BrainFax Marketing Strategy

Version 1.1 August 2011

Exmovere Holdings, Inc. 1650 Tysons Boulevard

Suite 1580 McLean, VA 22102

Tel: +1-703-663-4090 Fax: +1-703-663-7350

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BrainFax – Marketing Overview

Exmovere Holdings, Inc. has developed new models for use in detecting human emotions. Based on a cheek swab of an individual’s saliva, biochemical markers can be measured and compared to baseline metrics. Adrenaline, cortisol and pH are all present in saliva, and recent studies have pointed out significant correlations of these chemicals with emotional states and well-being. Exmovere’s emphasis on emotion detection and its proprietary algorithms will be applied to this latest research in order to provide a new mechanism for more clearly measuring and reporting a person’s emotional state. A laboratory-grade test for each individual or patient who submits a cheek swab, BrainFax will be used to:

Measure levels of adrenaline, cortisol and pH in the saliva sample Compare measured levels to baseline metrics associated with alternative emotions Report the individual’s most likely emotional state(s) at the time of the sample Provide a way for physicians, psychiatrists, psychologists, therapists and other

healthcare professionals to measure and document patient’s emotional states along with their other diagnoses

Practitioners in healthcare have long studied and attempted to match the connections between emotions and various health conditions. For example, feelings and emotions have been studied and evaluated as predictors of a variety of health conditions, including but not limited to depression, schizophrenia, bipolar disorder and others. And, emotions play a role in signaling or being symptoms of Alzheimers, obesity, heart disease and a number of immune and endocrine system ailments. These relationships are well documented through the resources and research sponsored by the National Institute of Health, National Institute of Mental Health, the Center for Disease Control, Department of Defense and a number of academic and private industry studies. There has also been recent evidence pointing to emotional histories, much like we all have genetics. These emotional histories and our experiences are directly tied to manifestations of both mental and physical health conditions that require treatment. However, despite all of the research, study and documentation to date, there are no independent and objective biophysical measurements that practitioners can use to document and report an individual’s emotions. BrainFax will change all that. The premise behind the new system is that all of the research done to date combined with company’s proprietary algorithms provides a unique model and measurement system. The system and its analytics deliver baseline metrics and associated emotional states which are used to derive typical or standardized protocols for various emotional states or moods. Similar to a meta analysis, BrainFax presents levels of salivary chemical levels, statistical analysis of results, and projections of emotional states all in one place based on thousands of existing, approved research studies and results.

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With access to BrainFax and its outputs, laboratory testing of an individual’s salivary outputs can be compared to these baselines. Target emotional states and moods can be objectively and precisely measured for the first time by the healthcare professionals responsible for various treatments and cures. The emotional state captured at a point in time can then be used by the practitioner in a number of ways:

Confirm diagnoses derived from office examinations and assessments

Track emotional states over time to compare with mental and physical health or disease states

Provide objective verification of diagnoses for insurance and liability purposes Support additional research into identifying connections between emotions and

disease There are thousands of scientific research studies from the medical archives that demonstrate the connections between emotions and both mental and physical disease states and illness. One of the largest in recent history was performed by the Department of Preventive Medicine at Kaiser Permanente (KP) San Diego with the cooperation of 17,421 adult Health Plan members and with the ongoing collaboration of Dr Robert Anda at the Centers for Disease Control and Prevention (CDC). The cooperating health plan members and their emotions, disease diagnoses and treatments were tracked starting in 1990 over the next 10+ years. One of the basic conclusions of the study reveals a powerful relation between our emotional experiences as children and our adult mental health, physical health, and major causes of mortality in the United States. In addition to these proven connections between emotions and health, there have been numerous studies that show strong correlations between biophysical indicators – such as cortisol, adrenaline and pH level – with emotional states. Feelings like stress, for example, trigger the adrenal glands to produce cortisol and adrenaline. Cortisol is very helpful in small doses (as part of the fight or flight response) but sustained high cortisol levels (the result of unremitting stress) have very destructive effects on the body and mind. Adrenalin, also produced by stressful events, can have similar effects. And, for pH – one of the body’s regulators – proper balance is required.

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Cortisol, adrenalin and pH have all been studied in connection with various emotional states. For example, among key emotional states tied to these 3 biochemicals, the following appear to be the most serious in their relation to mental and physical disease states:

anxiety

depression fatigue/lethargy pain euphoria anger

By measuring cortisol, adrenalin and pH, medical practitioners can develop a picture of the patient’s emotional state and how that may be contributing to related mental and physical conditions. As both cortisol and adrenaline pass through the body’s biophysical system, the last point of processing is the soft tissue in the mouth, which also affects the level of pH (acidity). Hormones in saliva have already been processed into useable forms and pass through the mouth on their way out of a person’s system.

How BrainFax Works

The building blocks of the new BrainFax service are the demonstrated and well-researched connections between hormone and pH levels and emotional states based on existing and ongoing research, field studies and Exmovere’s proprietary algorithms. Emotions detected by the process can then be used as input into diagnoses and as predictors of mental and physical health. Similar to the ranges used in blood serum testing, BrainFax presents a level of precision in understanding and detecting human emotions to identify precise moods.

