The Effect of Non-invasive Hemodynamic Goal-directed Therapy on the Incidence of Acute Kidney Injury in Circulatory Shock: a Randomized Clinical Trial
Phase: NA
Conditions: Hemodynamics Instability
Sponsor: University of Sao Paulo

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UNIVERSITY OF SÃO PAULO 
HEART INSTITUTE - HCFMUSP 
 
 
 
 
 
 
 
The Effect of Non-Invasive Hemodynamic Therapy Guided 
by Goals on Resuscitation Time in Septic Shock (GENIUS 
Trial): A Randomized Clinical Trial 
Version 4: August 8, 2024 
 
 
 
 
 
 
 
Principal Investigator: Prof. Dr. Ludhmila Abrahão Hajjar 
 
 
São Paulo, 2024 

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Sumary 
 
 
1. INTRODUCTION…………………………………………………………………….6 
2. OBJECTIVES ............................................................................................................... 8 
2.1. PRIMARY OBJECTIVE ....................................................................................... 8 
2.2. SECONDARY OBJECTIVES .............................................................................. 8 
3. STUDY DESIGN ......................................................................................................... 8 
4. INCLUSION CRITERIA ............................................................................................. 8 
5. EXCLUSION CRITERIA ............................................................................................ 9 
6. RANDOMIZATION .................................................................................................... 9 
7. PROCEDURES ............................................................................................................ 9 
7.1. NON-INVASIVE CARDIAC OUTPUT MONITORING .................................... 9 
7.2. TREATMENT PROTOCOL ............................................................................... 10 
7.2.1. GOAL-DIRECTED THERAPY GROUP ..................................................... 10 
7.2.2. CONVENTIONAL THERAPY GROUP ..................................................... 11 
7.2.3. SOLUTIONS, DRUGS, AND DILUTIONS USED ..................................... 12 
7.2.4. CLINICAL AND DEMOGRAPHIC DATA ASSESSMENT...................... 13 
7.2.5 Visit Procedures ............................................................................................. 15 
8. OUTCOMES .............................................................................................................. 16 
8.1. PRIMARY OUTCOME ...................................................................................... 16 
8.2. SECONDARY OUTCOMES .............................................................................. 16 
9. DEFINITION OF CLINICAL COMPLICATIONS .................................................. 16 
10. STATISTICAL ANALYSIS .................................................................................... 17 
11. REFERENCES ......................................................................................................... 18 
 
 
 
 
 
 

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SUMMARY 
Title: "The Effect of Non-Invasive Hemodynamic Therapy Guided by Goals on 
Resuscitation Time in Septic Shock (GENIUS Trial): A Randomized Clinical Trial" 
Principal Investigator: Prof. Dr. Ludhmila Abrahão Hajjar 
Introduction: 
Sepsis is a severe condition where the body responds inadequately to an infection. Septic 
shock is a subset of sepsis with significantly increased mortality due to severe circulatory 
and/or cellular metabolism abnormalities. Septic shock involves persistent hypotension 
(defined as the need for vasopressors to maintain a mean arterial pressure ≥ 65 mm Hg 
and a serum lactate level < 18 mg/dL [2 mmol/L]) despite adequate fluid resuscitation. 
Cardiac Output (CO) can be defined as the volume of blood ejected by the left ventricle 
per minute and is a very useful hemodynamic parameter in monitoring patients with signs 
of circulatory shock, as it can help define the etiology and manage such patients. Despite 
this, this parameter is rarely used in patients seen in Emergency Units, as its measurement 
generally involves invasive methods that are rarely available in this setting. 
The pulmonary artery catheter is considered the gold standard in determining CO, but 
being an invasive method, other devices capable of providing this hemodynamic variable 
less invasively have been developed over the last decades. Any method capable of 
providing CO without the need for pulmonary artery catheter insertion is called minimally 
invasive CO monitoring. The potential advantages of using these methods include easier 
measurements, faster acquisition of hemodynamic parameters, and the possibility of 
implementing monitoring strategies in settings such as emergency rooms. The assessment 
of these parameters allows for quicker determination of the etiology of circulatory shock, 
enabling early initiation of goal-directed therapy. 
It is known that the use of goal-directed therapy has been effective in reducing morbidity 
and mortality in the perioperative and postoperative periods of high-risk surgical patients; 
this strategy is also associated with reduced mortality, length of stay in ICU, and 
mechanical ventilation time in ICU patients who are fluid-responsive. However, there are 
no data so far regarding the impact of hemodynamic optimization strategies in septic 
shock patients during the first hours of shock. 

