8 94"9 8$# 8
(301) 9
(302) 8 "9"9/0 ''$ * '8"$99 #" 8 " "'9 * 9
(303) 8 8 < 9
(304) 8 " 9 " " ! 9
(305) 9* "*
(306) 9* '!
(307) ' * .' 8 894"9 * 9 !" " " " $"#9' $
(308) 8
(309) '98 0! 9 "9
(310) 9*!
(311) "' * ()* 8'+&&, -1 $'9 88 ''$ * *$ $4"9 9 * $(: 8'+&&%-
(312) 89" $ 89
(313) #'$! 8 " "*
(314) 89 !" "
(315) $ *" 6" #' ! =
(316) '" ()* +&6&- $"#9$ 88 9 >7& 9? " "4 '"8 ' 8" *" #6*0! 87'"98918*'"9' 89
(317) 8 $" $ $'* $89 $!"
(318) $ *!"#
(319) ! '"9"9 !" 889 9;' $
(320) 8
(321) 8 " #
(322) 0"8#" 9"9 '8
(323) '"9:
(324)
(325) *" ' * 8" 08@"'" $#
(326) 0 '"9' '"'* 9'"' 9 " ' 8 898 8$*
(327) ()* 8' +&&, -;&98$#" $" !'9
(328) *
(329) 9#$*
(330) ""#
(331)
(332) 8 "9"!" ' ()* +&6&-2 "8
(333) ' $
(334) 8 8 9 $"#9$ $
(335)
(336) 6
(337) '" 9# "98$*'" 8$/" 9!9/ 0 2
(338) 9* 8*
(339) ' $
(340) 8 89 ' $ " $)*$ ' 8 8989
(341) #'$! 61 7& 9.
(342) 9"! "87'8 "!#8 " "48 8 67.
(343) 12345. 89 9
(344) 2 98989
(345) 889 9 9
(346) 9 29
(347) 8!677"#$ !677%&'(8 99 8# 8 )8 9* 989!+9 !8)
(348) 9!,898 -. /01/" 2#
(349) 93!39!+ )3!+89(394! 5
(350) 89!6776&79
(351) - )! 3 8
(352) 9 #(9 !89 !9 89! + +9 )89 8 8++! 49!
(353) 98!9 # !9 ( #8)!99( 8-! ! -49
(354) 998 5
(355) 89 67/7&1 !98 !9-89 )! 9. 848) 9 9) 9!
(356) 98 - #8
(357) 39) 9 9 - -# !
(358) 98 # 9 ! !89 3 8 9 89! +- 9 58 9
(359) !989 88#8 8 89!9+8! 889
(360) 9
(361) 89 !9-89(+ -.)! 39 97: - -2# 3!389! !899 !
(362) 9989 5
(363) 89! 6776&29(
(364) 89
(365) 83!39!+ 3++#
(366) 989 !+ ( 3 )
(367) 89 +8,) # 8 !9 8 8)9 !9
(368) 89( ! ! 98 );98 ! ( ! !98+(83!3- 98! 9)8
(369) 89 1 998 3)!
(370) 99-9 3 89 (9--<88 !
(371) 3 8! 89 ! 1 + !+ !98 ) 3 !3 9!+ )! 9 !
(372) 9989 - 8 =
(373) >9 !67/7&7!98 3) 9 +988 8988!+ 5
(374) 8967/7#2>8-!67//&?- 39
(375) (88 8)#88939! ! ( - 89!3! 9
(376) 81)! 3 9889
(377) (899-
(378) 89# - 8
(379) 4 8!
(380) 4#8989 898 # 98 !
(381) 89
(382) 8
(383) ) 9$
(384) 9!6776&8889!+!98 (88989! +98!)9)89! 939)! 9899( 9#-49 ) 99(8989 @9 8A2 ) ! )#
(385) 9 89! + 9( 893!9-89 5
(386) 89!6776&1 9
(387) ! ! 67.
(388) 12345. 89
(389)
(390)
(391) 89 8
(392) 89
(393) . 8
(394) ! "6##$%"1&
(395) '(
(396) 89
(397) &
(398)
(399) 8 ) *"+ , 89 89
(400) &
(401) 8
(402) , '(-' ./ 0
(403)
(404) 8* 123 , 45
(405) ,0 8
(406) ,
(407) 08
(408) )6 7 88"6##9:6#7#%" 7
(409) & ) 8
(410) 0
(411) 8 0 8
(412) ,8 ,
(413) 0
(414) 89
(415) -3)"73
(416) *,68 . 0 8 8
(417) ,-3)"63" 3)"7": 0 8
(418)
(419)
(420)
(421)
(422) ,; <0 :"6##=%" >?>@AB B CDEFGAHDH?BIJKG?JLMNB JKFKBGHAJOKB PQRSTUVQW. JDONLAJKB >LA`AB. X6 0 618
(423) 618 . )*0, 668 - 893 JDOHabBB X7 *_ , )
(424) OA>@DHAcL?BB X6 ) 8 8
(425) ) '8
(426) 89 ) d * 0 . 8
(427) ', '()_ 8 8 889
(428) . DJAOB EDEAGIDH?BIJKG?JLAB X2 ,0
(429) & *
(430)
(431)
(432)
(433) ,0 TUYZ[V\]^
(434)
(435) & 0
(436) ) , ) * 0* 0
(437) 8 , )
(438) .