•Cortisol

•Adrenaline

•pH

Biophysical Metrics

•Correlations

•Baselines

•Algorithms

Emotion Detection •Objective

Measurement

•Tracking and Reporting

Mental and Physical Health

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Part of the new model embedded in the BrainFax system relies on saliva as the primary measurement substance. Since 1983, according to Dr. Richard Weinstein, there have been over 2,500 research studies and papers published supporting the use of salivary hormone testing. From most of these studies, it is clearly demonstrated that salivary tests are as good as or more accurate than blood tests. Blood serum and the ways in which cortisol and adrenalin, for example, are measured are not the same as in saliva. Chemicals in blood serum are attached to proteins or other cell structures which means they are already in use. Whereas, in saliva, these chemicals are refined, processed, and ready for use. Basically, the saliva tests provide a much more sensitive and accurate reading on the chemicals, hormones and indicators tied to alternative emotional states. Furthermore, saliva testing is much less invasive and less stressful for most patients. In a typical medical office, blood testing is the norm. Patients are asked to provide blood samples further increasing some patient’s stress due to being in a doctor’s office, a blood testing office, and having to deal with the pain of being punctured by a needle. The increased hormone levels associated with the added stress can make the results unreliable. By comparison, a cheek swab used to collect saliva is much less invasive and threatening. Part of the improved accuracy demonstrated in saliva research is due to the low impact of the technique on the patient. Thus far, though, most of the understanding we have about salivary testing is confined to the research laboratory. Practicing medical professionals are often left without a diagnostic tool based on hormone levels and other bio-chemicals specifically tied to emotional states and alternative mental or physical disease states. If during an office session a physician, psychologist, psychiatrist, licensed social worker, or therapist determines a diagnosis of physical or mental illness, the practitioner goes through a series of verbal or physical testing and evaluation prior to recording the final patient condition. Salivary testing of hormone levels – cortisol, adrenaline and pH – will provide the medical professional with an objective tool that can be used to confirm their recorded diagnosis. BrainFax brings salivary emotion detection to the mental and physical health professional marketplace on a large scale for the first time. There have been small, niche laboratories dedicated to salivary emotion detection serving small practitioner communities such as Chiropractors and other health professionals. However, over the past 10 years, according to a recent article scheduled for publication in Clinical Chemistry, “the use of saliva as a diagnostic fluid has gained attention over time and has become a translational research success story. Some of the current nanotechnologies have been demonstrated to have the analytical sensitivity required for the use of saliva as a diagnostic medium to detect and predict disease progression. However, these technologies have not yet been integrated into current clinical practice and work flow.”

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Based on the abstract of the article, titled Diagnostic potential of saliva: current state and future applications – currently available online at http://PubMed.gov – the authors state: “As a diagnostic fluid, saliva offers advantages over serum because it can be collected noninvasively by individuals with modest training, and it offers a cost-effective approach for the screening of large populations. There is minimal risk of contracting infections during saliva collection, and saliva can be used in clinically challenging situations, such as obtaining samples from children or handicapped or anxious patients, in whom blood sampling could be a difficult act to perform.” And, in summary, “Saliva has the potential to become a first-line diagnostic sample of choice owing to the advancements in detection technologies coupled with combinations of biomolecules with clinical relevance.” The actual implementation of BrainFax will include suggested data collection protocols to supplement models built from existing data and research. The purpose of the recommended regular saliva collection will be to:

develop an individualized baseline profile for the subject track daily changes between therapy sessions track specific events

With this additional detail, healthcare professionals will be able to refine or augment their recommended treatment regimens – including related prescription drugs – for their patients who use BrainFax. And, BrainFax will be continuously improved. As additional data and detail is added to the predictive database and the company’s algorithms applied, the tolerance around each metric will likely become smaller, improving the accuracy of test results even further. By using the research done on the connections between hormone levels and emotions, as well as the connections between emotions and mental health states, Exmovere Holdings, Inc. will be providing leading edge technology-based solutions in emotion detection products for healthcare professionals worldwide. BrainFax represents a new offering consistent with the company’s core competencies and product development strategies. Initially, due to the greater need for an objective measurement tool, the new product introduction and launch will focus on mental health professionals, specifically psychiatrists. By doing so, these professionals will be able to clinically assess and objectively confirm a patient’s emotional state at the time of or near their examination and diagnosis. The company’s launch plans will open up BrainFax to psychologists and licensed social workers next in order to provide additional support for practicing healthcare professionals who need the testing available to help determine a patient’s emotional state over time.

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Physicians also have needs for BrainFax. Particular segments or specialties – such as Pediatricians – can benefit from the depth and breadth of information available. In their practices, physicians also may need to prescribe drugs with emotional and mental side-effects. BrainFax can help ascertain the impact of these compounds on patients over time, but tracking moods through daily or periodic saliva testing. This in turn benefits their practice by helping generate additional revenues. To market BrainFax to the large potential markets where it can do the most good, Exmovere Holdings, Inc. will seek to partner several major laboratories in the U.S. – including Quest Diagnostics, Salimetrics, Labrix and other experienced salivary testing labs. Using these laboratories initially will ensure national coverage in the U.S. during the BrainFax launch, top of the line nanotechnologies for use in testing, as well as consistent standards and quality controls in salivary assays and reporting of emotion detection results. Using national and ultimately worldwide testing partners, distribution and use of BrainFax becomes cost-effective and almost a medical necessity. Cheek swabs are an economical commodity and can be purchased and distributed throughout the world. Using the swabs to collect saliva can be easily taught and self-administered. The potential to reach billions with a new technology that can assist with their diagnosis and treatment is also part of the Exmovere Holdings, Inc. company mission. While the National Institutes of Health, the National Institute of Mental Health, the Center for Disease Control and the World Health Organization have all sponsored studies and seen results which recognize saliva testing as a cost-effective, non-invasive alternative to blood tests, most of the prior tests have all been laboratory based. The results are both deep and broad for babies, women, and men. No other company has launched a broad effort to bring emotion detection tools to healthcare professionals worldwide.

BrainFax – the world’s first salivary emotion detection technology. Your healthcare professional knows how you feel.

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The Market

By focusing first on psychiatrists, Exmovere will focus BrainFax on a large, underserved market. According to the latest information available from the National Institute of Mental Health (NIMH), approximately 13% of adults in the U.S. use or receive mental health services every year. This includes care in inpatient or outpatient settings and/or use of prescription medication for mental or emotional problems. This percentage has remained stable over the last several years.

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Among different segments of the population, there are several key differences in the incidence of mental health issues. Young adults – in the 18 to 25 age group – have the highest rate among all age segments. And, women have higher incidence than men. Among major racial groups, White, Hispanic and Native American have the highest rates. However, the incidence among racial groups ranges from about 3% to about 6%, while in the youngest adult age group, the occurrence of serious mental illness is closer to 8%.

