afdf4492bffe0f9a22496108264042a3  pmc_30090102.pdf
ae13722d936efbabd0ecb6c748a21c70caf7ffea  pmc_30090102.pdf
937e374e65fe63bfd25b2d7383a2435774ec5625b5877b0df902257bf64e7d2a  pmc_30090102.pdf

Title:          Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study
Subject:        Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS).
Keywords:       multiple sclerosis, biomarkers, fingolimod, lymphocyte subpopulations, RNA-seq, transcriptome
Author:         Antonio García-Merino and Antonio José Sánchez López
Creator:        Adobe InDesign CS6 (Windows)
Producer:       Adobe PDF Library 10.0.1
CreationDate:   Mon Jul 23 09:35:49 2018 CEST
ModDate:        Mon Jul 23 10:38:58 2018 CEST
Tagged:         yes
UserProperties: no
Suspects:       no
Form:           none
JavaScript:     no
Pages:          18
Encrypted:      no
Page size:      595.276 x 779.528 pts
Page rot:       0
File size:      7006533 bytes
Optimized:      yes
PDF version:    1.6


name                                 type              encoding         emb sub uni object ID
------------------------------------ ----------------- ---------------- --- --- --- ---------
KKYRCZ+HelveticaNeueLTStd-Lt         Type 1C           Custom           yes yes yes    689  0
NZKJST+HelveticaNeueLTStd-Bd         Type 1C           Custom           yes yes yes    690  0
LWLXQX+HelveticaNeueLTStd-BdIt       Type 1C           WinAnsi          yes yes yes    698  0
JTMLOB+HelveticaNeueLTStd-LtIt       Type 1C           Custom           yes yes yes    699  0
CGAVUP+HelveticaNeueLTStd-MdIt       Type 1C           WinAnsi          yes yes yes    700  0
RNLHWL+MinionPro-Regular             Type 1C           Custom           yes yes yes    614  0
NHIJST+STIXGeneral-Regular           Type 1C           Custom           yes yes yes    620  0
KFZMCZ+MinionPro-Bold                Type 1C           Custom           yes yes yes    605  0
FVHIKJ+MinionPro-It                  Type 1C           Custom           yes yes yes    603  0
KKYRCZ+HelveticaNeueLTStd-Lt         Type 1C           WinAnsi          yes yes yes    611  0
KKYRCZ+HelveticaNeueLTStd-Lt         Type 1C           WinAnsi          yes yes yes    622  0
UCXUMF+STIXGeneral-Bold              Type 1C           WinAnsi          yes yes yes    628  0
FVHIKJ+MinionPro-It                  Type 1C           WinAnsi          yes yes no     630  0
SZYIKJ+SymbolMT                      Type 1C           Custom           yes yes no     632  0
RNLHWL+MinionPro-Regular             Type 1C           WinAnsi          yes yes no     631  0


Jhove (Rel. 1.28.0, 2023-05-18)
 Date: 2024-01-19 06:44:54 CET
 RepresentationInformation: pmc_30090102.pdf
  ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16)
  LastModified: 2020-02-05 11:45:11 CET
  Size: 7006533
  Format: PDF
  Version: 1.6
  Status: Well-Formed and valid
  SignatureMatches:
   PDF-hul
  MIMEtype: application/pdf
  Profile: Linearized PDF, Tagged PDF
  PDFMetadata: 
   Objects: 817
   FreeObjects: 1
   IncrementalUpdates: 1
   DocumentCatalog: 
    ViewerPreferences: 
     HideToolbar: false
     HideMenubar: false
     HideWindowUI: false
     FitWindow: false
     CenterWindow: false
     DisplayDocTitle: false
     NonFullScreenPageMode: UseNone
     Direction: L2R
     ViewArea: CropBox
     ViewClip: CropBox
     PrintArea: CropBox
     PageClip: CropBox
    PageLayout: SinglePage
    PageMode: UseOutlines
    Outlines: 
     Item: 
      Title: Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study
      Children: 
       Item: 
        Title: Introduction
       Item: 
        Title: Materials and Methods
        Children: 
         Item: 
          Title: Patients, Control Subjects, and Samples
         Item: 
          Title: MRI Measures and Clinical Response
         Item: 
          Title: Antibodies and Reagents for Flow Cytometry
