Reduce initial dose of the virus and optimize your immune systemPosted: April 4, 2020 Filed under: behavior, health, stress management, Uncategorized | Tags: coronavirus, COVID-19, immune system, public health, technology 6 Comments
Erik Peper and Richard Harvey
COVID-19 can sometimes overwhelm young and old immune systems and in some cases can result in ‘Severe Acute Respiratory Syndrome’ pneumonia and death (CDC, 2020). The risk is greater for older people, and people with serious heart conditions (e.g., heart failure, coronary artery disease, or cardiomyopathies), cancers, obesity, Type 2 diabetes, COPD, chronic kidney disease, hypertension, smoking, immune suppression or other health issues (CDC, 2020a) as well as young people who vape or smoke and those with immunological defects in type I and II interferon production (Gaiha, Cheng, & Halpern-Felsher, 2020; van der Made, 2020). As we age the immune system deteriorates (immunosenescence) that reduces the response of the adaptive immune system that needs to respond to the virus infection (Aw, Silva & Palmer, 2007; Osttan, Monti, Gueresi, et al., 2016). On the other hand, for young people and children the risk is very low and similar for Covid-19 as for seasonal influenza A and B in rates for hospitalization, admission to the intensive care unit, and mechanical ventilator ( Song et al, 2020).
Severity of disease may depend upon initial dose of the virus
In a brilliant article, How does the coronavirus behave inside a patient? We’ve counted the viral spread across peoples; now we need to count it within people, assistant professor of medicine at Columbia University and cancer physician Siddhartha Mukherjee points out that severity of the disease may be related to the initial dose of the virus. Namely, if you receive a very small dose (not too many virus particles), they will infect you; however, the body can activate its immune response to cope with the infection. The low dose exposure act similar to vaccination. If on the other hand you are exposed to a very high dose then your body is overwhelmed with the infection and is unable to respond effectively. Think of a forest fire. A small fire can easily be suppressed since there is enough time to upgrade the fire-fighting resources; however, during a fire-storm with multiple fires occurring at the same time, the fire-fighting resources are overwhelmed and there is not enough time to recruit outside fire-fighting resources.
As Mukherjee points out this dose exposure relationship with illness severity has a long history. For example, before vaccinations for childhood illnesses were available, a child who became infected at the playground usually experienced a mild form of the disease. However, the child’s siblings who were infected at home develop a much more severe form of the disease.
The child infected in the playground most likely received a relatively small dose of the virus over a short time period (viral concentration in the air is low). On the other hand, the siblings who were infected at home by their infected brother or sister received a high concentration of the virus over an extended period which initially overwhelmed their immune system. Higher virus concentration is more likely during the winter and in well insulated/sealed houses where the air is recirculated without going through HEPA or UV filters to sterilize the air. When there is no fresh air to decrease or remove the virus concentration, the risk of severity of illness may be higher (Heid, 2020).
The risk of becoming sick with COVID-19 can only occur if you are exposed to the coronavirus and the competency of your immune system. This can be expressed in the following equation.This equation suggests two strategies to reduce risk: reduce coronavirus load/exposure and strengthen the immune system.
How to reduce the coronavirus load/dose of virus exposure
Assume that everyone is contagious even though they may appear healthy. Research suggests that people are already contagious before developing symptoms or are asymptomatic carriers who do not get sick and thereby unknowingly spread the virus (Furukawa, Brooks, Sobel, 2020). Dutch researchers have reported that, “The proportion of pre-symptomatic transmission was 48% for Singapore and 62% for Tianjin, China (Ganyani et al, 2020). Thus, the intervention to isolate people who have symptoms of COVID-19 (fever, dry cough, etc.) most likely will miss the asymptomatic carriers who may infect the community without awareness. Only if you have been tested, do you know if you been exposed or recovered from the virus. To reduce exposure to the virus, avoid the “Three C’s” — closed spaces with poor ventilation, crowded places and close contact—and do the following:
- Follow the public health guidelines:
- Social distance (physical distancing while continuing to offer social support)
- Wear a mask and gloves to reduce spreading the virus to others.
- Wash your hands with soap for at least 20 seconds.
