I. INTRODUCTION 3 IV. REGULATORY 7 VI. BIBLIOGRAPHY 8

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2 INDEX I. INTRODUCTION 3 II. CLINICAL STUDIES ON ZYNAMITE 4 A. SPORTS PERFORMANCE 4 B. MENTAL ENERGY 5 III. PRECLINICAL STUDIES ON ZYNAMITE 6 IV. REGULATORY 7 V. MANUFACTURING PROCESS 7 VI. BIBLIOGRAPHY 8

3 I. INTRODUCTION Imagine an innovation that replaces caffeine with a clean label ingredient that has none of the negative side effects of caffeine and even works better! gives sustained mental and physical energy and focus without any negative side effects. WHAT DO TIRED PEOPLE NEED? Stressed or fatigued people lack enthusiasm and mostly feel exhausted and desperate. What they desire is a sustained boost of energy that improves physical performance, concentration, attention, alertness and mood. THE PROBLEM WITH CAFFEINE Because of the mental energy and focus provided by caffeine, billions of cups of coffee are consumed daily to assist people to cope. However, caffeine is addictive and most people consume too much of it and suffer from its side effects and withdrawal symptoms 1. CAFFEINE IN SPORTS PRODUCTS AND NOOTROPICS Many sports and nootropic products contain caffeine to increase alertness and boost physical energy but these products inevitably lead people to experience jitters, anxiety, irregular pulse, insomnia and nausea 2. is the ideal alternative. What is? is Nektium s patent-pending proprietary Mangifera indica extract standardized to 60% mangiferin. Mangifera indica, the common mango tree, is cultivated extensively in the tropical and subtropical regions of the world. Infusions and decoctions of mango leaves are used in traditional health systems and have been known for centuries for their health benefits 3,4. How does work? activates brain waves and increases Long-Term Potentiation in a remarkably similar pattern to caffeine 5,6. While caffeine antagonizes adenosine receptors, acts nonselectively on multiple CNS targets to stimulate brain activity without causing side-effects. is protected is protected by United States Patent Application Compositions for Enhancing Brain Activity. Nektium 3

4 II. CLINICAL STUDIES ON ZYNAMITE has been studied in 4 clinical studies: 2 for mental energy and 2 for sports performance. A. CLINICAL STUDIES ON SPORTS PEFORMANCE In collaboration with Professor Dr. Jose López Calbet, University of Las Palmas, Spain, the effect of on performance and muscle fatigue was studied in two randomized, double-blind, placebo-controlled trials in caffeine-free formulations containing polyphenols, commonly used as antioxidants in sports products. CLINICAL STUDY 1 After 48 hours of 140mg + 50mg luteolin intake, taken eight hourly, twelve physically active young men performed repeated bicycle ergometer Wingate sprint tests. Mean power output under fatigued conditions and under fatigued + bilateral thigh ischemia-reperfusion was significantly increased by 5-7% compared with the placebo. Improved mean power output 19.4% compared to placebo (see graph). Likewise, both formulations containing increased mean power output by 6% during repeated ergometer Wingate tests. improved both peak power output and also mean power output which sustains prolonged sprints. improved VO 2 peak by 5%, with a corresponding increase in brain oxygenation of 10-12% in women (see graph) 7. Watt Mean power output WG2 Placebo Watt Mean power output WG3 (after ischemia reperfusion) 5% 6.7% p=0.009 p=0.036 These effects on sports performance were achieved without additional consumption of oxygen (VO 2 mean) during the sprints, suggesting either improved muscle energy efficiency and/or centrally mediated enhanced capacity to recruit the exhausted muscle fibers. Peak power output (after ischemia) 19.4% p= Frontal lobe oxygenation (Average of 5 sprints) 11.0% p=0.017 CLINICAL STUDY 2 In a confirmatory study the effect of 140mg intake, taken eight hourly for 48 hours was tested in two caffeine-free combinations: a) with 50mg luteolin and b) with 600mg quercetin. Thirty young athletes (13 women and 17 men) performed bicycle ergometer Wingate sprints. Peak power output, mean power output, oxygen uptake, respiratory variables, cerebral vascular reactivity and cerebral oxygenation were analysed after exhaustion followed by bilateral thigh ischemiareperfusion. In the sprint performed after exhaustion, followed by ischemia-reperfusion, the combination of + quercetin increased the peak power by a remarkable Watt Conclusion 10.3% % p=0.017 p= The results from the two sports performance studies demonstrate that the formulations containing have an even stronger effect than those published for caffeine, including significant improvement in peak power output (paper submitted to Frontiers in Physiology, April 2018). Oxygenation % Placebo L Q Nektium 4

