Theoretical Bases for the Disinfection of the SARS-CoV-2- Contaminated Airways by Means of Ethanol Inhalation

*Pietro Salvatori*

#### **Abstract**

Ethyl alcohol, or ethanol (EtOH), is a linear alkyl chain alcohol, whose condensed structural formula is CH3CH2OH. Besides the common industrial and recreational uses (spirits, cosmetics, fuelling, etc.), EtOH is considered a medicament and listed in the European and US Pharmacopeias. Medically, EtOH is mainly employed as an antidote in methanol and ethylene glycol poisoning, as an excipient in many medicaments, as a sclerosant agent, and as a powerful disinfectant. Less recently, EtOH was shown to be both effective and safe in the treatment of pulmonary edema and cough. This chapter deals with EtOH use in SARS-CoV-2 infection and COVID-19 treatments.

**Keywords:** SARS-CoV-2, COVID-19, ethanol, inhalation, public health

#### **1. Introduction**

This section resumes and adequately updates as of September 4, 2022 my published article [1].

The SARS-CoV-2 outbreak has hit the global community and we are experiencing the third wave after the first phase—and likely, a fourth one—as well as more aggressive variants surge (Delta and Epsilon, Omicron, Centaurus). To this day, no specific therapy has been identified as effective. While mass immunization campaigns take a long time, and pose questions about their effectiveness against new variants and long-lasting protection, they are very likely to dramatically improve disease control. As consequence, attempts to understand the cold chain and potential active eradication of the virus become of the highest significance and the emphasis on prevention over pandemic control grows. In fact, the main objective still to be achieved for the control of any contagious disease is the individuation and—possibly—treatment of spreading subjects. According to this, research has been done on conjunctival cells, upper respiratory tract goblet cells, type 2 pneumocytes, and enterocytes as the main targets of the virus-binding receptors. Actually, epithelial cells of the nasal cavity and lower respiratory tract, including alveolar cells, are associated with SARS-CoV-2

entry factors, mainly angiotensin-converting enzyme 2 (ACE2) receptors [2] and therefore, COVID-19 infection occurs initially in the epithelial layer of the upper respiratory tract, followed by transfer to the lower respiratory tract [3]. According to Madas et al. [4], pneumonia may be prevented by stopping or significantly limiting the transit of viruses into the acinar airways during the gap between the start of early symptoms and any potential clinical worsening. As a result, even non-specific therapies like disinfecting the mouth, nose, and throat successfully keep the viral load in the upper airways low enough to stop or delay the disease's progression. A very comprehensive study [5] on Wuhan's population (about 10,000,000 individuals) demonstrates that, following a period of isolation, the incidence of symptomatic individuals was reduced to 0.00303%, providing an indication of the success of containment. Many of these infected individuals do not have any clinical manifestations of the disease; they are also known as "asymptomatic positives" or PAS (healthy carriers?). Observations show that PASs have a noticeable SARS-CoV-2 viral load, and this surely draws attention to their contribution to the epidemic's progression. Among a group of students, Nelson et al. [6] recently discovered that, in said group, contacts of people who tested positive returned positive at rates of 10.4 and 4.8% after 3 and 9 days, respectively. One of the latest researches by Atripaldi et al. [7] discovered that asymptomatic patients had a noticeable SARS-CoV-2 viral load. This highlighted the importance of asymptomatic (and pre-symptomatic) individuals in the development of the epidemic.

There still are no established criteria for identifying asymptomatic patients who will spread the infection to other subjects; thus, all of them should be regarded as being suitable for disinfection. Thus, early detection and potential treatment of asymptomatic positive people are of major importance The goal is to terminate the transmission chain and reduce or even end confinement time (and the related financial, social, and psychological costs), and promptly reintroduce recovered patients back in society. The 14-day quarantine is undoubtedly the only option that now is currently given to asymptomatic positive patients. It may be deduced from Liu et al.'s [8] study of SARS-CoV-2 contamination in quarantine rooms that unless the patient lives alone, or each person present in the household has their own private rooms, the strategy is likely to be unsuccessful. The objective is to highlight the extent of the issue, illustrate available solutions, and investigate the effectiveness and toxicological aspects that would support the use of inhaled ethanol (or ethyl alcohol) for airway disinfection in SARS-CoV-2-infected patients who are asymptomatic. For research publications published up to July 29, 2021, databases such as MEDLINE, Embase, Europe PubMed Central, medRxiv, and bioRxiv, as well as the gray literature, have been examined. Key findings were covered in our case reports (with five or more participants), cohort studies, randomized controlled trials, and records of trial registration:


*Theoretical Bases for the Disinfection of the SARS-CoV-2-Contaminated Airways by Means… DOI: http://dx.doi.org/10.5772/intechopen.108979*


The explanation for the suggested novel technique was supported (or rejected) based on reliable data.