         Item: 
          Title: Total RNA Isolation and cDNA Library Preparation for Transcriptome 
Sequencing (RNA-seq)
         Item: 
          Title: Statistic Analysis
         Item: 
          Title: Bioinformatics Analysis
         Item: 
          Title: Quantitative PCR (qPCR) Validation
         Item: 
          Title: Design of Predictive Model
         Item: 
          Title: Validation of Model
       Item: 
        Title: Results
        Children: 
         Item: 
          Title: Clinical and MRI Response
         Item: 
          Title: Characterization of Lymphocyte Subpopulations in MS Patients Before 
and After Fingolimod Treatment
         Item: 
          Title: Selected Lymphocyte Subpopulations Could Predict the Treatment Response 
to Fingolimod
         Item: 
          Title: Alteration of the Gene Expression Profile by Treatment
         Item: 
          Title: Differential Modulation of the Gene Expression Profiles in Responder 
and NR Patients
         Item: 
          Title: Baseline Signature in Responder Patients
         Item: 
          Title: GSEA of DEGs
         Item: 
          Title: Predictive Model of the Fingolimod Response
         Item: 
          Title: Validation of Predictive Model
       Item: 
        Title: Discussion
       Item: 
        Title: Conclusion
       Item: 
        Title: Ethics Statement
       Item: 
        Title: Author Contributions
       Item: 
        Title: Acknowledgments
       Item: 
        Title: Funding
       Item: 
        Title: Supplementary Material
       Item: 
        Title: References
   Info: 
    Title: Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study
    Author: Antonio García-Merino and Antonio José Sánchez López
    Subject: Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS).
    Keywords: multiple sclerosis, biomarkers, fingolimod, lymphocyte subpopulations, RNA-seq, transcriptome
    Creator: Adobe InDesign CS6 (Windows)
    Producer: Adobe PDF Library 10.0.1
    CreationDate: Mon Jul 23 10:05:49 CEST 2018
    ModDate: Mon Jul 23 11:08:58 CEST 2018
   ID: 0x5a58122e610f8745b4f59cf862fbeb06, 0x68dfa5906fc653449e3f7eb04bb34268
   Filters: 
    FilterPipeline: FlateDecode
    FilterPipeline: DCTDecode
   Images: 
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 5
      ImageHeight: 11
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 2044
      ImageHeight: 2258
      ColorSpace: black is zero
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1654
      ImageHeight: 1855
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1477
      ImageHeight: 1424
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1654
      ImageHeight: 1701
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 1477
      ImageHeight: 1634
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/png
      ImageWidth: 2050
      ImageHeight: 1822
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Filter: FlateDecode
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 6
      ImageHeight: 12
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1654
      ImageHeight: 1225
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 6
      ImageHeight: 12
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
    Image: 
     NisoImageMetadata: 
      FormatName: image/jpg
      CompressionScheme: JPEG
      ImageWidth: 1300
      ImageHeight: 1454
      ColorSpace: RGB
      BitsPerSample: 8
      BitsPerSampleUnit: integer
     Intent: RelativeColorimetric
     Name: X
   Fonts: 
    Type1: 
     Font: 
      BaseFont: RNLHWL+MinionPro-Regular
      FontSubset: true
      FirstChar: 25
      LastChar: 252
      FontDescriptor: 
       FontName: RNLHWL+MinionPro-Regular
       Flags: Serif, Nonsymbolic
       FontBBox: -290, -360, 1684, 989