- Avoid touching your face to prevent microorganisms and viruses to enter the body through mucosal surfaces of the nose mouth and eyes.
- Clean surfaces which could have been touched by other such as door bell, door knobs, packages.
- Avoid the person’s slipstream that may contain the droplets in the exhaled air. The purpose of social distancing is to have enough distance between you and another person so that the exhaled air of the other person would not reach you. The distance between people depends upon their activities and the direction of airflow.
In a simulation study, Professor Bert Blocken and his colleagues at KU Leuven and Eindhoven University of Technology reported that the plume of the exhaled air that potentially could contain the virus droplets could extend much more than 5 feet. It would depends upon the direction of the wind and whether the person is walking or jogging as show in Figure 1 (Blocken, 2020).
Figure 1. The plume of exhaled droplets that could contain the virus extends behind the person in their slipstream (photo from KU Leuven en TU Eindhoven).
The plume of exhaled droplets in the person’s slipstream may extend more than 15 feet while walking and more than 60 feet while jogging or bicycling. Thus. social distancing under these conditions is much more than 6 feet and it means avoiding their slipstream and staying much further away from the person.
- Increase fresh air to reduce virus concentration. The CDC recommends ventilation with 6 to 12 room air changes per hour for effective air disinfection (Nardell & Nathavitharana, 2020). By increasing the fresh outside air circulation, you dilute the virus concentration that may be shed by an infected asymptomatic or sick person (Qian & Zheng, 2018). Thus, if you are exposed to the virus, you may receive a lower dose and increase the probability that you experience a milder version of the disease. Almost all people who contract COVID-19 are exposed indoors to the virus. In the contact tracing study of 1245 confirmed cases in China, only a single outbreak of two people occurred in an outdoor environment (Qian et al, 2020). To increase fresh air (this assumes that outside air is not polluted), explore the following:
- Open the windows to allow cross ventilation through your house or work setting. One of the major reasons that the flu season spikes in the winter is that people congregate indoors to escape weather extremes. People keep their windows closed to conserve heat and reduce heating bill costs. Lack of fresh air circulation increases the viral density and risk of illness severity (Foster, 2014). See the superb graphic illustration by Bartzokas et al (Feb 26, 2021).in the New York Times of virus concentration in schools when the windows are opened. https://www.nytimes.com/interactive/2021/02/26/science/reopen-schools-safety-ventilation.html?smid=em-share
- Use an exhaust fans to ventilate a building. By continuously replacing the inside “stale” air with fresh outside air, the concentration of the virus in the air is reduced.
- Use High-efficiency particulate air (HEPA) air purifiers to filter the air within a room. These devices will filter out particles whose diameter is equal to 0.3 µ m. They will not totally filter out the virus; however, they will reduce it.
- Avoid buildings with recycled air unless the heating and air conditioning system (HAC) uses HEPA filters.
- Wear masks to protect other people and your community. The mask will reduce the shedding of the virus to others by people with COVID-19 or those who are asymptomatic carriers. This is superbly illustrated by Prather, Wang, & Schooley (2020) that not masking maximizes exposure, whereas universal masking results in the least exposure.
- Avoid long-term exposure to air pollution. People exposed to high levels of air pollution and fine particulate matter (PM2.5) are more at risk to develop chronic respiratory conditions and COVID-19 death rates. In the 2003 study of SARS, ecologic analysis conducted among 5 regions in China with 100 or more SARS cases showed that case fatality rate increased with the increment of air pollution index (Cui, Zhang, Froines, et al. , 2003). The higher the concentration of fine particulate matter (PM2.5), the higher the death rate (Conticini, Frediani, & Caro, 2020). As researchers, Xiao Wu, Rachel C. Nethery and colleagues (2020) from the Harvard T.H. Chan School of Public Health point out, “A small increase in long-term exposure to PM2.5 leads to a large increase in COVID-19 death rate, with the magnitude of increase 20 times that observed for PM2.5 and all cause mortality. The study results underscore the importance of continuing to enforce existing air pollution regulations to protect human health both during and after the COVID-19 crisis.“
- Breathe only through your nose. The nose filters, warms, moisturizes and slows the airflow so that airway irritation is reduced. Nasal breathing increases nitric oxide production that significantly increases oxygen absorption in the body. During inspiration through the nose the nitric oxide helps dilate the airways in your lungs and blood vessels (McKeown, 2016). More importantly for dealing with COVID-19, Nitric Oxide, produced and released inside the nasal cavities and the lining of the blood vessels, acts as an antiviral and a secondary strategy to protect against viral infections (Mehta, Ashkar & Mossman, 2012).