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Objective: 
To evaluate whether goal-directed hemodynamic therapy, through non-invasive 
hemodynamic monitoring, reduces the time of hemodynamic resuscitation in patients 
with septic shock. 
Methods: 
This is a multicenter, randomized, open-label study conducted in Emergency Units, 
Intensive Care Units, and Wards. Patients over 18 years old who are admitted to the 
emergency room with signs of septic shock (systolic blood pressure less than 90 mmHg 
and/or mean arterial pressure less than 65 mmHg and at least one of the following 
changes: lactate greater than 2 mEq/L, oliguria, neurological alteration, and capillary 
refill time greater than 3 seconds) and who have signed the Informed Consent Form (ICF) 
will be included in the study. Included patients will be randomized in a 1:1 ratio into two 
groups. The Goal-Directed Therapy Group will be monitored by the HemoSphere HPI™ 
(Edwards Life Sciences, Irvine, CA, USA) in the first 6 hours after randomization, using 
the parameters cardiac index (CI), stroke volume (SV), systolic blood pressure (SBP), 
mean arterial pressure (MAP), and HPI to determine medical management; all patients in 
this group will receive the first dose of antibiotics within the first hour of septic shock 
diagnosis, along with the infusion of 500ml of crystalloid solution; after this infusion, 
those with SV less than 35 ml/beat and CI less than 2.2 L/min/m² should receive 
additional aliquots of crystalloid solution until the SV no longer increases by 10% from 
the initial value; if after the first fluid infusion the patient presents SV greater than or 
equal to 35 ml/beat and MAP less than 65 mmHg, a vasoactive drug should be started; if, 
after achieving hemodynamic stability, the patient develops an HPI value greater than 
85%, further aliquots of crystalloid solution and/or adjustments to the dose of the 
vasoactive drug should be made; patients with SV greater than 35 ml/beat and CI less 
than 2.2 L/min/m² should be considered for the initiation of inotropic drugs. The 
Conventional Therapy Group will be assessed with the usual hemodynamic monitoring 
equipment found in emergency units, with the values of SBP, MAP, oxygen saturation, 
heart and respiratory rate, in addition to findings from physical examination, being 
evaluated; all patients should receive the first dose of antibiotics within the first hour of 
septic shock diagnosis; patients should receive fluid resuscitation with crystalloid solution 
at a rate of at least 30 ml/kg in the first 3 hours of treatment, and if after this resuscitation 
the SBP remains less than 90mmHg and/or MAP remains less than 65mmHg, vasoactive 

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drugs should be started; however, if at the time of septic shock diagnosis the patient 
presents with SBP< 90mmHg, MAP <65mmHg, or a drop in BP > 40 mmHg, vasoactive 
drugs such as norepinephrine should be promptly started before fluid resuscitation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
Sepsis is a severe condition where the body responds inadequately to an infection. Septic 
shock is a subset of sepsis with significantly increased mortality due to severe circulatory 
and/or cellular metabolism abnormalities. Septic shock involves refractory hypotension 
(defined as the need for vasopressors to maintain a mean arterial pressure ≥ 65 mmHg 
and a serum lactate level < 18 mg/dL [2 mmol/L]) despite adequate fluid resuscitation. 
There are four pathophysiological mechanisms related to the development of circulatory 
shock. The first is hypovolemia, which leads to a decrease in cardiac output (CO) and 
consequently reduces tissue oxygen supply due to a decrease in intravascular volume. 
The second mechanism is cardiogenic, where CO decreases due to reduced left and/or 
right ventricular contractility or due to a malignant arrhythmia. The third mechanism is 
obstructive, where CO decreases despite preserved ventricular contractility and 
euvolemia, caused by cardiac tamponade, pulmonary thromboembolism, or tension 
pneumothorax. The fourth mechanism is distributive, where there is a decrease in vascular 
tone, leading to decreased peripheral vascular resistance and poor volume distribution, 
caused by septic shock, anaphylaxis, or spinal cord injury. These mechanisms may 
present individually or in combination. CO is defined as the volume of blood ejected by 
the left ventricle per minute and can be calculated using the formula “Heart Rate x Stroke 
Volume”. This is a very useful parameter in the hemodynamic monitoring of patients with 
signs of circulatory shock, as it can help define the etiology and guide the hemodynamic 
management of patients. Despite this, this parameter is rarely used in patients seen in 
Emergency Units, as until recently its measurement involved invasive methods that are 
rarely available in this setting. 
Since its first description in 1970 by Drs. Swan and Ganz, the pulmonary artery catheter 
has been considered the gold standard for measuring CO. However, due to being an 
invasive method requiring trained professionals for its execution and interpretation, other 
devices capable of providing this hemodynamic variable in a less or non-invasive way 
have been developed over the past decades. 
Minimally invasive CO monitoring is defined as any technique that provides the 
parameter without inserting a catheter into the pulmonary artery. Pulse wave analysis is 
one such method, where algorithms are used to evaluate the characteristics of the arterial 