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: NHIJST+STIXGeneral-Regular
      FontSubset: true
      FirstChar: 27
      LastChar: 177
      FontDescriptor: 
       FontName: NHIJST+STIXGeneral-Regular
       Flags: Serif, Nonsymbolic
       FontBBox: -970, -443, 2000, 1023
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: KKYRCZ+HelveticaNeueLTStd-Lt
      FontSubset: true
      FirstChar: 29
      LastChar: 239
      FontDescriptor: 
       FontName: KKYRCZ+HelveticaNeueLTStd-Lt
       Flags: Nonsymbolic
       FontBBox: -166, -214, 1050, 967
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: NZKJST+HelveticaNeueLTStd-Bd
      FontSubset: true
      FirstChar: 30
      LastChar: 182
      FontDescriptor: 
       FontName: NZKJST+HelveticaNeueLTStd-Bd
       Flags: Nonsymbolic
       FontBBox: -166, -218, 1078, 975
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: UCXUMF+STIXGeneral-Bold
      FontSubset: true
      FirstChar: 61
      LastChar: 61
      FontDescriptor: 
       FontName: UCXUMF+STIXGeneral-Bold
       Flags: Serif, Nonsymbolic
       FontBBox: -998, -455, 2000, 1055
       FontFile3: true
      Encoding: WinAnsiEncoding
      ToUnicode: true
     Font: 
      BaseFont: FVHIKJ+MinionPro-It
      FontSubset: true
      FirstChar: 89
      LastChar: 120
      FontDescriptor: 
       FontName: FVHIKJ+MinionPro-It
       Flags: Serif, Nonsymbolic, Italic
       FontBBox: -201, -360, 1684, 1002
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: RNLHWL+MinionPro-Regular
      FontSubset: true
      FirstChar: 32
      LastChar: 46
      FontDescriptor: 
       FontName: RNLHWL+MinionPro-Regular
       Flags: Serif, Nonsymbolic
       FontBBox: -290, -360, 1684, 989
       FontFile3: true
      Encoding: WinAnsiEncoding
     Font: 
      BaseFont: SZYIKJ+SymbolMT
      FontSubset: true
      FirstChar: 28
      LastChar: 31
      FontDescriptor: 
       FontName: SZYIKJ+SymbolMT
       Flags: Symbolic
       FontBBox: 0, -220, 1113, 1005
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
     Font: 
      BaseFont: LWLXQX+HelveticaNeueLTStd-BdIt
      FontSubset: true
      FirstChar: 32
      LastChar: 121
      FontDescriptor: 
       FontName: LWLXQX+HelveticaNeueLTStd-BdIt
       Flags: Nonsymbolic, Italic
       FontBBox: -166, -218, 1129, 975
       FontFile3: true
      Encoding: WinAnsiEncoding
      ToUnicode: true
     Font: 
      BaseFont: JTMLOB+HelveticaNeueLTStd-LtIt
      FontSubset: true
      FirstChar: 30
      LastChar: 250
      FontDescriptor: 
       FontName: JTMLOB+HelveticaNeueLTStd-LtIt
       Flags: Nonsymbolic, Italic
       FontBBox: -165, -214, 1099, 951
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: FVHIKJ+MinionPro-It
      FontSubset: true
      FirstChar: 28
      LastChar: 243
      FontDescriptor: 
       FontName: FVHIKJ+MinionPro-It
       Flags: Serif, Nonsymbolic, Italic
       FontBBox: -201, -360, 1684, 1002
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
     Font: 
      BaseFont: CGAVUP+HelveticaNeueLTStd-MdIt
      FontSubset: true
      FirstChar: 32
      LastChar: 243
      FontDescriptor: 
       FontName: CGAVUP+HelveticaNeueLTStd-MdIt
       Flags: Nonsymbolic, Italic
       FontBBox: -165, -218, 1125, 947
       FontFile3: true
      Encoding: WinAnsiEncoding
      ToUnicode: true
     Font: 
      BaseFont: KFZMCZ+MinionPro-Bold
      FontSubset: true
      FirstChar: 30
      LastChar: 150
      FontDescriptor: 
       FontName: KFZMCZ+MinionPro-Bold
       Flags: Serif, Nonsymbolic
       FontBBox: -319, -360, 1684, 1024
       FontFile3: true
      EncodingDictionary: 
       BaseEncoding: WinAnsiEncoding
       Differences: true
      ToUnicode: true
   XMP: <x:xmpmeta xmlns:x="adobe:ns:meta/" x:xmptk="3.1-702">
   <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about=""