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There are significant opportunities for BrainFax to assist with mental healthcare professional’s diagnoses. According to NIMH, over 40% of services are provided on an outpatient basis, and over 50% involve use of prescription medications. As psychiatrists provide their professional services and expertise, the objective assessment and reporting provided by BrainFax can provide significant substantiation, documentation and verification. Faced with a choice of treatment regimens including both counseling or talk-based therapies as well as prescription drugs, psychiatrists can now measure emotional state or mood at the start of their doctor-patient relationship as well as track over time.

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Among all people in the U.S., there are over 36 million involved in some form of mental health services. While that number is almost double over the 10 year period from 1996 – 2006, the proportion of the adult population has remained relatively stable. One of the implications of these results is increased incidence and use of mental health services among children, 18 and younger, in the overall population.

Average annual costs of mental health support on a per person basis had remained between $1,500 and $1,600 per year since 2002.

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Prevalence among children aged 13 to 18 remains under half, but over 45%. And, the highest rates occur in older teen years, among 17 and 18 year olds.

The statistics underscore the importance of having non-invasive testing procedures and tools available for mental health professionals. As they examine and diagnose younger patients in particular, the use of BrainFax swabs can provide a simple, painless way to collect information and test for emotion detection. Rather than create additional tension and stress in patients by requiring invasive blood testing, salivary testing is easier and less invasive to administer.

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The Technology

Saliva testing has many advantages over blood testing. Saliva specimen collection does not require a blood draw and there are no risks to patients. Saliva collections are convenient and can be done at work or at home. When stored properly, saliva samples are stable for several weeks. With an accuracy of 92-96%, saliva testing is more accurate than blood testing. The ability to collect more than one specimen is another advantage of saliva testing because this can give providers more information than a single collection. There are several different ways of measuring the hormones in a person’s body. Most blood and serum tests look only at the level of hormones that are present in a person’s tissues. This is known as “bound hormone levels”. Saliva testing looks at the “unbound hormone levels” also known as “free fraction hormone levels” which are the hormone levels that are available to be used by the body’s tissues. This gives providers a better idea of the levels of hormones that are actually influencing the tissues, rather than just the level of hormones that are present in the tissues. Measuring free fraction hormone levels gives a provider more information than measuring bound hormone levels. To properly assess emotions through saliva testing, cortisol, adrenaline and pH must be measured and compared. BrainFax has been designed to use the measurements of all three in order to triangulate results and confirm the emotional assessment. Rationale for the use of this design is provided below. Cortisol The human adrenal glands do not secrete steroid hormones at a constant level throughout the day. The hormones – especially cortisol – are actually released in a cycle, with the highest value in the morning and the lowest value at night when functioning properly. This 24-hour cycle is called the circadian rhythm and is depicted below. An abnormal adrenal rhythm can influence many functions of the body including both mental and physical disease states.

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Adrenaline

Adrenaline is the body's activator, and is released in response to anxiety, exercise, or fear.

This is the basis of the so-called 'fight-or-flight' reaction. When a person or animal is

threatened, the options are usually either to stand its ground and fight, or run away as fast

as possible. Both responses would require extra supplies of blood and oxygen in the

muscles. Fright causes the brain to send signals to the renal glands which start pumping

large amounts of adrenalin into the bloodstream. This increases the heart and breathing

rate in preparation for the ensuing action. Levels of adrenaline in the saliva are typically

most highly correlated with extreme emotions, such as rage, anger, fear or heightened

levels of anxiety.

pH

Emotions do not have to be strong to cause a physical response. Your body responds to all

of your mental activities and emotions. Worry, anxiety, hate, joy, elation, and so on. Every

emotion affects your body. And if you are clinging to some past stress, that same emotion

is played over and over again for weeks, months, and years; your body continues to be

affected the same way over and over.

Emotions affect the pH of your saliva. Salivary test design using pH levels requires a two-

stage test. The pH of your saliva dances from low to high depending on what you’ve put

into your mouth recently. The “normal” pH of saliva is considered to be around 6.8.

However, it can go much lower and much higher than that. Chew on an orange, and your

saliva pH can drop like a rock. Swish a solution of water and baking soda in your mouth

(although I’m not sure why you would want to do that) and your saliva pH shoots up like a

rocket. The point is that your saliva pH changes instantly to handle current conditions,

including your emotions.

In the two-stage test, patients take a pH reading (with the BrainFax swab and litmus

paper) once in the morning before they have eaten anything and record that level. Next,

the patient introduces an acidic stimulus – a slice of lemon or teaspoon of lemon juice –

and measures the pH level of the saliva a second time and again record pH numbers.

According to research from Dr. Clark Brooks, the results can be interpreted as follows:

Numbers Go Up If your pH numbers go up, this indicates that your body can respond easily to strong stimuli (acid of the lemon). No matter what color your first number was, this change to higher is beneficial.

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Numbers Go Down If your numbers don’t go up but instead go down, something is bothering you; stress or anxiety is dominating your physiology. Take this as a sign that your life and health could be improved with a few changes.

Numbers Don’t Change When before and after numbers are virtually the same, this can be the strongest indication that emotional distress is a key factor. It’s time to take action. Emotional habits and the moods they create need to be re-examined and modified.

Based on these three tests – cortisol, adrenaline and pH – mental health professionals can objectively determine a patient’s emotional state. The purpose of the testing will be to provide the practitioner with a confirmation of their diagnosis and help them create a record or basis for any related medication prescriptions.

BrainFax begins by taking all published and laboratory results from saliva testing over the past 10 years. Archives of the NIH, NIMH, CDC, DOD as well as independent labs are used to produce a set of baseline biometrics and the moods that go with them. Comparing an individual patient’s lab results to these baselines provides the psychiatrist with an objective assessment of the emotional state of the individual. Similar to many blood serum tests, BrainFax provides a range of valences which correspond to the individual’s results.

For example, the following ranges apply to common blood test results:

A full list of reference ranges from common blood tests is available on Wikipedia at http://en.wikipedia.org/wiki/Reference_ranges_for_common_blood_tests. These reference ranges are a result of years of research, laboratory records and individual records which help create a national database.

