The neurobiological pathways of cannabinoids and pain, including migraine and headache, have been detailed, summarized and should be reviewed [1, 2, 51, 65, 68,69,70]. Briefly, the endocannabinoid system is distributed throughout the central and peripheral nervous system, is involved in inflammatory and pain processing, and plays regulatory physiological roles across virtually every organ system [19, 46, 71,72,73,74]. The endocannabinoid system interacts within its own pathways, as well as within major endogenous pain pathways, including inflammatory, endorphin/enkephalin, vanilloid/transient receptor potential cation channel subfamily V (TRPV), subfamily M (TRPM), subfamily A (TRPA), and nuclear receptors/transcription factors called the peroxisome proliferator-activated receptors (PPAR) [75].

The activities of the endocannabinoid system are based on the pre-synaptic G protein-coupled cannabinoid 1 (CB1) and 2 (CB2) receptors [76]. There is also a presumed third cannabinoid receptor, G protein-coupled receptor 55 (GPR55), termed CB3 [77]. The primary endogenous cannabinoid receptor ligands (endogenous cannabinoids, or endocannabinoids) are arachidonic acid derivatives, and they work via retrograde signaling receptor activation. The primary mediator of endocannabinoid signaling is N-arachidonoylethanolamine (anandamide, or AEA), and 2-arachidonoylglycerol (2-AG) is another primary endocannabinoid [71, 78,79,80]. Cannabis-based phytocannabinoids, as well as inherent endocannabinoids interact at the CB1 and CB2 receptors with variable affinities and actions [81,82,83].

The CB1 receptor is the most abundant G protein-coupled receptor in the brain and one of the most abundant in both the peripheral and central nervous system [81]. CB1 receptors are expressed primarily on presynaptic peripheral and central nerve terminals, and are found extensively through the anatomical pain pathways as well as many other neurological central and peripheral locations [19, 84,85,86,87]. CB1 receptors are associated with the “high” felt with some cannabis strains, activated by THC. Activation leads to hyperpolarization of the pre-synaptic terminal, closing of calcium channels with subsequent inhibition of released stored inhibitory and excitatory neurotransmitters, including glutamate, 5-hydroxytryptamine (5-HT; serotonin), gamma-aminobutyric acid (GABA), noradrenaline, dopamine, acetylcholine, D-aspartate, and cholecystokinin at inhibitory and excitatory synapses [19, 71, 73, 80, 86, 88,89,90], and can modulate pain pathways involving opioid, serotonin, and N-methyl-d-aspartate (NMDA) receptors through other indirect mechanisms [91].

The CB2 receptors are located primarily in the peripheral tissues and immune cells where they influence the release of cytokines, chemokines, and cell migration including neutrophils and macrophages, but do have some presence in the central nervous system [18, 86, 92,93,94,95], and may also contribute to pain relief by dopamine release modulation [96, 97].

Over 540 phytochemicals have been described in cannabis [98], 18 different chemical classes, and more than 100 different phytocannabinoids, although some are breakdown products [99, 100]. THC and CBD have been the most researched and are considered the major cannabinoids. There are many additional cannabinoids referred to as minor cannabinoids. The quantities of major and minor cannabinoids are widely variable between different types of cannabis strains. There is evidence for analgesic and anti-inflammatory effects in many of the cannabinoids, and this publication will focus primarily on these properties for the cannabinoids assessed in this study. However, a more extensive discussion and a comprehensive review of other medicinal properties of these, as well as many other cannabinoids, has been summarized and is available [28]. The cannabinoids analyzed in this study were limited to THC, THCA, CBD, and CBDA.

