Fetal Body Composition and Free-Breathing Magnetic Resonance Imaging
Phase: PHASE1
Conditions: IUGR, Gestational Diabetes, Pregnancy Related
Sponsor: University of California, Los Angeles

 
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Investigating Fetal Body Composition with Free-Breathing Magnetic Resonance Imaging 
 
 
Lead Study Investigators: 
Katie Strobel, MD, UCLA, Department of Pediatrics, Division of Neonatology 
 
Kara Calkins, MD, MS, UCLA, Department of Pediatrics, Division of 
Neonatology 
 
Holden Wu, PhD, UCLA, Department of Radiology 
 
Collaborators: 
Carla Janzen, MD, PhD, Department of Obstetrics and Gynecology, Division 
of Maternal Fetal Medicine 
 
Rinat Masamed, MD, Department of Radiology 
 
Tahmineh Romero, MS, Division of General Internal Medicine and Health 
Services Research 
Michelle Tsai, MD, Department of Obstetrics and Gynecology 
 
Thalia Wong, MD, Departments of Obstetrics and Gynecology, Division of 
Maternal Fetal Medicine 
Version Date: 4/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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CONTENTS 
 
Section 1. 
Statement of Problem................................................................................................ 
1.1 
Hypothesis....................................................................................................3 
1.2 
Specific Aims ...............................................................................................3 
1.3 
Background ..............................................................................................4-6 
1.4 
Justification for the Study ...........................................................................6 
 
Section 2. 
Study Design.............................................................................................................. 7 
2.1 
Primary Outcome ......................................................................................... 7 
2.2 
Secondary Outcomes................................................................................... 7 
 
   2.3     Risks and Benefits……………………………………………………………………………………..7 
 
  Section 3. 
Methods ..................................................................................................................8-9 
3.1 
Study Population......................................................................................... 8 
3.1.1 
Inclusion Criteria .......................................................................... 8 
3.1.2.   Exclusion Criteria........................................................................... 8 
3.2 
Detailed Study Procedures.......................................................................8-9 
3.2.1.   Screening..................................................................................... 9 
3.2.2.   Consent Procedures .................................................................... 9 
 
Section 4. 
Analytical Plan .................................................................................................. …10-11 
4.1 
Sample Size and Power Estimates .............................................................10 
4.2 
Available Population ..................................................................................10 
4.3 
Projected recruitment time .......................................................................10 
4.4 
Statistical Analysis Plan ..............................................................................10 
   4.5 
Data Monitoring Plan................................................................................11 
   Section 5.     Adverse Events………………………………………………………………………………………………….12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SECTION 1. 
 
STATEMENT OF THE PROBLEM 
 
1.1 OBJECTIVE 
This study’s goals are to: 1) use free-breathing magnetic resonance imaging (FB-MRI) to measure fetal 
body composition in the third trimester and 2) determine how the FB-MRI quantitative measurements 
compare to growth parameters at birth. 
 
1.2 HYPOTHESES AND SPECIFIC AIMS 
 
To accomplish our objectives, our aims and hypotheses are as follows: 
 
Specific Aim 1:  
In a prospective study in women with healthy pregnancies and women with fetuses that have 
intrauterine growth restriction (IUGR) and gestational diabetes, we will quantify fetal subcutaneous, 
visceral, and brown adipose tissue volumes and proton-density fat fraction (PDFF) using FB-MRI in the 
third trimester. 
Hypothesis 1: Using a FB-MRI technique we will find the following, 
1) The growth restricted fetus will have less visceral, subcutaneous, and brown adipose tissue 
volume and PDFF when compared to healthy fetuses and fetuses whose mothers have 
gestational diabetes. 
2) Fetuses whose mothers have gestational diabetes will have a greater subcutaneous and visceral 
adipose tissue volume and PDFF compared to healthy fetuses. 
 