Test Arterial/Venous Lower limit Upper limit

pH Arterial 7.34 7.44

Venous 7.31 7.41

Test Patient type Lower limit Upper limit Unit

Cortisol 9:00 AM 140 700 nmol/L

5 25 μg/dL

Midnight 80 350 nmol/L

2.9 13 μg/dL

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Exmovere Holdings, Inc. as part of the BrainFax service will create a similar database of research, ranges and test results using records and studies from NIH, NIMH, CDC and other publicly available records. To the extent that cooperation from national and international agencies or laboratories can be used as inputs as well – without violating current HIPAA rules and regulations – those results will be used as well. A small sample of the types of studies and key results is below.

Recommended Reading

To further understand the connections between cortisol, adrenaline and pH as well as how they are used in salivary assays to detect emotional states, the following research, reports and studies will be useful.

Salimetrics, one of the leading salivary assay labs in the U.S. has compiled archives of the latest uses and results of saliva testing. These listings represent the most important findings from 2011. Additional archives that summarize results from 2008 - 2010 are available at the company’s website in the Archives page.

08.11.11 - Psychological distress and salivary cortisol covary within persons during pregnancy.

Giesbrecht, G.F., et al. (2011). Psychoneuroendocrinology.

This study examined the possibility of a link between altered cortisol levels due to maternal psychological

distress during pregnancy and changes in fetal development. A robust association was found between

negative mood and salivary cortisol in mothers, suggesting that cortisol may plausibly transfer the effects of

maternal stress to the developing fetus. Abstract

08.11.11 - Allostasis and allostatic load in the context of poverty in early childhood.

Blair, C., et al. (2011). Dev Psychopathol.

The effect of early environmental adversity on children’s basal salivary cortisol levels was followed in this

longitudinal study of children from the age of 7 to 48 months. Elevated cortisol levels were found to be

related to poor housing quality, African-American ethnicity, low positive caregiving behavior, adult exits from

the home, and perceived economic insufficiency. Abstract

08.04.11 - Salimetrics Spit Camper wins research award!

Bridget Hatfield, Ph.D., a research associate working with the Center for Advanced Study of Teaching and Learning,

is among five researchers nationally receiving an Early Career Educational Psychology Research Award from the

Education Psychology Division (15) of the American Psychological Association. News Release

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07.26.11 - Assessing stress reactivity indexed via salivary cortisol in preschool-aged children.

Kryski, K.R., et al. (2011). Psychoneuroendocrinology.

To fulfill the need for a stressor paradigm that evokes mean increases in salivary cortisol in young children,

this study examines the ability of a standardized task (adapted from Lewis and Ramsay, 2002) to assess

cortisol reactivity in a group of preschool-aged children, with positive results. Abstract

07.26.11 - Direct and moderating links of salivary alpha-amylase and cortisol stress-reactivity to youth

behavioral and emotional adjustment.

Allwood, M.A., et al. (2011) Biol Psychol.

This study explores basal levels and stress responses of salivary alpha-amylase and cortisol as measures of

activity in the autonomic nervous system and HPA axis, respectively, in relation to behavioral and emotional

adjustment in children aged 7-16 years. Alpha-amylase was positively related to anxiety and also moderated

associations between cortisol reactivity and problem behavior. Abstract

07.12.11 - 2D:4D ratios in the first 2 years of life: Stability and relation to testosterone exposure and

sensitivity.

Knickmeyer, R.C., (2011). Horm Behav.

In this study on the development of 2D:4D ratios in infancy, salivary testosterone levels were measured and

DNA samples were genotyped for the CAG repeat polymorphism in the androgen receptor. Substantial

variability across age in the 2D:4D ratios and small sex differences compared to adults suggest that 2D:4D

may not function well as a proxy measure of prenatal testosterone exposure in infancy. The interaction of

salivary testosterone and CAG repeat length predicted digit ratios and change in digit rations in males.

2D:4D ratios in adults may reflect, in part, neonatal testosterone exposure. Abstract

07.12.11 - Influences of menstrual cycle position and sex hormone levels on spontaneous intrusive

recollections following emotional stimuli.

Ferree, N.K., et al. (2011). Conscious Cogn.

Salivary sex hormone levels were analyzed in women to investigate the relationship between the menstrual

cycle and the higher rates of spontaneous intrusive recollections (SIR) in women following emotional events

compared to men. Women in the luteal phase reported significantly more SIRs than did women in the

follicular phase, and SIR frequency significantly correlated with salivary progesterone levels. Implications for

disorders such as PTSD are discussed. Abstract

06.15.11 - Increased serum androstenedione in adults with autism spectrum conditions.

Ruta, L., et al. (2011). Psychoneuroendocrinology.

Current research in neurodevelopment is exploring possible associations between sex-steroid hormones,

autism spectrum conditions (ASC), and autistic traits. This study examined serum levels of the sex steroids

testosterone and estradiol, and their precusors, DHEA-S and androstenedione. ASC diagnosis strongly

predicted androstenedione levels, and serum androstenedione levels were significantly elevated in the ASC

individuals, adding support to the proposed relationship between sex hormones and brain development.

Abstract

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06.15.11 - Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity

throughout pregnancy: Comparison to salivary cortisol.

D’Anna-Hernandez, K.L. et al. (2011). Physiol Behav.

Cortisol levels in hair of women were evaluated and compared to diurnal salivary cortisol levels throughout

the course of pregnancy. Salivary and hair cortisol levels rose during pregnancy, and the areas under the

curve with respect to ground (AUCg) were also correlated for both measures throughout pregnancy. Hair

cortisol levels are a useful measure of long-term cortisol activity. Abstract

06.09.11 - No effect of social exclusion on salivary cortisol secretion in women in a randomized

controlled study.

Zöller, C., et al. (2010). Psychoneuroendocrinology.

The effects of social exclusion on mood and HPA-axis response (salivary cortisol) were examined in this

study using a standardized Cyberball paradigm. The social exclusion paradigm was not observed to affect

HPA-axis function, although significant effects on mood were observed. Abstract

06.09.11 - Neural pathways link social support to attenuated neuroendocrine stress responses.