THC is one of the most researched cannabinoids, and the cause of the psychoactive side effects of cannabis, suspected from modulation of glutamate and GABA systems [18, 83, 101,102,103]. It is a partial agonist at CB1 greater than CB2 receptors, which are its primary mechanisms of action. However, other mechanisms of action reflect its activity as an agonist at the PPAR-γ and TRPA1 receptors [83], a 5HT3A antagonist, a glycine receptor activation enhancer via allosteric modification, reduces elevated intracellular calcium levels from TRPM8 activity (cold and menthol receptor 1 (CMR1)), elevates calcium levels by TRPA1 or TRPV2, and stimulates G Protein Receptor 18 and other nuclear receptors [104,105,106,107,108,109,110,111,112,113]. It reduces NMDA responses by 30-40% [114,115,116], blocks capsaicin-induced hyperalgesia [117], inhibits CGRP activity [118], increases cerebral 5HT production, decreases 5HT reuptake, and inhibits 5HT release from platelets, all of which may influence trigeminovascular migraine circuitry [1, 68, 69, 119]. THC enhances analgesia from kappa opioid receptor agonist medications [120,121,122,123], stimulates production of beta-endorphin and increases proenkephalin mRNA levels in brainstem regions involved in pain processing [124,125,126], and intraventricular and intrathecal administration of THC produces analgesia similar to opioids [127].

THC is 20 times more anti-inflammatory than aspirin, twice as anti-inflammatory as hydrocortisone [128], and has well documented analgesic and anti-inflammatory benefits including arthritic and inflammatory conditions [83, 114, 127, 129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156]. There have been many positive studies across various chronic pain syndromes, showing benefit of THC in trials with smoked or vaporized cannabis comparing between different doses of THC, with benefit often noted at higher percentages [28, 47, 157,158,159,160,161,162,163,164,165,166,167,168,169]. However, compositions of other cannabinoids including CBD, minor cannabinoids, and other important compounds such as terpenes were not assessed in most of these trials. Given the entourage effects of cannabis [100, 170], where cannabinoids and terpenes influence activity of one another, resulting in strain-specific characteristics, effects and responses, it is often unclear if these studies showing positive (or negative) effects of cannabis are due to the THC alone, or due to synergy between undefined compositions of other cannabinoids and terpenes.

There have been a multitude of studies confirming benefit in various chronic pain syndromes with an oral-mucosal spray called Nabiximols (Sativex) [171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196], approved in 30 countries for various neurological symptoms. This is a tincture of cannabis made from cannabis plants [197]. Each spray delivers a standardized dose of 2.7 mg THC and 2.5 mg CBD, along with additional cannabinoids, flavonoids, and terpenes in unmeasured small amounts. Despite the standardized THC:CBD ratio, the actual concentrations of terpenes and other compounds are unknown. This again creates uncertainty as to what components are providing most of the benefit, although entourage effects are again suspected. There was also a study comparing between three varieties of this spray; 1:1 THC:CBD vs. THC alone vs. CBD alone and the sprays that contained THC showed the most pain benefit, over CBD alone [179]. Other cannabis extract studies of only THC and CBD in varying doses also showed pain benefit, although these did not evaluate each cannabinoid individually [187, 198].

The strong anti-emetic benefits of THC have also been well documented in adults [26, 83, 129, 130, 199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238] and children [235, 239,240,241], and migraine associated nausea and vomiting would certainly be another benefit of THC. In fact, the FDA has approved two synthetic forms of THC in the treatment of chemotherapy related nausea and vomiting; Dronabinol [242] and Nabilone [243]. Notably, these synthetic THC medications have also shown analgesic effects [55, 57, 62, 188, 244,245,246,247,248,249,250,251,252,253,254,255,256].

Besides THC, CBD is the other major cannabinoid. It has gained a lot of attention over the past several years due to its lack of any psychoactivity, as opposed to THC. In November 2017, The World Health Organization announced that in humans, CBD exhibits no evidence for abuse or dependence potential, and there is no evidence of public health related problems associated with the use of pure CBD [257]. In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes [258]. CBD has powerful analgesic and anti-inflammatory effects [23, 83, 114, 129,130,131, 137,138,139,140, 149, 259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281] mediated by both cyclooxygenase and lipoxygenase inhibition. Its anti-inflammatory effect is several hundred times more potent than aspirin [128, 282], although to date, there have been no clinical studies evaluating pure CBD in headache or chronic pain disorders. CBD has much lower affinity for CB1 or CB2 receptors, and acts as an antagonist of CB1 and CB2 agonists such as THC [276]. At low concentrations, its antagonism of CB1 underlies its neutralizing effects on the CB1 agonist THC side effects such as anxiety, tachycardia, and sedation [283,284,285,286,287,288]. CBD appears to attenuate some of these negative side effects of THC when the CBD:THC ratio is at least 8:1 (± 11.1), but may potentiate some of the THC side effects when the CBD:THC ratio is around 2:1 (± 1.4) [286, 288]. It is also an inverse agonist at the CB2 receptor, which may contribute to its anti-inflammatory effects [276].