5 II. CLINICAL STUDIES ON ZYNAMITE B. CLINICAL STUDIES ON MENTAL ENERGY The effect of on mental energy was studied in two randomized, placebo-controlled clinical trials. CLINICAL STUDY 3 The effect of a single dose of 500mg of was tested in 16 participants (7 men and 9 women). The study showed that significantly reduced fatigue after only 1.5 hours, analyzed with the Profile of Mood States questionnaire (POMS). reduced stress during the Calculation Performance Tests, evidenced by Galvanic skin response. Skin conductance (μs) Decreased stress p= Reduced fatigue p= before intake after intake before intake Score for fatigue after intake had no side effects and no change in heart-rate variability or blood pressure over the course of the study-variables typically affected by caffeinated products. During performance of two cognitively demanding challenges, a Number Sequence Test (NST) and a Number Connection Test (NCT), had a significant activating effect on the brain compared to placebo as determined by frequency analysis of the changes in electrical activity across six brain wave frequency ranges (colour coded) in the EEG of the association cortex (change from time-averaged baseline assigned as 100%) ; significance values: p<0.05, p< CLINICAL STUDY 4 A single dose of 420mg was studied in psychometric tests reflecting attention and reaction-time in 32 participants (16 men and 16 women). Performance in the cognitively challenging Calculation Performance Test was significantly improved and reaction times were significantly faster for compared to placebo. [%] of reference 0h % of max. reachable results NST Conclusion Placebo NCT Calculation performance p= Human EEG The results of these clinical studies demonstrate that enhances attention, reduces mental fatigue and improves reaction time-results typically shown for caffeine. The advantage of is that this extract also reduced stress, and there were no side-effects, including no changes in heart rate or blood pressure. NST Time in sec. NCT Reaction time Delta Theta Alpha 1 Alpha 2 Beta 1 Beta 2 NST: Number Sequence Test NCT: Number Connection Test p<0.05 p<0.001 p= Placebo Placebo Nektium 5

6 III. PRECLINICAL STUDIES ON ZYNAMITE REMARKABLE SIMILARITY TO CAFFEINE EEG The Central Nervous System (CNS) activities of were investigated using cuttingedge neurophysiological studies including in vivo functional electroencephalogram (EEG) in four brain regions, for six brain wave frequency ranges. In collaboration with Professor Wilfried Dimpfel, Justus- Liebig -University, Giessen, Germany, the EEG of was compared to that of caffeine. Results demonstrated that the pattern of electrical activation for both and caffeine are remarkably similar in the brain frontal cortex and in the hippocampus 5,6. The colored bars represent the six frequency bands studied. Caffeine % from baseline % from baseline Front. cortex δ ϑ α1 α2 β1 β2 Hippocampus δ ϑ α1 α2 β1 β2 SYNERGY WITH CAFFEINE LTP Long-Term Potentiation (LTP) enables the brain to form memories and helps athletes to automate coordination skills 8. In a study comparing the effect of, caffeine and +caffeine on LTP, had a greater effect on LTP than caffeine, while the combination of +caffeine demonstrated a remarkable synergy in increasing LTP 5,6. amplitude [mv] 4 3 Ex-vivo Control Caffeine TBS + Caffeine time [min] Nektium 6

IV. REGULATORY Mangifera indica (all parts, and explicitly stating Mango leaf) are included on the Belfrit List and on the Italian List, by decree 27th March 2014.

MANUFACTURING PROCESS DNA BARCODING: IDENTIFICATION OF SPECIES The botanical raw material used for first undergoes macroscopic inspection to ensure it conforms with reference plant material.