How to strengthen your immune system to fight the virus
The immune system is dynamic and many factors as well as individual differences affect its ability to fight the virus. It is possible that a 40 year-old person may have an immune systems that functions as a 70 year old, while some 70 year-olds have an immune system that function as a 40 year-old. Factors that contribute to immune competence include genetics, aging, previous virus exposure, and lifestyle (Lawton, 2020).
It is estimated that 70-80% mortality caused by Covid-19 occurred in people with comorbidity who are: over 65, male, lower socioeconomic status (SES), non white, overweight/obesity, cardiovascular heart disease, and immunocompromised. Although children comprised only a small percentage of the seriously ill patients, 83% of those children in the intensive care units had comorbidities and 60% were obese. The majority of contributing factors to comorbidities and obesity are the result of economic inequality and life style patterns such as the Western inflammatory diet (Shekerdemian et al, 2020; Zachariah, 2020; Pollan, 2020).
By taking charge of your lifestyle habits through an integrated approach, you may be able to strengthen your immune system (Alschuler et al, 2020; Lawton, 2020). The following tables, adapted from the published articles by Lawton (2020), Alschuler et al, (2020) and Jaffe (2020), list factors that support or decrease the immune system.
Factors that decrease immune competence
Factors that support immune competence
Phytochemicals and vitamins that support immune competence
Abhanon, T. (2020 March 26). Practical tips how to keep yourself safe.
Alschuler, L., Weil, A., Horwitz, R. Stamets, P., Chiasso, A.M., Crocker, R., & Maizes, V. (2020 March 26). Integrative considerations during the CPVID-19 pandemic. Explore, 26.
Aranow C. (2011). Vitamin D and the immune system. Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 59(6), 881–886.
Aw, D., Silva, A. B., & Palmer, D. B. (2007). Immunosenescence: emerging challenges for an ageing population. Immunology, 120(4), 435–446.
Bartzokas, N., Gröndahl, M., Patanjali, K, Peyton, M.,Saget, B., & Syam, U. (February 26, 2021). Why opening windows is a key to reopening schools. The New York Times. Downloaded March 1, 2021.
Blocken, B. (2020-04-08). Cited in, Belgishch onderzoek: fietsen, joggen of wandelen do je best niet achtr elkaar in tijden van corona. DeMorgen.
Brandhorst, S., Choi, I.Y., Wei, M., Cheng, C.W., Sedrakyan, S., Navarrete, G., Dubeau, L., et al. (2015). A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metabolism, 22(1), 86-99.
Campbell, J.P. & Turner, J.E. (2018). Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan. Frontiers in Immunology, 9, 648.
Casas R, Sacanella E, Estruch R. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases. Endocr Metab Immune Disord Drug Targets. 2014;14(4):245‐254.
CDC (2020, March 26). Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. Morbidity and Mortality Weekly Report. CDC. March 26, 2020.
CDC. (2020a, July 17). Evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from COVID-19. CDC-?Coronavirus Disease.
Conticini, D., Frediani, F., & Caro, D. (2020). Can atmospheric pollution be considred a co-factdor in the extremely high level of SARS-CoV-2 lethality in Northern Italy. Environmental Pollution, available online, 4 April 2020, 114465.
Cui, Y., Zhang, Z., Froines, J. et al. (2003). Air pollution and case fatality of SARS in the People’s Republic of China: an ecologic study. Environmental Health 2(15).
D’Acquisto F. (2017). Affective immunology: where emotions and the immune response converge. Dialogues in clinical neuroscience, 19(1), 9–19.
Foster, H. (2014 December 1). The reason for the season: why flu strikes in winter. SITN Science in the News.
