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Introduction
%-,M%
%-,-, " " " " " "" $ """&" " &" " M # 2 & "" & $ " $ " " $ $ " # * & " $ $ $$" - $ " $ & $ ": $ "&"# & " " $ $ " 6 & ($ ""$$" # $ - "" 1 #S & " & " $ & " F ' " F $ " F S " " $ " " " & FS "" " """ $" $ F' " " &"$ $ " F9 1 &"& $" ($ " $ & " " "" " "- '*9 '9 " $" $ $ - "" - & " $ $ $$" - #
Q Introduction
S $ " -$ $ " ""- $" " " &"& $" & $$ 1 @PA#2 & -$ " " & "$ " : $ " & " # "$ - " : " " @HA- " " # " " &" $" # % " " """$$ " $ & - " - $$" " O P " " $ " " @QA# ' $ "$" - $ " M "& " " $$" " @RA# & $$ " $ & " - $" "&"#8 - " - - $ " & $ ""&"# & & ($ " $" -" &"$ & : ") $ " $$ : $ " " $ " 7 " $ " " $" " & "" "&" M - & " "$ $ $ " $ " $$#'& &""" &"$ $" " " " $ @UA $ """ "& " " $ $ @WA# R Introduction
%-,-*$ * & "& & $ : "
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U Introduction
& - & & $ "# % & $$ " " @XA#"& $ " : $ " (# $" $$" "" & " - $ " 1 "& " " "" M " " & " $& $ @PIA & "&" " " " M $ $ $ " #8 & "- " : ; ; " @PPA- & & $ $$" @PHA# $$" 8! ($" " $& " " "" ($ "" " $ ! * : $ C#H "# S " " & - $$ & $ " $$ & " " - - & $ @PQA# 2&- ($ $ " - $"( ) &"- 1 $"($$ " #&"$ " &- - $ ) " " $6 :" :" &" # 9 :) $$ &( &"$& " )"&" " @PRA - - O "" P " @PUA " : $ " " "" : " $$# - " ( - M "( " $ )
W Introduction
" # - " $"( " & ($ " $ "- " - " & - & $$ &"$ # S - " "" " : "" " # 8 - ($ $$ "&"- " $ & " $ @PWA#, ($" " $$ " "" " ( @PV)HPA#'" & - $$ $ $& " & " " " &#
V Introduction
%-*4
%-*-, ' " " " ($ $$" & "$ PIZPII$ " @HHA#2&- " - " "" "& $ """" " " " " " " "" " & #* $ & "$ $ " " - & PIZWI " " " " @HQA#' " " - $ : / ") ) & " & " " @HRA- " """& " " &" #'" " - " " &" " " & "": """ "$ " @HUA# $ M M $ $ " & 6 " ($"#
$ " $ "$ " " " $ $ $ $ " "" "#=( @HWA# Y Introduction
"$ M "($" $$ " & & M# & $ - - " " $ "$$ " $$$ $ $ # M " " $ $ - & $" &" $ $ " " " $ " # ; ) " $ $ $ $$ " " "&" " $ "#," " - $ ") $ 1" " " $ "" " $ " : & $ :R") ) &# "&" &- ) " $ $" " " & & #% " $" "": @HVA " $ ) " " "" $ $@HYA# 8 ""- ) " $ $ "" " " & $ ) " $ # ' $ " " $ " $ $ "" " $ $ "$$ "@HXA# " $ - " $$ & ""$$" $$ "$ ": " $ $ # & $" " $$" $""-" :& "" "" " - ""&" "&" " $"( -$ :"&"@QIA# M $") ) $"( "" "" " M " "" $ - & $ @QPA# 8 - $$" ) " " ""
X Introduction
$$" $$ " " @QHA# 2&- $ M &- $ " $ " $ & " " $$" " @QQA# & "" $$" "$ $ " " " #8 " " ""$ " & - $ " & " " - " $ " $ M & $ @QRA# *$ QI[ " $ " " $ " " @QUA- "" & $ " :" &" &-" : " " " $ "" @QWA $$" $& " " $ @HWA# $ $ $ " $ 6 &- " "" &$ $ # &" " " $ " "# : " " " $@HXA# %-*-* : " "$ &- "" $ " & $$# - " " $ - " & &" " " " " : & & $ " " # S "" & && $ $ " $ " " "& $$- -$" "" "" #
PI Introduction
#H#H#P "" !" " " "" " " $$ : # " $ $$ " " "" & " "" ($ 1 # "" $& &- $ "" )" : " " $$ - $ " "- $ - M- $ $ " "" $ @QVA# "" " $ $ & " " " " $$ - - & $ " " : : $ ) $" $ @QYA$ ) " @QXA# " " ($" "$ - & " " $$ " $ " : " @RIA# ,&- $ " $ " $ $ $ " $ " @RPA# ; - & " " $ " $ $ 1 # " " - - $ " " " " $ $ ( M & " & &" $$ @RHA#' " $ ($ -& ""$ "" " : &$ " - - " $ @RQA# 9 & "" &"$ " " & "@RRA-" $) " @RUA# PP Introduction
% "" #=( @RWA# " ""$ "" "" & "$ " #'" M " $$" " - " &"$ ""- " & "$ @RVA# $ " $$- &" " " $ ( # " = " " = @RYA- &"$ =$ - " & " " " " Q""R " $ @RXA#' $ ! @UIA- $ 9 2R ," " $ &- " ! % ! $ WH "" HW "" # 8 - ! $ " ! ' & " ! % @UPA# &- $ " " ($ 1 $ M $- & "$ : & & '*,= $ - - " -( ( $$ " $ " $ # $ "
PH Introduction
" & " " - & " &"" &$ @UHA# #H#H#H' "" $":" "$ $ &"& " @UQA & " - "" " " " "# " $ ($ " $ & - - """ $ $ -"" '*,=$$ $ " #S "" "" $ " $ " $ $ "& " # ""$ " $& 6 " "" " " - " & " " $ " # - "" " $ $ $" : " &-"" "& " $ # ; M- $ " ($" $ " - "M $ %9-6# - $ : "" "" $ - " - & $" & "" $ & " " $" & # * & - " " : & " & " - & $ & $ & # 2&- " : $" " ( &"- $ : $ #