#### **2. Results**

#### **2.1 Extension of the problem**

As of now (September 4, 2022), the world's active cases are 610,144,519 and total deaths reached 6,503,374 [9]. Thus, lethality accounts for 1.07%. Between 17 and 20% of positives are asymptomatic (healthy carriers) [10]. Within 8 days (mean), 43% of asymptomatic positive patients develop symptoms (of any kind) [11]. As even more nations implement some form of quarantine laws, the effects on the social and economic sectors are extremely detrimental. The mean viral load elimination time for the upper and lower respiratory tracts, respectively is 14 days and 17 days, according to a fairly recent meta-analysis [12]. Interestingly, no live virus has ever been found 9 days after the sickness first appears. Patients who were asymptomatic and those who had symptoms were compared, and the results for the elimination time between the two groups were inconsistent. Among health workers, Bongiovanni [13] reports an average viral load elimination time of 22 days, which may be explained by their propensity to receive a higher viral load in their work environment, compared to the average population.

#### **2.2 Current efforts**

Metformin, ivermectin, and fluvoxamine have been studied in less severe COVID-19 infections [14].

Protease inhibitors are currently used in high-risk patients [15].

Highly specialized medications such as monoclonal and polyclonal antibodies are now being studied and used, but their high cost and possibility for effectiveness loss caused by the spread of new variations severely restrict their potential advantages [16].

It is necessary to investigate the potential of nonspecific medications in the absence of particular, well-established therapies for respiratory disinfection. Guenezan et al. [17] made an effort to disinfect positive but asymptomatic individuals. Povidone iodine mouthwash and nasal spray both significantly increased viral titer in a single small-randomized clinical study, although they had no impact on the lower respiratory tract.

According to a recent randomized clinical trial [18], medical professionals could significantly reduce their risk of contracting COVID-19 by using a nasal spray solution composed of dimethyl sulfoxide and ethanol.

#### **2.3 Ethanol efficiency**

Ethyl alcohol or ethanol is widely used in disinfection procedures. Additionally, a substantial amount of integrated evidence shows that ethanol does indeed have

antiviral properties, which may be related to the solvent's effects on lipids (pericapsid) and the denaturation of proteins (capsid) [19]. The temperature and phase in which the pericapsid is located (which derives from the cell membrane of the infected host) affect the outcome. The effectiveness of ethanol in an aqueous solution of 35.2% by weight (equivalent to 44% by volume) is the highest at about 50°C (crystalline phase) and diminished or rendered ineffective at about 25°C (gel phase) [20]. It is possible to assume an intermediate impact at human body temperature. Human coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus (SARS), Middle East Respiratory Syndrome (MERS), and Human Endemic Coronavirus, have been demonstrated to be significantly affected by ethanol where, on surfaces such as plastic and glass, these viruses can survive for days. Disinfectants, such as EtOH, have been demonstrated to diminish the coronavirus's infectiousness in a short amount of time. The said demonstrations showed a 62–71% effectiveness. Thankfully, SARS-CoV-2 is an enveloped virus that is extremely sensitive to ethanol; current experimental data show that an ethanol concentration of 30% v/v is able to inactivate SARS-CoV-2 in 30 seconds [21].


#### **2.4 Effects of ethanol on respiratory cells and microbiota**

1.The relationship between alcohol exposure time and dose and the effect it has on respiratory hairy cells is bimodal. Sisson [23] demonstrated (*in vitro*) that ethanol (10 mM concentration = 0.46 mg/ml) caused a 40% increase in beat frequency (6 Hz to 8.5 Hz) after only 10 minutes of treatment. A mechanism that is dependent on nitrogen oxide is responsible for this result. However, the same experiment performed with ethanol at a greater concentration (1 M = 46 mg/ ml) resulted in a decrease in the beat frequency, demonstrating that ethanol could a harmful impact by desensitizing ciliary motility, which makes it

stimulation-resistant (a process known as Alcohol-Induced Ciliary Dysfunction mediated by oxidative stress) [24].