            xmlns:xapMM="http://ns.adobe.com/xap/1.0/mm/"
            xmlns:stRef="http://ns.adobe.com/xap/1.0/sType/ResourceRef#"
            xmlns:stEvt="http://ns.adobe.com/xap/1.0/sType/ResourceEvent#">
         <xapMM:InstanceID>uuid:4c8938bb-a833-4a4a-8736-46728447d586</xapMM:InstanceID>
         <xapMM:OriginalDocumentID>adobe:docid:indd:7b7f4af8-a1e4-11dd-855d-ca4c1b90e82f</xapMM:OriginalDocumentID>
         <xapMM:DocumentID>xmp.id:B68ADE034B8EE811B997EF1303E8DFBB</xapMM:DocumentID>
         <xapMM:RenditionClass>proof:pdf</xapMM:RenditionClass>
         <xapMM:DerivedFrom rdf:parseType="Resource">
            <stRef:instanceID>xmp.iid:B58ADE034B8EE811B997EF1303E8DFBB</stRef:instanceID>
            <stRef:documentID>xmp.did:4FDEE1CD3F45E811B251A43665665126</stRef:documentID>
            <stRef:originalDocumentID>adobe:docid:indd:7b7f4af8-a1e4-11dd-855d-ca4c1b90e82f</stRef:originalDocumentID>
            <stRef:renditionClass>default</stRef:renditionClass>
         </xapMM:DerivedFrom>
         <xapMM:History>
            <rdf:Seq>
               <rdf:li rdf:parseType="Resource">
                  <stEvt:action>converted</stEvt:action>
                  <stEvt:parameters>from application/x-indesign to application/pdf</stEvt:parameters>
                  <stEvt:softwareAgent>Adobe InDesign CS6 (Windows)</stEvt:softwareAgent>
                  <stEvt:changed>/</stEvt:changed>
                  <stEvt:when>2018-07-23T13:05:49+05:30</stEvt:when>
               </rdf:li>
            </rdf:Seq>
         </xapMM:History>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:xap="http://ns.adobe.com/xap/1.0/">
         <xap:CreateDate>2018-07-23T13:05:49+05:30</xap:CreateDate>
         <xap:ModifyDate>2018-07-23T14:08:58+05:30</xap:ModifyDate>
         <xap:MetadataDate>2018-07-23T14:08:58+05:30</xap:MetadataDate>
         <xap:CreatorTool>Adobe InDesign CS6 (Windows)</xap:CreatorTool>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:dc="http://purl.org/dc/elements/1.1/">
         <dc:format>application/pdf</dc:format>
         <dc:title>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study</rdf:li>
            </rdf:Alt>
         </dc:title>
         <dc:description>
            <rdf:Alt>
               <rdf:li xml:lang="x-default">Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS).</rdf:li>
            </rdf:Alt>
         </dc:description>
         <dc:creator>
            <rdf:Seq>
               <rdf:li>Antonio García-Merino and Antonio José Sánchez López</rdf:li>
            </rdf:Seq>
         </dc:creator>
         <dc:subject>
            <rdf:Bag>
               <rdf:li>multiple sclerosis</rdf:li>
               <rdf:li>biomarkers</rdf:li>
               <rdf:li>fingolimod</rdf:li>
               <rdf:li>lymphocyte subpopulations</rdf:li>
               <rdf:li>RNA-seq</rdf:li>
               <rdf:li>transcriptome</rdf:li>
            </rdf:Bag>
         </dc:subject>
      </rdf:Description>
      <rdf:Description rdf:about=""
            xmlns:pdf="http://ns.adobe.com/pdf/1.3/">
         <pdf:Producer>Adobe PDF Library 10.0.1</pdf:Producer>
         <pdf:Trapped>False</pdf:Trapped>
         <pdf:Keywords>multiple sclerosis, biomarkers, fingolimod, lymphocyte subpopulations, RNA-seq, transcriptome</pdf:Keywords>
      </rdf:Description>
   </rdf:RDF>
</x:xmpmeta>
   Pages: 
    Page: 
     Sequence: 1
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 43, 755, 162, 717
      Annotation: 
       Subtype: Link
       Rect: 519, 708, 551, 676
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 474, 744, 549, 736
      Annotation: 
       Subtype: Link
       Rect: 477, 736, 549, 728
      Annotation: 
       Subtype: Link
       Rect: 451, 728, 549, 720
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 87, 528, 158, 519
      Annotation: 
       Subtype: Link