PQ Introduction
' " " " " $ ($" $ $" : !2' @URA - HIII " - " !2' $ 9 " *" & $ $ ) $" $ "#'" $ $$ - "" " $ " - "" " $ %9-,#; & "" " :=, " - & =$ =, ) = - $ =$ ," " " =, @UUA# S " "" $ - $ " " & " " 1 & & $ - ""- """ " "" H#U "" @UWA# " " " : $ !*%!# $ " &" $ & $ $ " " " & $& " 9%$ # $ - " " - """ : " @UVA# $ " &$$ -" :S @UYA,**@UXA "" " # S - - $$ &"$ % ," " * & + HIIX " " " $ # '"" ( $$$ " " $& 6 " "# - & ) $ $ " "$$ - 6 $ " "" $ $" $ & " " $ # PR Introduction
%-*-5 & $" && &" " " " M " ""$ " $ """ : $ # 8 ""- $ $ - "- "- -"H- - #'"" $& $ $ " " " : - "" & #8 - "" ""$ Q* $ - ""6 " H* $"- $ $ $ $ #; - & - $ $ ""& " - $ " " " 1 # ; " $ $ " : " " - "" $ " : " " 1 "- " $ " : " " " "" "" $ & "# ' - " & " " 1" " " #- $$ & : "& $ "# !'- " ! '$$" -: HIII HIIU !' " !6 " 1 " "- !' " - " )$$ " # $ - $ " M - & - "" " M 1 - $ $ " "" " 1$$ # "$ " M ( " "" ( " " - - PU Introduction
" $ #S " " - :&"$#8 " " - HU " "$ PR " & - "" &" $ Y " " #' - " & " : # $ & : P#Q &PIX $ - " "" VU PIX $ @WIA# ' - " %&"$ " # " - 1 ()"&" " " "&" ) " - " 1 " "# - "&" $ " $ " "- " $ $ " $ -$ &"# - ( "&" 1 ) " " :- "- $" " " -$ &"# S " " "" " " &" "" - $ & &" $& " $ " $ # ; " ""$ "" $ $ " " $ - : M " $ " $ " " $ # $- $ & $ "- "" - $$" " & $ & " "$ " $ #
PW Introduction
%&" " & " " " $ " " "" #% $" :;$ "@WPA""" " " $ $" " $ # $ - " $ $" $ '( @WHA- $& " " $$" &"$ " " #
PV Introduction
%-54
%-5-, 8 : $" - " " $ $ ""$ $ " & ( @WQA- "" $ $ # $ $ " " & # % $ " " -" : " :" - " $ " M "M " " " "" M#' $ $ " &"& " "" " "" " $ " " $ $ "- " : $ #'"" $ M " "" "" $" """ # ' "" " " $ : " $ "" "" " : "$ """ "#$ - " " " " " $ " M$ : $ " Q* # " & $ & "" & " 1 $ & # " - $ " $ $- " 1 - "- $" $ " "" : " " " & # &" " $ "
" " $ # "" : " M $- " "" - " "
PY Introduction
" $ - - )$ $" $ : " $ & / $ #S " $" $ " & @WRA $ - "" " "" $ "" M# , UIII M- UIII " $ - PIII )$ $" $ " $ & " "&" M &" " # "$ -$ M$ " ($ $ " & $"( # 2&- ($ $ " $" "" $ " & " & $ : - " - " ] "-& " ( # %-5-* ! " - " " &"& "" " " $ # "" & 1 : " $ & " " $ #'" & & "- " $" - " """ # #Q#H#P8 " " " M $ &"$ " " $ $ " " "" " - "" $ """ " @WUA# & " " - & $ $ & $
PX Introduction
" $ " $ # $ $ - $ &" PUI " $ "": " &@WWA# %&" &" " - : $ &" $" - " @WVA#2&- $$ " " $ $- & " " - $ # *$ " " $ - " &" " @WYA# '2- - "" : " $ PR#UII & P#PUI1 " $ HHW $ " " PHR " @WXA# S 1 $$ - $8- & % - $ " PH#III " $ " 1 " " " @VIA# $ $ : " " 1 - """ #8 1 $ $ : # ' $$ - " $" - " $" 1 " $"( @VPA# $ $ $$ $ "Q*$ " 1 &" & $" " " @VHA# ,&- &" 1 $ " :" #
HI Introduction
% && " ) $ $ #=( @VQA ; $ - M" " "# & : $ " $ - & $" "" " # = M 9 " &"$ = M = @VRA- M " " M "M# '" = $ & M-= $ M "M # M "M "" & = #$ - " RPUI $ " " " M# ' "" : " !2'- "" " " "! "# " $ - & " RII " $ $" "" " $ $ "&" "# $ &$ : "
HP Introduction
"& :" "" "" " & - & "" $ #" " & " $ : PU "$ 6 "! " "& @VUA# ' " &$ " - ""$ $ $ $ $$ "&" M "" # 2&- " &$ $ " " "- $ $ " - & # "- $$ " " $ ; ; " $ - " M - "
" " $ - " " """ $ " : $ : #S ( & $ 1 ($ - " $ " $ @VWA " $"( """ @VVA#
HH Introduction
2 " :) $ " $ #=( @VYA
'"" " & &" " " M $ " : ! ! @VXA T= T = "$ @YIA#
#Q#H#H% " $$ $ " $ $ Q* " $ " $ 1 # $ $" $ " :
HQ Introduction
$ " " : $ $ " $ " " "":" :#2&- $"( " " ) "$ $ : 6 && " & " " & - " : *9' $ & " " @VYA " "" " " # ; $" $ " $ $ & $ &" "&" $ 1 @YPA# 2&- " ($ "" & " - & "" ( $ - "& &$ " " " @YHA# ' ""- & " 1 " - Q* " PI#III-& $ & 6 1 " & $ &@YQA#8 - " HUI$ " : $&" Q* " : " @YRA# 8 -& ) " $ & $" &"$ $ " " $ " " " " $ & " @YUA#