Eisenberger, N.I., et al. (2007). NeuroImage.

This study examined relationships between levels of social support and assessments of neurocognitive

reactivity to a social rejection task (fMRI imaging during a Cyberball paradigm) and neuroendocrine

reactivity to a social stressor (salivary cortisol responses to the TSST procedure). Individuals who had

regular social support showed reduced neurocognitive reactivity to social stressors in two brain regions,

which in turn was associated with reduced cortisol reactivity. The hypothalamus mediated the relationship

between the two brain regions and cortisol responses, suggesting a link between activity in the two regions

and activation of the HPA axis. Abstract

06.09.11 - Effects of an early family intervention on children’s memory: The mediating effects of

cortisol levels.

Bugental, D., et al. (2010). Mind Brain Educ.

This study examined the effects of a home visitation intervention program on salivary cortisol levels and

memory abilities of at-risk pre-term children. Maternal participation in the program led to lowered basal

cortisol levels in the infants and higher verbal short-term memory at age 3. Abstract

05.27.11 - State, not trait, neuroendocrine function predicts costly reactive aggression in men after

social exclusion and inclusion.

Geniole, S.N., et al. (2011). Biol Psychol.

Aggression was measured in men randomly assigned to a social exclusion or social inclusion condition

during a computer ball-toss game. Salivary cortisol and testosterone were measured at three points.

Increases in cortisol and testosterone were found to predict aggressive behavior, while baseline cortisol and

testosterone did not. Abstract

05.27.11 - Diet and the evolution of human amylase gene copy number variation.

Perry, G.H., et al. (2011). Nature Genetics.

Copy number of the salivary amylase gene (AMY1) is correlated positively with salivary amylase protein

level, and individuals from populations with high-starch diets have, on average, more AMY1 copies than

those with traditionally low-starch diets. Abstract

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05.27.11 - The cortisol awakening response in context.

Clow, A., et al. (2010). Int Rev Neurobiol.

This discussion examines the initiation and control of the CAR, with a consideration of its relationship to

other awakening-induced processes, changes in hormones and the immune system, and mobilization of the

motor system. Abstract

05.27.11 - Diagnostic potential of Saliva: Current state and future applications.

Pfaffe, T., et al. (2011). Clin Chem.

This review examines the production and secretion of saliva, the salivary proteome, transportation of

biomolecules from blood into saliva, and the diagnostic potential of saliva for use in detection of

cardiovascular disease and oral and breast cancers. Abstract

05.18.11 - Predictors and patterns of participant adherence to a cortisol collection protocol.

Hall, D.L., et al. (2011). Psychoneuroendocrinology.

This study examined participant adherence to a multi-point salivary cortisol sampling protocol with respect

to various demographic factors and fatigue. Abstract

05.18.11 - Current developments in salivary diagnostics.

Miller, C.S., et al. (2010). Biomark Med.

Recent developments in the diagnostic use of salivary biomarkers are examined in this paper, with particular

emphasis on panels of markers that could potentially help with the identification and treatment of

periodontal disease and cardiovascular disease. Abstract

05.18.11 - Self-esteem moderates neuroendocrine and psychological responses to interpersonal

rejection.

Ford, M.B. & Collins, N.L. (2010). J Pers Soc Psychol.

Salivary cortisol was used in this study that explores interactions between interpersonal rejection,

physiological stress pathways, and defensive social action. Self-blame attributions were found to mediated

the link between low self-esteem and increased cortisol reactivity; cortisol reactivity, in turn, was found to

mediate the link between low self-esteem and increased partner derogation. Abstract

05.18.11 - Individual differences in biological stress responses moderate the contribution of early peer

victimization to subsequent depressive symptoms.

Rudolph, K.D., et al. (2011). Psychopharmacology (Berl).

Salivary cortisol and alpha-amylase were used to study possible relationships between individual differences

in biological stress responses, peer victimization, and the development of depressive symptoms in children.

Victimization was found to interact with high levels of cortisol measured in anticipation of a laboratory stress

task to predict rumination and depressive symptoms one year later. Victimization also predicted subsequent

depressive symptoms in girls with high sAA reactivity across the task. Abstract

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05.12.11 - Are salivary gonadal steroid concentrations influenced by acute psychosocial stress? A study

using the Trier Social Stress Test (TSST).

Schoofs, D., & Wolf, O.T. (2011). Int J Psychophysiol.

The effects of the TSST on the HPA axis, sympathetic nervous system, and HPG axis were studied using

salivary analytes. As expected the stress condition led to increased salivary concentrations of cortisol and

alpha-amylase. Levels of testosterone, progesterone, and estradiol were not affected, however, indicating

that acute psychosocial laboratory stress had no strong rapid effects on salivary gonadal steroids. Abstract

05.12.11 - Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive

function: The Vietnam Era Twin Study of Aging.

Franz, C.E., et al. (2011). Psychoneuroendocrinology.

This study examined the effects of cortisol levels on executive function abilities related to the prefrontal

cortex in humans. Higher average salivary cortisol output across three days in a sample of middle-aged

male twins was found to be associated with poorer performance in three domains: executive measures,

processing speed, and visual-spatial memory. Abstract

05.05.11 - Stress in migrant farmworkers during premigration.

Clingerman, E.M., & Brown, A. (2011). Biol Res Nurs.

Salivary cortisol was used in this study of the effects of stress on migrant farmworkers. Results indicated

that migrant workers experienced significant levels of stress prior to migration and that cortisol responses

varied significantly by the levels of perceived stress. Abstract

05.05.11 - Neurobiological and behavioral stress reactivity in children prenatally exposed to tobacco.

Huijbregts, S.C., et al. (2011). Psychoneuroendocrinology.

Salivary cortisol and salivary alpha-amylase levels were measured throughout a stressful neuropsychological

test session in three groups of children: those exposed prenatally to tobacco, those with disruptive behavior

problems, and normal controls. No significant differences in cortisol responses were found for the three

groups. sAA levels , sAA reactivity, and behavioral reactivity patterns, however, were found to be similar in

prenatally exposed children and those with behavior problems, compared to the normal controls. Abstract

04.29.11 - Salivary alpha-amylase levels as a biomarker of experienced fear.