       Rect: 59, 389, 156, 381
      Annotation: 
       Subtype: Link
       Rect: 56, 369, 158, 361
      Annotation: 
       Subtype: Link
       Rect: 73, 73, 158, 65
      Annotation: 
       Subtype: Link
       Rect: 175, 642, 412, 617
      Annotation: 
       Subtype: Link
       Rect: 175, 619, 510, 594
      Annotation: 
       Subtype: Link
       Rect: 175, 596, 541, 571
      Annotation: 
       Subtype: Link
       Rect: 175, 573, 529, 548
      Annotation: 
       Subtype: Link
       Rect: 175, 550, 527, 525
      Annotation: 
       Subtype: Link
       Rect: 175, 527, 366, 502
      Annotation: 
       Subtype: Link
       Rect: 175, 489, 260, 479
      Annotation: 
       Subtype: Link
       Rect: 272, 489, 365, 479
      Annotation: 
       Subtype: Link
       Rect: 373, 489, 436, 479
      Annotation: 
       Subtype: Link
       Rect: 175, 478, 277, 467
      Annotation: 
       Subtype: Link
       Rect: 285, 478, 402, 467
      Annotation: 
       Subtype: Link
       Rect: 410, 478, 459, 467
      Annotation: 
       Subtype: Link
       Rect: 467, 478, 515, 467
      Annotation: 
       Subtype: Link
       Rect: 462, 466, 542, 456
      Annotation: 
       Subtype: Link
       Rect: 175, 455, 259, 444
      Annotation: 
       Subtype: Link
       Rect: 406, 455, 526, 444
    Page: 
     Sequence: 2
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 72, 418, 77, 406
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 107, 395, 112, 383
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 172, 395, 176, 383
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 115, 349, 119, 337
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 124, 349, 128, 337
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 539, 567, 544, 554
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 330, 532, 335, 519
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 342, 509, 346, 496
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 514, 406, 518, 393
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 398, 314, 407, 301
       ActionDest: 398
    Page: 
     Sequence: 3
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 151, 719, 161, 707
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 212, 581, 221, 569
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 247, 444, 275, 431
       ActionDest: 51
      Annotation: 
       Subtype: Link
       Rect: 357, 447, 385, 434
       ActionDest: 51
      Annotation: 
       Subtype: Link
       Rect: 495, 133, 504, 120
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 420, 110, 429, 97
       ActionDest: 398
    Page: 
     Sequence: 4
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 248, 75, 257, 62
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 513, 213, 522, 200
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 334, 202, 343, 189
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 439, 202, 448, 189
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 386, 179, 396, 166
       ActionDest: 398
    Page: 
     Sequence: 5
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 180, 696, 190, 684
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 107, 685, 116, 672
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 224, 616, 233, 603
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 137, 593, 146, 580
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 256, 382, 265, 369
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 486, 708, 495, 695
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 458, 450, 511, 437
       ActionDest: 167
    Page: 
     Sequence: 6
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
    Page: 
     Sequence: 7
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 128, 69, 137, 56
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 362, 115, 397, 102