CBD also interacts with a multitude of ion channels, enzymes, and other receptors [18, 83, 129, 130, 225, 259]. It acts as a TRPV1 agonist, similar to capsaicin, although without the noxious sides effects, and also inhibits AEA uptake and metabolism [108,109,110, 289, 290]. It acts as a positive allosteric modulator at α1 and α1β glycine receptors [291], suggested to play a role in chronic pain after inflammation or nerve injury since glycine acts as an inhibitory postsynaptic neurotransmitter in the dorsal horn of the spinal cord. CBD acts as a μ opioid receptor ligand and a positive allosteric modulator at μ and δ opioid receptors suggesting that it may enhance opiate effects [83]. Additional mechanisms of action suggested to reflect its anti-inflammatory and analgesic effects, as well as other medicinal benefits, include TRPA1 agonist, TRPV1 agonist, TRPM8 antagonist [108,109,110], TRPV2 agonist in which it may mediate CGRP release from dorsal root ganglion neurons [292], T-type calcium2+ channel inhibitor [293], suppression of tryptophan degradation (precursor to 5HT) [294], phospholipase A2 modulator [295], 5-HT1A agonist [83, 296], regulator of intracellular calcium2+ [297, 298], fatty acid amide hydrolase (FAAH; breaks down AEA) inhibition [290], GPR55 antagonist [77], adenosine uptake competitive inhibitor [299], PPARγ agonist [300], 5-lipoxygenase and 15-lipoxygenase inhibitors [301], and antagonism of the abnormal-CBD receptor [83, 302].

Cannabinoid acids are the precursors to the cannabinoids in raw and live cannabis, and have no psychotropic qualities. They are decarboxylated by heat, UV exposure, and prolonged storage to form the active cannabinoids, although heat such as from smoking or vaporizing is the primary conversion factor. The two cannabinoid acids assessed in this study were THCA, which converts to THC, and CBDA, which converts to CBD.

THCA is a TRPA1 partial agonist [108], and TRPM8 antagonist [108] which may underlie a potential role in analgesia, and has been shown to have anti-inflammatory [140] and anti-nausea properties [303]. CBDA is often obtained through consumption of raw cannabis juice. It is a TRPA1 agonist [108], TRPV1 agonist [290], and TRPM8 antagonist [108] which may also reflect its potential as an analgesic. It is also anti-inflammatory [130, 140, 304] via selective COX2 inhibition, and has anti-nausea properties [237, 305].

The terpenes, or terpenoids, form the largest group of phytochemicals [99], and account for some pharmacological properties of cannabis, as well as many medicinal herbs, plants and essential oils. They are the source of flavors, aromas, and other characteristics that help differentiate cannabis strains. The terms terpenes and terpenoids are often used interchangeably in the literature, although technically, terpenes are basic hydrocarbons, while terpenoids contain extra functional groups of a wide range of chemical elements. Cannabis contains up to 200 different terpenes [100], and they are generally classified as primary and secondary terpenes, based on how frequent they occur in cannabis. They are lipophilic with wide ranging mechanisms of action sites including neurotransmitter receptors, G-protein receptors, muscle and neuronal ion channels, enzymes, cell membranes, and second messenger systems [100, 306, 307]. The terpenes work synergistically with the cannabinoids for a variety of therapeutic effects, and this phenomenon is known as the cannabis entourage effects [100, 170]. They have shown many medicinal benefits, including anti-inflammatory and analgesic properties [308]. This publication will focus primarily on the anti-inflammatory and analgesic evidence for the terpenes analyzed in this study, although a more extensive discussion and a comprehensive review of other medicinal properties of these, as well as many other terpenes has been summarized and is available [28]. The majority of this data comes from preclinical studies involving animal models or in vitro studies, and some of the reported benefits attributed to individual terpenes come from studies evaluating whole essential oils or plants in which the specified terpene may be a predominant constituent. However, therapeutic contribution from some of the other terpenes in some of these studies cannot be excluded. The terpenes analyzed in this study were limited to α-pinene, β-myrcene, D-limonene, linalool, β-caryophyllene, humulene, trans-nerolidol, and bisabolol.