Additionally, UHPLC chromatographic profiles are used to confirm the presence of characteristic markers and to quantify the content of mangiferin.

7 IV. REGULATORY Mangifera indica (all parts, and explicitly stating Mango leaf) are included on the Belfrit List and on the Italian List, by decree 27th March Capsules of Nektium s are authorized as food supplement in Belgium, France, Italy, and Spain, while the German authorities have been notified. V. MANUFACTURING PROCESS DNA BARCODING: IDENTIFICATION OF SPECIES The botanical raw material used for first undergoes macroscopic inspection to ensure it conforms with reference plant material. DNA barcoding by the Royal Botanical Garden, Madrid, is used to positively confirm its botanical identity. Additionally, UHPLC chromatographic profiles are used to confirm the presence of characteristic markers and to quantify the content of mangiferin. QUALITY ASSURANCE & CERTIFICATIONS is the result of high quality botanical raw material combined with meticulous manufacturing procedures. Nektium s facilities and production processes strictly comply with cgmp (independently audited and certified annually) and rigorous quality control programs that ensure a high-quality product. Nektium Pharma S.L. is authorized by the Spanish Health & Food Agency for the production of botanical and fruit extracts in conformance with RD 1712/1991 and Spanish Regulations. Nektium Pharma S.L. also holds a FSSC22000 Food Safety System Certification by NSF International. Nektium 7

8 VI. BIBLIOGRAPHY 1.Snel, J. & Lorist, M. M. Effects of caffeine on sleep and cognition. Prog. Brain Res. 190, (2011). 2.Salinero, J. J. et al. The use of energy drinks in sport: perceived ergogenicity and side effects in male and female athletes. Br. J. Nutr. 112, (2014). 3.Benard, O. & Chi, Y. Medicinal Properties of Mangiferin, Structural Features, Derivative Synthesis, Pharmacokinetics and Biological Activities. Mini-Reviews Med. Chem. 15, (2015). 6.Dimpfel, W., Wiebe, J., Gericke, N. & Schombert, L. (Mangifera indica leaf extract) and caffeine act in a synergistic manner on electrophysiological parameters of rat central nervous system. Food Nutr. Sci. accepted f, (2018). 7.Gelabert-Rebato, M. & López-Calbet, J. Mangifera indica L. leaf extract ( ) in combination with luteolin or quercetin enhances VO2peak and peak power output, and preserves skeletal muscle function during ischemia-reperfusion in humans. in Congress: 23. European College of Sports Science ECSS, 4-7 July 2018, Dublin, Ireland (2018). 4.Sekar, M. Molecules of Interest Mangiferin A Review. Annu. Res. Rev. Biol. 5, (2015). 5.Dimpfel, W., Gericke, N., Wiebe, J. & Schombert, L. Synergy between Mango leaf extract ( ) and caffeine with respect to stimulation of the central nervous system in rats. Synergy Forum, 9-10 March 2018, Bonn, Germany (2018). 8.Patten, A. R. et al. Long-term exercise is needed to enhance synaptic plasticity in the hippocampus. Learn. Mem. 20, (2013). Nektium 8

9 C/ Las Mimosas 8, Agüimes. Las Palmas. Spain Nektium Pharma S.L. All rights reserved. Zynamite is a registered brands owned by Nektium. This publication contains information of general nature only. While Nektium has used reasonable efforts to include accurate and up-to-date information, Nektium does not make any warranties or representations as to its accuracy. To the maximum extent permitted by law, Nektium does not assume any liability or responsibility for the reliability, accuracy, validity, usefulness or completeness of any information in this document. Reliance on this document is done solely at the risk of the reader. Rev

I. INTRODUCTION 3 II. SCIENTIFIC & CLINICAL RESEARCH 4-8 III. MANUFACTURING PROCESS 9 IV. BIBLIOGRAPHY 10

Rhodiol WHITEPAPER INDEX I. INTRODUCTION 3 II. SCIENTIFIC & CLINICAL RESEARCH 4-8 III. MANUFACTURING PROCESS 9 IV. BIBLIOGRAPHY 10 Nektium Pharma S.L. All rights reserved. Rhodiolife is a registered brands