HR Introduction
Q* " "" "$ " &$ : #=( @YWA " - ($ " " & 1 $ " """ <) ""$-9,$ $ " "" $#<) ""$ &"$ - "" $ & & "&" ( $ $ ($ "" M $" " $ " @YVA# $& " $$" M "" M " " 6 & &"$ !* - $ :- & :& 9 " # '" !* " $6 ($
HU Introduction
" VI @YYA- ($ " YI & $ & -& & $ @YXA#S ( + HIPI & $ - " *9'- 9'- $ ( $"(- $ $ # - !* " & $ : - " "-
" " " $ "" # ' " " "($ & " M$ $ " $ " :!* " & " " #$$" " " " : $ - " M " : $ - & ""& " " : " $ - $ - " )$ $" $ # $$" 8! $ " " "& " - " $ & $ $ "" "&"# $$ 8! M $ " " "M "&"# "" " $ %9-*# ' "- " " & $ " " $ @XIA# 2&- " & $ $ " $ M " ($ ""- & "& $& "$ $- " " "": "" M@XPA#
HW Introduction
#Q#H#Q!" &" & &$ -$ " $$" $ " $ # - & $" $" $ - $" " $ " $ :$ $ " & " # - " $ $ &"& $ " & $ # : " $$ & : @XHA- $" " $ $ 1 " $ &" " " " - & " $ - " 1 - ) " " & "" @XQA#8 - $" & $& & " & 1 @XRA ( - $ " $ $ - " " M$ @XUA"" &"$ &"&" " " @XW-XV-XQA# ' " & " M : & , "# HIIH @XYA# T $ " M M & M $$ " $ " " " " $ "" "& $ &"& " """ $ # ' UII : : " X " $ M $ #
HV Introduction
$ : #=( @XYA ; : " $ - " $ " " " " " &"& $ " "$ *9' $ "&"# ' " " " $ $ "$ $$ *9') $$ $ @XXA# $$ - P#XXX 9 " $ 9 " " $ " RY : " $ @PIIA " "" 1 " & " # " $" -* & & " % * " " $ $ : $ "
HY Introduction
# * & "&" " - " $& " M- $ " $ $ $" " & @PIPA# " QIII $ 1 & UUI $ " $" ""$@PIHA# ' - M $" $ """& $ " " :$ $ "$ - -"" & $ $ & $" $ & &&
" "$ # %-5-5 : $ " : " "$ & $" & $$ # 6 " " $ $ $ # ,&- ( & & " $ " - $ " - & $ "$ & $ " " $ $ $ @PIQA#; $ - $ " - : & " $ " $ $ # " $ - & " " ($ & "" #9& "- &"$ $ M $ "
HX Introduction
" $ - "& " : " $" " & "" & $" " $ # : " "& " $$" ( " " M @PIRA# ' & " &"! ! $6 - $ =$ = - % % ! ! &"$ $ : " M " 1 & "$ #% " "" " ($ $- "& " " & $" $" " # $ $ " : $" $ - " : - & " " $ 1 - " "$ " @PIUA#
!" & #=( @PIWA QI Introduction
; " "$ $ && " "" : - "" " # !"- " : ! &" " XI " " & - & ! $ ($" $$ @PIWA# S $ $" & $ - " " -"" & " $ $ - " " $ " " @PIVA#
Outline of the homology modeling process and its applications in drug discovery. Extracted from [108] 8 - $" 1 " " :$ $ @PIXA " $ 1 & $ : " $ " " M $ @PPI- PPP- PPHA# 2&- $ ""
QP Introduction
- $ " "& " $ 1 " & & " $ & " @PPQA 1 " & $ $ Q* " @PPRA#
% "Q* &" ( 1 " #=( @PPRA '"" : "&" $$" " $$ $ "&" $ " # " & $$ & M " " M $" &
" "$ $ #
QH Introduction
%-64
%-6-, $ $ & " $ "
" " # 8 : $" - "" $ $ $ $ & & "$ " "$ $# $ : & " " $ " " - $ : & $ $ # S " $$ " $ - & $ " # 2&- $ " $ & " "" $ - $ & ($ (@PPU-PPWA- & $" " ""& # " O ( P " "" $ $ $ $ " "" $ " # 8 - $$ & $ " : " :- -" ) - - $ : @PPVA# *$ - $ & " """ & " : - $ @PPYA# - $ $"( $ " " & & # & $"$ " "
QQ Introduction
) -$ $:: $ "@PPXA# ( $ " "" 6- "" @PHIA#'" "$ $ $ $ ( - ( " ( " & @PHPA- & " $" @PHHA#'& " " : H#V " PXXY HIIU 8*' "$ @PHQA : " @PHRA ""& $ & $ " # &$ " - $"( ($ &- "$ " " $ $$ ($" # "&" ": $ & " " : & ( @PHUA $ " &"
@PHW-PHVA# - &" $$ " ( $$ & " $ @PHYA- "- " $ " # - " " "" ( $ $ " ( " " ( " $" 1 & $ " @PHXA- $$ @PQIA- $ ( @PQPA $ " " @PQH- PQQA $ " ( & #' ($" - " "M $ & &"$ $ B " $ %9-:# " $ " " "" $ " - & " ($ "" - - #8 - $ $
QR Introduction
( $" " - & " - ] ) " $" " " - " " & & #8 - $ $ " " $ & ( ($ $ WI[ RI[ " $ &- $ " " $ - ($ - @PQRA# %-6-* '&6 -&" ( " " " - """ - ($ " $ - " $ " " ( " " "# ; - " $ & - $$" ": #2&- & $- " "&"- " $$#' - $" $ " " $" & 1 UI $ & $$ : " ( " " @PQU-PQWA#; $ * *-&"$ & % $ 6 & " " " "- " " $ @PQVA# - - " : ($" &$$ # % " - & " ( - " $ $ # :$ $ ": " " " $ &
QU Introduction