Buchanan, T.W., et al. (2011). Commun Integr Biol.

Salivary cortisol and salivary alpha-amylase were studied as indices of emotional arousal before and after

participants went through a fear-challenge course. Alpha-Amylase, but not cortisol, showed a highly specific

increase for participants with both emotional arousal and negative valence. Participants who had high

arousal and positive valence exhibited no increase in alpha-amylase. Abstract

04.29.11 - Asymmetry of salivary cortisol and alpha-amylase responses to psychosocial stress in

anorexia nervosa but not in bulimia nervosa.

Monteleone, P., et al. (2011). Psychol Med.

Salivary cortisol and salivary alpha-amylase responses to the Trier Social Stress Test (TSST) were studied in

individuals with anorexia nervosa or bulimia nervosa, and in healthy controls. Anorexia patients showed a

normal cortisol response to the TSST (at significantly increase hormone levels), but almost no response of

alpha-amylase. In contrast, bulemia patients showed a normal response of both alpha-amylase and cortisol

to the TSST (with elevated pre-stress levels of alpha-amylase). Abstract

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04.18.11 - The SIS release date is here!

The Salimetrics Infant’s Swab is set to be released in June, 2011. See product details here.

04.13.11 - ‘Immunogenetics of Aging’: Report on the activities of the 15th International HLA and

Immunogenetics Working Group and 15th International HLA and Immunogenetics Workshop.

Naumova, E., et al. (2011). Tissue Antigens.

This report presents information from studies that have examined human leukocyte antigen (HLA) genes,

cytokine genes, and some innate immunity genes in relation to successful aging and longevity. Abstract

04.13.11 - Children’s internalizing symptoms: The role of interactions between cortisol and respiratory

sinus arrhythmia.

El-Sheikh, M., et al. (2011). Physiol Behav.

The interactions of the HPA axis and the parasympathetic nervous system were examined using salivary

cortisol and respiratory sinus arrhythmia (RSA), respectively, as measures of activity in the two systems.

Children with higher cortisol levels in conjunction with higher RSA levels tended to exhibit the lowest levels

of depression and anxiety symptoms. Abstract

03.28.11 - Genome-wide association studies of sleep disorders.

Byrd-Craven, J., et al. (2010). J Social Personal Relationships.

This study used salivary cortisol and salivary alpha-amylase as measures of activity in the hypothalamic-

pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), respectively, in order to explore the

reactivity of the two systems to co-rumination in same-sex friendships among young women. At low levels

of negative affect the SNS system was more responsive than the HPA axis, but higher levels of negative

affect from excessive problem discussion was found to influence both systems. These results suggest that

examination of both stress systems may be important in order to understand the social dynamics of coping.

Abstract

03.28.11 - Genome-wide association studies of sleep disorders.

Raizen, D.M. & Wu, M.N. (2011). Chest.

This review examines recent advances in the study of sleep disorders through genome-wide association

studies. In particular, the identification of gene variants associated with restless legs syndrome and

narcolepsy have opened new areas of research that may lead to a better understanding of these disorders.

Abstract

03.17.11 - Biosocial influences on the family: A decade review.

D’Onofrio, B.M., & Lahey, B.B. (2010). J Marriage Family.

This review examines recent advances in biosocial family research, with a discussion of the need to

integrate measurement of biological factors. Abstract

03.17.11 - Effects of an early family intervention on children’s memory: The mediating effects of

cortisol levels.

Bugental, D.B., et al. (2010). Mind Brain Educ.

This study examines the use of an early family intervention program to reduce cortisol levels in at-risk

preterm infants, with subsequent improvements in short-term memory at age 3. Abstract

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03.02.11 - a-Amylase as a reliable and convenient measure of sympathetic activity: Don’t start

salivating just yet!

Bosch, J.A., et al. (2011). Psychoneuroendocrinology.

In this invited mini-review, the authors address the use of a-amylase as a non-invasive measure of

sympathetic nervous activity. They summarize research that has shown that parasympathetic nerves also

contribute to a-amylase release, as well as regulating saliva flow from the saliva glands. Failure to consider

differences in the structure and innervation of the various saliva glands and the resultant effects on salivary

levels of a-amylase may result in data that is hard to interpret and that does not represent a reliable

measure of SNS activity. Unstimulated whole saliva collected by the passive drool technique is

recommended for a-amylase determinations. Abstract

02.25.11 - Conference on Stress and the Brain to be held at Johns Hopkins University, April 28th-29th,

2011.

The Johns Hopkins University is sponsoring an interactive summit conference on Stress and the Brain –

Implications for Health, Development, and Learning, to be held April 28th-29th, 2011. The keynote speaker

will be Sir Michael Rutter. Read More

02.23.11 - Correlated genotypes in friendship networks

Fowler, J.H., et al. (2011). Proc. Natl. Acad. Sci.

Using information about respondents’ genes and friendship ties from two large independent studies–the

National Longitudinal Study of Adolescent Health, and the Framingham Heart Study Social Network– this

paper examines the question of whether any correlation exists among genotypes of people in

nonreproductive, friendship unions. Correlations for two genes were found, one positive and one negative,

suggesting that genotypic clustering does occur in social networks. Abstract

02.16.11 - Dr. Douglas A. Granger to give seminar on Salivary Analytes

The Pediatric Topics in Growth and Development Seminar Series at the University of Maryland

School of Medicine will feature Dr. Douglas A. Granger in a talk titled “Integration of Salivary Analytes into

Behavioral and Developmental Science,” March 1, 2011. Dr. Granger serves as director of the Center for

Interdisciplinary Salivary Bioscience Research at the Johns Hopkins University School of Nursing, as well as

Founder and Chief Scientific and Strategy Advisor at Salimetrics. Read More

02.10.11 - Oral Fluid Reveals More Heroin Use Than Previously Believed, According to Quest

Diagnostics Drug Testing Index.

Quest Diagnostics (Jan. 25, 2011). News Release.