It is possible that EtOH might have a harmful effect on the respiratory microbiome, but there is no solid evidence of this in the medical literature. In contrast, some helpful remarks could emerge from this. As a matter of fact, Sulaiman et al. [30] discovered that a poor clinical outcome was connected to an enrichment of the lower respiratory tract's microbiota with an oral commensal (*Mycoplasma salivarium*) and an enhanced SARS-CoV-2 virus load in a group of patients intubated with COVID-19. Intensive care patients with SARS-CoV-2 showed full depletion of *Bifidobacterium* and *Clostridium*, according to Rueca et al.'s [31] study of the nasal/oropharyngeal microbial flora.

#### **2.5 Ethanol toxicity**

The toxicity of acute inhalation of ethanol has mostly been researched in four real-world scenarios. From a toxicological perspective, there is a significant difference between ingested and inhaled ethanol, since the latter bypasses the first necessary metabolic step of ingested ethanol and instead travels straight to the left ventricle of the heart and the brain [32].

Surgical disinfection of the hands. Bessonneau [33] has demonstrated that the cumulative dose of ethanol inhaled in 90 seconds while surgically disinfecting hands with a gel containing ethanol at a concentration of 700 g/l is 328.9 mg. The blood alcohol content would be 203.9 mg, giving blood alcohol content (BAC) of 40.6 mg/L because the inhalation/absorption rate (i.e., the amount of ethanol that passes from the alveoli to the bloodstream) is 62%. Hypothetically, even if ethanol absorption was to happen instantly (rather than during 90 seconds), the blood alcohol level would still be well below the limit that is deemed toxic (500 mg/L in Italy and 800 mg/L in the majority of the United States). Healthcare workers may disinfect their hands up to 30 times per day [34], which results in a daily dose of inhaled ethanol of 9.86 grams, depending on the frequency of surgical hand disinfection associated with appropriate care activities with a high risk of contamination (for instance, by washing incontinent patients).

Liquid contained in some "e-cigarettes" (electronic cigarettes) may contain ethanol in various proportions. The usage of electronic cigarettes containing 23.5% ethanol and utilized with various suction mechanisms is reported in the study by More [35] along with statistics on ethanol absorption. The said statistics showed that the absorption of ethanol never exceeded 0.85 mg/l. The calculated blood alcohol content never went over 0.85 mg/l. The estimated blood alcohol level by projecting to triple or quadruple concentrations should be 0.85 mg/lx 3 = 2.55 mg/L in the first hypothesis and 3.4 mg/L in the second, which are both substantially below the toxic limit.

Patients with COVID-19-pneumonia are now being researched to see if ethanol inhalation could be a viable therapy option [36].

Additionally, a phase II clinical trial has been filed to assess the effectiveness and safety of inhaled ethanol in the early stage of COVID-19 therapy. The trial is now actively recruiting new participants [37, 38].

In rodents breathing, 65% v/v ethanol for 15 min every 8 hours (3 times a day), for five consecutive days (flow rate: 2 L/minute), Castro-Balado et al. [38] examined the mucosal or structural damages to EtOH in the lung, trachea, and esophagus. The calculated absorbed dosage was 1.2 g/kg/day. Under the same conditions, this dosage in humans would be equivalent to 151 g per day. Notably, neither the treated animals nor the controls' histology samples showed any signs of damage.

Numerous studies suggest that industrial exposure is not a problem in reproductive medicine (Irvine) [39] nor in oncology (Bevan) [40], despite the toxicity of chronic ethanol inhalation. In Bevan's [40] research, the occupational exposure limit (OEL) for the United Kingdom was examined (1000 ppm of ethanol = 1910 mg/m3 over an 8-hour shift). It was also determined that ingesting 10 g of ethanol (roughly one glass of alcohol) per day would be perfectly in line with the occupational exposure limit (OEL). These numbers are in perfect agreement with Bessonneau's [33] and Boyce's [34] reports.