# & - : & " $" " " " &" $" ($ & $ " " #*$ " -"& & " 2%* - 2M % * : 9 " , @PQYA- & " "" " : M # - & ($ $ $ " $ " " " ( " " # 8 $ & $ & $ $ $ - !T " : & " " $ : @PQX " " " & " " $ "" R # - $$ $& - &$ $ "& " $ # $$ $ & $ " " & $ $ # " " " "$ : & ""( "" " # % "& $ $ : - R -* "@PRIA ," $"@PRPA 9 " , # M " - $$ - " " " $ "" " " " # ; $ " :, $@PRHA*# @PRQA && & $ $ " $ " $ $ $ " " " " # S: "-$ "" "# "" " & " XII $ QW Introduction
$ @PRRA#, "& : : " " $ " $$ & &$ $ : # " $ " $ " "& " " % *= @PRUA# %-6-5 " : $ " " $ " : " " $ $ #
( " " " " $" #=( @PQHA
QV Introduction
8 $ $ & - " "& "- " $ " " : $" $ ($" ($ $$ #' ($" -^ , "" " & "" " - $$" $$ - " " : " RU#III $ # 8 ($" $ " " $ " " " $ ( $& " " " $ & " " ) @PRWA# ; - - " # & : " " : $ : " - $ " & & $ $ & & " # %&" " & :" " " M # * : $ " @PRVA6 "- $ " " $ " R#UII " $ 1 - &"& $ # $" - " & #' ( & " & " " !* - & " " - $ :@PRYA# ; : $ $ $ $ - " " & & "& 1 # & " & " 6 $ - $"( " :" " $ " # $" - , " % ,% QY Introduction
&"$ 9 " , -
" " " "# " - " " 1( " " "" " " $ @PRXA#,&- "( " " "# 8 $ & - " "" M "&" $ # 6 & , "% 6 2 ,%2 &-"&"$ 9,- " " " :O' P O, " P M" "&"$ & $ @PUIA#'" &- $$ " : $" ( & $& " ,% - "" " " $ &# ' - &$$ 6 - $$ & ,% ",%2 - &$" $ " M $ $ $ " $ # 8 - $$ : " : $ - " : $ - "" $ "#
QX
RI
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RP
Objectives
" 6 &$ 7
P# " $ " ( - " M " $" $ "- " "- $ $ " & " " & $ " #
H# ($" &"$ " ) " $ "#
Q# $ & $ #
R# &"$ & " " & " M $ " " # 6 & $" "" " $ %9-, $" $ " " $ " " & " " " " " " 1 1" "" " " "$ " " %9-;# " $ " ) :" 1 6 & &"$ &"" ) $$ $ " %9-6# 6 & $ M "& &"& $& $ " %9-:# 8 ""- 6 & $" &"$ "- " & $ & " ) " $ " %9-* %9-5#
RQ
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RU
Results and discussion
"& " - $ " " "
" - "" " $ " $$ " " &# - - $ :- " " : ") " &"$ # - " &"& -"" " " &"$ & " & & $ ) " M "# %"" " " " & $ - $ " &"& $ $ " " " $ # " $ &"& ($ " $ $ " " """&" $ #,&- &" ) $ O P & " "": - " " " "" & #$ & $ & "$ - -" : $ $ " ) " " $$" #2&- " $ " $ " $ & 6 " " #' ($" & - $ & : & " $ "" " " # " " $ & " " $ $ $&"# " " : ") "" $ " $ ) $ M $ $ " " #" : & "$ " " -"" &" ) " $
RV Results and discussion
" " & " $ " "#' - %2=* 8!* " " )$ " " $ & ) $ ( $" " "-!2' $ $ ) $ & " " $ &"$$ (" # - $ " $ - " QIII - " $ & " $ " $$" $"$ ") # S " " " $ $ $ " & $ $ - $$" $ $" " " $"$ # $ " $ ( " " - " " :&" : $ &"" " #8 ""-& " M "" ! $" $ " " " "&" && $ " " # M " $ " " " $"(1 " $$ "&" & $ " $ # ; - "$ " & " " &"& "" """$ # " $ $ & & & $ $ & & " $ " $ $ : # $ & $ 1 $ $ " " "" "# - 1 "" "" "
RY Results and discussion
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Anticipating drug side effects by comparative pharmacology
Chemogenomics Laboratory, Research Program on Biomedical Informatics (GRIB), Institut Municipal d’Investigació Mèdica and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain Drugs having similar side-effect profiles were successfully shown recently to have also affinity for a common target. Going one step further, this review highlights the fact that drugs connected by side-effect similarity have also similar affinity profiles over multiple targets. Given the current low levels of completeness of drug-target interaction data, one may expect that the number of common targets for which drug neighbours in a side-effect network have some level of affinity is likely to increase in the near future. This observation suggests that preclinical comparative pharmacology, based on in vitro data but supported strongly by modern in silico methods for drug metabolite prediction and affinity profiling, represents an attractive strategy to anticipate clinical drug side effects.