Testing more than 320,000 oral fluid samples collected from the general U.S. workforce in 2010 has found a

higher user rate for the heroin marker 6-acetylmorphine (6-AM) when compared to the results from urine

testing. News Release

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01.27.11 - The effects of maltreatment and neuroendocrine regulation on memory performance.

Cicchetti, D., et al. (2010). Child Dev.

In the setting of a week-long camp for maltreated children, memory performance, behavioral symptoms,

and morning salivary cortisol levels were evaluated. The results of the study illustrate the effects of

maltreatment and hypocortisolism on children’s recognition memory errors. Abstract

01.27.11 - Genetic and environmental influences on cortisol regulation across days and contexts in

middle-aged men.

Franz, C.E., et al. (2010). Behav Genet.

The heritability of salivary cortisol concentrations was examined as part of the Vietnam Era Twin Study of

Aging. Significant cortisol heritability estimates for identical twins were found for laboratory measures, but

not when samples were collected independently while the subjects were at home. The authors suggest that

cortisol results were correlated in identical twins only when they were both exposed to the same mild

challenge of the unfamiliar laboratory experience. Abstract

01.14.11 - Salimetrics Introduces New Saliva Collection Device for Infants

In response to requests from researchers for a safe, effective, and easy-to-use saliva collection device for

use with infants, Salimetrics has now introduced the Salimetrics Infant’s Swab (SIS). This new swab has the

following features:

Small size appropriate for the mouths of infants (5 x 90 mm).

No choking hazard. The extra length allows one end of the swab to be held by an adult while the other end is placed in the infant’s mouth.

The taste and texture of the durable polymer used in the SIS are acceptable to infants.

Better recovery of sample volumes (typically in range of 200-1000 µL). Samples may be recovered by centrifugation, or by compression in a needle-less syringe while in the field, so that the actual volume collected can be determined, followed by repetition if necessary. Reports from researchers indicate the SIS helps them avoid the problem of samples with insufficient volume for testing.

Excellent analyte recovery characteristics (>95% for cortisol).

No assay interference for a broader range of analytes. The SIS may used to collect saliva for determination of the following analytes: alpha-amylase, chromogranin A, cortisol, cotinine, C-reactive protein, SIgA, and testosterone.

The SIS is made of the same synthetic polymer used in our regular Salimetrics Oral Swab (SOS) and in the Salimetrics Children’s Swab (SCS), making possible consistency in collection method over the course of longitudinal studies.

These results are only a partial list of the most recent results from over 2,500 studies. They do, though, show the dramatic potential of BrainFax to offer psychiatrists and opportunity to objectively measure and track key indicators of emotional states or moods in their patients. The body of research does also point to the longer term potential of BrainFax to bring new technologies and testing to not only hormones and pH, but most of the same types of indicators currently used in blood testing. BrainFax promises to significantly advance psychiatry and other medical disciplines with its ability to tie emotional states and disease states (both mental and physical) together through saliva testing.

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BrainFax Design

Based on the combined metrics from all NIH, NIMH, CDC and other professional outcomes, BrainFax will make distinct connections between the laboratory-level readings and respondents emotional state and moods. Exmovere’s proprietary algorithms are applied against the available data to provide precise interpretations. The following diagram explains more about how BrainFax works.

Key elements of the BrainFax system include in-home administration of saliva sample collection, expert panel validation of baselines and methodology, and creation of standards for determining emotional states. Medical professionals and healthcare experts will have access to lab reports from BrainFax that is similar to what they receive today from blood serum testing. All parts of the system will remain in compliance with HIPAA laws. Each of these design elements and system attributes is described in more detail below.

Saliva Sample

Collection

Ship to Lab

Lab Testing

Stat Modeling

Compare to baseline

MetricsExmovere Algorithms

Mood ID

Online Reporting

Patient, in office

or at home

Expert Panel

Validation

and

Standards

HIPAA

Compliant

Access for

Healthcare

Professional

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In-home administration of sample collection is an important part of BrainFax application and use. One of the more important reasons for this part of the design is based on the need for multiple samples throughout the day. Because an individual’s cortisol levels vary throughout the day, a single reading will not be adequate. Rather than have patients provide samples at the practitioner’s office, it will be easier and more cost-effective to administer at home. The collection devices – cheek swabs – are easy to distribute and use. Similarly, samples need to be taken twice to accurately capture pH readings. And, finally adrenaline readings can be monitored with the multiple readings as well.

One of the benefits of in-home sample collection will be the psychiatrist’s ability to compare mood states when the patient is at home and compare those to readings taken when the patient is in the office. With the wealth of information becoming available on younger segments of the population, including infant, adolescent, and pre-teen, the opportunity to monitor mood states in different settings can potentially have a dramatic impact on behavior modification and prescribed therapies. Rather than depend only on what a patient says or does while in the office, by using BrainFax, mental health professionals can capture substantially more information and data to help the patient.

Perhaps the most important aspect of in-home sample collection, though, is the ease of use and non-invasive BrainFax protocol. Based on the types of swabs manufactured, parents of younger patients can administer the sample collection procedures at home. Pre-teens, teens, and adults as well can take saliva samples with the BrainFax swabs in the comfort of their own homes. If these patients were to provide samples in the psychologist, psychiatrist or therapist office, their stress levels could be elevated resulting in higher levels of cortisol and adrenaline as well as affecting pH balance. These elevated readings would cause analytics and emotion detection to present false readings. To capture true and accurate readings of cortisol, adrenaline and pH levels, as well as promote ease of use, BrainFax is best administered at home by the patients themselves.

The following represent different types of swabs and collection vials, designed for alternative population and demographic segments, which can easily be used to collect saliva samples at home. These are typical of what’s available on the market today.

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To aid labs with sample storage and compliance with HIPAA regulations, most have storage boxes like the ones below.