Chronic ethanol use is not the same as chronic ethanol abuse, which can result in lung damage (alveolar macrophage dysfunction, increased susceptibility to bacterial pneumonia, and tuberculosis) [41].

The greatest amount of ethanol that can be instantly administered to a healthy adult is 2.5 g, given that the blood volume is roughly 5 L and the maximum permissible blood level of ethanol is 500 mg/L.

Elimination of ethanol occurs at a rate of 120 to 300 mg/L/hour [42]. Alcohol dehydrogenase breaks down 95% of EtOH that has been consumed (or breathed), while the remaining 5% is removed—unaltered—by exhaled air, urine, perspiration, saliva, and tears.

#### **2.6 Inhaled ethanol therapeutic window**

On this subject, no focused research was found.

The highest permitted ethanol dose or concentration, however, will be determined using previous data from regulatory reports [40].

Each type of inhalation treatment is potentially more effective compared to any other mode of delivery for treating airway diseases [22].

#### **3. Discussion**

#### **3.1 Dimension of the problem**

The SARS-CoV-2 outbreak pattern exhibits a rather steady trend combined with local upsurges, most likely as result of variant selection and superspreader events [43]. In addition to the immeasurable worth of the suffering and lives lost (4,203,776 to date), the world's lost economic output has tremendously increased to roughly 3.94 trillion U.S. Dollars [44]. These findings logically support the intensive treatment of positive asymptomatic people in an effort to limit or, ideally, stop the spread of the infection.

#### **3.2 Current efforts**

In a study evaluating metformin, ivermectin, and fluvoxamine, none of the drugs were effective in avoiding hypoxemia, ER visits, hospital stays, or deaths related to COVID-19 [14].

*Theoretical Bases for the Disinfection of the SARS-CoV-2-Contaminated Airways by Means… DOI: http://dx.doi.org/10.5772/intechopen.108979*

Protease inhibitors seem to have the potential to cause a rebound infection and appear to be ineffective against some SARS-CoV-2 strains [45, 46].

There is currently no published research on the regular use of monoclonal antibodies to treat SARS-CoV-2 positive and asymptomatic individuals. Furthermore, their high price and the probable loss of efficacy owing to variants seem to substantially restrict any benefit.

In the pharynx and oral cavity, povidone-iodine [17] has demonstrated excellent efficiency in lowering the viral titer. Povidone-iodine gargles, however, does not reach the lower respiratory tract, which is a notable limitation. However, as it focuses on the management of a crucial stage in the chain of viral transmission, this work deserves special attention. Of course, inhaling ethanol removes the previously mentioned limitation.

Actually, the experience of Hosseinzadeh [18] has shown that ethanol (together with dimethyl sulfoxide) can be delivered as a nasal spray in a safe and efficient way. In this randomized clinical trial involving volunteer healthcare providers without a history of SARS-CoV-2 infection or COVID-19, it has been clearly demonstrated that such a prophylactic measure can considerably prevent COVID-19 in the treated group. Namely, the risk of COVID-19 was about eightfold higher in those who used routine care than in those who used dimethyl sulfoxide-ethanol spray.

#### **3.3 Ethanol efficiency**

There is no question regarding ethanol's ability to kill or inactivate SARS-CoV-2, even at concentrations as low as 30% v/v in just 30 seconds, according to experimental and clinical data [21].

Alcohol is probably ineffective against intracellular viruses. It is crucial to extend ethanol inhalation by at least 3 days, since viral multiplication happens in 48–72 hours, which is then followed by cellular death and shedding. Additionally, ethanol is fundamentally effective against all SARS-CoV-2 variants and other "enveloped" viruses due to its non-specificity. This particular characteristic broadens the ethanol's range of activity against the SARS-CoV-2 pandemic and suggests its use in potential future viral epidemics.

The determined theoretical lowest dose of ethanol (= 153 μg) required to eradicate the fictitious virus load is relatively low when compared to daily exposure to many different jobs.

#### **3.4 Ethanol effects on respiratory cells and microbiota**

Alcohol's impact on respiratory hairy cells has been demonstrated by Sisson [23] to be a bimodal function of both exposure time and dosage. Low concentrations of ethanol (10 mM = 0.46 mg/ml) cause an increase in ciliary clearance, which may help to speed up the viral load's elimination once it has, theoretically, been made inactive by ethanol's own physicochemical features.