1. Introduction !" # $%&' ( " " " # $ &') " $*&' ) # # # ' ( # $+&' ) # ,-./ 0 $1&' - -. $2&'! " " -. # $3&' ! # " " -. $4 %5&'6 0 # 7
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% "#$%&'( )*#+,- Figure 1. Network of drugs connected by side-effect similarity, with focus on a particular network path composed of 14 drugs (left). For five drug-pair connections, the probability of sharing a target higher than 25% and side effect similarity P value below 0.1, as reported in reference [21], is also shown (values in italics).
Figure 2. The process of transferring the primary target of a drug to its side-effect neighbours in the network path.
Figure 3. The bioactivity profiles over ten targets of four drugs connected by side-effect similarity (see Figure 2). The dashed line indicates the activity level of 10 μM. Arrows mark current missing data for which low micromolar affinity is predicted.
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N H2N N H2N N N N 2 H 3 O N N 1: cyproheptadine S O 4 O N
N N N N N N S H N S H N O N N Cl 5 6: tiotidine
H N 2 H N N S N NH N NH N NH 7: impromidine 8: cipralisant O
H2N N N N N H 9: histamine 10 ( ;- $" "$ " $
' 94
PRV
P# $ " " " $ " " " " " $ " & & $ $ $ # " " $ " $ $ " $ #
H# " $ "" $ " $ " ) & $ " YHR#III &" HRI#III 1 " R#III $ # " $"$ " &"$ " ) $ " #
Q# ' " " ) &" $" : " $ " &#' & $ " $ $" $ " ( : $ " " #
R# ' " " : $"$ " $ M " PU[ " ""1" " $ $ " & # "$ $ &$ $$ & #
U# ) " $ - "-%2=*-8!*- !2'-& "" " $$ $ " ($" " ) $ # $$" $$ $ " & $& $" & : $
PRY Conclussions
$ " & " " &#
W# &"$ 8! & ) " " $ " 1 & " " & "& $ ! * :- : " " &"$ " $ " " #
V# &"$ !2'= $& $ $"$ " ) $ " - & " "" " $$" & " M : "" " " " $" #
Y# : " : $ $ "- $& " " ) - " " & $ " $ $ "# : & " $ " $ " " $ & $ " $ $ & #
PRX
' 9%4
PUP References
P# 2 : T 7 ! - HIIH-*=:7PWWH)R H# = =#% , g ,+ g! # HIIX- ,5;7HUXMHWX Q# d7 #"" $ HIIR-6+H7PWV)PYR R# 9# ,# - *# - ,# A ? ! ' (#, ,HIIP-6+7QRWMUY U# S 2C- T": '- - S ": %+- 8+-T T-& % $$ +2-2 2- :: ,- , ,+- :&T9-= 6: ,-& 2+-% $+#7 #+#, # "#HIIX-:B7VMQR W# ! C# & - ! " $ S# 8"7 / @ R # +# # % # HIIU-*7HWVMHYI V# %" * #7 # 9 &** &#HIIU-6P7RU)UY# Y# 9 "" -% ;R* 9 % " -'"( -, '2 -2 : T -;" &T" - 2 :9- % -* ^' ) "& 79 D # 9 $$" HIPI-<QBUW)WX
PUH References
X# " "- % & 7 # + " " HIIY-6,7WYVMWXQ PI# % $ !# 7 # ** &HIIU-,+PR7PIIP)PIIV PP# , " ' - '# "- + '# ":- *& - 2 "- +# , " -'"" !# *& -T *" : - %" %# * - + # =$$ - , '# 2 - *& !# 2 ""- ")&- ' T: - %M - + # , - +" =# - , "- ",# ^& %" :7 #9 HIII-*:7HUMX# PH# * " # - 9 2# % 9 " 8# 97 #
HIIV-=P7VU)XI PQ# , " -#,7' M #' #$#,##HIIQ-5B7QYQMQXW PR# d T -2 :T -% d$7
