School of Medicine

Wayne State University School of Medicine

Dr. Senthil Sundaram

         Senthil Kumar Sundaram, M.D                                      

3901 Beaubien Street                                            Office: 313-993-2870            
Children’s Hospital of Michigan                              Home: 248-430-4940
PET Center                                                            Mobile: 248-807-1314
Departments of Pediatrics and Neurology             Email: ssundaram@pet.wayne.edu
Detroit, MI 48201.      
 
  
Major research accomplishments
1.    Discovered the grossly underdeveloped arcuate fasciculus (language pathway) endophenotype in
      children with developmental delay/mental retardation using Diffusion Tensor Imaging (DTI). Designed
      a study to identify the genetic causes of this endophenotype for which I have been awarded a 5 year
      R01 grant by NIH.
2.    Discovered recurrent copy number variants (CNV) in Tourette Syndrome (TS). Some of the same
      CNVs have been implicated in closely related neurodevelopmental disorders such as autism,
      schizophrenia and ADHD. This is the first study to demonstrate the common genetic mechanisms of
      TS, autism, schizophrenia even though phenotypic co-morbidity of these conditions is well known.
3.    Identified the causal mutation for Tourette Syndrome using massively parallel exome sequencing
      in 10 members of a large pedigree. In this project, we successfully analyzed terabytes of data from
      cutting-edge exome sequencing to localize candidate genes.
4.    Identified abnormal frontal lobe connectivity in autism spectrum disorder using diffusion tensor
      imaging.
5.    Developed a simplified kinetic model to analyze FDG-PET studies and used it to evaluate
      anti-angiogenic clinical trial in renal cell carcinoma conducted at National Institutes of Health (NIH).
 
Education
1.         Medical School (MD)
         Thanjavur Medical College, Thanjavur, Tamil Nadu, India
         Period: 1991 – 1996
2.        Graduate Medical Education / Residency in Nuclear Medicine
         All India Institute of Medical Sciences (AIIMS), New Delhi,India
         Period: 1997 – 2000.
 
Post-Doctoral Fellowships/ Training
 1.Fogarty International Visiting Fellow
    Nuclear Medicine Department
    National Institutes of Health (NIH), Bethesda, MD
    Period: 2000- 2003.
2. A short course in bioinformatics at NIH (3 credits) – 2001
3. A short course in IDL (Interactive Data Language), Bethesda, MD - 2001
4. Research Associate
    Radiology Department
    University of Wisconsin, Madison
    Period: 2003 - 2004
 
Faculty appointments
Assistant Professor of Pediatrics and Neurology
Wayne State University
PET center, Children’s hospital of Michigan
Period: Jan2005 – present
 
Funding
1. R01 Award from NICHD / NIH
Issue Date: 09/17/2009
Grant Number: 1R01HD059817-01A1
Principal lnvestigator: Senthil Sundaram
Project Title: Diffusion tensor imaging biomarker in developmental delay
Project Period: 09/30/2009 - 08/31/2014 (Two-phase award with first 2 years issued under American
Recovery and Reinvestment act of 2009)
Goal: To investigate developmentally delayed children with Diffusion Tensor Imaging and Genomic studies.   
 