Alpha-pinene (α-pinene) is the most commonly occurring terpene in nature [309], and accounts for the aroma of fresh sage, pine needles, and conifers, but is produced by many herbs such as basil, parsley, and dill as well. It has anti-inflammatory effects in human chondrocytes, suggesting anti-osteoarthritic activity [310, 311], anti-inflammatory effects by PGE-1 [312], and anti-nociception properties [313].

Beta-myrcene (β-myrcene), or myrcene, is common in lemongrass, basil, bay leaves, wild thyme, parsley, hops, and tropical fruits such as mango. It has potent anti-inflammatory, analgesic, and anxiolytic properties [314,315,316], and has benefit in muscle relaxation [317], and prominent sedation/hypnotic, helpful in sleep [317, 318]. Its analgesic effects were antagonized by naloxone suggesting an opioid-mediated mechanism [315, 316]. Its significant anti-inflammatory effects [319] occur via prostaglandin E2 [315] and it has anti-catabolic effects in human chondrocytes suggesting anti-osteoarthritic activity and the ability to halt or slow down cartilage destruction and osteoarthritis progression [320].

D-limonene (limonene) is prominent in the rinds of citrus fruits, and the second most commonly occurring terpene in nature [309]. It has analgesic [321], anti-inflammatory [320, 322,323,324,325], and antidepressant effects [321, 326]. It contributes to muscle relaxation and sleep [317], and is a powerful anxiolytic [327,328,329,330], which extended anxiolytic benefit to patients with chronic myeloid leukemia (CML) [331]. It increases the metabolic turnover of dopamine in the hippocampus and serotonin in the prefrontal cortex and striatum, suggesting that anxiolytic and antidepressant-like effects may occur by the suppression of dopamine activity related to enhanced serotonergic neurons, especially via 5-HT1A [332].

Linalool is found in flowers and spices including citrus, lavender, rosewood, birch trees, and coriander. It exhibits anti-inflammatory and analgesic activity [333,334,335] as well as anti-nociception via activation of opioidergic and cholinergic systems [333], anticonvulsant via anti-glutamatergic and GABA neurotransmitter systems [336,337,338,339,340], anti-anxiety/stress [341,342,343,344], sedation [343, 345,346,347], and anti-insomnia properties [100]. Its local anesthetic effects [348] were equivalent to procaine and menthol [349], and analgesic effects have been attributed to adenosine A 2A activity [350] and ionotropic glutamate receptors including AMPA, NMDA and kainate [351]. Morphine opioid usage in gastric banding surgical patients was significantly decreased following lavender inhalation vs. placebo, and this was attributed to the linalool concentration [352].

Beta-caryophyllene (β-caryophyllene) is found in spices and plants including cloves, cinnamon, black pepper, hops, rosemary, oregano, and basil. It has analgesic effects in inflammatory and neuropathic pain [353], and has potent anti-inflammatory effects [354,355,356,357], with local anesthetic properties [358]. Anti-inflammatory effects appear to occur via PGE-1 [359], with similar efficacy as indomethacin and etodolac [360, 361], and comparable to phenylbutazone [359, 360]. β-caryophyllene is a selective cannabinoid receptor 2 (CB2) agonist [362,363,364]. CB2 receptors have been implicated in anxiety and depression, and β-caryophyllene has shown anxiolytic and antidepressant effects [365].

Humulene (α-caryophyllene) is an isomer of β-caryophyllene and plays a role in many of the distinguishing characteristics between different cannabis strains. It is found in herbs and spices such as clove, basil, hops, sage, spearmint and ginseng, in addition to some vegetables and fruits. It has strong anti-inflammatory properties comparable to dexamethasone systemically, topically, and in allergic airway inflammation [354,355,356, 366, 367], as well as anti-nociceptive and analgesic properties [367].