There is currently not enough research on how short-term ethanol administration affects respiratory microbiome. On the other hand, certain recommendations can be made in this regard. In fact, patients in the intensive care unit who had abnormally high levels of *M. salivarium* in the lower tract or low levels of clostridia in the upper tract had worse outcomes. It is noteworthy that ethanol totally inactivates SARS-CoV-2, mycoplasma, and SARS-CoV-2 (Eterpi et al.) [47]. Additionally, certain strains of clostridia are known to independently produce ethanol on their

own [48]; this ability has been used in commercial ABE fermentation to create acetone, butanol, and ethanol [49]. The lack of nasopharyngeal clostridia may hypothetically result in decreased or nonexistent local ethanol production, which would then let SARS-Cov-2 remain active at this level and move to the lower respiratory tract [3].

#### **3.5 Ethanol toxicity**

Rules governing acute ethanol exposure vary by nation or state and are subject to laws. The maximum Blood Alcohol Concentration (BAC) for the general public in the USA is between 500 and 800 mg/L. The regulation also restricts the maximum amount of chronic ethanol exposure in the workplace. For instance, the occupational exposure limit (OEL) for ethanol in the United Kingdom is 1000 parts per million (ppm) of ethanol, or 1910 mg/m3, during an 8-hour shift, which is equivalent to consuming 10 g of ethanol (about one glass of alcohol) daily, according to estimates [40]. These numbers much exceed the amount that would theoretically be needed to reduce the virus load in the respiratory tract. There have been many and vocal concerns made concerning the potential mucosal harm that inhaled ethanol might cause. These worries appear to have been completely dispelled by the thorough study by Castro-Balado et al. [38]. Interestingly, in the RCT from Hosseinzadeh [18], collateral effects are not mentioned, perhaps because were lacking or minimal and tolerable.

#### **3.6 Inhaled ethanol therapeutic window**

One must inevitably connect to the current experience because no focused research on this subject was found [33, 40].

Therefore, it appears acceptable and rational to declare that the hazardous risk of such acute inhalation—that is, about 330 mg—may be viewed as negligible [33]. This is because surgical cleaning with 70% ethanol for 90″ is a daily habit and should generally be suggested and implemented. In reality, even if this dose was administered instantaneously to a healthy adult, the amount of ethanol in the air patients would inhale would be 0.078 mg/ml or 330 mg/5 L (airway volume). This quantity is significantly lower than both the legal limit of 500 mg/L (0.5 mg/ml) and the experimentally determined threshold of alcohol-induced ciliary dysfunction, which is 46 mg/ml [23]. Given that the lung and blood volumes are similar, equivalent numbers for the blood's ethanol concentration—which is far lower than the 500 mg/L legal lethal dose— could be derived.

However, this dose is a thousand times greater than the minimal dose of 153 μg needed to inactivate the calculated viral load in the lungs [22].

Each type of inhalation treatment is potentially more successful than any other method of administration for treating airway diseases [22]. Aerosol treatment enables lower doses, access to "hidden" regions, improved targeting of certain cells or compartments, etc., all of which boost the bioavailability of medications.

The size of the particles generated—classified according to the Aerodynamic Median Mass Diameter, or AMMD—well relates to the site to be treated. For the purpose of this chapter, the AMMD of the aerosol particles should be 5 μm.

Because of the relatively fresh technique suggested in this chapter, it is expected that there are little consolidated data in medical literature.

*Theoretical Bases for the Disinfection of the SARS-CoV-2-Contaminated Airways by Means… DOI: http://dx.doi.org/10.5772/intechopen.108979*

Focusing on the issue's dimension revealed that, in terms of threats to personal and societal health as well as associated economic costs, the disinfection of asymptomatic positive patients is crucial. There are currently no viable or affordable solutions to the issue.

Within a well-defined framework, the review and update of information attest to the high effectiveness and tolerable toxicity of inhaled ethanol. As a result, it is appropriate to administer inhaled ethanol to SARS-CoV-2-positive patients who are asymptomatic. A clinical trial should be carried out to examine its efficacy and tolerance in particular scenarios, as already suggested by Prof. Shintake [50] on March 17, 2020, and Dr. Amoushahi et al. [51] on May 25, 2020. Certainly, the research would be speedy, affordable, and straightforward to carry out.