Specific Aim 2:  
In a prospective study in pregnant women and their fetuses, we will compare volume and PDFF 
measurements of fetal visceral, subcutaneous, and brown adipose tissue obtained with FB-MRI to birth 
growth parameters of these infants.   
Hypothesis 2: The volume and PDFF of fetal visceral and subcutaneous adipose tissue will correlate 
positively with birth weight and length z-score. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
4
 
 
1.3a. BACKGROUND: 
Pediatric obesity is a public health crisis with increasing prevalence worldwide. 19% of children and 
adolescents in the United States are obese1.  Pediatric obesity is associated with an increased risk for 
adult onset metabolic syndrome, which refers to the co-occurrence of obesity, insulin resistance, 
dyslipidemia, hypertension, and non-alcoholic fatty liver disease2.  There is also a tremendous amount of 
evidence suggesting that obesity and the metabolic syndrome have fetal origins due to abnormal fetal 
growth and maternal conditions3-6.   
 
Impaired fetal growth is a major cause of perinatal morbidity and mortality.  Infants with intrauterine 
growth restriction (IUGR) and infants who are born small for gestational age (SGA) and large for 
gestational age (LGA) have an increased risk for future obesity, insulin resistance, cardiovascular disease, 
and associated metabolic complications.  IUGR infants have been found to have insulin resistance due to 
epigenetic changes in the liver and reduced pancreatic beta cell mass3.  IUGR infants also exhibit satiety 
dysregulation secondary to impaired leptin and ghrelin4.   
 
Maternal conditions such as obesity and hyperglycemia in pregnancy may also play a role in the infant’s 
risk factors for obesity. Meta-analyses demonstrated that a maternal body mass index (BMI) in the 
obese range, glycemia, and birthweight are related to childhood obesity and insulin resistance5,6.  In 
short, a person’s fetal experience and birth weight appear to be surrogates for future metabolic health.  
 
Body composition parameters can also be important biomarkers for future metabolic health.  Body 
composition is the measurement of the different tissues of the body including adipose tissue muscle, 
and bone.  Fat can be categorized by location (visceral vs. subcutaneous) and type (white vs. beige vs. 
brown).  Visceral fat is located beneath the abdominal muscles while subcutaneous fat sits directly 
beneath the skin. Visceral fat is composed of mainly white fat and is metabolically active.  Visceral fat 
releases free fatty acids into the circulation which can lead to insulin resistance7, dyslipidemia7, 
hypertension8,9, and fatty liver8,9.  Studies demonstrated a significant correlation between the 
proportion of visceral adiposity in children and adults with obesity and the metabolic syndrome7.  In 
infants, increased fat mass gains and rapid weight gain (weight z-score >0.67 in the first two years of life) 
have been associated with later onset obesity, insulin resistance, hypertension, and non-alcoholic fatty 
liver disease8,9.   
 
In contrast to white adipose tissue, brown adipose tissue is responsible for thermogenesis and energy 
expenditure, and is generally located near the spine, and supraclavicular, axillary, and supraclavicular 
regions. Traditionally, brown adipose tissue was thought to be only present in the newborn.  However, 
research now demonstrates that brown adipose tissue is present in children and adults10.When 
compared to white adipose tissue, brown adipose tissue has a higher water:adipose tissue ratio, is 
mitochondria-rich, and has a dense supply of capillaries for oxygen consumption. Research 
demonstrates that brown adipocytes may protect against insulin resistance and obesity.  There is now 
research being conducted on how to convert visceral white adipose tissue to brown adipose tissue11. 
 
It is important to be mindful that body composition can be measured using different technologies: dual-
energy X-ray absorptiometry (DXA), computed tomography (CT), ultrasound, air displacement 
plethysmography (ADP, commercially known as the PeaPod), and magnetic resonance imaging (MRI).  
DXA and ADP cannot be used in a fetal model due to poor image quality. DXA is able to estimate the 
amount of subcutaneous and visceral adipose tissue within the android region, and correlates well with 

 
5
CT12.  However, DXA and CT both require radiation, which is undesirable for the fetus and child. While 
ultrasound does not involve radiation, is an inexpensive imaging tool, and can be used in the utero and 
extra-utero environment, ultrasound is dependent on the skill of the sonographer and results can be 
variable. In contrast, MRI is a noninvasive imaging tool that does not involve ionizing radiation and can 
be used to accurately and longitudinally quantify the volume of adipose tissue.  MRI can also measure 
the proton-density fat fraction (PDFF) in percent, which is used as a biomarker for tissue fat content. 
 