3# ;$ "HIPI-*,7VYMYR PU# #%" -# -=#2 7 #* * &HIIY-,5PQ7UYR)UYX PW# C"%:-" , M 7'
# ! ( # E ) '$$" # # +# ,"# % #HIIX-,+7PPWP)PPXH
PUQ References
PV# - ! #, &- 2 M 2 - 2#S7 ' % % ! / #4 O P #'& HIPI- *RHQUYX-PX $ PY# % " - % d-d T - * 2 7 ( 3 # , $ HIIY-6,Q7PYR)PXQ PX# ' " 9MMP- '" &- ""MM 7 '
@ 4 # , HIIX-,+PH7%U HI# % - ' "- M - ' " 8:- "T -d , -' % 7 % M ' # ! === = , " % # HIIX- *++=7RWUR)RWUV# HP# ,# =" B 8# " B # B%# T7 % 3 3 @ # %' J%' = & " HIPI-*,7HPMQU HH# S# ! : S" - , # % " ,: '# , :7 9 4 # * * & PXXY- 5R7PWI)PVY HQ# :- # %#- , , - # ^ - S# #7 4 #,##&#PXXW-,;7QMUI#
PUR References
HR# $ : '- 8- * S- 8 !+#7 $@ #'&**" &&#HIIP-6;P)Q7Q)HW# HU# % d ;: - , 2 - :: 9 :- , T 7 "%!E #9 " ' HIIH-5+P7RIH)RIR HW# $ $ : ^' 2$: 7E #9 HIIR-65*VIPX7YUU)WP# HV# d-+ - :#7! @ 4 43 # HIIY-*6PQ7QWW)VR# HY# S "" !# 7 4 * #** &HIIW-,,HQ)HR7PIRW)UQ HX# *# 7 #+! "#HIIV-,:*P7QYMUH QI# S-, :,'#7 3 -,- / 3#+,#PXXW-5=PU7HYYV)XQ# QP# , '#T -' % -, "% :-% S M"- , " - '"( ; - ! = "- 2 S" 7 ! 0 E'2# !9'% HIIU-,+*RY7PVHVHMPVHVV
PUU References
QH# :'#7 @ #+ ,"#HIIY-6BPP7HIXV)PIV# QQ# !# % - % T# T"7 A
? * * & HIIH-<PV7XIQ)PP QR# +S-C+- ?% HIIX-5*:UXQV7PWP)U# QU# '" # 2&7 E # * * &HIIY-,5PX]HI7YXR)XIP QW# T : -T")2 M - % 7 #9 #!#$#HIIY-*:7YXHMXIR QV# % - ! " $$ - + , )8 - "# ,# , 7 " 4! # , )& , " HIIV-<7YUP)YWI QY# T-' : ,-= 2-2 %-S" %- !#7 4 #+#,##HIIR-6<7YYYMYXX QX# % $ ' 2 :7 M E 4 # ;$ " "HIIY-,*7QPYMQHQ RI# =#+ -'#,MM"" 7 $@ # , " PUW References
HIIX-,;7RQVR)RQYP RP# =" )! 6 -+ , 7& # ;$ " " HIIY-,*7QUXMQWU RH# $,#27 #** & HIIW-,,PU]PW7VWQ)VWV RQ# + # %7 E 4 4 #9 #!#$#HIIX-*;7PPMHW RR# C" + "" 79 # ;$ " "HIIY-,*7QVHMQVY RU# , "" T - "" - * 7 ! " #+## #,"# HIIW-6;7UPH)UHR RW# +# %$ "- ' - *& # %$ 7 4 H #;# "##HIIY-;7PPRXMPPUY RV# 9# - # :- # - # - 9# 8"$$- '# ! -'#+ -%#"-,#! -!# -*#,"- # =# 2 C " 7 43 ! ! *54 *-< / # +# # # $ # % # HIIR-66H7WRQMWUP RY# 7 $7]]# # #:] ]
PUV References
RX# !" , - " '" - ' *::- , = - + 2 -T 2- " %$ - % & - $ % :7 $ % #9 " ' HIPI-5B* 7HRX)HUR UI# 7 $7]]$ # # "# #&] UP# S d- < +- %M: ;- g +- S +- %2#7 ' D #9 " ' #HIIX-,7QV UH# T C# ": -'"( C#TM &-'"(%#T "& 9 :" !# %& :7 ! " # % # * * & " HIIW-57RX)WU UQ# 9 :" ! %& :j- T C ": - % = : :7 $@ 3 # ;$ " "HIIR-B7RPHMRPV UR# 2 '+- 2 "" '- =,- + ,- ;!- * *- "" %*- 2" C'- % +- - "" S'- *& $ '!- *" !- *"" - 8 %,- '- C-9 -;" =2-;" S- ! +- ! +!- " - %" * - S ,S %$ ,#7 %&'#!4 %&'#! 4 # 9 "#' # HIIX-5<* 7WYI)WYU UU# 7 $7]]# "# UW# 7 $7]]# # #:] "] PUY References