The Authors post the following propositions:

It must be made clear that ethanol treatment is not believed to be an alternative to vaccination but rather must be considered complementary with it because vaccination appears to not prevent infection and disease from subintrant variants [52]. IF IT IS FOUND THAT THIS TREATMENT IS EFFECTIVE, THE FOLLOWING HEALTH BENEFITS COULD BE EXPECTED:

reduction of the viral load on the respiratory tract, if not elimination, in a period of time much less than the duration of the normal cycle.

lowering the viral pressure on the immune system of the infected person to decrease the disease's course.

decrease in the quantity of virus that is actively released when someone coughs or sneezes.

reduction in the spread of the infection.

Minimal biological/health consequences (lethality, pulmonary fibrosis, psychiatric disorders, etc.).

#### **4. Proposal for a study**

#### **4.1 Aim and scope**

A study in which ethanol is administered as an inhaled vapor to SARS-CoV-2 positive asymptomatic patients.

The aim is to eradicate or, at the very least, lower the viral load of the respiratory tract, of course, in a span of time much shorter than the natural one.

The predicted health advantages include the following:


#### **4.2 Dosage and timing**

Given that the lowest concentration of ethanol that is effective against SARS-CoV-2 is 30% v/v (Kratzel) [20], it is considered reasonable and wise to use a concentration that is between the one mentioned above and the one used for surgical disinfection (70%) [33].

In essence, the following dose is suggested: 1 ml of normal saline solution at 50% v/v (galenic preparation) =390 mg (i.e., 50% by volume = 39% by weight, then 1 ml =390 mg), in 2 at 5 minutes. Although the proposed dose is in absolute terms slightly higher than the dose inhaled during surgical disinfection, it can be assimilated because it is delivered over a longer time.

#### **4.3 Delivery system**

Each type of inhalation treatment is potentially more successful than any other method of administration for treating airway illnesses [22]. Aerosol treatment enables lower doses, access to "hidden" areas, improved targeting of certain cells or compartments, etc., all of which boost the bioavailability of medications.

According to the Aerodynamic Median Mass Diameter, or MMAD, the size of the particles produced is closely tied to the area that has to be treated.


#### **4.4 Scheduling**

Every 8 hours (6- to 10-hour intervals), for 7 days, there will be one activation (treatment), for a total of 21 administrations. When two-thirds of the solution has been administered, the administration might be terminated, according to the distillation curve.

#### **4.5 Candidates**


#### **4.6 Inclusion criteria**

Age > 18 years old; ability to give informed consent.

#### **4.7 Exclusion criteria**

Alcoholism or a history of adverse reactions to ethanol, drug addiction or previous treatment for alcoholism/drug addiction, currently on disulfiram or cimetidine, non-drinkers of alcohol (no absolute criteria), any liver disease, uncontrolled diabetes, acute or chronic pancreatitis, serious respiratory diseases, tuberculosis or other mycobacterial infections, confirmed or suspected pregnancy, active psychosis, inability to give legally valid informed consent.

#### **4.8 Measures**


#### **4.9 Type of study**

Randomized clinical trial. Arm A: treatment as above, quarantine as prescribed. Arm B: no treatment, quarantine as prescribed.

#### **4.10 Sample size**

This is to be estimated with accuracy using biostatistical knowledge. Although the predicted difference between the two groups (treatment and controls) is projected to be roughly 60%, if we anticipate recruiting 150 participants in total, we are not far from very concrete evidence.

#### **4.11 Primary outcome**

Reduction of the mean time to eliminate the viral load (see MEASURES) from 17 to 7 days.

#### **4.12 Secondary outcome**


• Comparison of the mean timeframes for viral load (see *MEASURES*) decreases in the general population and among medical professionals.

If the proposed treatment were successful in improving health, tremendous benefits could be anticipated:


### **Abbreviations**


*Theoretical Bases for the Disinfection of the SARS-CoV-2-Contaminated Airways by Means… DOI: http://dx.doi.org/10.5772/intechopen.108979*

### **Author details**

Pietro Salvatori Head & Neck Surgeon, former Head of the ENT Department at the Humanitas San Pio X Hospital, Milan, Italy

\*Address all correspondence to: pietro.salvatori@me.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 9**