Fetal MRI is becoming increasingly utilized as an adjunct to ultrasound for maternal or fetal conditions 
related to pregnancy.  The American College of Obstetricians and Gynecologists released a statement in 
2017 stating that MRI is not dangerous and should be used prudently to answer a clinical question.  
Today, MRI is commonly utilized in cases of placenta accreta13 and fetal anomalies such as congenital 
diaphragmatic hernia, congenital heart disease, and neurological anomalies.  There are difficulties with 
fetal MRI due to lack of control of fetal movement.  Our group has developed a free-breathing (FB) MRI 
technique and has utilized this technology in adults, pregnant women, adolescents, and infants14-18. 
 
To date, there has been little research pertaining to fetal body composition using MRI.  Previously, using 
T1-weighted MR images, it has been difficult to detect adipose tissue in the second trimester19,20.  
Blondiaux et al (2018) looked at subcutaneous adipose tissue in T1-weighted images starting in the 
second trimester and found the signal was isointense at 26 weeks and all areas were hyperintense by 33 
weeks in a progressive fashion from the nuchal region, buttocks, thigh and back21. However, now using 
3T MRI for fetal imaging, subcutaneous adipose tissue is more easily identified in the mid and late 
second trimester22. 
 
1.3b. PRELIMINARY DATA: 
Our research group’s goal is to use FB-MRI to better understand the early 
origins of obesity so that we can develop strategies to prevent and treat this 
disease.  In adolescents, we have performed FB-MRI scans to quantify 
hepatic fat and compared these results to reference breath-held (BH) MRI 
scans16.   BH-MRI exhibited artifacts and on average covered only 74% of the 
liver16. In contrast, FB-MRI demonstrated significantly higher image quality 
and covered 100% of the liver16. Moreover, when image artifacts in BH-MRI 
were avoided, hepatic PDFF from FB-MRI significantly correlated with BH-
MRI with a concordance correlation coefficient of >0.9916.  In infants, we 
have used FB-MRI to quantify subcutaneous adipose tissue, visceral adipose 
tissue, brown adipose tissue, and hepatic fat (Figure 1)18. Of note, elevated 
hepatic PDFF was measured in an infant born large for gestational age to a 
mother with insulin resistance and was noted to be greater compared to 
control infants18. In summary, these data show that FB-MRI can measure body 
composition and suggest that the capabilities of FB-MRI can be extended to 
the fetus. 
 
 
1.4  JUSTIFICATION FOR THE STUDY: 
Significance and Innovation 
Pediatric obesity is a significant public health problem in the United States. Pediatric obesity is easy to 
diagnose, but difficult to treat.  If there were early predictors in utero of risk for developing obesity, then 
early intervention programs could be applied and close nutritional monitoring by the general 

 
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pediatrician could be performed.  To solve this problem, we propose a novel imaging technology, FB-
MRI, to quantify body composition.  Based on our preliminary evidence, we believe FB-MRI will allow: 
• 
Early prediction of preliminary growth 
• 
Close nutritional monitoring given known amount of adipose tissue 
While we know this is an expensive tool that cannot be practically used in the clinical setting, this can be 
a tool to help further research on pediatric obesity.  This may also lead to development of further cost 
effective tools for the clinical setting.  
 
Investigators 
Katie Strobel is well positioned to lead this study under the close guidance of her mentors Dr. Calkins and 
Dr. Wu.  This study team is multi-disciplinary in nature and emphasizes team science.  Dr. Strobel is a 
fellow physician who has worked with Dr. Calkins for the last three years on research on neonatal growth 
in the congenital gastrointestinal anomaly population.  Her work in the gastroschisis population is funded 
by NIH T32 Gastroenterology grant.  She will also be obtaining a Masters in Clinical Research during her 
fellowship.   
 
Dr. Calkins has a Masters in Clinical Research and has been conducting clinical/translational research with 
a focus on biomarker science, predictive modeling, and pediatric liver diseases for over seven years.  The 
Neonatology division has provided Dr. Calkins with start-up funds to conduct her clinical/translational 
research, and she has secured a career development award along with private foundation funding.  
Moreover, the Neonatology division provides full support for Dr. Calkins’ research assistants.  
 