Furukawa, N.W., Brooks, J.T., & Sobel, J. (2020, July). Evidence supporting transmission of severe acute respiratory syndrome coronavirus 2 while presymptomatic or asymptomatic. Emerg Infect Dis. [June3, 2020]. https://doi.org/10.3201/eid2607.201595
Ganyani, T., Kremer, C., Chen, D., Torneri, A, Faes, C., Wallinga, J., & Hensm N. (2020). Estimating the generation interval for COVID-19 based on symptom onset data doi:https://doi.org/10.1101/2020.03.05.20031815
Gaiha, S.M., Cheng, J. & Halpern-Felsher, B. (2020). Association between youth smoking, electronic cigarette use, and coronavirus disease 2019. Journal of Adolescent Health. Published online August 11, 2020. doi: https://doi.org/10.1016/j.jadohealth.2020.07.002
Glaser, R. & Kiecolt-Glaser, J.K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews of Immunology, 5(3), 243-251.
Holt-Lunstad, J., Smith, T.B., Baker, M., Harris, T., & Stephenson, D. (2015). Loneliness and social isolation as risk factors for mortality: a meta-analytic review. Perspect Psychol Sci. 10(2), 227-237. doi:10.1177/1745691614568352
Heid, M. (2020-04-09). The Germ-Cleaning Power of an Open Window. Elemental by Medium.
Hunter J., Arentz, S, Goldenberg. J., et al. (2021). Zinc for the prevention or treatment of acute viral respiratory tract infections in adults: a rapid systematic review and meta-analysis of randomised controlled trials.
BMJ Open, 11:e047474. http://dx.doi.org/10.1136/bmjopen-2020-047474
Jagetia GC, Aggarwal BB. “Spicing up” of the immune system by curcumin. J Clin Immunol. 2007;27(1):19‐35.
Jaffe, R. (2020). Reduce risk, boost immunity defense and repair abilities, and stay resilient. PERQUE Integrative Health.
Kaplow, S. (2020, April 29). COVID-19 and the Risk from Recirculated Air in Buildings. Green Building Law Update.
Koh, K.B. (2018). Stress, Emotion, and Immunity. In: Stress and Somatic Symptoms. Springer, Cham, 43-54.
Kuo M. (2015). How might contact with nature promote human health? Promising mechanisms and a possible central pathway. Frontiers in psychology, 6, 1093.
Lawton, G. (2020). You’re only as young as your immune system. New Scientist, 245(3275), 44-48.
Lee, G. Y., & Han, S. N. (2018). The Role of Vitamin E in Immunity. Nutrients, 10(11), 1614.
Lewis ED, Meydani SN, Wu D. Regulatory role of vitamin E in the immune system and inflammation. IUBMB Life. 2019;71(4):487‐494.
Li, Y., Yao, J., Han, C., Yang, J., Chaudhry, M. T., Wang, S., Liu, H., & Yin, Y. (2016). Quercetin, Inflammation and Immunity. Nutrients, 8(3), 167.
Malaguarnera L. (2019). Influence of Resveratrol on the Immune Response. Nutrients, 11(5), 946.
Martineau, A.R., Jolliffe, D.A., Hooper, R.L, Greenberg, L., Aloia, J.F ..(2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. British Medical Journal; 356:i6583 | doi: 10.1136/bmj.i6583
McKeown, P. (2020). Practical 40 minute free breathing session with Patrick McKeown to improve respiratory health.
Mehta, D. R., Ashkar, A. A., & Mossman, K. L. (2012). The nitric oxide pathway provides innate antiviral protection in conjunction with the type I interferon pathway in fibroblasts. PloS one, 7(2), e31688.
Mukherjee, S. (2020). How does the coronavirus behave inside a patient? We’ve counted the viral spread across peoples; now we need to count it within people. The New Yorker, April 6, 2020.
Nardell, E.A. & Nathavitharana, R.R. (2020). Airborne Spread of SARS-CoV-2 and a Potential Role for Air Disinfection. JAMA. Published online June 01, 2020. doi:10.1001/jama.2020.7603
Mukherjee, S., Dudley, J. I., & Das, D. K. (2010). Dose-dependency of resveratrol in providing health benefits. Dose-response : a publication of International Hormesis Society, 8(4), 478–500.