Nerolidol (trans-nerolidol) is found in many herbs and spices including lavender, lemon grass, ginger, jasmine, tea tree, oranges, and present in orange and other citrus peels. It has anti-insomnia and sedative properties [368].

Alpha-bisabolol (α-bisabolol, bisabolol, levomenol) is produced by some flowers used in making tea, such as the chamomile flower. It has anti-inflammatory effects in the skin [369], as well as anti-nociceptive properties [370].

Cannabis sativa strains are generally described by patients as uplifting, energetic, creative, euphoria, spacey, cerebrally-focused effects, and better for day use, while Cannabis indica strains are typically described as calming, relaxing, sedative, full body effects such as “body buzz”, and better for night use. Research suggests these effects are not likely due purely to CBD:THC ratios, as there are no significant differences in CBD:THC ratios between Sativa and Indica strains. Rather these different subjective effects are likely due to varying ratios of major cannabinoids as well as minor cannabinoids, terpenes and probably additional phytochemicals [100, 371,372,373,374]. High CBD strains are Sativa or Indica strains that have been crossed with high CBD hemp strains (1:1 CBD:THC up to approximately 5:1 CBD:THC), while pure CBD strains (ratios of > 10:1 CBD:THC, which can be up to approximately 50:1 CBD:THC) are considered hemp strains. Most strains utilized today are Hybrids designed with standardized ratios of CBD, THC, other cannabinoids, and other compounds such as terpenes and flavonoids, targeting specific symptoms, responses, and end user effects.

Although not of statistical significance, there were some pattern use trends noted. The majority of patients across all pain groups including the positive ID Migraine™, headache as primary symptom, chronic pain, and arthritis groups all preferred Hybrid cannabis strains followed by Indica, Sativa, and higher CBD strains (1:1 CBD:THC, 3:1 CBD:THC) when patients with headache as primary symptom were included. However, when these patients were excluded, the arthritis group preferred Indica strains. When comparing headache and migraine to non-headache groups, Indica strains were preferred in the insomnia/sleep disorders group, Sativa strains in the mental health condition/PTSD group, and Hybrid strains were still preferred in the gastrointestinal disorder/Crohn’s Disease group. Perhaps the headache, chronic pain, and gastrointestinal disorder/Crohn’s groups preferred similar Hybrid strains due to underlying inflammatory pathophysiology. The positive ID Migraine™ and headache as primary symptom patients most commonly preferred the “OG Shark” Hybrid strain specifically, although this pattern was also noted in the chronic pain and arthritis groups, so was not unique to headache and migraine. This is a high THC/THCA, low CBD/CBDA strain with β-caryophyllene followed by β-myrcene as the predominant terpenes. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, along with documented anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Given the prominent features of pain with nausea and vomiting in migraine headache, the fact that headache and migraine patients preferred a strain such as this, with its associated cannabinoid and terpene profile, would make sense given the known therapeutic effects of this cannabinoid and these terpenes. Furthermore, there were additional terpenes present in this strain of lower percentages, some of which also have analgesic and anti-inflammatory properties.

Substituting cannabis for alcohol, illicit drugs and/or prescription medications has been commonly observed in cross sectional surveys, suggesting a harm reduction role in the use of these substances, as well as implications for abstinence-based substance use treatment strategies [375,376,377]. The “opioid-sparing effect” of cannabinoids has been well described with extensive supporting evidence showing that combining cannabis with opiates decreases opiate dose requirements [166, 378]. CB1 receptors are 10 times more concentrated then mu-opioid receptors in the brain, and cannabinoid receptors co-localize with opioid receptors in many regions involved in pain pathways. This is suspected to contribute to synergistic augmentation of the analgesic opioid effects and decreased opioid dose requirements [8, 122,123,124,125, 166, 379,380,381,382,383,384], and studies have shown cannabis use did not affect blood levels of oxycodone or morphine [8, 166]. Cannabinoid receptor agonists increase endogenous opioid peptide release, and chronic THC use increases endogenous opioid precursor gene expression in supraspinal and spinal structures involved in pain perception [119, 126, 166, 379].