Dr. Wu has worked on the development of new MRI technologies and their translation to clinical 
applications for over ten years. Dr. Wu’s research focuses on new quantitative MRI methods and 
biomarkers, robust free-breathing 3D MRI, and MRI-guided interventions for body cancers and diseases. 
He is especially committed to the research of new MRI techniques to improve the characterization of 
NAFLD. The research in Dr. Wu’s lab is supported by intramural Radiology and University grants, industry 
projects, and federal agencies.  
 
Dr. Calkins and Dr. Wu have applied for an NIH/NIDDK R01 grant for their free-breathing MRI research in 
children and infants, and have received a very promising score (11th percentile), and anticipate funding 
in the near future. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SECTION 2.   
 
2.1 STUDY DESIGN 
This is a prospective pilot study that will be used to generate data to provide a power analysis for a larger, 
longitudinal study that will follow fetuses at risk for obesity. 
 
2.2 PRIMARY OUTCOMES: 
The primary outcome will be visceral adipose tissue volume and PDFF for the three patient populations: 
mothers with growth restricted fetuses, mothers with gestational diabetes, and mothers with healthy 
pregnancies. 
 
2.3 SECONDARY OUTCOMES: 
The secondary outcomes will be subcutaneous and brown adipose tissue volume and PDFF, as well as 
hepatic PDFF, for the three patient populations listed above.  Another secondary outcome will be growth 
parameters of the neonates. 
 
2.4 POTENTIAL RISKS AND BENEFITS: 
Subjects may receive no benefit from participating in this study. However, information from this study 
may improve the understanding of childhood obesity, inform management strategies, and may help 
prognosticate which infants are at higher risk for obesity. 
 
The research MRI scans required for this study do not require sedation, involve ionizing radiation, or 
require any contrast administration. MRI scans are a painless test.  In other words, the FB-MRI 
performed for research purposes will NOT require contrast or sedation. However, patients/subjects 
can experience claustrophobia inside the MRI scanner. Patients with a history of claustrophobia will 
be excluded from this study. Noise from the scanner during an MRI scan will be mitigated by providing 
earplugs and headsets to the patients/subjects. Lastly, because MRI scans use magnetic fields, 
subjects with any metal (e.g., internal metal clips or implants) will be excluded from the study.  All 
subjects will be asked to remove any metal (i.e. earrings, metal belts, etc).  
 
Because information will be collected from each subjects’ medical record, there is the possibility of a 
breach of confidentiality. However, all precautionary measures will be taken to ensure that 
confidentiality and privacy is maintained, and that data is stored securely. All conversations with 
subjects and their families will occur in a private setting.   
 
All data will be coded.  A code will be kept, but it will be kept on a password protected computer and 
in a password protected file separate from the data.  All clinical data will be entered in RedCap, a 
secure web-based data management system provided by the Clinical Translational Science Institute at 
UCLA that only the research team will have access to.  Continuous data generated from the radiological 
studies will be entered into a password protected Excel Sheet, on a password protected computer, 
that only the study team has access to. Research MRI data and analyzed information will be stored on 
a password protected computer with encrypted storage media.  
 
All informed consents/assents will be stored in Dr. Calkins’ office, which is only accessible with a key 
by the study team, in a locked cabinet in accordance to local IRB guidelines.  

 
8
 
 
 
SECTION 3.  METHODS 
 
3.1 STUDY POPULATION 
In this study, anticipating a 10-15% dropout rate, we plan to recruit 18 mothers: 6 healthy pregnant 
women, 6 women with IUGR fetuses, and 5 mothers with gestational diabetes. 
 