Neupane, B., Jerrett, M., Burnett, R.T., Marrie, T., Arain, A., Loeb, M. (2018). Long-term exposure to ambient air pollution and risk of hospitalization with community-acquired pneumonia in older adults. Am J Respir Crit Care Med, 181(1), 47‐53.
Ostan, R., Monti, D., Gueresi, P., Bussolotto, M., Franceschi, C., & Baggio, G. (2016). Gender, aging and longevity in humans: An update of an intriguing/neglected scenario paving the way to a gender-specific medicine. Clinical Science, 130(19), 1711-1725.
Qian, H., & Zheng, X. (2018). Ventilation control for airborne transmission of human exhaled bio-aerosols in buildings. Journal of thoracic disease, 10(Suppl 19), S2295–S2304. https://doi.org/10.21037/jtd.2018.01.24
Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: an overview. Journal of nutritional science, 5, e47.
Perez de Heredia, F., Gomez-Martinez, S., &Marcos, A. (2012). Chronic and degenerative diseases Obesity, inflammation and the immune system. Proceedings of the Nutrition Society, 71, 332–338.
Pollan, M. (2020). The sickness in our food supply. The New York Review of Books. June 11, 2020 issue. https://www.nybooks.com/articles/2020/06/11/covid-19-sickness-food-supply/
Prasad A. S. (2008). Zinc in human health: effect of zinc on immune cells. Molecular medicine (Cambridge, Mass.), 14(5-6), 353–357.
Prather, K. A., Wang, C.C., * Schooley, R.T. (2020). Reducing transmission of SARS-CoV-2. Science, 10.1126/sciennce.abc6197
Price MA, Butow PN, Bell ML, et al. Helplessness/hopelessness, minimization and optimism predict survival in women with invasive ovarian cancer: a role for targeted support during initial treatment decision-making?. Support Care Cancer. 2016;24(6):2627‐2634.
Qian, H., Miao, T, Liu, L, Zheng, Z, Luo, D., & Li, Yuguo. (2020). Indoor transmission of SARS-CoV-2. MedRxiv The preprint server for health sciences. https://doi.org/10.1101/2020.04.04.20053058
Reed, R.G. & Raison, C.L. (2016). Stress and the Immune System. In: Esser, C. (eds) Environmental Influences on the Immune System. Springer, Vienna, 97-126.
Sarkar, D., Jung, M. K., & Wang, H. J. (2015). Alcohol and the Immune System. Alcohol Research : Current Reviews, 37(2), 153–155.
Segerstrom, S. C. & Miller, G. E. (2004). Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychological bulletin, 130(4), 601–630.
Shekerdemian L.S., Mahmood N.R., Wolfe, K.K., et al (2020). International COVID-19 PICU Collaborative. Characteristics and outcomes of children with coronavirus disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units.JAMA Pediatr. Published online May 13, 2020. doi:10.1001/jamapediatrics.2020.1948
Simpson, N., Haack, M., Mullington, J.M. (2017). Sleep and Immune Regulation. In: Chokroverty S. (eds). Sleep Disorders Medicine. Springer, New York, NY, 195-203.
Song, X., Delaney, M., Shah, r.K. et al. (2020). Comparison of clinical features of Covid-19 vs seasonal influenza A and B in US children. JAMA Network Open, 3(9):e2020495
Uchino, B. N., Vaughn, A. A., Carlisle, M., & Birmingham, W. (2012). Social support and immunity. In S. C. Segerstrom (Ed.), Oxford library of psychology. The Oxford handbook of psychoneuroimmunology (p. 214–233). Oxford University Press.
Can changing your breathing pattern reduce coronavirus exposure?Posted: April 1, 2020 Filed under: Breathing/respiration, health, relaxation, self-healing, Uncategorized | Tags: coronavirus, COVID-19 9 Comments
This blog is based upon our breathing research that began in the 1990s, This research helped identify dysfunctional breathing patterns that could contribute to illness. We developed coaching/teaching strategies with biofeedback to optimize breathing patterns, improve health and performance (Peper and Tibbetts, 1994; Peper, Martinez Aranda and Moss, 2015; Peper, Mason, and Huey, 2017).