Joint venture and laboratory partners with Exmovere Holdings, Inc. in the launch and introduction of BrainFax will provide all needed saliva collection swabs and storage collection boxes. Rather than wait for psychiatry practice offices to request swabs initially, Exmovere and its partners plan to distribute swabs to known or interested offices throughout the United States. In addition, early baselines – validated by the company’s expert panel – will be provided along with reference to all of the research studies and professional resources used to construct BrainFax. Exmovere and its partners will also provide 2 or 3 lab results tests to each interested psychiatrist, free of charge, at the beginning of the national launch of the new service. This will expose most psychiatry offices and practitioners to BrainFax, allow them to read actual results for their patients and compare what they get back from the lab results to their own exam results and diagnoses.

To facilitate the verification and validation of baseline results, developed from a complete dataset gathered from existing research, an expert panel will be recruited by Exmovere Holdings, Inc. as part of the BrainFax launch and service development. The panel will consist of recognized experts from psychology, psychiatry and therapy fields, as well as the broader medical community. Experience with or research pertaining to the use of saliva testing will be a key attribute for panel members. The purpose of the panel will be to testify to the quality of the database and to provide BrainFax usage protocols for the system to ensure that the readings are as meaningful as possible. The experts have the task of evaluating and validating results across a wide spectrum of segments, including but not limited to age, gender, race, geography, lifestyle and other factors which may be relevant to interpretation of future test result.

Members will be recruited from current leading hospitals and institutions as well as private practice. For example, the following experts were recently identified as leading edge experts in salivary assays and diagnostics.

Eric Anslyn, PhD, at the University of Texas (UT) at Austin has developed a sensor array platform

suited for point-of-care diagnostics; it is based on a micromachined bead-based platform that is

amenable to multianalyte detection and quantitation. The UT research group teamed with experts in

salivary diagnostics at the University of Kentucky, Lexington, for the collection and analysis of

clinical samples.

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Daniel Malamud, PhD, MA, and his research team at New York University, New York City, are involved

in the identification and characterization of antibacterial and antiviral molecules, as well as assay

development, using oral fluid as a noninvasive diagnostic method. This research team is involved in

designing a point-of-care detection system for the identification of bacterial and viral pathogens.

Anup Singh, PhD, Sandia National Laboratories, Livermore, Calif., is developing microfluidic systems

for the analysis of biological molecules. His research group is developing an integrated microfluidic

system for simultaneous detection of multiple analytes in saliva and in other oral fluids.

David Stahl, PhD, University of Washington, Seattle, is involved in studies of microbial community

structure and function in many habitats, including the human mouth. Dr. Stahl’s group is developing

DNA microarray-based technology for the rapid and unambiguous detection of microbial biomarkers

in oral fluids.

David Walt, PhD, Tufts University, Medford, Mass., is using a bead-based fiber-optic–based detection

platform to investigate salivary diagnostics in the context of end-stage renal disease, asthma and

opportunistic infections

Many of these experts have been focused on oral-related health issues, dental practices and more general physical health uses of salivary diagnostics research. For example, the Wrigley Oral Healthcare Program sponsors Salivary Research Awards each year. The 2011 award winners can be reviewed at the company’s website.

Similar experts from psychiatry, psychology and therapy will be sought out and recruited to be part of the BrainFax panel. The purpose of the panel will be to review testing and results, assist Exmovere Holdings, Inc. with establishing baselines, and prepare support for creating BrainFax standards for emotion detection using salivary assays for key emotional states, including euphoria, anger, stress, fear and other emotions. Based on the company’s algorithms and the BrainFax system, these will be used as predictors for many of the emotional and mood states found in the Clinical Syndromes of the DSM IV, the key diagnostic reference for mental health professionals.

Market Potential

According to the U.S. Bureau of Labor Statistics, there are over 325,000 practicing

psychologists, psychiatrists and therapists in the U.S. market today. Slightly more than half

of these (54%) are in private practice and another 10-15% work primarily in hospital and

in-patient care facilities. The remaining 25-30% are employed in government institutions,

research facilities, universities and government-sponsored agencies. For the initial BrainFax

launch, the relevant target is the combination of private practice and in-patient care

psychiatrists – roughly 22,500 working professionals in the United States.

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The World Health Organization recently estimated there are on average 10 psychiatrists per

100,000 of the worlds population. The range of service varies considerably from a high of

about 15 in the U.S. to a low of 1 in many third world countries and lesser developed

economies. At this rate, based on current estimates of the world population, the

implication is that there are well over 500,000 practicing psychiatrists worldwide.

For these professionals, with normal office hours, their schedules permit working with 6-8

patients per day. During one week, for the total target of 22,500 professionals in the U.S.

that amounts to just under 1 million patients, or close to 30 million each month. If each

patient requires 2 or 3 swabs per day to capture the right information at the right time for

each patient, BrainFax could be responsible for as many as 90 million tests each month.

Worldwide, once BrainFax goes global based on reliable international labs and testing

results, the potential grows by a factor of at least 20 times based on the relationship of the

number of U.S. psychiatrists to the number worldwide. Based on international practice,

though, it may be more realistic to assume that not all patients will be considered for

BrainFax because payments for lab results may be prohibitive in some countries and

economies. Even with a factor of 10x, BrainFax could be responsible for over 900 million

tests per month.

Expansion to other practitioners of mental health care – including licensed social workers,

psychologists and therapists brings the total number of professionals in the U.S. to close to

225,000 based on the latest BLS statistics. Worldwide this number is even larger. As

BrainFax expands, the number of tests each month will begin to grow into a several billion.

As Exmovere Holdings, Inc. creates awareness and usage of BrainFax in the psychiatry

field, sales can be expected to grow rapidly and significantly. Assuming a $10 net revenue

contribution from each unit – after paying lab, testing and reporting fees to its joint venture

and lab testing partners – generates company contribution of about $900 million per month

or over $1.8 billion per year once the new service reaches a full-scale level of penetration

and usage in the U.S. marketplace.

In Years 1 – 5, the company can expect growth to increase rapidly. With marketing and

advertising support, creation of BrainFax standards, use and application of the saliva-based

emotion detection services, additional demand will be created. And, internationally, the

World Health Organization already supports the basis for BrainFax based on the

organization’s most recent research and findings. With the additional resources of the

WHO behind creating awareness and use around the world, the company expects to build a

multi-billion dollar service as the BrainFax offering matures.