       ActionDest: 179
    Page: 
     Sequence: 8
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 186, 639, 195, 626
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 342, 639, 374, 626
       ActionDest: 195
      Annotation: 
       Subtype: Link
       Rect: 397, 570, 437, 557
       ActionDest: 213
    Page: 
     Sequence: 9
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 217, 107, 256, 93
       ActionDest: 213
      Annotation: 
       Subtype: Link
       Rect: 492, 95, 501, 82
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 513, 83, 522, 70
       ActionDest: 469
    Page: 
     Sequence: 10
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 48, 587, 87, 573
       ActionDest: 213
      Annotation: 
       Subtype: Link
       Rect: 439, 575, 491, 562
       ActionDest: 231
    Page: 
     Sequence: 11
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 176, 513, 229, 500
       ActionDest: 231
      Annotation: 
       Subtype: Link
       Rect: 120, 428, 153, 415
       ActionDest: 292
      Annotation: 
       Subtype: Link
       Rect: 230, 110, 269, 97
       ActionDest: 310
      Annotation: 
       Subtype: Link
       Rect: 87, 87, 126, 74
       ActionDest: 310
      Annotation: 
       Subtype: Link
       Rect: 309, 720, 350, 707
       ActionDest: 310
      Annotation: 
       Subtype: Link
       Rect: 383, 697, 423, 684
       ActionDest: 310
      Annotation: 
       Subtype: Link
       Rect: 397, 628, 426, 615
       ActionDest: 310
      Annotation: 
       Subtype: Link
       Rect: 384, 559, 417, 546
       ActionDest: 331
      Annotation: 
       Subtype: Link
       Rect: 517, 455, 526, 442
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 531, 455, 540, 442
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 346, 420, 355, 408
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 359, 420, 368, 408
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 368, 317, 377, 304
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 382, 317, 391, 304
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 467, 156, 476, 143
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 481, 156, 490, 143
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 505, 133, 514, 120
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 519, 133, 528, 120
       ActionDest: 469
    Page: 
     Sequence: 12
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 170, 157, 179, 144
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 189, 111, 198, 98
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 336, 145, 340, 132
       ActionDest: 398
    Page: 
     Sequence: 13
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 73, 76, 82, 63
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 481, 99, 490, 86
       ActionDest: 469
    Page: 
     Sequence: 14
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 170, 191, 179, 178
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 93, 110, 102, 97
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 182, 76, 191, 63
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 397, 260, 406, 247
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 454, 237, 463, 224
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 356, 225, 361, 212
       ActionDest: 398
      Annotation: 
       Subtype: Link
       Rect: 474, 179, 483, 166
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 327, 133, 336, 120
       ActionDest: 469
    Page: 
     Sequence: 15
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 175, 662, 184, 649
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 216, 627, 225, 615
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 142, 501, 151, 488
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 202, 443, 211, 431