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pulse wave, as the shape and speed of the wave depend on various factors, such as 
vasomotor tone, aortic impedance, and ventricular ejection. This wave can be obtained 
through the insertion of an arterial catheter or through automatic tonometers located on 
the fingers and/or radial artery. 
By analyzing the arterial pulse wave, it is possible to determine not only CO but also 
other hemodynamic monitoring parameters (Blood Pressure, Heart Rate, Stroke Volume, 
Stroke Volume Variation, and Systemic Vascular Resistance) continuously. The potential 
advantages of non-invasive methods include ease of measurement, quicker skill 
acquisition, and the possibility of rapidly implementing a monitoring strategy in settings 
such as emergency rooms. 
The evaluation of these different monitoring parameters allows for quicker determination 
of the etiology of circulatory shock, enabling early initiation of goal-directed therapy, 
which is defined as a set of measures aimed at preventing tissue hypoxia through well-
defined goals of fluid replacement, use of vasopressor and inotropic medications, and 
blood component transfusion. 
It is known that the use of goal-directed therapy has been effective in reducing morbidity 
and mortality in the perioperative and postoperative periods of high-risk surgical patients, 
and in reducing morbidity and length of stay in patients undergoing cardiac surgery. This 
strategy is also associated with reduced mortality, length of stay in ICU, and mechanical 
ventilation time in ICU patients who respond to fluid replacement. A prospective, 
international, multicenter study is being conducted to validate the use of a goal-directed 
hemodynamic strategy in reducing postoperative complications in non-cardiac surgery. 
The timing of the intervention also appears to be essential for the results of hemodynamic 
therapy, as Gerent et al. showed that hemodynamic optimization only in the postoperative 
period, in oncology patients undergoing high-risk surgeries, did not reduce 30-day 
mortality or severe clinical complications. 
There is currently no data regarding the impact of a hemodynamic optimization strategy 
on patients in the first hours of septic shock. 
 
 

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2. OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate whether goal-directed hemodynamic 
therapy, using non-invasive hemodynamic monitoring, reduces the time to 
hemodynamic resuscitation in patients with septic shock. 
2.2. SECONDARY OBJECTIVES 
1. Identify the number of patients with acute kidney injury within 72 hours; 
2. Identify the occurrence of myocardial injury within 30 days; 
3. Identify the occurrence of acute myocardial infarction within 30 days; 
4. Identify mortality at 30 days and 180 days; 
5. Identify the length of hospital stay; 
6. Identify the amount of fluid administered, fluid balance, and the amount of vasoactive 
and inotropic drugs administered at 6, 24, 48, and 72 hours; 
7. Identify the cost-effectiveness of therapies; 
8. Assess the quality of life of patients after 30 and 180 days of inclusion in the study. 
3. STUDY DESIGN 
This is a multicenter, randomized, open-label study conducted in Emergency Units, 
Intensive Care Units, and Wards. 
4. INCLUSION CRITERIA 
Adult patients who meet the following criteria will be included: 
 
Age > 18 years; 
 
Patients admitted to Emergency Units, Intensive Care Units, and Wards within 3 
hours of the diagnosis of Septic Shock: 
o Systolic Blood Pressure (SBP) < 90 mmHg and/or Mean Arterial 
Pressure (MAP) < 65 mmHg (with or without norepinephrine at a dose 
less than 0.5 mcg/kg/min) + Clinical signs of infection and at least one of 
the following: 
 
Lactate > 2 mEq/L; 
 
Oliguria (urine output < 0.5 mL/kg/h for at least 6 hours); 

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 
Neurological alteration (mental confusion, decreased level of 
consciousness, psychomotor agitation, temporal-spatial 
disorientation); 
 
Capillary refill time > 3 s (after digital compression for 10 
seconds); 
 
Poor skin perfusion. 
 