Full Publications
1.     Sundaram SK, Huq AHM, Wilson B, Chugani HT. Tourette syndrome is associated with recurrent exonic copy number variants. (Accepted in Neurology and to appear in June 1, 2010 issue).
2.     Sundaram SK, Huq AHM, Sun Z, Wilson BJ, Yu W, Chugani HT. Whole exome sequencing identifies novel, nonsynonymous variants in a large pedigree with Tourette Syndrome.(Manuscript under preparation for submisison to Annals of Neurology)
3.     Sundaram SK, Wilson B, Chugani HT, Huq AHM. Rare copy number variants are associated with infantile spasms. (Manuscript under internal review).
4.     Wilson BJ, Sundaram SK, Huq AHM, Jeong JW, Halverson SR, Behen ME, Bui D, Chugani HT. Abnormal Language Pathway in Children with Angelman Syndrome: A Diffusion Tensor Imaging Study. (Under review in Developmental Medicine and Child Neurology). (Corresponding Author).
5.     Kumar A, Sundaram SK, Sivaswamy L, Behen ME, Makki MI, Ager J, Janisse J, Chugani HT, Chugani DC. Alterations in Frontal Lobe Tracts and Corpus Callosum in Young Children with Autism Spectrum Disorder. Cereb Cortex 2009 Dec 17. [Epub ahead of print]
6.     Kumar A, Juhasz C, Asano E, Sundaram SK, Makki MI, Chugani DC, Chugani HT. Diffusion tensor imaging study of the cortical origin and course of the corticospinal tract in healthy children. Am J Neuroradiol 2009;30:1963-70.
7.     Govindan RM, Makki MI, Sundaram SK, Juhasz C, Chugani HT. Diffusion tensor analysis of temporal and extra-temporal lobe tracts in temporal lobe epilepsy. Epilepsy Res. 2008 Jul;80(1):30-41. Epub 2008 Apr 233.
8.     Sundaram SK, Kumar A, Makki MI, Behen ME, Chugani HT, Chugani, DC. Diffusion Tensor Imaging of Frontal Lobe in Autism Spectrum Disorder. Cereb Cortex. 2008 Nov;18(11):2659-65. Epub 2008 Mar 20. (First and Corresponding author)
9.     Sundaram SK, Sivaswamy L, Makki MI, Behen ME, Chugani HT. 2008. Absence of arcuate fasciculus in children with global developmental delay of unknown etiology: a diffusion tensor imaging study. J Pediatr. 152:250-255. (First and Corresponding author).
10.   Sundaram SK, Chugani HT, Chugani DC. PET Methods with Potential for Increased Understanding of Mental Retardation and Developmental Disabilities. Mental retardation and Developmental Disabilities Review. Ment Retard Dev Disabil Res Rev. 2005;11(4):325-30.
11.   Sundaram SK, Muzik O, Chugani DC, Mu F, Mangner TJ, Chugani HT. Quantification of protein synthesis in the human brain using L-[1-11C]-leucine PET: incorporation of factors for large neutral amino acids in plasma and for amino acids recycled from tissue. Journal of Nuclear Medicine. 2006 Nov;47(11):1787-95.
12.   Holmes JH, Sorkness RL, Meibom SK, Sundaram SK, Perlman SB, Converse AK, Pyzalski RW, Hahn AD, Korosec FR, Grist TM, Fain SB.Noninvasive mapping of regional response to segmental allergen challenge using magnetic resonance imaging and [F-18]fluorodeoxyglucose positron emission tomography. Magn Reson Med. 2005 Jun;53(6):1243-50.
13.    Sundaram SK, Freedman NMT, Carrasquillo JA, Carson JM, Whatley M, Libutti SK, Sellers D, and Bacharach SL. Simplified Kinetic Analysis of Tumor 18F-FDG Uptake: A Dynamic Approach. Journal of Nuclear Medicine, 45: 1328-1333, 2004.
14.   Freedman NMT, Sundaram SK, Kurdziel K, Carrasquillo JA, Whatley M, Carson JM, Sellers D, Libutti SK, Yang JC, Bacharach SL. Comparison of SUV and patlak slope to monitor cancer therapy using serial PET scans. European Journal of Nuclear Medicine and Molecular Imaging, 46 – 53, 30(1), 2003.
15.   Sundaram SK, Bal C S. Radionuclide cisternography. Indian Journal of Nuclear Medicine, 23-26; 15(1):2000.
 
Editorials
1.     Bacharach SL, Sundaram SK. FDG in Cardiac and Oncologic Imaging: The bitter with the sweet. Journal of Nuclear Medicine.1542-1544, 43(11), 2002.
 
Editorials on my articles
1.     An editorial will accompany the following publication:
       Sundaram SK, Huq AHM, Wilson B, Chugani HT. Tourette syndrome is associated with recurrent exonic copy number variants. (Accepted in Neurology and to appear in June 1, 2010 issue).
Invited Speaker
1.    Invited to give grand rounds in the Department of Pediatrics, Wayne state University on “Brain Connectivity and genomics in global developmental delay”, March 2010.
2.    Invited to speak on “Neuroimaging in developmental delay” at a seminar at Sinai-Grace Hospital, Detroit, September 2009.
3.    Invited to speak on “Diffusion Tensor Imaging studies in developmental delay” at Michigan State University, Lansing, July 2009.
4.     Invited to speak on “connectivity and genomics in developmental delay” at Neurology Grand Rounds at Wayne State University,
      October 2008.
5.     Invited speaker at an international symposium “Neuro-imaging of developmental disorders” held at Dubrovnok, Croatia between
       September 12-16, 2008.
6.    Invited to speak on “Genotype and Imaging Endophenotype Relationship in Children with Developmental Delay” at a seminar at
     Center for molecular medicine and genetics at Wayne State University - September 2008.
7.    Invited speaker to give a lecture on “Quantitation in PET” at the International Symposium on “Advances in Diagnostic Medical
      Physics” & Workshop on “Cyclotron - PET/CT” July 13-16, 2006, New Delhi, India.
 