(439)
(440) &) )_ 89) . 67.
(441) 12345 789. !"#$%"&%
(442) 8 '%('#)*%$+"#+'&%"% ,)' * . -#&"! '.*-,!*/0. 89:; 12 ' #&%" '.%" !.7-"&%"&+&','.'3+!'."('
(443) 9<
(444) 8 =)'.!'/!&'6> %($"&)/5.'=+&". 8<9 .!''."(' (+/0')&%"#',+/0 &#* #/!'." ,=$$'.) 0%,)*!$ $+"'#.%,)'."%? 7"@
(445) 8 12 !"%& !"'&'. &%".%#+'.'6/%-'+A#'.' 89:; 5"%)'." "B,-'+A#'.'C !"+*'.* '!,!/!" '#&%"%"&% .#*,"/ $%' "&%, .&7)',).' ,'#!%"/).' .#*&""$'/!'.'#=.@. 3 16 %&'#)*%4 / &%".%#+'.'$%"5,/'.%'&* /% '(&%/!"&%"/0'$'6/%,). +'/%'."(' 12 !#&#+'&% 0, /!76/%'.,*&#)*%6%2 / ,'%'! "5'.)) %",%'. !.%/0&%7)"%'#'. 66.
(446) 12345. 389 6 2
(447) 8
(448) 8
(449) !!" #8$ %&! !
(450) 6''(8). *+,-.+/012 8
(451) 8"!8
(452) 8"!
(453) !"!
(454) 8"! A" !"!!
(455) $
(456) 8 8" E $. 32405*-2 :6;<$ "> :. "BC :. "6D :. 62405*-,2 6=6;<$ !?" >86' :. !?" BC=D6 :. !?" 6D=DC :. 72405*-892 !:6$ @!!:6' :. @!!:D6 :. @!!:DC :. ?!8" !?:!8" F9 F9!?!:6 !!:68G 8G !98! A89E '=B 6=7 !?!:7 8 8
(457) A 98 8$"8 !888=!?:8 :66 H
(458) 8!?:8=8
(459) 8 !?" B<!66 8!H
(460) 8!888F:!
(461) !? :!8G !:669B<H
(462) 88$"8 98. #! "#2
(463) 98 !8$8: 8 : A
(464) 8! 8:!" "8 !!?:!98 I
(465) : "! $8! 8 8 8! " !A !889"@ 8 !
(466) 8!! 8 1! ? 8 8!8 !!" !"8 8 8!A A
(467)
(468) !!!!
(469) J8"8:
(470)
(471) ":!
(472) 8!!8A$88$$8! "K88!8
(473) !? !!8!"!8!?!!?! 588 !?
(474) !A A
(475) !$ !?
(476) 8"!$
(477) 8!8
(478) !? %1!98 !
(479) 6'B'). L"!"!"9""!8 8E88 8! "A89!! 8!888 "!! 8 A " 8!! M!!:
(480)
(481) 8!
(482) 8":8!
(483) 8! !;A?88!8!9!
(484) !$ 8 ! !
(485) 98!;"88 !
(486) 8"98
(487) ?8!8 8A8E 8
(488) A A !88 @!!
(489) A $8
(490) 8
(491) 8"?!"8!;"8@!
(492) 8! $88 67.
(493) 12345. 89
(494) 989 9 9
(495) 8
(496)
(497)
(498) 6
(499) !8"#$%
(500) % 89
(501) & % 8!$9 "
(502) $
(503) 9 9
(504) 9 99$&9'( 8 9
(505) 8
(506) &. %89 )8
(507) &&)
(508) 9 *8"$
(509) 8"$ 899)8!99
(510) (
(511) 89
(512) 9 8 "
(513) 9$) (
(514) !! ! $
(515) +,) &
(516) +,(#!- 989 8!)9.9$ )
(517) #!%/-
(518)
(519) $&#! 9$)
(520) 8$#9
(521) 89 89
(522) $9+99 0#.9
(523) !
(524) !(")8!)89,
(525)
(526) )
(527)
(528) !81)22198 63' 49 63'5
(529) ( 6369&)
(530)
(531) !((
(532) !(
(533) 9&9 ". 8! 89
(534) ! 89#!$
(535) !
(536) 8(9$&'89
(537) 89"8!
(538) 9 9 89 989 8999 !8
(539) + $0!'9
(540) )
(541) 9 8! 9 8
(542) 9
(543) 9 !. 89)
(544) !8% 9
(545)
(546) 8&7963 836*89)889989
(547) &1
(548) 9)929 1"$ 8
(549) +, 8! )$0 89
(550) & 9:;! " &9
(551) )!89'8
(552) #
(553)
(554) +, .9
(555) ! & & 8$
(556) )899 9&
(557) 0 &9
(558) 8 89'#9
(559) 998". (
(560) 898#
(561) 99 9990'& 9)9'$09
(562)
(563) )&$ 9 !