Signed Informed Consent Form. 
5. EXCLUSION CRITERIA 
 
Hospital admission time greater than 24 hours; 
 
Significant edema in the fingers; 
 
Severe peripheral vasoconstriction; 
 
Use of norepinephrine at a dose greater than or equal to 0.5 mcg/kg/min; 
 
Presence of significant aortic insufficiency; 
 
Patients undergoing renal replacement therapy; 
 
Patients with ST-segment elevation myocardial infarction; 
 
Patients requiring invasive mechanical ventilation; 
 
Patients already participating in another study. 
6. RANDOMIZATION 
Patients who have met the inclusion and exclusion criteria and have signed the Informed 
Consent Form will undergo randomization. 
Randomization will be conducted in a 1:1 ratio into two groups: the Goal-Directed 
Therapy group and the Conventional Therapy group. 
7. PROCEDURES 
7.1. NON-INVASIVE CARDIAC OUTPUT MONITORING 
Non-invasive cardiac output (CO) monitoring will be performed using the ClearSight™ 
System (Edwards Life Sciences, Irvine, CA, USA), which continuously provides this 
hemodynamic parameter by measuring the digital arterial pressure waveform beat-to-
beat. 

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The digital artery pressure is acquired non-invasively using a technique called vascular 
unloading or “continuous vascular unloading technique,” achieved through a finger cuff 
placed on the middle phalanx of the second, third, or fourth finger, which utilizes 
photoplethysmography combined with an external pressurization system. The system's 
objective is to maintain the blood volume in the vessel constant at the pressure value 
where the artery oscillation is maximum. The volume variation is detected by measuring 
the light transmission in an optical system composed of a transmitter and a photodetector 
positioned opposite each other, with the blood vessel (digital artery) located between 
them. Volume changes are compensated by the cuff attached to the pressurization system, 
representing instantaneous arterial pressure. As the blood volume increases/decreases 
(cardiac systole/diastole), the light transmission decreases/increases, and the cuff pressure 
increases/decreases, respectively, to maintain the volume constant and the transmural 
pressure close to zero. 
This radial artery pulse wave is transformed into a brachial artery pulse wave through an 
extensive clinical database within the device's platform, which corrects the pressure 
gradient that exists between the brachial and digital arteries. 
By analyzing the brachial artery pulse wave, the system estimates CO using the 
hemodynamic version of Ohm's law, demonstrated in the formula Zin=ΔP/Q, where Zin 
corresponds to the vessel impedance (calculated by peripheral vascular resistance and 
arterial compliance), ΔP is calculated through systolic blood pressure and the area under 
the pulse wave curve, and Q is the flow calculated from the previous data. 
 
7.2. TREATMENT PROTOCOL 
7.2.1. GOAL-DIRECTED THERAPY GROUP 
Patients allocated to the Goal-Directed Therapy group will be monitored using the 
HemoSphere HPI device (Edwards Life Sciences, Irvine, CA, USA) during the first 6 
hours after randomization, which may extend to the first 24 hours of treatment at the 
discretion of the attending team. The parameters Cardiac Index (CI), Stroke Volume (SV), 
Systolic Blood Pressure (SBP), Mean Arterial Pressure (MAP), and HPI will be 
continuously acquired. All patients must receive the first dose of antibiotics within the 