Journal Reviewer
1. NeuroImage
2. Lancet
3. Neurology
4. Pediatric Radiology
5. Journal of Child Neurology
6. Cortex
7. Journal of Pediatric Neurology
8. Pediatric Neurology
 
Abstracts at International Meetings
  1.     Sundaram SK, Huq AHM, Sun Z, Wilson BJ, Yu W, Chugani HT.
        Whole exome sequencing identifies novel, nonsynonymous variants in a large pedigree with Tourette Syndrome.(Submitted to the Child Neurology Society Meeting to be held at Rhode Island in October 2010)
2.     Sundaram SK, Chugani HT, Huq AHMM. Genetic basis of unidentifiable arcuate fasciculus in children with developmental delay. (2009).  Neurology, 72(11): Suppl. 3, A396-A396.
3.     Sundaram SK, Wilson B, Chugani HT, Huq AHM. Increased Genomic Copy Number Variation in Infantile Spasms. Annals of Neurology (2009). 66 (Suppl. 13), S121.
4.     Wilson BJ, Sundaram SK, Huq AHMM, Chugani HT. Abnormal Language Pathway in Children with Angelman Syndrome: A Diffusion Tensor Imaging (DTI) Study. Annals of Neurology (2009). 66(Suppl. 13), S109.
5.     Sundaram SK, Sun Z, Muzik O, et al. Mutflow: A Mutation Discovery Workflow  (2009). Neurology. 72(11), Suppl 3. A397.
6.     Sinsoongsud P, Sundaram SK, Behen ME, Chugani DC, Chugani HT.
       Reversed asymmetry of cerebral protein synthesis in children with autism spectrum disorder. Annual Meeting of Society for Neuroscience Oct 17-21, 2009.
7.     Ajay Kumar, Senthil K. Sundaram, Diane C. Chugani, Otto Muzik, Michael E. Behen, Fanrong Mu, and Harry T. Chugani. Evaluation of Hippocampal Protein Synthesis in Human Brain Using L-[1-11C]-Leucine PET: Implications for Lateralization of Memory Function. Ind J Nuc Med 2008; 23: 113.
8.     Kumar A, Asano E, Sundaram SK, Juhasz C, Makki M, Janisse J, Chugani DC, Sood S, Chugani HT. Evaluation of the cortical origin of corticospinal tract and its location in the posterior limb of internal capsule in children. AES 2008; A_500748.
9.     Senthil Sundaram, Ajay Kumar, Michael Behen, Fanrong Mu, Diane Chugani, Harry Chugani. Decreased protein synthesis in children with idiopathic developmental delay: A C-11 leucine PET study. Ind J Nuc Med 2008; 23: 114.
10.   Ajay Kumar, Senthil K.Sundaram, Lalitha Sivaswamy, Michael E. Behen, Malek I. Makki, Harry T. Chugani and Diane C. Chugani. A DTI study of frontal lobe association tracts, corpus callosum and corticospinal tract in children with autism spectrum disorder. CNS 2008; P33.
11.   Sundaram SK, Sivaswamy L, Makki MI, Behen ME and Chugani HT.Agenesis of Arcuate Fasciculus in children with global developmental delay of unknown etiology: A diffusion tensor imaging study. Poster presentation at the annual scientific meeting of ISMRM (2007).
12.   Sundaram S, Chugani D, Munian Govindan R, Asano E, Juhasz C, Chakraborty P,Muzik O,Sood S,Chugani H.Alpha-methyl-L-tryptophan Positron Emission Tomography (AMT-PET) predicts surgical outcome in children with intractable neocortical epilepsy.  Annals of Neurology (2006), 60 (S10), Supplement: ANA and CNS meeting Programs, S137.
13.   Govindan, RM, Sundaram, SK, Muzik, O, Chakraborty PK, Chugani DC, Chugani HT. Kinetic analysis of alpha-[C-11]methyl-L-tryptophan (AMT) abnormalities in pet studies of children with intractable epilepsy. Epilepsia.2006, 47(4); 85.
14.   Muzik O, Sundaram SK, Mu F, Mangner TJ, Chugani DC, Chugani HT. A simplified approach for determining an index of brain protein synthesis using 1-[11C]-leucine PET. J Nucl Med 2005, 46(2): 124P.
15.   Muzik O, Sundaram SK, Mu, F, Mangner, T, Chugani, DC, Chugani, HT. Semi-Quantitative Assessment of Brain Protein Synthesis Using L-[1-11C]-leucine PET. J Neurol Sci 2005; 238 (1): S258.
16.   Sundaram SK, Carrasquillo JA, Carson JM, Whatley M, Sellers D, Libutti SK, Yang JC, Bacharach SL. Relationship between blood flow and FDG metabolism in renal cell cancer: Implications for therapy? J Nucl Med. 2003, 44(5); 82.
17.   Buvat I, Hapdey S, Carson JM, Sundaram SK, Libutti SK, Yang JC, Carasquillo JA, Whatley M, Sellers D, Bacharach SL. Non-parametric simplified kinetic method for characterization of tumor metabolism in FDG PET.J Nucl Med. 2003, 44(5); 62-63.
18.   Sundaram SK, Freedman N, Carrasquillo JA, et al. Can Simplified Kinetic Patlak analysis be used to monitor tumor therapy? Journal of Nuclear Medicine 43 (5): 565 Suppl. S MAY 2002.
19.   Freedman N, Sundaram SK, Carson JM, et al. Patlak tumor images revisited.    Journal of Nuclear Medicine. 43 (5), 365 Suppl. S MAY 2002.
20.   Freedman N, Kurdziel KA, Sundaram SK, et al. Comparison of SUV and Patlak slope to monitor cancer therapy using serial PET scans. Journal of Nuclear Medicine 42 (5): 121 Suppl. S MAY 2001.
21.   Sundaram SK, Bandopadhyaya G P, Kumar R, Malhotra A, Sriram M. Modified (F-15) diuretic renography in suspected PUJ obstruction in children. Abstract book of 20th international Congress of Radiology. ICR-98. 1998; 96.
 