The synergistic effect of concomitant cannabis/cannabinoids and opioids in lowering both pain and opioid dose requirements without affecting serum opioid levels has been demonstrated prospectively [166]. A large meta-analysis showed that 17 of 19 pre-clinical studies provided good evidence of these synergistic effects from opioid and cannabinoid co-administration and that the median effective dose (ED50) of morphine administered with THC is 3.6 times lower than the ED50 of morphine alone, while the ED50 for codeine administered with THC was 9.5 times lower than the ED50 of codeine alone [378]. The combination of cannabis/cannabinoids and opioids appears to allow for opioid treatment at lower doses with fewer side effects, allowing easier detoxification and weaning due to lessening of tolerance and withdrawal from opiates, and rekindling of opiate analgesia after prior dosages have worn off [124]. Some pain specialists have suggested the use of medicinal cannabis treatment in addition to or in replacement of opiate treatments to help reduce overdose mortality and morbidity associated with opiate use [385]. Prospective studies have shown that chronic pain patients who use cannabis have improved pain and functional outcomes, and a significant reduction in opioid use [386], and medical cannabis use was associated with decreased opiate use, improvement in quality of life, and better side effect profile in a retrospective cross-sectional survey of chronic pain patients [387].

Notably, the most common prescription medications replaced by medicinal cannabis in this study were opiates/opioids in a large percentage within every pain group, up to 72.8% of patients in the chronic pain as primary illness group. Given the opioid epidemic, particularly in the United States, cannabis has been discussed as an option that may help in the opioid/opiate detoxification and weaning process and perhaps assist in combating the epidemic of opioid related death [377, 385, 388,389,390]. States with medicinal cannabis laws have been shown to have a 24.8% decreased annual opioid overdose mortality rate compared with states without medicinal cannabis laws. The association between medicinal cannabis law implementation and decrease in annual opioid overdose mortality strengthened over time to a decrease of 33.7% by year 5 [391].

The synergistic interactions between the phytocannabinoids, terpenes and other cannabis compounds resulting in various therapeutic benefits and responses have been termed the cannabis entourage effects [100, 170]. This synergy between the cannabinoids, terpenes, and other compounds leads to variable benefits, user effects, and strain characteristics. In addition, synergistic interactions between cannabis and opioid pathways may be a promising new weapon in the battle of the opioid epidemic. Further study is needed to determine optimal combinations for specific synergies and composition ratios of the cannabis constituents to best target different symptoms and diseases. Medicinal cannabis production has become a very sterile, scientific, standardized production process, and an emerging new industry. Similar to the broad category of anticonvulsants with many varieties targeting variable neurochemical pathways and channels with different responses and side effects, cannabis should also be thought of a broad category of medicine, of which further therapeutic delineations and disease targeting differentiations between strains is necessary.

There are multiple limitations to this study beginning with its survey design and inherent limitations. Many of the patients who reported headache as a primary symptom for which they were treating with medicinal cannabis, had also reported other diseases or symptoms that they were using medicinal cannabis for. So, some of the answers provided may not have been specific for only headache treatment, but potentially other symptoms or a combination of symptoms including headache. This could also influence reported preferred strains being used since some strains are used more commonly for some symptoms, while other strains may be used for other symptoms. There may be some inaccuracy of patient numbers within the different pain groups of chronic pain, arthritis, and headache. For example, some patients who reported chronic pain as the primary illness for which they were using medicinal cannabis did not specify their type of chronic pain further. It is unknown if some of these patients may have been treating chronic pain of arthritis or headache types, but reporting it as chronic pain, and therefore some of these patients may have been more accurately listed in a different more specific category. Variability in patients’ cannabis knowledge could potentially influence self-reporting accuracy. When documenting the preferred cannabis types and strains within each of the pain and non-pain groups, many patients did not provide an answer for their preferred type or strain. If a preferred cannabis type was not provided, but a preferred strain was provided, then their preferred type was presumed to correlate to their reported preferred strain, and counted as such. In addition, reported preferred cannabis types and strains sometimes did not correlate (reported strain did not fall under the correct reported type). Therefore, the preferred cannabis types and strains listed within each category, and their inferred potential benefits, may be inaccurate based on this inconsistent reporting by some patients, and the validity of the preferred cannabis type and strain data requires prospective validation.