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first hour after the diagnosis of septic shock, in addition to a rapid infusion (within less 
than 10 minutes) of 500ml of crystalloid solution. 
After this first fluid infusion, patients who present with SV less than 35 ml/beat and CI 
less than 2.2 L/min/m² should receive additional aliquots of 250ml of crystalloid solution 
until the SV stops increasing by at least 10% compared to the initial value. If this SV 
value stops increasing after a new aliquot of crystalloid solution but SBP remains less 
than 90mmHg and/or MAP remains less than 65mmHg, the use of a vasoactive drug such 
as norepinephrine should be started. 
The treatment goal in this group will be to maintain CI greater than or equal to 2.2 
L/min/m², SV greater than or equal to 35 ml/beat, and SBP greater than or equal to 90 
mmHg and/or MAP greater than or equal to 65 mmHg. In patients who achieve these 
goals and develop an HPI value greater than 85%, a new aliquot of 250ml of crystalloid 
solution and/or a new adjustment in the doses of the vasoactive drug should be 
administered. 
In patients with SV greater than 35 ml/beat and CI less than 2.2 L/min/m², the initiation 
of inotropic drugs, such as dobutamine, should be considered. 
 
7.2.2. CONVENTIONAL THERAPY GROUP 
Patients allocated to the Conventional Therapy group will be monitored using the usual 
devices found in emergency units. The parameters to be evaluated include invasive or 
non-invasive blood pressure (depending on the attending team's judgment), heart rate, 
oxygen saturation, respiratory rate, urine output, and findings from the clinical history 
and complete physical examination, such as capillary refill time and signs of pulmonary 
and/or systemic congestion. All patients must receive the first dose of antibiotics within 
the first hour of septic shock diagnosis. 
Patients should receive fluid resuscitation with crystalloid solution, with an infusion of 
about 30 ml/kg in less than 3 hours. The investigator may evaluate the patient's tolerance 
and use a lower volume at their discretion. After this resuscitation, for those who still 

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have refractory hypotension, the use of vasoactive drugs such as norepinephrine should 
be started (Surviving Sepsis Campaign 3). 
The treatment goal will be to maintain SBP greater than or equal to 90 mmHg, MAP 
greater than or equal to 65 mmHg, heart rate (HR) between 50 and 100 beats per minute, 
and oxygen saturation greater than or equal to 94%, ideally with perfusion optimization. 
Echocardiography will be allowed in both groups, according to the indication of the 
attending team. It is suggested to maintain hemoglobin levels above 7 g/dl in all study 
patients, with the prescription of blood components being made at the discretion of the 
attending team. 
 
7.2.3. SOLUTIONS, DRUGS, AND DILUTIONS USED 
The type of solution, vasoactive, and/or inotropic drugs, and dilutions used in patients 
will be chosen according to the clinical experience of the attending teams. However, the 
following are suggested: 
 
Fluid resuscitation: administer aliquots of 500 ml or 250 ml of Ringer's Lactate; 
 
Vasoactive drugs: start with norepinephrine (dilution: 1 ampoule + 100 ml of 
Normal Saline); if doses greater than 0.2 mcg/kg/min are required, vasopressin 
may be added (dilution: 1 ampoule + 50 ml of Normal Saline); 
 
Inotropic drugs: start with dobutamine (dilution: 20 ml + 80 ml of Normal 
Saline) at a dose of 5 mcg/kg/min. 
The dose titrations and medications will be performed periodically by the attending 
team (suggested every 15 minutes), with the goal of maintaining the hemodynamic 
parameters at the values established by the protocol. 

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Figure 1: Treatment algorithm for the Goal-Directed Therapy Group. CI: Cardiac Index; SV: Stroke 
Volume; SBP: Systolic Blood Pressure; MAP: Mean Arterial Pressure. 
7.2.4. CLINICAL AND DEMOGRAPHIC DATA ASSESSMENT 
The collected data will be stored in an electronic form. At the time of randomization, 
demographic data, clinical signs and symptoms, personal pathological history, laboratory, 
and imaging exams from hospital admission will be recorded. 
Laboratory tests will be requested and collected according to the attending team, with the 
following tests suggested at randomization: complete blood count, coagulation profile, 
C-reactive protein, sodium, potassium, magnesium, ionized calcium, phosphorus, urea, 
creatinine, AST, ALT, GGT, alkaline phosphatase, total and fractionated bilirubin, 
albumin, troponin, creatine kinase-MB, creatine phosphokinase, B-type natriuretic 
peptide, lactate dehydrogenase, D-dimer, lactate, arterial blood gas (pH, pO2, pCO2, 
bicarbonate, base excess, O2 saturation); after 2 hours and at 6 hours, arterial blood gas 
and lactate will be collected; after 24 hours, the same tests suggested at randomization; 
after 72 hours and 7 days, complete blood count, C-reactive protein, urea, creatinine, B-
type natriuretic peptide, and troponin will be collected. If the patient is transferred to 
another hospital sector during hospitalization, these tests will be performed according to 
the medical team attending the case. Imaging tests will be requested and performed at the 