For example, people with asthma were taught to reduce their reactivity to cigarette smoke and other airborne irritants (Peper and Tibbitts, 1992; Peper and Tibbetts, 2003). The smoke of cigarettes or vaping spreads out as the person exhales. If the person was infected, the smoke could represent the cloud of viruses that the other people would inhale as is shown in Figure 1.
Figure 1. Vaping by young people in Riga, Latvia (photo by Erik Peper).
To learn how to breathe differently, the participants first learned effortless slow diaphragmatic breathing. Then were taught that the moment they would become aware of an airborne irritant such as cigarette smoke, they would hold their breath and relax their body and move away from the source of the polluted air while exhaling very slowly through their nose. When the air was clearer they would inhale and continue effortless diaphragmatically breathing (Peper and Tibbetts, 1994). From this research we propose that people may reduce exposure to the coronavirus by changing their breathing pattern; however, the first step is prevention by following the recommended public health guidelines.
- Social distancing (physical distancing while continuing to offer social support)
- Washing your hands with soap for at least 20 seconds
- Not touching your face
- Cleaning surfaces which could have been touched by other such as door bell, door knobs, packages.
- Wear a mask to protect other people and your community. The mask will reduce the shedding of the virus to others by people with COVID-19 or those who are asymptomatic carriers.
Reduce your exposure to the virus when near other people by changing your breathing pattern
Normally when startled or surprised, we tend to gasp and inhale air rapidly. When someone sneezes, coughs or exhales near you, we often respond with a slight gasp and inhale their droplets. To reduce inhaling their droplets (which may contain the coronavirus virus), implement the following:
- When a person is getting too close
- Hold your breath with your mouth closed and relax your shoulders (just pause your breathing) as you move away from the person.
- Gently exhale through your nose (do not inhale before exhaling)-just exhale how little or much air you have
- When far enough away, gently inhale through your nose.
- Remember to relax and feel your shoulders drop when holding your breath. It will last for only a few seconds as you move away from the person. Exhale before inhaling through your nose.
- When a person coughs or sneezes
- Hold your breath, rotate you head away from the person and move away from them while exhaling though your nose.
- If you think the droplets of the sneeze or cough have landed on you or your clothing, go home, disrobe outside your house, and put your clothing into the washing machine. Take a shower and wash yourself with soap.
- When passing a person ahead of you or who is approaching you
- Inhale before they are too close and exhale through your nose as you are passing them.
- After you are more than 6 feet away gently inhale through your nose.
- When talking to people outside
- Stand so that the breeze/wind hits both people from the same side so that the exhaled droplets are blown away from both of you (down wind).
These breathing skills seem so simple; however, in our experience with people with asthma and other symptoms, it took practice, practice, and practice to change their automatic breathing patterns. The new pattern is pause (stop) the breath and then exhale through your nose. Remember, this breathing pattern is not forced and with practice it will occur effortlessly.
The following blogs offer instructions for mastering effortless diaphragmatic breathing.
Peper, E., Martinez Aranda, P., & Moss, E. (2015). Vulvodynia treated successfully with breathing biofeedback and integrated stress reduction: A case report. Biofeedback. 43(2), 103-109.
Peper, E., Mason, L., Huey, C. (2017). Healing irritable bowel syndrome with diaphragmatic breathing. Biofeedback. (45-4). /
Peper, E., and Tibbetts, V. (1992). Fifteen-Month follow up with asthmatics utilizing EMG/Incentive inspirometer feedback. Biofeedback and Self-Regulation. 17 (2), 143-151.
Peper, E. & Tibbetts, V. (1994). Effortless diaphragmatic breathing. Physical Therapy Products. 6(2), 67-71. Also in: Electromyography: Applications in Physical Therapy. Montreal: Thought Technology Ltd.
Peper, E. and Tibbitts, V. (2003). Protocol for the treatment of asthma. In: Zheng, Y. (ed). Clinical Practice of Biofeedback. Beijing: High Education Press (HEP). 163-176. ISBN 7-04-011420-8