3.1.1 INCLUSION AND EXCLUSION CRITERIA 
INCLUSION CRITERIA: 
• 
Pregnant women with singleton pregnancies (healthy cohort) 
• 
Pregnant women with fetuses with weights < 10th percentile weight for gestational age (IUGR 
cohort) 
• 
Pregnant women with gestational diabetes (diabetes cohort) 
 
EXCLUSION CRITERIA: 
• 
Pregnant minors 
• 
Major congenital anomalies or disease processes in the fetus 
• 
Fetus with known chromosomal anomalies 
• 
Mothers who do not plan to deliver at UCLA 
• 
Multiple pregnancy (i.e. twins, triplets, etc) 
• 
History of claustrophobia 
• 
Contraindications to MRI such as metallic devices in the body that are not MRI compatible 
 
3.2.1. SCREENING 
 
Screening will occur by a variety of methods by all primary investigators, collaborators and their 
colleagues.  Medical charts for the potentially eligible subjects at UCLA Obstetrics and Gynecology clinics 
will be screened to determine eligibility by PI Strobel and collaborators.  A HIPAA waiver will be obtained 
and the information will only be collected if consent is provided.  The number of subjects screened, 
eligible, and consented will be recorded to track recruitment. 
 
3.2.2. CONSENT/ASSENT PROCEDURES 
 
Consent/assent will be obtained before enrollment for all subjects and per local institutional review board 
guidelines. Consent will be diligently sought in an ethical manner and obtained using a multidisciplinary 
approach (research coordinator, principal investigators and co-investigators).  Consents/assents will be 
provided to both English and Spanish; the process of consenting/assenting will occur in the subject’s 
primary language.  Subjects will be provided with written material, including a study flier/brochure, and will 
be given ample time to review the material and to ask questions.  Consent will also be obtained again prior to 
MRI procedure. 
 
The research team will work with the primary medical team to coordinate the introduction of the study either 
before or after their medical visit in order minimize disturbing the family and work-flow of the clinic.  
 
3.2.3. MRI IMAGING AND CLINICAL INFORMATION OBTAINED 

 
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A.  MRI Exams 
All MRI scans will be performed on 3 T scanners (e.g., Skyra or Prisma, Siemens) in the outpatient Magnetic 
Resonance Research Center (MRRC) at 300 UCLA Medical Plaza without sedation.  Our newly developed 
FB-MRI quantification technique leverages a multi-echo 3D stack-of-radial sampling trajectory with golden-
angle acquisition ordering to suppress motion artifacts and enable free-breathing imaging of the abdomen 
in around 5 minutes. In addition, our FB-MRI technique is compatible with data under sampling to 
accelerate the free-breathing scan to 1-2 min. In this study, we will optimize the parameters of our FB-MRI 
technique (spatial resolution, spatial coverage, acceleration factor) to balance trade-offs between scan 
time, image quality, fat quantification accuracy, and patient comfort/compliance.  Subjects will be 
provided ear plugs to limit amount of noise from MRI machines.  Time to complete scan and study will be 
recorded. 
 
B.  Clinical Information Obtained: 
Data will be collected and include: maternal age, gravida and para status, gestational age at time of image, 
gestational age at birth, maternal demographic data, maternal anthropometrics, and pregnancy 
information.  Neonatal data will also be collected such as delivery, demographics and anthropometrics. 
This information will be collected and entered  into a web-based database (RedCap) using coded name.   
 
C. MRI Data Analysis: 
MRI scans will be reviewed by co-investigator Dr. Masamed and any clinically concerning incidental 
findings will be reported to the primary care clinician. No formal interpretation is rendered, and copies of 
images cannot be provided. MRI data will be reconstructed by Siemens scanner software to produce 3D 
fat-water separated images and PDFF maps.  The FB-MRI radial data will be transferred to a separate 
workstation for custom reconstruction of 3D fat-water-separated images and PDFF maps and analysis. 
PDFF values will be directly measured from regions of interest in the 3D PDFF maps to characterize fat 
content.  The distribution/extent of subcutaneous fat, visceral fat, and brown fat will be manually 
delineated/drawn on the 3D MRI images and PDFF maps and used to calculate volume of different types 
of adipose tissue.  This work will be performed by PI Strobel with validation from PI Wu.    
 