14 
 
discretion of the attending medical team. The results of both laboratory and imaging tests 
will be obtained from the patient's medical records during their hospitalization period. 
At the time of randomization, 2 hours and 6 hours after, the following parameters will be 
recorded: heart rate, respiratory rate, systolic, diastolic, and mean arterial pressure, 
oxygen saturation, and urine output. For patients allocated to the Goal-Directed Therapy 
group, CI and SV values will also be recorded. The amount and type of fluid administered, 
fluid balance, the amount and type of vasoactive drugs, and the amount and type of 
inotropic drugs will be recorded at the following times: randomization, 2 hours, 6 hours, 
24 hours, 48 hours, and 72 hours. 
Quality of life will be assessed at inclusion, at the 30-day visit, and at the 6-month visit 
using the EuroQol 5 Dimensions (EQ-5D) questionnaire, which consists of an instrument 
that evaluates five dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), where the patient marks the level of impairment in each dimension, 
in addition to a visual scale ranging from zero to 100, regarding their perception of health 
on the day of the test, with 100 indicating the best possible health level, and zero 
indicating the worst possible level. This questionnaire has been validated for use in the 
Brazilian population. 
 
Figure 2: EuroQol 5 Dimensions (EQ-5D) questionnaire. 

15 
 
7.2.5 Visit Procedures 
 
 
 
 

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8. OUTCOMES 
8.1. PRIMARY OUTCOME 
 
Time to resuscitation: After 6 hours of treatment, the number of patients who 
achieve the following goals: 
o Mean arterial pressure > 65mmHg + 
 
Urine output greater than 0.5 mL/kg/h for more than 2 hours, 
and/or 
 
Decrease of more than 10% in serum lactate compared to the 
initial value 
8.2. SECONDARY OUTCOMES 
 
Number of patients with Acute Kidney Injury within 72 hours 
 
Occurrence of Myocardial Injury within 30 days 
 
Occurrence of Acute Myocardial Infarction within 30 days 
 
Mortality at 30 days and 6 months 
 
Length of hospital stay 
 
Amount of fluid administered, fluid balance, and the amount of vasoactive and 
inotropic drugs administered at the time of randomization, 2 hours, 6 hours, 24 
hours, 48 hours, and 72 hours 
 
Cost-effectiveness of therapies 
 
Assessment of quality of life at hospital admission, 30 days, and 6 months 
 
9. DEFINITION OF CLINICAL COMPLICATIONS 
 
Acute Kidney Injury: According to the AKIN classification, acute kidney injury 
is defined as an abrupt (within 72 hours) reduction in kidney function, 
characterized by an absolute increase in serum creatinine of ≥ 0.3 mg/dL; or a 
percentage increase in creatinine of ≥ 50% (1.5 times baseline creatinine); or a 
reduction in urine output to less than 0.5 mL/kg/h for six hours or more. 
 
Myocardial Injury: Presence of elevated troponin levels above the 99th 
percentile. 

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 
Acute Myocardial Infarction: Presence of Myocardial Injury, associated with at 
least one of the following factors: 
o Symptoms of acute myocardial ischemia; 
o Dynamic changes in the Electrocardiogram; 
o Evidence of new segmental myocardial contractility loss, diagnosed by 
Echocardiogram and/or Cardiac MRI. 
10. STATISTICAL ANALYSIS 
The sample size was calculated based on the hypothesis that 60% of patients in the Goal-
Directed Therapy group will achieve hemodynamic resuscitation after 6 hours of 
treatment, while in the Conventional Therapy group, this resuscitation will occur in 45% 
of patients. With a power of 80% and an alpha error of 0.05, 380 patients will be required, 
to be randomized into two groups of 190 patients each. Results with descriptive 
probability levels (p-values) less than 0.05 will be considered significant. 
 
 
 
 
 
 
 
 
 
 

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