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 223, 420, 232, 408
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 148, 398, 157, 385
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 245, 305, 254, 293
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 217, 236, 227, 224
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 274, 213, 283, 201
       ActionDest: 469
      Annotation: 
       Subtype: Link
       Rect: 64, 133, 73, 120
       ActionDest: 570
      Annotation: 
       Subtype: Link
       Rect: 190, 75, 199, 63
       ActionDest: 570
      Annotation: 
       Subtype: Link
       Rect: 341, 685, 350, 672
       ActionDest: 570
      Annotation: 
       Subtype: Link
       Rect: 361, 673, 370, 661
       ActionDest: 570
      Annotation: 
       Subtype: Link
       Rect: 309, 558, 318, 546
       ActionDest: 570
      Annotation: 
       Subtype: Link
       Rect: 325, 558, 334, 546
       ActionDest: 570
    Page: 
     Sequence: 16
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 306, 501, 549, 488
      Annotation: 
       Subtype: Link
       Rect: 306, 489, 414, 477
      Annotation: 
       Subtype: Link
       Rect: 244, 412, 289, 402
      Annotation: 
       Subtype: Link
       Rect: 59, 402, 117, 392
      Annotation: 
       Subtype: Link
       Rect: 176, 383, 225, 373
      Annotation: 
       Subtype: Link
       Rect: 230, 355, 289, 345
      Annotation: 
       Subtype: Link
       Rect: 59, 345, 95, 335
      Annotation: 
       Subtype: Link
       Rect: 210, 317, 289, 307
      Annotation: 
       Subtype: Link
       Rect: 208, 288, 286, 278
      Annotation: 
       Subtype: Link
       Rect: 120, 260, 204, 250
      Annotation: 
       Subtype: Link
       Rect: 195, 231, 287, 221
      Annotation: 
       Subtype: Link
       Rect: 244, 193, 289, 183
      Annotation: 
       Subtype: Link
       Rect: 59, 184, 95, 174
      Annotation: 
       Subtype: Link
       Rect: 173, 155, 265, 145
      Annotation: 
       Subtype: Link
       Rect: 161, 117, 244, 107
      Annotation: 
       Subtype: Link
       Rect: 199, 89, 255, 79
      Annotation: 
       Subtype: Link
       Rect: 384, 431, 473, 421
      Annotation: 
       Subtype: Link
       Rect: 331, 402, 395, 392
      Annotation: 
       Subtype: Link
       Rect: 394, 383, 468, 373
      Annotation: 
       Subtype: Link
       Rect: 418, 355, 549, 345
      Annotation: 
       Subtype: Link
       Rect: 320, 345, 366, 335
      Annotation: 
       Subtype: Link
       Rect: 385, 317, 449, 307
      Annotation: 
       Subtype: Link
       Rect: 331, 288, 423, 278
      Annotation: 
       Subtype: Link
       Rect: 331, 260, 424, 250
      Annotation: 
       Subtype: Link
       Rect: 331, 231, 414, 221
      Annotation: 
       Subtype: Link
       Rect: 413, 222, 549, 212
      Annotation: 
       Subtype: Link
       Rect: 320, 212, 346, 202
      Annotation: 
       Subtype: Link
       Rect: 388, 174, 466, 164
      Annotation: 
       Subtype: Link
       Rect: 436, 146, 499, 136
      Annotation: 
       Subtype: Link
       Rect: 381, 117, 470, 107
      Annotation: 
       Subtype: Link
       Rect: 365, 89, 439, 79
    Page: 
     Sequence: 17
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 263, 709, 289, 699
      Annotation: 
       Subtype: Link
       Rect: 59, 700, 116, 690
      Annotation: 
       Subtype: Link
       Rect: 120, 672, 289, 661
      Annotation: 
       Subtype: Link
       Rect: 59, 662, 179, 652
      Annotation: 
       Subtype: Link
       Rect: 96, 624, 142, 614
      Annotation: 
       Subtype: Link
       Rect: 210, 605, 289, 595
      Annotation: 
       Subtype: Link
       Rect: 59, 595, 117, 585
      Annotation: 
       Subtype: Link
       Rect: 70, 557, 168, 547
      Annotation: 
       Subtype: Link