D.  Satisfaction Survey: 
A satisfaction survey will be obtained from participant regarding consent process, coordination of scan, 
MRI scan time and how we can improve our study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
10 
 
 
 
SECTION 4.  ANALYTICAL PLAN 
 
4.1 SAMPLE SIZES AND POWER ESTIMATES 
 
This study will not be powered considered that this is a pilot study.  Previous studies by our group in 
infants/children have used a sample size of 10 to 20 subjects, and these sample sizes were feasible and 
adequate to develop a new protocol  
 
4.2 AVAILABLE POPULATION 
Recruitment will occur in the UCLA Santa Obstetrics and Gynecology clinic (2001 Santa Monica Blvd. Santa 
Monica, CA), UCLA Westwood Obstetrics and Gynecology clinic (200 Medical Plaza St. Los Angeles, CA), 
and UCLA Maternal Fetal Medicine clinic (200 Medical Plaza. Los Angeles, CA).  We anticipate based on 
available data, that there are approximately 10 mothers with growth restricted fetuses per month seen in 
the UCLA maternal fetal medicine clinic.  There are approximately 12 mothers with gestational diabetes 
seen per month per Obstetrics and Gynecology clinic (Westwood and Santa Monica).  There are 
approximately 40 healthy mothers seen per month per clinic.   
 
4.3 PROJECTED RECRUITMENT TIME 
Based on the available population and expected consent rate, we anticipate it will take approximately six 
months to recruit mothers for each cohort.  Patients will have MRIs performed in the third trimester (28 
weeks to 40 months), and infant data will be collected after completion of pregnancy. 
Table.  Study timeline, * means completed 
Career Development Plans 
Y1 
Y2 
Y3 
-IRB approval for prospective study 
-Complete retrospective data analysis 
-Meet with OB groups for patient recruitment 
-Prospective study fetal MRI data collection 
-Complete data collection, prepare manuscript, and 
submit abstracts 
X 
X 
* 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
4.4 STATISTICAL ANALYSIS PLAN 
Comparisons will be considered statistically significant at the p<0.05 level.  No adjustments for multiple 
comparisons will be made considering the exploratory nature of this study. The effect sizes measured in 
this exploratory grant will be used as the basis for power calculations for future grant applications. 
 
Data will be reported in terms of medians and interquartile ranges and frequencies.  Ultrasound growth 
parameters and birth growth parameter z-scores will be calculated per fetal growth, WHO, and Fenton 
growth charts, respectively. Generalized linear models for repeated measures will be used to compare 
weight and length z-scores to each type of adipose volume and PDFF measurement.  Generalized linear 
models for repeated measures will be used to compare maternal BMI prior to pregnancy to adipose tissue 
volumes and PDFFs. Generalized linear models for repeated measures will be used to compare ultrasound 
growth parameters to adipose tissue volumes and PDFFs.  ANOVA analyses will compare visceral, 
subcutaneous, and brown adipose tissue volumes, and hepatic PDFF across different groups (gestational 
diabetes, IUGR and healthy infants). 

 
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4.5 DATA MONITORING PLAN 
    
   A Data Safety Monitoring Plan is not required considering the nature of this study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
12 
 
 
 
SECTION 5. ADVERSE EVENTS 
5.1 
Report adverse events 
 
   Any adverse events will be reported to the OHRPP. 
 
5.2 
Potential Adverse Events 
 
There is some risk with MRI that are similar to risks associated with a clinical MRI.. While the time required 
is limited, there is risk for claustrophobia.. in order to minimize this risk, mothers with a history or 
suspicion of claustrophobia will be excluded from participation.  Morever, should the subject experience 
any sensation of claustrophobia, the research related procedure will be terminated.  Should 
claustrophobia occur, terminating the FB-MRI will result in the alleviation of symptoms.  Noise from the 
scanner during MRI exam will be mitigated by providing earplugs and headsets to the patients/subjects.  
Lastly, because of MRIs using a magnetic fields, subjects with any metal will be excluded from the study.  
All subjects will be asked to remove any metal objects prior to study (e.g. earrings, belts). 
 
Because there is a component of chart review required, there is a possibility of breech of confidentiality.  
However, all precautionary measurements will be taken to ensure that confidentiality and privacy are 
maintained, and data will be stored securely.  All conversations with subjects will occur in a private setting.  
All personal information, research data and records will be de-identified, coded and securely stored to 
prevent access by unauthorized personnel.   
 
5.3 
Interim Monitoring Plan and Stopping Rules 
 
   We will not conduct a preliminary analysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
13 
 
 
 
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