UV# 7 $7]]$$## #] (# " UY# ;",-, ,-; $& -- '-29- ;" - ,- % g- ;$ 7 A /! # * * &# = S ")C2BHIIR7HHQ)HQX# UX# 7 $7]]#$# ]$ ]" ]# " WI# 7 $7]]# $ #] ] WP# 7 $7]]$ "# WH# 7 $7]]# ( # ] WQ# & ,#79 #! 9 "' % %'#HIIX-,+;HV7PPIVX)YR WR# ! 7 & ' 0& ' 2# 9 " ' HIIX- 5<* 7*PWXM*PVR WU# !"*#* -d)* - 6 +#% $" ' +# * 7 ' ' ( ! > # *$ , " HIIR-,,7HPQU)HPRH WW# "" # , - + '# # -' % ""- ;" & - d - , " , - *& - % '- "" '# &- +# *"" - '# ; 7 $@ @
PUX References
@# ! "# ##% # HIIW-5;,7RHUMRRI WV# '$ - +- %'7 I 3 # + ," "# HIIP-5,+H7QPP)HU WY# '# ; - + ,# 7 ' #' #&# # HIIU-<67YWVMXII WX# -#2#- -#=#- '-%#- -'#- *"" -#- * "-,#- -;#-!"-8#-9 -#- -'#-% "" - #- d -#- -+#,#- ; -#'#7 ! # @ # 9 " ' HIIV-5:7HXP)HXV VI# #*#8 -+#, -+# -!# ""-'#2-+#=#!"" - ;##& -!# : -# -T#8" -#2"-=## % -%##=-'# 7 ' #9 " ' HIPI* 5B7*HPP) HHH VP# %" *-S"!#7! #' , "#HIPI-,=*Q7PUP)U VH# + * S - ' :: + , 7 ' > # ;$ % " "HIIU-,:7HVUMHYR VQ# *# %" - !" S"7 ! #' , "HIPI-,=*7UPMPUU
PWI References
VR# $ D E ,==* @' !- % * - " - % 9 I)PH)HHVPWR)U :- I)PH)HHVPWU)Q $$ :A %$$" P PXXQ- %$$" H PXXR- %$$" QPXXU-%$$" RPXXV %$$" U =#+# #-PXXRB**57P)UB=#+# #-PXXUB*5*7P)WB =#+# #-PXXW7*5<7P)UB=#+# #-PXXVB*:+7P)W- =#+# #-PXXXB*;67WPI)WUIB$ &" VU# ' $" " $7]]# $#] $j # " VW# !" * - 2 , - %M 7
# ;$ " "HIIV-,,7RMPP VV# , -2#d# "#7! 4 # #HIIQ- ,57HPPYMHPHY VY# %##=# - %# $$7 " 4 ' ' ( > # ! " * HIIW-,*7HIWV)HIYW VX# S2-2 2-' : - )'"&+- d-2gg- "%- T-,2S-; -%M: =- '- C : - d %- g +- : S#7 ' % # 9 " ' # HIIH- 5+P7QU)V# YI# T ,#7 J$ # 9& 8 %$# HIIH-*6<7XP)PIP
PWP References
YP# ' T & -TMM 8 " 7' > # * * & HIIX-,6V)Y7QYW)XQ YH# d g 7' ? ;$ % " "HIIX-,=7PRUMPUU YQ# = C# T - d # S" ^ !# T&7 # 9 #HIIH-6*+WXPH7HPY)HQ# YR# +M: - g-T %%- :" -S"+-* ',-S " '-M :'-$@ #!% "#HIIX-<X7PIIIHIU YU# , +#7 ' 3 4 4 #** &HIIU-,+HQ)HR7PWHX)QV YW# ," '#'-, "*##% -+ g -g + 7 ' M DD $@ 4 #! HIIV-<7HXHIMHXQH YV# '# , 6 - ' !# ""- % ! 6 :- T -,:# 7! > #! HIIY-B7WPHMWHU YY# 8##-T M"#8#-S "" #+# #-,=#8#- ,#*#- +##- T ;#- % - ,7 ' 3 4 4 #+ " ," " "PXVV- ,,*Q7UQU)URH PWH References
YX# 2" ,# - + S :- g: 8 - "" " -#9# -2"S - "9#% "&-! " $=# 7 ' 3#9 " ' HIII- *B7PHQU)HRH XI# , C M&7 D / ' & "/ #9 ! #HIIX-6U7VIWM VQP XP# !=- '"" T- T S- S- % "& 9- M :'-8 - -S "*-2 %- g- - S : +- # ! %$ $ HIIR-QVU)YW# XH# " 7" 4 3 ? "HIIY-=7HQU XQ# *& = -=,#, - < ^ ;# d 7 ' 4 # 9 HIII-6+:WVYY7YHQ)W# XR# -:',#7 > #= +PXYW-:7YHQ)W# XU# # &- = C# T - *& +# $ 7 ! ' ' ( # % PXXV- * > # , HIIW-<7QYH PWQ References
XV# 8:- + d:- 9:- )+ % - : - ; - ': T - : T- ,: ,: 7/ 0!2 # , !" " HIIU-:7W XY# # , - *# # S - # , M- # 2 - %# % 7 ' J # #% HIIH-*=B7PXPH)PXQR XX# 9& 9- 2 M" #7 E # * " '""# HIIR- 5R7QQU)RW# PII# 9 " $ 9 " 7 ! # ""#PXXX-=<H7PWP)Q# PIP# % ,2- C- *7
#9 " ' #HIIW-56* 7PYP)W PIH# % ,2 +- d ,- 9 T- *- =": #7
#9 " ' #HIIX-5<* 7HVR)Y PIQ# C " ! "" -, g -'"( T#%"-' ) C -+ ! :7' @ # HIIU- *,7PVRQ)PVRR# PIR# + ""- , - ,# : - % % "- *: ,# 2: - d % - % PWR References