 Book Chapters
1. Sundaram SK. Quantification of tissue metabolism using FDG-PET. Chapter in “Advances in diagnostic medical physics”. Edited by GS Pant. Himalaya publishing house. 2006.
2. Senthil Kumar Sundaram, Ajay Kumar and Bandopadhyaya. Radiopharmaceuticals in Clinical Nuclear Medicine. A chapter in "Basic physics and radiation safety in nuclear medicine". Edited by GS Pant. Himalaya Publishing House, Mumbai.227-240. (2008).
3.  Senthil Kumar Sundaramand Ajay Kumar. PET quantification. A chapter in "Basic physics and radiation safety in nuclear medicine". Edited by GS Pant. Himalaya Publishing House, Mumbai. 461-474. (2008).
 
Teaching
    Years at Wayne State - 5
1. Advise students and postdoctoral fellows on (2-3 hr weekly) on PET data analysis, quantification and physiologic modeling of PET
    tracers
2. Advised students and postdoctoral fellows (2-3 hr weekly) on analysis and interpretation of Diffusion Tensor Imaging (DTI) and
    genomic techniques.
3. Gave a lecture for clinical and research fellows, residents on protein synthesis studies in PET (N=15). “Protein Synthesis in
    Tuberous sclerosis – mechanisms and utility of PET”
4. Gave a lecture for clinical and research fellows, residents
    “Kinetics of α[11C]methyl-L-tryptophan (AMT) uptake in epileptogenic cortex” (N =15)
5. Gave a lecture in the anatomy department of Wayne State University on “Diffusion tensor Imaging (DTI) in global developmental
    delay”.
6. Gave a lecture for clinical and research fellows, residents on PET quantification (N=15). “Protein Synthesis PET: Quantification and
     applications”
7. Mentored K23 Career Development Award mentor for
               Lalitha Sivaswamy, MD
               Title:    "Imaging biomarkers in autism"
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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