       Rect: 186, 529, 288, 519
      Annotation: 
       Subtype: Link
       Rect: 116, 491, 207, 481
      Annotation: 
       Subtype: Link
       Rect: 173, 462, 257, 452
      Annotation: 
       Subtype: Link
       Rect: 70, 424, 153, 414
      Annotation: 
       Subtype: Link
       Rect: 219, 386, 271, 376
      Annotation: 
       Subtype: Link
       Rect: 231, 358, 287, 348
      Annotation: 
       Subtype: Link
       Rect: 225, 329, 289, 319
      Annotation: 
       Subtype: Link
       Rect: 59, 320, 77, 310
      Annotation: 
       Subtype: Link
       Rect: 167, 282, 253, 272
      Annotation: 
       Subtype: Link
       Rect: 70, 244, 137, 234
      Annotation: 
       Subtype: Link
       Rect: 141, 215, 198, 205
      Annotation: 
       Subtype: Link
       Rect: 182, 177, 266, 167
      Annotation: 
       Subtype: Link
       Rect: 161, 130, 258, 120
      Annotation: 
       Subtype: Link
       Rect: 121, 92, 215, 82
      Annotation: 
       Subtype: Link
       Rect: 331, 709, 426, 699
      Annotation: 
       Subtype: Link
       Rect: 331, 671, 414, 661
      Annotation: 
       Subtype: Link
       Rect: 523, 633, 549, 623
      Annotation: 
       Subtype: Link
       Rect: 320, 624, 349, 614
      Annotation: 
       Subtype: Link
       Rect: 447, 595, 528, 585
      Annotation: 
       Subtype: Link
       Rect: 331, 557, 414, 547
      Annotation: 
       Subtype: Link
       Rect: 374, 529, 472, 519
      Annotation: 
       Subtype: Link
       Rect: 451, 500, 507, 490
      Annotation: 
       Subtype: Link
       Rect: 331, 453, 399, 443
      Annotation: 
       Subtype: Link
       Rect: 445, 434, 514, 424
      Annotation: 
       Subtype: Link
       Rect: 392, 405, 446, 395
      Annotation: 
       Subtype: Link
       Rect: 377, 377, 468, 367
      Annotation: 
       Subtype: Link
       Rect: 388, 358, 455, 348
      Annotation: 
       Subtype: Link
       Rect: 427, 339, 497, 329
      Annotation: 
       Subtype: Link
       Rect: 431, 310, 515, 300
      Annotation: 
       Subtype: Link
       Rect: 524, 291, 549, 281
      Annotation: 
       Subtype: Link
       Rect: 320, 282, 391, 272
      Annotation: 
       Subtype: Link
       Rect: 487, 244, 549, 234
      Annotation: 
       Subtype: Link
       Rect: 320, 234, 340, 224
      Annotation: 
       Subtype: Link
       Rect: 447, 206, 549, 196
      Annotation: 
       Subtype: Link
       Rect: 331, 177, 380, 167
      Annotation: 
       Subtype: Link
       Rect: 395, 139, 479, 129
      Annotation: 
       Subtype: Link
       Rect: 410, 111, 484, 101
      Annotation: 
       Subtype: Link
       Rect: 430, 73, 480, 63
    Page: 
     Sequence: 18
     Annotations: 
      Annotation: 
       Subtype: Link
       Rect: 45, 38, 114, 30
      Annotation: 
       Subtype: Link
       Rect: 122, 38, 179, 30
      Annotation: 
       Subtype: Link
       Rect: 440, 38, 549, 30
      Annotation: 
       Subtype: Link
       Rect: 247, 700, 289, 690
      Annotation: 
       Subtype: Link
       Rect: 59, 690, 81, 680
      Annotation: 
       Subtype: Link
       Rect: 202, 662, 267, 652
      Annotation: 
       Subtype: Link
       Rect: 123, 624, 207, 614
      Annotation: 
       Subtype: Link
       Rect: 169, 595, 249, 585
      Annotation: 
       Subtype: Link
       Rect: 226, 567, 284, 557
      Annotation: 
       Subtype: Link
       Rect: 331, 709, 426, 699
      Annotation: 
       Subtype: Link
       Rect: 493, 595, 549, 585
      Annotation: 
       Subtype: Link
       Rect: 306, 586, 390, 576
  Checksum: 7c4fd8ca
   Type: CRC32
  Checksum: afdf4492bffe0f9a22496108264042a3
   Type: MD5
  Checksum: ae13722d936efbabd0ecb6c748a21c70caf7ffea
   Type: SHA-1
  Checksum: 937e374e65fe63bfd25b2d7383a2435774ec5625b5877b0df902257bf64e7d2a
   Type: SHA-256