(564) " 9&
(565)
(566) %3
(567) $ 673$98
(568) #9 9 9<=>?@'$0!8
(569) 8)9!.$
(570) !
(571) 8890
(572) !( )(9
(573) &8#
(574) 9
(575)
(576) $9 (
(577)
(578)
(579)
(580) 9A9 )
(581)
(582) + $
(583) ! 9& 90 81)22!$! " 8)$
(584) ' 9)8
(585)
(586) 9)$ 8#
(587) 9 9
(588) & / 38 9#9 (
(589)
(590)
(591)
(592) 9 9$0!( 8! )$( 1)22B) 9
(593) 9
(594) & !$8 !' #98
(595) $8
(596) ! 9 9 <=>?@'$09
(597) &9 % 8" 8% 8!8!% ! "
(598) (
(599) 893
(600) $ 67'78 67CA99
(601) 9)$ 9)!! 8!$9 99!8!
(602) %8! 889
(603) 9
(604) 9 &)
(605)
(606) )
(607)
(608) $#9'!(
(609) )8(' !&9&DEFG8
(610) $8
(611) 9
(612) 9
(613) 9 H 336I99 6/'J&
(614) 6K1
(615) ((!$8
(616) 9#' #9$
(617) 9! 8!$9 !
(618) &%! 1)22 % &9 9& DEFL 9(
(619)
(620)
(621) 3M6/6;*9)
(622) .. 6NO#
(623) 9!(908"+9
(624) 9&9 "
(625) )!8!( 8(
(626)
(627) (O9 % 9)$
(628) )8!' $0!( 89 0 ! " &9&$$&8
(629) $05&. 9 63'B
(630) $ 6K'29
(631) 6N1!$8
(632) 09#'#99)9
(633) 9 90
(634) )8089(9
(635) 89
(636) & *9)
(637) .. 6K1!%$9
(638) % $8!, &)8 !( 67.
(639) 12345. 89
(640)
(641)
(642)
(643) 2
(644) 9 9
(645) 8
(646) !"#$
(647) 8%9
(648) 8%&'% (
(649) )6**+,)- .
(650)
(651) 9
(652) /
(653) 8%9
(654) 0 1
(655) 9
(656)
(657) 0
(658) 9
(659) 8 9 8
(660) 23!456&7
(661)
(662) )6**81
(663) 8%
(664) )6*99,)5 9 9 89 9
(665)
(666) 8
(667) 23!45 & :
(668) )6*9*,)7
(669)
(670) 9 9 .8
(671)
(672) /9
(673)
(674) 9
(675) 8 9
(676) ;
(677)
(678) 9<
(679) 8% ) =>?>@ABCDEFGH@GBIFJKLK>@@ 5
(680) <M 8 ;8 9 8% ;9
(681) <
(682) 0;N ; <
(683) 9)O %9.
(684) 9
(685)
(686) /9
(687)
(688) 98/8% )1 8
(689) 9
(690) <
(691)
(692) 89 8% .
(693) 9 ;9. .8
(694) < <;89
(695) 89
(696) 8
(697) P7Q 8
(698) M9 2 8 M9 89
(699) 9
(700) < 8%) 789; M9 %99
(701) 9;88% 9.8
(702)
(703) /98
(704) 8%0
(705) 98
(706) )5
(707) <99
(708)
(709) 8%
(710) 9
(711)
(712) .8
Powiązane dokumenty
Even in the case of pitching around the leading edge of the first profile, the thrust is delivered mostly by the suction force of the second profile (figures 8.2
Homozygo- tyczne zarodki Brca1(-/-), podobnie jak w przypadku innych modeli myszy, za- mierały w życiu płodowym, jednak doży- wały nawet 13,5 dnia życia płodowego, ale
Estimate of the (a) selection functions versus number of revolutions and (b) breakage functions based on data at 100 revolutions for natural and recycled
In hoofdstuk 2 wordt kort geschetst wat wordt verstaan onder het kantoor en welke techni- sche mogelijkheden het kantoor momenteel ter beschikking heeft. Hoofdstuk 3 is
Mimo że fenotyp dziecięcy w okresie dojrze- wania i dorosłości się zmienia, to jednak za- chowują się typowe proporcje ciała z mikro- somią (dorosłe osoby z postacią klasyczną
Dotychczasowe wyniki badań sugerują, że obecność allela D nie zwiększa ryzyka uszkodzenia serca, zapoczątkowującego jego niewydolność, ale może działać jako
Oceniając wartości parametrów analizy czaso- wej i widmowej w spoczynku w badanej grupie cho- rych z kardiologicznym zespołem X, wykazano ob- niżoną zmienność częstości rytmu
Warto jednak zauważyć, że odsetek zgonów z tego powodu się zmniejsza, co jest spowodowane coraz lepszymi możliwościami leczenia tej grupy pacjentów, ale również wiąże się