% & &-% *: - % 7 ' E & # 9 " ' HIPI-5B* 7*QQW)X PIU# & ' & ' 0& ' 2 *+,+# 9 " ' HIPI- 5B* 7PRH)Y PIW# 2# S- 2 M 2 - )% # d- S # :7' # $ " " HIIQ-*<7QV)RV PIV# , '# 7' ' 4 " 9 # " ^2 $ % -HIIX-,*PI7XRI)WI# PIY# & 9- ! : %%7 # # * * & HIIX-,6PQ)PR7WVW)YQ PIX# d & - * - ;" & - +S -* 68 -, " "- ; - + - ' 7 '
4 # "# HIIX- ,+H7HIV# PPI# % =*- !=7 ! / 3 # , HIIW-<7RPI# PPP# * :+#7 > #;$ % "#HIIW-,;Q7QVR)YR# PPH# T !+- : ,8- '"(& =7 # 4 PWU References
5 4 @ > # + ", "# HIIY-65H7PXY)HIY# PPQ# , %: -*+ 7 > M
# ;$ % " "HIIX-,=7QUVMQWH PPR# ' M6 + :7 #4 # ;$ % " "HIIX- ,=7UVQ)UYR PPU# T" 'MM - + 1 2 - 8""- % & S - = + - ' - + # + : - M" / ' ' ' # , HIIV- *W7YVR) YYI PPW# , +- )! 6 =- C"& %- %" C#7 4 3 # ," #HIIX-:X7PIUP)V# PPV# g !$:- , # 8M""" - 8 8 7 & ! ! ' I !# ! " ^'""** &HIIY-*7HR)RW PPY# =#*& - $8# -*& #, -, ,7! # !E # *% HIIV-*7VX)YV PPX# "*- 8!#7$ 4 @#9 &** &#HIIU-6U7RPI)HI# PWW References
PHI# 8!- , * " +%#7 ! @ # ( "# HIIV-*+Q7QRR)WX PHP# = '## "- d d - + 8# S 7 & @ 4 @ # ( " HIIX-,B;7HHMQP PHH# 8;'6 -2% +!7! #+#" #! "#HIIIB6+7PIXQ)PIP PHQ# +#,-' B, "# -!-,%-% *B *#8 -,*7 ! $ ( ! # PXXY)HIIU# ' ,# HIIV-,;<PW7PVUH)PVUX PHR# % -*#- -#- -#7A N ##!#*#HIIU- ,,7QURUMQUUX PHU# % +- + : +- %: %- '- , : "& *- , " :,-'MM T-S %-2 +- -" :,- *& +S#7 / #+,#HIIX-:*X7QPIQ)V# PHW# ,#! ' !#*$ 7' ! ( / / E @# ( " " HIIU-B;H-HPRMHHU# PHV# % g-!#*# =" -!#*#7 I @ # *, " & HIIU-,7RPMHPQ#
PWV References
PHY# 2 + : , 6 7% / ! 4% " # ( " " HIIW-B=P7QPMRP# PHX# d - : *# 2"" - ) d7 L @# 8 ! # HIIX-BH7PUY)WW PQI# 8 ^J )d27 @ #=($ ;$ *, ( "#HIIX-:P7HX)QV PQP# # '"( , : 8 : '# S M 7 @ @# =<%# HIIX-XX7QWVMRII# PQH# 8" 9 -9+,( " , "-+ ;, ""- * g & 7 @ # =($ ;$ #*, #( "#HIIX-:P7P)PR PQQ# S" , - '"( - 2" 8 - % $ T - M , ""- '(" !" @ # * * & HIIY- ,5V]Y7§QIQ)PI PQR# 2 7 @ 4 # 9 #HIIX-6;+VHUH7HIY)PH PQU# #C" +-% @ #( " '$$" ! "HIIX-*6,7QUWM QVI
PWY References
PQW# " +# , "7 #( " HIIX-,B;7WHMWU PQV# g8-2 -! :6T- <2-,<2-S <9- 2 -d8-2 d-g +- dg#7& # 9 " ' # HIPI- 5B* 7VYV)XP PQY# 8 7 # D 3 0# 2 # ( "PXXU-,+5H7PQV)RU# PQX# % :" T- " *%-'" - T" =#7 ' J #* , &#HIIY-6+R7UQX)UP# PRI# 7 $7]] "# "# #&] "] # PRP# 7 $7]]# "# #&]" $"] PRH# 7 $7]]# $# ] PRQ# 7 $7]]## ] PRR# %- T ,- * :" ,- $ "" ,- % - ! ": =- ' +- " =- '- + +- % -%: "-"" - !=- :!-! #7 / @ 4 # 9 " ' # HIIY- 5;* 7XPX)HH#
PWX References
PRU# , " T - , $ ""- & - +" + -! :7! #," "% "HIPI-;7QRQ PRW# , -+ , 7! # * * &HIIX-,6X)PI7RVX)YU PRV# S *%-T (-'- *-% & &%-M*- - 2 " ,#7 3 3 I #9 " ' #HIIY- 5;* 7XIP)W PRY# *- 8- T" =- '" #7 ! 3 # +' , ' # HIIU- ,*H7PHP)X# PRX# 2# , ""7 $ &/" / # + " " * & "" HIIX-67V PUI# 7 $7]]# "# #&]]
PVI